Multicentre Double-blind Placebo-controlled Parallel Group Randomized Clinical Trial of Efficacy and Safety of Subetta in the Treatment of Impaired Glucose Tolerance
Phase: PHASE3
Conditions: Impaired Glucose Tolerance
Sponsor: Materia Medica Holding

 
 
 
 
 
 
 
 
 
 
 
 
 
Multicenter double-blind placebo-controlled parallel-group randomized 
clinical trial of efficacy and safety of Subetta in the treatment of 
impaired glucose tolerance 
 
 
 
Phase III 
 
 
 
 
 
 
 
 
 
 
Sponsor 
OOO «NPF «MATERIA MEDICA HOLDING» 
Protocol number 
MMH-SU-006 
Version date: 
May 30, 2019 
ClinicalTrials.gov Id: 
NCT03725033 
 

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Protocol Summary 
 
This document represents the protocol summary for the study on human subjects. The study will 
be carried out in accordance with ICH GCP, National Standard of the Russian Federation GOST 
52379-2005 "Good Clinical Practice", Helsinki Declaration of World Medical Association, 
relevant requirements of the regulatory authorities as well as the study procedures. 
Title of Study 
Multicenter double-blind placebo-controlled parallel-group randomized clinical trial of efficacy 
and safety of Subetta in the treatment of impaired glucose tolerance. 
Phase: III 
Sponsor: OOO "NPF "MATERIA MEDICA HOLDING", Moscow, Russia 
Protocol No. MMH-SU-006 
Objective of the study 
 To assess efficiency and safety of Subetta in the treatment of impaired glucose tolerance1 
(IGT). 
Endpoints  
Primary endpoint 
1. Changes in 2-hour fasting plasma glucose (OGTT2) at 12 weeks versus baseline. 
Secondary endpoints 
1. Percentage of subjects with 2-hour plasma glucose <7.8 mmol/L after 12-week therapy. 
2. Changes in fasting plasma glucose at 12 weeks versus baseline.  
3. Changes in HbA1c at 12 weeks versus baseline. 
Safety assessment  
 Presence and nature of adverse events during the therapy, their intensity (severity), relation to 
the product, outcome 
 Percentage of patients with clinically relevant laboratory abnormalities after 12-week therapy 
 Changes in vital signs.  
                                               
1 Impaired glucose tolerance (IGT) is a condition characterized by plasma glucose concentration of 7.8 to 11.0 
mmol/L 120 min after oral glucose tolerance test (OGTT), with fasting plasma glucose <7.0 mmol/L. 
2 Oral glucose tolerance test (OGTT) should be carried out in the morning against regular diet and regular physical 
activity. The test should be preceded by an overnight fast (8-14 hours, water allowed). A carbohydrate-containing 
meal (30–50g) should be consumed on the evening before the test. Once fasting blood has been drawn, the patient 
should consume 75g anhydrous glucose (or 82.5g glucose monohydrate) in 250-300 ml water for 5 minutes. 
Smoking is prohibited during the test. Repeat blood samples are taken after 2 hours. Plasma glucose test will be 
made in central laboratory, therefore to avoid glycolysis and wrong results the blood should be collected into a tube 
containing preservative (sodium fluoride) provided by the sponsor. 

