CTRI/2021/12/038391 [Registered on: 02/12/2021] Trial Registered Prospectively
Last Modified On:
21/08/2023
Post Graduate Thesis
No
Type of Trial
Interventional
Type of Study
Drug
Study Design
Randomized, Parallel Group, Active Controlled Trial
Public Title of Study
Clinical trial to study efficacy and safety of lobeglitazone sulfate and the combination of lobeglitazone sulphate and glimepiride for the treatment of type 2 diabetes mellitus
Scientific Title of Study
A randomized, double-blind, double-dummy, parallel-group, multi-centre, active-controlled study to evaluate efficacy and safety of lobeglitazone sulfate and fixed dose combination of lobeglitazone sulfate and glimepiride in subjects with type-2 diabetes mellitus.
Trial Acronym
Secondary IDs if Any
Secondary ID
Identifier
GPL/CT/2020/013/III; Version 6.0; Dated: 18-Oct-2021
Protocol Number
Details of Principal Investigator or overall Trial Coordinator (multi-center study)
Name
Designation
Affiliation
Address
Phone
Fax
Email
Details of Contact Person Scientific Query
Name
Dr Rahul Kodgule
Designation
GM-Clinical Development Branded Generics
Affiliation
Glenmark Pharmaceuticals Ltd
Address
Glenmark Pharmaceuticals Ltd
Glenmark House, B D Sawant Marg
Chakala, Andheri(East)
District: Mumbai
State: Maharashtra
Intuitional Ethics Committee of Thumbay Hospital New Life
Approved
Life care Hospital Institutional Review Board
Approved
Medisys Clinisearch Ethical Review Board
Approved
Medstar Speciality Hospital Ethics Committee
Approved
Penta-Med Ethics Committee
Approved
Sanjivani Hospital Ethics Committee
Submittted/Under Review
Shivam Ethics Committee
Approved
Supe Hospital Ethics Committee
Approved
Regulatory Clearance Status from DCGI
Status
Approved/Obtained
Health Condition / Problems Studied
Health Type
Condition
Patients
(1) ICD-10 Condition: E119||Type 2 diabetes mellitus without complications,
Intervention / Comparator Agent
Type
Name
Details
Intervention
FDC of Lobeglitazone Sulfate and Glimepiride
Dosage Form: Oral Tablet
Dose: Lobeglitazone Sulfate 0.5 mg and Glimepiride 1 mg
Dosage Frequency: Once daily
Mode of Administration: Once daily in the morning shortly before or during breakfast or first meal preferably at similar time of the day
Intervention
Lobeglitazone Sulfate
Dosage Form: Oral Tablet
Dose: Lobeglitazone Sulfate 0.5 mg (or Matching Placebo)
Dosage Frequency: Once daily
Mode of Administration: Once daily in the morning with food preferably at similar time of the day
Comparator Agent
Pioglitazone 15 mg (or Matching Placebo)
Dosage Form: Oral Tablet
Dose: Pioglitazone 15 mg
Dosage Frequency: Once daily
Mode of Administration: Once daily in the morning with food preferably at similar time of the day
Inclusion Criteria
Age From
18.00 Year(s)
Age To
65.00 Year(s)
Gender
Both
Details
Subjects must be willing and able to provide written informed consent.
2. Male and female subjects ≥ 18 and ≤ 65 years of age, diagnosed with T2DM.
3. Subjects who have received stable dose of metformin ≥ 1500 mg/day as monotherapy for at least 10 weeks prior to screening and having inadequate glycemic control at screening defined as HbA1c levels of ≥7.5% to ≤10.5%. For FDC Lobeglitazone/glimepiride arm inclusion criteria for HbA1c will be ≥8% to ≤11%.
4. Willing and able to comply with all aspects of the protocol.
5. Subjects with left ventricular ejection fraction of ≥50% as measured using 2D echocardiography at screening.
6. Must agree to the following requirements during the study:
a. If male with a partner of childbearing potential, he must be willing to use condoms in combination with a second effective method of contraception, i.e., spermicide. Each man will be considered as potent unless surgically sterilized (with appropriate post vasectomy documentation of the absence of sperm in the ejaculate).
b. Male subjects should agree not to donate sperm for 180 days following administration of the study drug.
c. Females subjects of childbearing potential, including pre-menopausal women defined as all females physiologically capable of becoming pregnant, are eligible if they are using highly effective methods of contraception during dosing of study treatment; must have a negative serum pregnancy test result at screening. She must be willing to use a highly effective form of contraception for the duration of the study and for at least 3 months after the last dose of study medication. Highly effective contraception methods include:
- Use of oral (estrogen and progesterone), injected or implanted hormonal methods of contraception, or other form of hormonal contraception that have comparable efficacy (failure rate less than 1%)
- In case of use of oral contraception, woman should have been stable on the same pill for a minimum of 3 months before taking study treatment
- Intrauterine device (IUD)
- Intrauterine hormone-releasing system or other forms of hormonal contraception.
