summary id# 5123 clinical study summary: study b9r- it...

CT Registry ID#5123 Page 1

Humatrope Copyright © 2006 Eli Lilly and Company. All rights reserved.

Summary ID# 5123

Clinical Study Summary: Study B9R- IT-GDFT

The Genetics and Neuroendocrinology in Children with GHD: A Part of GeNeSIS

Date summary approved by Lilly: 28 August 2006

Brief Summary of Results

This was a pilot study conducted in one European country in preparation of participation in an international more comprehensive study (GeNeSIS) for the characterization of genetic defects associated with hypopituitarism and the development of an accurate growth prediction model. The GeNeSIS study analysis at the 2004 datalock incorporates data belonging to this study.

Title of Study: The Genetics and Neuroendocrinology in children with GHD: A part of GeNeSIS Investigator(s): This multicenter study included 19 principal investigators. Study Center(s): This study was conducted at 19 study centers in 1 country. Length of Study: 1 year Date of first subject visit: 12 September 2001 Date of last subject visit: 01 September 2003

Phase of Development: 4

Objectives: Primary objectives:

• To characterize gene defects associated with hypopituitarism, growth disorder or short stature. [DNA analysis study]

• To develop accurate growth prediction models using clinical data (auxologic parameters, bone age) and biochemical data (insulin-like growth factor-I [IGF-I] and insulin-like growth factor binding protein-3 [IGFBP-3], urinary bone markers) [Growth prediction study].

Secondary Objectives: To collect any adverse event, whether or not considered drug-related



Study Design: open-label, multicenter, national study. It was a part of GeNeSIS - The Genetics and Neuroendocrinology of Short Stature International Study - which is an open-label, multicenter, multinational, observational study, established as a post-marketing research program. It collects information on the clinical management of patients with short-stature, growth disorder or disorders of hypothalamic-pituitary function according to standard pediatric endocrinology practice, as documented by the attending endocrinologist. DNA Analysis Study: Patients, who fulfilled inclusion criteria, were eligible to enter B9R-IT-GDFT, in the DNA analysis study. Once a patient was enrolled in this study, a blood sample for genetic analysis was taken at baseline and sent to the central lab for analysis.

Growth Prediction Study: Patients who meet inclusion criteria and who have not yet received any growth hormone (GH) therapy were eligible to participate in the growth prediction study. Once a patient was

enrolled in this study, a blood sample for evaluation of IGFs was taken at baseline. After one month of GH

therapy a sample of urine for bone markers evaluation was also taken and sent to the central lab for

analysis.

Discussion of Design and Control This was an open-label, multicenter, national study for a total treatment period of 12 months (52 weeks) involving about 60 GHD pre-pubertal patients who at enrolment received Humatrope therapy administered from Visit 1 at the currently approved dosage for pediatric GHD (0.025-0.035 mg/Kg/day). All subjects, regardless of which study they were enrolled in (DNA and Growth prediction), underwent baseline anthropometric measurements and collection of blood sample for measurement of IGF-I, IGF-BP3 and blood chemistry and hematology for safety (if not available previously). At Visit 1, after giving informed consent, physical examination of patients to determine the diagnosis was performed according to the Schedule of Events, and blood sample was collected for thyroid function test (performed in a Local Laboratory), DNA analysis (only subjects enrolled in this study) (a central laboratory), IGF-I and IGF-BP3 (a central laboratory). A hand-wrist x-ray was performed to determine bone age. In addition, the subjects enrolled in Growth Prediction Study were given a urine collection kit and instructions to collect urine at home approximately 1 month after the start of somatropin therapy. One month (+ 1 week) after Visit 1, an interim history was collected including any adverse event, clinical evaluation, Humatrope® therapy information. At this visit, the patient brought his/her 24 hour urine collection for central laboratory to determine deoxypiridinoline crosslinks, galactosylhydroxylysine and glucosylgalctosylhydroxylysine. At Visit 2, after 3 months (+ 3 weeks) of GH treatment, an interim history was collected including any adverse event, clinical evaluation, Humatrope® therapy information. At Visit 3, after 6 months (+ 4 weeks), a blood sample was collected for IGF-I, IGF-BP3 performed in a different Central Lab. Clinical evaluation including any adverse event and Humatrope® therapy information was collected. At Visit 4, after 12 months (+ 4 weeks), a blood sample was collected for IGF-I, IGF-BP3 performed in a different Central Lab. A hand-wrist x-ray was performed to determine bone age. Clinical evaluation including any adverse event and Humatrope® therapy information was collected. Number of Subjects: Planned: 60. Entered: 36. Completed: 32.



