Conditions: Type2 Diabetes Mellitus
Keywords: Oral insulin
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 143
Healthy volunteers: no

Brief summary:
This is an open label Phase II/III study to evaluate the efficacy and safety of test drug, Insulin Tregopil (IN-105) compared with Insulin Aspart (IAsp) in Type 2 Diabetes Mellitus patients. on stable dose of Metformin and insulin Glargine. The study will be conducted in 2 parts, Part I and Part II. The study duration will be approximately 37 weeks for Part I and for Part II of the study respectively

Detailed description:
Part I of the study is a Phase II multi-center, randomized, open label clinical study to evaluate the efficacy and safety of Insulin Tregopil (2 dose levels: 30 mg, 45 mg) compared with IAsp in the treatment of T2DM patients. Part II of the study is the Phase III, multi-center, randomized, open label clinical study to evaluate the efficacy and safety of Insulin Tregopil (30 mg or 45 mg based upon the outcome of Part I data) compared with IAsp in the treatment of T2DM patients. For Part I and Part II, the study duration will be approximately 37 weeks (3 weeks Screening, 8 weeks Run-in, 24 weeks Treatment, 2 weeks Safety follow-up). An Independent Data and Safety Monitoring Board (DSMB) will evaluate the data from Part I of the study. Part II of the study will be initiated after approval from the office of Drugs Controller General of India (DCGI) and Data Safety Monitoring Board (DSMB) recommendation based on review of data from Part I of the study. In both Part I and Part II of the study, T2DM patients with glycated hemoglobin (HbA1c) 7.5 to 10% (both inclusive), on stable dose of metformin ± oral antidiabetic drugs (OADs) ± basal insulin who are eligible for insulin glargine administration as per investigator discretion and who satisfy the selection criteria will be enrolled. The eligible patients will go through a Run-in period of 8 weeks. At the end of 8 weeks Run-in period, eligibility will be checked and patients will enter the treatment period of 24 weeks and will be allocated to 3 treatment arms (Part I) or randomized to 2 treatment arms (Part II); if found eligible for randomization. A total of 90 patients in part 1 and 268 patients in part 2 will be randomised to the treatment arms from approximately 40 centers in India.

Arms:
arm 1: Strength of each tablet is 15mg arm 2: Strength of each tablet is 15mg arm 3: Pre-filled pen: 100 U/L

Interventions: intervention 1: Insulin Tregopil intervention 2: Insulin Aspart
Intervention descriptions: intervention 1: Drug: Insulin Tregopil (IN-105) Mode of Administration: To be administered orally 10 ± 2 minutes prior to each major meal (breakfast, lunch and dinner) starting at the Randomization visit. intervention 2: Drug: Insulin Aspart Mode of Administration: To be administered within 5 minutes prior to each major meal (breakfast, lunch and dinner) starting at the Randomization visit

Protocol document:
Prot_SAP_000.pdf: 
Sponsor: Biocon Limited 
Protocol Number: TREGO-DM2-03-I-01
Drug Name: Insulin Tregopil (IN-105) 
Version 3.0
21 May 2018
Confidential
Page 1 of 12 
 
 
 
