efficacy and safety of intranasal glucagon for …...adult glucagon protocol v2 09-27-13 (2)...

adult glucagon protocol v2 09-27-13 (2) printdate: 1/7/2015 9:44 AM

Efficacy and Safety of Intranasal

Glucagon for Treatment of Insulin

Induced Hypoglycemia in Adults with

Diabetes

Version 2.0

09/27/13 1

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Table of Contents 12

Chapter 1. Background Information and Study Synopsis ..................................................... 1-1 13

1.1 BACKGROUND INFORMATION ............................................................................................................................... 1-1 14 1.1.1 Marketed glucagon for injection ............................................................................................................. 1-1 15 1.1.2 Intranasal product under study : AMG504-1 ......................................................................................... 1-2 16 1.1.2.1 Previous studies on intranasal glucagon ............................................................................................. 1-2 17 1.1.2.2 Clinical studies on AMG504-1 ............................................................................................................. 1-2 18 1.1.2.3 Safety of AMG504-1 ............................................................................................................................. 1-3 19 1.1.2.4 Pharmacokinetic and pharmacodynamic properties ............................................................................ 1-4 20 1.1.2.5 Dose Selection ...................................................................................................................................... 1-8 21 1.1.3 Summary of Rationale for the Study ...................................................................................................... 1-10 22

1.2 STUDY OBJECTIVE .............................................................................................................................................. 1-11 23 1.3 SYNOPSIS OF PROTOCOL ..................................................................................................................................... 1-11 24 1.4 GENERAL CONSIDERATIONS ............................................................................................................................... 1-13 25

Chapter 2. Study Participant Eligibility and Enrollment ...................................................... 2-1 26

2.1 IDENTIFYING ELIGIBLE STUDY PARTICIPANTS AND OBTAINING INFORMED CONSENT ......................................... 2-1 27 2.2 STUDY PARTICIPANT ELIGIBILITY CRITERIA ........................................................................................................ 2-1 28 2.3 SCREENING EVALUATION AND BASELINE TESTING .............................................................................................. 2-2 29

2.3.1 Historical Information ............................................................................................................................ 2-2 30 2.3.2 Baseline Testing Procedures ................................................................................................................... 2-2 31

Chapter 3. Study procedures .................................................................................................... 3-1 32

3.1 OVERVIEW ........................................................................................................................................................ 3-1 33 3.2 GLUCAGON PREPARATIONS .................................................................................................................................. 3-1 34

3.2.1 Intranasal Glucagon ............................................................................................................................... 3-1 35 3.2.2 Intramuscular Glucagon ......................................................................................................................... 3-1 36

3.3 PROCEDURES PRIOR TO INDUCING HYPOGLYCEMIA ............................................................................................. 3-1 37 3.4 PROCEDURES FOR INDUCING HYPOGLYCEMIA ...................................................................................................... 3-2 38 3.5 GLUCAGON ADMINISTRATION .............................................................................................................................. 3-3 39

3.5.1 Intranasal Administration ....................................................................................................................... 3-3 40 3.5.2 Intramuscular Administration ................................................................................................................. 3-3 41

3.6 POST-ADMINISTRATION PROCEDURES .................................................................................................................. 3-3 42 3.7 PROCEDURES FOR INSUFFICIENT RESPONSE TO GLUCAGON ADMINISTRATION .................................................... 3-4 43 3.8 END OF ADMISSION .............................................................................................................................................. 3-4 44 3.9 FOLLOW-UP PHONE CALL ..................................................................................................................................... 3-4 45 3.10 BLOOD SAMPLES FOR BIOBANK STORAGE .......................................................................................................... 3-4 46 3.11 VOLUME OF BLOOD DRAWS ............................................................................................................................... 3-5 47

Chapter 4. Adverse Events ........................................................................................................ 4-1 48

4.1 DEFINITION ........................................................................................................................................................... 4-1 49 4.2 RECORDING OF ADVERSE EVENTS ........................................................................................................................ 4-1 50 4.3 REPORTING SERIOUS OR UNEXPECTED ADVERSE EVENTS .................................................................................... 4-1 51 4.4 POTENTIAL ADVERSE EFFECTS OF STUDY DRUGS ................................................................................................ 4-2 52

4.4.1 Glucagon by Intramuscular Injection ..................................................................................................... 4-2 53 4.4.2 Glucagon by Intranasal Administration .................................................................................................. 4-2 54

Chapter 5. Miscellaneous Considerations................................................................................ 5-1 55

5.1 BENEFITS .............................................................................................................................................................. 5-1 56 5.2 PARTICIPANT REIMBURSEMENT ............................................................................................................................ 5-1 57 5.3 PARTICIPANT WITHDRAWAL ................................................................................................................................ 5-1 58 5.4 CONFIDENTIALITY ................................................................................................................................................ 5-1 59 5.5 T1D EXCHANGE CLINIC REGISTRY ...................................................................................................................... 5-1 60

Chapter 6. Statistical Methods.................................................................................................. 6-1 61

6.1 SAMPLE SIZE ........................................................................................................................................................ 6-1 62


6.2 ANALYTIC CONSIDERATIONS ............................................................................................................................... 6-3 63 6.3 ANALYSIS OF PRIMARY OUTCOME ....................................................................................................................... 6-3 64

6.3.1 Definition of Primary Outcome ............................................................................................................... 6-3 65 6.3.2 Non-Inferiority Analysis .......................................................................................................................... 6-4 66

6.4 ANALYSIS OF EXPLORATORY OUTCOMES ............................................................................................................. 6-4 67 6.4.1 Time from Treatment to Outcome ........................................................................................................... 6-4 68 6.4.2 Treatment Comparison of Continuous Glucose Levels ........................................................................... 6-4 69 6.4.3 Symptoms of Hypoglycemia .................................................................................................................... 6-4 70

6.5 SAFETY AND TOLERABILITY ................................................................................................................................. 6-5 71 6.6 ADDITIONAL TABULATIONS ................................................................................................................................. 6-5 72 6.7 PHARMACOKINETIC/PHARMACODYNAMIC ANALYSIS .......................................................................................... 6-5 73

6.7.1 Analysis Cohort ....................................................................................................................................... 6-5 74 6.7.2 Pharmacokinetic Analysis ....................................................................................................................... 6-5 75 6.7.3 Pharmacodynamic Analysis .................................................................................................................... 6-6 76 6.7.4 PK/PD relationship ................................................................................................................................. 6-7 77 6.7.5 Inferential Statistics ................................................................................................................................ 6-7 78

6.8 INTERIM MONITORING PLAN ................................................................................................................................ 6-7 79

Chapter 7. DATA COLLECTION AND MONITORING ..................................................... 7-1 80

7.1 CASE REPORT FORMS ........................................................................................................................................... 7-1 81 7.2 QUALITY ASSURANCE AND MONITORING ............................................................................................................. 7-1 82

Chapter 8. References ................................................................................................................ 8-1 83

Appendix 1 Nasal and Non-Nasal Score Questionnaire ............................................................ 1 84

Appendix 2 Clarke Hypoglycemia Awareness Survey .............................................................. 1 85

Appendix 3 Edinburgh Hypoglycemia Scale: Experimental Hypoglycemia .......................... 1 86

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adult glucagon protocol v2 09-27-13 (2) printdate: 1/7/2015 9:44 AM 1-1

Chapter 1. BACKGROUND INFORMATION AND STUDY SYNOPSIS 88

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1.1 Background Information 90 Glucagon has been used for treatment of severe hypoglycemia for at least 55 years [1]. 91

Glucagon is also used to temporarily inhibit movement of the gastrointestinal tract for 92

gastrointestinal imaging purposes [2]. Originally, glucagon was available only as an extract 93

from the pancreata of pigs and cattle. Recombinant human glucagon was introduced in the US in 94

1998 by Eli Lilly and by Novo Nordisk. AMG504-1 uses synthetic glucagon. 95

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1.1.1 Marketed glucagon for injection 97

Glucagon for injection, rDNA origin is a polypeptide hormone identical to human glucagon, 98

which is manufactured by recombinant DNA technology and has the same molecular structure as 99

animal-sourced glucagon. Glucagon causes an increase in blood glucose concentration. Glucagon 100

acts only on liver glycogen, converting it to glucose. Parenteral administration of glucagon 101

relaxes smooth muscle of the stomach, duodenum, small bowel, and colon. 102

Glucagon is used for the emergency treatment of severe hypoglycemia in patients treated with 103

insulin when unconsciousness precludes oral carbohydrates. For adults and for children weighing 104

more than 44 lbs (Lilly Glucagon) or 55 lbs (Novo GlucaGen HypoKit), the recommended dose 105

of glucagon is 1 mg by subcutaneous (SC), IM or IV injection. For children weighing less than 106

44 lbs (Lilly Glucagon) or 55 lbs (Novo GlucaGen HypoKit), the recommended dose of 107

glucagon is 0.5 mg. 108

In a study of 29 healthy volunteers, a SC dose of 1 mg glucagon resulted in a mean peak glucose 109

concentration of 136 mg/dL 30 minutes after injection for the 25 evaluable patients. Similarly, 110

following IM injection, the mean peak glucose level was 138 mg/dL, which occurred at 26 111

minutes after injection. No difference in glucodynamic activity between animal-sourced and 112

rDNA glucagon was observed after SC and IM injection. 113

Glucagon has been studied following IM, SC, and IV administration in adult volunteers. 114

Administration of the IV glucagon showed dose proportionality of the pharmacokinetics between 115

0.25 and 2.0 mg [3]. Calculations from a 1 mg dose showed a small volume of distribution 116

(mean, 0.25 L/kg) and a moderate clearance (mean 13.5 mL/min/kg). The half-life ranged from 8 117

to 18 minutes. 118

Maximum plasma concentrations of 7.9 ng/mL were achieved approximately 20 minutes after 119

SC administration. With IM dosing, maximum plasma concentrations of 6.9 ng/mL were attained 120

approximately 13 minutes after dosing. 121

Glucagon is extensively degraded in liver, kidney, and plasma. Urinary excretion of intact 122

glucagon has not been measured. 123

Severe adverse reactions are very rare, although nausea, vomiting and hypokalemia may occur 124

occasionally. Generalized allergic reactions, including urticaria, respiratory distress, and 125

hypotension have been reported in patients who received glucagon. In the event of lack of 126

response to the administration of glucagon, IV glucose should be administered to the patient. 127

128

Because glucagon is unstable in solution, commercially available products consist of lyophilized 129

glucagon powder that must be mixed with a diluent immediately prior to IV, SC or IM injection. 130

While this procedure is routine in a hospital setting, it can be complex, intimidating and prone to 131


potentially serious errors, especially in an emergency situation for a care-giver, companion or 132

stranger who is not trained in reconstitution and injection techniques. This has stimulated 133

considerable prior efforts directed at alternative delivery of glucagon, in particular intranasal 134

(IN) administration. 135

136

1.1.2 Intranasal product under study : AMG504-1 137 AMG504-1 is a novel, nasally-administered glucagon powder formulation for treatment of 138

severe hypoglycemia, a commonly encountered life-threatening emergency in which the patient, 139

typically an insulin-using diabetic, requires third-party assistance to correct the hypoglycemia. 140

The drug product is a dry powder formulation consisting of synthetic human glucagon, 141

dodecylphosphocholine and beta-cyclodextrin. The formulation is designed such that a dose 142

containing 1 mg of glucagon is contained within 10 mg of drug product (3 mg glucagon = 30 mg 143

powder). AMG504-1 is administered using a specially designed device that gently propels the 144

powder into the nostril. The test article is designed for nasal administration and absorption 145

therefore participants do not need to inhale after dosing with the powder. The device performs as 146

expected regardless of the orientation of the device (i.e., right side up or rotated 180°). 147