Main Criteria for Inclusion DNA Analysis Study:

• Fulfillment of criteria defined in the scoring system • They have never received any growth hormone therapy • GHD defined as:

- peak response of GH under any pharmacological stimulation



Variables: Safety:

• Date of birth, sex, visit date • Diagnosis • Specific medical conditions, significant historical diagnoses, growth promoting

medications prior to study entry • Medications • Pre-existing conditions (data collected on “Pre-existing Conditions and Adverse Events”

running record) • Humatrope therapy: dose at entry into the study (dose per injection, unit, number of

injections per week), date of first dose of growth hormone after entry into the study • Adverse events

The frequency and percentage of adverse events for patients receiving Humatrope therapy were summarized in multiple ways including by body system and by underlying disorders. Serious adverse events were listed in detail for each individual patient. Detailed summaries of neoplastic disease recurrence were also presented. Efficacy: The following efficacy issues were explored: height and annualized height velocity. The participating physicians were contacted if the following data are not provided:

• Date of birth, sex, visit date • Diagnosis • GH testing results • Measurements (length or height) • Humatrope therapy (for Humatrope-treated patients): prescribed dose at entry into the

study (dose per injection, unit, number of injections per week) • Patients who, at the end of B9R-IT-GDFT, will be entered into GeNeSIS, will be

followed-up to the final height attainment (when their height velocity has dropped below 2 cm/year)

Gene defects: The following efficacy issues were explored: height and annualized height velocity. The participating physicians were contacted if the following data are not provided:

• Date of birth, sex, visit date • Diagnosis • GH testing results • Measurements (length or height) • Humatrope therapy (for Humatrope-treated patients): prescribed dose at entry into the

study (dose per injection, unit, number of injections per week) • Patients who, at the end of B9R-IT-GDFT, will be entered into GeNeSIS, will be

followed-up to the final height attainment (when their height velocity has dropped below 2 cm/year)

Bioanalytical: Not applicable Pharmacokinetic/Pharmacodynamic: Not applicable Health Outcomes: Not applicable Evaluation Methods: Statistical: Patients entered in the study were included in any given analysis only if they have the necessary data available for the analysis in question. Student’s t-test was used for the comparison of means from two variables when more variables or unpaired test were performed. Analysis of variance (ANOVA) was used. Growth Prediction was performed after 3 months of treatment as follows: baseline data (height, weight, bone age, pubertal stage, IGF-1 and IGFBP-3), urinary bone turnover markers (deoxypiridinoline crosslinks, galactosylhydroxylysine and glucosylgalctosylhydroxylysine) after 4 weeks, and height, IGF-1 and IGFBP-3 after 3 months were collected and was calculated using a mathematical algorhytm. The results were expressed as 1st year height velocity (HV) using the formulae 1-year HV(cm)=3.543-(2.337xBA)-(0.010xIGF-I)+(0.100xDPD)+(0.299x3month HV).



Results:

The last patient was entered into treatment on 31 July 2002, instead of the planned date of 30 September 2001 because of the very low rate of enrollment of patients.

Patient Demographics

Completers’ demographics at baseline are summarized in Table 1.



