Trial Outcomes & Findings for Clinical Trial of Efficacy and Safety of Subetta in the Combined Treatment of Patients With Type I Diabetes Mellitus (NCT NCT01868594)

Last Updated: 2019-05-30

Results Overview

The HbA1C test was performed using a method that is certified by the National Glycohemoglobin Standardization Program (NGSP) (www.ngsp.org) and standardized or traceable to the Diabetes Control and Complications Trial (DCCT) reference assay.

Recruitment status

COMPLETED

Study phase

PHASE4

Target enrollment

200 participants

Primary outcome timeframe

baseline and 12, 24 and 36 weeks of the treatment

Results posted on

2019-05-30

Participant Flow

The study enrolled patients using intensive insulin regimen (Short-acting and Long-acting human insulins) with type 1 diabetes who were not meeting glycemic control (HbA1c\>7.0%). Eligible patients were assessed by endocrinologists. The study was performed in 15 medical institutions in Russia from May 2013 to October 2015.

Selection procedures were carried out after participant enrollment to determine whether the patient could participate in the study in accordance with the inclusion/exclusion criteria. Of the 200 patients enrolled, 49 did not meet inclusion criteria after screening procedures, they were not randomized

Participant milestones

Participant milestones
Measure	Subetta Short-acting and Long-acting human insulins + Subetta (1 tablet 4 times a day). Subetta: oral administration, per 1 intake - 1 tablet (keep in the mouth until complete dissolution, not at mealtime). Subetta: Efficacy and Safety of Subetta in the combined treatment of patients with type I diabetes mellitus	Placebo Short-acting and Long-acting human insulins + Placebo (1 tablet 4 times a day). Placebo: oral administration, per 1 intake - 1 tablet (keep in the mouth until complete dissolution, not at mealtime). Placebo
Overall Study STARTED	76	75
Overall Study COMPLETED	72	72
Overall Study NOT COMPLETED	4	3

Reasons for withdrawal

Reasons for withdrawal
Measure	Subetta Short-acting and Long-acting human insulins + Subetta (1 tablet 4 times a day). Subetta: oral administration, per 1 intake - 1 tablet (keep in the mouth until complete dissolution, not at mealtime). Subetta: Efficacy and Safety of Subetta in the combined treatment of patients with type I diabetes mellitus	Placebo Short-acting and Long-acting human insulins + Placebo (1 tablet 4 times a day). Placebo: oral administration, per 1 intake - 1 tablet (keep in the mouth until complete dissolution, not at mealtime). Placebo
Overall Study Do not meet inclusion criteria	4	3

Baseline Characteristics

Clinical Trial of Efficacy and Safety of Subetta in the Combined Treatment of Patients With Type I Diabetes Mellitus

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Subetta n=72 Participants Short-acting and Long-acting human insulins + Subetta (1 tablet 4 times a day). Subetta: oral administration, per 1 intake - 1 tablet (keep in the mouth until complete dissolution, not at mealtime). Subetta: Efficacy and Safety of Subetta in the combined treatment of patients with type I diabetes mellitus	Placebo n=72 Participants Short-acting and Long-acting human insulins + Placebo (1 tablet 4 times a day). Placebo: oral administration, per 1 intake - 1 tablet (keep in the mouth until complete dissolution, not at mealtime). Placebo	Total n=144 Participants Total of all reporting groups
Age, Continuous	37.2 years STANDARD_DEVIATION 9.6 • n=5 Participants	35.0 years STANDARD_DEVIATION 10.4 • n=7 Participants	36.1 years STANDARD_DEVIATION 10.0 • n=5 Participants
Sex: Female, Male Female	34 Participants n=5 Participants	36 Participants n=7 Participants	70 Participants n=5 Participants
Sex: Female, Male Male	38 Participants n=5 Participants	36 Participants n=7 Participants	74 Participants n=5 Participants
Weight	77.7 kilogram STANDARD_DEVIATION 15.2 • n=5 Participants	74.4 kilogram STANDARD_DEVIATION 13.5 • n=7 Participants	76.0 kilogram STANDARD_DEVIATION 14.4 • n=5 Participants

PRIMARY outcome

Timeframe: baseline and 12, 24 and 36 weeks of the treatment

Population: Intention-to-Treat set

Outcome measures

Outcome measures
Measure	Subetta n=72 Participants Short-acting and Long-acting human insulins + Subetta (1 tablet 4 times a day). Subetta: oral administration, per 1 intake - 1 tablet (keep in the mouth until complete dissolution, not at mealtime). Subetta: Efficacy and Safety of Subetta in the combined treatment of patients with type I diabetes mellitus	Placebo n=72 Participants Short-acting and Long-acting human insulins + Placebo (1 tablet 4 times a day). Placebo: oral administration, per 1 intake - 1 tablet (keep in the mouth until complete dissolution, not at mealtime). Placebo
Changes in the Mean Value of HbA1c 12 weeks	-0.71 percentage of HbA1c Standard Deviation 0.91	-0.49 percentage of HbA1c Standard Deviation 1.02
Changes in the Mean Value of HbA1c 24 weeks	-0.66 percentage of HbA1c Standard Deviation 0.94	-0.27 percentage of HbA1c Standard Deviation 1.13
Changes in the Mean Value of HbA1c 36 weeks	-0.59 percentage of HbA1c Standard Deviation 0.99	-0.20 percentage of HbA1c Standard Deviation 1.14