148

1.1.2.1 Previous studies on intranasal glucagon 149 Results of the first attempts to administer glucagon intranasally were published beginning about 150

thirty years ago [4]. Using a variety of liquid and powder formulations in crude devices 151

administered to almost 300 study participants, researchers demonstrated that intranasally 152

administered glucagon was well tolerated. Reported side-effects were limited to short-lived nasal 153

irritation (generally mild) and occasional sneezing. Additional information on these earlier 154

studies can be found in the Investigator’s Brochure. 155

156

Pharmacokinetic data reported in these studies indicated the speed of glucagon absorption was 157

similar after IN or IM dosing although blood glucagon levels peaked higher and remained 158

elevated longer following injection than following intranasal dosing. Plasma glucose levels rose 159

at a similar rate and reached levels indicative of recovery from severe hypoglycemia within 160

similar intervals, but continued to rise or remained at near-peak levels for a longer period with 161

injected glucagon. 162

163

1.1.2.2 Clinical studies on AMG504-1 164 AMG504-1 has recently been tested in two clinical studies: a Phase I and Phase II study in 165

healthy volunteers and in patients with type 1 diabetes, respectively. It has also been tested in a 166

Phase I study to evaluate the effects of common cold and of concomitant administration of nasal 167

decongestant. 168

169

AMG504-1 was tested during the Phase I study in fasted healthy volunteers as part of 4-way 170

cross-over study to evaluate the safety and PK/PD of 3 dose levels of glucagon administered 171

intranasally compared to the commercially available 1 mg injected dose. On each of 4 separate 172

dosing days, 16 participants (ages 20-52 years, 6 female) received either 5, 10 or 20 mg of 173

AMG504-1 (equivalent to 0.5, 1.0 or 2.0 mg of glucagon respectively) intranasally using the 174

Unit Dose Powder device or 1 mg of glucagon injected subcutaneously. Participants were 175

closely monitored for safety observations and blood samples were drawn prior to and repeatedly 176

until 4 hours post-dosing for glucagon and glucose levels. 177

178

AMG504-1 was also tested in a Phase II study on patients with type 1 diabetes (protocol No. 179

AMG 102). This was a single site, randomized, three-way, crossover study. The primary 180


objective was to evaluate the safety and efficacy of intranasal and subcutaneous glucagon in 181

reversing insulin-induced hypoglycemia in patients with type 1 diabetes. The secondary 182

objective was to evaluate the pharmacokinetics and pharmacodynamic of intranasal and 183

subcutaneous glucagon in the same population. A total of 18 participants were enrolled in and 184

completed the study. AMG504-1 was well tolerated at each dose level (10 mg, 20 mg and 30 185

mg, equivalent to 1, 2 or 3 mg of glucagon respectively). 186

187

AMG 504-1 was also tested in adult participants with common cold with and without 188

concomitant administration of nasal decongestant (Study AMG104). This was a single center, 189

single dose, open-label, repeated measures, parallel design study. The objectives of this study 190

were to evaluate the safety and to compare the pharmacokinetics and pharmacodynamics of a 3 191

mg dose of glucagon in male and female participants: 1) with and without nasal congestion 192

and/or nasal discharge associated with common cold; 2) with and without the concomitant 193

administration of a nasal decongestant. A total of 36 participants were enrolled in and 35 194

completed the study. AMG504-1 was well tolerated and no serious adverse events or deaths 195

were reported during this study. 196

197

Details of the studies are provided in the Investigator’s Brochure and summarized below. 198

199

1.1.2.3 Safety of AMG504-1 200

The safety profile of glucagon has been well characterized as reflected in the labeling for 201

currently available injectable glucagon. Adverse reactions are very rare except for occasional 202

nausea and vomiting. Generalized allergic reactions including urticaria, respiratory distress and 203

hypotension have been reported in patients receiving glucagon. In addition to these undesirable 204

side effects associated with glucagon per se, the data generated in Phase I and II studies suggests 205

intranasal dosing with AMG504-1 may cause transient mild to moderate nasal and ocular signs. 206

In the Phase I study in healthy patients, up to 50% of participants receiving IN glucagon reported 207

symptoms of nasal congestion and/or discomfort and up to 19% reported mild ocular effects 208

(hyperemia, increased lacrimation, eyelid edema). All adverse effects were mild to moderate and 209

transient. Forty percent of participants receiving the injected glucagon reported nausea and 3 210

participants (20%) vomited. There were no adverse gastrointestinal signs reported in participants 211

given IN glucagon. 212

In the Phase II study, the most common adverse events following intranasal dosing were mild to 213

moderate nasal irritation and/or congestion and transient mild lacrimation in some participants at 214

each dose level. Following the administration of commercially available injectable glucagon, one 215

participant complained of severe nausea and the most frequent adverse events were nausea and 216

vomiting experienced by seven (39%) and five (28%) of the 18 participants, respectively. None 217

of the intranasally dosed participants vomited and nausea was only reported four times (13%) 218

following 38 dosing events with AMG504-1. There were no serious drug related adverse events 219

and no patients were withdrawn from the study for safety reasons. 220

In the congestion study (Study AMG104), nasal and non-nasal symptoms such as transient nasal 221

discomfort, rhinorrhea and nasal congestion, lacrimation increased and ocular hyperaemia were 222

reported by most of the participants. Overall, the incidence of adverse nasal and non-nasal 223

symptoms was greater in participants with common cold (with or without concomitant nasal 224

decongestant) than in participants without common cold, for whom the incidence of nasal and 225

non-nasal symptoms was similar to that observed in studies AMG101 and AMG102. Two 226


patients experienced a mild bout of epistaxis that may have been caused by inadvertent blunt 227

trauma to the nasal mucosa by the dosing device during dosing. 228

229

In this same study, IN glucagon was followed by nausea and vomiting in eight (44%) and 1 230

(5.6%) of the 18 participants respectively while they had a common cold. When these same 231

participants returned for a second dose after full recovery from their cold, nausea was reported in 232

only two (12%) participants and none (0%) experienced vomiting (i.e., similar to that observed 233

in studies AMG101 and AMG102). As for the cohort who received concomitant 234

oxymethazoline, seven (39%) and five (28%) of the 18 participants experienced nausea and 235

vomiting respectively. These data suggest that systemic tolerability of AMG504-1 may be 236

reduced in participants who are experiencing common cold and/or receiving decongestant 237

medication. 238

239

1.1.2.4 Pharmacokinetic and pharmacodynamic properties 240

Figure 1 and Figure 2 provide the time concentration profile for glucagon and glucose 241

respectively of the Phase I study on healthy participants. Glucagon levels in all participants were 242

below the limit of detection (100 pg/mL) prior to dosing. After dosing, there were no significant 243

levels of glucagon detected in participants given 0.5 mg IN and only a very small, non-244

significant glucose response was observed in these participants. 245

In participants given 1 or 2 mg of glucagon intranasally, blood glucagon levels increased 246

substantially above baseline to peak at 134.7 and 484.5 pg/mL at 15 minutes post-dosing for the 247

1 and 2 mg dose levels respectively. Following SC injection, the glucagon level was higher (Cmax 248

3818 pg/mL) and peaked at 20 minutes post-dosing. After IN dosing with 1 mg, mean blood 249

glucose peaked at 128 mg/dL (7.1 mmol/L) approximately 24 minutes post-dosing and returned 250

to baseline levels by 1 hour post-dosing. The glycemic excursions observed for 2 mg IN and 1 251

mg SC were virtually identical with peak mean glucose levels of 151 mg/dL (8.4 mmol/L) and 252

153 mg/dL (8.5 mmol/L) for the 2 mg IN and 1 mg SC respectively. Time to peak levels were 253

also very similar (28 min for 2 mg IN and 25 min for 1 mg SC). For both treatments, blood 254

glucose levels returned to near baseline levels between 1 and 1.5 hours post-dosing. 255

Glucagon (2 mg) given IN resulted in a similar glycemic response as 1 mg given SC, with a 256

noticeably lower exposure of glucagon needed to achieve essentially the same response. The 257

glucodynamic response is rapid and short-lived following both subcutaneous injection and 258

intranasal administration. Although a dose-response effect is seen with increasing doses of 259

intranasal glucagon, there is evidence of a saturable response, in that the increase in blood 260

glucose above baseline is not proportional to the increase in blood glucagon levels. The same has 261

been observed following IV dosing of glucagon in humans. 262


Figure 1. Mean (SE) glucagon levels (pg/mL) in healthy fasted volunteers following a single 263

dose at 0.5 mg, 1 mg or 2 mg glucagon IN or 1 mg glucagon SC 264

Nominal Time (h)

0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0

Mea

n (

SE

) S

erum

Glu

cagon C

once

ntr

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L)

0

1000

2000

3000

4000

5000

AMG 504-1 (0.5 mg) IN

AMG 504-1 (1 mg) IN

AMG 504-1 (2 mg) IN

Glucagon Solution (1 mg) SC

LOQ = 100 pg/mL

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Figure 2. Mean (SE) glucose levels (mmol/L) in healthy fasted volunteers following a single 266

dose at 0.5 mg, 1 mg or 2 mg glucagon IN or 1 mg glucagon SC 267

Nominal Time (h)

0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0

Mea

n (

SE

) S

erum

Glu

cose

Co

nce

ntr

atio

n

(mm

ol/

L)

4

5

6

7

8

9

AMG 504-1 (0.5 mg) IN Day 1

AMG 504-1 (1 mg) IN Day 1

AMG 504-1 (2 mg) IN Day 1

Glucagon Solution (1 mg) SC Day 1

268

269

The PK results of the Phase II study on patients with type I diabetes, also indicated that glucagon 270

administered via IN delivery was absorbed from the nasal mucosa and that the absorption was 271

dependent on the dose level but not proportional to the dose level. Glucagon exposure was 272

greater for the 2 and 3 mg IN dose levels than for the 1 mg IN dose level. This lack of dose 273


proportionality via the IN route for glucagon systemic exposure, suggests a saturable absorption 274

process via the nasal mucosa. Seven out of 12 patients with type I diabetes in the 1 mg IN 275

treatment and 4 out of 18 participants in the 2 mg IN treatment showed no substantial serum 276

glucagon concentrations post-dosing, but all participants dosed at 3 mg IN or 1 mg SC had 277

detectable levels of glucagon post-treatment. In all patients in whom post-treatment glucagon 278

levels were detected, glucagon concentrations exceeded the lower limit of quantitation of the 279

assay (LLOQ, 100 pg/mL) within 10 minutes of dosing indicating that, regardless of the route, 280

glucagon is very rapidly absorbed. Figure 3 shows the mean serum unadjusted glucagon levels of 281

the patients in time. 282

In the Phase II study hypoglycemia was induced by insulin infusion. This resulted in 283

hypoglycemia in all treatment groups with mean nadir glucose levels observed at the 5 minute 284

post-treatment time point (Figure 4). Thereafter, mean glucose levels increased in all treatment 285

groups to within the normal blood glucose (BG) range by 15 minutes post-treatment. From 15 to 286

60 minutes post-treatment, mean BG levels after 1 mg IN remained fairly low (~ 4 mmol/L, 72 287

mg/dL) before increasing steadily to peak at 3 hours post-dose. In the 2 and 3 mg IN groups, 288

mean BG levels stabilized between 4.8 and 6.2 mmol/L (86 to 112 mg/dL) until 90 minutes post-289

dosing before slowly increasing to peak mean levels at 3 hours post-dosing. Mean BG values in 290

the 1 mg SC group were similar to those observed in the 2 and 3 mg IN groups for the first 30 291

minutes post-dosing. Thereafter, mean BG levels in the SC group increased to levels ranging 292

from 8.2 and 8.8 mmol/L (148 to 158 mg/dL) until the end of the sampling period. Given the 293

very short half-life of glucagon, the increase in mean BG levels after 1 to 1.5 hours post-dosing 294

is considered largely attributable to the naturally occurring hyperglycemia seen in patients with 295

type 1 diabetes in the absence of exogenous insulin and to the intake of carbohydrates in those 296

participants who were fed prior to the end of the sampling period. 297

Based on unadjusted glucose data, the median time to return to normal blood glucose levels 298