Table 1. Summary of Baseline Patient Demographics

-ANOVA p-values-

Group N Mean SD Median Q1 Q3 Min Max Raw Ranked

Age at diagnosis

All 32 5.09 3.73 4.73 1.90 7.57 0.03 14.67 0.775 0.727

Female 11 4.82 3.77 4.54 1.83 6.85 0.03 12.19

Male 21 5.23 3.79 4.92 2.00 7.67 0.06 14.67

Baseline bone age GP SDS (BAGP-CA)/SD

All 27 -3.73 1.19 -3.61 -4.36 -2.80 -6.41 -1.63 0.516 0.482

Female 9 -3.51 1.38 -3.41 -4.26 -2.42 -5.71 -1.63

Male 18 -3.84 1.11 -3.66 -4.36 -3.04 -6.41 -2.46

Baseline bone age GP delay (BAGP-CA)

All 31 -2.31 1.06 -2.34 -2.89 -1.42 -4.63 -0.54 0.523 0.395

Female 11 -2.14 1.22 -1.65 -3.51 -1.05 -4.26 -0.86

Male 20 -2.40 0.98 -2.41 -2.86 -1.92 -4.63 -0.54

Baseline bone age Greulich-Pyle

All 31 3.12 2.88 2.72 0.85 4.41 -0.47 10.37 0.790 0.717

Female 11 2.93 2.92 2.03 0.85 3.91 -0.14 9.73

Male 20 3.22 2.93 2.91 1.07 4.90 -0.47 10.37

Baseline relative bone age GP (BAGP/CA)

All 31 0.42 0.37 0.52 0.34 0.67 -1.00 0.80 0.783 0.840

Female 11 0.44 0.31 0.55 0.27 0.62 -0.16 0.80

Male 20 0.40 0.40 0.47 0.35 0.68 -1.00 0.75

baseline age (yrs)

All 32 5.28 3.60 4.84 2.18 7.61 0.47 14.72 0.811 0.862

Female 11 5.07 3.61 4.63 2.21 7.02 0.82 12.21

Male 21 5.39 3.68 5.06 2.14 7.75 0.47 14.72




Table 1. Summary of Baseline Patient Demographics (concluded)

Target height (cm)

All 32 165.50 8.32 167.33 158.38 171.25 149.65 181.50



Table 2. Disease Characteristics of Protocol Completers (N=32)

Diagnosis No (%) Level 1 GHD

Level 2

Number of patients (%)

32 (100.0) Idiopathic

Organic 23 (71.9) 9 (28.1)

Level 3 Classic Congenital

Level 4 UNK Abnormal pituitary development UNK

Number of patients (%) 23 (100) 23 (100) 8 (88.9)

1 (11.1)

Level 4 Abnormal pituitary development UNK

Level 5 Ectopic posterior pituitary Pituitary aplasia/absence Pituitary hypoplasia UNK

Number of patients (%)

8 (100) 4 (50) 1 (12.5) 3 (37.5) 24 (100)

The number of years on GH Treatment for all GHD patients is reported in Table 3.

Table 3. Total Years on GH Therapy

Years Number of Patients (%) 0 - 1 17 (53.1) > 1-2 15 (46.9) All 32 (100)



Tanner Stage values at baseline and endpoint are presented in Table 4.

Table 4. Tanner Stages at Baseline and Endpoint

Tanner Stage at Baseline Females n (%) Males n (%) B1 11 (100) G1 19 (95) G2 1 (5) Tanner Stage at Last Visit Females n (%) Males n (%) B1 9 (81.8) G1 16 (80) B2 2 (18.2) G2 1 (5) Unknown 3 (15)

Abbreviations: B = breast; G = gonad; n = number of patients.

Efficacy Measures Growth Prediction Model Results: For the females an HV of 12.98± 4.82 cm/year was predicted after three months of observation and at the first year the HV was 13.05±3.91 cm/year; for the males an HV of 13.95±5.39 cm/year was predicted and at the first year the HV was 12.93±5.02 cm/year.

Height, height SDS, weight, weight SDS IGF-I SDS, IGF-I/IGFB-3 ratio, statisticall increased in all treatment groups and by age because pts. were going according with pts. enrolled characteristics .