SECONDARY outcome

Timeframe: baseline and 4, 12, 24 and 36 weeks of the treatment

Population: Intention-to-Treat set

Outcome measures

Outcome measures
Measure	Subetta n=72 Participants Short-acting and Long-acting human insulins + Subetta (1 tablet 4 times a day). Subetta: oral administration, per 1 intake - 1 tablet (keep in the mouth until complete dissolution, not at mealtime). Subetta: Efficacy and Safety of Subetta in the combined treatment of patients with type I diabetes mellitus	Placebo n=72 Participants Short-acting and Long-acting human insulins + Placebo (1 tablet 4 times a day). Placebo: oral administration, per 1 intake - 1 tablet (keep in the mouth until complete dissolution, not at mealtime). Placebo
Change in Fasting Plasma Glucose (Based on the Data of Biochemical Analysis) 24 weeks	-0.7 mmol / l Standard Deviation 4.9	0.7 mmol / l Standard Deviation 5.4
Change in Fasting Plasma Glucose (Based on the Data of Biochemical Analysis) 4 weeks	-0.5 mmol / l Standard Deviation 5.1	0.3 mmol / l Standard Deviation 4.6
Change in Fasting Plasma Glucose (Based on the Data of Biochemical Analysis) 12 weeks	-0.2 mmol / l Standard Deviation 4.8	0.8 mmol / l Standard Deviation 4.9
Change in Fasting Plasma Glucose (Based on the Data of Biochemical Analysis) 36 weeks	-0.8 mmol / l Standard Deviation 4.8	1.1 mmol / l Standard Deviation 5.4

SECONDARY outcome

Timeframe: baseline and 4, 8, 12, 18, 24, 30 and 36 weeks of the treatment

Population: Intention-to-Treat. 2 patients (1 in Subetta group and 1 in Placebo group) was excluded from the analysis due to lake of diaries

A 7-point patient self-monitoring of blood glucose (SMBG): three measurements of blood glucose before the meal; three measurements of postprandial blood glucose (1-2 h after the start of the meal) and one measurement at 3:00 a.m.

Outcome measures

Outcome measures
Measure	Subetta n=71 Participants Short-acting and Long-acting human insulins + Subetta (1 tablet 4 times a day). Subetta: oral administration, per 1 intake - 1 tablet (keep in the mouth until complete dissolution, not at mealtime). Subetta: Efficacy and Safety of Subetta in the combined treatment of patients with type I diabetes mellitus	Placebo n=71 Participants Short-acting and Long-acting human insulins + Placebo (1 tablet 4 times a day). Placebo: oral administration, per 1 intake - 1 tablet (keep in the mouth until complete dissolution, not at mealtime). Placebo
Change in Average Daily Blood Glucose From a 7-point Patient Self-monitoring of Blood Glucose (SMBG) 8 weeks	-0.2 mmol / l Standard Deviation 1.7	-0.1 mmol / l Standard Deviation 2.0
Change in Average Daily Blood Glucose From a 7-point Patient Self-monitoring of Blood Glucose (SMBG) 12 weeks	-0.2 mmol / l Standard Deviation 1.6	-0.2 mmol / l Standard Deviation 2.0
Change in Average Daily Blood Glucose From a 7-point Patient Self-monitoring of Blood Glucose (SMBG) 18 weeks	-0.1 mmol / l Standard Deviation 2.2	-0.1 mmol / l Standard Deviation 1.9
Change in Average Daily Blood Glucose From a 7-point Patient Self-monitoring of Blood Glucose (SMBG) 36 weeks	-0.1 mmol / l Standard Deviation 1.9	0.0 mmol / l Standard Deviation 2.0
Change in Average Daily Blood Glucose From a 7-point Patient Self-monitoring of Blood Glucose (SMBG) 4 weeks	-0.1 mmol / l Standard Deviation 1.4	0.1 mmol / l Standard Deviation 1.8
Change in Average Daily Blood Glucose From a 7-point Patient Self-monitoring of Blood Glucose (SMBG) 24 weeks	-0.3 mmol / l Standard Deviation 1.7	0.0 mmol / l Standard Deviation 2.0
Change in Average Daily Blood Glucose From a 7-point Patient Self-monitoring of Blood Glucose (SMBG) 30 weeks	0.0 mmol / l Standard Deviation 1.8	-0.1 mmol / l Standard Deviation 1.8

SECONDARY outcome

Timeframe: baseline and 12, 24 and 36 weeks of the treatment

Population: Intention-to-Treat set

Blood samples (for measurement of fasting plasma glucose, concentrations of plasma total cholesterol, HDL cholesterol, LDL cholesterol and triglycerides) are taken under standard conditions: after night break in food taking (at least 12 hours) and prior to administering of insulin morning dose (prandial), prior to any morning medicines intake (including the study drug and permitted concomitant therapy).