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Study design  
Design: a multicenter, double-blind, placebo-controlled, parallel-group randomized trial.  
The study will enroll outpatients adults aged 18-70 years with impaired glucose tolerance (IGT) 
who did not receive glucose-lowering agents previously. Persons with pre-diabetes3, obesity 
(especially with visceral or abdominal obesity), dyslipidemia (with high triglycerides and/or low-
density lipoproteins), hypertension, diabetes in first-degree relatives will be considered as 
potential candidates to participate in the study. 
After the patient's information sheet and the form of informed consent for participation in the 
study are signed on the screening (visit 0; day from -7 to 0), complaints and history are collected, 
registration of concomitant conditions and diseases, objective examination, calculation of body 
mass index (BMI), oral glucose tolerance test (OGTT), fasting blood glucose. Furthermore, 
blood samples4  (for testing HbA1c, chemistry and hematology, HLA genotyping) and urine 
sample will be collected; concomitant therapy will be recorded, diet and physical activity 
recommendations will be given. All women of childbearing potential will be administered 
pregnancy tests. 
If eligibility criteria are met and there are no non-inclusion criteria on Visit 1 (Day 1), the patient 
is randomized to one of two groups: the Subetta group (patients will take 2 tablets twice a day 
for 12 weeks) or placebo group (patients will take a placebo according to the scheme of Subetta 
for 12 weeks). 
In the course of the study, two more visits in 4 (Visit 2) and 12 (Visit 3) weeks are planned, 
during these weeks complaints are recorded, a patient's examination is recorded, therapy 
compliance and safety are assessed. On Visit 3 OGTT, fasting blood glucose, blood samples (for 
HbA1c, chemistry and hematology) and urinalysis will be performed. 
The duration of observation period shall be up to 13 weeks.  
During the study the treatment for underlying conditions will be allowed with the exception of 
the drugs indicated in the section “Prohibited concomitant therapy”. 
Inclusion and exclusion criteria 
Inclusion criteria 
1. 
Outpatients aged 18 to 70 years. 
2. 
Impaired glucose tolerance (plasma glucose from 7.8 to 11.0 mmol / L 2 hours after a 75 g 
oral glucose consumption during an oral glucose tolerance test, while fasting plasma 
glucose <7.0 mmol / L). 
                                               
3 Prediabetes: Fasting plasma glucose = 6.1–6.9 mmol/L orand 2) 2-hour plasma glucose post-OGTT = 7.8–11.0 
mmol/lL or/and 3) HbA1c 5.7–6.4%. 
4 All investigations are carried out in a central laboratory. 

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3. 
HbA1c is 5.7–6.4%. 
4. 
The body mass index is 25.0-39.9 kg / m2. 
5. 
Consent to use reliable contraceptive methods during the study (for men and women with 
reproductive potential). 
6. 
The presence of the signed informed consent form to participate in the clinical trial. 
Exclusion criteria 
1. 
Type I or II diabetes mellitus. 
2. 
Use of any medications indicated in the section “Prohibited concomitant medications”. 
3. 
Acute or exacerbation/decompensation of chronic disease of any etiology at the time of 
examination or during the previous week. 
4. 
Uncontrolled arterial hypertension with blood pressure: systolic blood pressure > 160 mm 
Hg and/or diastolic blood pressure > 100 mm Hg. 
5. 
Acute coronary syndrome, myocardial infarction, acute impairment of cerebral circulation 
during the previous 6 months prior to enrollment. 
6. 
Unstable or life-threatening arrhythmia during the previous 3 months prior to enrollment. 
7. 
Acute and chronic heart failure with functional class III or IV (according to the 
classification of the New York Heart Association, 1964). 
8. 
Respiratory failure. 
9. 
Chronic kidney disease (classes C3-5 A3). 
10. Hepatic insufficiency (class C according to Child-Pugh).  
11. Presence or suspicion of oncology disease.  
12. The presence of an allergy / hypersensitivity to any component of the medication 
administered during the treatment.  
13. Alcohol consumption > 2 alcohol units5 for males and > 1 alcohol unit for females per day. 
14. Mental illness or drug abuse in anamnesis.  
15. Bariatric surgery in anamnesis, any surgery for 3 months before enrollment.  
16. Pregnancy, breast-feeding; childbirth less than 3 months before enrollment. 
17. Participation in other clinical trials for 3 months before enrollment in this study.  
18. Patients who are related to any of the on-site research personnel directly involved in the 
conduct of the trial or are an immediate relative of the study investigator. ‘Immediate 
relative’ means husband, wife, parent, son, daughter, brother, or sister (regardless of 
whether they are natural or adopted). 
                                               
5 1 alcohol unit − 15 g of ethanol or approximately 40 g of hard liquors or 140 g of wine or 300 g of beer. 

