NNC 0148-0000-0106
Trial ID: NN1952-3646
Clinical Trial Report
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Synopsis
Trial Registration ID-number
EudraCT number – EU only
NCT01028404
2009-013282-26
Title of Trial
A Trial Investigating the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of NNC 01480000-0106 in Healthy Subjects and Subjects with Type 1 and Type 2 Diabetes
Investigator(s)
Dr. Tim Heise, MD
Trial Site(s)
Profil Institut für Stoffwechselforschung GmbH, Hellersbergstr. 9, D-41061 Neuss, Germany.
Publications
NA
Trial Period
Development Phase
19-Nov-2009 to 07-Jun-2010
Phase 1
Objectives
Primary Objective:
 To assess the safety and tolerability of single ascending doses of oral insulin 106 in healthy subjects (Trial
Part 1), and of a single dose level of oral insulin 106 in subjects with type 1 and type 2 diabetes mellitus (Trial
Part 2)
Secondary Objectives:
 To assess the pharmacokinetics of single ascending doses of oral insulin 106 in healthy subjects
 To assess the pharmacodynamic effect of single ascending doses of oral insulin 106 in healthy subjects, as
assessed by the glucose infusion rate (GIR)
 To evaluate the dose relationship of the pharmacokinetics and pharmacodynamics of oral insulin 106 in healthy
subjects
 To explore the pharmacokinetics of a single dose of oral insulin 106 in subjects with type 1 or type 2 diabetes in
the fasting condition
 To explore the pharmacodynamic effect of a single dose of oral insulin 106 in subjects with type 1 or type 2
diabetes in the fasting condition, as assessed by GIR
 To explore the relative bio-efficacy of a single dose of oral insulin 106 as compared to a single subcutaneous (sc)
dose of insulin aspart in subjects with type 1 or type 2 diabetes, as assessed by GIR
 To explore the effect of food on the pharmacokinetics of a single dose of oral insulin 106 in subjects with type 1
or type 2 diabetes
 To explore the pharmacodynamic effect of a single dose of oral insulin 106 as compared to placebo on
postprandial blood glucose concentrations during a meal test in subjects with type 1 or type 2 diabetes
 To explore the variability of the pharmacokinetic and pharmacodynamic properties of oral insulin 106 and
compare to that of insulin aspart in subjects with type 1 or type 2 diabetes
Methodology
This first human dose trial with insulin 106 is a single centre trial, consisting of two trial parts: 1) a single ascending
dose part in healthy subjects, and 2) an exploratory crossover part in subjects with type 1 or type 2 diabetes mellitus.
Trial Part 1:
Trial Part 1 was a placebo- and active-controlled, single ascending dose, sequential group trial. A total of six dose
groups was completed. Each dose group consisted of ten subjects, of which six subjects were randomised to receive
NNC 0148-0000-0106
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300, 900, 1800, 3600, 7200 or 14400 nmol oral insulin 106, two subjects were randomised to receive oral placebo,
and two subjects were randomised to receive 162 nmol sc insulin aspart. The dosing of oral insulin 106 and oral
placebo was performed double-blind. The subjects were dosed in the fasting state, using a 12-hour euglycaemic
clamp, and each subject received one single dose only. After completion of each dose group, an evaluation of blinded
safety data, pharmacokinetic data, pharmacodynamic data and PK/PD modelling results was performed to allow
progression to the next dose level.
The trial activities for each dose group consisted of a pre-screening visit (Visit 0) to obtain the informed consent (at
least 1 day prior to Visit 1), a screening visit (Visit 1) to determine the eligibility of the subjects for trial
participation, a dosing visit (Visit 2) at which the subjects resided in-house at the clinical site, and a follow-up visit
(Visit 3). The dosing visit (Visit 2) comprised a check-in day (Day 0), followed by a dosing day (Day 1) and a safety,
pharmacokinetic and pharmacodynamic assessment period up to 48 hours post-dose (until Day 3). The dosing visit
(Visit 2) was performed within 3-28 days after screening (Visit 1). Subjects returned for a follow-up visit (Visit 3) at
3–14 days after their discharge from the clinic on Day 3 of Visit 2.
