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

• Sponsor: Materia Medica Holding (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01868646
• Collaborator: (none)
• Enrollment: 190
• Locations: 17
• Arms: 2
• Actual Duration (Months): 37.3
• Patients Per Site: 11.2
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Type II Diabetes Mellitus	Drug: Subetta; Drug: Placebo	Phase 4

Detailed Description

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 190 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Supportive Care
• 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 II Diabetes Mellitus
• Actual Study Start Date: May 7, 2013
• Actual Primary Completion Date: Jun 15, 2016
• Actual Study Completion Date: Jun 15, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Subetta	Drug: Subetta; 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).
Placebo Comparator: Placebo	Drug: Placebo; 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).

Outcome Measures

Primary Outcome Measures

1. Changes in the Mean Value of HbA1c [In 12, 24 and 36 weeks of the treatment as compared to the baseline]

   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.

Secondary Outcome Measures

1. Change in Fasting Plasma Glucose [In 4, 12, 24 and 36 weeks of the treatment as compared to the baseline]

   Based on the data of biochemical analysis

2. Change in Average Daily Blood Glucose From a 7-point Patient Self-monitoring of Blood Glucose (SMBG) [During the whole study period (on weeks 4, 8, 12, 18, 24, 30 and 36 of the treatment) as compared to the baseline]

   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.

3. Mean Value of C-peptide [In 12, 24 and 36 weeks of the treatment as compared to the baseline]

   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).

4. Changes in Lipids (Concentrations of Plasma Total Cholesterol, HDL Cholesterol, LDL Cholesterol and Triglycerides) [In 12, 24 and 36 weeks of the treatment as compared to the baseline]

   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).

5. Changes in Dosage of Insulin (Basal Dose Insulin Measured in IU/Day) [In 36 weeks of the treatment as compared to the baseline]

   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.

6. Changes in Dosage of Insulin (Basal Dose Insulin Measured in IU/ kg of Body Weight) [In 36 weeks of the treatment as compared to the baseline]

   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.

7. Percentage of Patients With Changed Daily Dose of Per Oral Blood Sugar- Lowering Drugs [In 36 weeks of the treatment]

8. Changes in the Mean Absolute Value of Body Weight (kg) [In 36 weeks of the treatment as compared to the baseline]

9. Changes in the Mean Absolute Value of Body Mass Index (BMI) (kg/m^2) [baseline and 36 weeks of the treatment]

10. Satisfaction of Diabetes Treatment Based on Diabetes Treatment Satisfaction Questionnaire Data [In 36 weeks of the treatment]

    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).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Diagnosed type II diabetes mellitus (according to WHO criteria, 1999 - 2006).

2. Patient's age from 18 to 65 years inclusive.

3. Level of glycosylated hemoglobin 7.0- 10.0 %.

4. 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.

5. Body mass index ≥25.0 and ≤40.0kg/m^2.

6. Constant body weight (without fluctuations > 10% during not less than 3 months prior to inclusion in the trial).

7. Glomerular filtration rate ≥ 60 ml/ min/1.73m^2.

8. Stable dose of basal insulin for the last 3 months.(Permissible fluctuations are ±10%.)

9. 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.

10. 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; 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).

1. 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.

1. 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.

2. 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.

3. Medical history of pancreatectomy or transplantation of pancreatic/islet cells.

4. Medical history of renal transplantation.

5. Malignant neoplasms/suspected malignant neoplasms.

6. Exacerbations or decompensation of chronic diseases affecting a patient's ability to participate in the clinical trial.

7. The results of analysis of liver enzymes (alanine aminotransferase, aspartate aminotransferase) more than threefold exceeding of upper limit of normal values.

8. Level of fasting triglycerides >5.64 mmol/L.

9. Medical history of bariatric surgical operations.

10. Medical history of polyvalent allergy

11. Allergy/ intolerance to any of the components of medications used in the treatment.

12. Intake of medicines listed in the section "Prohibited concomitant treatment" for 3 months prior to the inclusion in the trial.

13. Pregnancy, breast-feeding.

14. Drug addiction, alcohol usage in the amount exceeding 2 units of alcohol per day.

15. Mental disorders of a patient.

16. Night work.

17. Participation in other clinical trials in the course of 3 months prior to the inclusion in the trial.

18. 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.

19. Other factors impeding patient's participation in the trial (for example, planned business trips or journeys).

20. 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.

