Clinical trial NCT06473662
Conditions: Type 2 Diabetes Treated With Insulin
Sponsor: Roger New
Start date: 2018-10-22; Completion date: 2020-07-11
Enrollment: 153 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The aim of the study was to compare the pharmacodynamic properties of different doses of regular human insulin administered in capsule form twice daily in a randomised twelve-week open-label trial.

Detailed description:

Arms: arm 1: Capsule containing 75iu recombinant human insulin administered two times per day arm 2: Capsule containing 150iu recombinant human insulin administered two times per day arm 3: Capsule containing 300iu recombinant human insulin administered two times per day
Interventions: intervention 1: Oral insulin
Intervention descriptions: intervention 1: Capsule administered by mouth with a glass of water two times per day, once before breakfast and once before supper

Protocol documents:
Prot_SAP_000.pdf: 
 
 
Page 1 of 37 
 
 
Study to Evaluate the Safety 
and Efficacy of Oral Insulin 
Formulation in Type 2 Diabetes 
Mellitus Subjects 
 
NCT06473662 
 
06/19/2024 
 
 


 
 
Page 2 of 37 
 
STUDY OBJECTIVES 
Primary Objective 
To evaluate the safe and effective dose of USVCAP (75 IU, or 150 IU, or 300 IU) after twice daily 
treatment with selected fixed dose (75 IU, or 150 IU, or 300 IU) of USVCAP for 12 weeks 
Secondary Objective 
To assess the immunogenicity of the investigational product 
INVESTIGATIONAL PLAN 
Overall Study Design and Plan-Description 
Overview of Study Design 
This was a phase IIb, open-label, randomized, comparative study to evaluate the safety and efficacy 
of USVCAP formulation in T2DM subjects uncontrolled with metformin hydrochloride treatment. 
Total of 153 subjects who met the eligibility criteria were randomized in a ratio of 1:1:1 to any one 
of the following 3 treatment groups: 
• Group A: USVCAP 75 IU, BD for 12 weeks 
• Group B: USVCAP 150 IU, BD for 12 weeks 
• Group C: USVCAP 300 IU, BD for 12 weeks  
Each subject had following study periods and visits: 
• Screening period (Visit 1): It lasted for up to 21 days after signing the informed consent 
form (ICF) 
• Treatment period (Visit 2 to Visit 7): Eligible subjects were randomly assigned to any one 
of the above treatment groups at Visit 2 by randomization process through an interactive 
web response system (IWRS). Each subject from all 3 treatment groups received *assigned 
fixed dose of USVCAP (i.e. IP) as per allocated treatment groups for 12 weeks. 
*Assigned fixed dose in the study is defined as: Fixed dose of USVCAP (i.e. IP) administered 
to subject twice daily for 12 weeks based on the treatment group (Group A, Group B, or Group 
C) allocated at randomization visit. 
• Upon randomization: 
o Subjects allocated to Group A were prescribed with the assigned fixed dose of USVCAP 
(75 IU BD) from next day of randomization (Day 1) for 12 weeks 
o Subjects allocated to Group B and Group C, underwent a run-in period of 1 week with 
each previous lower dose/s, prior to initiation of assigned fixed dose of USVCAP. They 
additionally visited the study site for a step-wise increase of dose/s at each run-in 
period/s. These visits were called dose escalation (DE) visits (Visit DE 1 and Visit DE 
2) in the trial. The dose increase were done once for Group B and twice for Group C 
subjects as depicted in Table 2 and Table 3. Upon completion of the run-in period/s, the 


 
 
Page 3 of 37 
 
subjects received the assigned fixed dose of USVCAP further for 12 weeks (Table 2). 
Therefore, the overall duration of treatment with USVCAP for subjects in Groups B and 
C was 13 and 14 weeks, respectively 
o End-of-treatment: The end-of-treatment (EOT) for each randomized subject was defined 
as Day when 12-weeks of twice daily administration of assigned fixed dose of IP was 
completed by a subject (Table 2 and Table 3) 
o Visit 7 was the EOT visit: It was conducted on next day after the subject had completed 
twice daily administration of assigned fixed dose of IP for 12 weeks (Table 2) 
• Post-treatment safety follow-up period: It was of 4-weeks duration after the subject had 
completed administration of the last dose of assigned fixed dose of IP. Visit 8 was the end-
of-study (EOS) Visit in the study. 
The Investigator followed the schedule of study assessments and procedures provided in Table 2. 
A window period of +2 days was allowed at every visit from Visit 3 to Visit 8 and at Visit DE 1 
and Visit DE 2. 
Pre-study oral anti-diabetic treatment (i.e. monotherapy with metformin hydrochloride) was 
continued at same dose and regimen from screening up to EOT period. A subject diary was provided 
to the subjects for recording the IP dosage, capillary glucose measurements, AEs, details on 
hypoglycaemic episodes, and any change in concomitant medications, as applicable. 
The following Standard of Care was provided to each subject throughout the treatment period: 
1. Step-wise dose escalation in subjects assigned to receive higher doses of USVCAP (i.e. 
subjects assigned to received fixed dose of 150 IU and 300 IU, BD) 
2. Pre-study oral anti-diabetic monotherapy (i.e. metformin hydrochloride) continued at same 
dose and regimen 
3. Capillary glucose measurements 
4. Consumption and maintenance of healthy diet and lifestyle regimen 
5. Treatment for complications related to insulin therapy (e.g. hypoglycaemia, hypokalaemia, 
etc.) or any other complications as per Investigator’s practice and standard treatment 
guidelines 
The Schedule of Study Procedures and Assessments is given in Table 3. 
Table 1 Duration of Run in period(s) and treatment for doses of IP per each Allocated 
Treatment Group 
Treatment 
Group 
Assigned 
fixed dose of 
USVCAP 
Treatment duration 
with assigned fixed 
dose of USVCAP 
Run-in period/s with 
lower dose/s of USVCAP 
Overall total duration 
of 
treatment 
with 
USVCAP 
Group A 
75 IU BD 
12 weeks 
Not applicable 
12 weeks 
Group B 
150 IU BD 
12 weeks 
75 IU dose, BD for 1 week 
13 weeks 
Group C 
300 IU BD 
12 weeks 
Overall 2 weeks of run-in 
period 
75 IU BD for 1 week 
150 IU BD for 1 week 
14 weeks 
 


 
 
 
Page 4 of 37 
 
Table 2 Schedule of Study Procedures and Assessments: As per allocated treatment groups 
Study period 
Screening 
period 
Start 
of 
Treatment period 
Run-in period 
Treatment period 
Post- treatment 
Follow-up 
Visit Title 
Screening 
Randomization/ 
Enrolment visit 
Dose Escalation Visit(s) 
(only for subjects in Group B 
and Group C) 
Treatment visits for assigned 
dose group 
EOTa 
EOSb 
Visit # 
1 
2 
DE 1c 
DE 2d 
3 
4 
5 
6 
7 
8 
Group A 
(assigned dose 75 IU) 
Days -21 to 0 
Day 0 
N/A 
N/A 
8 
15 
30 
60 
85 
114 
Group B 
(assigned dose 150 IU) 
Days -21 to 0 
Day 0 
8 
N/A 
15 
22 
37 
67 
92 
121 
Group C 
(assigned dose 300 IU) 
Days -21 to 0 
Day 0 
8 
15 
22 
29 
44 
74 
99 
128 
Window period 
 
 
+ 2 days (applicable for 
both DE1 and DE 2 visits) 
+ 2 days (applicable at each visit) 
+ 2 days 
Informed Consent 
X 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
Xe 
 
 
 
 
 
 
 
Medical and Surgical history (including 
relevant details related to T2DM) 
X 
Xf 
 
 
 
 
 
 
 
Prior medication 
(including anti-diabetic therapy) 
X 
Xg 
 
 
 
 
 
 
 
Demographics with height (cm) 
X 
 
 
 
 
 
 
 
 
Physical examination 
X 
X 
 
X 
X 
X 
X 
X 
X 
Body weight (kg) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Waist circumference (cm) 
X 
X 
 
X 
X 
X 
X 
X 
X 
Body mass index (kg/m2) 
X 
X 
 
X 
X 
X 
X 
X 
X 
Vital signsh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Randomization 
 
X 
 
 
 
 
 
 
 
Dispensing of IP 
 
Xi 
Xj 
Xk 
X 
X 
X 
X 
 
 
(as per allocated treatment group) 
 
 
 
 
 
 
 
 
 
 
Accountability & compliance check of 
IP 
 
X 
X 
X 
X 
X 
X 
X 
X 
 


 
 
 
Page 5 of 37 
 
Study period 
Screening 
period 
Start 
of 
Treatment period 
Run-in period 
Treatment period 
Post- treatment 
Follow-up 
Visit Title 
Screening 
Randomization/ 
Enrolment visit 
Dose Escalation Visit(s) 
(only for subjects in Group B 
and Group C) 
Treatment visits for assigned 
dose group 
EOTa 
EOSb 
Visit # 
1 
2 
DE 1c 
DE 2d 
3 
4 
5 
6 
7 
8 
Group A 
(assigned dose 75 IU) 
Days -21 to 0 
Day 0 
N/A 
N/A 
8 
15 
30 
60 
85 
114 
Group B 
(assigned dose 150 IU) 
Days -21 to 0 
Day 0 
8 
N/A 
15 
22 
37 
67 
92 
121 
Group C 
(assigned dose 300 IU) 
Days -21 to 0 
Day 0 
8 
15 
22 
29 
44 
74 
99 
128 
Window period 
 
 
+ 2 days (applicable for 
both DE1 and DE 2 visits) 
+ 2 days (applicable at each visit) 
+ 2 days 
Capillary glucose measurements 
 
During the run-in period for Group B and C, at 
mid-week up to 1 day prior to withdrawal of 
blood samples for FPG and 2-hour PPG tests. 
Weekly basis (i.e. once every week) 
 
Every week for 4 time-points in a day (i.e. at fasting: 8-10 hours of overnight fasting, and 2-
hours post-breakfast, post lunch and dinner). All 4 time-points were measured on the same day 
Dispensing of subject diary 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Subject diary review and collection 
 
 
X 
X 
X 
X 
X 
X 
X 
 
Recording of AEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Recording of concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory investigations 
FPGn 
X 
 
