A Novel Dual-Hormone Insulin-and-Pramlintide ArtificialPancreas for Type 1 Diabetes: ARandomized Controlled CrossoverTrialDiabetes Care 2020;43:597–606 | https://doi.org/10.2337/dc19-1922

OBJECTIVE

The rapid insulin-alone artificial pancreas improves glycemia in type 1 diabetes butdaytimecontrol remains suboptimal.Wepropose twonovel dual-hormoneartificialpancreas systems.

RESEARCH DESIGN AND METHODS

We conducted a randomized crossover trial comparing a rapid insulin-alone artificialpancreas with rapid insulin-and-pramlintide and with regular insulin-and-pramlintideartificial pancreas systems in adultswith type 1 diabetes. Participantswere assigned tothe interventions in random order during three 24-h inpatient visits. Each visit waspreceded by an outpatient hormonal open-loop run-in period of 10–14 days. Thedual-hormone artificial pancreas delivered pramlintide in a basal-bolus manner,using a novel dosing algorithm, with a fixed ratio relative to insulin. The primaryoutcome was time in the range 3.9–10.0 mmol/L.

RESULTS

Compared with the rapid insulin-alone artificial pancreas system, the rapid insulin-and-pramlintide system increased the time in range from 74% (SD 18%) to 84%(13%) (P 5 0.0014), whereas the regular insulin-and-pramlintide system did notchange the time in range (69% [19%]; P5 0.22). The increased time in range withthe rapid insulin-and-pramlintide system was due to improved daytime con-trol (daytime time in range increased from 63% [23%] to 78% [16%], P5 0.0004).Therewere 11 (1 per 2.5 days) hypoglycemic events (<3.3mmol/Lwith symptomsor <3.0 mmol/L irrespective of symptoms) with the rapid insulin-alone system,compared with 12 (1 per 2.3 days) and 18 (1 per 1.4 days) with the rapid andregular insulin-and-pramlintide systems, respectively. Gastrointestinal symp-toms were reported after 0% (0 of 112) of meals with the rapid insulin-alonesystem, compared with 6% (6 of 108) and 11% (11 of 104) with the rapid andregular insulin-and-pramlintide systems, respectively; none of the symptoms weresevere.

CONCLUSIONS

A novel rapid insulin-and-pramlintide artificial pancreas improves glucose controlcompared with a rapid insulin-alone artificial pancreas (ClinicalTrials.gov numberNCT02814123).

1Department of Biomedical Engineering, McGillUniversity, Montreal, Quebec, Canada2The Research Institute of McGill UniversityHealth Centre, Montreal, Quebec, Canada3Royal VictoriaHospital,McGill University HealthCentre, Montreal, Quebec, Canada4Montreal Children’s Hospital, McGill UniversityHealth Centre, Montreal, Quebec, Canada

Corresponding author: Ahmad Haidar, ahmad.haidar@mcgill.ca

Received 26 September 2019 and accepted 22November 2019

Clinical trial reg. no. NCT02814123, clinicaltrials.gov

This article contains Supplementary Data onlineat https://care.diabetesjournals.org/lookup/suppl/doi:10.2337/dc19-1922/-/DC1.

© 2020 by the American Diabetes Association.Readersmayuse this article as longas thework isproperly cited, the use is educational and not forprofit, and the work is not altered. More infor-mation is availableathttps://www.diabetesjournals.org/content/license.

See accompanying article, p. 518.

Ahmad Haidar,1,2 Michael A. Tsoukas,2,3

Sarah Bernier-Twardy,1

Jean-Francois Yale,2,3 Joanna Rutkowski,1

Anne Bossy,1 Evelyne Pytka,1 Anas El Fathi,1

Natalia Strauss,1 and Laurent Legault4

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More than 70% of people with type 1diabetes do not achieve glycemic targetsdespite advances in insulin analogs, ed-ucational programs, insulin pumps, andglucose sensors (1). The artificial pan-creas is a novel technology that auto-mates insulin pump delivery in type 1diabetes based on glucose sensor read-ings and a dosing algorithm (2). Random-ized trials have shown that the artificialpancreas reduces hyperglycemia andhypoglycemia compared with sensor-augmented pump therapy (3). However,significant durations of hyperglycemiaare still reported with the artificial pan-creas (5–8 h/day above 10mmol/L) (4,5),particularly postprandially.Pramlintide is an analog of amylin, a

hormone that is cosecreted with insulinin healthy individuals but is deficient inpeople with type 1 diabetes. Pramlintideis indicated to be injected at mealtimes,where it delays gastric emptying, sup-presses glucagon secretion, and increasessatiety (6). Studies assessing addingprandial pramlintide injections to insulin-alone artificial pancreas (7–9) reporteda reduction in postprandial glucoseexcursions (7,8).Here, we present a novel dual-hormone

artificialpancreasthatdeliverspramlintide,in addition to insulin, in a glucose-responsive, basal-bolus manner, andwith a fixed ratio relative to insulin tomimic a coformulation. Efforts to de-velop coformulations of insulin andpramlintide are underway (10–12), whichwould eliminate the need of deliveringpramlintideby injection, enhancepatientcompliance (13), and allow the use ofconventional single-chamber insulin pumpstodeliver both hormones.Weundertook arandomized trial comparing the insulin-and-pramlintide artificial pancreas withinsulin-alone artificial pancreas in adultswith type 1 diabetes. Two configurationsof the dual-hormone artificial pancreaswere tested, one that used rapid-actinginsulin and another that used regular in-sulin. Regular insulin was tested because itmay match better with meal absorption inthe setting of pramlintide.