21. 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Municipal budgetary authority "Khimki Central Clinical Hospital"	Moscow region		Russian Federation	141400
2	State Healthcare Institution of Moscow "Central research institute of gastroenterology" of Department of health care of Moscow	Moscow		Russian Federation	111123
3	State Educational Institution of Higher Professional Education "Moscow State Medical Academy named after I.M. Sechenov"	Moscow		Russian Federation	119991
4	Nonstate Health Care Institution "Central Clinical Hospital №2 named after N.A. Semashko of Public Limited Company "Russian Railways"	Moscow		Russian Federation	129128
5	Nizhny Novgorod regional State Budgetary Health Institution " Nizhny Novgorod regional Clinical Hospital named after N.A. Semashko "	Nizhny Novgorod Region		Russian Federation	603126
6	State Budgetary Educational Institution of High Professional Training "Rostov State Medical University" of Ministry of Health of Russian Federation, Department of Endocrinology	Rostov-on-Don		Russian Federation	344022
7	Co.Ltd " Diabet Center"	Samara		Russian Federation	443067
8	The State Budgetary Educational Institution of Higher Professional Education "Smolensk National Research Medical University" Ministry of Health of the Russian Federation	Smolensk		Russian Federation	214019
9	St. Petersburg State Budgetary Health Care Institution "City Polyclinic №6"	St. Petersburg		Russian Federation	191482
10	St. Petersburg State Budgetary Health Care Institution "Saint Venerable Martyr Elizaveta Municipal Hospital"	St. Petersburg		Russian Federation	195257
11	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	St. Petersburg		Russian Federation	197022
12	St. Petersburg Sate Budgetary Institution "Consultative-Diagnostic Polyclinic №1 of Coastal Area"	St. Petersburg		Russian Federation	197183
13	St. Petersburg State Budgetary Health Care Institution "Consultative-Diagnostic Center № 85", Diabetes Center №2	St. Petersburg		Russian Federation	198260
14	St. Petersburg State Budgetary Health Care Institution "City Polyclinic №77 of Nevsky District", The City Diabetes Center №4	St.Petersburg		Russian Federation	192177
15	Vladimir region State budgetary institution of health care "Regional clinical hospital"	Vladimir		Russian Federation	600023
16	Independent Health Care Institution of Voronezh Region "Voronezh Regional Clinical Consultative-Diagnostic Center"	Voronezh		Russian Federation	394018
17	State Budgetary Health Care Institution of Yaroslavl Region "Regional Сlinical Hospital"	Yaroslavl		Russian Federation	150062

Sponsors and Collaborators

• Materia Medica Holding

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Materia Medica Holding
• ClinicalTrials.gov Identifier: NCT01868646
• Other Study ID Numbers: MMH-SU-004
• First Posted: Jun 4, 2013
• Last Update Posted: May 31, 2019
• Last Verified: May 1, 2019

• Keywords provided by Materia Medica Holding: Combined Treatment of Patients With Type II Diabetes Mellitus
• Additional relevant MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2

Study Results

Participant Flow

Pre-assignment Detail	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 190 patients enrolled, 42 did not meet inclusion criteria after screening procedures, they were not randomized

Arm/Group Title	Subetta	Placebo
Arm/Group Description	Standard therapy of type II 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). One tablet contains: affinity purified antibodies to the C-terminal fragment of the beta subunit receptor insulin - 0.006g*, affinity purified antibodies to endothelial NO synthase - 0.006g*. *applied onto isomalt crystals as a mixture of three active aqueous-alcoholic dilutions of the drug substance - diluted 100^12, 100^30, 100^200 times, respectively. Excipients: isomalt, crospovidone, magnesium stearate.	Standard therapy of type II 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
Period Title: Overall Study
STARTED	76	72
COMPLETED	73	67
NOT COMPLETED	3	5

Baseline Characteristics

Arm/Group Title	Subetta	Placebo	Total
Arm/Group Description	Standard therapy of type II 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 II diabetes mellitus	Standard therapy of type II 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	Total of all reporting groups
Overall Participants	73	67	140
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	57.9 (7.1)	57.3 (6.2)	57.6 (6.7)
Sex: Female, Male (Count of Participants)
Female	59 80.8%	54 80.6%	113 80.7%
Male	14 19.2%	13 19.4%	27 19.3%
Weight (kilogram) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilogram]	85.7 (13.0)	89.0 (11.7)	87.1 (12.5)
Height (centimeter) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [centimeter]	164.1 (7.7)	165.3 (7.3)	164.7 (7.5)
BMI (kilogram/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilogram/m^2]	31.7 (4.0)	32.5 (3.6)	32.1 (3.8)