Outcome measures

Outcome measures
Measure	Subetta n=72 Participants Short-acting and Long-acting human insulins + Subetta (1 tablet 4 times a day). Subetta: oral administration, per 1 intake - 1 tablet (keep in the mouth until complete dissolution, not at mealtime). Subetta: Efficacy and Safety of Subetta in the combined treatment of patients with type I diabetes mellitus	Placebo n=72 Participants Short-acting and Long-acting human insulins + Placebo (1 tablet 4 times a day). Placebo: oral administration, per 1 intake - 1 tablet (keep in the mouth until complete dissolution, not at mealtime). Placebo
Changes in Lipids (Concentrations of Plasma Total Cholesterol, HDL Cholesterol, LDL Cholesterol and Triglycerides) Total cholesterol (24 weeks)	0.1 mmol / l Standard Deviation 1.1	0.4 mmol / l Standard Deviation 1.2
Changes in Lipids (Concentrations of Plasma Total Cholesterol, HDL Cholesterol, LDL Cholesterol and Triglycerides) HDL cholesterol (12 weeks)	0.1 mmol / l Standard Deviation 0.3	0.0 mmol / l Standard Deviation 0.3
Changes in Lipids (Concentrations of Plasma Total Cholesterol, HDL Cholesterol, LDL Cholesterol and Triglycerides) HDL cholesterol (24 weeks)	0.0 mmol / l Standard Deviation 0.3	0.0 mmol / l Standard Deviation 0.3
Changes in Lipids (Concentrations of Plasma Total Cholesterol, HDL Cholesterol, LDL Cholesterol and Triglycerides) LDL cholesterol (12 weeks)	0.2 mmol / l Standard Deviation 0.8	0.2 mmol / l Standard Deviation 0.6
Changes in Lipids (Concentrations of Plasma Total Cholesterol, HDL Cholesterol, LDL Cholesterol and Triglycerides) Triglycerides (36 weeks)	-0.1 mmol / l Standard Deviation 0.6	0.1 mmol / l Standard Deviation 0.8
Changes in Lipids (Concentrations of Plasma Total Cholesterol, HDL Cholesterol, LDL Cholesterol and Triglycerides) Total cholesterol (12 weeks)	0.2 mmol / l Standard Deviation 1.0	0.2 mmol / l Standard Deviation 0.9
Changes in Lipids (Concentrations of Plasma Total Cholesterol, HDL Cholesterol, LDL Cholesterol and Triglycerides) Total cholesterol (36 weeks)	0.2 mmol / l Standard Deviation 1.0	0.3 mmol / l Standard Deviation 1.2
Changes in Lipids (Concentrations of Plasma Total Cholesterol, HDL Cholesterol, LDL Cholesterol and Triglycerides) HDL cholesterol (36 weeks)	0.1 mmol / l Standard Deviation 0.3	0.0 mmol / l Standard Deviation 0.3
Changes in Lipids (Concentrations of Plasma Total Cholesterol, HDL Cholesterol, LDL Cholesterol and Triglycerides) LDL cholesterol (24 weeks)	0.0 mmol / l Standard Deviation 0.9	0.3 mmol / l Standard Deviation 0.9
Changes in Lipids (Concentrations of Plasma Total Cholesterol, HDL Cholesterol, LDL Cholesterol and Triglycerides) LDL cholesterol (36 weeks)	0.1 mmol / l Standard Deviation 0.8	0.3 mmol / l Standard Deviation 0.9
Changes in Lipids (Concentrations of Plasma Total Cholesterol, HDL Cholesterol, LDL Cholesterol and Triglycerides) Triglycerides (12 weeks)	-0.1 mmol / l Standard Deviation 0.6	0.1 mmol / l Standard Deviation 0.8
Changes in Lipids (Concentrations of Plasma Total Cholesterol, HDL Cholesterol, LDL Cholesterol and Triglycerides) Triglycerides (24 weeks)	-0.1 mmol / l Standard Deviation 0.6	0.0 mmol / l Standard Deviation 0.6

SECONDARY outcome

Timeframe: baseline and 36 weeks of the treatment

Population: Intention-to-Treat set

Insulin dose should be corrected by a patient on a daily basis taking into consideration data on blood glucose self- monitoring during a day and amount of food carbohydrates. Physician can correct insulin dose based on the same data.