(Tonset) ranged between approximately 9 and 13 min post glucose nadir. This rapid increase in 299

median glucose level was observed across all treatments, and was comparable between the IN 300

and SC delivery routes. The range in Tonset was much wider in the 1 and 2 mg IN groups than in 301

the 3 mg IN or 1 mg SC groups. 302

The systemic exposure to glucose within the first 1.5 hours post-treatment as defined by Cmax and 303

AUC increased with increasing dose across the 1 to 3 mg IN dose levels and was slightly higher 304

following the SC treatment. The truncated AUC values between 0.083 hrs and 1.5 hrs showed 305

that most of the glucose increase takes place soon after IN (2 mg and 3 mg) and SC treatments, 306

which is clinically very relevant for patients to rapidly regain consciousness and recover from the 307

hypoglycemia. 308

Based on nadir-adjusted glucose data, the greatest glucose excursion from the nadir increased 309

with increasing IN dose but was higher in the SC treatment group. However, there was no 310

statistically difference (p> 0.05) in glucose excursion from 0.083 hrs to 1.5 hrs following 3 mg 311

IN and the SC treatments, suggesting similar increase in glucose levels between the 3 mg IN and 312

the 1 mg SC. 313

The Phase II study patients were defined as responders if they achieved normal blood glucose 314

levels (3.8-6.0 mmol/L, 68-108 mg/dL) following insulin-induced hypoglycemia. Nine (9) of 11 315

(81.8%) participants responded to the 1 mg IN treatment, 13 of 14 (92.9%) responded to the 2 316

mg IN treatment and 100% responded to 3 mg IN and 1 mg SC treatments. All of the responders 317

in all of the dose groups achieved the target glucose level within 15 minutes of nadir with the 318


exception of one participant in the 3 mg IN dose group (25 minutes post-nadir) and one 319

participant in the 1 mg SC group (35 minutes post-nadir). 320

Overall, despite the non-linearity of glucagon pharmacokinetics across the IN dose range, the 321

glucose response was higher at the highest IN dose level. There were 100 % responders in the 3 322

mg IN and the 1 mg SC groups, even though the glucagon exposure in the 3 mg IN group was 323

less that observed after the subcutaneous treatment. 324

325

Figure 3. Mean (±SE) Serum Unadjusted Concentrations of Glucagon in Patients with 326

Type 1 Diabetes Following a Single Dose at 1, 2 or 3 mg glucagon IN or 1 mg Glucagon SC 327

328

329

Figure 4. Mean (±SE) Plasma Unadjusted Concentrations of Glucose in Patients with Type 330

1 Diabetes Following a Single Dose at 1, 2 or 3 mg glucagon IN or 1 mg Glucagon SC 331

332

333


Preliminary analysis of the available data (blood glucose) from the nasal congestion study 334

(AMG104) suggest nasal congestion, with or without concomitant use of a nasal decongestant 335

did not have an appreciable effect on the post-treatment glycemic profile (see Figure 5). 336

337

Figure 5. Mean (SE) plasma unadjusted concentrations of glucose (mmol/L) in otherwise 338

healthy participants with or without common cold and with or without conconcomitant use 339

of a decongestant following a single dose of 3 mg glucagon IN (Linear) 340

341

342 343

344

1.1.2.5 Dose Selection 345 The PK/PD results from studies AMG101 and AMG102 and the observation in the Phase II 346

study (AMG102) that glucagon was detected post-treatment in all participants treated at 3 mg but 347

not in all participants at 2 mg suggest that 3 mg IN may be more effective than 2 mg IN for the 348

treatment of hypoglycemia. Although the glucagon exposure observed after 3 mg IN treatment 349

was considerably less than the exposure observed after a 1 mg SC injection, all participants in 350

both treatment groups had detectable levels within 10 minutes of dosing. Moreover, despite the 351

lower systemic glucagon exposure, treatment with 3 mg of glucagon IN resulted in a similar 352

glycemic response as that observed after SC injection. 353

354

Based on data generated to date, the PK profile for a 3 mg dose IN glucagon (i.e. 30 mg of 355

AMG504-1) results in a Cmax that is ~37% that seen after injection and an AUC that is 356

approximately 35% that seen after an injection (1 mg IM or SC in adults). Importantly, the mean 357

Cmax and mean AUC for a 3 mg dose IN glucagon (i.e. 30 mg of AMG504-1) vs. a 2 mg dose IN 358

glucagon (i.e. 20 mg of AMG504-1) are not that much different (although the CV is considerably 359

better for the 3 mg dose) suggesting a saturable IN absorption potential. 360

361


The systemic safety profile of IN glucagon is encouraging. In healthy volunteers, injection of 362

glucagon was followed by nausea in 40% and vomiting in 20% of treated participants. In 363

contrast, there were no significant GI adverse signs after IN dosing at 0.5, 1.0 or 2 mg. 364

365

In adult patients with T1D (Study AMG102), injection of glucagon was followed by nausea and 366

vomiting in seven (39%) and five (28%) of the 18 participants, respectively. In contrast, none of 367

the participants vomited and nausea was only reported four times (13%) following 38 dosing 368

events with AMG504-1 at dose levels of 1.0, 2.0 or 3.0 mg of glucagon (nausea seen in 1 or 2 369

participants all each IN dose groups). 370

371

In the congestion study (Study AMG104), IN glucagon was followed by nausea and vomiting in 372

eight (44%) and 1 (5.6%) of the 18 participants respectively while they had a common cold. 373

When these same participants returned for a second dose after full recovery from their cold, 374

nausea was reported in only two (12%) participants and none (0%) experienced vomiting. As for 375

the cohort who receive concomitant oxymethazoline, seven (39%) and five (28%) of the 18 376

participants experienced nausea and vomiting respectively. These data suggest that systemic 377

tolerability of AMG504-1 may be reduced in participants who are experiencing common cold. 378

379

The local tolerability of IN glucagon appears to be acceptable regardless of the dose level 380

administered. In healthy volunteers (Study AMG101), up to 50% of participants receiving IN 381

glucagon reported symptoms of nasal congestion and/or discomfort and up to 19% reported mild 382

ocular effects (hyperemia, increased lacrimation, eyelid edema). 383

384

In adult patient with T1D (Study AMG102), the most frequently observed adverse events 385

experienced by patients and judged to be possibly related to the Test product were in the Nervous 386

System Disorders and Eye Disorders System Organ Class following the 1 mg IN, equivalent to 387

10 mg of AMG-504-1, (i.e. each 16.7% of patients); Respiratory, Thoracic and Mediastinal 388

Disorders following the 20 mg dose of AMG-504-1 (i.e. 66.7% of patients); and Eye Disorders 389

following the 30 mg dose of AMG-504-1 (i.e. 75.0% of patients). Almost all of these adverse 390

events consisted of nasal and non-nasal symptoms such as transient nasal discomfort, nasal 391

congestion, rhinorrhea and lacrimation increased. One (1) patient (5.6%) experienced a mild bout 392

of epistaxis that may have been caused by inadvertent blunt trauma to the nasal mucosa by the 393

dosing device during dosing. 394

395

In the AMG 104 study, AMG 504-1 was tested in participants with common cold and of 396

concomitant administration of nasal decongestant. The severity of adverse events ranged from 397

mild to severe. All events were transient. The most frequently observed adverse events 398

experienced by patients and judged to be possibly related to the Test product were in the 399

Respiratory, Thoracic and Mediastinal Disorders with 83.3% for cohort 1 period 1, 64.7% for 400

cohort 1 period 2 and 94.4% for cohort 2 period 1 and Eye Disorders System Organ Class with 401

72.2% for cohort 1 period 1, 76.5% for cohort 1 period 2 and 77.8% for cohort 2 period 1. 402

Almost all of these adverse events consisted of nasal and non-nasal symptoms such as transient 403

nasal discomfort, rhinorrhea and nasal congestion, lacrimation increased and ocular hyperaemia. 404

One (1) patient (5.6%) in cohort 1 period 1 and another (5.9%) in cohort 1 period 2 experienced 405

a mild bout of epistaxis that may have been caused by inadvertent blunt trauma to the nasal 406

mucosa by the dosing device during dosing. 407

408

Given the long history of the safe use of glucagon in humans and the findings of nonclinical 409

studies conducted with AMG504-1 as well as the findings of the Phase I and Phase II studies in 410


healthy volunteers, otherwise healthy participants with common cold and in patients with type 1 411

diabetes respectively, the Sponsor expects an acceptable safety profile following the use of 412

AMG504-1 in this planned Phase III study. 413

414

1.1.3 Summary of Rationale for the Study 415 Glucagon, the treatment of choice for severe hypoglycemia outside of the hospital setting, is 416

currently available only as a powder that must be mixed with a diluent immediately prior to 417

administration by injection. Although this is a very simple procedure for insulin-using 418

individuals, participants experiencing severe hypoglycemia cannot inject themselves with 419

glucagon because of the disabling effects of severe neuroglycopaenia. For any non-medical 420

person who is confronted with an emergency situation in which a patient with diabetes is in a 421

hypoglycemic coma or suffering hypoglycemia-related convulsions, reconstitution and injection 422

of the current injectable glucagon is a complex and daunting procedure. 423

424

Unlike many other peptide drugs (i.e., insulin) for which a precise dose-response is critical to 425

both safety and effectiveness, glucagon is different. The drug has a very short half-life, an 426

outstanding safety profile and minimal off-target effects. Importantly, the drug has to be used 427

relatively infrequently to treat a serious medical emergency condition. It is widely 428

acknowledged that the currently approved level of 1 mg by injection is more than what is 429

required in the majority of cases. This has been very well demonstrated in studies with IV 430

glucagon (Lilly NDA 020928) showing that, despite huge variations in glucagon Cmax and AUC, 431

the glucose response was essentially the same. These data indicate that, beyond achieving a 432

glucagon level required to generate hepatic glucose production, glucagon PK per se is not 433

important. 434

435

When used at the recommended dose of 1 mg by injection, glucagon often causes a substantial, 436

although transient, hyperglycemia that is often accompanied by nausea and vomiting. The data 437

generated to date with AMG504-1 suggest the resulting glucagon PK, although less than that 438

observed with injected glucagon, results in a therapeutic blood glucose increment with a very 439

low incidence of gastrointestinal adverse effects. 440

441

This observation has been reported previously in a study conducted to compare intranasal 442

glucagon with SC glucagon to treat insulin-induced hypoglycemia in children with T1D [5]. In 443

that study, despite lower PK exposure, intranasal glucagon was shown to be as efficient as 444

injected glucagon in treating the hypoglycemia. Importantly, there was a much greater incidence 445

of severe nausea following injection (10 of 11 children) than after intranasal dosing (1 of 11 446

children). 447

448

The purpose of administering glucagon is to cause blood glucose to return to within the normal 449

range so that patients either regain consciousness if comatose, or restore cognitive function 450

sufficiently to be able to consume carbohydrate and enable full recovery from the hypoglycemic 451

episode. 452

453

This study therefore proposes an increase in blood glucose levels to within the normal range as 454

the primary endpoint as it is a direct indication of the efficacy of treatment. Resolution of 455

hypoglycemia-related clinical signs, when they occur, will also be assessed in evaluating the 456

response to treatment. 457

458


As outlined in this protocol, this pivotal Phase III study intends to evaluate the treatment 459

response in a two-way crossover study in which adults with type 1 diabetes or insulin-treated 460

type 2 diabetes will be subjected to controlled insulin-induced hypoglycemia. 461