SYNOPSIS 
 
Name of Sponsor/Company: 
Biocon Limited 
Name of Finished Product: 
Insulin Tregopil (IN-105) Tablets 
Name of Active Ingredient: 
Methoxy triethylene glycol propionyl–insulin. 
Title of Study: An Open Label, Multi-center, Randomized, Parallel Group Phase II/III Clinical Study to
Evaluate the Efficacy and Safety of Insulin Tregopil (IN-105) Compared with Insulin
Aspart in the Treatment of Patients with Type 2 Diabetes Mellitus on Stable Dose of 
Metformin and Insulin Glargine. 
Protocol No: 
TREGO-DM2-03-I-01 
Study centers: 
The study will be conducted at approximately 40 centers in India. 
Study duration: The study duration will be ap
Part I and for Part II of the study. 
proximately 37 weeks for 
Phase: II/III 
Part I 
Primary Objective 
To compare the efficacy of 2 doses of Insulin Tregopil versus Insulin Aspart (IAsp) in Type 2 Diabetes Mellitus 
(T2DM) patients who are on stable dose of metformin and insulin glargine. 
Secondary Objective 
To compare the safety of 2 doses of Insulin Tregopil versus IAsp in T2DM patients who are on stable dose of 
metformin and insulin glargine. 
Part II 
Primary Objective 
To compare the efficacy of Insulin Tregopil versus IAsp in T2DM patients who are on stable dose of metformin 
and insulin glargine. 
Secondary Objective 
To compare the safety of Insulin Tregopil versus IAsp in T2DM patients who are on stable dose of metformin 
and insulin glargine. 
Exploratory Objective 
To evaluate the additional glycemic variables and cardiovascular outcomes of Insulin Tregopil and IAsp in 
T2DM patients who are on stable dose of metformin and insulin glargine. 
Methodology: The study will be conducted in 2 parts, Part I and Part II. Part I of the study is a Phase II 
multi-center, randomized, open label clinical study to evaluate the efficacy and safety of Insulin Tregopil 
(2 dose levels: 30 mg, 45 mg) compared with IAsp in the treatment of T2DM patients. Part II of the study is
the Phase III, multi-center, randomized, open label clinical study to evaluate the efficacy and safety of Insulin
Tregopil compared with IAsp in the treatment of T2DM patients. For Part I and Part II, the study duration will
be approximately 37 weeks (3 weeks Screening, 8 weeks Run-in, 24 weeks Treatment, 2 weeks Safety
follow-up). An Independent Data and Safety Monitoring Board (DSMB) will evaluate the data from Part I of
the study. Part II of the study will be initiated after approval from the office of Drug Controller General of 
India and DSMB recommendation based on review of data from Part I of the study. Additionally, evaluation
of data by DSMB will be performed during Part II of the study. Further details of the DSMB meetings including
frequency of meetings for evaluation of data will be provided in the Statistical Analysis Plan (SAP)/DSMB
charter. 
In both Part I and Part II of the study, T2DM patients with glycated hemoglobin (HbA1c) 7.5 to 10% (both
inclusive), on stable dose of metformin ± oral antidiabetic drugs (OADs) ± basal insulin who are eligible for
insulin glargine administration as per investigator discretion and who satisfy the selection criteria will be
enrolled. The eligible patients will go through a Run-in period of 8 weeks. At the time of enrollment into the
Run-in period, all OADs except stable dose of metformin will be discontinued; insulin glargine will be
administered subcutaneously. The Run-in period will have an initial 4 weeks of insulin glargine dose titration 


Sponsor: Biocon Limited 
Protocol Number: TREGO-DM2-03-I-01
Drug Name: Insulin Tregopil (IN-105) 
Version 3.0
21 May 2018
Confidential
Page 2 of 12 
 
 
 
period and subsequent 4 weeks of dose stabilization period. The patients who are already on a basal insulin 
will be switched over to/continued on insulin glargine and those who are insulin naïve will be started on insulin 
glargine. Initiation and titration of insulin glargine dose will be instructed to the patient by 
investigator/designee as per the titration algorithm and/or as per the investigator judgement wherein the 
deviation in dose from the recommended titration algorithm must be documented and explained. The titration 
will be monitored by a centralized titration review team and such deviations will be evaluated by the titration 
review team to conclude if the explanation is agreeable or a protocol deviation needs to be reported. Additional 
1 week (i.e., up to 5 weeks) of titration is permitted, however, the total duration of Run-in period should not 
be extended beyond 8 weeks. 
At the end of 8 weeks Run-in period, patients will enter the treatment period of 24 weeks and will be allocated 
(randomization by minimization method) to 3 treatment arms (Part I) or randomized to 2 treatment arms 
(Part II); if found eligible for randomization according to the following randomization criteria: HbA1c ≥ 7% 
and ≤ 9%, fasting plasma glucose (FPG) ≤ 140 mg/dL, 2-hour post-prandial glucose (PPG) ≥ 180 mg/dL after 
standardized test meal evaluated at central laboratory, and acceptable compliance as concluded by the 
investigator discretion, and based on the specified compliance criteria. The blood sample for randomization 
criteria assessment will be drawn at the Day -7 visit. Any new information received during the Run-in period 
indicating ineligibility of the patient based on selection criteria will result in exclusion of the patient from 
randomization into the treatment period. Randomization will ensure an equal distribution of study patients 
across the treatment arms of the study. 
In both Part I and Part II of the study, the patient allocation into the treatment arms will be stratified by: Baseline 
HbA1c at randomization: 7 to 8% or > 8%; OAD/basal Insulin use at Screening: (metformin alone; metformin 
+ other OADs; metformin ± OADs + basal insulin); Baseline body mass index (BMI) at randomization: 
≤ 25 kg/m2 and ˃ 25 kg/m2; Gender: Male/Female; Metformin dose: ≥ 1500 mg/day; < 1500 mg/day. 
Part I of the study will have 3 treatment arms: Insulin Tregopil 30 mg, Insulin Tregopil 45 mg, and IAsp arms. 
Patients will be allocated (by minimization method) in 1:1:1 ratio into the 3 treatment arms. The first 5 patients 
in the Insulin Tregopil 45 mg arm in Part I of the study will be observed for any safety concerns like severe 
hypoglycemia for approximately up to 24 hours after administration of first dose before continuing with 
allocation of patients in this arm. 
Part II of the study will have 2 treatment arms: Insulin Tregopil arm (starting dose of 30 mg with titration up 
to a maximum dose of 45 mg or starting dose of 45 mg; determined by Part I data evaluation) and IAsp arm. 
In the Insulin Tregopil arms, the respective doses (30 mg, 45 mg) of Insulin Tregopil will be administered 
orally 10 ± 2 minutes prior to each major meal (breakfast, lunch and dinner) starting at the randomization visit 
.H owever, at Baseline (V9) visit, the first dose of the study drug/comparator drug will be administered after 
completion of STM (i.e., after collection of last PD blood samples at 240 minutes). In the IAsp arm, specific 
doses of IAsp will be administered subcutaneously, within 5 minutes prior to each major meal starting at the 
randomization visit.However, at Baseline (V9) visit, the first dose of the study drug/comparator drug will be 
administered after completion of STM (i.e., after collection of last PD blood samples at 240 minutes). 
In the first 4 weeks post-randomization, titration of Insulin Tregopil and IAsp dose will be performed based on 
the titration criteria specified and respective dose titration algorithms. The titration will be based on meal-
specific average of the self-monitored blood glucose (SMBG) levels (pre-meal and/or post-meal [as 
applicable] for IAsp and post-meal for Insulin Tregopil) on 2 days as per the SMBG values performed in the 
week leading up to the titration visit. The optimum dose regimen identified at the end of the titration period of 
4 weeks will be administered for the rest of the treatment period up to 24 weeks, except in patients where 
investigator discretion for additional titration in the presence of persistent lack of PPG control is allowed; up 
to a maximum of 8 weeks after randomization. Persistent lack of PPG control is considered, if 3 values in a 
single week for a particular meal and/or average meal-specific SMBG values over a week or more show a 
2-hour PPG > 180 mg/dL. 2-hour PPG value following a standardized test meal will be used for confirmation 
of lack of PPG control before allowing titration of prandial insulin between 4 and 8 weeks after randomization. 
The titration will be performed as per the titration algorithm, while investigator discretion is allowed; where 
in, the deviation in dose from the recommended titration algorithm must be documented and explained. The 
titration will be monitored by a centralized titration review team and such deviations will be evaluated by the 
titration review team to conclude if the explanation is agreeable or a protocol deviation needs to be reported. 