Trial Part 2:
Trial Part 2 was initiated following completion of Trial Part 1. Trial Part 2 was a single dose, randomised, open-label,
four-period crossover trial in a group of 12 subjects with type 1 diabetes and 12 subjects with type 2 diabetes,
investigating one selected dose level of oral insulin 106.
Each subject was randomly allocated to a treatment sequence by which the subject during the four separate in-house
dosing visits received each of the following treatments:
 A single dose of 14400 nmol oral insulin 106 administered in the fasting state (using a 12-hour euglycaemic
glucose clamp),
 A single sc dose of 162 nmol sc insulin aspart administered in the fasting state (using a 12-hour euglycaemic
glucose clamp),
 A single dose of 14400 nmol oral insulin 106 administered 15 minutes prior to a standardised meal
 A single dose of oral placebo administered 15 minutes prior to a standardised meal.
In this exploratory crossover part, the trial activities for the group of 24 subjects with type 1 and type 2 diabetes
consisted of a pre-screening visit (Visit 0) to obtain the informed consent (at least 1 day prior to Visit 1), a screening
visit (Visit 1) to determine the eligibility of the subjects for trial participation, four in-house dosing visits (Visits 2, 3,
4 and 5) separated by a 1-week wash-out period between each dosing visit, and a follow-up visit (Visit 6). The inhouse dosing visits (Visits 2, 3, 4 and 5) comprised a check-in day (Day 0), followed by a dosing day (Day 1) and a
safety, pharmacokinetic and pharmacodynamic assessment period up to 24 hours post-dose (until Day 2). The first
dosing visit (Visit 2) was performed within 3-28 days after screening (Visit 1).
Number of Subjects Planned and Analysed
Trial Part 1:
Planned: 60, screened: 90; randomised: 60; withdrawn: 0; completed: 60.
Trial Part 2:
Planned: 24 subjects (12 subjects with type 1 diabetes, 12 subjects with type 2 diabetes), screened: 45; randomised:
24; withdrawn: 2; completed: 22 (12 subjects with type 1 diabetes, 10 subjects with type 2 diabetes)
Diagnosis and Main Criteria for Inclusion
Trial Part 1:
Healthy male subjects, age between 18 and 55 years (both inclusive), body mass index between 18 and 28 kg/m2
(both inclusive), fasting plasma glucose value ≤6 mmol/L (108 mg/dL)
NNC 0148-0000-0106
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Trial Part 2:
Type 1 diabetes mellitus or type 2 diabetes mellitus (as diagnosed clinically) for ≥12 months, age between 18 and 65
years (both inclusive), body mass index between:
o 18 and 28 kg/m2 (both inclusive) for subjects with type 1 diabetes
o 22 and 35 kg/m2 (both inclusive) for subjects with type 2 diabetes
o HbA1C ≤8.5 %
Test Product, Dose and Mode of Administration, Batch Number
Insulin 106 (NNC 0148-0000-0106) in a GIPET® I gastro-resistant tablet was administered orally as tablets of
300, 900, 1800, 3600 and 7200 nmol, Batch numbers: BN-09-08-08, BN-09-08-11, BN-09-08-14, BN-09-08-20, BN09-08-23,
Duration of Treatment
Trial Part 1:
One single dosing day: one single dose of oral insulin 106 or placebo or insulin aspart
Trial Part 2:
Four separate dosing days: two single doses of oral insulin 106 (with and without meal), one single dose of placebo
and one single dose of insulin aspart.
Reference Therapy, Dose and Mode of Administration, Batch Number
 placebo (GIPET® I) gastro-resistant tablet, oral, Batch number: BN-09-08-05
 insulin aspart (NovoRapid®) in 3 mL FlexPen®, sc
Criteria for Evaluation – Efficacy
Pharmacokinetics and Pharmacodynamics
 Concentration time curves of insulin 106
 Concentration time curves of insulin aspart
 Glucose infusion rates (GIR)
 Concentration time curves of blood glucose
Criteria for Evaluation – Safety
The primary endpoint was safety and tolerability
 Adverse events
 Hypoglycaemic episodes
 Blood glucose
 Laboratory safety variable (haematology, biochemistry, urinalysis)
 Clinical parameters (Vital signs, ECGs, Physical examination)
Statistical Methods
Safety Evaluation
No formal statistical hypothesis was planned or tested. The safety endpoints (see safety criteria above) were
summarised using listings, tables and graphical presentations of the safety population.