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

Intention-to-Treat set

Arm/Group Title	Subetta	Placebo
Arm/Group Description	Standard therapy of type II 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 II diabetes mellitus	Standard therapy of type II 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
Measure Participants	73	67
12 weeks	-0.53 (1.06)	-0.01 (1.06)
24 weeks	-0.54 (1.00)	-0.07 (1.19)
36 weeks	-0.54 (1.11)	0.15 (1.07)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Subetta, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0002
	Comments	The p-value associated with "treatment" factor of changes from baseline to Week 12, 24 and 36 endpoint between Subetta and Placebo treatment groups. Model includes treatment, visit and treatment*visit interaction.
	Method	Mixed Models Analysis
	Comments

2. Secondary Outcome

Title	Change in Fasting Plasma Glucose
Description	Based on the data of biochemical analysis
Time Frame	In 4, 12, 24 and 36 weeks of the treatment as compared to the baseline

Outcome Measure Data

Analysis Population Description

Intention-to-Threat set

Arm/Group Title	Subetta	Placebo
Arm/Group Description	Standard therapy of type II 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 II diabetes mellitus	Standard therapy of type II 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
Measure Participants	73	67
4 weeks	-0.5 (2.6)	-0.1 (3.2)
12 weeks	0.0 (2.5)	0.9 (3.3)
24 weeks	0.0 (2.9)	0.9 (4.1)
36 weeks	0.0 (3.1)	1.0 (3.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Subetta, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0426
	Comments	The p-value associated with "treatment" factor of changes from baseline to Week 4, 12, 24 and 36 endpoint between Subetta and Placebo treatment groups. Model includes treatment, visit and treatment*visit interaction.
	Method	Mixed Models Analysis
	Comments

3. Secondary Outcome

Title	Change in Average Daily Blood Glucose From a 7-point Patient Self-monitoring of Blood Glucose (SMBG)
Description	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.
Time Frame	During the whole study period (on weeks 4, 8, 12, 18, 24, 30 and 36 of the treatment) as compared to the baseline

Outcome Measure Data

Analysis Population Description

Intention-to-Treat set. The SMBG in 3 patients (2 in the Subetta and 1 in the Placebo) was excluded from the analysis due to mistakes in diaries.

Arm/Group Title	Subetta	Placebo
Arm/Group Description	Standard therapy of type II 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 II diabetes mellitus	Standard therapy of type II 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
Measure Participants	71	66
4 weeks	-0.3 (1.5)	-0.5 (1.8)
8 weeks	-0.3 (1.6)	-0.5 (1.7)
12 weeks	-0.4 (1.7)	-0.4 (2.1)
18 weeks	-0.2 (1.6)	-0.4 (1.6)
24 weeks	-0.5 (1.6)	-0.5 (1.7)
30 weeks	-0.3 (1.7)	-0.5 (1.5)
36 weeks	-0.5 (1.9)	-0.6 (1.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Subetta, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5990
	Comments	The p-value associated with "treatment" factor of changes from baseline to Week 4, 8, 12, 18, 24, 30 and 36 endpoint between Subetta and Placebo treatment groups. Model includes treatment, visit and treatment*visit interaction.
	Method	Mixed Models Analysis
	Comments

4. Secondary Outcome

Title	Mean Value of C-peptide
Description	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).
Time Frame	In 12, 24 and 36 weeks of the treatment as compared to the baseline

Outcome Measure Data

Analysis Population Description

Intention-to-Treat set.

Arm/Group Title	Subetta	Placebo
Arm/Group Description	Standard therapy of type II 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 II diabetes mellitus	Standard therapy of type II 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
Measure Participants	73	67
0 week	615.3 (418.9)	607.6 (425.4)
12 weeks	628.3 (400.8)	607.7 (405.6)
24 weeks	643.3 (419.2)	641.6 (426.3)
36 weeks	589.6 (343.5)	540.0 (328.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Subetta, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6215
	Comments	The p-value associated with "treatment" factor of mean value at baseline to Week 12, 24 and 36 endpoint between Subetta and Placebo treatment groups. Model includes treatment, visit and treatment*visit interaction.
	Method	Mixed Models Analysis
	Comments

5. Secondary Outcome

Title	Changes in Lipids (Concentrations of Plasma Total Cholesterol, HDL Cholesterol, LDL Cholesterol and Triglycerides)
Description	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).
Time Frame	In 12, 24 and 36 weeks of the treatment as compared to the baseline

Outcome Measure Data

Analysis Population Description

Intention-to-Treat set.

