Clinical trial NCT01868594: Clinical Trial of Efficacy and Safety of Subetta in the Combined Treatment of Patients With Type I Diabetes Mellitus
Official title: Multicentre Double-blind Placebo-controlled Parallel-group Randomized Clinical Trial of Efficacy and Safety of Subetta in the Combined Treatment of Patients With Type I Diabetes Mellitus
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Type I Diabetes Mellitus
Keywords: Combined treatment of patients with type I diabetes mellitus
Lead sponsor: Materia Medica Holding
Sponsor class: INDUSTRY
First posted: 2013-06-04
Enrollment: 200
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: SUPPORTIVE_CARE

Brief summary: The purpose of this study is:

* to assess clinical efficacy of Subetta in the combined treatment of type I diabetes mellitus;
* to assess safety of Subetta in the combined treatment of type I diabetes mellitus.

Detailed description: Patients with type I diabetes mellitus are included in the trial. It is concerned those patients, who by the time of the trial receive basal bolus insulin therapy of type I diabetes mellitus, including basal insulin (using long acting medications) and prandial insulin (short and ultra short acting medications), and with poor glycemic control (HbA1c=7.0-10.0%). 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.

HbA1c, fasting plasma glucose, microalbuminuria, estimated glomerular filtration rate, ophthalmoscopy, blood pressure measurement, patient self-monitoring of blood glucose, frequency of hypoglycemia, endocrinologist examination were performed within screening period. Patients without severe diabetes complications are randomized in 2 groups.

If a patient meets inclusion criteria and does not show exclusion criteria he/she is randomized in one of 2 groups: Group 1 - patients receiving standard type I diabetes mellitus therapy + Subetta at a dose of 1 tablet 4 times a day; Group 2 - the group receiving standard type I diabetes mellitus therapy + Placebo under the regimen used for Subetta. The invented names of the drugs containing basal and prandial (meal) insulin 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±1 and 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.

Eligibility criteria: Inclusion Criteria:

1. Diagnosed type I diabetes mellitus (according to WHO criteria, 1999 - 2006).
2. Disease duration no less than 6 months.
3. Patient's age from 18 to 65 years inclusive.
4. Level of glycosylated hemoglobin 7.0- 10.0 %.
5. Glomerular filtration rate ≥ 60 ml/ min/1.73m\^2.
6. Stable dose of basal insulin for the last 3 months. (Permissible fluctuations are ±10%.)
7. 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.
8. Availability of signed patient information sheet (Informed Consent form) for participation in the clinical trial.

Exclusion Criteria:

1. Acute diabetes mellitus complications for 3 months prior to inclusion in the trial (diabetic ketoacidosis, hyperosmolar hyperglycemic state, lacticemia, severe hypoglycemia and hypoglycemic coma).
2. Diabetic retinopathy, preproliferative, proliferative or terminal stages (based on the results of oculist examination during screening period or 6 months prior to the trial).
3. Diabetic nephropathy, proteinuria stage, chronic kidney disease on 3, 4 or 5 stage.
4. 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; post-infarction 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).
5. 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.
6. 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.
7. Severe concomitant pathology including clinically significant cardiovascular 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/m2), renal insufficiency, liver failure.
8. Medical history of pancreatectomy or transplantation of pancreatic/islet cells.
9. Medical history of renal transplantation.
10. Malignant neoplasms/suspected malignant neoplasms.
11. Exacerbations or decompensation of chronic diseases affecting a patient's ability to participate in the clinical trial.
12. Level of fasting triglycerides \>5.64 mmol/L.
13. Medical history of bariatric surgical operations.
14. Medical history of polyvalent allergy.
15. Allergy/ intolerance to any of the components of medications used in the treatment.
16. Intake of medicines listed in the section "Prohibited concomitant treatment" for 3 months prior to the inclusion in the trial.
17. Pregnancy, breast-feeding.
18. Drug addiction, alcohol usage in the amount exceeding 2 units of alcohol per day.
19. Mental disorders of a patient.
20. Night work.
21. Participation in other clinical trials in the course of 3 months prior to the inclusion in the trial.
22. 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.
23. Other factors impeding patient's participation in the trial (for example, planned business trips or journeys).
24. 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.
25. 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.