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19. Patients who work for MATERIA MEDICA HOLDING (i.e. the company's employees, 
temporary contract workers, appointed officials responsible for carrying out the research or 
immediate relatives of the aforementioned). 
Criteria for Withdrawal or Termination 
1. Screening failure.  
2. Acute or exacerbation/decompensation of chronic disease of any etiology, with clinically 
relevant symptoms persisting for more than 5 days. 
3. Inability or refusal of patient to comply with the protocol requirements. 
4. Necessity in medical products prohibited within the study. 
5. Development of adverse event requiring cancellation of investigational product. 
6. Desire of patient to complete the study ahead of schedule due to inefficacy of therapy or any 
other reason. 
7. Pregnancy.  
8. Cases not specified by the protocol when, according to the investigator’s opinion, further 
participation in the study harms the patient. 
9. Incorrect inclusion of ineligible patient. 
10. Participation in another clinical study. 
11.   Unblinding. 
 
Number of subjects 
It is planned to include 842 patients, which is expected to allow at least 286 patients (143 
patients in both groups - Subetta and Placebo) to complete all protocol procedures. 
Interim analysis 
The study provides 1 intermediate "non-blind" analysis. At the request of the sponsor, a blind 
interim analysis can be performed to clarify population characteristics and possible correction of 
the sample size (only in the direction of increase). 
Treatment 
 
Group 1 
Name of the medicinal product: Subetta 
Active ingredient: affinity purified antibody to С-terminal fragment of insulin receptor beta-
subunit – 0.006 g*, affinity purified antibodies to endothelial NO synthase - 0.006 g* 
* Mixture of water-ethanol dilutions 10012, 10030, 100200 of active substance used for saturation 
of isomalt.   

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Excipients: isomalt, crospovidone, magnesium stearate. 
Method of administration: Tablet for oral use. 2 tablets twice daily. The tablets should be held 
in mouth until completely dissolved 15 min prior to meal.  
 
Dosage form: Tablets. 
Description: White to off-white, flat, cylinder-shaped, beveled edge tablets scored on one side, 
with integral edges. 
Storage conditions: Store at a temperature not exceeding 25°C. 
Group 2 
Name of the medicinal product: Placebo 
Active ingredient: NA 
Excipients: isomalt, crospovidone, magnesium stearate. 
Method of administration: Tablet for oral use. 2 tablets twice daily. The tablets should be held 
in mouth until completely dissolved 15 min prior to meal.  
Dosage form: Tablets. 
Description: White to off-white, flat, cylinder-shaped, beveled edge tablets scored on one side, 
with integral edges. 
Storage conditions: Store at a temperature not exceeding 25°C. 
Treatment duration 
Subetta/Placebo treatment duration is 12 weeks. 
Observation period 
The duration of observation period shall be up to 13 weeks (screening up to 1 week, study 
therapy 12 weeks). 
Symptomatic (Standard) treatment 
Throughout the study, patients should adhere to the recommendations for lifestyle modifications 
(good nutrition and regular physical activity). 
Patients may receive treatment for co-morbid conditions with medicines that are not listed in the 
"Prohibited concomitant treatment" section. 
Prohibited concomitant therapy 
The medicines specified in cl. 1 and 2 belong to prohibited ones at baseline (during any period of 
time) and during the study. 
The medicines specified in cl. 3-17 belong to prohibited ones within 3 months prior to 
enrollment and during the study. 

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1. Oral and other antidibetic drugs: 
 
biguanides (metformin, phenformin, etc.) 
 
sulphonylurea derivatives (glibenclamide, tolbutamide, etc.) 
 
thiazolidinediones (rosiglitazone, pioglitazone, etc.) 
 
alpha-glucosidase inhibitors (acarbose, miglitol) 
 
dipeptidyl peptidase 4 inhibitors (DPP-4): sitagliptine, vildagligptine, saxagliptine, 
linagliptine, alogliptine, gosogliptine 
 
glucagon-like peptide receptor analogues (GLP-1): exenatide, liraglutide, lixisenatide, 
dulaglutide, etc. 
 
sodium-dependent glucose cotransporter type 2 inhibitors (SGLT2): dapagliflozin, 
empagliflozin, canagliflozin 
2. Insulins and their analogs 
3. Glucocorticosteroids for systemic use and topical glucocorticosteroids 
4. Thyroid hormones 
5. Oral contraceptives 
6. Danazol 
7. Chlorpromazine 
8. Beta-2-sympathomimetics for injections 
9. Appetite-stimulating drugs 
10. Drugs for treatment of obesity 
11. Nitric oxide release modulators, including nebivolol 
12. Nitric oxide donators (long-acting nitrates and nitrate-like agents, except for on-demand 
nitrates used in angina episodes) 
13. Diuretics 
14. Biologically active food supplements 
15. Phytodrugs 
16. Products manufactured by Materia Medica Holding (Divaza, Impaza, Afalaza) 
17. Drugs known to have caused allergic reactions 
 