Outcome measures

Outcome measures
Measure	Subetta n=72 Participants Short-acting and Long-acting human insulins + Subetta (1 tablet 4 times a day). Subetta: oral administration, per 1 intake - 1 tablet (keep in the mouth until complete dissolution, not at mealtime). Subetta: Efficacy and Safety of Subetta in the combined treatment of patients with type I diabetes mellitus	Placebo n=72 Participants Short-acting and Long-acting human insulins + Placebo (1 tablet 4 times a day). Placebo: oral administration, per 1 intake - 1 tablet (keep in the mouth until complete dissolution, not at mealtime). Placebo
Changes in Dosage of Insulin (Basal, Prandial and Total Daily Dose Insulin Measured in IU) Basal insulin (36 weeks)	0.4 IU Standard Deviation 2.4	0.9 IU Standard Deviation 2.9
Changes in Dosage of Insulin (Basal, Prandial and Total Daily Dose Insulin Measured in IU) Prandial insulin (36 weeks)	-1.6 IU Standard Deviation 6.9	-0.9 IU Standard Deviation 4.5
Changes in Dosage of Insulin (Basal, Prandial and Total Daily Dose Insulin Measured in IU) Total daily dose insulin (36 weeks)	-1.2 IU Standard Deviation 8.3	0.0 IU Standard Deviation 6.2

SECONDARY outcome

Timeframe: baseline and 36 weeks of the treatment

Population: Intention-to-Treat set

Outcome measures

Outcome measures
Measure	Subetta n=72 Participants Short-acting and Long-acting human insulins + Subetta (1 tablet 4 times a day). Subetta: oral administration, per 1 intake - 1 tablet (keep in the mouth until complete dissolution, not at mealtime). Subetta: Efficacy and Safety of Subetta in the combined treatment of patients with type I diabetes mellitus	Placebo n=72 Participants Short-acting and Long-acting human insulins + Placebo (1 tablet 4 times a day). Placebo: oral administration, per 1 intake - 1 tablet (keep in the mouth until complete dissolution, not at mealtime). Placebo
Changes in Dosage of Total Insulin Measured in IU/kg of Body Weight	-0.02 IU/kg Standard Deviation 0.09	-0.01 IU/kg Standard Deviation 0.08

SECONDARY outcome

Timeframe: 36 weeks of the treatment

Population: Intention-to-Treat set. 6 patients (1 in the Subetta group and 5 in the Placebo group) was excluded from the analysis due to lake of questionnaires.

The Diabetes Treatment Satisfaction Questionnaire allows to assess the degree of satisfaction with treatment for diabetes and its complications - retinopathy and nephropathy, how patients' satisfaction and perceived hyper- and hypoglycemia have changed compared to the initial period (before the treatment). The Diabetes Treatment Satisfaction Questionnaire contains six items scored on 7-point scales from +3 (equals "very satisfied") to -3 (equals "very dissatisfied"), with 0 (equals "no change"). These are summed to produce a total Treatment Satisfaction score. Two questions concerning "Perceived Hyperglycaemia" and "Perceived Hypoglycaemia" respectively, are calculated separately. According to these two items, low scores represent good perceived blood glucose control (+3 means "most of the time" of Hyperglycaemia or Hypoglycaemia whereas -3 means "none of the time" of Hyperglycaemia or Hypoglycaemia).

Outcome measures

Outcome measures
Measure	Subetta n=71 Participants Short-acting and Long-acting human insulins + Subetta (1 tablet 4 times a day). Subetta: oral administration, per 1 intake - 1 tablet (keep in the mouth until complete dissolution, not at mealtime). Subetta: Efficacy and Safety of Subetta in the combined treatment of patients with type I diabetes mellitus	Placebo n=67 Participants Short-acting and Long-acting human insulins + Placebo (1 tablet 4 times a day). Placebo: oral administration, per 1 intake - 1 tablet (keep in the mouth until complete dissolution, not at mealtime). Placebo
Satisfaction of Diabetes Treatment Based on Diabetes Treatment Satisfaction Questionnaire Data Satisfaction	9.7 score on a scale Standard Deviation 6.6	8.4 score on a scale Standard Deviation 6.5
Satisfaction of Diabetes Treatment Based on Diabetes Treatment Satisfaction Questionnaire Data Hypoglycemia	-0.4 score on a scale Standard Deviation 1.6	-0.6 score on a scale Standard Deviation 1.4
Satisfaction of Diabetes Treatment Based on Diabetes Treatment Satisfaction Questionnaire Data Hyperglycemia	-0.7 score on a scale Standard Deviation 1.5	-0.6 score on a scale Standard Deviation 1.6