462

The procedure to evaluate the efficacy of AMG504-1 consists essentially of inducing 463

hypoglycemia by an IV infusion of regular insulin diluted in normal saline. The insulin infusion 464

will be used to decrease the glucose to a target <50 mg/dL. The insulin infusion will be stopped 465

once the plasma glucose is <60 mg/dL. Five minutes after stopping the insulin infusion, 466

participants will be treated with either a 3 mg glucagon dose intranasally (i.e., 30 mg of 467

AMG504-1) or 1 mg of glucagon (GlucaGen, Novo Nordisk) administered by IM injection in the 468

deltoid muscle of the non-dominant arm. During the 5-minute period after the insulin infusion 469

has stopped, the glucose level is expected to continue to decrease an additional 15-20 mg/dL. 470

471

It is believed that a nadir of <50 mg/dL will be low enough to generate clinical symptoms in 472

most participants yet high enough to avoid impairment of consciousness. Blood glucose levels 473

and adverse events will be carefully monitored for 90 minutes post-dosing. After a wash-out 474

period of 7 days or more, participants will return to the clinic and the procedure repeated with 475

each participant crossed over to the other treatment. As such, each participant will undergo two 476

episodes of insulin-induced hypoglycemia in random order and receive AMG504-1 during one 477

episode and commercially available glucagon (GlucaGen, Novo Nordisk) by IM injection during 478

the other episode. 479

480

1.2 Study Objective 481 The primary objective of the protocol is to assess the efficacy and safety of 3 mg glucagon 482

administered intranasally in comparison with commercially-available intramuscular glucagon. In 483

addition, the pharmacokinetics of intranasal and intramuscular glucagon will be evaluated. 484

485

1.3 Synopsis of Protocol 486

A. Study Design 487

Multi-center randomized crossover trial 488

489

B. Patient Population 490

Type 1 diabetes receiving daily insulin from the time of diagnosis for at least 2 years or 491

type 2 diabetes receiving multiple daily insulin doses for at least 2 years 492

Age 18.0 to <65.0 years 493

494

C. Sample Size 495 82 participants completing the study, with 75 having type 1 diabetes and 7 having type 2 496

diabetes. 497

498

D. Protocol 499 The study protocol will consist of: 500

Screening visit 501

Two daytime clinical research center (CRC, or comparable setting) visits, with random 502

assignment to receive intranasal glucagon during one session and intramuscular glucagon 503

during the other. 504

505


Screening Visit 506

Eligibility assessed and consent obtained 507

Collection of urine and blood samples for local urinalysis, hematology and serum 508

chemistry and for females of child-bearing potential, a urine pregnancy test 509

EKG performed 510

511

CRC Visits 512

Two CRC visits 7-28 days apart: 513

Participant fasts for at least 8 hours 514

If blood glucose not >90 mg/dL, oral carbohydrates or intravenous glucose will be given 515

to raise the the glucose level so that the starting glucose level will be >90 mg/dL. 516

Hypoglycemia induced by an IV infusion of regular insulin diluted in saline, with 517

frequent glucose monitoring, to lower the glucose to the target value of <50 mg/dL. 518

Once the glucose level is <60 mg/dL, the insulin infusion is stopped and 5 minutes later, 519

intranasal or intramuscular glucagon given 520

Blood samples taken for glucose and glucagon at time 0 (immediately prior to treatment) 521

and at 5, 10, 15, 20, 25, 30, 40, 50, 60 and 90 minutes post-dosing 522

At the end of the study procedures, the participant will be offered a meal and will be 523

discharged when the investigator deems the participant’s condition to be stable. 524

525

E. Main Outcomes 526 Primary Outcome: 527

The proportion achieving either an increase in glucose to >70 mg/dL or an increase of 528

>20 mg/dL within 30 minutes after receiving study glucagon, without receiving any other 529

measure to increase the blood glucose level such as intravenous glucose, additional 530

glucagon, or exogenous carbohydrates. 531

532

Other Main Outcomes: 533

Time from treatment to return of blood glucose to >70 mg/dL or an increase of >20 534

mg/dL 535

Safety and tolerability observations, including nausea/vomiting and nasal 536

symptoms/signs 537

Recovery from clinical symptoms of hypoglycemia if present as documented using the 538

hypoglycemia symptoms questionnaire 539

540

541


F. Schedule of Study Visits and Examination Procedures 542

543

Screening Testing

Visit 1 Wash-out

Testing

Visit 2

-28 to -1

days 0 >7 days 7-28 days

Informed Consent Form Signed X

Medical History X X X

EKG X

Clarke Hypoglycemia Awareness

Survey X

Physical Examination including Nasal

Inspection X X X

Local hematology (including

hematocrit), HbA1c, serum chemistry

and urinalysis

X

Urine Pregnancy Test X X X

Insulin Induced Hypoglycemia and

Glucagon Administration Procedures X X

Glucose Level Safety Assessments X X

Assessment of Nasal and Non-Nasal

Symptom Scores X X

Edinburgh Hypoglycemia Scale X X

Blood sample for Central Lab HbA1c,

c-peptide, glucose, and T1D

autoantibodies

X

Samples for Biobank Storage (T1D

participants only) X X

Blood Samples for Insulin

Determinations X X

Blood PK and PD Sampling X X

Adverse Event Monitoring X X

544

1.4 General Considerations 545 The study is being conducted in compliance with the ethical principles that have their origin in 546

the Declaration of Helsinki, with the protocol described herein, and with the standards of Good 547

Clinical Practice. 548

549

The study Procedure Manual provides details of the examination procedures and intranasal and 550

intramuscular administrations procedures. 551

552

There is no restriction on the number of study participants to be enrolled by a site. 553 554


Chapter 2. STUDY PARTICIPANT ELIGIBILITY AND ENROLLMENT 555

556

2.1 Identifying Eligible Study Participants and Obtaining Informed Consent 557 The study will include 82 participants who complete both glucagon dosing visits, with 75 having 558

type 1 diabetes and 7 having type 2 diabetes. Participants who do not complete both glucagon 559

dosing visits may be replaced. 560

561

Potential eligibility will be assessed as part of a routine-care examination. Prior to completing 562

any procedures or collecting any data that are not part of usual care, written informed consent 563

will be obtained. For potential study participants who are considered potentially eligible for the 564

study based on a routine-care exam, the study protocol will be discussed with the potential study 565

participant by a study investigator and clinic coordinator. The potential study participant will be 566

given the Informed Consent Form to read. Potential study participants will be encouraged to 567

discuss the study with family members and their personal physician(s) before deciding whether 568

to participate in the study. 569

570

2.2 Study Participant Eligibility Criteria 571 Inclusion 572

To be eligible, the following inclusion criteria must be met: 573 1. Clinical diagnosis of either type 1 diabetes receiving daily insulin since the time of diagnosis 574

for at least 2 years or type 2 diabetes receiving multiple daily insulin doses for at least 2 575

years. 576

2. At least 18.0 years of age and less than 65.0 years. 577

3. Body mass index (BMI) greater than or equal to 20.0 and below or equal to 35.0 kg/m2 578

4. Weighs at least 50 kg (110 lbs) 579

5. Females must meet one of the following criteria: 580

a) Of childbearing potential but agrees to use an accepted contraceptive regimen as 581

described in the study procedure manual throughout the entire duration of the study (from 582

the screening visit until study completion). 583

or 584

b) Of non-childbearing potential, defined as a female who has had a hysterectomy or 585

tubal ligation, is clinically considered infertile or is in a menopausal state (at least 1 year 586

without menses). 587

6. In good general health with no conditions that could influence the outcome of the trial, and in 588

the judgment of the Investigator is a good candidate for the study based on review of 589

available medical history, physical examination and clinical laboratory evaluations. 590

7. Willingness to adhere to the protocol requirements 591

592

Exclusion 593

An individual is not eligible if any of the following exclusion criteria are present: 594 1. Females who are pregnant according to a positive urine pregnancy test, actively attempting to 595

get pregnant, or are lactating. 596

2. History of hypersensitivity to glucagon or any related products or severe hypersensitivity 597

reactions (such as angioedema) to any drugs. 598

3. Presence of cardiovascular, gastrointestinal, liver or kidney disease, or any other conditions 599

which in the judgment of the investigator could interfere with the absorption, distribution, 600

metabolism or excretion of drugs or could potentiate or predispose to undesired effects. 601

4. History of pheochromocytoma (i.e. adrenal gland tumor) or insulinoma. 602


5. History of an episode of severe hypoglycemia (as defined by an episode that required third 603

party assistance for treatment) in the 1 month prior to enrolling in the study. 604

6. Use of daily systemic beta-blocker, indomethacin, warfarin or anticholinergic drugs. 605

7. History of epilepsy or seizure disorder. 606

8. Regularly consumes 3 or more alcoholic beverages per day. 607

9. Use of an Investigational Product in another clinical trial within the past 30 days 608

10. Donated 225 mL or more of blood in the previous 8 weeks before the first glucagon dosing 609

visit. 610

611

2.3 Screening Evaluation and Baseline Testing 612

2.3.1 Historical Information 613 A history will be elicited from the potential study participant and extracted from available 614

medical records. Data to be collected will include: age, gender, ethnicity and race, diabetes 615

history and current management, other medical conditions and medications being used, alcohol 616

and smoking habits. 617

618

2.3.2 Baseline Testing Procedures 619 The following procedures are needed to assess eligibility and/or to serve as baseline measures for 620

the study: 621

622

1. Physical examination: Standard physical examination, including vital signs (blood pressure, 623

pulse rate and body temperature), height and weight, and nasal inspection. 624

625

2. Laboratory tests (performed locally): 626

Biochemistry: Sodium, potassium, chloride, glucose, urea nitrogen, creatinine, bilirubin 627

total, alkaline phosphatase, AST, ALT and albumin. 628

Hematology: White blood cell count including differential, red blood cell count, 629

hemoglobin/hematocrit with indices, platelet count. 630

Urinalysis: Color, appearance, specific gravity, pH, leukocyte esterase, protein, 631

glucose, ketones, bilirubin, blood, nitrite, urobilinogen. Microscopic 632

examination will only be performed if dipstick test is positive for 633

leukocyte esterase, blood, nitrite or protein. 634

635

The physician in charge or designee will assess each abnormal value to determine if the 636

patient should be excluded from the study. 637

638

3. Other tests: 639

12-lead EKG 640

Urine pregnancy test for female patients with child-bearing potential. 641

Local HbA1c 642

Clarke Hypoglycemia Awareness survey (refer to Appendix 2). 643

644


Chapter 3. STUDY PROCEDURES 645

646

3.1 Overview 647 The study will consist of two outpatient visits each lasting about 6 hours, with induced 648

hypoglycemia followed by treatement with either intranasal or intramuscular glucagon 649

The time window for the second visit is 7-28 days after the first visit. 650

If the second visit cannot be completed by day 28, it may still be completed with 651

approval of the Coordinating Center. 652

653

Prior to dosing on the first visit, the order of treatments for the two visits will be randomly 654

assigned. 655

656

A general outline of the study design is presented below. 657

658

Cohort

Visit A B

1 IN GlG IM GlG

2 IM GlG IN GlG

IN: intranasal, IM: intramuscular, GlG: glucagon 659

660

661

662

3.2 Glucagon Preparations 663

3.2.1 Intranasal Glucagon 664 A glucagon dose of 3 mg (equivalent to 30 mg of AMG 504-1 dry powder) will be administered 665

in a nostril with a prefilled delivery device that delivers a single dose upon activation. 666

667

AMG Medical will be responsible for ensuring that AMG504-1 is manufactured in accordance 668

with GMP and that the labeling complies with applicable regulatory requirement(s). 669