Sponsor: Biocon Limited 
Protocol Number: TREGO-DM2-03-I-01
Drug Name: Insulin Tregopil (IN-105) 
Version 3.0
21 May 2018
Confidential
Page 3 of 12 
 
 
 
The maximum dose of Insulin Tregopil is 45 mg prior to each of the 3 major meals of the day. 
Note: after randomization, up-titration of Insulin Tregopil and IAsp is allowed for up to a maximum of 8 weeks
and no titration of insulin glargine (an inherent ± 10% variation is acceptable) or metformin is allowed
throughout the treatment period. Up-titration of Insulin Tregopil and IAsp is not allowed between 8 and
24 weeks of treatment period. Only down-titration for safety related reasons and re-up titration to the last higher
dose based on the titration criteria, titration algorithm and the hypoglycemia criteria is allowed. Patients will 
be switched back to standard of care after 24 weeks of treatment period and will be followed-up for 2 weeks 
after the completion of treatment period during which adverse events (AEs) related to Insulin Tregopil or 
IAsp will be assessed. 
The rescue criteria and hypoglycemia criteria will apply to patients enrolled in both Part I and Part II of the
study. The data from Part I and Part II of the study will be analyzed and will be presented in the clinical study
report. 
Surveillance of insulin titration will be performed centrally (review of SMBG values, insulin dose change,
FPG, PPG and HbA1c values) by a Titration review team. The team will daily review the information received
and follow-up on significant deviations from the titration algorithm. Detailed plan on data review by titration
review team and communication plan for titration advice from the titration review team to the investigator will
be detailed in a separate titration review manual. 
Efficacy assessments will include: HbA1c assay, 9-point SMBG; standardized test meal for PPG assessment,
FPG, continuous glucose monitoring (CGM), glycated albumin, fasting insulin, C-peptide, proinsulin; Diabetes
Treatment Satisfaction Questionnaire, Diabetes Treatment Satisfaction Questionnaire change and Diabetes 
Self-management Questionnaire; body weight. 
Safety assessments will include: vital signs, physical examination, 12-lead electrocardiogram (ECG), standard
clinical laboratory evaluations including hematology, clinical chemistry (including fasting lipid profile),
3-point SMBG, symptomatic hypoglycemia self-monitoring, urinalysis and review of AEs. 
7-point SMBG will be performed during titration period. 
Planned number of patients: 
Part I: Approximately 90 patients will be allocated to the 3 treatment arms 
(Insulin Tregopil 30 mg, Insulin Tregopil 45 mg and IAsp arms) in a 1:1:1 
ratio, with 30 patients in each arm. 
Part II: Approximately 268 patients will be randomized to Insulin 
Tregopil and IAsp arms in 1:1 ratio (approximately 134 patients in each
arm). Insulin Tregopil dose (30 mg or 45 mg) in Part II will be determined 
based on the evaluation of Part I data. 
Inclusion/exclusion criteria: 
The same inclusion and exclusion criteria will be applicable for Part I and 
Part II of the study: 
Inclusion criteria 
 