Xl 
X 
X 
X 
 
X 
X 
 
2-hour PPGm 
X 
 
Xl 
Xl 
X 
X 
 
X 
X 
 
HbA1c 
X 
 
 
 
 
 
 
 
X 
 
Haematology – RBC 
X 
 
 
 
 
 
 
 
 
 
Hb, platelets, WBC with differential 
blood count 
 
 
 
 
 
 
 
 
 
 
Lipid profile: Total cholesterol, HDL, 
LDL, VLDL, and triglycerides after at 
least 12 hours of fasting 
 
X 
 
 
 
 
 
 
 
X 
 
Liver function tests- 
ALT, AST, ALP & Total bilirubin 
X 
 
 
 
 
 
 
 
X 
 


 
 
 
Page 6 of 37 
 
Study period 
Screening 
period 
Start 
of 
Treatment period 
Run-in period 
Treatment period 
Post- treatment 
Follow-up 
Visit Title 
Screening 
Randomization/ 
Enrolment visit 
Dose Escalation Visit(s) 
(only for subjects in Group B 
and Group C) 
Treatment visits for assigned 
dose group 
EOTa 
EOSb 
Visit # 
1 
2 
DE 1c 
DE 2d 
3 
4 
5 
6 
7 
8 
Group A 
(assigned dose 75 IU) 
Days -21 to 0 
Day 0 
N/A 
N/A 
8 
15 
30 
60 
85 
114 
Group B 
(assigned dose 150 IU) 
Days -21 to 0 
Day 0 
8 
N/A 
15 
22 
37 
67 
92 
121 
Group C 
(assigned dose 300 IU) 
Days -21 to 0 
Day 0 
8 
15 
22 
29 
44 
74 
99 
128 
Window period 
 
 
+ 2 days (applicable for 
both DE1 and DE 2 visits) 
+ 2 days (applicable at each visit) 
+ 2 days 
Renal function tests- Serum creatinine, 
BUN, eGFR, sodium, potassium, 
chloride 
 
X 
 
 
 
 
 
 
 
X 
 
Total protein 
X 
 
 
 
 
 
 
 
X 
 
A/G ratio 
X 
 
 
 
 
 
 
 
X 
 
Calcium, Phosphorus, Vitamin D, PTH 
X 
 
 
 
 
 
 
 
X 
 
Urine Pregnancy test (females of 
childbearing potential or ≤ 1 year 
postmenopausal prior to enrolment 
 
X 
 
 
 
 
 
 
 
X 
X 
Insulin antibody test 
X 
 
 
 
 
 
 
 
X 
X 
Urine analysis: Routine 
X 
 
 
 
 
 
 
 
 
 
Serology tests for HIV, HBV, HCV 
X 
 
 
 
 
 
 
 
 
 
12-Lead ECG 
X 
 
 
 
 
 
 
 
X 
 
AE: adverse event; A/G ratio: albumin to globulin ratio ALP: alkaline phosphatase; ALT: alanine aminotransferase; AST: aspartate aminotransferase; BP: blood pressure; 
BUN: blood urea, nitrogen; DE: dose escalation; ECG: electrocardiogram; eGFR: estimated glomerular filtration rate; EOT: end of treatment; FPG: fasting plasma 
glucose; HIV: human immunodeficiency virus; HBV: hepatitis B virus; HCV: hepatitis C virus; EOS: end-of-study; EOT: end-of-treatment, IP: investigational product; 
PPG: postprandial plasma glucose; PR: pulse rate; PTH: parathyroid hormone RR: respiratory rate; SAE: serious adverse event; T2DM: type 2 diabetes mellitus 
a: Visit 7 was the EOT visit. was conducted on the next day after the subject had completed twice daily administration of fixed assigned dose of IP for 12-weeks.  
b: Visit 8 was the EOS visit. It occurred at completion of 4-week post-treatment follow-up period 
c: It was applicable for Group B and Group C subjects d: It was applicable for Group C subjects only 
e: Review of eligibility criteria prior to randomization 
f: Review of MH and surgical details prior to randomization 


 
 
 
Page 7 of 37 
 
g: Review of any change in prior dose of metformin hydrochloride (non-IP) or prior medications 
h: Systolic and diastolic BP (mmHg), PR (beats/min), RR (breaths/min) were measured after the subject was in supine position for 5 minutes and body temperature (°F). i: 
For all groups USVCAP capsules were dispensed considering 75 IU dose, BD 
j: For Group B and C subjects USVCAP capsules were dispensed considering 150 IU dose, BD dose after reviewing the FPG and 2-hour PPG results. k For Group C 
subjects USVCAP capsules were dispensed considering 300 IU dose, BD after reviewing the FPG and 2-hour PPG results 
l: It was evaluated prior to dispensing doses at DE 1 and DE 2 visits m: Blood samples were collected 2-hours after meal 
n: Additional FPG measurements can be taken if capillary glucose measurements are abnormal, as defined in the protocol 
 


 
 
 
Page 8 of 37 
 
Description of Study Visits 
Visit 1/Up to 21 days  
The screening procedure and assessments started only after signing of the ICFs. A subject was 
enrolled within 21 days of performing procedures/investigations for screening. Upon obtaining 
the informed consent, the subjects were allocated a unique subject identification (Subject ID) 
number and were screened to confirm the eligibility for participating in this study. Subjects 
who fulfilled the eligibility criteria were randomized in the study, while subjects who did not 
fulfilled the eligibility criteria were termed as ‘screen failures’ 
The screening procedures and assessments were conducted as described below: 
• Informed consent procedure: Written and signed informed consent were obtained from 
all subjects prior to conduct of any study procedures. 
• Inclusion and exclusion criteria were checked 
• Recording of medical/surgical history including relevant details related to T2DM 
o Date of diagnosis of T2DM. If complete date was not available, the year and month 
was recorded. If month was not available, at least year of diagnosis was recorded 
o History of alcohol dependency/drug abuse and/or was a current alcohol/drug abuse 
dependent 
o History of smoking or tobacco chewing and/or was a current smoker/tobacco user 
• Recording of prior medication history (including current anti-diabetic medication, 
previous anti-diabetic therapy within 3 months prior to enrolment) 
• Collection of demographic information, including height (cm) 
• Recording of findings from physical examination 
o Recording of body weight (kg), waist circumference (cm) and body mass index 
(BMI) (kg/m2) 
o Recording of vital signs: Systolic BP (SBP) and diastolic BP (DBP) (mm/Hg), pulse 
rate (PR) [beats/min], respiratory rate (RR) [breaths/min] in supine position after 5 
minutes of rest and body temperature (degree Fahrenheit [°F]) 
• Laboratory investigations: 
o Blood samples were withdrawn from the subject to conduct the following 
laboratory investigations at a central laboratory: 
 Fasting Plasma Glucose 
 Postprandial plasma glucose (2-hours after meal) 
 HbA1c 
 Haematology: Red blood cells (RBCs) count, haemoglobin (Hb), platelet count, 
white blood cells (WBCs) count including differential count 
 Lipid profile: Total cholesterol, high density lipoprotein (HDL), low density 
lipoprotein (LDL), very low density lipoprotein (VLDL), and triglycerides after 
12 hours of fasting 
 Liver 
function 
tests: 
Alanine 
aminotransferase 
(ALT), 
aspartate 
aminotransferase (AST), Alkaline phosphatase (ALP), and total bilirubin 


 
 
 
Page 9 of 37 
 
 Renal function tests: Serum creatinine, blood urea nitrogen (BUN), sodium, 
potassium, chloride, and estimated glomerular filtration rate (eGFR) 
 Total protein & Albumin to globulin ratio (A/G ratio) 
 Calcium, phosphorus, vitamin D, Parathyroid hormone (PTH) 
 Serology tests: human immunodeficiency virus (HIV), hepatitis B virus (HBV), 
and hepatitis C virus (HCV) tests 
 Insulin Antibody test- Anti insulin antibody test 
o Urine samples were collected for: 
 Urine pregnancy test (UPT): Only for female subject of childbearing potential 
or who are ≤ 1 year postmenopausal prior to enrolment 
 Urinalysis: routine examination 
• Recording of 12 Lead electrocardiogram recording (ECG) 
• Recording of AE/ serious adverse events (SAEs), if any 
• Recording of concomitant medications, if any 
Visit 2 (Baseline Visit/ Randomization/ Enrolment Visit) 
The following procedures and assessments were performed at this visit: 
• Review of inclusion and exclusion criteria obtained during screening procedures and 
assessments 
• Review of medical and surgical history recorded at Visit 1 
• The following details were recorded at this visit: 
o Findings of physical examination 
o Body weight (kg) and waist circumference (cm) and body mass index (BMI) 
(kg/m2) 
o Vital signs: SBP and DBP (mmHg), PR (beats/min), RR (breaths/min) after 5 
minutes of rest and body temperature (degree Fahrenheit [°F]) in supine position 
o AE/SAE, if any 
o Prior and concomitant medications, if any 
• Training to perform capillary glucose measurements. (Appendix 16.1.13 for detail). 
• Subject randomization using IWRS (prior to dispensing of 1st dose of IP) 
• Dispensing of IP: The subjects were dispensed IP doses during the treatment period 
(including the run-in period) as per the dose required per allocated treatment groups 
(Group A, Group B or Group C). 
o At this visit only: All subjects randomised to Group A, B, and C were dispensed 
USVCAP capsules of dose strength 75 IU 
o Subjects randomised to Group A were prescribed 1 capsule of USVCAP (i.e. 
assigned fixed dose 75 IU, BD for 12 weeks) from next day (i.e. Day 1) after 
randomisation. They were instructed to visit the study site for their next scheduled 
visit (Visit 3 [Day 8 [+2 days]) 


 
 