RESEARCH DESIGN AND METHODS

Study DesignWe conducted an open-label, random-ized, crossover study in type1diabetes tocompare 1) rapid insulin-and-pramlintideartificial pancreas with rapid insulin-alone artificial pancreas and 2) regular

insulin-and-pramlintide artificial pancreaswith rapid insulin-alone artificial pan-creas. Each intervention lasted 24 h.The intervention visits were separatedby a median of 14 days (interquartilerange [IQR] 14–27).

ParticipantsFrom February 2017 to July 2018, par-ticipants were enrolled at the ResearchInstitute ofMcGill University Health Cen-tre. Participantswere required to be.18years old and using an insulin pump for atleast 6months. People with gastroparesiswere excluded. Other exclusion criteriawere applied (Supplementary Data).Participants provided written informedconsent. The study was approved by ourethics committee.

Randomization and MaskingWe used blocked randomization to gen-erate allocation sequences, which weredisclosed after the admission visit. Par-ticipants and investigators were notblinded to the allocation. Participantswere blinded to hormonal infusions andglucose data during intervention visits. Forsafety reasons, investigators had access toglucose levels.

Study ProceduresBefore each artificial pancreas interven-tion, we optimized participants’ insulintherapy parameters (basal rates, carbo-hydrate-to-insulin ratios, and insulin sen-sitivity factors) for 10–14 days (seeSupplementary Data for details). Dur-ing the optimization periods before therapid insulin-alone interventions, partici-pants used their usual rapid-acting in-sulin. During the optimization periodsbefore the rapid insulin-and-pramlintideinterventions, participants wore a sec-ond pump (MiniMed Paradigm Veo orMiniMed 630G) to deliver pramlintide(Symlin; AstraZeneca) (14). During theoptimization periods before the regularinsulin-and-pramlintide interventions, par-ticipants used regular insulin (Humulin R;Eli Lilly) instead of rapid-acting insulinand wore a second pump to deliver pram-lintide.At theendof the study, participantsanonymously completed a treatment sat-isfaction survey with regard to the optimi-zation periods (Supplementary Data).

Participants installed a glucose sensor(G5; Dexcom) 24–48 h before each arti-ficial pancreas intervention. Participantsarrived at the research facility around

0700 h and received interventions until0800 h the next morning. The glucosesensor was calibrated two to three timesper intervention using capillary glucose.Self-selected meals were served at 0800,1200, 1700, and 2100 h. Meals werestandardized between visits of each par-ticipant, but were different between par-ticipants. Participants were allowed tohave walks, which were standardizedbetween visits. Nineteen out of 28 par-ticipants had walks (average duration25 min).

The dosing algorithms of the artificialpancreas systems were initialized usingbasal rates, carbohydrate-to-insulin ra-tios, and total daily insulin dose at the endof the respective optimization periods.Every 10 min, the glucose sensor readingwas entered manually into a laptop,which ran the dosing algorithms to rec-ommend basal rates every 10 min andboluses at mealtimes. Study personneldelivered basal insulin and pramlintidemanually by programming a new tem-porary basal every 10min. At mealtimes,study personnel delivered the bolusesmanually through the pumps. The insulin-and-pramlintideartificial pancreas systemsdelivered basal-bolus pramlintide andinsulin, with a fixed ratio of 6 mg ofpramlintide per unit of insulin.

Basal dosing algorithmswerebasedonadaptive model predictive control (15)and were identical in the three interven-tions. The algorithm switches betweendynamical models in real time (16), au-tomatically accommodating different ki-netics of insulins as well as the pramlintideeffect on meal absorption. The amountof prandial insulin was calculated usingcarbohydrate content, carbohydrate-to-insulin ratio, and premeal glucose levels.The total amount of prandial insulin wascalculated in an identical manner in thethree interventions, but the pattern ofdelivery was different between interven-tions. The rapid insulin-alone artificial pan-creas delivered prandial insulin as a singlebolus at the onset of themeals. The rapidinsulin-and-pramlintide artificial pancreasdelivered three pairs of prandial insulinand pramlintide mini-boluses beginningat mealtime and separated by 10 min.The regular insulin-and-pramlintide arti-ficial pancreas also delivered prandial in-sulin and pramlintide with three pairs ofmini-boluses but beginning 20 min priorto the meals as opposed to mealtime (toaccount for the slow pharmacokinetics of

598 An Insulin-and-Pramlintide Artificial Pancreas Diabetes Care Volume 43, March 2020

regular insulin). The immediate bolus was25–100% of the total bolus, and the twoextended boluses combined for 0–75% ofthe total bolus. The split between imme-diate and extended boluses depended onthe premeal glucose level (lower premealglucose levels led to lower immediateboluses and higher extended boluses).For small meals, all prandial insulin andpramlintideweredeliveredas immediateboluses since the amount of prandialpramlintide was small.Venous blood samples were taken

every 10–30 min to measure plasmaglucose (2300 STAT Plus Analyzer; YSI).During the three interventions, if plasmaglucose fell below 3.3 mmol/L and wasaccompanied with symptoms, or fellbelow 3.0 mmol/L irrespective of symp-toms, 16 g oral glucose (four tablets 34 g) was given. Participants were asked2 h after meals and after the night if theyexperienced nausea, vomiting, bloating,or heartburn in the preceding hours, andranked the symptoms asmild,moderate,moderate-to-severe, or severe.

Study OutcomesThe primary outcomewas the time spentin target range (3.9–10.0 mmol/L) (17).Secondary outcomes included times spentbelow and above the target range, glu-cose variability, and gastrointestinal sideeffects. Outcomes were calculated usinginterpolated plasma glucose measure-ments, but sensor readings were usedwhen plasma levels were not available(e.g., lack of venous access).