Patients may enter the study only if they meet all of the following inclusion 
criteria: 
1. Male and female patients between the ages of 18 to 70 years, both 
ages inclusive, who have provided written informed consent for 
participation in the study and willing  to comply with study 
procedures. 
2. Patients with an established diagnosis of T2DM and a duration of 
diabetes mellitus of at least 6 months at Screening based on 
criteria given below as per American Diabetes Association 
(ADA) 2017 guidelines: 


Sponsor: Biocon Limited 
Protocol Number: TREGO-DM2-03-I-01
Drug Name: Insulin Tregopil (IN-105) 
Version 3.0
21 May 2018
Confidential
Page 4 of 12 
 
 
 
o 
HbA1c ≥ 6.5% OR 
o 
FPG ≥ 126 mg/dL. (fasting is defined as no caloric 
intake for at least 8 hours.) OR 
o 
2-hour prandial glucose (PG) level of ≥ 200 mg/dL 
during an oral glucose tolerance test (OGTT). The test 
should be performed as described by the World Health 
Organisation (WHO), using a glucose load containing 
the equivalent of 75 g anhydrous glucose dissolved in 
water. OR 
o 
In a patient with classic symptoms of hyperglycemia or 
hyperglycemic   crisis,   a   random   plasma   glucose 
≥ 200 mg/dL. 
(If there is suspicion, the investigator can do a fasting plasma C-
peptide [Levels < 0.3 nmol/L is indicative of Type 1 Diabetes 
Mellitus (T1DM) and would need the patient to be excluded]). 
3. Patients should be on a stable dose of metformin (at least 1500 mg 
daily [daily dose of at least 1000 mg is permitted if intolerant to 
1500 mg dose]) for a period of at least 3 months prior to 
Screening. 
4. Patients eligible for initiation of or already receiving insulin 
glargine. 
5. Body mass index of 18.5 to 35.0 kg/m2 (both values inclusive). 
6. Patients on stable diet and physical activity practices in the 
3 months prior to Screening with stable weight, (with no more 
than 5 kg gain or loss), in the 3 months prior to Screening; this 
information will be obtained from the patient history. 
7. Hemoglobin ≥ 10.0 g/dL. 
8. HbA1c of 7.5 to 10.0% (both inclusive). 
9. All women of childbearing potential (i.e., pre-menopausal) 
should use at least 2 reliable forms of contraception during the 
study, one of which must be a physical barrier method and should 
agree to continue the contraceptive measures during the study and 
for at least 10 days after receiving the last dose of the 
investigational medicinal product (IMP)/comparator drug. 
a. 
Periodic 
abstinence 
(e.g., 
calendar 
method, 
ovulation-symptothermal, and post-ovulation methods) 
and withdrawal method are not acceptable methods of 
contraception. 
b. Post-menopausal females must have had no regular 
menstrual bleeding for at least 1 year prior to Screening. 
Follicle-stimulating hormone (FSH) test can be done for 
confirmation if necessary as per investigator discretion 


Sponsor: Biocon Limited 
Protocol Number: TREGO-DM2-03-I-01
Drug Name: Insulin Tregopil (IN-105) 
Version 3.0
21 May 2018
Confidential
Page 5 of 12 
 
 
 
(Plasma  FSH  level  of  >  40  IU/L  is  indicative  of 
menopause). 
c. 
Female patients who report surgical sterilization must 
have had the procedure at least 6 months prior to 
Screening. If not, appropriate contraceptives should be 
used as described above. 
10. All female patients of childbearing potential (irrespective of 
sterilization status) must have negative serum pregnancy test 
result at Screening. 
11. Male patients must be using 2 acceptable methods of 
contraception one of which must be a physical barrier method, 
(e.g., spermicidal gel plus condom; condom plus partner is 
sterilized at least 6 months prior) for the entire study duration and 
for at least 10 days following the last IMP/comparator drug 
administration. 
Exclusion criteria 
 