 
Page 10 of 37 
 
o Subjects randomised to Groups B and C were prescribed 1 capsule of USVCAP 
(i.e. lower dose [75 IU BD] based on the assigned fixed doses - 150 IU, BD for 12 
weeks [Group B] and 300 IU, BD for 12 weeks [Group C]) from next day after 
randomisation (i.e. on Day 1). They were instructed to visit the study site for their 
next scheduled visit (Visit DE 1/Day 8 [+2 days]) 
o Subjects randomised to Group B and C were instructed to provide blood samples to 
evaluate FPG and 2-hour PPG levels prior to next scheduled visit (Visit DE 1) in a 
manner such that, results were available before the day of Visit DE 1 
• Accountability and compliance check 
o Dispensing of subject diary to record IP and non-IP dosing details, AEs (including 
hypoglycaemic episodes), capillary glucose measurements, details of hypoglycaemic 
episode, and change in concomitant medications 
Visit: Dose Escalation 1 (Visit DE 1, for Group B and Group C subjects) 
This visit was conducted only for the subjects who were randomized to treatment Group B and 
Group C. The following study procedures and assessments were done at this visit: 
• The following details were recorded at this visit: 
o Body weight (kg) 
o Recording of vital signs: SBP and DBP (mmHg), PR [beats/min], respiratory rate (RR) 
[breaths/min] in supine position after 5 minutes of rest and body temperature (°F) 
o Concomitant medications 
o AE/SAE, if any 
• Subject diary was collected and reviewed 
• Subject diary was dispensed 
• Accountability and compliance check of IP: 
o Accountability check was done by recording number of capsules dispensed to the 
subjects (as per the dose) versus number of capsules used and/or the number of 
capsules lost/destroyed in the accountability log and appropriate details were 
transcribed from log to eCRF 
o Compliance check was done by calculating number of capsules (as per dose 
dispensed) consumed by the subject versus total capsules required to be consumed 
• Review of FPG and PPG test result value prior to dispensing of IP 
• Dispensing of IP: 
o Subjects in Group B, after reviewing the data of fasting and PP glucose, were 
dispensed USVCAP capsules of dose strength 150 IU BD and were prescribed 1 
capsule of USVCAP (i.e. assigned fixed dose 150 IU, BD for 12 weeks) orally one 
hour prior to breakfast and dinner until the next scheduled visit. They were 
instructed to visit the study site for their next scheduled visit (Visit 3 [Day 15/+2 
days]) 
o Subjects in Group C, after reviewing the data of fasting and PP glucose, were 
dispensed USVCAP capsules of dose strength 150 IU and was prescribed 1 capsule 
of USVCAP (i.e. lower dose (150 IU, BD) based on the assigned fixed dose – 300 


 
 
 
Page 11 of 37 
 
IU, BD for 12 weeks) orally twice daily one hour before breakfast and dinner until 
the next scheduled visit. They were instructed to provide blood samples to evaluate 
FPG and 2-hour PPG levels prior to next scheduled visit (Visit DE 2) in a manner, 
such that results were available before the day of Visit DE 2. 
Visit Dose Escalation 2 (Visit DE 2, for Group C subjects only) 
This visit was conducted only for subjects who are randomized to treatment Group C and have 
completed DE visit 1. The following study procedures and assessments were done at this visit: 
• The following details should be recorded at this visit: 
o Body weight (kg) 
o Vital signs: SBP and DBP (mmHg), PR [beats/min], respiratory rate (RR) 
[breaths/min] in supine position after 5 minutes of rest and body temperature (°F) 
o Concomitant medications 
o AE/SAE, if any 
• Subject diary was collected and reviewed 
• Subject diary was dispensed at each visit 
• Review of FPG and 2-hour PPG test result value prior to dispensing of IP 
• Accountability and compliance check of IP 
o Accountability check was done by recording number of capsules dispensed to the 
subjects (as per the dose) versus number of capsules used and/or the number of 
capsules returned/lost/destroyed in the accountability log 
o Compliance check was done by calculating number of capsules (as per dose 
dispensed) consumed and number of capsules required to be consumed 
• Dispensing of IP: 
o Subjects in Group C, after reviewing the data of fasting and PP glucose, were 
dispensed USVCAP capsules of dose strengths 150 IU and was prescribed 2 
capsules of USVCAP (i.e. assigned fixed dose 300 IU, BD for 12 weeks) until next 
visit. Subject was instructed to visit the study site for next scheduled visit (Visit 3 
[Day 22/+ 2 days]) 
Visit 3 to Visit 6 
The following procedures and assessments were performed for all subjects in all 3 treatment 
groups at each visit from Visit 3 to Visit 6: 
The following details should be recorded at this visit: 
• Findings from physical examination 
• Body weight (kg), waist circumference (cm) and body mass index (BMI) (kg/m2) 
• Vital signs: SBP and DBP (mmHg), PR [beats/min], respiratory rate (RR) [breaths/min] 
in supine position after 5 min of rest and body temperature (°F) 
• AE/SAEs (including details of hypoglycaemic episode) 
• Concomitant medications 


 
 
 
Page 12 of 37 
 
• Subject diary was collected and reviewed at each visit (Visits 3 to 6) 
• Subject diary was dispensed at each visit (Visits 3 to 6) 
• Accountability and compliance check of IP 
o Accountability check was done by recording number of capsules dispensed to the 
subjects (as per the dose) versus number of capsules used and/or the number of 
capsules lost/destroyed in the accountability log 
o Compliance check was done by calculating number of capsules (as per dose 
dispensed) consumed by the subject versus total capsules required to be consumed 
• Laboratory investigations 
o Fasting plasma glucose (at Visits 3, 4 and 6 only) 
o 2-hours postprandial plasma glucose (at Visits 3, 4 and 6 only) 
• Dispensing of IP at Visits 3, 4, 5, and 6 as per the treatment groups: 
o Subjects in Group A were dispensed USVCAP capsules of dose strengths 75 IU at 
each visit up to Visit 6 and were prescribed 1 capsule of USVCAP (i.e. assigned 
fixed dose: 75 IU, BD) orally twice daily before breakfast and dinner at each 
scheduled visit until 1 day prior to next scheduled visit (i.e. Visit 7/Day 85 [+2 
days]) 
o Subjects in Group B were dispensed USVCAP capsules of dose strength 150 IU at 
each visit up to Visit 6 and were prescribed 1 capsule of USVCAP (i.e. assigned 
fixed dose: 150 IU, BD) orally twice daily before breakfast and dinner until 1 day 
prior to next scheduled visit (i.e. Visit 7/ Day 92 [+2 days]) 
o Subjects in Group C were dispensed USVCAP capsules of dose strength 150 IU at 
each visit up to Visit 6 and were prescribed 2 capsules of USVCAP (i.e. assigned 
fixed dose: 300 IU, BD) orally twice daily before breakfast and dinner until 1 day 
prior to next scheduled visit (i.e. Visit 7/ Day 99 [+2 days]) 
Visit 7 (End-of-treatment visit) 
This was the EOT visit for all subjects. It occurred on the next day after the subject had 
completed administration of twice daily doses of assigned fixed dose IP for 12 weeks. The 
following procedures and assessments were performed at this visit: 
• The following details should be recorded at this visit 
o Findings of physical examination 
o Body weight (kg), waist circumference (cm), and body mass index (BMI) (kg/m2) 
o Vital signs: SBP and DBP (mmHg), PR [beats/min], RR [breaths/min] in supine 
position after 5 min of rest and body temperature (°F) 
o Change in concomitant medications, if any 
o AE/SAE, (including details of hypoglycaemic episodes), if any 
o 12-lead ECG 
• Subject diary was collected and reviewed 
• Laboratory investigations: 


 
 
 
Page 13 of 37 
 
o Blood samples were withdrawn from the subject to conduct the laboratory 
investigations at central laboratory. 
 Fasting plasma glucose 
 2-hours PPG level 
 HbA1c level 
 Lipid profile: Total cholesterol, high density lipoprotein (HDL), low density 
lipoprotein (LDL), very low-density lipoprotein (VLDL), and triglycerides after 
12 hours of fasting 
 Liver function tests: ALT, AST, ALP and total bilirubin 
 Renal function tests: Serum creatinine, BUN, sodium, potassium, chloride, and 
eGFR 
 Total protein & A/G ratio 
 Calcium, phosphorus, vitamin D, PTH 
 Urine samples were collected for UPT, only for females of childbearing 
potential or who are ≤ 1 year postmenopausal prior to enrolment 
 Insulin Antibody test - Anti insulin antibody test 
Visit 8 (End-of-Study Visit) 
This was the EOS visit for all subjects. It occurred at completion of 4-weeks of post-treatment 
follow-up per the treatment group. The following procedures and assessments were performed 
at this visit: 
• The following details were recorded at this visit: 
o Findings from physical examination 
o Body weight (kg), waist circumference (cm), and body mass index (BMI) (kg/m2) 
o Vital signs: SBP and DBP (mmHg), HR [beats/min], RR [breaths/min] in supine 
position after 5 min of rest and body temperature (°F) 
o Change in concomitant medications, if any 
o AE/SAE, (including details of hypoglycaemic episodes) if any 
o Urine samples were collected for UPT, only for females of childbearing potential 
or who are ≤ 1 year postmenopausal prior to enrolment 
o Insulin Antibody test - Anti insulin antibody test 
Discussion of Study Design, Including Choice of Control Group 
The proposed oral formulation USVCAP addresses most concerns regarding delivery of insulin 
through oral route. USVCAP is a formulation containing recombinant human insulin and 
excipients. The excipients are added to promote absorption of active drug substance in jejunum. 
The technology used in the unique formulation, can enhance the passage of large molecules 
such as peptides, and proteins across the intestinal wall from lumen into the bloodstream. The 
formulation is stable and is designed in such a way that the dry powder dissolves rapidly in the 
liquid in the small intestine, bringing all components of the formulation (including peptides) in 
contact with the cell wall at the same time.11 


 
 