670

Each dose of AMG504-1 is packaged in a nasal dosing device that is contained in a protective 671

plastic canister. 672

673

3.2.2 Intramuscular Glucagon 674 The intramuscular preparation of glucagon will be GlucaGen HypoKit (Novo Nordisk). 675

676

The dose will consist of 1 mg of recombinant human glucagon USP which will be constituted in 677

the commercially provided prefilled disposable syringe containing 1 mL of diluting solution. 678

Preparation of the glucagon will be performed when the participant’s blood glucose level is 679

approaching or reaches 60 mg/dL. 680

681

3.3 Procedures Prior to Inducing Hypoglycemia 682 Participants will arrive at the clinical center in the morning, having fasted for at least 8 hours 683

prior to dosing. A study investigator will be present at the bedside during the insulin infusion 684

and for the 90 minutes following the glucagon administration. 685


686 The following procedures will be performed 687

The glucose level will be checked 688

o If >300 mg/dL, ketones will be checked 689

o If ketones are found to be moderate or greater, the visit will be postponed. 690

691

Assessment of a severe hypoglycemic event (requiring the assistance of another person) 692

since the screening visit. 693

o If a severe hypoglycemic event has occurred in the 2 weeks prior to the 694

admission, the visit will be postponed until it has been at least 2 weeks since the 695

last severe hypoglycemic event. 696

697

For females of child bearing potential, a urine pregnancy test will be performed 698

o If positive, the participant will be discontinued from the study 699

700

Measurement of glucose 701

o If the glucose level is not >90 mg/dL, oral or intravenous glucose will be given to 702

raise the glucose level so that the starting glucose level will be >90 mg/dL. 703

704

Physical examination including nasal inspection 705

706

Assessment of nasal symptoms (including rhinorrhea, nasal stuffiness/congestion, nasal 707

itching, and sneezing) and non-nasal symptoms (itching/burning eyes, tearing/watering 708

eyes, redness of eyes, and itching of ears or palate), individually graded using a 4-point 709

scale (see Appendix 1) 710

711

Assessment of hypoglycemia symptoms using the Edinburgh Hypoglycemia Scale 712

(Appendix 3) 713

714

Measurement of vital signs (blood pressure, pulse rate and body temperature) 715

716

Insertion of 2 intravenous catheters (one for insulin infusion in one arm and one for blood 717

sampling in the other arm) 718

719

Collection of blood sample for: 720

o Central laboratory assessment of HbA1c, c-peptide, glucose and diabetes 721

autoantibodies (first visit only) 722

o Samples for storage in the T1D Exchange biobank (T1D participants only) 723

724

3.4 Procedures for Inducing Hypoglycemia 725 The plasma glucose level must be >90 mg/dL to start the procedure. If the starting plasma 726

glucose level is >200 mg/dL, a priming dose of 2-4 units of IV insulin may be given. 727

Hypoglycemia will be induced by an intravenous infusion of regular insulin diluted in normal 728

saline at a rate of 2 mU/kg/min. The infusion rate may be adjusted as necessary up to a rate of 3 729

mU/kg/min to reach the target glucose level of <50 mg/dL. Once the plasma glucose level 730

reaches <90 mg/dL, the infusion rate may be decreased at investigator discretion to 1.5 or 1.0 731

mU/kg/min. 732

733


Plasma glucose levels will be measured using a bedside rapid glucose analyzer (Analox, YSI or 734

equivalent). During the insulin infusion to induce hypoglycemia, glucose levels will be measured 735

no more than 10 minutes apart while the glucose level is >100 mg/dL and no more than 5 736

minutes apart when the plasma glucose level is <100 mg/dL. 737

738

Hypoglycemia symptoms will be assessed using the Edinburgh Hypoglycemia Scale (Appendix 739

3) once the plasma glucose is <75 mg/dL. 740

741

Once the plasma glucose level is <60 mg/dL, the insulin infusion will be stopped and the 742

Edinburgh Hypoglycemia Scale will be repeated. A blood sample will be collected for 743

pharmacokinetics (glucagon) and pharmacodynamics (glucose) 5 minutes after the insulin 744

infusion has been stopped (immediately prior to glucagon administration). The insulin level also 745

may be measured. 746

747

If the plasma glucose level is >60 mg/dL after receiving insulin for at least 3 hours, the assigned 748

glucagon for the visit will be administered and the post-administration procedures described 749

below will be followed. 750

751

3.5 Glucagon Administration 752 Either intranasal or intramuscular glucagon will be given according to the random assignment. 753

The glucagon will be administered 5 minutes after the insulin infusion has been stopped. 754

755

3.5.1 Intranasal Administration 756 The intranasal doses of glucagon will be administered with the patient lying in a fully reclined 757

lateral position on the opposite side of the nostril being administered (i.e., dose is given in the 758

left nostril of a patient lying in right lateral recumbency). 759

760

The tip of the device is gently entered in the nostril to the point where the index and middle 761

finger of the administrator are just touching the external nare of the patient. At that point, the 762

bottom of the device is pushed with the thumb until the device is activated and powder is 763

discharged into the nostril. The drug is absorbed from the nasal cavity; thus the patient does not 764

need to inhale after dosing and continues breathing normally throughout the process. 765

766

3.5.2 Intramuscular Administration 767 A dose of 1 mg of glucagon in a concentration of 1 mg/mL will be injected intramuscularly in 768

the deltoid muscle of the participant’s non-dominant arm with the participant lying in a fully 769

reclined lateral position on the opposite side of the arm being administered (i.e., dose is given in 770

the left arm of a patient lying in right lateral recumbency). 771

772

3.6 Post-Administration Procedures 773 Plasma glucose levels will be measured using a YSI (or equivalent device) for safety, and serial 774

blood sampling will be performed for pharmacokinetics (glucagon) and pharmacodynamics 775

(glucose) assessments 5, 10, 15, 20, 25, 30, 40, 50, 60 and 90 minutes following administration 776

of glucagon. The ending time window for completion of each blood draw for inclusion in 777

analyses will be the midpoint between consecutive planned measurements. Any sample not 778

drawn by this time will be considered missed. The 90 minute blood draw will be done as close 779

to 90 minutes as possible. Blood samples for analysis of insulin may be collected at 30 and 60 780

minutes following administration of glucagon. More frequent glucose testing can be performed 781


on the YSI at investigator discretion. Duplicate quality control samples may be sent to the 782

laboratories for glucose and glucagon measurements. 783

784

Procedures will include the following: 785

Assessment of nasal and non-nasal scores 15, 30, 60 and 90 minutes after the glucagon 786

administration (see Appendix 1). 787

788

Assessment of hypoglycemia symptoms using the Edinburgh Hypoglycemia Scale 789

(Appendix 3) at 15, 30, 45, and 60 minutes post-glucagon administration. 790

791

Measurement of blood pressure, pulse rate and body temperature approximately 45 792

minutes after glucagon administration, with subsequent monitoring at discretion of 793

physician in charge or designee 794

795

For the visit with intramuscular administration, examination of the injection site 90 796

minutes after glucagon administration. 797

798

For the visit with intranasal administration, nasal inspection approximately 90 minutes 799

after glucagon administration. 800

801

3.7 Procedures for Insufficient Response to Glucagon Administration 802 If a participant’s glucose level remains <55 mg/dL at 30 minutes or <60 mg/dL at 45 minutes 803

following administration of the glucagon, oral carbohydrate or IV glucose will be given. 804

805

If at anytime the glucose level is <40 mg/dL or the participant is experiencing severe symptoms 806

of hypoglycemia, at investigator discretion oral or IV glucose may be given. If at any time 807

symptoms suggestive of hypoglycemic seizure develop, IV glucose will be given, and if 808

unresolved, will be followed by IV lorazapam or equivalent emergency benzodiazepine 809

according to institutional policy. 810

811

If oral or IV glucose is given or additional glucagon is given, any remaining blood samples for 812

the admission will still be collected. 813

814

3.8 End of Admission 815 Before departure from the clinical site, the glucose and insulin dosing and stability of the 816

participant will be evaluated by the study physician to ensure the safety of the participant. The 817

participant will be offered a meal. 818

819

3.9 Follow-up Phone Call 820 Clinic personnel will contact the participant by phone on the day following the CRC visit to 821

discuss any side effects or other potential adverse events that have occurred. 822

823

3.10 Blood Samples for Biobank Storage 824 The T1D Exchange Biobank is designed to support ongoing and future research by qualified 825

investigators by collecting information and biosamples from people with T1D. Samples will be 826

used only for the study of T1D and its complications. Within this overarching purpose, multiple 827

T1D Exchange studies will collect blood samples specifically for the T1D Exchange Biobank, 828

whose policies and procedures will govern the release of data and samples to investigators. The 829


T1D Exchange Biobank is directed by the Biobank Operations Center at Benaroya Research 830

Institute, Seattle, WA and the Jaeb Center for Health Research (JCHR) who are responsible for 831

the oversight of the operations of this database and biosample repository. Specifically, the JCHR 832

IRB reviews and approves specific protocols under which data and samples may be obtained and 833

shared, and ensures that adequate provisions protect the privacy and confidentiality of 834

participants and data. 835

836

Enrolled participants with T1D will have samples collected for storage in the T1D Exchange 837

Biobank. Blood may be drawn prior to starting the insulin infusion and at the glucose nadir for 838

each admission and may include DNA, RNA, peripheral blood mononuclear cells (PBMC), 839

serum and plasma. Participants will have the option to decline collection of samples to be stored 840

in the T1D Exchange Biobank. 841

842

3.11 Volume of Blood Draws 843 The total volume of blood withdrawn is estimated to be 184 mL at clinical centers that reinfuse 844

blood and 263 mL at clinical centers that do not reinfuse blood. These amounts include the 845

volume required for samples for the Biobank. 846


847

Chapter 4. ADVERSE EVENTS 848 849

4.1 Definition 850 A reportable adverse event is any untoward medical occurrence in a study participant, 851

irrespective of whether or not the event is considered treatment-related that occurs during or 852

within 24 hours following each discharge. 853

854

4.2 Recording of Adverse Events 855 Throughout the course of the study, all efforts will be made to remain alert to possible adverse 856

events or untoward findings. 857

858

All adverse events whether volunteered by the participant, discovered by study personnel during 859

questioning, or detected through physical examination, laboratory test, or other means will be 860

reported on an adverse event form, unless the event is already being captured on a study case 861

report form (e.g., local symptoms or signs related to the intranasal glucagon administration or 862

pain at the intramuscular injection site). 863

864

The following applies to adverse events not already being captured on a study case report form. 865

Each such adverse event form will be classified by the investigator with respect to relationship to 866

study drug or procedures and intensity. 867

868

The study investigator will assess the relationship of each adverse event to be related or 869

unrelated by determining if there is a reasonable possibility that the adverse event may have been 870

caused by the treatment. Reasonable possibility is not the same as “any possibility.” The 871

following should be considered when evaluating the relationship: 872

• Timing of event 873

• Patient’s history 874

• Prevalence of finding in population at risk 875

• Other possible causes - diseases, exposures, therapies, etc 876

• Known pharmacology of study drug (and control) or side effect of device 877

878

The intensity of adverse events will be rated on a three-point scale: (1) mild, (2) moderate, or (3) 879

severe. It is emphasized that the term severe is a measure of intensity: thus, a severe adverse 880

event is not necessarily serious. For example, itching for several days may be rated as severe, but 881

may not be clinically serious. 882

883

Each reported adverse event is reviewed by the Medical Montor to verify the coding and the 884

reporting that is required. Adverse events will be coded using the MedDRA dictionary. 885

886

Adverse events that continue after the study participant’s discontinuation or completion of the 887

study will be followed until their medical outcome is determined or until no further change in the 888

condition is expected. 889

890

4.3 Reporting Serious or Unexpected Adverse Events 891 A serious adverse event is any untoward occurrence that: 892

Results in death. 893


Is life-threatening; (a non life-threatening event which, had it been more severe, might have 894

become life-threatening, is not necessarily considered a serious adverse event). 895