Pharmacokinetic Evaluation
The following pharmacokinetic endpoints were derived from the insulin 106 (I106) concentration-time curves and
the insulin aspart (IAsp) concentration-time curves measured during the first 24 hours after dosing in Trial Part 1 and
Trial Part 2:
 AUCIns,0-2h,SD area under the serum insulin concentration-time curve from 0 to 2 hours after a single dose
 AUCIns,0-6h,SD area under the serum insulin concentration-time curve from 0 to 6 hours after a single dose
 AUCIns,0-12h,SD area under the serum insulin concentration-time curve from 0 to 12 hours after a single dose
 AUCIns,0-24h,SD, area under the serum insulin concentration-time curve from 0 to 24 hours after a single dose
 AUCIns,0-∞,SD area under the serum insulin concentration-time curve from 0 to infinity after a single dose
 Cmax,Ins,SD maximum observed serum insulin concentration after a single dose
NNC 0148-0000-0106
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tmax,Ins,SD time to maximum observed serum insulin concentration after a single dose
t1/2,Ins,SD terminal half-life
MRTIns,SD mean residence time
CL/FIns,SD apparent serum clearance of insulin after administration
Vz/FIns,SD apparent volume of distribution of insulin after oral or subcutaneous administration, estimated during
the terminal phase
Trial Part 1
The dose-exposure relationship was evaluated in an ANOVA approach using the secondary pharmacokinetic
endpoints (AUCIns,0-6h,SD, AUCIns,0-12h,SD and Cmax,Ins,SD log transformed) as the dependent variable and insulin dose as
fixed effect (placebo not used, IAsp set to its own level). The residual variance was depending on the insulin
preparation (I106/IAsp). The point-estimates for every dose were plotted together with the 95% confidence interval
(CI) against the dose. The assumption of dose-proportionality was explored by scatter plots of the PK endpoints
against dose. Dose-proportionality of AUC Ins,0-12h,SD and C max,Ins,SD was evaluated using linear regression of the logtransformed endpoint on log(dose) and the hypothesis of dose-linearity was tested (hypothesis of the slope of the
regression line being equal to 1). As the subjects in each dose group had all received the same dose of I106 (nmol)
the evaluation of dose-proportionality was also evaluated with use of the actual dose (nmol/kg body weight).
Trial Part 2:
The secondary pharmacokinetic endpoints (AUCIns,0-6h,SD, AUCIns,0-12h,SD and Cmax,Ins,SD) were evaluated separately for
subjects with type 1 diabetes and for subjects with type 2 diabetes in an ANOVA approach with the endpoints (logtransformed) as dependent variable, with treatment (I106 fasting/IAsp fasting/I106 15 min pre-meal) and possibly
period as fixed effects, subject as a random effect, and residual variance depending on the treatment.
Based on this model point-estimates with 95% CI were calculated for all the treatments. To assess the food effect, the
I106 fasting – I106 fed contrast was also estimated with 95% CI.
Based on the above mentioned model, a test for no difference in variability in the mean AUC’s between the two
insulin preparations in fasting state was performed by calculating the ratio of the residual variance estimates and
evaluating whether this ratio was significantly greater than 1 in an F-distribution with the appropriate degrees of
freedom.
The rest of the pharmacokinetic endpoints were described by means of summary statistics.