Arm/Group Title	Subetta	Placebo
Arm/Group Description	Standard therapy of type II 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 II diabetes mellitus	Standard therapy of type II 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
Measure Participants	73	67
Total cholesterol (12 weeks)	0.1 (1.1)	0.1 (1.2)
Total cholesterol (24 weeks)	0.1 (1.2)	0.1 (0.9)
Total cholesterol (36 weeks)	0.3 (1.1)	0.0 (1.1)
HDL cholesterol (12 weeks)	0.0 (0.2)	0.0 (0.2)
HDL cholesterol (24 weeks)	0.0 (0.2)	0.0 (0.2)
HDL cholesterol (36 weeks)	0.0 (0.3)	0.0 (0.2)
LDL cholesterol (12 weeks)	0.1 (0.8)	0.0 (0.9)
LDL cholesterol (24 weeks)	0.1 (0.9)	0.1 (0.8)
LDL cholesterol (36 weeks)	0.2 (0.8)	0.1 (0.9)
Triglycerides (12 weeks)	0.2 (0.8)	0.2 (0.9)
Triglycerides (24 weeks)	0.1 (0.9)	0.0 (0.8)
Triglycerides (36 weeks)	0.1 (0.9)	-0.1 (0.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Subetta, Placebo
	Comments	Analysis of Total cholesterol changes from baseline to Week 12, 24 and 36 endpoint between Subetta and Placebo treatment groups.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6155
	Comments	The p-value associated with "treatment" factor of changes from baseline to Week 12, 24 and 36 endpoint between Subetta and Placebo treatment groups. Model includes treatment, visit and treatment*visit interaction.
	Method	Mixed Models Analysis
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Subetta, Placebo
	Comments	Analysis of HDL cholesterol changes from baseline to Week 12, 24 and 36 endpoint between Subetta and Placebo treatment groups.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7507
	Comments	The p-value associated with "treatment" factor of changes from baseline to Week 12, 24 and 36 endpoint between Subetta and Placebo treatment groups. Model includes treatment, visit and treatment*visit interaction.
	Method	Mixed Models Analysis
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Subetta, Placebo
	Comments	Analysis of LDL cholesterol changes from baseline to Week 12, 24 and 36 endpoint between Subetta and Placebo treatment groups.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4195
	Comments	The p-value associated with "treatment" factor of changes from baseline to Week 12, 24 and 36 endpoint between Subetta and Placebo treatment groups. Model includes treatment, visit and treatment*visit interaction.
	Method	Mixed Models Analysis
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Subetta, Placebo
	Comments	Analysis of Triglycerides changes from baseline to Week 12, 24 and 36 endpoint between Subetta and Placebo treatment groups.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3609
	Comments	The p-value associated with "treatment" factor of changes from baseline to Week 12, 24 and 36 endpoint between Subetta and Placebo treatment groups. Model includes treatment, visit and treatment*visit interaction.
	Method	Mixed Models Analysis
	Comments

6. Secondary Outcome

Title	Changes in Dosage of Insulin (Basal Dose Insulin Measured in IU/Day)
Description	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.
Time Frame	In 36 weeks of the treatment as compared to the baseline

Outcome Measure Data

Analysis Population Description

Intention-to-Treat

Arm/Group Title	Subetta	Placebo
Arm/Group Description	Standard therapy of type II 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 II diabetes mellitus	Standard therapy of type II 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
Measure Participants	73	67
Mean (Standard Deviation) [IU/day]	-0.9 (2.4)	3.5 (9.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Subetta, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0605
	Comments
	Method	t-test, 2 sided
	Comments

7. Secondary Outcome

Title	Changes in Dosage of Insulin (Basal Dose Insulin Measured in IU/ kg of Body Weight)
Description	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.
Time Frame	In 36 weeks of the treatment as compared to the baseline

Outcome Measure Data

Analysis Population Description

Intention-to-Treat set

Arm/Group Title	Subetta	Placebo
Arm/Group Description	Standard therapy of type II 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 II diabetes mellitus	Standard therapy of type II 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
Measure Participants	73	67
Mean (Standard Deviation) [IU/kg]	-0.01 (0.03)	0.04 (0.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Subetta, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0726
	Comments
	Method	t-test, 2 sided
	Comments