Patients will not be allowed to enter the study for any of the following 
reasons: 
1. History or presence of a medical condition or disease that in the 
investigator’s opinion would place the patient at an unacceptable 
risk from study participation or interfere  with the patient’s 
compliance to the study procedures. 
2. History of hypersensitivity or known contraindication to any of 
the active or inactive ingredients or excipients of Insulin 
Tregopil, insulin, insulin analog preparations (including IAsp), 
or metformin. 
3. Patients known to be positive for autoimmune antibodies 
indicative of T1DM. e.g., Glutamate decarboxylase antibodies, 
anti-insulin antibodies. 
4. Treatment  with  glucagon-like   peptide   1   agonists   within 
12 weeks prior to Screening. 
5. History of regular use (> 2 weeks of continuous therapy) of any 
premix or prandial insulin prior to Screening. (previous use of 
prandial insulin is allowed in case of hospitalization or for 
gestational diabetes or a severe condition; requiring intermittent 
use of prandial insulin for less than 2 weeks, but not during the 
last 6 months prior to Screening visit). 
6. Ongoing treatment with OADs (eg, thiazolidinedione's) 
contraindicated or unapproved for combination treatment with 
insulin  (according  to   applicable   product   information)   at 


Sponsor: Biocon Limited 
Protocol Number: TREGO-DM2-03-I-01
Drug Name: Insulin Tregopil (IN-105) 
Version 3.0
21 May 2018
Confidential
Page 6 of 12 
 
 
 
Screening visit. 
7. Presence of gastrointestinal (GI) disorders or conditions known 
to significantly alter the absorption of orally administered drugs 
or significantly alter upper GI or pancreatic function including 
but not limited to GI motility disorders like gastroesophageal 
reflux disease, irritable bowel syndrome, inflammatory bowel 
disease (Crohn’s disease), malabsorption syndrome. 
8. Patients on or likely to start use of drugs including but not 
limited to colesevelam, acarbose, pramlintide, regular use of 
metoclopramide, domperidone; which interfere with the 
absorption of oral drugs at the time of Screening or within 
5 times the half-life of the drug, whichever is longer. 
9. History of ≥ 2 episodes of severe hypoglycemia (as per ADA 
2017) within the 6 months before Screening and/or presence of 
hypoglycemia unawareness as judged by the investigator. 
10. History of > 1 episode of hyperglycemic hyperosmolar coma or 
hospitalization for uncontrolled diabetes (e.g., diabetic 
ketoacidosis), within the 6 months prior to Screening. 
11. Any clinically significant abnormality in 12-lead ECG or safety 
laboratory tests deemed clinically relevant by the investigator at 
Screening. 
12. Serological evidence of human immunodeficiency virus, 
hepatitis B (HbsAg) or anti-hepatitis C antibodies at Screening. 
13. History of drug or alcohol dependence or abuse during the 1 year 
prior to Screening. 
14. Have received another investigational drug within 90 days (or as 
per local regulations, if any) prior to Screening or if the 
Screening visit is within 5 half-lives of another investigational 
drug (whichever is longer). 
15. Previous participation in this study (participation is defined as 
enrolment in the Run-in period). 
16. Patients with the following secondary complications of diabetes: 
o 
Active proliferative retinopathy as confirmed by a 
dilated ophthalmoscopy (by the investigator, site 
ophthalmologist or an optometrist; as per standard site 
practice) within 6 months prior to Screening. 
o 
Renal dysfunction indicated by modification of diet in 
renal   disease,   estimated   glomerular   filtration  rate 
<  45  mL/min/1.73  m2   and/or  diabetic  nephropathy 
and/or clinical nephrotic syndrome at Screening. 


Sponsor: Biocon Limited 
Protocol Number: TREGO-DM2-03-I-01
Drug Name: Insulin Tregopil (IN-105) 
Version 3.0
21 May 2018
Confidential
Page 7 of 12 
 
 
 
o 
History or presence of severe form of neuropathy or 
signs and symptoms of severe cardiac autonomic 
neuropathy. 
o 
Patients with non-traumatic amputation (at any time) or 
clinically 
significant 
vascular 
procedure 
as 
a 
complication of diabetes within 1 year prior to 
Screening. 
o 
History of diabetic foot ulcer or non-healing diabetic 
ulcers in the 1 year prior to Screening. 
17. Any elective surgery requiring hospitalization planned during 
the study period. 
18. Clinically significant major organ disease at the time of 
Screening includes but not limited to: 
o 
Uncontrolled (despite treatment)  or untreated severe 
hypertension defined as systolic blood pressure above or 
equal to 180 mmHg or diastolic blood pressure above or 
equal to 100 mmHg (Stage 2 as per American Heart 
Association classification of hypertension) 
o 
Uncontrolled 
hyperlipidemia 
(total 
cholesterol 
>  400mg/dL  or   very   high   serum   triglycerides 
[≥ 500 mg/dL] levels as per American Association of 
Clinical Endocrinologists classification) 
o 
Uncontrolled hyperthyroidism or hypothyroidism as per 
investigator’s assessment (investigator may conduct 
thyroid function test, if required for assessment). 
o 
Impaired hepatic function (alanine aminotransferase or 
aspartate aminotransferase value > 2 times the upper 
limit   of   the   reference   range   or   serum   bilirubin 
> 1.5 times the upper limit of the reference range). 
19. Clinically significant cardiovascular and/or cerebrovascular 
disease within 12 months before Screening including, but not 
limited to unstable angina, myocardial infarction, Class III or 
Class IV congestive heart failure according to the New York 
Heart Association criteria, valvular heart disease, cardiac 
arrhythmia requiring treatment, pulmonary hypertension, 
cardiac surgery, coronary angioplasty, stroke or transient 
ischemic attack. 
20. Patients who needed in the last 12 months or may require during 
the study period, systemic (including oral, intravenous, 
intramuscular)    glucocorticoid    therapy    for    more    than 
2 consecutive weeks. 