Requires inpatient hospitalization or prolongation of existing hospitalization. 896

Results in persistent or significant disability/incapacity or substantial disruption of the ability 897

to conduct normal life functions (sight threatening). 898

Is a congenital anomaly or birth defect. 899

Is considered a significant medical event by the investigator based on medical judgment (e.g., 900

may jeopardize the participant or may require medical/surgical intervention to prevent one of 901

the outcomes listed above). 902

903

Unexpected adverse events are those that are not identified in nature, severity, or frequency in 904

the current Clinical Investigator’s Brochure. 905

906

Serious adverse events or unexpected adverse events with possible relationship to study 907

treatment or procedures must be reported to the Coordinating Center immediately via completion 908

of a serious adverse event form. If the study participant required hospitalization, the hospital 909

discharge summary must also be sent to the Coordinating Center. 910

911

The Coordinating Center will notify all participating investigators of any adverse event that is 912

serious, unexpected, and related to the study drug or procedures. Notification will be made 913

within 10 days after the Coordinating Center becomes aware of the event. 914

915

Each principal investigator is responsible for reporting serious study-related adverse events and 916

abiding by any other reporting requirements specific to the governing Institutional Review 917

Board. 918

919

The Coordinating Center will notify the IND holder of any serious adverse event, irrespective of 920

causality, within 24 hours after becoming aware of its occurrence. 921

AMG Medical, Inc. will be responsible for evaluating the events for expedited reporting, and for 922

reporting them to the Food and Drug Administration (FDA) and applicable regulatory agencies. 923

924

4.4 Potential Adverse Effects of Study Drugs 925

4.4.1 Glucagon by Intramuscular Injection 926 The safety profile of glucagon has been well characterized as reflected in the labeling for 927

currently available injectable glucagon. Adverse reactions are very rare except for occasional 928

nausea and vomiting. Generalized allergic reactions including urticarial, respiratory distress and 929

hypotension have been reported in patients receiving glucagon (additional details can be found in 930

the Investigator Brochure). 931

932

4.4.2 Glucagon by Intranasal Administration 933 Intranasal administration of glucagon is not a novel concept as the earliest publication on this 934

approach appeared in 1983. Since this original manuscript, numerous studies have been 935

published describing results obtained in almost 300 participants treated intranasally with various 936

glucagon formulations (see Appendix A in the Investigator Brochure). These publications 937

describe studies conducted in healthy and diabetic adults and children exposed to various levels 938


of both spontaneous and insulin-induced hypoglycemia. With the exception of transient nasal 939

irritation and infrequent headache and nausea, there were no significant adverse effects. 940

Importantly, the post-treatment glucose responses with 1 or 2 mg of glucagon intranasally 941

generally mimicked those observed following an injection although the magnitude and duration 942

of elevated glucose levels was reduced for intranasal compared to injected glucagon. 943

Based on data generated in a Phase I study (AMG 101) and in a Phase II study (AMG 102), 944

intranasally administered AMG504-1 appears to have an acceptable safety profile. 945

946

In the AMG 101 Phase I study, other than mild to moderate transient signs of nasal and/or ocular 947

irritation in some participants, all dose levels appeared to have been well tolerated. 948

949

In the AMG 102 Phase II study in adult patients with type 1 diabetes following insulin-induced 950

hypoglycemia, the severity of the adverse events reported ranged from mild to severe, with only 951

2 severe adverse events: one being observed after the administration of the 2 mg IN and the other 952

with 1 mg glucagon administered SC. All adverse events were transient in nature. No serious 953

adverse events or deaths were reported during this study. The most frequently observed adverse 954

events experienced by patients and judged to be possibly related to the Test product were in the 955

Nervous System Disorders and Eye Disorders System Organ Class following the 1 mg IN dose 956

(i.e. each 16.7% of patients); Respiratory, Thoracic and Mediastinal Disorders following the 2 957

mg IN dose (i.e. 66.7% of patients); and Eye Disorders following the 3 mg IN dose (i.e. 75.0% of 958

patients). Almost all of these adverse events consisted of nasal and non-nasal symptoms such as 959

transient nasal discomfort, nasal congestion, rhinorrhea and increased lacrimation. One (1) 960

patient (5.6%) experienced a mild bout of epistaxis that may have been caused by inadvertent 961

blunt trauma to the nasal mucosa by the dosing device during dosing. 962

963

In the congestion study (Study AMG104), nasal and non-nasal symptoms such as transient nasal 964

discomfort, rhinorrhea and nasal congestion, lacrimation increased and ocular hyperaemia were 965

reported by most of the participants. Overall, the incidence of adverse nasal and non-nasal 966

symptoms was greater in participants with common cold (with or without concomitant nasal 967

decongestant) than in participants without common cold, for whom the incidence of nasal and 968

non-nasal symptoms was similar to that observed in studies AMG101 and AMG102. Two 969

patients experienced a mild bout of epistaxis that may have been caused by inadvertent blunt 970

trauma to the nasal mucosa by the dosing device during dosing. 971

972

In this same study, IN glucagon was followed by nausea and vomiting in eight (44%) and 1 973

(5.6%) of the 18 participants respectively while they had a common cold. When these same 974

participants returned for a second dose after full recovery from their cold, nausea was reported in 975

only two (12%) participants and none (0%) experienced vomiting (i.e., similar to that observed 976

in studies AMG101 and AMG102). As for the cohort who received concomitant 977

oxymethazoline, seven (39%) and five (28%) of the 18 participants experienced nausea and 978

vomiting respectively. These data suggest that systemic tolerability of AMG504-1 may be 979

reduced in participants who are experiencing common cold and/or receiving decongestant 980

medication. 981


Chapter 5. MISCELLANEOUS CONSIDERATIONS 982 983

5.1 Benefits 984 AMG504-1 may be beneficial for treatment of hypoglycemia. Participants will not directly 985

benefit from participating in the study. However, the information gained from the conduct of the 986

study may be beneficial to them and the general population of people with diabetes. 987

988

The c-peptide result will be provided to the participants. 989

990

5.2 Participant Reimbursement 991 For participants who complete the study, a payment of $500 will be made: $50 for the enrollment 992

visit and $225 for each CRC admission. Payment for partial completion of the study will be 993

prorated. Additional travel reimbursement may be available for participants for whom such 994

expenses are a hardship. 995

996

5.3 Participant Withdrawal 997 Participation in the study is voluntary, and a participant may withdraw at any time. The 998

investigator may withdraw a participant who is not complying with the protocol. Participants 999

who are withdrawn prior to completing both admissions may be replaced. 1000

1001

5.4 Confidentiality 1002 For security purposes, each participant will be assigned a coded identifier. All study data will be 1003

shared with the Jaeb Center for Health Research in Tampa, FL, which is the coordinating center 1004

for the study. Laboratories will receive specimens and certain study information, such as the 1005

assigned ID number and date of specimen collection. All laboratories and specimen storage 1006

facilities will sign agreements with the Jaeb Center that will require compliance with 1007

HIPAA/HITECH/future regulations. Protected Health Information (PHI) that does not directly 1008

identify a participant may be shared with Benaroya Research Institute in Seattle, WA, which is 1009

the Biobank Operations Center for the T1D Exchange and with AMG Medical. 1010

1011

Study data will be entered on the Coordinating Center’s secure website through an SSL 1012

encrypted connection. The Coordinating Center websites are maintained on Unix and Linux 1013

servers running Apache web server software and on a Windows server running IIS, all with 1014

strong encryption. The study website is password-protected and restricted to users who have 1015

been authorized by the Coordinating Center to gain access. No directly identifiable health 1016

information of an enrolled participant will be released by the Coordinating Center. 1017

1018

5.5 T1D Exchange Clinic Registry 1019 Participants with T1D who are not already enrolled in the T1D Exchange clinic registry will 1020

become part of the registry when joining this study. As a registry participant, information from 1021

the medical record may be entered into the registry database at least once a year. This will 1022

include information related to how his or her diabetes has been treated, blood sugar monitoring, 1023

problems that occur related to diabetes, other medical problems, blood tests that have been done, 1024

medicines that are taken, and whether anyone else in the family has diabetes or other related 1025

diseases. Registry participants may be asked to complete questionnaire(s) either on a computer, 1026

paper, or over the phone to get additional information about their diabetes, completion of which 1027

will be optional. Participants may receive a $20 gift card for questionnaire completion. 1028

Participants will have an opportunity to provide their email address to be contacted in the future 1029

about other studies for which they may be eligible. 1030


Chapter 6. 1031

STATISTICAL METHODS 1032 1033

The approach to sample size and statistical analyses are described below. 1034

1035

6.1 Sample Size 1036 Table 6-1 below provides sample size estimates based on the primary outcome of achieving 1037

either an increase in blood glucose to >70 mg/dL (3.9 mmol/L) or an increase of >20 mg/dL 1038

within 30 minutes after receiving study glucagon without receiving additional interventions to 1039

increase the blood glucose level across varying amounts of correlation within participant (to 1040

account for the cross-over design). 1041

1042

Table 6-1. Sample Size Estimates for Non-Inferiority Limits, Levels of Power, and 1043

Amounts of Correlation 1044 Table 6-1 shows the number of subjects required in the study in order to assess the non-1045

inferiority of intranasal glucagon treatment and intramuscular glucagon treatment among 1046

subjects with T1D using the following assumptions: 1047

80% power 1048

A response rate of 95% for both treatments 1049

A non-inferiority limit of 10 percentage points (absolute value) 1050

One-sided alpha level of 0.025 1051

1052

Also provided is the sensitivity analysis of sample size to account for the variance reduction that 1053

could result from using the same participant for each treatment. To be conservative, the 1054

correlation was assumed to be zero. 1055

1056

Non-Inferiority Limit

(upper 97.5%

confidence limit on the

difference)

Power

Correlation

0

0.1

0.2

0.3

10% 80% 75 74 72 68

1057

Given the above assumptions, the sample size required would be 75 participants with T1D. An 1058

additional 7 participants with T2D will also be enrolled and an exploratory analysis will be 1059

performed on the total population (T1D and T2D; N=82). 1060

No adjustment in sample size is made for potential loss to follow-up because participants that are 1061

lost to follow-up or drop-out will be replaced. The sample size indicated in the cells denotes the 1062

number of participants completing the study. 1063

1064

The following considerations were taken into account to justify the choice of the target 1065

achievement in the two groups as well as the choice of acceptable non-inferiority limit: 1066

1067

Response Rate 1068

Injection group 1069

The assumed response rate of 95% for glucagon by injection reflects that glucagon is not always 1070

effective under real-world use. In AMG Medical’s recently completed phase II study 1071

(AMG102), one participant out of 18 (5.6%) treated with glucagon by injection required 30 1072


minutes to achieve a BG increase of 20 mg/dL and in excess of 30 minutes to achieve a BG > 68 1073

mg/dL (3.8 mmol/L). 1074

1075

AMG504-1 group 1076

In the same phase II study, treatment with 2 mg intranasally was 93% effective while 3 mg was 1077

100% effective in causing patients to return to a BG > 68 mg/dL (3.8 mmol/L) by 30 minutes. 1078

As AMG504-1 has not been used in the setting of the lower BG levels targeted in this phase III 1079

clinical study (i.e., 45-50 mg/dL), a slightly lower percent efficacy of 95% has been projected. 1080