8. Secondary Outcome

Title	Percentage of Patients With Changed Daily Dose of Per Oral Blood Sugar- Lowering Drugs
Time Frame	In 36 weeks of the treatment

Outcome Measure Data

Analysis Population Description

Intention-to-Treat set

Arm/Group Title	Subetta	Placebo
Arm/Group Description	Standard therapy of type II 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 II diabetes mellitus	Standard therapy of type II 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
Measure Participants	73	67
Number [percentage of patients]	4.1	9.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Subetta, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3108
	Comments
	Method	Fisher Exact
	Comments

9. Secondary Outcome

Title	Changes in the Mean Absolute Value of Body Weight (kg)
Time Frame	In 36 weeks of the treatment as compared to the baseline

Outcome Measure Data

Analysis Population Description

Intention-to-Treat set. Data on body weight in one patient from the placebo group were absent

Arm/Group Title	Subetta	Placebo
Arm/Group Description	Standard therapy of type II 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 II diabetes mellitus	Standard therapy of type II 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
Measure Participants	73	66
Mean (Standard Deviation) [kg]	-0.1 (2.2)	0.4 (3.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Subetta, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2934
	Comments
	Method	t-test, 2 sided
	Comments

10. Secondary Outcome

Title	Changes in the Mean Absolute Value of Body Mass Index (BMI) (kg/m^2)
Time Frame	baseline and 36 weeks of the treatment

Outcome Measure Data

Analysis Population Description

Intention-to-Treat set. Data on body weight in one patient from the placebo group were absent

Arm/Group Title	Subetta	Placebo
Arm/Group Description	Standard therapy of type II 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 II diabetes mellitus	Standard therapy of type II 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
Measure Participants	73	66
Mean (Standard Deviation) [kg/m^2]	-0.04 (0.78)	0.14 (1.33)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Subetta, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3410
	Comments
	Method	t-test, 2 sided
	Comments

11. Secondary Outcome

Title	Satisfaction of Diabetes Treatment Based on Diabetes Treatment Satisfaction Questionnaire Data
Description	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).
Time Frame	In 36 weeks of the treatment

Outcome Measure Data

Analysis Population Description

Intention-to-Treat set. 8 patients (6 in the Subetta group and 2 in the Placebo group) was excluded from the analysis due to lake of questionnaires.

Arm/Group Title	Subetta	Placebo
Arm/Group Description	Standard therapy of type II 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 II diabetes mellitus	Standard therapy of type II 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
Measure Participants	67	65
Satisfaction	9.8 (5.7)	8.3 (6.1)
Hyperglycemia	-1.1 (1.6)	-0.9 (1.7)
Hypoglycemia	-1.1 (1.5)	-1.0 (1.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Subetta, Placebo
	Comments	Satisfaction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1577
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Subetta, Placebo
	Comments	Hyperglycemia
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5262
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Subetta, Placebo
	Comments	Hypoglycemia
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7417
	Comments
	Method	t-test, 2 sided
	Comments