In the same manner, IGFB-3 SDS was statistically increased during the study in males and total population (p



All results are summarized in the following pages (Table 5- Table 15):

Table 5. Summary of Height Velocity (cm/year)

SUMMARY OF HEIGHT VELOCITY SDS -ANOVA p-values-


Baseline height velocity

All 15 7.20 6.55 4.62 3.55 6.51 2.68 24.67 0.649 0.560

Female 5 8.35 9.17 4.79 4.62 4.96 2.68 24.67

Male 10 6.62 5.32 4.22 3.55 6.51 3.10 16.60

Change from 3 months to 1 Year

All 30 -0.76 2.75 -0.83 -2.49 1.66 -7.28 6.13 0.489 0.388

Female 10 -0.26 2.24 -0.57 -1.68 1.78 -4.28 2.62

Male 20 -1.01 2.99 -0.86 -2.81 0.27 -7.28 6.13

Change from baseline to 1 Year

All 15 5.15 6.07 6.86 2.68 9.49 -8.10 12.35 0.547 0.187

Female 5 3.75 5.35 5.31 2.69 6.02 -4.79 9.49

Male 10 5.85 6.55 7.27 6.50 9.91 -8.10 12.35

Change from baseline to 3 months

All 14 6.48 5.44 6.89 3.64 8.07 -4.31 16.66 0.226 0.096

Female 5 4.05 3.19 3.64 2.96 6.87 -0.51 7.29

Male 9 7.83 6.10 7.96 6.06 11.21 -4.31 16.66

First year height velocity (cm/yr)

All 32 12.97 4.60 11.91 9.93 14.59 6.46 26.86 0.941 0.656

Female 11 13.05 3.91 12.18 10.10 16.37 7.66 19.89

Male 21 12.93 5.02 11.51 9.93 13.63 6.46 26.86

Height velocity first 3 months of GH Rx

All 30 13.63 5.15 12.41 10.54 15.38 6.71 29.82 0.636 0.668

Female 10 12.98 4.82 12.22 9.56 15.38 7.92 24.16

Male 20 13.95 5.39 12.44 10.72 16.14 6.71 29.82



Table 6. Summary of Height Velocity SDS

SUMMARY OF HEIGHT VELOCITY SDS -ANOVA p-values-


Baseline height velocity SDS

All 12 -1.38 2.64 -2.05 -2.57 -1.20 -3.75 6.56 0.701 0.523

Female 4 -1.82 1.30 -1.31 -2.59 -1.05 -3.75 -0.92

Male 8 -1.16 3.18 -2.07 -2.57 -1.62 -3.28 6.56

Change from baseline to 1 Year

All 12 6.58 5.03 7.93 3.52 9.12 -5.66 14.25 0.647 0.331

Female 4 5.58 2.99 5.00 3.13 8.03 3.10 9.22

Male 8 7.09 5.92 8.39 5.77 9.89 -5.66 14.25

First year height velocity SDS

All 31 4.51 2.92 5.04 2.10 6.12 -0.68 12.16 0.610 0.545

Female 11 4.14 3.17 2.53 2.10 5.50 -0.68 9.93

Male 20 4.71 2.83 5.26 2.76 6.24 -0.20 12.16



Table 7. Summary of BMI (kg/m2)

Group N Mean SD Median Q1 Q3 Min Max t-test

p-value signed p-value

Baseline

All 31 16.1 2.4 15.8 14.4 17.5 11.7 21.7

Female 11 15.3 2.2 15.8 13.5 17.3 11.7 18.5

Male 20 16.5 2.5 15.8 14.5 17.6 12.8 21.7

After 1 Year

All 28 15.2 2.1 14.8 13.4 16.2 12.6 20.5

Female 9 14.5 1.7 14.0 13.2 15.3 12.6 17.6

Male 19 15.5 2.2 15.3 13.6 16.5 13.0 20.5

Change from Baseline to 1 Year

All 27 -0.6 1.2 -0.7 -1.5 0.3 -3.3 1.8 0.012 0.014

Female 9 -0.6 1.3 -0.5 -0.9 -0.1 -3.3 1.8 0.252 0.164

Male 18 -0.7 1.2 -0.9 -1.8 0.6 -2.5 1.1 0.029 0.038

Model Effects Baseline After 1 Year Change

ANOVA Comparison (Raw Data)