Statistical AnalysisWe anticipated that the insulin-and-pramlintide artificial pancreas would in-crease the percentage of time in targetrange by 7% (SD 10%) (7,18–21) com-pared with the rapid insulin-alone artificialpancreas.We intended to do the followingpairwise comparisons: 1) rapid insulin-and-pramlintide artificial pancreas withrapid insulin-alone artificial pancreas and2) regular insulin-and-pramlintide artifi-cial pancreas with rapid insulin-alone ar-tificial pancreas. Therefore,wedid apoweranalysis using the formula for the pairedStudent t testwith5%significance level (22).We calculated that 19 participants wouldprovide 80% power. Hence, we aimed toinclude 28 participants to account for anyuncertainty in the power calculations.Our analyses were on a modified

intention-to-treat basis. Participants who

did not complete the rapid insulin-aloneartificial pancreas intervention and at leastone insulin-and-pramlintide interventionwere not included in the analysis andwere replaced in the enrollment process.

A linear mixed model was fitted to thedatawhile adjusting for theperiod effect.To examine for carryover effect, a modelwas fitted with the treatment by periodinteraction term. Residual values wereexamined for normality, and if skewed,the data were transformed using thesquare root function. P values ,0.05were regarded as significant (22). Re-sults are reported as median (IQR) ormean (SD).

RESULTS

Supplementary Figure 1 shows the flowof participants. Twenty-eight participantscompleted the rapid insulin-alone artifi-cial pancreas intervention and at leastone insulin-and-pramlintide artificial pan-creas intervention, and were includedin the analysis (43% female, mean age25 years [13], HbA1c 7.8% [0.9] [62 (10)mmol/mol], duration of diabetes 23 years[14], total daily insulin 0.65 units/kg[0.16]) (Supplementary Table 1). Out ofthose 28 participants, 1 did not com-plete the rapid insulin-and-pramlintideintervention and2did not complete theregular insulin-and-pramlintide intervention.

Meanbasal rate at the end of the rapidinsulin-alone optimization period was0.99 units/h, at the end of the rapidinsulin-and-pramlintide optimization pe-riod was 0.94 units/h, and at the end ofthe regular insulin-and-pramlintide was1.01 units/h. The mean carbohydrate-to-insulin ratio at the end of the rapidinsulin-aloneoptimizationperiodwas9.8g/unit, at the end of the rapid insulin-and-pramlintide optimization periodwas10.4 g/unit, and at the end of the regularinsulin-and-pramlintide was 9.1 g/unit.Figure 1 compares the glucose profilesduring the artificial pancreas visits. Sam-ple tests are in the SupplementaryData.

The rapid insulin-and-pramlintide ar-tificial pancreas increased the mean per-centage of time spent in the target rangecompared with the rapid insulin-aloneartificial pancreas from 74% to 84% (P50.0014), reduced mean glucose from 7.9to7.4mmol/L (P50.0053), reduced timespent .10.0 mmol/L from 22% to 12%(P 5 0.00012), reduced glucose coeffi-cient of variance from 30.3% to 26.8%

(P50.035), and reduced SD from 2.4 to2.0mmol/L (P5 0.0053) (Table 1). Therewere no benefits associated with the reg-ular insulin-and-pramlintide artificial pan-creas comparedwith the rapid insulin-aloneartificial pancreas in time spent in targetrange (P 5 0.22), mean glucose (P 50.95), time .10.0 mmol/L (P 5 0.49),glucose coefficient of variance (P50.09),or SD (P5 0.17) (Table 1). No treatmentby period interaction was found, and nodifferencewas observeddue to the orderof interventions (data not shown).

The benefits of the rapid insulin-and-pramlintide artificial pancreas were dueto improved glucose control during theday. During the day (0800–2300 h), therapid insulin-and-pramlintide artificial pan-creas increased the time in target rangecompared with the rapid insulin-aloneartificial pancreas from 63% to 78% (P50.0004), reduced mean glucose from 8.7to 7.9 mmol/L (P 5 0.0011), reducedglucose coefficient of variance from 29.3%to 25.6% (P5 0.017), and reduced glucoseSD from 2.5 to 2.0 mmol/L (P 5 0.0019)(Table 1). During the night (2300–0800 h),the rapid insulin-and-pramlintide arti-ficial pancreas and the rapid insulin-aloneartificial pancreas achieved a similar timein target range (94–95%) (Table 1).

Figure 2 shows postprandial glucoseprofiles stratified by premeal glucose lev-els. During rapid insulin-alone artificialpancreas visits, postprandial glucose in-creased after themeals and peaked after60 min, irrespective of premeal glucoselevels. However, during insulin-and-pramlintide artificial pancreas visits,postprandial glucose profiles dependedon premeal glucose levels. When pre-meal glucose levels were .10 mmol/L,postprandial glucose levels immediatelydecreased toward euglycemia. Whenpremeal glucose levels were between5 and 10 mmol/L, postprandial glucoseprofiles were relatively flat. When pre-meal glucose levels were ,5 mmol/L,postprandial glucose levels immedi-ately increased toward euglycemia. Thesetailored postprandial glucose profilesresulted from the use of pramlintide andthe quasi-dual-wave prandial dosing al-gorithm that splits immediate and ex-tended boluses (pramlintide and insulin)depending on the premeal glucose level.During rapid insulin-and-pramlintide vis-its, premeal glucose levels .10 mmol/Lled to mean 81% of the prandial doses asimmediate (and19%asextended),whereas

care.diabetesjournals.org Haidar and Associates 599

premeal glucose levels between 5 and10mmol/L led to 66% as immediate (and34% as extended), and premeal glucoselevels ,5 mmol/L led to 34% as imme-diate (and 66% as extended). Duringregular insulin-and-pramlintide visits,the immediate components were 99%,75%, and 45%, respectively.