 
 
 
 

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Study design scheme 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Schedule of study procedures  
 
Visit 
 
Procedure 
 
Visit 0 
(Day -7 to 0) 
Screening 
Visit 1 
(Day 1) 
Screening, 
randomization 
Visit 2 
(Week 4±3 
days) 
Visit 3 
(Week 12±3 
days) 
Informed consent 
+ 
 
 
 
Study subject registration in IVRS and 
assignment of a personal code 
+ 
 
 
 
Collection of complaints 
+ 
+ 
+ 
+ 
Medical history   
+ 
 
 
 
Registration of co-morbid conditions 
and diseases 
+ 
+ 
 
 
Physical examination 
+ 
+ 
+ 
+ 
Registration of vital signs (heart rate, 
respiratory rate, blood pressure) 
+ 
+ 
+ 
+ 
BMI calculation 
+ 
 
 
 
Concomitant therapy 
+ 
+ 
+ 
+ 
Eligibility assessment 
+ 
+ 
 
 
Randomization of the study subject 
 
+ 
 
 
Study drug supply 
 
+ 
+ 
 
Study drug accountability and return, 
compliance assessment 
 
 
+ 
+ 
Recommendations (good nutrition and 
regular physical activity)  
+ 
+ 
+ 
+ 
Evaluation of treatment safety 
 
+ 
+ 
+ 
End of visit 
+ 
+ 
+ 
+ 
SCREENING
Up to 13 weeks 
Visit 3 
(Week 12±3 days) 
Group 2: Placebo 2 tablets twice daily for 12 weeks 
RANDOMIZATION
Group 1: Subetta 2 tablets twice daily for 12 weeks 
STUDY 
TERMINATION 
Visit 2 
(Week 4±3 days) 
Visit 1 
(Day 1) 
Visit 0 
(Day -7 to 0) 
Group 1 and 2 patients: 
 Lifestyle modification: good nutrition and regular physical 
activity 

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Completion of the patient's 
participation in the study 
 
 
 
+ 
Investigations: 
OGTT* 
+ 
 
 
+ 
Blood sampling for HbA1c  
+ 
 
 
+ 
Blood sampling for HLA genotyping 
+ 
 
 
 
Blood and urine samples for safety 
analysis 
+ 
 
 
+ 
Pregnancy test** 
+ 
 
 
 
* Fasting blood glucose will be determined at OGTT (prior to glucose loading) 
** If applicable 
 
 
Statistical Analyses. 
SAS 9.4 will be used for data processing and statistical calculations6. 
Samples  
Total set: all patients included in the study who have signed Informed Consent Form for 
participation in the study. All AEs including those occurred prior to the study therapy will be 
considered throughout the study for this sample.  
Safety population:  all patients who received at least one dose of the study drug. This sample will 
be used for the study treatment safety and tolerability analyze, since all the AEs identified after 
the study drug administration will be recorded.    
Full Analysis Set. This sample includes all enrolled and randomized patients, except for those 
who met at least one of the following criteria: 
1) non-compliance with inclusion / exclusion criteria;  
2) the patient has not taken as minimum a single dose of the study drug; 
3) lack of any data of the patient after prescription of the study drug. 
This sample is the most consistent with the “Intention-to-treat” principle, will be used for 
the Intention-to-treat analysis (ITT analysis) of the the study therapy efficacy. 
Per protocol set. This sample includes all patients who completed the therapy as per the study 
protocol 
without 
any 
missing 
scheduled 
visits. This 
sample 
will 
be 
used 
for 
the Per Protocol analysis (PP- analysis) of the the study therapy efficacy. 
Per Protocol set will not include the patients whose data are completely or partially invalid for 
analysis due to a protocol deviation. 
Protocol deviations that lead to complete or partial data invalidity: 
1. Violation of visit schedule.  
2. Inappropriate distribution/supply of the study drug.  
                                               