Sponsor: Biocon Limited 
Protocol Number: TREGO-DM2-03-I-01
Drug Name: Insulin Tregopil (IN-105) 
Version 3.0
21 May 2018
Confidential
Page 8 of 12 
 
 
 
21. History of cancer within the past 5 years prior to Screening, 
except successfully treated non-melanoma skin cancer or 
cervical carcinoma in situ. 
22. Patients who have donated blood or plasma within 12 weeks 
prior to Screening (450 mL blood or equivalent). 
23. Patients having hematological disorders (including but not 
limited to sickle cell disease, acquired and inherited hemolytic 
anemias, severe iron deficiency anemia) which can affect the 
HbA1c assessment. 
24. Patients who take acetaminophen (paracetamol) containing 
medications on a regular basis and are unable or unwilling to 
substitute with a medication not containing acetaminophen 
(paracetamol) the day before placement of the sensor and 
throughout each 7-day CGM sensor periods. 
25. Patients, who in the opinion of the investigator, may not be able 
to understand and/or comply with the study procedures including 
answering the study questionnaires, maintaining a stable diet and 
exercise pattern (e.g., tendency to go on prolonged fast), frequent
time zone travels etc., will be excluded from the study. 
Additional post Run-in inclusion criteria for Part I and Part II 
(Randomization criteria): 
 
FPG of ≤ 140 mg/dL; 
 
2-hour PG of ≥ 180 mg/dL after standardized test meal; 
 
HbA1c ≥ 7% and ≤ 9%. 
Note: All the above assessments will be performed at the central 
laboratory. One retest for the above values performed at central 
laboratory may be permitted with the last observation considered 
confirmatory. 
 
Acceptable compliance will be evaluated by the investigator as 
per the specified criteria below: 
o 
≥ 80% compliance with insulin glargine administration 
(dose and timing) during Run-in. 
o 
≥ 10/14 time points of the SMBG measurements during 
Run-in period (each of the SMBG measurements 
includes 14 total time points i.e., 2 days of the 7-point 
SMBG that will be performed on any 2 days of the week 
leading to the titration visit). 
 
Any new information received during the Run-in period indicating 
ineligibility of the patient will result in exclusion of the patient at 
treatment period entry/randomization. 
Test product, dose and mode of 
administration: 
Investigational medicinal product (study drug): Insulin Tregopil (IN-105) 
Formulation: 15 mg tablet 


Sponsor: Biocon Limited 
Protocol Number: TREGO-DM2-03-I-01
Drug Name: Insulin Tregopil (IN-105) 
Version 3.0
21 May 2018
Confidential
Page 9 of 12 
 
 
 
Dose 1: Dose 1 is the dose for 30 mg Insulin Tregopil arm. Dose starts at 
30 mg thrice daily (TID) oral; (2 tablets of 15 mg each administered
10 ± 2 minutes prior to the 3 major meals of the day) and titration 
determined by the investigator as per the titration algorithm and titration
criteria specified in the protocol. 
Dose 2: Dose 2 is the dose for 45 mg Insulin Tregopil arm. Dose starts at 
45 mg TID (3 tablets of 15 mg each administered 10 ± 2 minutes prior to 
the 3 major meals of the day) and titration determined by the investigator
as per the titration algorithm and titration criteria specified in the protocol. 
Mode of Administration: Oral; intact tablet to be swallowed with water. 
Comparator product, dose, and 
mode of administration: 
Comparator: Insulin Aspart 100 U/mL; prior to the 3 major meals of the 
day (within 5 minutes prior to each meal). 
Dose will start at 4 U/meal and titration is determined by the investigator 
as per titration algorithm and titration criteria specified in the protocol. 
Mode of Administration: Subcutaneous injection in the abdominal wall, 
the thigh, the upper arm, the deltoid region or the gluteal region. 
Supportive drugs: 
 
Insulin glargine 100 U/mL; once daily; dose determined by the
investigator as per titration algorithm and specified titration 
criteria 
Mode of Administration: Subcutaneous injection 
Dose preferably administered in the evening; at the same time 
every day. 
 