GENDER 0.190 0.259 0.792

ANOVA Comparison (Ranked Data)

GENDER 0.340 0.276 0.652



Table 8. Summary of BMI SDS



Baseline

All 26 -0.43 1.57 -0.26 -1.51 0.68 -4.86 1.92

Female 9 -1.08 1.94 -1.51 -1.60 0.46 -4.86 1.40

Male 17 -0.08 1.26 0.06 -0.91 0.68 -2.95 1.92

After 1 Year

All 23 -0.93 1.30 -0.38 -2.19 0.17 -3.06 1.31

Female 7 -1.30 1.38 -2.03 -2.56 -0.10 -2.62 0.80

Male 16 -0.77 1.28 -0.19 -1.87 0.18 -3.06 1.31


All 22 -0.30 1.06 -0.27 -0.91 0.18 -2.47 2.67 0.205 0.163

Female 7 0.07 1.23 0.03 -0.85 0.09 -1.02 2.67 0.880 0.938

Male 15 -0.47 0.97 -0.44 -1.23 0.28 -2.47 0.97 0.083 0.151

Model Effects Baseline After 1 Year Change

ANOVA Comparison (Raw Data)

GENDER 0.125 0.381 0.276

ANOVA Comparison (Ranked Data)

GENDER 0.212 0.398 0.708



Table 9. Summary of Height



Baseline

All 31 94.0 20.9 92.3 77.0 110.0 56.5 142.4

Female 11 90.3 19.5 87.8 70.5 103.2 64.5 129.4

Male 20 96.1 21.9 93.8 82.1 112.9 56.5 142.4

After 1 Year

All 28 103.4 19.1 102.5 87.2 116.6 74.5 151.7

Female 9 98.2 13.9 101.7 86.0 108.3 77.8 118.0

Male 19 105.8 21.1 103.0 88.4 122.6 74.5 151.7


All 27 11.6 3.5 10.7 9.3 13.3 6.2 22.0



Table 10. Summary of Height SDS



Baseline

All 26 -3.24 0.94 -3.12 -3.74 -2.74 -5.58 -1.21

Female 9 -3.76 1.04 -3.70 -4.36 -3.15 -5.58 -1.99

Male 17 -2.96 0.77 -3.01 -3.48 -2.36 -4.30 -1.21

After 1 Year

All 23 -2.20 0.98 -1.84 -3.22 -1.33 -3.68 -0.86

Female 7 -2.56 1.18 -2.98 -3.48 -0.94 -3.57 -0.86

Male 16 -2.04 0.87 -1.83 -2.77 -1.38 -3.68 -0.92


All 22 1.02 0.56 0.92 0.69 1.20 0.17 2.46



Table 11. Summary of Weight (kg)