Characteristics of Hormonal DeliveriesInsulin delivery was similar on rapid insulin-and-pramlintide and rapid insulin-aloneartificial pancreas visits. However, insulindelivery was higher on regular insulin-and-pramlintide artificial pancreas visitscompared with rapid insulin-alone visits(Table 1).On rapid insulin-and-pramlintide arti-

ficial pancreas visits, total pramlintidedelivery per day was 279 mg (92) (3.5mg/kg [0.9]) and per night was 53mg (19)(0.66 mg/kg [0.18]). The mean prandialpramlintide dose (immediate plusextended boluses) for a meal was34 mg (17). Twelve percent of the prandialpramlintidedoseswere,15mg,35%were

between15and30mg, 27%werebetween30 and 45 mg, and 26% were .45 mg.

On regular rapid insulin-and-pramlintideartificial pancreas visits, total pramlintidedelivery per day was 320 mg (107) (4.1mg/kg [1.1]) and per night was 52mg (16)(0.66 mg/kg [0.18]). The mean prandialpramlintide dose for a meal was 39 mg(21). Thirteen percent of the prandialpramlintidedoseswere,15mg,24%werebetween15and30mg, 29%werebetween30 and 45 mg, and 34% were .45 mg.

Adverse EventsThere were 11 hypoglycemic events re-quiring oral treatment on rapid insulin-aloneartificial pancreas visits, 12on rapidinsulin-and-pramlintide artificial pancreasvisits, and 18 on regular insulin-and-pramlintide artificial pancreas visits(Table 2). On rapid insulin-alone artificialpancreas visits, there was no nausea,vomiting, bloating, or heartburn. Onrapid insulin-and-pramlintide artificialpancreas visits, there were 108meals, 6 ofwhich were followed by gastrointestinal

symptoms (3 mild and 3 moderate, allwere transient) (Table 2). On regularinsulin-and pramlintide artificial pancreasvisits, there were 104 meals, 11 of whichwere followed by gastrointestinal symp-toms (2mild,6moderate, and3moderateto severe). No gastrointestinal symp-toms were reported during the nights inany intervention. The three participants thatreported moderate gastrointestinal symp-toms on the rapid insulin-and-pramlintideartificial pancreas visits also reportedsymptoms on the regular insulin-and-pramlintide visits.

There was no elevated ketones (.1.0mmol/L) in any artificial pancreas visits.During insulin-and-pramlintide interven-tions, there was no failure in pramlintidedelivery via the pump. One participantexperienced irritations at thepramlintideinfusion sites during the optimizationperiods.

Outcomes From the Run-in PhaseParticipants reported higher treatmentsatisfaction with the rapid insulin-and-pramlintide therapy than the rapid insulin-alone therapy (Supplementary Data).Eighty-two percent (23 of 28) of partic-ipants strongly agreed (8 of 28), agreed(13 of 28), or slightly agreed (2 of 28) thatusing rapid insulin and pramlintide madetheir blood glucose control more even orpredictable. Seventy-nine percent (23 of29) of participants strongly agreed (9 of29), agreed (9 of 29), or slightly agreed(5 of 29) that using rapid insulin andpramlintide provided benefits that rapidinsulin-alone has not provided them.Ninety percent (26 of 29) of participantsstrongly agreed (12 of 29), agreed (8 of29), or slightly agreed (6 of 29) that if acoformulation product of rapid insulinand pramlintide was available on themarket, they would use it. Treatmentsatisfaction was not improved with theregular insulin-and-pramlintide therapycompared with the rapid insulin-alonetherapy (Supplementary Data).

The analyses of glucose levels duringthe optimization periods are reported inSupplementary Table 2. The time intarget range was higher during the rapidinsulin-and-pramlintide therapy comparedwith the rapid insulin-alone therapy(difference 5% [12], P5 0.039), and meanglucose was lower with the rapid insulin-and-pramlintide therapy compared withthe rapid insulin-alone therapy (difference20.7mmol/L[1],P50.037).However,time

Figure 1—The median (IQR) profiles of glucose levels and hormonal deliveries during artificialpancreas visits. Meal and hormonal bolus values are (IQR). Hormonal boluses were composed ofimmediate and extended components on the dual-hormone visits. Small vertical lines indicatehypoglycemia events. Solid lines indicate glucose levels and basal insulin. Dotted lines indicatebasal pramlintide. Note that the shaded IQR areas indicate the upper and lower 25% ofparticipants. For example, the figure shows that during the insulin-alone visits, 25% of theparticipants had glucose levels .14 mmol/L after breakfast.

600 An Insulin-and-Pramlintide Artificial Pancreas Diabetes Care Volume 43, March 2020

spent,3.9mmol/Lwashigherduring therapid insulin-and-pramlintide therapy com-pared with the rapid insulin-alone ther-apy (difference 1.2% [20.1 to 2.8], P 5

0.0092). None of the outcomes differedbetween the regular insulin-and-pramlintidetherapy and the rapid insulin-alonetherapy.

Out of 103 days when participants wereasked about gastrointestinal side effectsduring the rapid insulin-and-pramlintiderun-inperiods,participants reported5days

Table 1—Comparisons of insulin-alone artificial pancreas, rapid insulin-and-pramlintide artificial pancreas, and regularinsulin-and-pramlintide artificial pancreas

Rapid insulin-alone (n 5 28)

Rapidinsulin-and-pramlintide(n 5 27)

Regularinsulin-and-pramlintide(n 5 26)

Rapid insulin-and-pramlintide minus

insulin-alone(n 5 27), P value¶

Regular insulin-and-pramlintide minus

insulin-alone(n 5 26), P valueU

24-h outcomes (0800–0800 h)Time spent at glucose levels (%)