Pharmacodynamic Evaluation
The following pharmacodynamic endpoints were derived from the glucose infusion rate-time curves measured during
the euglycaemic glucose clamp running for 12 hours after dosing in Trial Part 1 and Trial Part 2:
 AUCGIR,0-2h,SD area under the glucose infusion rate-time curve from 0 to 2 hours after a single dose
 AUCGIR,0-6h,SD, area under the glucose infusion rate-time curve from 0 to 6 hours after a single dose
 AUCGIR,0-12h,SD area under the glucose infusion rate-time curve from 0 to 12 hours after a single dose
 GIRmax,SD maximum glucose infusion rate after a single dose
 tGIRmax,SD time to maximum glucose infusion rate after a single dose
The following pharmacodynamic endpoints were derived from the blood glucose concentration-time curves
measured during the meal test for 12 hours after dosing in Trial Part 2:
 AUCBG,0-2h,SD, area under the blood glucose concentration-time curve from 0 to 2 hours after a single dose
 AUCBG,0-6h,SD, area under the blood glucose concentration-time curve from 0 to 6 hours after a single dose
 AUCBG,0-12h,SD, area under the blood glucose concentration-time curve from 0 to 12 hours after a single dose
 Cmax,BG,SD, maximum blood glucose concentration after a single dose
 Tmax,BG,SD, time for maximum blood glucose concentration after a single dose
The secondary pharmacodynamic endpoints (AUCGIR,0-6h,SD, AUCGIR,0-12h,SD and GIRmax) were analysed with the same
model and estimates as the secondary pharmacokinetic endpoints, except that:
NNC 0148-0000-0106
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 Only fasting data would be used, as no GIR data for the pre-meal treatment groups exist
 Placebo would be set to its own level (Dose=0)
Before the model was fitted, it was checked that the effect was independent of placebo dose level, by plotting the
average of the two placebo-AUC’s for each dose level versus dose level.
Dose-linearity of AUCGIR,0-12,SD was evaluated visually by plot of the point-estimates of the model for every dose
together with the 95% confidence interval (CI) against the dose. The dose-linearity of GIRmax,SD was evaluated in the
same way as the AUCGIR,0-12,SD.
The secondary endpoints AUCBG,0-2h,SD, AUCBG,0-6h,SD and Cmax,BG,SD were also analysed with the same model as
above. However, only the pre-meal data (data from the treatment groups: I106 pre-meal and placebo pre-meal)
obtained during the meal test period was used. In this model the I106 pre-meal – placebo pre-meal contrast was the
one of interest.
The relative bio-efficacy of I106 against IAsp was estimated from the model as:
AUCGIR ,012,SD (I106 fasting) / Dose(I106 fasting)
AUCGIR , 012,SD (IASP fasting) / Dose(IASP fasting)
The remaining endpoints were described by means of descriptive statistics.
Demography of Trial Population
Trial Part 1:
The trial population in Trial Part 1 consisted of 60 healthy male subjects with a mean age of 37.6 years ranging from
20 to 53 years, mean body weight was 82.5 kg ranging from 56.9 to 100.1 kg and mean body mass index was 25.1
kg/m2 ranging from 19.4 to 28.0 kg/m2. The majority of the subjects were white (96.7%). No noteworthy differences
were observed in age and weight of subjects among the three treatment groups (I106, IAsp and placebo).
Trial Part 2:
The trial population in Trial Part 2 consisted of 12 subjects with type 1 diabetes (3 females, 9 males) and 12 subjects
with type 2 diabetes (2 females, 10 males). All subjects were white. Mean age for subjects with type 1 diabetes was
43.3 years (range 2364 years) and mean age for subjects with type 2 diabetes was 51.4 years (range 4461 years).
Subjects with type 2 diabetes had a higher mean body mass index (mean 28.8 [range: 22.5  34.3]) than subjects with
type 1 diabetes (mean 24.4 [range: 20.6  27.8]).
Efficacy Results
Trial Part 1
 The pharmacokinetic (PK) results demonstrated a rapid absorption of oral insulin 106 (in a GIPET I gastroresistant tablet) with the time to maximum serum concentration (tmax) ranging from 0.751.88 hours post dose
over the tested dose range (300 to 14400 nmol) in fasting state. In comparison, tmax for sc insulin aspart was 1.75
hours.
 Oral insulin 106 (in a GIPET I gastro-resistant tablet) had a short terminal serum half life (t1/2) with harmonic
mean t1/2 values increasing from 0.64 to 2.17 hours over the tested dose range (330 to 14400 nmol) in fasting state.
Insulin aspart showed harmonic mean t1/2 of 0.92 hours.