 
Page 14 of 37 
 
The rationale for combining insulin and oral drug therapy is derived from a better 
understanding of the pathophysiology of non-insulin dependent diabetes mellitus and of the 
mechanisms of action of the oral drugs: 
1) T2DM subjects are both insulin-deficient and insulin-resistant, thus requiring quite high 
doses of exogenous insulin 
2) Peripheral insulin delivery leads to hyperinsulinemia which could play a role in the 
pathogenesis of late diabetic complications; 
3) Metformin hydrochloride (by improving glucose metabolism and insulin sensitivity) 
and alpha-glucosidase inhibitors (by slowing down the digestion of complex 
carbohydrates and sucrose) are able to reduce the amounts of insulin needed to control 
postprandial hyperglycaemia15 
For subjects who fail to respond to the initial therapy, there are several agents that are available 
and can be used with metformin. Insulin is the preferred second-line medication for subjects 
with increased HbA1c or with symptoms of hyperglycaemia despite initial therapy with 
metformin and lifestyle intervention.6 Most recommendations agree that if HbA1c level is > 
8.5-9% irrespective of the dose of oral anti-diabetic drug (OAD), insulin should be initiated 
particularly in combination with metformin.16 The consensus statement by the American 
Association of Clinical Endocrinologists/ American College of Endocrinology (AACE/ACE) 
on the comprehensive T2DM management recommends insulin doses based on HbA1c levels 
(HbA1c < 8%; TDD: 0.1-0.2U/kg; HbA1c >8%; TDD: 0.2-0.3U/kg).17 
The current study was undertaken to generate evidence on the safety, efficacy and 
immunogenicity of USVCAP Formulation in Type 2 Diabetes Mellitus Subjects Uncontrolled 
with Metformin Hydrochloride Treatment in real world settings.  
The safety of USVCAP formulation in Type 2 Diabetes Mellitus Subjects Uncontrolled with 
Metformin Hydrochloride Treatment was determined by incidence and severity of treatment 
emergent adverse events (TEAEs) that occurred during the study period, including occurrence 
of hypoglycaemic episodes in each treatment group during the study period; and change in 
laboratory investigations post 12-week administration of USVCAP. Efficacy of the treatment 
was assessed by change in glycated haemoglobin (HbA1c) level post 12-week twice daily 
administration of selected fixed dose of USVCAP (75 IU, or 150 IU or 300 IU) from baseline, 
comparison of change in HbA1c between the 3 fixed dose levels studied to examine dose 
response relationship post 12-week administration of USVCAP and change in FPG and 2-hour 
PPG levels in each treatment group post 12-week administration of USVCAP. The 
immunogenicity was assessed by evaluating incidence of treatment-emergent antibody 
response (TEAR).  
Selection of Study Population 
Inclusion Criteria 
1. Male or female aged 35 to 60 years (both inclusive) 
2. Type 2 diabetes mellitus diagnosed < 2 years prior to enrolment 
3. Glycated haemoglobin level ≥ 7% and ≤ 9.5% 
4. On stable oral monotherapy with metformin hydrochloride (1000 mg to 2500 mg/day) 
and regular diet and exercise regimen at least 12 weeks prior to enrolment 
5. Body mass index between 18 to 30 kg/m2 
6. Ability to perform capillary blood glucose measurements 


 
 
 
Page 15 of 37 
 
7. Willing to provide informed and written consent for the clinical trial 
8. Able to comply with all requirements of clinical trial protocol 
Exclusion Criteria 
1. Subject with history or evidence of hypersensitivity to insulin or metformin 
hydrochloride or its excipients 
2. Suffering from type 1 diabetes mellitus 
3. Received treatment with sulphonylureas or alphaglucosidase inhibitors, Glucagon-like 
peptide-1 (GLP-1) receptor agonists or Sodium-glucose co-transporter 2 (SGLT2) 
inhibitors or meglitinides or pramlintide or thiazolidinediones within 3 months prior to 
enrolment 
4. Previously treated with insulin within 3 months prior to enrolment 
5. History of episodes of hypoglycaemia during 3 months prior to enrolment. 
6. Reduced 
awareness of hypoglycaemia or inability to identify and tackle 
hypoglycaemic episodes 
7. History of substantial weight loss defined as 5% decrease in body weight within the last 
6 months 
8. Medical history of unstable angina within 1 year prior to enrolment 
9. History of tobacco or nicotine more than two packs/day within 3 months prior to 
enrolment 
10. Is, at the time of signing informed consent, a user of recreational or illicit drugs or has 
had a recent history (within 1 year prior to enrolment) of drug or alcohol abuse or 
dependence. (Note: Alcohol abuse includes heavy alcohol intake as defined by >3 
drinks per day or >14 drinks per week, or binge drinking). 
11. History of gastrointestinal disorders which may potentially interfere with absorption of 
the IP 
12. Treatment 
with systemic corticosteroids or with inhalational corticosteroids 
(Beclomethasone or budesonide) within the 3 months prior to enrolment 
13. Likelihood of requiring treatment during the study period with prohibited medications 
mentioned (as defined in this clinical trial protocol) 
14. Female subject who is pregnant, lactating or planning pregnancy during the trial 
15. Female subject of childbearing age who is not willing to use adequate method of 
contraception during the study period 
16. Life expectancy of less than 6 months from screening 
17. Elective surgery or any other surgical procedure/s requiring general anaesthesia 
during the clinical trial 
18. Has participated in another research trial within 12 weeks prior to screening 
19. History of diabetic ketoacidosis requiring hospitalization within 6 months prior 
toenrolment, case of proliferative retinopathy or advanced neuropathy 
20. Subject having any of the following laboratory results at screening 
a. Estimated glomerular filtration rate (eGFR) <45 mL/min/1.73 m2 


 
 
 
Page 16 of 37 
 
b. Alanine aminotransferase (ALT) and/or Aspartate aminotransferase (AST) >3 times 
of upper limit normal 
c. Blood urea nitrogen (BUN) > 30 mg/dL 
21. Subject who has a positive serology for hepatitis B virus (HBV) or hepatitis C (HCV) 
or human immunodeficiency virus (HIV) infections at screening 
22. Subject who has undergone pancreatectomy or pancreas islet transplant or renal 
transplant 
23. Subject receiving or has received any immunomodulation medications within 1 year 
prior to enrolment 
24. Subject with history or evidence of diabetic complications (e.g. diabetic retinopathy, 
diabetic neuropathy, or diabetic nephropathy, etc.), cardiac disorders, or any other 
systemic complication due to diabetes, which in the opinion of the Investigator signifies 
subjects’ ineligibility for the trial 
25. Has any concurrent disease or medical/surgical condition, which required treatment of 
more than 3 months and which in the opinion of the Investigator does not allow 
participation of the subject in this study. 
Study Specific Discontinuation/Withdrawal Criteria 
The subjects could withdraw their consent to continue participation in the study without 
providing any reason, or the Investigator could decide in the interest of the safety of the subject 
to withdraw the subject from trial at any time during the study period. 
The subject was withdrawn from the study treatment or discontinued from the trial due to any 
one of the following reason: 
• Subjects’ voluntary withdrawal of consent 
• Protocol violation 
• Subject’s non-compliance to the administration of IP as per the protocol 
• Any AE or SAE requiring withdrawal of subject in the opinion of the Investigator 
• Requirement of prohibited concomitant medication 
• Requirement of dose reduction for both IP and non-IP 
• Study termination by the Sponsor 
• Study termination based on the advice by CDSCO or any other competent authority 
• Subjects who experience 2 or more than 2 episodes of hypoglycaemia within a day 
• Subjects diagnosed with uncontrolled hyperglycaemia as defined in the protocol 
The Investigator discussed with the subject, the most appropriate way to withdraw from the 
study to ensure the subject’s health and safety. The subject was called to visit the study site and 
all study assessments and procedures were performed as per the EOT visit (i.e. Visit 7) (Table 
3). In case of an ongoing SAE, the subjects were followed up till recovery or stabilization of 
SAE, whichever was appropriate without compromising on subject’s safety. 


 
 
 
Page 17 of 37 
 
STUDY TREATMENT OF SUBJECTS 
Treatment Administered 
• Group A: USVCAP 75 IU, BD for 12 weeks 
• Group B: USVCAP 150 IU, BD for 12 weeks 
• Group C: USVCAP 300 IU, BD for 12 weeks 
Investigational Product  
The investigational product, USVCAP was administered at doses 75 IU, 150 IU, and 300 IU, 
orally, twice daily. 
Dosage form: It was supplied by the sponsor as 75 IU and 150 IU capsules for oral 
administration. 
Dosage: Each subject allocated to treatment Groups A, B, or C received treatment with 
USVCAP IP as follows: 
For subjects randomized to Group A (USVCAP 75 IU BD for 12 weeks) administered the IP 
as follows: 
USVCAP 75 IU BD: Day 1 until Day 84 
For subjects randomized to Group B (i.e. USVCAP 150 IU BD for 12 weeks) and Group C 
(i.e. USVCAP 300 IU BD for 12 weeks): 
There was a run-in period/s of 1 week with each lower dose/s prior to initiation of the assigned 
fixed dose of USVCAP (Table 2). Upon completion of the run-in period/s, the subjects received 
the assigned fixed dose of USVCAP further for 12 weeks. 
The Investigator considered the dose increase for each subject in Group B and Group C only if 
there was no evidence of lack of tolerability with dose/s of IP prescribed during run-in period/s 
and that the safety of the subject was unlikely to be compromised after administration of 
subsequent higher dose/s of the IP. 
The dose increase at each DE visit was considered only after laboratory test results for FPG 
and 2-hour PPG levels were available to the Investigator. 
For subjects in Group B (USVCAP 150 IU BD for 12 weeks): 
• Run-in period 
o USVCAP 75 IU BD: Day 1 until Day 7 
• Treatment period 
o USVCAP 150 IU BD: Day 8 until Day 91 
For subjects in Group C (USVCAP 300 IU BD for 12 weeks): 
• Run-in periods 
o USVCAP 75 IU BD: Day 1 until Day 7: 75 IU BD 
o USVCAP 150 IU BD: Day 8 until Day 14 
• Treatment period 
o USVCAP 300 IU, BD: Day 15 until Day 98 


 
 
 
Page 18 of 37 
 
The USVCAP doses were administered as per the trial protocol until the EOT. The subjects 
were withdrawn from the trial if there was requirement for change in dose during the treatment 
period (including run-in period and/or assigned fixed dose period), due to any reason(s). 
Mode of administration: 1 hour before breakfast and dinner, orally with water 
Duration of Treatment:  
Treatment period: Each subject was treated with assigned fixed dose of USVCAP (Group A or 
Group B or Group C) for 12 weeks. 
Overall duration of treatment with IP (including run-in period/s): 
• Group A=12 weeks 
• Group B=13 weeks 
• Group C=14 weeks 
During the post-treatment follow-up period, subjects were advised treatment for T2DM as per 
standard treatment guidelines. 
Non-investigational Product 
It was metformin hydrochloride capsules 250 mg, 500 mg, 850 mg or 1000 mg doses. 
Dosage: Subjects continued their pre-study oral anti-diabetic monotherapy (i.e. metformin 
hydrochloride) as per pre-study dose and regimen from screening until the EOT, the dose 
adjustment for which, was not allowed during the entire treatment period. 
Mode of administration: Orally with water along with meals 
Duration of Treatment 
• Approximately 17-19 weeks based on the randomized treatment group (i.e. Group A, 
Group B, or Group C). 
Treatment during Post-Treatment Follow-Up Period: 
• During the post-treatment follow-up period, subjects were advised treatment for T2DM 
as per standard treatment guidelines 
Investigational Medicinal Product Handling and Accountability 
Dispensing, Packaging and Labelling 
The IP was supplied by the sponsor designee/pharmacist to the sites sufficiently, as required 
for all the subjects. The Investigator/designee dispensed the treatment to subjects as per the 
randomization codes assigned by IWRS. 
The dose and total number of capsule/s to be dispensed to the subject were as per the 
requirement of dosing at corresponding visit per each treatment group. The IP was supplied to 
the sites. 
The label of IP included with the following information, but not limited to: 
• Study Identification Code 
• Kit Code 
• Batch Number 
• Manufacturing Date 