(mmol/L)3.9–10.0 74 (18) 84 (13) 69 (19) 11 (16), 0.0014‡ 26 (20), 0.22‡3.9–7.8 54 (18) 55 (17) 50 (19) 2 (17), 0.50 24 (17), 0.34,2.8 0.0 (0.0–0.0) 0.0 (0.0–0.0) 0.0 (0.0–0.6) 0.0 (0.0–0.0), 0.34 0.0 (0.0–0.0), 0.29,3.3 0.0 (0.0–2.6) 0.0 (0.0–1.5) 1.2 (0.0–3.8) 0.0 (20.5 to 0.0), 0.78 0.1 (0.0–3.1), 0.027,3.9 1.2 (0.0–7.0) 0.0 (0.0–8.4) 7.3 (3.4–10.7) 0.0 (21.8 to 0.5), 0.43 3.3 (0.0–7.5), 0.0084.7.8 42 (19) 40 (19) 43 (20) 22 (15), 0.50 1 (18), 0.86.10.0 22 (17) 12 (12) 24 (20) 210 (13), 0.00012 3 (18), 0.49.13.9 0 (0–6) 0 (0–0) 1 (0–10) 0 (26 to 0), 0.0019 0 (21 to 5), 0.37

Mean glucose (mmol/L) 8.0 (1.4) 7.4 (1.0) 8.0 (1.4) 20.6 (0.9), 0.0014 0.0 (1.5), 0.95SD of glucose (mmol/L) 2.4 (0.9) 2.0 (0.5) 2.8 (1.2) 20.5 (0.9), 0.0053 0.4 (1.3), 0.17CV of glucose (mmol/L) 30.3 (9.1) 26.8 (6.9) 34.0 (10.5) 24.2 (9.3), 0.035 4.6 (12.0), 0.090Total basal insulin (units) 24.5 (9.5) 23.8 (8.9) 27.5 (10.9) 20.7 (4.2), 0.35 2.8 (6.2), 0.048Total bolus insulin (units) 23.1 (6.1) 22.6 (7.4) 25.5 (8.2) 20.5 (3.1), 0.35 2.8 (4.1), 0.0028Total pramlintide (mg) 278 (92) 318 (106)

Day outcomes (0800–2300 h)Time spent at glucose levels (%)

(mmol/L)3.9–10.0 63 (23) 78 (16) 61 (26) 16 (22), 0.0004 23 (27), 0.673.9–7.8 40 (22) 44 (21) 39 (24) 6 (23), 0.18 21 (20), 0.90,2.8 0.0 (0.0–0.0) 0.0 (0.0–0.0) 0.0 (0.0–0.0) 0.0 (0.0–0.0), 0.34 0.0 (0.0–0.0), 0.13,3.3 0.0 (0.0–0.3) 0.0 (0.0–1.9) 0.0 (0.0–1.6) 0.0 (0.0–0.0), 0.50 0.0 (0.0–0.0), 0.89,3.9 0.0 (0.0 –6.6) 0.0 (0.0–6.5) 0.4 (0.0–6.2) 0.0 (22.7 to 0.5), 0.66 0.0 (21.3 to 4.7), 0.76.7.8 56 (24) 51 (24) 57 (27) 26 (23), 0.17 1 (23), 0.93.10.0 32 (24) 17 (16) 34 (29) 216 (21), ,0.0001 3 (28), 0.70.13.9 0 (0–10) 0 (0–0) 2 (0–16) 0 (210 to 0), 0.002 0 (22 to 7), 0.34

Mean glucose (mmol/L) 8.7 (1.9) 7.9 (1.3) 8.9 (2.2) 20.9 (1.4), 0.0011 0.2 (2.3), 0.70SD of glucose (mmol/L) 2.5 (0.9) 2.0 (0.6) 2.5 (1.0) 20.6 (0.9), 0.0019 0.1 (1.2), 0.81CV of glucose (mmol/L) 29.3 (10.0) 25.6 (8.0) 28.7 (9.3) 24.4 (8.8), 0.017 0.4 (9.3), 1.00Total basal insulin (units) 15.3 (6.7) 15.3 (6.2) 19.4 (9.5) 20.1 (3.4), 0.79 3.8 (6.7), 0.016Total bolus insulin (units) 23.1 (6.1) 22.6 (7.4) 25.5 (8.2) 20.5 (3.1), 0.35 2.8 (4.1), 0.0028Total pramlintide (mg) 228 (76) 269 (99)

Overnight outcomes (2300–0800 h)Time spent at glucose levels (%)

(mmol/L)3.9–10.0 94 (11) 95 (9) 83 (13) 1 (12), 0.65 211 (15), 0.00243.9–7.8 80 (18) 77 (23) 73 (18) 24 (25), 0.39 27 (25), 0.14,2.8 0.0 (0.0–0.0) 0.0 (0.0–0.0) 0.0 (0.0–0.0) 0.0 (0.0–0.0), NA 0.0 (0.0–0.0), 0.019,3.3 0.0 (0.0–0.0) 0.0 (0.0–0.0) 0.0 (0.0–7.8) 0.0 (0.0–0.0), 0.37 0.0 (0.0–3.3), 0.013,3.9 0.0 (0.0–1.1) 0.0 (0.0–0.0) 11.3 (0.0–22.6) 0.0 (0.0–0.0), 0.71 0.0 (0.0–14.8), 0.0063.7.8 16 (15) 19 (22) 16 (20) 5 (20), 0.23 0 (24), 0.92.10.0 2 (5) 2 (5) 5 (11) 21 (6), 0.65 3 (11), 0.18.13.9 0 (0–0) 0 (0–0) 0 (0–0) 0 (0–0), 0.35 0 (0–0), NA