Adverse Events

Subetta

Serious events: 2 serious events

Other events: 16 other events

Deaths: 0 deaths

Placebo

Serious events: 3 serious events

Other events: 18 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Subetta n=76 participants at risk Standard therapy of type I diabetes mellitus + Subetta (1 tablet 4 times a day). Subetta: oral administration, per 1 intake - 1 tablet (keep in the mouth until complete dissolution, not at mealtime). Subetta: Efficacy and Safety of Subetta in the combined treatment of patients with type I diabetes mellitus	Placebo n=75 participants at risk Standard therapy of type I diabetes mellitus + Placebo (1 tablet 4 times a day). Placebo: oral administration, per 1 intake - 1 tablet (keep in the mouth until complete dissolution, not at mealtime). Placebo
Vascular disorders Hypertension arterial	1.3% 1/76 • Adverse/Serious adverse events were registered during 36 weeks of therapy and 30 days after the end of therapy. Adverse/Serious adverse events were registered in patients of the Full Analysis Set (n=151, Safety Population)	0.00% 0/75 • Adverse/Serious adverse events were registered during 36 weeks of therapy and 30 days after the end of therapy. Adverse/Serious adverse events were registered in patients of the Full Analysis Set (n=151, Safety Population)
Injury, poisoning and procedural complications Fracture of humerus	1.3% 1/76 • Adverse/Serious adverse events were registered during 36 weeks of therapy and 30 days after the end of therapy. Adverse/Serious adverse events were registered in patients of the Full Analysis Set (n=151, Safety Population)	0.00% 0/75 • Adverse/Serious adverse events were registered during 36 weeks of therapy and 30 days after the end of therapy. Adverse/Serious adverse events were registered in patients of the Full Analysis Set (n=151, Safety Population)
Infections and infestations Parotid abscess	0.00% 0/76 • Adverse/Serious adverse events were registered during 36 weeks of therapy and 30 days after the end of therapy. Adverse/Serious adverse events were registered in patients of the Full Analysis Set (n=151, Safety Population)	1.3% 1/75 • Adverse/Serious adverse events were registered during 36 weeks of therapy and 30 days after the end of therapy. Adverse/Serious adverse events were registered in patients of the Full Analysis Set (n=151, Safety Population)
Vascular disorders Chronic venous insufficiency	0.00% 0/76 • Adverse/Serious adverse events were registered during 36 weeks of therapy and 30 days after the end of therapy. Adverse/Serious adverse events were registered in patients of the Full Analysis Set (n=151, Safety Population)	1.3% 1/75 • Adverse/Serious adverse events were registered during 36 weeks of therapy and 30 days after the end of therapy. Adverse/Serious adverse events were registered in patients of the Full Analysis Set (n=151, Safety Population)
Vascular disorders Varicose veins of lower extremities	0.00% 0/76 • Adverse/Serious adverse events were registered during 36 weeks of therapy and 30 days after the end of therapy. Adverse/Serious adverse events were registered in patients of the Full Analysis Set (n=151, Safety Population)	1.3% 1/75 • Adverse/Serious adverse events were registered during 36 weeks of therapy and 30 days after the end of therapy. Adverse/Serious adverse events were registered in patients of the Full Analysis Set (n=151, Safety Population)
Metabolism and nutrition disorders Type I diabetes mellitus with ketoacidosis	0.00% 0/76 • Adverse/Serious adverse events were registered during 36 weeks of therapy and 30 days after the end of therapy. Adverse/Serious adverse events were registered in patients of the Full Analysis Set (n=151, Safety Population)	1.3% 1/75 • Adverse/Serious adverse events were registered during 36 weeks of therapy and 30 days after the end of therapy. Adverse/Serious adverse events were registered in patients of the Full Analysis Set (n=151, Safety Population)