 
 
 
Page 19 of 37 
 
• Expiry Date 
• Dose strength of each capsule 
• Quantity statement 
• Direction for Use 
• Storage Condition 
• The statement “For Clinical Trial Use Only” 
• Sponsor/Manufactured by 
The label of the box containing IP included with the following information but not limited to: 
• Study Identification Code 
• Kit Code 
• Batch Number 
• Manufacturing Date 
• Expiry Date 
• Quantity statement 
• Direction for Use 
• Storage Condition 
• Site Number 
• The statement “For Clinical Trial Use Only” 
• Sponsor/Manufactured by 
Handling, Storage, and Disposal 
Investigational product 
The IP was not used beyond the expiration date stamped on the label/box. Do not freeze or 
expose to excessive heat or direct sunlight. The IP was stored between 2° to 8°C (both 
inclusive). 
Study Drug Accountability Procedures 
The Investigator was responsible for the overall conduct of the study. Under no circumstances, 
the Investigator allowed the IP to be used other than as directed by study protocol. An accurate 
record of the receipt of IP from Sponsor/designee, dispensing of the IP to subject and return/lost 
or destroyed IP by the subject was maintained. Upon completion of the study, the used and/or 
unused IP capsules and other supplies (if any) were shipped to Sponsor for storage or 
destruction as per sponsor’s communication. 
Identity of Investigational Products 
The investigational product (IP) is USVCAP Formulation a solid oral dosage form in 
capsules. Each capsule contains IP in dose strengths 75 IU or 150 IU.  
Method of Assigning Patients to Treatment Groups 
One hundred and fifty-three (153) subjects were enrolled in the study. These subjects were 
randomized in a ratio of 1:1:1 to receive IP from any one of the following 3 treatment groups: 


 
 
 
Page 20 of 37 
 
• Group A: USVCAP 75 IU, BD for 12 weeks 
• Group B: USVCAP 150 IU, BD for 12 weeks 
• Group C: USVCAP 300 IU, BD for 12 weeks 
Eligible subjects were randomly assigned to any one of the above treatment groups by a 
randomization code generated by an interactive web response system (IWRS). 
The subjects were randomized in the study using permuted block randomization into 3 
treatment groups. The randomization list was prepared using a validated computer program, 
statistical analysis system® (SAS®) for Windows version 9.4/Proc PLAN (SAS® Institute Inc., 
Cary, NC, USA). An IWRS method containing randomization codes was used to randomize 
the eligible subject to the treatment groups. 
Selection of Doses in the Study 
The investigational product, USVCAP was administered at doses 75 IU, 150 IU, and 300 IU, 
orally, twice daily. 
Selection and Timing of Dose for Each Patient 
Each subject allocated to treatment Groups A, B, or C received treatment with USVCAP IP as 
follows: 
For subjects randomized to Group A (USVCAP 75 IU BD for 12 weeks) administered the IP 
as follows: 
USVCAP 75 IU BD: Day 1 until Day 84 
For subjects randomized to Group B (i.e. USVCAP 150 IU BD for 12 weeks) and Group C 
(i.e. USVCAP 300 IU BD for 12 weeks): 
Therewas a run-in period/s of 1 week with each lower dose/s prior to initiation of the assigned 
fixed dose of USVCAP (Table 2). Upon completion of the run-in period/s, the subjects received 
the assigned fixed dose of USVCAP further for 12 weeks. 
Blinding 
Not applicable as this is an open-label study. 
Maintenance of Study Treatment Randomization Codes 
Final randomization list and codes are kept strictly confidential and are filed securely by the 
independent biostatistician. The randomization codes were accessible only to authorized 
persons until completion of the study. 
Emergency Unblinding of an Individual Subject in the Study 
Not applicable as this is an open-label study. 
Medication(s)/Treatment(s) Permitted and Not Permitted Before and/or During 
the Study 
Prior medication 
All subjects were enquired for prior treatment/surgery at the time of screening: 
• Surgical and medical history (including T2DM history) were recorded 
• Relevant prior treatment (including and anti-diabetic treatment) was documented in the 
electronic case report form (eCRF). 


 
 
 
Page 21 of 37 
 
Concomitant Medications  
• All prescription and non-prescription medications received by the subjects during the 
study were recorded in the eCRF. Any concomitant medications/treatment taken by the 
subject for treatment of hypoglycaemia were also documented and recorded in the eCRF 
and subject diary, as appropriate. 
Medications/Treatments Permitted 
The following medications were permitted during the study: 
• Pre-study oral monotherapy with Metformin hydrochloride (at dose and regimen and 
documented at screening visit) 
• Any other non-prohibited medications deemed necessary for the well-being and safety 
of the subject was permitted. The Investigator took care that such a non-prohibited 
medication did not interfere the trial results. If such a medication was required, the 
subject was not enrolled or withdrawn from the study 
Subjects with inadequate glycaemic control 
Hypoglycemia: Study subject who had hypoglycaemia, needed immediate treatment for the 
safety of the subject. It was important for subject to recognize signs and symptoms of 
hypoglycemia. Subjects enrolled in the study were educated on signs and symptoms of 
hypoglycemia and were instructed to keep glucose tablets handy. To treat hypoglycaemia, 
they were instructed to immediately take 04 tablets of glucose (total 15- 20 grams of 
glucose). 
Capillary glucose level of < 70 mg/dL indicates hypoglycaemia. The Investigator specifically 
instructed the subjects to perform capillary glucose measurements in case they experienced 
any symptoms suggestive of hypoglycaemia. Such glucose measurements were to be 
preferably conducted prior to treatment/management of hypoglycaemic episode.After 15 
minutes of intake of glucose tablets, repeat capillary glucose measurement was to be done to 
check if the capillary glucose level was >70 mg/dL. If the capillary glucose level was still 
<70 mg/dl, then another 04 glucose tablets was be taken and capillary glucose measurement 
again taken after 15 minutes. Once capillary glucose level was above 70 mg/dL, the subject 
was required to consume a meal or snack to prevent recurrence of hypoglycaemia. 
Uncontrolled hyperglycaemia: Uncontrolled hyperglycaemia was diagnosed with either 
capillary glucose or plasma glucose measurements. 
Capillary glucose: Capillary glucose values of fasting > 95 mg/dL and 2 hours postprandial 
>126 mg/dL despite taking correct dose of study medication and regular diet was suggestive 
of uncontrolled hyperglycaemia. After a high capillary glucose measurement (as suggested 
above), subject was instructed to repeat capillary glucose measurements daily. After 03 
consecutive abnormal capillary glucose measurement value, subject called the Investigator to 
inform above the high glucose levels and got his/her advice. 
At each site visit, the Investigator reviewed the capillary glucose measurements recorded in 
the patient diary. If more than 60% of the capillary glucose measurement values taken since 
the last visit were more than the above stated value, then Investigator withdrawn the subject 
from the study and shifted to other hypoglycemic medication. 
Plasma glucose: When, in two consecutive plasma glucose measurements, the following 
fasting plasma glucose (FPG) values were noted: 
• From baseline to week 6 - >270 mg/dL 


 
 
 
Page 22 of 37 
 
• From week 6 to week 12 - >240 mg/dL 
Such subjects were withdrawn from the study & shifted to other anti-diabetic medication. 
Prohibited Medications 
The following were the prohibited medications during the study: 
• Any anti-diabetic treatment other than pre-study oral monotherapy with metformin 
hydrochloride 
• Systemic glucocorticoids and other drugs that are known to impact the glycaemic control 
• Any other drug/therapy which could affect implementation of the protocol difficult or 
interpretation of the trial results. 
Treatment Compliance 
Subjects were asked to return used and unused capsules of IP at each visit. The number of 
unused capsules received at each visit during the treatment period (except Visit 2), including 
number of capsules destroyed or lost at each visit were recorded in the IP accountability log. 
Compliance to study treatment at each visit was checked by reconciling the number of capsules 
required to be consumed and the number of capsules consumed at each corresponding visit. 
Overall treatment Compliance was calculated in terms of percentage as: 
 
 
Efficacy and Safety Measurements Assessment 
Efficacy Assessment 
Glycated Haemoglobin (HbA1c), Fasting Plasma Glucose (FPG) and Postprandial Plasma 
Glucose 
The efficacy assessments HbA1c, FPG and 2-hour PPG were assessed at the central laboratory 
identified for the study. 
It was performed as follows: 
• At screening to confirm the eligibility of the subject in the study 
• During the treatment period and at EOT to evaluate to assess the safety and the treatment 
response 
• At the EOS to evaluate the post-treatment safety of the subjects after twice daily 
administration of IP for 12 weeks 
The blood samples for HbA1c, FPG and 2-hour PPG were withdrawn from the subject for the 
following tests: 
• Glycated haemoglobin at Visit 1 and Visit 7 
• Fasting plasma glucose level under fasting condition i.e. at least 8–10 hours of 
overnight fasting at Visits 1, 3, 4, 6, and 7 for all subjects 
For Group B subjects: Prior to Visit DE 1 
For Group C subjects: Prior to Visit DE 1 and Visit DE 2 


 
 