1081

Importantly, even if either treatment fails to meet the narrow definition of the primary endpoint 1082

of an increase in glucose level to >70 mg/dL within 30 minutes in every patient, the primary 1083

clinical outcome of an increase in blood glucose of >20 mg/dL will be satisfactory from a 1084

clinical perspective because sufficient recovery from clinical signs of hypoglycemia will occur at 1085

levels below 70 mg/dL which, in turn, will permit the patient to consume carbohydrate and fully 1086

recover [6]. 1087

1088 Non-inferiority Margin 1089

The proposed non-inferiority margin of 10 percentage points has been chosen based on the 1090

limited data available for glucagon injection ([7], simulated emergency study), the considerable 1091

data for an analogous product (EpiPen for treatment of anaphylaxis) and considerations of actual 1092

use in an emergency. 1093

1094

Injectable Glucagon 1095

We are not aware of published data documenting patient/caregiver treatment success rates in 1096

actual clinical situations wherein the currently injected glucagon must be given to treat an 1097

episode of severe hypoglycemia. However, one study has been published in which parents of 1098

children and adolescents with T1D used a currently available glucagon kit in a simulated 1099

emergency situation [7]. Parents were asked to pretend it was 3:00 am and their child was 1100

unconscious. They were then given an unopened emergency glucagon kit (GlucaGen® HypoKit, 1101

Novo Nordisk) and asked to administer the medication into a wrapped piece of meat to simulate 1102

a thigh. In this study, 69% of the parents experienced difficulties with the product and 10% 1103

completely failed to deliver the medication. 1104

1105

EpiPen 1106

Considerable data supporting the challenge associated with using emergency medicines are 1107

available in studies on the use of the EpiPen for treatment of anaphylactic reactions. The EpiPen 1108

is considerably easier to use than injectable glucagon as there is no reconstitution required, the 1109

needle is not exposed prior to use and the device is designed such that administration requires a 1110

very limited number of simple steps. Despite this simplicity, there are considerable challenges 1111

associated with correct use of this device – even by medical personnel. 1112

1113

Mehr [8] published data from a study conducted to determine the rate of correct use of EpiPen 1114

among physicians at a pediatric hospital. Of the 100 participants, only two doctors demonstrated 1115

all administration steps correctly. Errors included failure to hold the pen in place for the 1116

prescribed time, failure to apply pressure to activate and accidental self-injection. In 37% of the 1117

cases, the demonstration would not have delivered epinephrine to the patient. Similar data were 1118

generated in a study conducted to determine the ability of families with food allergic children 1119

and pediatricians to properly use self-injectable epinephrine [9]. One hundred one families and 1120

46 attending physicians or residents were enrolled in the study. Only 32% of the family member 1121


participants correctly demonstrated the use of the device. Among medical personnel, only 18% 1122

of the physicians and 36% of the residents demonstrated it correctly. 1123

1124

The 10 point non-inferiority margin is comparable to the complete failure rate (10%) reported in 1125

the Harris study [7]. However, the Harris study was only a simulation with highly experienced 1126

caregivers (i.e., parents of young children with diabetes) and may underestimate the failure rate 1127

associated with actual use during a hypoglycemic emergency. On the contrary, the 10 point 1128

margin is considerably smaller than the failure rates reported for EpiPen (37%), an emergency 1129

medication administration device that is much more user-friendly than injectable glucagon. 1130

1131

Emergency use 1132

The data described above indicate administration of emergency injectable medication, even in a 1133

form factor as simple as the EpiPen, is very challenging and that, even in the hands of medical 1134

personnel, administration errors are frequent and can result in failure to administer the 1135

medication. Importantly, all of the data cited above were generated in the absence of the extreme 1136

stress that a user would face were it a true emergency. 1137

1138

Compared with the EpiPen, glucagon injection is much more complex (i.e., many more steps, 1139

most of which are more complicated), much more intimidating (i.e., large, completely exposed 1140

needle that requires considerable manipulation) and more error-prone. In contrast, AMG504-1 is 1141

a needle free glucagon delivery system that requires no mixing and is administered by simply 1142

inserting the tip of the device into the nostril and depressing the trigger to release the powder. 1143

1144

Taking into account the findings described above, we believe AMG504-1 will be successfully 1145

administered the majority of the time while, in the hands of a nonmedical person, failure to 1146

properly administer or even attempt to administer glucagon injection will occur more frequently. 1147

1148

6.2 Analytic Considerations 1149 The central lab glucose measurements will be used for the analyses. If a central lab 1150

measurement is missing, then the YSI (or equivalent) measurement from that timepoint will be 1151

used. If a YSI value is not available for that timepoint, a value will be determined through 1152

appropriate interpolation methods; extrapolation methods will be used for truncated glucose 1153

measurements. 1154

1155

If a participant receives additional intervention treatment to raise blood glucose, measurements 1156

will be censored at the previous protocol blood glucose measurement time after the intervention 1157

was administered. 1158

1159

The primary analysis will be conducted using only data from the cohort of participants with type 1160

1 diabetes. 1161

1162

Descriptive statistics will be reported for the participants with type 2 diabetes. 1163

1164

6.3 Analysis of Primary Outcome 1165

6.3.1 Definition of Primary Outcome 1166 The primary outcome is the proportion of participants who achieve either an increase in blood 1167

glucose to >70 mg/dl (3.9 mmol/L) or an increase of >20 mg/dL within 30 minutes after 1168

receiving study glucagon, without receiving additional actions to increase the blood glucose 1169

level. 1170


1171

6.3.2 Non-Inferiority Analysis 1172 The primary analysis will be a treatment group comparison of the primary outcome (defined 1173

above). Non-inferiority of intranasal glucagon will be declared if the upper limit of a 1-sided 1174

97.5% confidence interval constructed on the difference in proportions (intramuscular glucagon 1175

– intranasal glucagon), is less than the non-inferiority limit of 10%. The confidence interval of 1176

the difference in proportions will be calculated using methods to account for the correlation due 1177

to the cross-over design. 1178

1179

6.4 Analysis of Exploratory Outcomes 1180

6.4.1 Time from Treatment to Outcome 1181 A Kaplan-Meier curve for each treatment group will be constructed for the time to occurrence of 1182

central lab blood glucose >70 mg/dL or an increase of >20 mg/dL after receiving study 1183

glucagon. 1184

1185

A treatment group comparison of the time from treatment to return of blood glucose to >70 1186

mg/dL or an increase of >20 mg/dL after receiving study glucagon also will be performed using 1187

Cox proportional hazard models accounting for the correlation due to the cross-over design, 1188

adjusted for starting blood glucose and treatment period. Due to the discrete time data (5, 10, or 1189

30 minute intervals), methods accounting for the tied event times will be employed. 1190

1191

If the proportional hazards assumption does not hold for the adjustment factors (starting blood 1192

glucose, treatment period), a stratified model will be used. If the proportional hazards 1193

assumption does not hold for the treatment group variable, a model with time-dependent 1194

covariate will be used. 1195

1196

6.4.2 Treatment Comparison of Continuous Glucose Levels 1197 A treatment comparison of blood glucose over the 90 minutes following administration of 1198

glucagon will be completed using a linear mixed model with repeated measures that accounts for 1199

the correlation due to the cross-over design and the correlation due to multiple measures, 1200

adjusting for starting glucose level and time period. Least-square means will be calculated for 1201

blood glucose in each treatment group and the difference in blood glucose between treatment 1202

groups (intramuscular – intranasal). Residuals from the model will be assessed numerically and 1203

graphically to ensure an approximately normal distribution. If the distribution appears skewed or 1204

if influential outliers are discovered, a transformation will be attempted. If an acceptable 1205

transformation is not found, non-parametric methods will be implemented. 1206

1207

If a participant received additional intervention to raise blood glucose, measurements taken after 1208

the time of intervention will be excluded from the analysis. 1209

1210

6.4.3 Symptoms of Hypoglycemia 1211 Hypoglycemia symptoms will be assessed using the Edinburgh Hypoglycemia Scale. Responses 1212

to each symptom on the Edinburgh Hypoglycemia Scale questionnaire will be tabulated per 1213

instructions on the questionnaire at each time point for both treatment groups. The total score on 1214

the questionnaire will be computed at each time point for both treatment groups as the sum of the 1215

scores for each symptom. 1216

1217

The total score will be compared between treatment groups through a linear mixed model with 1218

repeated measures accounting for the correlation due to the cross-over design (same participant 1219


received both treatments) and the correlation due to multiple measures of the questionnaire 1220

(questionnaire administered multiple times during testing). The starting score and treatment 1221

period will be included as covariates in the model. 1222

1223

6.5 Safety and Tolerability 1224 Responses to each question on the Nasal and Non-Nasal Score Questionnaire will be tabulated at 1225

each time point for both treatment groups. The scoring for each response will follow the scale 1226

displayed on the questionnaire (‘None’=0, ‘Mild’=1, ‘Moderate’=2, ‘Severe’=3). The total score 1227

on the questionnaire will be computed as the sum of the scores for each question. The total score 1228

will be tabulated at each time point for both treatment groups. 1229

1230

The total score will be compared between treatment groups through a linear mixed model that 1231

accounts for the correlation due to the cross-over design and the correlation due to repeated 1232

measures of the questionnaire. The starting score will serve as a covariate in the model along 1233

with the treatment period. 1234

1235

Other adverse events/symptoms (including nausea/vomiting) will be tabulated for each treatment 1236

group. 1237

1238

6.6 Additional Tabulations 1239 The following will be tabulated according to treatment group: 1240

Baseline demographic and clinical characteristics 1241

o Responses to the Clarke Hypoglycemia Awareness Survey will be tabulated for 1242

each participant per the instructions on the questionnaire. 1243

Completion rate for each visit 1244

o Summary statistics for days to complete the second visit will be computed 1245

Mean/standard deviation will be calculated if the distribution does not 1246

appear to be skewed, otherwise median and quartiles will be used 1247

Protocol deviations 1248

1249

6.7 Pharmacokinetic/Pharmacodynamic Analysis 1250

6.7.1 Analysis Cohort 1251 Patients who provide evaluable data for at least one of the treatments will be included in the 1252

pharmacokinetic and pharmacodynamic analyses. Concentration data of the remaining patients 1253

will be presented separately. 1254

1255

6.7.2 Pharmacokinetic Analysis 1256 PK analysis of glucagon will be performed using SAS 9.2 or later. PK parameters will be 1257

calculated using non-compartmental analysis (NCA). Actual sampling times will be used for all 1258

calculations. 1259

The following PK parameters will be calculated using raw concentrations of glucagon: 1260

AUC0-t Area under the curve from time zero to the last quantifiable concentration 1261

(Clast), calculated with the linear trapezoidal method. 1262

Cmax Maximum observed concentration 1263

tmax Time to maximum concentration. 1264


AUC0- Area under the curve extrapolated to infinity, calculated as AUC0-t + 1265

Clast/λz, where Clast is the last measurable concentration at tlast, and λz is the 1266

terminal rate constant. 1267

CL/F Systemic clearance, calculated as Dose/ AUC0- 1268

λz First-order terminal elimination rate constant, calculated by log-linear 1269

regression analysis using a minimum of three quantifiable concentration 1270

values over the terminal elimination phase (i.e. terminal mono-exponential 1271

decline). 1272

t1/2 Terminal elimination half-life, calculated as 0.693/λz. 1273

1274

The following PK parameters will be calculated using baseline-adjusted concentrations of 1275

glucagon: 1276

AUC0-t Area under the curve from zero to time of the last quantifiable 1277

concentration (Clast), calculated with the linear trapezoidal method. 1278

Cmax Maximum concentration. 1279

tmax Time to maximum concentration. 1280

Baseline glucagon concentrations will be calculated as the mean of concentrations from samples 1281

obtained prior to dosing. 1282

Other PK parameters will be calculated if required. Individual concentrations and PK parameters 1283

of glucagon will be summarized with descriptive statistics by treatment. 1284

1285

6.7.3 Pharmacodynamic Analysis 1286 The PD analysis of glucose will be performed using using SAS 9.2 or later. PD parameters will 1287

be calculated using non-compartmental analysis (NCA). Key PD parameters will be derived to 1288

assess the exposure to glucose and duration of exposure above, below and within the normal 1289

glucose range. The normal range for glucose will be considered to be (70 to 108 mg/dL) 3.9 to 1290