Other adverse events

Additional Information

Michael Putilovskiy, MD, PhD, Clinical Research and Medical Information Director

Materia Medica Holding

Phone: +74952761571

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Subetta n=76 participants at risk Standard therapy of type I diabetes mellitus + Subetta (1 tablet 4 times a day). Subetta: oral administration, per 1 intake - 1 tablet (keep in the mouth until complete dissolution, not at mealtime). Subetta: Efficacy and Safety of Subetta in the combined treatment of patients with type I diabetes mellitus	Placebo n=75 participants at risk Standard therapy of type I diabetes mellitus + Placebo (1 tablet 4 times a day). Placebo: oral administration, per 1 intake - 1 tablet (keep in the mouth until complete dissolution, not at mealtime). Placebo
Blood and lymphatic system disorders Inflammation of inguinal lymphonodus on the right	0.00% 0/76 • Adverse/Serious adverse events were registered during 36 weeks of therapy and 30 days after the end of therapy. Adverse/Serious adverse events were registered in patients of the Full Analysis Set (n=151, Safety Population)	1.3% 1/75 • Adverse/Serious adverse events were registered during 36 weeks of therapy and 30 days after the end of therapy. Adverse/Serious adverse events were registered in patients of the Full Analysis Set (n=151, Safety Population)
Endocrine disorders Goiter	1.3% 1/76 • Adverse/Serious adverse events were registered during 36 weeks of therapy and 30 days after the end of therapy. Adverse/Serious adverse events were registered in patients of the Full Analysis Set (n=151, Safety Population)	0.00% 0/75 • Adverse/Serious adverse events were registered during 36 weeks of therapy and 30 days after the end of therapy. Adverse/Serious adverse events were registered in patients of the Full Analysis Set (n=151, Safety Population)
Endocrine disorders Subclinical hypothyreoidism	1.3% 1/76 • Adverse/Serious adverse events were registered during 36 weeks of therapy and 30 days after the end of therapy. Adverse/Serious adverse events were registered in patients of the Full Analysis Set (n=151, Safety Population)	0.00% 0/75 • Adverse/Serious adverse events were registered during 36 weeks of therapy and 30 days after the end of therapy. Adverse/Serious adverse events were registered in patients of the Full Analysis Set (n=151, Safety Population)
Gastrointestinal disorders Bacterial food poisoning	1.3% 1/76 • Adverse/Serious adverse events were registered during 36 weeks of therapy and 30 days after the end of therapy. Adverse/Serious adverse events were registered in patients of the Full Analysis Set (n=151, Safety Population)	0.00% 0/75 • Adverse/Serious adverse events were registered during 36 weeks of therapy and 30 days after the end of therapy. Adverse/Serious adverse events were registered in patients of the Full Analysis Set (n=151, Safety Population)
Gastrointestinal disorders Heartburn	1.3% 1/76 • Adverse/Serious adverse events were registered during 36 weeks of therapy and 30 days after the end of therapy. Adverse/Serious adverse events were registered in patients of the Full Analysis Set (n=151, Safety Population)	0.00% 0/75 • Adverse/Serious adverse events were registered during 36 weeks of therapy and 30 days after the end of therapy. Adverse/Serious adverse events were registered in patients of the Full Analysis Set (n=151, Safety Population)
Gastrointestinal disorders Epigastric pain	0.00% 0/76 • Adverse/Serious adverse events were registered during 36 weeks of therapy and 30 days after the end of therapy. Adverse/Serious adverse events were registered in patients of the Full Analysis Set (n=151, Safety Population)	1.3% 1/75 • Adverse/Serious adverse events were registered during 36 weeks of therapy and 30 days after the end of therapy. Adverse/Serious adverse events were registered in patients of the Full Analysis Set (n=151, Safety Population)
Gastrointestinal disorders Dentalgia	0.00% 0/76 • Adverse/Serious adverse events were registered during 36 weeks of therapy and 30 days after the end of therapy. Adverse/Serious adverse events were registered in patients of the Full Analysis Set (n=151, Safety Population)	1.3% 1/75 • Adverse/Serious adverse events were registered during 36 weeks of therapy and 30 days after the end of therapy. Adverse/Serious adverse events were registered in patients of the Full Analysis Set (n=151, Safety Population)
General disorders Increase in body temperature to 38.5 C	0.00% 0/76 • Adverse/Serious adverse events were registered during 36 weeks of therapy and 30 days after the end of therapy. Adverse/Serious adverse events were registered in patients of the Full Analysis Set (n=151, Safety Population)	2.7% 2/75 • Adverse/Serious adverse events were registered during 36 weeks of therapy and 30 days after the end of therapy. Adverse/Serious adverse events were registered in patients of the Full Analysis Set (n=151, Safety Population)
General disorders Increase in body temperature up to 38.2 С	0.00% 0/76 • Adverse/Serious adverse events were registered during 36 weeks of therapy and 30 days after the end of therapy. Adverse/Serious adverse events were registered in patients of the Full Analysis Set (n=151, Safety Population)	1.3% 1/75 • Adverse/Serious adverse events were registered during 36 weeks of therapy and 30 days after the end of therapy. Adverse/Serious adverse events were registered in patients of the Full Analysis Set (n=151, Safety Population)
Hepatobiliary disorders Diabetic hepatosis	1.3% 1/76 • Adverse/Serious adverse events were registered during 36 weeks of therapy and 30 days after the end of therapy. Adverse/Serious adverse events were registered in patients of the Full Analysis Set (n=151, Safety Population)	0.00% 0/75 • Adverse/Serious adverse events were registered during 36 weeks of therapy and 30 days after the end of therapy. Adverse/Serious adverse events were registered in patients of the Full Analysis Set (n=151, Safety Population)
