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

Study Overview
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Brief Summary
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The purpose of this study is: to assess clinical efficacy of Subetta in the combined treatment of type II diabetes mellitus; to assess safety of Subetta in the combined treatment of type II diabetes mellitus.

Detailed Description
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Patients with type II diabetes mellitus are included in the trial. It is concerned those patients, who by the time of the trial receive basal insulin with metformin or metformin and sulfonylurea derivatives and with lack of optimal glycemic control (HbA1c>7.0%). For patients, which will be included in the trial (mainly middle aged patients without severe complications of diabetes), HbA1c>7.0% is the marker showing that optimal individual goal of glycemic control is not achieved. If a patient meets inclusion criteria and does not show exclusion criteria he/she is randomized in one of 2 groups: Group 1 - the group receiving standard type II diabetes mellitus therapy + Subetta at a dose of 1 tablet 4 times a day; Group 2 - the group receiving standard type II diabetes mellitus therapy + Placebo under the regimen used for Subetta. The invented names of the drugs containing basal insulin, metformin and sulfonylurea derivatives used as standard type II diabetes mellitus therapy, should be unchanged for each patient during the whole trial. All patients will receive glucometers and the appropriate glucose test strips, so they could self monitor blood glucose and register this data in their diaries. The trial duration is 38 weeks; the main stages of the trial are conducted during screening, then in 4 weeks (Visit 2), in 12 weeks (Visit 3), in 24 weeks (Visit 4) and in 36 weeks (Visit 5). In 1 week after randomization and the onset of the trial therapy and between the visits to the study site (on weeks 8±1, 18±1and 30±1) an investigator collects data on patient's health and complaints (phone visits) to decide whether it is necessary to arrange unplanned visit to the site.

Official Title
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Multicentre Double-blind Placebo-controlled Parallel-group Randomized Clinical Trial of Efficacy and Safety of Subetta in the Combined Treatment of Patients With Type II Diabetes Mellitus

Conditions
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Type II Diabetes Mellitus