Primary outcomes:
measure: Changes in the Mean Value of HbA1c
timeFrame: baseline and 12, 24 and 36 weeks of the treatment
Secondary outcomes:
measure: Change in Fasting Plasma Glucose (Based on the Data of Biochemical Analysis)
timeFrame: baseline and 4, 12, 24 and 36 weeks of the treatment
measure: Change in Average Daily Blood Glucose From a 7-point Patient Self-monitoring of Blood Glucose (SMBG)
timeFrame: baseline and 4, 8, 12, 18, 24, 30 and 36 weeks of the treatment
measure: Changes in Lipids (Concentrations of Plasma Total Cholesterol, HDL Cholesterol, LDL Cholesterol and Triglycerides)
timeFrame: baseline and 12, 24 and 36 weeks of the treatment
measure: Changes in Dosage of Insulin (Basal, Prandial and Total Daily Dose Insulin Measured in IU)
timeFrame: baseline and 36 weeks of the treatment
measure: Changes in Dosage of Total Insulin Measured in IU/kg of Body Weight
timeFrame: baseline and 36 weeks of the treatment
measure: Satisfaction of Diabetes Treatment Based on Diabetes Treatment Satisfaction Questionnaire Data
timeFrame: 36 weeks of the treatment
Other outcomes:
Locations:
city: Moscow region
country: Russian Federation
facility: Municipal budgetary authority "Khimki Central Clinical Hospital"
city: Moscow
country: Russian Federation
facility: State Healthcare Institution of Moscow "Central research institute of gastroenterology" of Department of health care of Moscow
city: Moscow
country: Russian Federation
facility: State Educational Institution of Higher Professional Education "Moscow State Medical Academy named after I.M. Sechenov"
city: Moscow
country: Russian Federation
facility: Nonstate Health Care Institution "Central Clinical Hospital №2 named after N.A. Semashko of Public Limited Company "Russian Railways"
city: Nizhny Novgorod
country: Russian Federation
facility: The State Budgetary Institution of Health Care of the Nizhny Novgorod Region "City clinical hospital No. 10 "
city: Nizhny Novgorod
country: Russian Federation
facility: Nizhny Novgorod regional State Budgetary Health Institution " Nizhny Novgorod regional Clinical Hospital named after N.A. Semashko "
city: Rostov-on-Don
country: Russian Federation
facility: State Budgetary Educational Institution of High Professional Training "Rostov State Medical University" of Ministry of Health of Russian Federation, Department of Endocrinology
city: Samara
country: Russian Federation
facility: Co.Ltd " Diabet Center"
city: St. Petersburg
country: Russian Federation
facility: Private company "Polyclinic Complex"
city: St. Petersburg
country: Russian Federation
facility: St. Petersburg State Budgetary Health Care Institution "City Polyclinic №6"
city: St. Petersburg
country: Russian Federation
facility: St. Petersburg State Budgetary Health Care Institution "Saint Venerable Martyr Elizaveta Municipal Hospital"
city: St. Petersburg
country: Russian Federation
facility: State Budgetary Educational Institution of High Professional Training "St. Petersburg State Medical University named after academician I.P. Pavlov" of Ministry of Health of Russian Federation, Therapy Faculty Board
city: St. Petersburg
country: Russian Federation
facility: St. Petersburg Sate Budgetary Institution "Consultative-Diagnostic Polyclinic №1 of Coastal Area"
city: Voronezh
country: Russian Federation
facility: Independent Health Care Institution of Voronezh Region "Voronezh Regional Clinical Consultative-Diagnostic Center"
city: Yaroslavl
country: Russian Federation
facility: State Budgetary Health Care Institution of Yaroslavl Region "Regional Сlinical Hospital"
Study officials:
References:
citation: Mkrtumyan A, Romantsova T, Vorobiev S, Volkova A, Vorokhobina N, Tarasov S, Putilovskiy M, Andrianova E, Epstein O. Efficacy and safety of Subetta add-on therapy in type 1 diabetes mellitus: The results of a multicenter, double-blind, placebo-controlled, randomized clinical trial. Diabetes Res Clin Pract. 2018 Aug;142:1-9. doi: 10.1016/j.diabres.2018.04.044. Epub 2018 May 26.