Immune system disorders Allergic reactions	0.00% 0/76 • Adverse/Serious adverse events were registered during 36 weeks of therapy and 30 days after the end of therapy. Adverse/Serious adverse events were registered in patients of the Full Analysis Set (n=151, Safety Population)	1.3% 1/75 • Adverse/Serious adverse events were registered during 36 weeks of therapy and 30 days after the end of therapy. Adverse/Serious adverse events were registered in patients of the Full Analysis Set (n=151, Safety Population)
Infections and infestations Angina	0.00% 0/76 • Adverse/Serious adverse events were registered during 36 weeks of therapy and 30 days after the end of therapy. Adverse/Serious adverse events were registered in patients of the Full Analysis Set (n=151, Safety Population)	1.3% 1/75 • Adverse/Serious adverse events were registered during 36 weeks of therapy and 30 days after the end of therapy. Adverse/Serious adverse events were registered in patients of the Full Analysis Set (n=151, Safety Population)
Infections and infestations Acute respiratory viral infection	6.6% 5/76 • Adverse/Serious adverse events were registered during 36 weeks of therapy and 30 days after the end of therapy. Adverse/Serious adverse events were registered in patients of the Full Analysis Set (n=151, Safety Population)	4.0% 3/75 • Adverse/Serious adverse events were registered during 36 weeks of therapy and 30 days after the end of therapy. Adverse/Serious adverse events were registered in patients of the Full Analysis Set (n=151, Safety Population)
Infections and infestations Acute respiratory disease	0.00% 0/76 • Adverse/Serious adverse events were registered during 36 weeks of therapy and 30 days after the end of therapy. Adverse/Serious adverse events were registered in patients of the Full Analysis Set (n=151, Safety Population)	4.0% 3/75 • Adverse/Serious adverse events were registered during 36 weeks of therapy and 30 days after the end of therapy. Adverse/Serious adverse events were registered in patients of the Full Analysis Set (n=151, Safety Population)
Infections and infestations Acute bronchitis	0.00% 0/76 • Adverse/Serious adverse events were registered during 36 weeks of therapy and 30 days after the end of therapy. Adverse/Serious adverse events were registered in patients of the Full Analysis Set (n=151, Safety Population)	4.0% 3/75 • Adverse/Serious adverse events were registered during 36 weeks of therapy and 30 days after the end of therapy. Adverse/Serious adverse events were registered in patients of the Full Analysis Set (n=151, Safety Population)
Infections and infestations Parodontosis	0.00% 0/76 • Adverse/Serious adverse events were registered during 36 weeks of therapy and 30 days after the end of therapy. Adverse/Serious adverse events were registered in patients of the Full Analysis Set (n=151, Safety Population)	1.3% 1/75 • Adverse/Serious adverse events were registered during 36 weeks of therapy and 30 days after the end of therapy. Adverse/Serious adverse events were registered in patients of the Full Analysis Set (n=151, Safety Population)
Infections and infestations Epididymitis	0.00% 0/76 • Adverse/Serious adverse events were registered during 36 weeks of therapy and 30 days after the end of therapy. Adverse/Serious adverse events were registered in patients of the Full Analysis Set (n=151, Safety Population)	1.3% 1/75 • Adverse/Serious adverse events were registered during 36 weeks of therapy and 30 days after the end of therapy. Adverse/Serious adverse events were registered in patients of the Full Analysis Set (n=151, Safety Population)
Injury, poisoning and procedural complications Contusion of the hand	0.00% 0/76 • Adverse/Serious adverse events were registered during 36 weeks of therapy and 30 days after the end of therapy. Adverse/Serious adverse events were registered in patients of the Full Analysis Set (n=151, Safety Population)	1.3% 1/75 • Adverse/Serious adverse events were registered during 36 weeks of therapy and 30 days after the end of therapy. Adverse/Serious adverse events were registered in patients of the Full Analysis Set (n=151, Safety Population)
Investigations Palpitations	1.3% 1/76 • Adverse/Serious adverse events were registered during 36 weeks of therapy and 30 days after the end of therapy. Adverse/Serious adverse events were registered in patients of the Full Analysis Set (n=151, Safety Population)	0.00% 0/75 • Adverse/Serious adverse events were registered during 36 weeks of therapy and 30 days after the end of therapy. Adverse/Serious adverse events were registered in patients of the Full Analysis Set (n=151, Safety Population)
Investigations Increased blood pressure to 150/90 mm Hg, headache, nausea	0.00% 0/76 • Adverse/Serious adverse events were registered during 36 weeks of therapy and 30 days after the end of therapy. Adverse/Serious adverse events were registered in patients of the Full Analysis Set (n=151, Safety Population)	1.3% 1/75 • Adverse/Serious adverse events were registered during 36 weeks of therapy and 30 days after the end of therapy. Adverse/Serious adverse events were registered in patients of the Full Analysis Set (n=151, Safety Population)
Investigations Increased body temperature	0.00% 0/76 • Adverse/Serious adverse events were registered during 36 weeks of therapy and 30 days after the end of therapy. Adverse/Serious adverse events were registered in patients of the Full Analysis Set (n=151, Safety Population)	1.3% 1/75 • Adverse/Serious adverse events were registered during 36 weeks of therapy and 30 days after the end of therapy. Adverse/Serious adverse events were registered in patients of the Full Analysis Set (n=151, Safety Population)