 The systemic exposure of oral insulin 106 (in a GIPET I gastro-resistant tablet) appeared to increase
proportionally with dose, as measured by the maximum concentration (Cmax) and the area under the serum
concentration curve (AUC(0-6h), AUC(0-12h)). Across all dose levels of oral insulin 106, mean Cmax ranged from 152
to 7780 pM and mean AUC(0-12h) ranged from 141 to 19955 hpM. For sc insulin aspart, mean Cmax was 712 pM
and mean AUC(0-12h) was 2079 hpM.
 The inter-individual variability in the PK endpoints of oral insulin 106 (in a GIPET I gastro-resistant tablet) was
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significantly larger compared to that of insulin aspart with a coefficiant of variation (CV) of 200% for AUC for
oral insulin 106 compared to a CV of 25% for AUC for sc insulin aspart
The pharmacodynamic (PD) results demonstrated a rapid onset of action of oral insulin 106 (in a GIPET I gastroresistant tablet) with mean GIR effect (measured as AUCGIR, 0-12 h) increasing from 204 to 3078 mg/kg over the
tested dose range (300 to 14400 nmol) in the fasting state of healthy subjects
Increasing doses of oral insulin 106 (in a GIPET I gastro-resistant tablet) showed increasing GIR effect over
tested dose range in the fasting state in healthy subjects, although the GIR effect increased less than proportionally
with dose
The PD effects appeared to correspond relatively well with the PK exposure over the tested dose range.
The inter-individual variability in GIR endpoints of oral insulin 106 (in a GIPET I gastro-resistant tablet) was
significantly larger compared to that of sc insulin aspart (CV: 95-445% compared to CV: ~25% )
A single dose of 14400 nmol oral insulin 106 (in a GIPET I gastro-resistant tablet) had a GIR effect (AUCGIR and
GIRmax) that was comparable to a sc dose of 162 nmol insulin aspart
Trial Part 2
 A single dose of 14400 nmol oral insulin 106 (in a GIPET I gastro-resistant tablet) administered to subjects with
type 1 or type 2 diabetes in fasting state showed PK results that were comparable to the results seen in healthy
subjects
 The inter-individual variability in the pharmacokinetic (PK) endpoints of oral insulin 106 (in a GIPET I gastroresistant tablet) in the fasting state was larger compared to that of sc insulin aspart with a coefficiant of variation
(CV) of 64184% for AUC for oral insulin 106 compared to a CV of 161% for AUC for sc insulin aspart
 The relative bio-efficacy of oral insulin 106 (in a GIPET I gastro-resistant tablet) compared to sc insulin aspart
under fasting conditions was ~0.5% in subjects with type 1 diabetes and ~0.7% in subjects with type 2 diabetes
 Oral insulin 106 (in a GIPET I gastro-resistant tablet) mean AUC(0-12 h) values of 15770 and 1592 hpM for
subjects with type 1 diabetes and mean AUC(0-12 h) values of 11349 and 1556 hpM were measured in the fasting
and fed state, respectively, indicating an approximately 80-90% reduction of AUC with food. In addition, oral
insulin 106 (GIPET I) mean Cmax as well as median tmax were reduced with the presence of food.
 In the meal test, effect of oral insulin 106 (in a GIPET I gastro-resistant tablet) on mean post-prandial BG(AUC)
was small, with ~2030% suppression of post-prandial BG after active treatment compared to placebo in subjects
with type 1 diabetes. No effect was seen in subjects with type 2 diabetes
 In the meal test, large individual variability in PK and post-prandial BG after oral insulin 106 (in a GIPET I
gastro-resistant tablet) was seen, resulting in hypo- or hyperglycemia in subjects with type 1 or type 2 diabetes
Safety Results
General
 Few AEs were reported during this trial and all subjects recovered
 No serious AEs were reported
 There were no clinically significant findings for:
 Vital signs
 Physical examinations
 Laboratory safety variables (haematology, biochemistry, urinalysis)
 ECG recordings
Trial Part 1
 Single ascending doses up to 14400 nmol (2400 Units) oral insulin 106 (in a GIPET I gastro-resistant tablet)
were well tolerated by healthy male subjects during glucose clamp conditions
 In total, 7 non- serious AEs were reported in 7 out of 60 dosed subjects and 5 of the AEs were recorded as
possible related to treatment with oral insulin 106
 The AEs comprised headache, nausea and vomiting. They were all mild or moderate in severity and all subjects
recovered
 There was no apparent dose-related trend in type, frequency or severity in the AEs
 In total, 81 hypoglycaemic episodes were reported during the clamp period. The majority of these hypoglyceamic
NNC 0148-0000-0106
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episodes were classified as asymptomatic (according to the American Diabetes Association classification: plasma
glucose  3.9 mmol/L) and considered not to be clinically relevant
 No hypoglycaemic episodes were reported after completion of glucose clamp procedures
 Maximum Tolerated Dose was not established due to the pre-defined maximum dose (amount of sodium caprate
corresponding to two tablets)
Trial Part 2
 A single dose of 14400 nmol (2400 Units) oral insulin 106 (in a GIPET I gastro-resistant tablet) was well
tolerated by subject with type 1 and type 2 diabetes during glucose clamp and meal test conditions
 In total, 5 non-serious AEs were reported by 3 out of 12 subjects with type 1 diabetes and one of the AEs was
recorded as possibly related to treatment.