Baseline

All 31 15.0 8.1 13.0 10.1 16.6 4.6 44.1

Female 11 12.7 5.2 12.5 9.0 14.4 5.8 25.3

Male 20 16.3 9.1 14.0 11.3 19.3 4.6 44.1

After 1 Year

All 28 17.1 8.5 15.5 11.8 18.8 7.6 45.4

Female 9 14.1 3.4 14.8 13.0 16.8 8.5 18.3

Male 19 18.6 9.9 16.0 11.0 23.4 7.6 45.4


All 27 2.9 1.4 2.9 2.0 3.8 0.5 6.5



Table 12. Summary of Weight SDS



Baseline

All 26 -2.9 2.0 -2.5 -3.8 -1.6 -9.7 0.2

Female 9 -4.0 2.4 -3.6 -4.3 -2.1 -9.7 -1.8

Male 17 -2.3 1.5 -2.1 -3.7 -1.3 -4.6 0.2

After 1 Year

All 23 -2.2 1.4 -2.3 -3.2 -0.8 -4.7 0.2

Female 7 -2.9 1.7 -3.2 -4.4 -0.8 -4.7 -0.2

Male 16 -1.9 1.2 -2.2 -2.8 -0.9 -4.1 0.2


All 22 0.9 1.2 0.8 -0.1 1.3 -0.7 5.0 0.002



Table 13. Summary of IGF-I SDS



Baseline

All 30 -2.67 2.37 -2.34 -3.62 -1.24 -7.88 0.67

Female 11 -2.23 2.48 -1.92 -2.60 0.25 -7.66 0.67

Male 19 -2.93 2.34 -2.86 -4.00 -1.24 -7.88 0.36

After 1 Year

All 28 -0.72 1.80 -0.91 -1.69 0.77 -4.04 2.51

Female 9 0.03 1.74 0.25 -1.16 0.87 -2.65 2.51

Male 19 -1.08 1.76 -1.25 -2.37 0.66 -4.04 2.40


All 26 2.25 2.09 2.22 1.02 3.35 -1.13 6.26



Table 14. Summary of IGFB-3 SDS



Baseline

All 25 -1.21 2.11 -0.57 -3.27 -0.14 -5.25 2.11

Female 9 -1.12 2.24 -0.57 -3.34 0.07 -4.47 1.90

Male 16 -1.26 2.10 -0.71 -2.91 -0.16 -5.25 2.11

After 1 Year

All 27 0.25 1.72 0.17 -0.74 1.81 -3.25 2.79

Female 9 0.27 1.88 0.17 -1.64 1.96 -1.95 2.79

Male 18 0.24 1.69 0.23 -0.72 1.63 -3.25 2.52


All 21 1.67 2.01 1.84 0.33 2.71 -1.72 6.27 0.001



Table 15. Summary of IGF-I/IGFB-3 Ratio



Baseline

All 25 31.90 18.10 26.99 21.94 39.53 4.39 78.69

Female 9 38.89 24.78 31.66 23.25 50.84 6.49 78.69

Male 16 27.96 12.27 26.66 20.31 36.72 4.39 48.48

After 1 Year

All 27 44.02 19.90 40.89 25.95 60.59 6.39 92.76

Female 9 50.77 16.95 51.89 36.32 64.98 25.95 74.21

Male 18 40.65 20.84 39.50 24.49 53.43 6.39 92.76


All 21 18.23 18.06 20.10 -0.82 26.92 -6.06 58.85



Table 16. Summary of Serious Adverse Events on GH Treated

MedDRA SOC Term MedDRA Preferred Term

All Patients

Number of patients 32 Patients with >=1 SAE 5

(15.63%) Gastrointestinal disorders Any 1 (3.13%) Vomiting 1 (3.13%) Infections and infestations Any 2 (6.25%) Pharyngitis 1 (3.13%) Pneumonia 1 (3.13%) Injury, poisoning and procedural complications

Any 1 (3.13%)

Head injury 1 (3.13%) Metabolism and nutrition disorders Any 2 (6.25%) Hypoglycaemia 2 (6.25%)

Table 17. Summary of Treatment Emergent Adverse Events (TEAEs)

n % All 3

2 100.0

Patient has >=1 AE recorded (Y/N) N

11 34.4

Y 21 65.6



Table 18. Summary of TEAEs by System Organ Class


All Patients

Blood and lymphatic system disorders Any 1 (3.13%) Anaemia 1 (3.13%) Eye disorders Any 1 (3.13%) Conjunctivitis 1 (3.13%) Gastrointestinal disorders Any 2 (6.25%) Diarrhoea 1 (3.13%) Vomiting 1 (3.13%) General disorders and administration site conditions

Any 2 (6.25%)