Metabolism and nutrition disorders Fasting hyperglycemia	2.6% 2/76 • Adverse/Serious adverse events were registered during 36 weeks of therapy and 30 days after the end of therapy. Adverse/Serious adverse events were registered in patients of the Full Analysis Set (n=151, Safety Population)	4.0% 3/75 • Adverse/Serious adverse events were registered during 36 weeks of therapy and 30 days after the end of therapy. Adverse/Serious adverse events were registered in patients of the Full Analysis Set (n=151, Safety Population)
Metabolism and nutrition disorders Ketoacidosis	0.00% 0/76 • Adverse/Serious adverse events were registered during 36 weeks of therapy and 30 days after the end of therapy. Adverse/Serious adverse events were registered in patients of the Full Analysis Set (n=151, Safety Population)	2.7% 2/75 • Adverse/Serious adverse events were registered during 36 weeks of therapy and 30 days after the end of therapy. Adverse/Serious adverse events were registered in patients of the Full Analysis Set (n=151, Safety Population)
Musculoskeletal and connective tissue disorders Pain in the shoulder	0.00% 0/76 • Adverse/Serious adverse events were registered during 36 weeks of therapy and 30 days after the end of therapy. Adverse/Serious adverse events were registered in patients of the Full Analysis Set (n=151, Safety Population)	1.3% 1/75 • Adverse/Serious adverse events were registered during 36 weeks of therapy and 30 days after the end of therapy. Adverse/Serious adverse events were registered in patients of the Full Analysis Set (n=151, Safety Population)
Musculoskeletal and connective tissue disorders Heavy legs	1.3% 1/76 • Adverse/Serious adverse events were registered during 36 weeks of therapy and 30 days after the end of therapy. Adverse/Serious adverse events were registered in patients of the Full Analysis Set (n=151, Safety Population)	0.00% 0/75 • Adverse/Serious adverse events were registered during 36 weeks of therapy and 30 days after the end of therapy. Adverse/Serious adverse events were registered in patients of the Full Analysis Set (n=151, Safety Population)
Musculoskeletal and connective tissue disorders Leg cramps	1.3% 1/76 • Adverse/Serious adverse events were registered during 36 weeks of therapy and 30 days after the end of therapy. Adverse/Serious adverse events were registered in patients of the Full Analysis Set (n=151, Safety Population)	0.00% 0/75 • Adverse/Serious adverse events were registered during 36 weeks of therapy and 30 days after the end of therapy. Adverse/Serious adverse events were registered in patients of the Full Analysis Set (n=151, Safety Population)
Musculoskeletal and connective tissue disorders Cervicalgia	0.00% 0/76 • Adverse/Serious adverse events were registered during 36 weeks of therapy and 30 days after the end of therapy. Adverse/Serious adverse events were registered in patients of the Full Analysis Set (n=151, Safety Population)	2.7% 2/75 • Adverse/Serious adverse events were registered during 36 weeks of therapy and 30 days after the end of therapy. Adverse/Serious adverse events were registered in patients of the Full Analysis Set (n=151, Safety Population)
Nervous system disorders Headache	6.6% 5/76 • Adverse/Serious adverse events were registered during 36 weeks of therapy and 30 days after the end of therapy. Adverse/Serious adverse events were registered in patients of the Full Analysis Set (n=151, Safety Population)	2.7% 2/75 • Adverse/Serious adverse events were registered during 36 weeks of therapy and 30 days after the end of therapy. Adverse/Serious adverse events were registered in patients of the Full Analysis Set (n=151, Safety Population)
Pregnancy, puerperium and perinatal conditions Pregnancy	1.3% 1/76 • Adverse/Serious adverse events were registered during 36 weeks of therapy and 30 days after the end of therapy. Adverse/Serious adverse events were registered in patients of the Full Analysis Set (n=151, Safety Population)	0.00% 0/75 • Adverse/Serious adverse events were registered during 36 weeks of therapy and 30 days after the end of therapy. Adverse/Serious adverse events were registered in patients of the Full Analysis Set (n=151, Safety Population)
Respiratory, thoracic and mediastinal disorders Vasomotor rhinitis	0.00% 0/76 • Adverse/Serious adverse events were registered during 36 weeks of therapy and 30 days after the end of therapy. Adverse/Serious adverse events were registered in patients of the Full Analysis Set (n=151, Safety Population)	1.3% 1/75 • Adverse/Serious adverse events were registered during 36 weeks of therapy and 30 days after the end of therapy. Adverse/Serious adverse events were registered in patients of the Full Analysis Set (n=151, Safety Population)
Respiratory, thoracic and mediastinal disorders Throat irritation	0.00% 0/76 • Adverse/Serious adverse events were registered during 36 weeks of therapy and 30 days after the end of therapy. Adverse/Serious adverse events were registered in patients of the Full Analysis Set (n=151, Safety Population)	1.3% 1/75 • Adverse/Serious adverse events were registered during 36 weeks of therapy and 30 days after the end of therapy. Adverse/Serious adverse events were registered in patients of the Full Analysis Set (n=151, Safety Population)
Vascular disorders Increased blood pressure	1.3% 1/76 • Adverse/Serious adverse events were registered during 36 weeks of therapy and 30 days after the end of therapy. Adverse/Serious adverse events were registered in patients of the Full Analysis Set (n=151, Safety Population)	0.00% 0/75 • Adverse/Serious adverse events were registered during 36 weeks of therapy and 30 days after the end of therapy. Adverse/Serious adverse events were registered in patients of the Full Analysis Set (n=151, Safety Population)