 A total of four non-serious AEs were reported in three out of 12 subjects with type 2 diabetes. One of the AEs was
recorded as possibly related to treatment and one was recorded as probably related to treatment.
 The AEs comprised nausea, vomiting, headache, diarhoea, nasopharyngitis, neck pain and hyperhidrosis. They
were all mild or moderate in severity and all subjects recovered.
 There were no apparent trend in type, frequency or severity in the AEs for the four treatments
 In total, 28 treatment emergent hypoglycaemic episodes were reported during the four treatment periods. Of these,
23 hypoglycaemic episodes occurred in subjects with type 1 diabetes and 5 hypoglycaemic episodes occurred in
subjects with type 2 diabetes. All hypoglycaemic episodes were classified as asymptomatic (according to the
American Diabetes Association classification) and not considered clinically relevant. Three (3) of the
hypoglycaemic episodes occurred during glucose clamp, six hypoglycaemic episodes occurred in relation to the
meal test and 19 hypoglycaemic episodes occurred later than 12 hours post-dose when other insulin treatment was
resumed.
Conclusions
 Single doses of oral insulin 106 (in a GIPET I gastro-resistant tablet) up to 14400 nmol (2400 U) were well
tolerated by healthy subjects and subjects with type 1 or type 2 diabetes during glucose clamps and meal test
conditions
 The PK results of oral insulin 106 (in a GIPET I gastro-resistant tablet) demonstrated:
 Rapid absorption on all dose levels in fasting state
 Proportional increase with dose
 No difference was observed between healthy subjects and subjects with type 1 or type 2 diabetes
 The PD results of oral insulin 106 (in a GIPET I gastro-resistant tablet) demonstrated:
 Rapid onset of action in fasting state
 Increasing GIR effect over tested dose range
 PD effects appeared to be relatively well correlated to PK exposure
 In the fasting state, the inter-individual variability in PK and PD properties was larger after treatment with oral
insulin 106 (in a GIPET I gastro-resistant tablet) compared to sc insulin aspart
 Relative bio-efficacy of oral insulin 106 (in a GIPET I gastro-resistant tablet) compared to sc insulin aspart was
~0.5% in subjects with type 1 diabetes and ~0.7% in subjects with type 2 diabetes
 Exposure of oral insulin 106 (in a GIPET I gastro-resistant tablet) was decreased by meal intake, indicating
complete stop of absorption with presence of food
 In the meal test, the glucose lowering effect of oral insulin 106 (in a GIPET I gastro-resistant tablet) on postprandial BG levels was small, with ~2030% suppression of post-prandial glucose in subjects with type 1 diabetes
and no effect in subjects with type 2 diabetes was observed
 In the meal test, large inter-individual variability in pharmacokinetics and post-prandial BG after treatment with
oral insulin 106 (in a GIPET I gastro-resistant tablet) was seen in subjects with type 1 or type 2 diabetes
The trial was conducted in accordance with the Declaration of Helsinki (2008) and ICH Good Clinical Practice
(1996).
The results presented reflect data available in the clinical database as of 15-Jul-2010.