 
Page 23 of 37 
 
• Postprandial glucose level (2-hours after meal) at Visits 1, 3, 4, 6 and 7 for all subjects.  
For Group B subjects: Prior to Visit DE 1 
For Group C subjects: Prior to Visit DE 1 and Visit DE 2 
• All samples were sent to central laboratory for evaluation. FPG and 2-hour PPG test 
results at Visit DE 1 and Visit DE 2 should be available prior to dosing. 
Capillary glucose measurements 
Capillary glucose measurements were performed by the subjects using a self-monitoring blood 
glucose device throughout the treatment period (from Visit 2 to Visit 7), once every week (mid-
week). 
During run-in period(s) (from Visit 2 to DE 1 [in Group B subjects] and from Visit 2 to Visit 
DE 1 and from Visit DE 1 to Visit DE 2 [in Group C] subjects), capillary glucose measurements 
were performed at mid-week. 
The capillary glucose measurements were performed at the following 4 time points: 
• Fasting: After 8 hours of overnight fast 
• 2-hours post-breakfast 
• 2-hours post-lunch 
• 2-hours post-dinner 
The measurements for all 4 timepoints were performed on the same day. All capillary glucose 
measurements were recorded by subject in the respective visit subject diary. 
Hypoglycemia 
It was important for subjects in the study to recognize signs and symptoms of hypoglycemia. 
Subjects enrolled in the study were educated on signs and symptoms of hypoglycemia and were 
instructed to keep glucose tablets handy & take 4 glucose tablets (total 15 -20 grams of glucose) 
immediately to treat hypoglycemia, if it occurs. 
Capillary glucose level of < 70 mg/dL indicates hypoglycaemia. The Investigator specifically 
instructed the subjects to perform capillary glucose measurements in case they experienced any 
symptoms suggestive of hypoglycaemia. Such glucose measurements were to be preferably 
conducted prior to treatment/management of hypoglycaemic episode. After 15 minutes of 
intake of glucose tablets, repeat capillary glucose measurement was to be done to check if the 
capillary glucose level was >70 mg/dL. If the capillary glucose level was still <70 mg/dl, then 
another 04 glucose tablets was be taken and capillary glucose measurement again taken after 
15 minutes. Once capillary glucose level was above 70 mg/dL, the subject was required to 
consume a meal or snack to prevent recurrence of hypoglycaemia. 
If more than two episodes of hypoglycemia occurred within a day (despite taking correct dose 
of study medication and regular diet), then the subject was advised to visit the site immediately 
for further medical management & was withdrawn from the trial. 
Uncontrolled hyperglycemia 
Capillary glucose: Fasting capillary glucose values which were more than 110% of the 1st 
fasting capillary glucose measurement value taken in the study, despite taking the correct dose 
of study medication and regular diet, was suggestive of uncontrolled hyperglycaemia. After a 
high capillary glucose measurement (as stated above), the subject was instructed to repeat 


 
 
 
Page 24 of 37 
 
capillary glucose measurements daily. After 03 consecutive high fasting capillary glucose 
measurement value, the subject called the Investigator to inform about the high glucose levels 
and got his/her advice. 
At each site visit, the Investigator reviewed the capillary glucose measurements recorded in the 
patient diary. If more than 60% of the fasting capillary glucose measurement values taken since 
the last visit were more than 110% of the 1st fasting capillary glucose measurement value, then 
Investigator took fasting plasma glucose (FPG) measurements (which could be routine as per 
the Schedule of Study Procedures and Assessments or additional test) and then based on the 
fasting plasma glucose value, decided on subject withdrawal. 
Plasma glucose: 
Confirmed diagnosis of uncontrolled hyperglycemia were made if the following fasting plasma 
glucose (FPG) values are noted: 
• From baseline to week 5 - >250 mg/dL 
• From week 6 to end of study - >220 mg/dL 
Such subjects were withdrawn from the study & shifted to other anti-diabetic medication unless 
the fasting plasma glucose measurements were equal to or less than the 1st fasting plasma 
glucose measurement taken in the study. 
Safety Measurements 
Adverse Events 
Definition of Adverse Event 
As per ICH-GCP, an AE is defined as “any untoward medical occurrence in a subject or clinical 
investigation subject administered a pharmaceutical product and that does not necessarily have 
a causal relationship with this treatment”. An AE can therefore be any unfavourable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of an IP, whether or not considered related to the IP (ICH E6: 1.2). 
All abnormal laboratory findings should be classified as “clinically significant” or “non-
clinically significant” by Investigator as per his clinical judgment. Only “clinically significant” 
abnormal laboratory values should be considered as an AE. 
Worsening of a pre-existing medical condition (e.g. hypertension) during the study period 
should be considered as an AE, if there is either an increase in severity, frequency, or duration 
of the condition or an association with significantly worse outcome. Pre-existing conditions 
recorded at screening that have not worsened during the study period are not considered AEs. 
Serious Adverse Event 
An SAE is defined as an AE at any dose fulfils one or more of the following criteria: 
• Results in death 
• Is life-threatening* 
• Requires hospitalization or prolongation of existing hospitalization* 
• Results in persistent or significant disability/incapacity 
• results in congenital anomaly/birth defect 
• Is an important medical event: important medical event in the definition of “serious” 


 
 
 
Page 25 of 37 
 
refers to those events which may not be immediately life-threatening, or result in death, 
or hospitalization, but from medical and scientific judgment may jeopardize the subject 
and/or may require medical or surgical intervention to prevent one of the other 
outcomes listed above. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions 
that do not result in hospitalization 
*NOTE: The term "life-threatening" in the definition of "serious" refers to an event in 
which the subject was at risk of death at the time of the event; it does not refer to an 
event, which hypothetically might have caused death if it were more severe. 
• Hospitalization is to be considered ‘only hospital stay’ for ≥ 24 hours. The following 
hospitalizations should not be reported as SAEs: 
• Hospitalization or prolongation of hospitalization needed for procedures required by 
the clinical trial protocol 
• Hospitalization or prolongation of hospitalization as part of a routine procedure 
followed by the centre 
• Hospitalization for a survey visit, annual physicals, or social reasons 
• Elective (pre-planned) hospitalizations for a pre-existing condition that had not 
worsened from baseline (e.g. elective or scheduled surgery arranged prior to start of the 
study) 
• Admissions not associated with an AE (e.g. social hospitalization for purposes of 
respite care) 
Methods and Timing for Assessing, Recording and Analysing Safety Parameters 
All AEs and SAEs were collected on eCRFs from the time the subject signs the ICF until the 
EOS. Any SAE that was ongoing at the time the subject exits the study was followed until the 
event was resolved or there was a satisfactory explanation, which qualified 1 of the following 
outcomes: 
• Resolved (With residual effects or without residual effects) 
• Death 
• Unknown (Despite adequate follow-up) 
Documentation and Reporting of Immediately Reportable Adverse Events 
All SAEs were recorded from the time the subject signed the ICF in the study until the EOS. 
All SAEs, regardless of causal relationship were reported by the site to sponsor/CRO, the 
Licensing Authority i.e. the Drugs Controller General of India, and the Chairman of Ethics 
Committee of the site within 24 hours of occurrence through Appendix XI of Schedule Y. 
• Follow-up information on an existing SAE was reported by the Investigator. 
Appropriate hospitalization or autopsy reports were made available, as applicable. All 
SAEs were followed-up until resolution (i.e., asymptomatic, stabilization of the event 
or death) 
• The Investigator and sponsor/CRO prepared and submitted a detailed analysed report 
of all the SAEs to the Head of the Institution where the trial was being conducted, to 
the Chairman of the Ethics Committee that accorded approval for conduct of the trial 
and the Licensing Authority within 14 days of occurrence of SAE (as per the Appendix 


 
 
 
Page 26 of 37 
 
XI of Schedule Y). 
• If the SAE resolved after the submission of the 14 days analysed report, the Investigator 
and sponsor/sponsor designee prepared and submitted a second analysed report upon 
resolution of the SAE 
Procedures for Eliciting Reports of and Reporting Adverse Event and Intercurrent Illnesses 
Eliciting, Documentation and Reporting of Adverse Events 
Information on AE was derived by questioning the subjects in general terms (e.g. "How do you 
feel?” or “How have you been feeling since the last questioning?” respectively), by subjects' 
spontaneous reports, by observation, or by reviewing subject’s diary. 
AEs were documented on the source documents and eCRFs. Trained study monitors checked 
the entries in the source documents. The AEs were followed-up until resolution or until its 
resolution or until it is judged to be permanent. If the subject was lost-to-follow up due to an 
AE, then the details of the AE was recorded as per the availability of the information from the 
subject. 
The AE was transcribed to the AE eCRF-pages. The following information was recorded for 
each AE: 
1. Description of the AE (verbatim term/diagnosis) 
2. Date of onset 
3. Date of resolution 
4. Severity 
5. Causality or relationship to the study medication 
6. Seriousness 
7. Action taken (with regards to IP) 
8. Other action (to treat the event) 
9. Outcome 
Rating of Adverse Events 
• The Investigator described severity, relatedness, and outcome of every AE. The severity 
of the AE was graded according to NCI-CTCAE version 4.0 on a five- point scale 
(Grade 1 to Grade 5). 
The duration of the event was described by the start date and end date. 
The causal relationship of an AE to the use of the IP was described in terms of related or not 
related to the IP, wherein related AEs included ‘Certain’, ‘Probable’ and ‘Possible’ and not 
related included ‘Unlikely’ and ‘Unassessable. 
Causality 
term 
Assessment criteria 


 
 
 
Page 27 of 37 
 
Certain 
• Event or laboratory test abnormality, with plausible time relationship 
to drug intake 
• Cannot be explained by disease or other drugs 
• Response to withdrawal plausible (pharmacologically, 
pathologically) 
• Event definitive pharmacologically or phenomenologically (i.e. an 
objective and specific medical disorder or a recognized 
pharmacological phenomenon) 
• Re-challenge satisfactory, if necessary 
Probable 
• Event or laboratory test abnormality, with reasonable
 
time relationship to drug intake 
• Unlikely to be attributed to disease or other drugs 
• Response to withdrawal clinically reasonable 
• Re-challenge not required 
Possible 
• Event or laboratory test abnormality, with reasonable
 
time relationship to drug intake 
• Could also be explained by disease or other drugs 
• Information on drug withdrawal may be lacking or unclear 
Unlikely 
• Event or laboratory test abnormality, with a time to drug intake that 
makes a relationship improbable (but not impossible) 
• Disease or other drugs provide plausible explanations 
Unassessable 
• Report suggesting an adverse reaction 
• Cannot be judged because information is insufficient or contradictory 
• Data cannot be supplemented or verified 
The outcome of all AEs were reported based on the following definitions, independent of 
whether they were serious or non-serious AEs, their severity, or their relationship to the IP: 
• Recovered: Fully recovered, or by medical or surgical treatment the condition has 
returned to the level observed at the first study related activity after the subject signed 
the informed consent 
• Recovering: The condition is improving, and the subject is expected to recover from 
the event. This term should only be used when the subject has completed the study 
• Recovered with sequelae: As a result of the AE, the subject suffered persistent and 
significant disability/incapacity (e.g. became blind, deaf, paralyzed) 
• Not recovered 
• Fatal 
• Unknown: This term should only be used in cases where the subject is lost to follow-
up 
Each AE was followed to satisfactory clinical resolution. 