Mean glucose (mmol/L) 6.6 (0.9) 6.5 (1.0) 6.2 (1.1) 0.0 (0.9), 0.83 20.4 (1.4), 0.20SD of glucose (mmol/L) 2.5 (0.9) 2.0 (0.6) 2.5 (1.0) 20.6 (0.9), 0.0019 0.1 (1.2), 0.81CV of glucose (mmol/L) 15.9 (10.2) 17.4 (7.6) 24.6 (9.3) 1.2 (10.3), 0.56 9.2 (12.5), 0.0011Total basal insulin (units) 9.2 (3.5) 8.5 (3.5) 8.1 (3.3) 20.6 (1.7), 0.67 20.9 (2.7), 0.11Total bolus insulin (units) 0.0 (0.0) 0.0 (0.0) 0.0 (0.0) 0.0 (0.0), NA 0.0 (0.0), NATotal pramlintide (mg) 51 (21) 49 (20)

Data are displayed as mean (SD) or median (IQR). A P value,0.05 is regarded as significant. CV, coefficient of variation. NA, not applicable. ‡Primarycomparisons. ¶Paired comparisons included participants that completed insulin-alone and rapid insulin-and-pramlintide interventions (n 5 27).UPaired comparisons included participants that completed insulin-alone and regular insulin-and-pramlintide interventions (n 5 26).

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withgastrointestinal symptoms(3mildand2 moderate). Out of 104 days when par-ticipants were asked during the regularinsulin-and-pramlintide run-in periods,participants reported 14 days withsymptoms (3 mild, 5 moderate, and1 severe).

CONCLUSIONS

Insulin-alone artificial pancreas systemsimprove glucose control compared with

conventional pump therapy (3), but hy-perglycemia (.10 mmol/L) remainscommonandoccursonaverage5–8hperday (4,5). In this study, we comparedtwo novel insulin-and-pramlintide artificialpancreas systems with rapid insulin-alone artificial pancreas. The rapidinsulin-and-pramlintide artificial pan-creas increased the time in target range,reduced mean glucose level, and re-duced glucose variability. The regular

insulin-and-pramlintide artificial pancreasdid not improve glucose control comparedwith the rapid insulin-alone artificialpancreas.

Prior to this study, we conducted pre-liminary experiments (data not shown)where we noted a risk of early post-prandial hypoglycemia after pramlintideboluses (23,24). A 20–30% reduction ofthe insulin-to-carbohydrate ratios to mit-igate this risk led to late postprandial

Figure 2—Median (IQR) postprandial glucose levels during artificial pancreas visits. During rapid insulin-and-pramlintide visits, insulin and pramlintideboluses had mean 81% immediate component when premeal glucose levels were.10 mmol/L, 66% immediate component when premeal glucoselevels were between 5 and 10 mmol/L, and 34% immediate component when premeal glucose levels were,5 mmol/L. During regular insulin-and-pramlintide visits, the immediate components were 99%, 75%, and 45%, respectively.

602 An Insulin-and-Pramlintide Artificial Pancreas Diabetes Care Volume 43, March 2020

Table

2—Hypoglycem

iaratesandgastro

intestin

alsid

eeffe

ctsdurin

gartifi

cialpancre

asvisits

Rapid

insulin-alo

ne

(n5

28)Rapid

insulin-an

d-pram

lintid

e(n

527)

Regu

larinsulin-an

d-pram

lintid

e(n

526)

Number

ofpatien

tswith

atleast

one

hypoglycem

iceven

treq

uirin

gtreatm

ent¶9(32%

)8(30%

)13

(50%)

Number

ofhypoglycem

iceven

tsreq

uirin

gtreatm

ents¶

11(1

per

2.5days)

12(1

per

2.3days)

18(1

per

1.4days)

Number

ofhypoglycem

iceven

tsreq

uirin

gmultip

letreatm

ents¶4(36%

)3(25%

)12

(62%)

Number

ofnoctu

rnal

hypoglycem

iceven

tsreq

uirin

gtreatm

ents¶

11

7

Number

ofmild

hypoglycem

iceven

ts,3.9

mmol/L

2625

32

Mild

Moderate

Moderate

tosevere

SevereMild

Moderate

Moderate

tosevere

SevereMild

Moderate

Moderate

tosevere

Severe

Number

ofpatien

tsexp

eriencin

gany

gastrointestinal

symptom

0(0%

)0(0%

)0(0%

)0(0%

)2(7%

)3(11%

)‡0(0%

)0(0%

)1(4%

)3(12%

)2(8%

)0(0%

)

Number

ofmeals

followed

by*

Anygastro

intestin

alsym

ptom

0(0%

)0(0%

)0(0%

)0(0%

)3(3%

)3(3%

)U0(0%

)U0(0%

)2(2%

)6(6%

)U3(3%

)U0(0%

)Nausea

0(0%

)0(0%

)0(0%

)0(0%

)2(2%

)1(1%

)0(0%

)0(0%

)1(1%

)3(3%

)2(2%

)0(0%

)Vomiting

0(0%

)0(0%

)0(0%

)0(0%

)0(0%

)0(0%

)0(0%

)0(0%

)0(0%

)0(0%

)0(0%

)0(0%

)Bloatin

g0(0%

)0(0%

)0(0%

)0(0%

)1(1%

)0(0%

)0(0%

)0(0%

)1(1%

)1(1%

)0(0%

)0(0%

)Heartb

urn

0(0%

)0(0%

)0(0%

)0(0%

)0(0%

)2(2%

)0(0%

)0(0%

)1(1%

)2(2%

)1(1%

)0(0%

)