Intervention / Treatment
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* Drug: Subetta
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosed type II diabetes mellitus (according to WHO criteria, 1999 - 2006). Patient's age from 18 to 65 years inclusive. Level of glycosylated hemoglobin 7.0- 10.0 %. Dose of basal insulin ≥10 units/day combined with metformin or with metformin and sulfonylurea derivatives during not less than 3 months prior to inclusion in the trial. Body mass index ≥25.0 and ≤40.0kg/m^2. Constant body weight (without fluctuations > 10% during not less than 3 months prior to inclusion in the trial). Glomerular filtration rate ≥ 60 ml/ min/1.73m^2. Stable dose of basal insulin for the last 3 months.(Permissible fluctuations are ±10%.) Usage of contraceptive methods by both gender patients of reproductive age during the trial and within 30 days after ending the participation in the trial. Availability of signed patient information sheet (Informed Consent form) for participation in the clinical trial. Exclusion Criteria: Acute diabetes mellitus complications for 3 months prior to inclusion in the trial (diabetic ketoacidosis, hyperosmolar hyperglycemic state, lacticemia, severe hypoglycemia and hypoglycemic coma). Diabetic retinopathy, preproliferative, proliferative or terminal stages (based on the results of oculist examination during screening period or 6 months prior to the trial). Diabetic nephropathy, proteinuria stage, chronic kidney disease on 3, 4 or 5 stage. Diabetic microangiopathy: ishemic heart disease (medical history of a sudden coronary death with successful reanimation, medical history of myocardial infarction, stable exertional angina III or IV FC; unstable angina; postinfarction cardiosclerosis; chronic heart failure III or IV FC); cerebrovascular diseases (medical history of acute cerebrovascular accident; progressive vascular leukoencephalopathy; vascular dementia); chronic obliterative peripheral vascular diseases (clinically significant); diabetic neuroosteoarthropathy; diabetic foot (clinically significant). Heart rhythm disorder: II-III atrioventricular block; sick sinus syndrome; long QT interval syndrome; complete left bundle branch block; block of 2/3 bundle branches; WPW syndrome; ventricular arrhythmia of III grade according Laun-Wolf; paroxysmal supraventricular tachycardia; paroxysmal/recurrent ventricular tachycardia; atrial flutter and fibrillation; ventricular flutter and fibrillation; heart pacemaker implant. Uncontrolled arterial hypertension characterized by the following blood tension values: systolic blood pressure over 160 mm Hg and/or diastolic blood pressure over 100 mm Hg. Severe concomitant pathology including clinically significant cardio- vascular diseases of III - IV functional class (according to New York Heart Association classification, 1964), nervous and endocrine system diseases, including morbid obesity (body mass index≥40.0 kg/m^2), renal insufficiency, liver failure. Medical history of pancreatectomy or transplantation of pancreatic/islet cells. Medical history of renal transplantation. Malignant neoplasms/suspected malignant neoplasms. Exacerbations or decompensation of chronic diseases affecting a patient's ability to participate in the clinical trial. The results of analysis of liver enzymes (alanine aminotransferase, aspartate aminotransferase) more than threefold exceeding of upper limit of normal values. Level of fasting triglycerides >5.64 mmol/L. Medical history of bariatric surgical operations. Medical history of polyvalent allergy Allergy/ intolerance to any of the components of medications used in the treatment. Intake of medicines listed in the section Prohibited concomitant treatment for 3 months prior to the inclusion in the trial. Pregnancy, breast-feeding. Drug addiction, alcohol usage in the amount exceeding 2 units of alcohol per day. Mental disorders of a patient. Night work. Participation in other clinical trials in the course of 3 months prior to the inclusion in the trial. Patients, who from the investigator's point of view, will fail to comply with the observation requirements of the trial or with the intake regimen of the investigated medicines. Other factors impeding patient's participation in the trial (for example, planned business trips or journeys). Patient is related to the research personnel of the investigative site, who are directly involved in the trial or are the immediate relative of the researcher. The immediate relative includes husband/wife, parents, children or brothers (or sisters), regardless of whether they are natural or adopted. Patient works for OOO NPF Materia Medica Holding (i.e. is the company's employee, temporary contract worker or appointed official responsible for the carrying out the research) or the immediate relative.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Subetta<br> | Drug: Subetta<br>* Each Subetta tablet contains a mixture of affinity purified polyclonal antibodies to β-subunit of the rINS (6 mg) and antibodies to eNOS (6 mg) in released-active form produced by the patented technology in accordance with the applicable European Pharmacopeia requirements. Standard therapy of type II diabetes mellitus + Subetta (1 tablet 4 times a day) for 36 weeks. Subetta: oral administration, per 1 intake - 1 tablet (keep in the mouth until complete dissolution, not at mealtime).<br>|
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* Placebo (identical to Subetta in shape and taste tablet containing exсipients). Standard therapy of type II diabetes mellitus + Placebo (1 tablet 4 times a day) for 36 weeks. Placebo: oral administration, per 1 intake - 1 tablet (keep in the mouth until complete dissolution, not at mealtime).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in the Mean Value of HbA1c | 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. | In 12, 24 and 36 weeks of the treatment as compared to the baseline | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Fasting Plasma Glucose | Based on the data of biochemical analysis | In 4, 12, 24 and 36 weeks of the treatment as compared to the baseline | 
| Change in Average Daily Blood Glucose From a 7-point Patient Self-monitoring of Blood Glucose (SMBG) | 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. | During the whole study period (on weeks 4, 8, 12, 18, 24, 30 and 36 of the treatment) as compared to the baseline | 
| Mean Value of C-peptide | Blood samples (for measurement of fasting plasma glucose, concentrations of plasma C-peptide, total cholesterol, HDL cholesterol, LDL cholesterol and triglycerides) are taken under standard conditions: after night break in food taking (at least 8 hours) and prior to administering of insulin morning dose (if patient receives intermediate insulin twice-daily), prior to any morning medicines intake (including the study drug, metformin, sulfonylurea derivatives, permitted concomitant therapy). | In 12, 24 and 36 weeks of the treatment as compared to the baseline | 
| Changes in Lipids (Concentrations of Plasma Total Cholesterol, HDL Cholesterol, LDL Cholesterol and Triglycerides) | 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). | In 12, 24 and 36 weeks of the treatment as compared to the baseline | 
| Changes in Dosage of Insulin (Basal Dose Insulin Measured in IU/Day) | Changes in basal insulin dose is based on the mean value of 3 consecutive measuring of level of fasting blood glucose. If value of fasting blood glucose at 7:00 AM on January 21, 2012 - 4.2 mmol/L, at 7:30 AM on January 22, 2012- 5.0 mmol/L, at 7:00 AM on January 23, 2012 4.8 mmol/L, then the mean level of blood glucose =4.7 mmol/L (4.2 +5.0 +4.8 divided by 3). It is not recommended to change the dose. If the mean value of fasting blood glucose is lower than 4.0 mmol/L and a patient shows unreasonable signs or symptoms of hypoglycemia, then dose of basal insulin should be reduced by 2 units. If value of fasting blood glucose for 3 consecutive days was ≥7 mmol/L, then dose of basal insulin should be increased by 2 units and more (depending on individual values). Based on the same values investigator can change dose of per oral blood sugar-lowering drugs. | In 36 weeks of the treatment as compared to the baseline | 
| Changes in Dosage of Insulin (Basal Dose Insulin Measured in IU/ kg of Body Weight) | Changes in basal insulin dose is based on the mean value of 3 consecutive measuring of level of fasting blood glucose. If value of fasting blood glucose at 7:00 AM on January 21, 2012 - 4.2 mmol/L, at 7:30 AM on January 22, 2012- 5.0 mmol/L, at 7:00 AM on January 23, 2012 4.8 mmol/L, then the mean level of blood glucose =4.7 mmol/L (4.2 +5.0 +4.8 divided by 3). It is not recommended to change the dose. If the mean value of fasting blood glucose is lower than 4.0 mmol/L and a patient shows unreasonable signs or symptoms of hypoglycemia, then dose of basal insulin should be reduced by 2 units. If value of fasting blood glucose for 3 consecutive days was ≥7 mmol/L, then dose of basal insulin should be increased by 2 units and more (depending on individual values). Based on the same values investigator can change dose of per oral blood sugar-lowering drugs. | In 36 weeks of the treatment as compared to the baseline | 
| Percentage of Patients With Changed Daily Dose of Per Oral Blood Sugar- Lowering Drugs |  | In 36 weeks of the treatment | 
| Changes in the Mean Absolute Value of Body Weight (kg) |  | In 36 weeks of the treatment as compared to the baseline | 
| Changes in the Mean Absolute Value of Body Mass Index (BMI) (kg/m^2) |  | baseline and 36 weeks of the treatment | 
| Satisfaction of Diabetes Treatment Based on Diabetes Treatment Satisfaction Questionnaire Data | 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). | In 36 weeks of the treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Combined Treatment of Patients With Type II Diabetes Mellitus