6.0 mmol/L. Actual sampling times will be used for all calculations. 1291

The following PD parameters will be calculated using raw concentrations of glucose: 1292

AUEC0-1.5 Area under the effect concentration time curve from time zero (pre-dose) 1293

up to 1.5 hours 1294

Cmax Maximum concentration 1295

tmax Time to maximum concentration 1296

AUECAbove Area under the effect concentration-time curve above the normal range 1297

AUECBelow Area under the effect concentration-time curve below the normal range 1298

AUECWithin Area under the effect concentration-time curve within the normal range 1299

TAbove Time to concentrations above normal range 1300


TBelow Time to concentrations below normal range (after TAbove) 1301

TWithin Time to concentrations within normal range 1302

DurationAbove Duration above normal range 1303

DurationBelow Duration below normal range 1304

DurationWithin Duration within normal range 1305

The following PD parameters will be calculated using baseline-adjusted concentrations of 1306

glucose. 1307

AUEC0-1.5 Area under the effect concentration-time curve from time zero (pre-dose) 1308

up to 1.5 hours 1309

Cmax Maximum concentration 1310

tmax Time to maximum concentration 1311

Baseline glucose concentrations will be calculated as the mean of concentrations from samples 1312

obtained when the insulin infusion is stopped and immediately prior to dosing (i.e., times -0.08 1313

and 0.00 hours). 1314

Other PD parameters of glucose may be calculated if required. Individual concentrations and PD 1315

parameters of glucose will be summarized with descriptive statistics by treatment. 1316

1317

6.7.4 PK/PD relationship 1318 Exploratory analyses will be performed to evaluate exposure-response relationship, a 1319

fundamental component for the understanding of drug effect and supporting efficacy endpoints. 1320

The relationship between the exposure (concentrations and parameters) of glucagon and glucose 1321

will be explored using graphical displays. 1322

1323

6.7.5 Inferential Statistics 1324 For exploratory purposes, an ANOVA model will be used to compare ln-transformed parameters 1325

of glucagon and glucose (baseline-adjusted AUC0-1.5, AUEC0-1.5, glucagon Cmax, glucose Cmax) 1326

between the intranasal (Treatment 1) and injected (Treatment 2) formulations. The ANOVA 1327

model will include patient as random effect and treatment as fixed effect. Ratios of geometric 1328

least-squares mean (LSM) along with 90% confidence intervals will be derived. 1329

1330

6.8 Interim Monitoring Plan 1331 There is no plan for interim efficacy monitoring. 1332

1333

1334


Chapter 7. DATA COLLECTION AND MONITORING 1335 1336

7.1 Case Report Forms 1337 The main study data are collected during the two glucagon dosing visits. Data will be collected 1338

on a customized excel worksheet for recording of glucose levels, insulin infusion data, blood 1339

draws, time of glucagon dosing, and safety assessments. These data will be directly imported 1340

from the excel file into the study database at the Coordinating Center. The primary data used the 1341

analyses will be transmitted directly from the laboratories to the Coordinating Center and will 1342

not be entered into case report forms. 1343

1344

7.2 Quality Assurance and Monitoring 1345 Designated personnel from the Coordinating Center will be responsible for maintaining quality 1346

assurance (QA) and quality control (QC) systems to ensure that the clinical portion of the trial is 1347

conducted and data are generated, documented and reported in compliance with the protocol, 1348

GCP and the applicable regulatory requirements. Adverse events will be prioritized for 1349

monitoring. 1350

1351

The primary outcome data for the study will be the PK and PD results from the laboratories 1352

performing these analyses. Monitoring with include duplicate masked samples for quality 1353

control assessment. 1354

1355

A risk-based monitoring (RBM) plan will be developed and revised as needed during the course 1356

of the study. The primary study data for efficacy analyses are glucose and glucagon values 1357

determined at separate central laboratories, which will be blinded to all other study data 1358

including the glucagon formulation which was received. As a result, the data of most importance 1359

for monitoring at the site are participant eligibility and adverse events. Therefore, the RBM plan 1360

will focus on these areas. As much as possible, remote monitoring will be performed in real-1361

time with on-site monitoring performed to evaluate the verity and completeness of the key site 1362

data. 1363

1364

AMG Medical, Inc., JCHR, or their representatives may visit the study facilities at any time in 1365

order to maintain current and personal knowledge of the study through review of the records, 1366

comparison with source documents, observation and discussion of the conduct and progress of 1367

the study. The Coordinating Center will permit trial-related monitoring, audits, IRB/IEC review, 1368

and regulatory inspection(s) by providing direct access to source data/documents. 1369

1370

1371

1372


Chapter 8. REFERENCES 1373 1374

1. Carson, M.J. and R. Koch, Clinical studies with glucagon in children. J Pediatr, 1955. 1375

47(2): p. 161-170. 1376

2. Miller, R.E., et al., Hypotonic roentgenography with glucagon. Am J Roentgenol, 1974. 1377

121(2): p. 264-274. 1378

3. Glucagon for Injection® (rDNA origin) [Label] (02/24/2004). September 13, 2012]; 1379

Available from: http://www.accessdata.fda.gov/scripts/cder/drugsatfda. 1380

4. Pontiroli, A.E., M. Alberetto, and G. Pozza, Intranasal glucagon raises blood glucose 1381

concentrations in healthy volunteers. BMJ, 1983. 287(6390): p. 462-463. 1382

5. Stenninger, E. and J. Aman, Intranasal glucagon treatment relieves hypoglycaemia in 1383

children with Type 1 (insulin-dependent) diabetes mellitus. Diabetologia, 1993. 36(10): p. 1384

931-935. 1385

6. Cryer, P.E., Hypoglycemia in diabetes: pathophysiology, prevalence, and 1386

preventionHypoglycemia in diabetes: pathophysiology, prevalence, and prevention. 2nd 1387

ed. 2012: American Diabetes Association. 1388

7. Harris, G., et al., Glucagon administration – underevaluated and undertaught. Practical 1389

Diabetes International, 2001. 18(1): p. 22-25. 1390

8. Mehr, S., M. Robinson, and M. Tang, Doctor – How do I use my EpiPen? Pediatric 1391

Allergy and Immunology, 2007. 18(5): p. 448-452. 1392

9. Sicherer, S.H., J.A. Forman, and S.A. Noone, Use Assessment of Self-Administered 1393

Epinephrine Among Food-Allergic Children and Pediatricians. Pediatrics, 2000. 105(2): 1394

p. 359-362. 1395

1396

1397

http://www.accessdata.fda.gov/scripts/cder/drugsatfda

adult glucagon protocol v2 09-27-13 (2) printdate: 1/7/2015 9:44 AM Appendix 1-1

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APPENDIX 1 NASAL AND NON-NASAL SCORE QUESTIONNAIRE 1399

1400 Please circle the number that corresponds best to the effects/symptoms you are experiencing at 1401

this time, or have experienced since last questioning. 1402

1403

0 = I am not experiencing this (no symptoms at all). 1404

1 = I am only experiencing a mild case of this and it is easily tolerated. 1405

2 = I am experiencing a moderate level of this symptom. It is bothersome but tolerable. 1406

3 = I am experiencing a severe level of this symptom. It is hard to tolerate and interferes 1407

with my activities. 1408

1409

Symptoms

Scale

0

None

1

Mild

2

Moderate

3

Severe

1. Runny nose 0 1 2 3

2. Nasal congestion (nostrils

plugged) 0 1 2 3

3. Nasal itching 0 1 2 3

4. Sneezing 0 1 2 3

5. Watery eyes 0 1 2 3

6. Itchy eyes 0 1 2 3

7. Redness of eyes 0 1 2 3

8. Itching of ears 0 1 2 3

9. Itching of throat 0 1 2 3


1410

APPENDIX 2 CLARKE HYPOGLYCEMIA AWARENESS SURVEY 1411 1412 1. Check the category that best describes you: (check one only) 1413

1414 I always have symptoms when my blood sugar is low A

I sometimes have symptoms when my blood sugar is low R

I no longer have symptoms when my blood sugar is low R

1415 2. Have you lost some of the symptoms that used to occur when your blood sugar was low? 1416 1417

Yes R

No A

1418 3. In the past six months how often have you had moderate hypoglycemia episodes? (Episodes where 1419

you might feel confused, disoriented, or lethargic and were unable to treat yourself) 1420 1421 Never A

Once or twice R

Every other month R

Every month R

More than once a month R

1422 4. In the past year how often have you had severe hypoglycemic episodes? (Episodes where you were 1423

unconscious or had a seizure and needed glucagon or intravenous glucose) 1424 1425

Never A 5 times R 11 times R

1 time R 6 times R 12 times or more R

2 times R 7 times R

3 times R 8 times R

4 times R 9 times R

1426 5. How often in the last month have you had readings < 70 mg/dL (3.8 mmol/L) with symptoms? 1427 1428

Never 1 time/week 4 to 5 times/week

1 to 3 times 2 to 3 times/week Almost daily

1429 6. How often in the last month have you had readings < 70 mg/dL (3.8 mmol/L) without symptoms? 1430 1431

Never 1 time/week 4 to 5 times/week

1 to 3 times 2 to 3 times/week Almost daily

1432 If answer to question 5 < answer to question 6 R

If answer to question 6 < answer to question 5 A

1433 1434 1435 1436 1437 1438


7. How low does your blood sugar need to go before you feel symptoms? 1439 1440 60-69 mg/dL, 3.3 - 3.8 mmol/L A

50-59 mg/dL; 2.8 – 3.3 mmol/L A

40-49 mg/dL; 2.2 – 2.7 mmol/L R

less than 40 mg/dL less than 2.2 mmol/L R

1441 8. To what extent can you tell by your symptoms that your blood sugar is low? 1442

1443 Never R

Rarely R

Sometimes R

Often A

Always A

1444 1445

Final score: Total Number of “R” responses: ________ 1446


APPENDIX 3 EDINBURGH HYPOGLYCEMIA SCALE: EXPERIMENTAL 1447

HYPOGLYCEMIA 1448 1449

I am going to list a series of 15 symptoms that you may or may not be experiencing. Please 1450

indicate the number that corresponds best to the effects/symptoms you are experiencing at this 1451

time (right now) or have experienced since last questioning with a number of 1 to 7, 1 1452

representing no symptoms, 7 representing severe symptoms. 1453

1454

1 = I am not experiencing this (no symptoms at all) 1455

2 = I am only experiencing a very mild case of this and it is easily tolerated 1456

3 = I am only experiencing a mild case of this and it is tolerated 1457

4 = I am experiencing a mild to moderate case of this and it is tolerated 1458

5 = I am experiencing a moderate case of this and it is tolerated 1459

6 = I am experiencing a moderate to severe level of this symptom. It is bothersome but tolerable. 1460

7 = I am experiencing a severe level of this symptom. It is hard to tolerate. 1461

1462 Intensity

Not at all A great deal

1 2 3 4 5 6 7

Symptoms

Weakness 1 2 3 4 5 6 7

Difficulty speaking 1 2 3 4 5 6 7

Double vision 1 2 3 4 5 6 7

Nausea 1 2 3 4 5 6 7

Headache 1 2 3 4 5 6 7

Drowsiness 1 2 3 4 5 6 7

Trembling 1 2 3 4 5 6 7

Inability to concentrate 1 2 3 4 5 6 7

Blurred vision 1 2 3 4 5 6 7

Earache 1 2 3 4 5 6 7

Anxiety 1 2 3 4 5 6 7

Hunger 1 2 3 4 5 6 7

Tiredness 1 2 3 4 5 6 7

Pain in joints 1 2 3 4 5 6 7

Confusion 1 2 3 4 5 6 7

Sweating 1 2 3 4 5 6 7

Warmness 1 2 3 4 5 6 7

McCrimmon et all, 2003 1463 1464

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