6 Licensee: OOO "NPF "Materia Medica Holding", No. 70100045 

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3. Administration of prohibited therapy.  
4. Increase or decrease ≥ 25% in the amount of the study therapy administered.  
5. Inability to assess the patient's compliance using the formula (e.g. loss of pack with the 
product).  
6. Major discrepancies between source documents and CRF detected during monitoring or 
another authorized check.  
7. Violation of the procedure for obtaining Informed consent.  
8. Non-compliance with the clinical study protocol procedures.  
9. Inability to collect all patient's data used for evaluation of the study endpoints (e.g. lack 
of entries in source documents required for verification of inclusion/exclusion criteria, 
safety and efficacy criteria).  
10. Other protocol deviations resulting in full or partial data invalidity. 
Evaluation of sample size 
The sample size has been assessed on the basis of the following rules and assumptions: 
1. Statistical provisions. 
1.1 
the power of the statistical tests “P = (1 - β )” is assumed to be 80% (the 
probability of correct rejection of the null hypothesis is 0.8); 
1.2 
the probability of a type I error “α” is allowed to be less than 5% (the probability 
of the erroneous acceptance of an alternative hypothesis is less than 0.05); 
1.3 
the statistical tests are 2-sided unless otherwise specified; 
1.4 
the calculation of the sample size is based on the assumptions about the expected 
effects, declared in the primary efficacy endpoint of the Protocol; 
1.5 
the ratio between the sample sizes of Subetta and Placebo groups is 1:1 (1 Subetta 
patient - 1 Placebo patient); 
1.6 
statistical hypotheses - null and alternative hypotheses on superiority of the study 
product over placebo under the dosing regimen used 
1.7 
one unblinded interim analysis on 50% sample was expected allowing to 
terminate the study both due to the effect confirmation (according to O'Brien-
Fleming) and due to acceptance of null hypothesis (Pocock). 
   a) primary endpoint: 
H0: Δµ1-Δµ2 = 0 
Ha: Δµ1-Δµ2 ≠ 0 
where Δµ1 - mean reduction (initial – final score) in Subetta group,  
Δµ2 – mean reduction (initial – final score) in Placebo group;          

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1.8    calculation of sample size for statistical criteria will be made using the following 
formula: 
n1 = kn2 
    
         
            
  
 
 
where n1, n2 is sample size in IP and placebo groups, respectively 
ε = Δµ1-Δµ2 is expected difference between mean reductions of value between 
Subetta and Placebo groups 
k – coefficient of Subetta/Placebo sample ratio (1 : 1) 
ϭ – standard deviation of reduction 
zα/2 – tabular value of two-sided z-test for α  
zβ – tabular value of one-sided z-test for β, R-coefficient taking into account 
interim analysis depending on the accepted functions of error and analysis 
position (in this design equal to 1.1334). 
1.9    terminal sample size was determined using the formula:  
NT=NPP/(1-Rw) 
where NT – terminal sample size 
NPP – result of calculation in cl. 1.8, i.e. scheduled number of subjects 
completing the study per protocol 
Rw – withdrawal rate. 
2.  Assumptions on expected clinical study effects: difference in reduction of 2-hour 
plasma glucose (at OGTT) between Product and Placebo groups will be no less than ε = 1.1 at 
standard deviation of σ = 3.11. 
A priori estimates for tested parameter variables in the groups: 
Primary endpoint: 
Changes in 2-hour fasting plasma glucose (OGTT) at 12 weeks vs. baseline. 
Placebo group: 
characteristics of 2-hour plasma glucose level (at OGTT) at the start of the study. 
SD=0.94 [39] 
After 3 months 
SD=2.3 [1.87; 2.987] [40] 
Change (3 m) –0.2 [–1; 0,6] [40] 