Metformin (Extended release/immediate release tablets) to be
continued at the stable dose regimen; once daily or twice daily or 
as applicable. 
Criteria for evaluation: 
Part I 
Primary Endpoint: 
Change from Baseline in HbA1c at 24 weeks. 
Secondary Endpoint: 
Number of severe or clinically significant hypoglycemia events during 24 weeks of treatment period. 
Part II 
Primary Endpoint: 
Change from Baseline in HbA1c at 24 weeks. 
Secondary Endpoints: 
 
Change from Baseline in HbA1c at 12 weeks. 
 
Proportion of patients achieving HbA1c < 7% at Week 12, and Week 24; without reported clinically 
significant or severe hypoglycemic events between end of Week 8 and Week 24 (i.e., after the titration
period of 8 weeks for prandial insulin [Insulin Tregopil/IAsp]). 
 
Frequency of hypoglycemia events during the 24 week treatment period. 
 
Change from Baseline in weight at Week 24. 
 
Change in lipid profile (triglycerides, low-density lipoprotein, high-density lipoprotein, and total 
cholesterol) from Baseline over 24 weeks. 
 
Change from Baseline in the mean 60 minutes, 90 minutes and 120 minutes PPG excursion assessed 


Sponsor: Biocon Limited 
Protocol Number: TREGO-DM2-03-I-01
Drug Name: Insulin Tregopil (IN-105) 
Version 3.0
21 May 2018
Confidential
Page 10 of 12 
 
 
 
from standardized test meal at Week 12 and Week 24. 
 
Change from Baseline in the mean PPG excursion (overall mean and meal-specific [breakfast, lunch 
and dinner] mean) at 60 minutes and 120 minutes assessed from 9-point SMBG at Week 8, 12, 16, 
and 24. 
 
Incidence and severity of AEs based on laboratory and clinical safety parameters over 24 weeks. 
 
Immunogenicity: incidence and change from Baseline in the relative levels of anti-drug antibody over 
24 weeks. 
 
Area under the glucose curve (AUC/time) below 70 mg/dL derived from CGM at Baseline and 
Week 24. 
Exploratory Endpoints: 
 
Proportion of treatment-emergent major cardiovascular AEs (cardiovascular mortality, non-fatal 
stroke, non-fatal myocardial infarction). 
 
Change in glycated albumin, levels over 24 weeks 
 
Change in fasting insulin, C-peptide and proinsulin levels in Insulin Tregopil arm over 24 weeks. 
 
Patient reported outcomes, by Diabetes Treatment Satisfaction Questionnaire change score; change 
from Baseline over 24 weeks. 
 
Change in patient reported outcomes of monitoring of primary diet and physical exercise pattern from 
Baseline over 24 weeks by Diabetes Self-Management questionnaire. 
 
Area under the glucose curve (AUC)/time above 180 mg/dL (over 180 minutes post-meal for 3 major 
meals of the day) derived from CGM at Baseline and Week 24. 
 
Percentage of time with glucose in the following ranges 
o 
≤ 70 mg/dL 
o 
˃ 180 mg/dL (over 180 minutes post-meal for 3 major meals of the day). 
 
Exploratory measures of glycemic control and variability derived from CGM at Baseline  and 
Week 24. 
Statistical methods: 
Sample size determination 
Part I of the study is an exploratory study and no statistical rationale is defined for the estimation of sample 
size. The minimum number of 30 patients in each of Insulin Tregopil 45 mg, Insulin Tregopil 30 mg and IAsp 
treatment arms are deemed adequate for the assessment of safety and efficacy. 
The primary objective of Part II of the study is to compare the efficacy of Insulin Tregopil versus IAsp in 
T2DM patients who are on stable dose of metformin and insulin glargine. This will be done by evaluating if 
Insulin Tregopil is non-inferior to IAsp in terms of glycemic control effect as assessed by mean change from 
Baseline in HbA1c after 24 weeks of treatment using a non-inferiority margin of 0.4%. Sample size in Part II 
of the study is determined based on this primary objective. 
Using a one-sided confidence interval (CI) with a confidence level of 97.5%, a non-inferiority margin of 0.4%, 
a true difference of 0, and based on previous clinical studies and literature a standard deviation of 1% in change 
in HbA1c after 24 weeks of treatment, a total of 114 patients per treatment arm would give 85% power to 
conclude non-inferiority when comparing Insulin Tregopil versus IAsp. In order to account for an expected 
rate of patients discontinuing from study drug/comparator drug of 15% (based on previous clinical studies), 
and further taking the (conservative) assumption that these patients are excluded from the Per Protocol analysis 
set, 134 patients should be randomized into each of IAsp and Insulin Tregopil treatment arms (a total of 
268 patients). 