 
 
 
Page 28 of 37 
 
Hypoglycaemic events 
Hypoglycaemia is the most common adverse reaction associated with insulins. The importance 
of symptomatic awareness of hypoglycaemia was explained to the subjects. Subjects and 
caregivers were educated to recognize and manage hypoglycaemia. Self-monitoring of blood 
glucose plays an essential role in the prevention and management of hypoglycaemia. Subjects 
were instructed to inform the study site in case of event of hypoglycaemia. Hypoglycaemic 
treatment and management was recorded separately in eCRF. See Appendix 16.1.13 for details. 
Vital Signs 
Vitals signs, including pulse rate (beats/min), respiratory rate (breaths/min), systolic and 
diastolic BP (mmHg), and body temperature (°F) was recorded at every study visit in supine 
position after 5 min of rest. Any abnormal vital signs judged by the Investigator as ‘clinically 
significant’ (except at screening) was considered as an AE and was recorded appropriately. 
Physical Examination 
A complete physical examination was assessed and recorded at every study visit, except Visit 
DE 1 and Visit DE 2. The physical examination comprised of total body examination including, 
general appearance, skin, head, eyes, ear, nose, throat, cardiovascular system, respiratory 
system, breast examination, lymphatic system, neurological examination, gastrointestinal 
system, musculoskeletal system, urogenital system, and other, as applicable. Any abnormal 
physical examination findings judged by the Investigator as ‘clinically significant’ (except at 
screening) were considered as an AE and was recorded appropriately.  
12-Lead Electrocardiogram 
A standard 12-Lead ECG was performed at screening (Visit 1) and Visit 7. Interpretation of 
the tracing was done by the Investigator and was documented on the ECG eCRF page, 
appropriately. Each ECG tracing was labelled with the protocol number, subject initials (where 
regulations permit), subject number, date, and was kept as a source document at the study site. 
A photocopy or digitally scanned copy of the tracing was also stored and labelled with protocol 
number, subject initials (where regulations permit), subject number, date. Any abnormal 
findings judged by the Investigator as ‘clinically significant’ (except at screening) were 
considered as an AE and were recorded appropriately. 
Laboratory Investigations 
All laboratory investigations were performed at the central laboratory. During each scheduled 
blood collection visit, the subject should visit the study site under fasting condition i.e. at least 
8 – 10 h of overnight fasting. At any time during the study (except at screening), abnormal 
laboratory parameters which are clinically relevant (e.g., require dose modification and/or 
interruption of study treatment, lead to clinical symptoms or signs, or require therapeutic 
intervention), whether specifically requested in the protocol or not, were recorded on the AE 
eCRF page. 
Blood samples were withdrawn from the subjects and the following laboratory investigations 
were performed at central laboratory:  
• At Visit 1 and Visit 7 
o Glycated haemoglobin (HbA1c) 
o Lipid profile: total cholesterol, HDL, LDL, and triglycerides after 12 hours of 
fasting 
o Liver function tests: ALT, aspartate AST, total bilirubin 


 
 
 
Page 29 of 37 
 
o Renal function tests: Serum creatinine, BUN, sodium, potassium, chloride, and 
eGFR. Serology tests: human immunodeficiency virus, hepatitis B virus, and 
hepatitis C virus tests (only at Visit 1) 
• At Visit 1, 7 and 8 
o Urine samples were collected for: Urine pregnancy test (UPT): Only for females 
of childbearing potential or who are ≤ 1 year postmenopausal prior to enrolment  
• At Visits, 1, 3, 4, and 6: 
o Fasting plasma glucose level (also prior to dosing at Visit DE 1 and DE 2); 
o 2-hour PPG level (also prior to dosing at Visit DE 1 and DE 2) 
• At Visit 1 only: 
o Haematology: RBCs count, Hb, platelet count, WBCs count including differential 
count (only at Visit 1) 
o Serology tests: human immunodeficiency virus (HIV), hepatitis B virus (HBV), 
and hepatitis C virus (HCV) tests 
o Urinalysis: routine examination (also at Visit 8) 
o Urine samples were collected for the following tests 
o At Visit 1, 7, and 8: Urine pregnancy test (UPT): Only for females of childbearing 
potential or who are ≤ 1 year postmenopausal prior to enrolment 
o At Visit 1 only: Urinalysis: routine examination 
Any additional laboratory tests if required during the study period could be done at local 
accredited laboratory. 
Immunogenicity Assessment: Insulin Antibody test - Anti-insulin antibody 
(AIA) 
The immunogenicity of the IP was assessed using validated assays. Blood samples (1 x 3.5 
mL) were collected at screening visit (Visit 1), End of treatment visit (Visit 7) and Post 
treatment follow-up visit (Visit 8) for testing presence of anti-insulin antibodies to the IP. The 
procedure for sample handling, storage and analysis was provided in the central laboratory 
manual. 
Emergency Contact 
In case of any emergency, the site contacted the medical monitor from the CRO. The medical 
monitor provided guidance in case of any emergency related to safety of the subject. 
Other Study Assessment 
Body Weight, Waist circumference and Body mass index 
Body weight was measured at every study visit in kg. Body mass index (BMI) (kg/m2) and 
waist circumference (cm) was calculated at all study visits, except Visit DE 1 and Visit DE 2. 
Body mass index (BMI) was calculated by formula: 
𝐵𝐵𝐵𝐵𝐵𝐵= 𝑊𝑊𝑊𝑊𝑊𝑊𝑊𝑊ℎ𝑡𝑡 (𝑘𝑘𝑘𝑘)
ℎ𝑒𝑒𝑒𝑒𝑒𝑒ℎ𝑡𝑡2 (𝑚𝑚)2 


 
 
 
Page 30 of 37 
 
Appropriateness of Measurements 
All clinical measurements were performed using standard methods that were generally 
recognized as being reliable, accurate, and relevant. 
Primary Variable(s):  
Efficacy Assessment: 
• Glycated haemoglobin (HbA1c) 
• Fasting plasma glucose (FPG) 
• 2-hour post prandial plasma glucose (2-hour PPG) 
Safety Assessments: 
• AEs and SAEs (serious and non-serious AEs) were collected for relatedness, severity, 
seriousness, and outcome, including events of hypoglycaemia were collected once the 
signed informed consent was obtained from the subject 
• Vital signs: Pulse rate (PR), respiratory rate (RR), systolic blood pressure (BP) and 
diastolic BP (in supine position after 5 minutes of rest), and body temperature (at all 
visits) 
• Physical examination 12-Lead electrocardiogram (ECG) 
• Laboratory investigations: 
o Lipid profile: Total cholesterol, high density lipoprotein (HDL), low density 
lipoprotein (LDL) very low-density lipoprotein (VLDL) and triglycerides after at 
least 12 hours of fasting 
o Liver function tests: ALT, AST, and total bilirubin 
o Renal function tests: serum creatinine, eGFR, sodium, potassium, chloride, and 
BUN 
o Urine pregnancy test (UPT): Only for female subjects who are of childbearing 
potential or who are ≤ 1 year postmenopausal prior to enrolment in the study. 
The Investigator described severity, relatedness, and outcome of every AE. The severity of 
the AE was graded according to NCI-CTCAE version 4.0 on a five- point scale (Grade 1 to 
Grade 5). 
https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03/Archive/CTCAE_4.0_2009-05-
29_QuickReference_8.5x11.pdf 
Secondary variable(s):  
Immunogenicity Assessments 
• Insulin Antibody test: Anti-insulin antibody (AIA) 
Pharmacovigilance-Relevant Information 
Not Applicable. 
 
 
 


 
 
 
Page 31 of 37 
 
Data Quality Assurance 
Audits and Inspections 
Not applicable. 
Data Handling 
The Investigator maintained all documentation relating to this study. Essential documents (as 
defined in the ICH-GCP) are retained until at least 2-years after the last approval of a marketing 
application in an ICH region, and until there were no pending or contemplated marketing 
applications in an ICH region or at least 2-years have elapsed since the formal discontinuation 
of clinical development of the IP. These documents must be retained for a longer period, 
however, if required by the applicable regulatory requirement(s) or if needed by sponsor. 
In any case, all study records are for at least 5 years after the completion or discontinuation of 
the study. The Investigator notified sponsor or its designee of any changes in the archival 
arrangements, including but not limited to archival at an off-site facility, transfer of ownership 
of the records in the event the Investigator left the site. Sponsor notified the Investigator in 
writing when the study-related records were no longer needed. 
 