Adverse Events

Time Frame	Adverse/Serious adverse events were registered during 36 weeks of therapy and 30 days after the end of therapy.
Adverse Event Reporting Description	Adverse/Serious adverse events were registered in patients of the Full Analysis Set (n=148, Safety Population)
Arm/Group Title	Subetta		Placebo
Arm/Group Description	Standard therapy of type II 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 II diabetes mellitus		Standard therapy of type II 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
All Cause Mortality
	Subetta		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Subetta		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/76 (1.3%)		1/72 (1.4%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Brain tumor NOS	0/76 (0%)		1/72 (1.4%)
Nervous system disorders
Brain stem stroke	1/76 (1.3%)		0/72 (0%)
Other (Not Including Serious) Adverse Events
	Subetta		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	22/76 (28.9%)		24/72 (33.3%)
Blood and lymphatic system disorders
hypochromic anaemia	0/76 (0%)		1/72 (1.4%)
Eye disorders
retinal angiopathy	1/76 (1.3%)		0/72 (0%)
Diabetic edematous maculopathy	1/76 (1.3%)		0/72 (0%)
Edema of the upper eyelid of the right eye	1/76 (1.3%)		0/72 (0%)
Gastrointestinal disorders
duodenitis	0/76 (0%)		1/72 (1.4%)
burning tongue	0/76 (0%)		1/72 (1.4%)
epigastric burning	0/76 (0%)		1/72 (1.4%)
Periodic pain in the left hypochondrium	3/76 (3.9%)		0/72 (0%)
Periodic dull aching pain in the right hypochondrium	1/76 (1.3%)		0/72 (0%)
Nausea	1/76 (1.3%)		0/72 (0%)
Drawing pains in the right hypochondrium	0/76 (0%)		1/72 (1.4%)
chronic gastritis	0/76 (0%)		1/72 (1.4%)
chronic colitis	0/76 (0%)		1/72 (1.4%)
Chronic parenchymal pancreatitis	1/76 (1.3%)		1/72 (1.4%)
Chronic hemorrhagic gastritis	1/76 (1.3%)		0/72 (0%)
irritable bowel syndrome	1/76 (1.3%)		0/72 (0%)
Edema of the lower lip	1/76 (1.3%)		0/72 (0%)
General disorders
esurience	1/76 (1.3%)		0/72 (0%)
Complaints about general fatigue, a feeling of total severity and swelling	1/76 (1.3%)		0/72 (0%)
Hepatobiliary disorders
Fatty liver hepatosis	1/76 (1.3%)		1/72 (1.4%)
Immune system disorders
allergic reaction	0/76 (0%)		1/72 (1.4%)
Infections and infestations
bilateral lacunar tonsillitis	1/76 (1.3%)		0/72 (0%)
Asymptomatic bacteriuria	0/76 (0%)		1/72 (1.4%)
upper respiratory infection	1/76 (1.3%)		4/72 (5.6%)
acute respiratory infection	4/76 (5.3%)		10/72 (13.9%)
upper respiratory tract infection	3/76 (3.9%)		0/72 (0%)
acute pneumonia	1/76 (1.3%)		0/72 (0%)
pulpitis	0/76 (0%)		1/72 (1.4%)
rhinitis	1/76 (1.3%)		0/72 (0%)
rhinosinusitis	1/76 (1.3%)		0/72 (0%)
Erysipelas of the right lower leg	0/76 (0%)		1/72 (1.4%)
pharyngitis	1/76 (1.3%)		0/72 (0%)
Injury, poisoning and procedural complications
Fracture of radial head to the right	0/76 (0%)		1/72 (1.4%)
Fracture of terminal phalanx of 5th toe of left foot	0/76 (0%)		1/72 (1.4%)
Investigations
Increased blood pressure	4/76 (5.3%)		2/72 (2.8%)
rapid pulse	0/76 (0%)		1/72 (1.4%)
Metabolism and nutrition disorders
Fasting hyperglycemia	1/76 (1.3%)		0/72 (0%)
hypercholesterinemia	0/76 (0%)		1/72 (1.4%)
Dyslipidemia, worsening	0/76 (0%)		1/72 (1.4%)
Increased appetite	0/76 (0%)		1/72 (1.4%)
Musculoskeletal and connective tissue disorders
Pain in the knee joints	1/76 (1.3%)		0/72 (0%)
melosalgia	1/76 (1.3%)		0/72 (0%)
Pain in the lumbar spine	1/76 (1.3%)		1/72 (1.4%)
back pain	1/76 (1.3%)		0/72 (0%)
cervical vertebral osteochondrosis	1/76 (1.3%)		0/72 (0%)
Nervous system disorders
headache	0/76 (0%)		1/72 (1.4%)
occipital headache	1/76 (1.3%)		0/72 (0%)
Diabetic distal sensory lower limb polyneuropathy, worsening	1/76 (1.3%)		0/72 (0%)
Increased numbness in the fingers, feets	1/76 (1.3%)		0/72 (0%)
Psychiatric disorders
Tingling in the region of the heart that occurs after excitement on a background of a stressful situ	1/76 (1.3%)		0/72 (0%)
Twitching of the right eye against a background of stress	0/76 (0%)		1/72 (1.4%)
phobic disorder	1/76 (1.3%)		0/72 (0%)
Skin and subcutaneous tissue disorders
skin itch	1/76 (1.3%)		0/72 (0%)
Urticaria	1/76 (1.3%)		0/72 (0%)
A papular rash in the area of the forearms, hands, right knee joint	1/76 (1.3%)		0/72 (0%)
Urticaria on the extremities	1/76 (1.3%)		0/72 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.