Pyrexia 2 (6.25%) Infections and infestations Any 16

(50.00%) Bronchitis 5 (15.63%) Bronchopneumonia 1 (3.13%) Ear infection 3 (9.38%) Gastroenteritis 3 (9.38%) Influenza 2 (6.25%) Nasopharyngitis 1 (3.13%) Pharyngitis 2 (6.25%) Pneumonia 1 (3.13%) Tonsillitis 1 (3.13%) Varicella 5 (15.63%) Wound infection 1 (3.13%) Injury, poisoning and procedural complications Any 2 (6.25%) Head injury 1 (3.13%) Multiple fractures 1 (3.13%) Metabolism and nutrition disorders Any 3 (9.38%) Hypoglycaemia 2 (6.25%) Iron deficiency 1 (3.13%) Nervous system disorders Any 1 (3.13%) Dizziness 1 (3.13%) Psychiatric disorders Any 1 (3.13%) Vomiting psychogenic 1 (3.13%) Respiratory, thoracic and mediastinal disorders Any 1 (3.13%) Cough 1 (3.13%)

(continued)



Table 18. Summary of TEAEs by System Organ Class (concluded)


All Patients

Skin and subcutaneous tissue disorders Any 2 (6.25%) Skin lesion 1 (3.13%) Urticaria 1 (3.13%)

Table 19. Summary of Drug Related Treatment-Emergent Specific Medical Conditions (SMC)

All Patients

Number of patients 32

Patients with >=1drug related SMC (Intestinal disturbances)

2 ( 6.25%)

Table 20. Summary of Treatment-Emergent Specific Medical Conditions (SMC)

All Patients

Number of patients 32 Patients with >=1 SMC (Recurrent otitis media)

1 (3.13%)



Table 21. Frequencies of TEAE and SMC in Patients by GH Dose Group

GH doses are starting doses (mg/Kg/wk)

All < 0.15 0.15 - < 0.30 0.30 - < 0.45

n % n % n % n % Patient has >=1 AE recorded (Y/N) N

11

34.4 0 0 4 44.4 7 31.8

Y 21

65.6 1

100.0 5 55.6 15 68.2

Patients with >=1 SMC N

31

96.9 1

100.0 8 88.9 22 100.0

Y 1 3.1 0 0 1 11.1 0 0 Patients with >=1 SMC drug related N

30

93.8 1

100.0 9 100.0 20 90.9

Y 2 6.3 0 0 0 0 2 9.1

Table 22. Comparison of TEAEs between GH dosage groups

GH doses are starting doses (mg/Kg/wk) < 0.15 0.15 - < 0.30 0.30 - < 0.45 All Patient has >=1 AE recorded (Y/N) n % n % n % n % Yes 1 100.

0 5 55.6 15 68.2 21 65.6

All 1 100.0

9 100.0 22 100.0 32 100.0

No 4 44.4 7 31.8 11 34.4



Table 23. Listing of Serious Adverse Events (SAE)

Patient group Therapy Diagnosis

Age (y) at GH Start, Gender,

History of neoplasia

Age at SAE, Years since

GH Rx start, Years since

GeNeSIS entry to SAE onset

Actual term, MedDRA SOC,

MedDRA Preferred Term

SAE duration Severity, Causal,

Relationship

Seriousness, Criteria,

Discontinuation

due to AE Naive

GH treated Pituitary hypoplasia

MINOR HEAD TRAUMA Injury, poisoning and procedural

complications Head injury

1 Day Severe

Not related

Yes Hospitalization

No

Naive GH treated

Pituitary aplasia

VOMITING Gastrointestinal disorders

Vomiting

1 Day Moderate

Not related

Yes Hospitalization

No Naive

GH treated Pituitary aplasia

HYPOGLYCEMIA Metabolism and nutrition disorders

Hypoglycaemia

1 Day Moderate

Not related

Yes Hospitalization

No Naive

GH treated Classic

ACUTE PHARYNGITIS Infections and infestations

Pharyngitis

7 Days Mild

Not related

Yes Hospitalization

No Naive

GH treated Ectopic posterior

pitui

PNEUMONIA Infections and infestations

Pneumonia

10 Days Severe

Not related

Yes Hospitalization

No

Naive GH treated

Classic

KETOTIC HYPOGLYCAEMIA Metabolism and nutrition disorders

Hypoglycaemia

3 Days Moderate Related

Yes Hospitalization

No



References

(1) Tanner JM, Whitehouse RH, 1976. Archives of Disease in childhood, Vol 51, p 170.

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