Sponsor: Biocon Limited 
Protocol Number: TREGO-DM2-03-I-01
Drug Name: Insulin Tregopil (IN-105) 
Version 3.0
21 May 2018
Confidential
Page 11 of 12 
 
 
 
Analysis methods 
In general, continuous variables will be summarized using descriptive statistics such as mean, standard 
deviation, 95% confidence interval (CI), median, minimum, and maximum. Categorical variables will be 
summarized using proportions (counts and percentages). All statistical hypothesis tests will be performed at 
5% level of significance (two-sided test). All statistical analysis will be performed using SAS® version 9.4 (or 
higher version) for Windows (SAS Institute Inc., USA). 
Unless otherwise specified, “Baseline” is defined as the last observed value of the parameter of interest prior 
to the first intake of study medication (this includes unscheduled visits). For numerical variables, change from 
Baseline will be calculated as the difference between the value of interest and the corresponding Baseline value. 
Data on patient disposition (number of patients screened, number of screen failures with reasons, number of 
patients enrolled, number of Run-in failures with reasons, number of patients randomized, number of patients 
completed, number of patients discontinued and reason for discontinuation) will be presented using counts and 
percentages. Number of patients enrolled in each study center will be summarized as counts and percentages. 
Demographic and Baseline evaluations for the intent-to-treat analysis set will be presented for Insulin Tregopil 
and IAsp arms. 
Detailed statistical methodology for the analysis of efficacy and safety data, statistical hypothesis and handling 
of missing data, data presentation for Part I and Part II data will be described in SAP and will be finalized 
before database lock. 
Efficacy 
The primary endpoint is change from Baseline in HbA1c at 24 weeks. 
Change from Baseline in HbA1c at 24 weeks of treatments will be analyzed using mixed model for repeated 
measures (MMRM) where all available post-baseline HbA1c measurements obtained up to EoT will be entered 
as the dependent variables; visit and treatment are included as fixed factors, with Baseline HbA1c and 
stratification factor variables as covariates. Furthermore, the interaction terms of visit by treatment, visit by 
stratification factors and visit by Baseline HbA1c will be included in the model. An unstructured covariance 
matrix for HbA1c measurements within the same patient will be employed. Regarding missing data, this 
analysis approach relies on the assumption that data are missing at random. The estimated differences between 
each Insulin Tregopil and IAsp at Week 24 and corresponding two-sided p-value and 95% CI will be presented. 
Possible effects of other covariates may also be investigated. Details of such analyses will be described in the 
SAP. 
The model will be fitted to all the data simultaneously (all treatment arms) and from this model the relevant 
treatment differences will be estimated. 
In Part I of the study, efficacy data will be evaluated and compared for Insulin Tregopil 45 mg versus IAsp and 
Insulin Tregopil 30 mg versus IAsp using descriptive statistics. Additionally, Part I primary efficacy endpoint 
data will be evaluated and compared for Insulin Tregopil 45 mg versus IAsp and Insulin Tregopil 30 mg versus 
IAsp using the same statistical analysis methods which are planned for Part II study data without testing any 
hypothesis. 
In Part II of the study, efficacy data will be evaluated for Insulin Tregopil versus IAsp using Non-inferiority 
test hypothesis. 
Non-inferiority will be considered confirmed if the upper bound of the 2-sided 95% CI is below or equal to 
0.4%. 
Non-inferiority test hypothesis: 
H0: D > 0.4% against HA: D ≤ 0.4% 
where D is the difference in mean change in HbA1c (Baseline to Week 24) between the 2 treatment arms 
Non-inferiority of Insulin Tregopil against IAsp will be tested. 
After non-inferiority is established, superiority of Insulin Tregopil against IAsp may be tested. Superiority for 
change in HbA1c will be claimed if the upper limit of the two-sided 95% CI for the estimated difference in 
mean change in HbA1c is below 0%. 
 
When establishing non-inferiority for change in HbA1c, the analysis will be based on the Intent-to-treat (ITT) 
and supplemented by an analysis with the Per protocol analysis set as supportive evidence. The ITT will be 


Sponsor: Biocon Limited 
Protocol Number: TREGO-DM2-03-I-01
Drug Name: Insulin Tregopil (IN-105) 
Version 3.0
21 May 2018
Confidential
Page 12 of 12 
 
 
 
 
used in the analysis when concluding superiority. 
Safety 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities and will be tabulated in
incidence tables by system organ class (SOC) and preferred term (PT). Treatment-emergent AEs will be
summarized by SOC, PT, and treatment arms. Treatment-emergent AEs will be further summarized by
maximum severity and relationship to study medication. Prior and concomitant medications will be
summarized by treatment. 
Number of hypoglycemic events during 24 weeks of treatment will be summarized by treatment. Details of
various analyses and summary data presentations for hypoglycemic data will be described in the SAP. 
Other routine safety assessments such as vital signs, 12-lead ECG and safety laboratory tests will be
summarized by treatment arms using statistics for continuous or categorical data, as appropriate.