Data

aredisp

layedas

number

(%)o

rnumbers.¶

Hypoglycem

iceven

tsare

defined

asplasm

aglu

cose

concen

tration,3.3

mmol/L

with

symptomsor,3.0

mmol/L

irrespective

ofsym

ptoms,an

dwere

treatedwith

16goralcarb

ohydrate

(Fig.2showsthetim

esofhypoglycem

iaeven

ts).*There

were

atotalo

f112,108,an

d104

meals

durin

ginsulin-alo

neartifi

cialpancreas,rap

idinsulin-and

-pram

lintid

eartifi

cialpancreas,

andregu

larinsulin-an

d-pram

lintid

eartifi

cialpancreas

visits,resp

ectively.‡Th

ethree

particip

ants

that

reported

moderate

gastrointestin

alsym

ptomsontherap

idinsulin-an

d-pram

lintid

eartifi

cialpancreas

visitsalso

reported

symptomsontheregu

larinsulin-an

d-pram

lintid

eartifi

cialpancreas

visits.UThemeals

that

were

followed

bymoderate

ormoderate-to-severe

symptomsontherap

idandregu

larinsulin-an

d-pram

lintid

eartifi

cialpancreas

visitshad

amed

ianpram

lintid

epran

dial

bolusof22

and59

mg,

respectively.

care.diabetesjournals.org Haidar and Associates 603

hyperglycemia (6,25,26).We thus adopteda strategy that spreads prandial insulinandpramlintideover 20min,mimicking adual-wave bolus, to avoid early postpran-dial hypoglycemia without the needto excessively reduce the insulin-to-carbohydrate ratios (27).As a physiological mechanism against

hyperglycemia, high glucose levels delaygastric emptying in healthy individualsand in type 1 diabetes (28,29), althoughthis mechanism is weakened in type 1diabetes due to the absence of endog-enous amylin (28,29). Conversely, as aphysiological mechanism against hypo-glycemia, low glucose levels accelerategastric emptying in healthy individuals(30) and in type 1 diabetes (30,31). Ourpramlintide prandial dosing logic alignswith these two physiological defensemechanisms (Fig. 2). At high premealglucose levels, more immediate pramlin-tide is delivered todelay gastric emptyingand prevent aggravation of postprandialhyperglycemia (28,32). At low premealglucose levels, less immediate pramlintideis delivered to avoid interference withthe physiological hypoglycemia-inducedacceleration of gastric emptying.Somewhat surprisingly (23,33), we ob-

served only a modest increase in gastro-intestinal side effects with the rapidinsulin-and-pramlintide artificial pancreas.This may have been due to variousreasons. First, participants were exposedtopramlintide for 10–14days prior to theinsulin-and-pramlintide artificial pancreasvisits. Second, our prandial delivery strat-egy spread the delivery of pramlintideover 20 min, which must have led tolower peak plasma levels compared withif pramlintide was delivered as a singlebolus. Third, our prandial pramlintide dosesdecreased with smaller meal sizes andwere lower forparticipantswith lowinsulindoses. Fourth, continuousbasal pramlintidedelivery may have increased the partici-pants’ tolerance to pramlintide (34).Basal pramlintide did not improve glu-

cose control at night, due to the sufficiencyof the rapid insulin-alone system, but theincreased basal pramlintide in responseto increasing glucose levels prior to themeals (10–12, 15–17, and 19–21 h) (Fig.1) may have contributed to improvedglucose control during the day. This glucose-responsive pramlintide delivery alignswith natural physiology (in healthy indi-viduals, increasing glucose levels from5.0 to 11.0 mmol/L led to higher plasma

amylin levels from 2.1 to 18.9 pmol/L[28]). Nevertheless, our study doesnot compare glucose-responsive basalpramlintide delivery against constant basalpramlintide delivery, nor does it com-pare basal-bolus pramlintide deliveryagainst bolus pramlintide delivery. Itmay be possible for our findings tobe reproducedbydelivering pramlintideat mealtimes only, using a dual-chamberpump, but this will necessitate an addi-tional infusion set and an additional drugmanipulation.

A required long optimization wouldbe a barrier to adoption. However, oursystem should not normally require anoptimization period, and our previousstudies (19–21) with the rapid insulin-alone system without prior optimizationhad comparable results to this study. Theoptimization periodswere needed in thisstudy to mitigate against two potentialbiases. First, the systems are initializedusingdaily insulindose, carbohydrate-to-insulin ratios, and basal rates, but theseparametersprior to the studyare tailoredfor rapid insulin-alone therapy and thusare not appropriate to initialize the twodual-hormone systems. To initialize thedual-hormone systems properly, we needparameters that result from a prolongeduse of insulin and pramlintide concom-itantly, and this requires a run-in period.Second, without a run-in period, the gas-trointestinal outcomes during the dual-hormone artificial pancreas interventionswould reflect theacuteeffect of pramlintide.However, most gastrointestinal symptomsare transient, and we are interested inestimating the nontransient effects asthey better reflect prolonged use in real-world settings.

At the endof theoptimizationphaseofthe rapid insulin-and-pramlintide inter-vention, we reduced the insulin-to-carbohydrate ratios compared with therapid insulin-alone by only 6%. This find-ing appears at first glance to contradictthose of other studies reporting a re-duction of 15–25% (6,26) when addingpramlintide to prandial insulin, but ourstudy uniquely delivered prandial insulinand pramlintide as dual-wave boluses. Inanother study that added pramlintide tosquare-wave prandial insulin boluses, aminimaldecreaseof the insulindose (7.8%)was also needed (27), despite using largepramlintide boluses (60 mg).

On the other hand, during the artificialpancreas interventions, nocturnal basal

insulin rates were not lower with therapid insulin-and-pramlintide system com-pared with the rapid insulin-alone system,despite delivering basal pramlintideand achieving a similar mean glucoselevel (4–8 h) (Fig. 1). Other studies withbasal pramlintide also reported little(27) or no reduction (14,34) in basalinsulin needs. Moreover, one studyshowed that nocturnal basal pramlintidedelivery had no effect on glucagonlevels (33). Another study reportedthat endogenous glucose production(a surrogate of basal insulin needs) isnot reduced with pramlintide boluses(28), despite a reduction in glucagonlevels. These findings and the results ofour study indicate that basal pramlintidedelivery has little or no effect on basalinsulin needs.