 


 
 
 
Page 32 of 37 
 
Statistical Methods Planned in the Protocol and Determination of 
Sample Size 
The following is an outline of the statistical methodology that was used to report and analyse 
this study. A more detailed description is provided in a separate statistical analysis plan (SAP) 
that includes additional exploratory analysis not explicitly mentioned in the following sections. 
Study Analyses Sets 
The analyses was performed on the following trial populations. 
• Randomized population: The randomized population consisted of all subjects who were 
randomized in the study 
• Safety population: The safety population consisted of all subjects who were randomized 
and had received at least one dose of the IP. 
• Full Analysis Population: The full analysis set population consists of all the subjects 
who are randomized into the study, received at least one dose of the IP from the 
assigned dose by randomization, and had at least one post baseline assessment. 
• Per Protocol (PP) population: The per-protocol (PP) population was all the subjects in 
the FAS population who had completed the study and did not had any major protocol 
deviation. 
Demographic and Other Baseline Characteristics 
The demographic variables such as age, gender, ethnicity, body weight and height etc. and 
baseline status (medical history, physical exam, etc.) was summarized for both PP and full 
analysis populations. 
The descriptive statistics for continuous variables were presented with number (n) of non- 
missing observations, missing observations, Mean, Standard Deviation (SD), Median, 
Minimum and Maximum. For categorical data, descriptive statistics were presented with 
number of exposed subjects, and number (N) with percentage of observations in the various 
categories of the endpoint, where percentage were based on the exposed subjects. 
Descriptive statistics were provided for body weight, waist circumference and BMI parameters. 
In addition, individual results were reviewed for any treatment-emergent changes of possible 
clinical significance. 
Prior and concomitant medications were coded using the standard WHODD dictionary prior to 
analysis. Counts and percentages were presented by drug class and generic term for descriptive 
summarization. 
Efficacy Analyses 
Primary Analysis 
The primary endpoint was change in HbA1c level post 12-week administration of selected 
fixed dose of USVCAP (75 IU, or 150 IU or 300 IU) from baseline visit within each treatment 
group. The actual measurement of efficacy endpoint was summarized using number of subjects 
(n), mean, SD, median, and minimum and maximum (range) and 95% confidence interval (95% 
CI) for each treatment group at both baseline and EOT (End of treatment) visits along with 
change from baseline to EOT for each treatment group. 


 
 
 
Page 33 of 37 
 
The statistical analysis for the primary endpoint were carried out to compare the change in 
HbA1c post 12-week administration of selected dose of USVCAP from baseline visit within 
each of the 3 dosing groups by using paired t-test. 
In addition to evaluate primary efficacy within each randomly assigned groups as planned, we 
also evaluated a subgroup analysis on those patients who had uncontrolled hyperglycaemia and 
those who had not to see the robustness of the data on primary efficacy parameter. 
Secondary Analysis 
The secondary endpoint of comparing the change in HbA1c post 12-week administration of 
USVCAP from baseline between the 3-fixed dose groups to examine the dose response 
relationship between them; analysis of covariance (ANCOVA) with dose groups (treatment 
groups), visit and interaction between visit and treatment as factors and baseline HbA1c value 
as covariates using Proc mixed was used. ANCOVA model determined the statistically 
significant difference between different dose groups on change in HbA1c from baseline to 12-
week treatment with USVCAP, controlling for the effect of the baseline HbA1c value as 
covariate. Also, applying same ANCOVA model and coefficient estimate for dose factor, 
further pairwise comparisons of the three experimental dose levels for change in HbA1c post 
12-week treatment with USVCAP examined the dose response relationship. 
Similarly, ANCOVA model were also applied to analyze the change in fasting and postprandial 
plasma glucose in each treatment group. 
Details of the analysis were provided in statistical analysis plan. 
Safety Analysis 
In this trial, safety analysis was used to perform the safety population (defined above). All 
safety endpoints were analysed based on descriptive statistics as described above for 
continuous and categorical variables and presented visit wise. The analysis of safety 
assessments in this study included summaries of the following categories of safety data 
collected for each subject. 
• Adverse events (AEs) 
• Physical examination 
• Vital signs 
• 12-lead ECG 
• Laboratory investigations 
Adverse Events 
AEs and SAEs were coded by 20.1 version of MedDRA body system and preferred term and 
tabulated by indicating number and percentage of subjects and number of events. All the AEs 
were listed and categorized as TEAE and SAE before dosing and after dosing. All AEs, which 
occur after the first dose of the IP, were categorized as TEAEs i.e. AEs with onset date on or 
after the first dose of the IP. The TEAEs were tabulated and summarized for each treatment 
group as; overall TEAEs experienced by subjects during the study, TEAEs experienced by 
subjects during run-in period/s and TEAEs experienced by subjects during treatment with 
actual assigned dose of IP. All AEs were collected, evaluated and tabulated by system organ 
class (SOC), preferred term (PT), date of onset, relationship to the test drug, seriousness, 
severity, frequency, action taken, and outcome for each treatment group. Narratives of all SAEs 


 
 
 
Page 34 of 37 
 
were presented. AE were compared between treatment groups by using Chi square/Fisher’s 
exact test. 
Vital Signs 
Descriptive statistics were provided by treatment group for PR, RR, systolic and diastolic BP, 
and body temperature, etc. The vital signs were generated by visit as absolute values and the 
change from baseline were recorded. In addition, individual results were reviewed for any 
treatment-emergent changes of possible clinical significance. 
Physical Examination 
Descriptive statistics were provided by treatment group for each body system and the change 
from baseline were also recorded. 
12-Lead Electrocardiogram 
Descriptive statistics were provided. In addition, individual results were reviewed for any 
treatment-emergent changes of possible clinical significance. 
Laboratory Assessments 
Descriptive statistics were provided by treatment group for each clinical laboratory parameter 
and the change from baseline were also recorded. In addition, individual results were reviewed 
for any treatment-emergent changes of possible clinical significance. 
Concomitant Medications 
Summary tables were provided for prior/concomitant medications in the study. 
Immunogenicity analyses 
Partial correlation was used to measure the relationship between the percent change in HbA1c 
and percent change in anti-insulin antibodies with absolute change in total insulin dose as 
covariate from baseline to Visit 7 and Visit 8. Change in level of serum anti-insulin antibodies 
from baseline to Visit 7 and Visit 8 were compared through paired t-test within each treatment 
arms. 
Statistical Significance 
The level of significance in the primary analysis were set to 5%. The analyses was performed 
upon completion of the main trial period. All secondary analyses were also be performed at the 
5% significance level. 
Replacement of Subjects 
The subject who discontinued from trial/withdrawn from the study treatment were not replaced. 
Withdrawn Subject Data Collection 
The subject could withdraw their consent from the trial, or this could be the Investigator’s 
decision to discontinue the subject from trial; if they decided to do so, at any time and 
irrespective of the reason all efforts should be made to document the reason for treatment 
withdrawal/discontinuation from the trial (see section 11.5.1) and this should be documented 
in the e-CRF. 
The Investigator/designee involved in the study documented the reason for the subject 
withdrawal as follows: 
Subject’s voluntary withdrawal of consent 


 
 
 
Page 35 of 37 
 
Subject’s non-compliance to the IP: Repeated missing of study medication doses 
Protocol violation: Repeated non-follow-up for safety or efficacy procedures required for the 
study. Protocol violation may be also considered when the subject is not included as per 
protocol-defined eligibility criteria. 
Any AE or SAE requiring subject withdrawal in the opinion of the Investigator: An AE form 
must be completed. Clinically significant abnormal value not explained by a laboratory error 
or being not a known or abnormal value commonly observed in this type of population was 
also considered as an AE or SAE, and recorded on AE form as applicable. 
Requirement of prohibited medication: Recording of the details of prohibited medication were 
completed on the concomitant medication CRF page and the subject were withdrawn from the 
study. 
Requirement of dose reduction for both IP and non-IP: If there was requirement for change in 
dose of the IP (which is not mentioned in the protocol) or non-IP at any point of time during 
the study period, the subject were withdrawn from the study. 
Study termination by Sponsor: Upon notification of the sponsor for termination of the study 
Study termination based on the advice by CDSCO or any other competent authority: If the 
regulatory authority(ies) directly connects to the site/CRO to terminate the study, the same was 
immediately done by the Investigator/information were communicated to the sites. The CRO 
must notify the site regarding such communications. In case of communications directly 
reaching the Investigator, the Investigator must inform the CRO designee (e.g. study site 
monitor) or both Sponsor designee and CRO designee 
Any, other reason: If none of the above-mentioned reasons are applicable, then the reason for 
subject withdrawal were mentioned; “any other reason” and the reason were specified on the 
eCRF page. In case of pregnancy, the subject’s study treatment must permanently stop and 
study discontinuation and early withdrawal procedures should be conducted. 
Determination of Sample Size 
It was estimated that 52 evaluable subjects per dose group were needed to be enrolled in each 
treatment group assuming a reduction of 0.5 in HbA1c, common standard deviation (SD) of 
1.0 at baseline and at Week 12 in each dose group with 90% power and 2.5% level of 
significance. However, 13 extra subjects, accounting for 65 subjects per group in total were 
enrolled into this study with an aim to compensate for an estimated drop-out rate of 20%. Thus, 
a total number of 195 subjects were to be randomly assigned to either of the three dose 
(treatment) groups in this study in the ratio of 1:1:1. The detailed description of sample size 
calculation is represented in the table below: 
Single Mean - Paired t-test 
Pre-test mean 
7.5 
Post-test mean 
7 
Mean Difference from Pre-to Post test 
0.5 
Standard deviation in Pre-test 
1 
Standard deviation in Post-test 
1 
Effect size 
0.5 
Power (%) 
90 
Alpha Error 
2.5 
1 or 2 sided 
2 
Minimum required sample size for each selected fixed dose treatment 
52 


 
 
 
Page 36 of 37 
 
group 
Minimum required sample size for all three-selected fixed dose treatment 
groups 
156 
Considering 20% drop-out, required sample size for each selected fixed 
dose treatment group per 
65 
Considering 20% drop-out, required sample size for all three-selected 
fixed dose treatment groups 
 
195 
Missing Data 
The missing observations were imputed using Last Observation Carried Forward (LOCF) 
appropriately. 
Procedures for Reporting Deviations from Original Statistical Plan 
Any post-hoc, or unplanned, analyses not identified in SAP were clearly identified in the 
respective clinical study report (CSR). 
Change in Conduct of the Study and Planned Analysis 
Changes in Conduct of the Study 
Following changes were made in conduct of study due to COVID-19 pandemic and nationwide 
lockdown implemented by Government of India: 
• The home visits were arranged by investigator sites for laboratory sampling. The 
samples were processed in local hospital labs or central lab’s local centres.  
• Due to home visit physical examination and vital sign were not performed for these 
subjects and protocol deviations were filed. 
• Telephonic contacts by the site team was done to record the AEs, concomitant 
medications and subject’s clinical status as an alternate option to clinical visit. The 
participants whose blood samples were collected (hospital visit/home visit) within the 
one week of window period, were considered in the per-protocol population. 
For site No. 20, the protocol approval was received however site initiation visit was not done 
because of nation-wide lockdown by the government of India due to COVID-19 Pandemic. 
Change in Planned Analysis 
Not applicable. 
 
 


 
 
 
Page 37 of 37