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Standard deviation of change in 3 months (in assumption of independence of scoring for 
DM) 
SDΔ~311. 
Study drug group: 
Based on interim study, change in glucose level in experimental group in 3 months was:  
Change (3 m) = 1.96 [1,7; 2,22] 
Let us take standard deviation of change in experimental group similar to control group. 
Software code for evaluation of sample size: 
Proc seqdesign errspend; 
Design nstages=2 
Info=cum(0.5,1) 
Method(alpha)=UNI(rho=0.5 tau=0) 
Method(beta)=UNI(rho=0 tau=0) 
Stop=both 
Alpha=0.05 
Beta=0.2; 
Samplesize model=twosamplemeans(meandiff=1.1 stddev=3.11); 
Run; 
Therefore, the value of expected effect is rated as εΔ=1.1 mmol/L (the most conservative 
scoring) – the worst case for Subetta and the best for Placebo) at standard deviation σΔ=3.11 
mmol/L. Thus, sample size will be 143 subjects per study group. Taking into account the 
claimed withdrawal coefficient, this will require enrollment of 842 subjects.  
Therefore, overall size of the required sample will be 842 subjects ensuring the study 
completion per protocol by at least 286 subjects. 
Therefore, the sample size has been found to be (143) patients in each of the groups 
(Product and Placebo) to estimate superiority of the study drug over placebo.  
Taking into account potential withdrawal of at least 66% subjects7 (Cw=0.66) during the study 
for various reasons, at least 842 patients should sign PIS and ICF. 
Statistical criteria  
All statistical calculations will be performed using two groups of statistical criteria:  
 parametric – to obtain effective estimates for random parameters in case the relevant 
conditions of method/model applicability are not violated (e.g. sphericity, normality, 
risk proportionality, etc.);  
                                               
7 Based on blinded interim analysis. 

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 non-parametric – in all other cases. 
Parametric criteria 
The application of parametric criteria will be accompanied by a check of models for 
applicability (e.g. Kolmogorov-Smirnov test, Shapiro-Wilk test). 
The following parametric methods and approaches are to be used: 
1. To assess the differences of continuous variables obtained in one group at two 
different visits – Student t-test for paired samples. 
2. To assess the temporal dynamics of the compared values – analysis of variance 
(ANOVA) or covariance (ANCOVA) in the modification with repeated measures. 
3. In case of multiple comparisons between the groups will apply a variety of corrections 
for multiplicity Dunnett, Tukey, Scheffe, Holm adaptive test, etc. 
4. In case of abnormal data distribution, approaches with the Generalized Linear Models 
and /or Mixed Linear Models will be used.  
5. Selection of the type of distribution, clarification of the factor and covariance 
structures of the model is carried out with fit statistics such as AIC (Akaike  
 information criterion). 
To perform the above-mentioned statistical tests and techniques, it is assumed that the 
following SAS procedures are used:  
 
UNIVARIATE – check for normality of the compared distributions; 
 
CORR, MEANS – calculation of descriptive statistics; 
 
TTEST – Student t-test with all the modifications; 
 
GLM – analysis of Generalized Linear Models for studying temporal dynamics 
(ANOVA, ANCOVA); 
 
GENMOD – analysis of Generalized Linear Models. 
 
MIXED – analysis of Generalized Linear Models. 
Non-parametric criteria 
Below, there are the main types of possible comparisons with the respective criteria: 
1. To assess the dynamics of the compared indicators – Friedman test, non-parametric 
analogue of analysis of variance with repeated measures. 
2. For the frequency analysis of 2×2 cross tables – χ2-test (if the compared frequencies are 
greater than 5) or Fisher exact test (if one of the compared frequencies is less than 5). 
3. For the frequency analysis of cross tables with independent strata – Cochran–Mantel–
Haenszel test (modification of the χ2-test for multiple comparisons). 

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4. For the frequency analysis of data on the presence / absence of an event or outcome 
during repeated measures (cross tables with dependent strata) – survival analysis. 
To perform the above-mentioned non-parametric statistical analysis options, it is assumed that 
the following SAS procedures are used: 
 FREQ – Friedman test, χ 2-test and / or Fisher exact test; Cochran–Mantel–Haenszel test 
   LIFETEST, PHREG – survival analysis  
   NPAR1WAY – Mann-Whitney U-test. 
Safety parameters  
Adverse events recorded during the study will be grouped into frequency tables by severity, 
seriousness and relationship with the study drug. 
Data presentation 
Descriptive statistics will be provided for each study continuous / interval variable. Statistic data 
will be presented by mean, standard deviation, min and max values. Comparisons suggesting 
statistical conclusion will have the relevant confidence intervals. Outliers will be analyzed 
individually. The data will be grouped by visits. The categorical variables will be presented as 
frequency tables by visits.