Our data did not support the use ofregular insulin and pramlintide in the ar-tificial pancreas. Other studies reportedbenefits of delivering regular insulin andpramlintide, but these studies used reg-ular insulin and placebo as a comparator(25,26,33,35), were limited to prandialdelivery (25,35), reported late postpran-dial hyperglycemia (25,26), or did notdeliver insulin and pramlintide at the sametime(i.e., notmimickingacoformulation)(35). In our study, postprandial controlwas improved with regular insulin andpramlintide (Fig. 2), but this benefit wasoffset by the slow glucose-lowering ef-fect of regular insulin betweenmeals andduring the night. Compared with rapid-acting insulins, regular insulin is associ-atedwith;0.5-fold lower plasma insulinlevels 60 min after delivery, and 1.5- to1.8-fold longer time-to-maximum glucoseexcursion (36).

With the rapid insulin-alone artificialpancreas, more patients will approachHbA1c levels of 7% (4,5). For HbA1c levelsnear 7%, studies in type 2 diabetes haveshown that the relative contribution ofpostprandial glucose to HbA1c levels is70% (37,38), compared with 30% forHbA1c levels near 10%. In other words,as the HbA1c level decreases, postpran-dial glucosecontributesmore than fastingglucose to HbA1c. Since adding pramlintideto the artificial pancreas targets post-prandial hyperglycemia, the rapid insulin-and-pramlintide artificial pancreas maybe the next logical treatment in patientsapproaching, yet not achieving, HbA1ctargets despite using the insulin-aloneartificial pancreas.

604 An Insulin-and-Pramlintide Artificial Pancreas Diabetes Care Volume 43, March 2020

Participants reported higher treatmentsatisfaction with the rapid insulin-and-pramlintide therapy during the optimi-zationperiod than the rapid insulin-alonetherapy (Supplementary Data), with theabsolutemajority stating that theywoulduse a coformulation if it were commerciallyavailable. This was paralleled with anincreased time in target range and re-duced mean glucose, but with a slightincrease in hypoglycemia. Unlike duringthe artificial pancreas interventions,this increased hypoglycemia may be ex-plained by the dual-wave boluses duringthe optimization period not reducing theimmediate insulin and pramlintide bo-luses at low premeal glucose levels(immediate boluses were always 50%).Gastrointestinal symptoms during theoptimization period were low and com-parable to those recorded during the artifi-cial pancreas interventions (SupplementaryData).Our study has several limitations. First,

our study was conducted in inpatient set-tings for only 1 day, and it did not includevigorous exercise. It is unknown howpramlintide and vigorous exercise to-gether affect hypoglycemia and nau-sea. Second, our study lacked allocationblinding. Third, we delivered insulin andpramlintide using two pumps, and theirmixing in a coformulation may alter theiraction. However, two studies showedthat injecting pramlintide and insulinmixed in a syringe did not affect theirabsorptions or actions (39). Fourth, weused manual control to operate the arti-ficial pancreas systems, but this was un-likely tohaveaffectedtheclinicaloutcomessincehormonaldeliverieswouldhavebeenthe same ifwe used an automated system.Fifth, eight enrolled participants were notincluded in the analysis due to dropout/exclusion (four of whomdropped out beforethe first intervention) (SupplementaryData).Our study is the first to propose two

novel insulin-and-pramlintideartificialpan-creas systems. The rapid insulin-and-pramlintide artificial pancreas improvedglucose control compared with the rapidinsulin-alone system without increasinghypoglycemia and with a modest in-crease in transient mild-to-moderategastrointestinal side effects in some pa-tients. The regular insulin-and-pramlintideartificial pancreas did not improve glucosecontrol compared with the rapid insulin-alone artificial pancreas. Studies with the

rapid insulin-and-pramlintide artificial pan-creas in free-living outpatient settings arenow warranted.

Funding. This study was supported by fundingfrom JDRF (2-SRA-2016-246-M-R).Duality of Interest. A.H. received research sup-port/consulting fees from Eli Lilly, Medtronic, Aga-Matrix, and Dexcom and has pending patents inthe artificial pancreas area. M.A.T. received re-search support from AgaMatrix, consulting feesfrom Sanofi, and speaker honoraria from Eli Lilly,Novo Nordisk, Boehringer Ingelheim, Janssen,and AstraZeneca. J.-F.Y. received research sup-port from Sanofi, Bayer, and Novo Nordisk andconsulting fees and speaker honoraria fromSanofi, Eli Lilly, Novo Nordisk, Boehringer Ingelheim,Janssen, Takeda, Abbott, Merck, and AstraZeneca.A.B. is a nurse clinician and insulin pump trainerfor Medtronic Canada and Omnipod Canada.E.P. received consulting fees from Animas andspeaker honoraria from Medtronic and Animas.L.L. has pending patents in the field of artificialpancreas, received consulting fees from Dex-com, and has received support for clinical trialsfrom Merck, AstraZeneca, and Sanofi. No otherpotential conflicts of interest relevant to thisarticle were reported.Author Contributions. A.H. and L.L. supervisedthe study. A.H., M.A.T., J.-F.Y., N.S., and L.L. designedthe study. A.H. designed the dosing algorithm.A.H., M.A.T., S.B.-T., J.-F.Y., J.R., A.B., E.P., N.S., andL.L. conducted the study. A.H., J.R., and A.E.F.performed the data analysis, including the statis-tical analyses. All authors read and approved thefinal version of the manuscript. A.H. is theguarantor of this work and, as such, had fullaccess to all the data in the study and takesresponsibility for the integrity of the data andthe accuracy of the data analysis.

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