- Female subjects are eligible to participate if they are of non-childbearing potential defined as premenopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 month of spontaneous amenorrhea (in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) >40 MIU/mL and estradiol >141 pmol/L is confirmatory). Female subjects who have undergone female sterilization (e.g., surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy, or bilateral tubal ligation at least six weeks before taking investigational drug are eligible. In case of oophorectomy alone, female subjects are eligible only when the reproductive status of the woman has been confirmed by follow up hormone level assessment)
ExclusionCriteria
Details
.History of Type 1 diabetes mellitus or secondary diabetes mellitus or diabetes insipidus
2. History of metabolic acidosis or diabetic ketoacidosis
3. FPG < 126 mg/dL or >270 mg/dL at screening.
If FPG is < 126 mg/dL or > 270 mg/dL at screening, FPG will be repeated within 1 week. If repeat FPG is < 126 mg/dL or > 270 mg/dL, subject will be excluded from the study
4. History of more than one episode of severe hypoglycemia (defined as requiring assistance of another person due to disabling hypoglycemia) within 6 months prior to screening visit
5. BMI ≥ 45.0 kg/m2 at screening
6. Subjects with elevated thyroid stimulating hormone (TSH) level at screening requiring initiation of intervention (subjects with elevated TSH and no intervention is initiated will be included in the study).
7. Severe hepatic insufficiency and/or significant abnormal liver function defined as aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) > 3 × ULN or total serum bilirubin >2.0 mg/dL at screening
8. Congestive heart failure defined as New York Heart Association (NYHA) class III/IV, unstable or acute congestive heart failure.
9. Significant cardiovascular history defined as: myocardial infarction, unstable angina pectoris, transient ischemic attack, unstable or previously undiagnosed arrhythmia, cardiac surgery or revascularization (coronary angioplasty or bypass grafts), or cerebrovascular accident.
10. Subjects with edema at screening during run-in period or at randomization visit
11. History of osteoporosis or history of bone fracture any time before screening or subjects receiving treatment for osteoporosis.
12. Subjects with uncontrolled hypertension with sitting systolic BP ≥ 160 mmHg and/or diastolic BP ≥ 100 mmHg at screening. Note: Subjects with SBP ≥ 160mmHg and < 180mmHg or a DBP ≥ 100 mmHg and < 110mmHg will be able to enter the run-in period, provided their hypertension treatment is adjusted as deemed appropriate by the investigator. These subjects cannot be randomized if they meet the blood pressure exclusion criterion of SBP ≥ 160 mmHg or DBP ≥ 100 mmHg measured at randomization visit.
13. Any abnormality on 12-lead ECG at screening that in the opinion of the investigator is clinically significant and is judged as potential risk for subject’s participation in the study.
14. For male subjects with mean QTcF ≥450 msec or female subjects with mean QTcF ≥470 msec, triplicate ECG will be performed. If mean QTcF is ≥450 msec in males or mean QTcF is ≥470 msec in females on triplicate ECG, subject will be excluded from the study.
15. Patients with history of hereditary QT prolongation syndrome or patients having history of Torsades de pointes.
16. Patients with history of abdominal surgery or intestinal obstruction.
17. Patients with history of acute pancreatitis.
18. Uninvestigated macroscopic haematuria at screening, during the run-in period or within 1 month before screening
19. History of haemoglobinopathy and/or haemoglobin at screening <10 g/dL for men; haemoglobin at screening <9 g/dL for women
20. Donation or transfusion of blood, plasma, or platelets within the past 3 months prior to enrolment
21. History of malignancy within the last 5 years prior to enrolment, excluding non-melanoma skin cancer (e.g. basal or squamous cell skin carcinoma) or treated carcinoma-in-situ of cervix. Subjects with current or past history of bladder cancer.
22. History of Intolerance, contraindication or potential allergy/hypersensitivity to any of the ingredients of study medication or any other Thiazolidinediones or Sulfonylureas
23. Subject with a positive result for hepatitis B surface antigen or hepatitis C antibody at screening.
24. Subject is known to be seropositive for human immunodeficiency virus (HIV) based on history.
25. Subject not willing to comply with dietary and exercise plan provided at screening or with protocol procedures.
26. Subject with any condition or laboratory finding or physical examination finding which, in the judgment of the Investigator, may render the subject unable to complete the study or which may pose a significant risk to the subject.
27. Employee of the clinical study site or any other individuals involved with the conduct of the study, or immediate family members of such individuals.
28. Concurrent enrolment in another interventional clinical study.
29. Previous participation in another interventional clinical study within 3 months prior to screening or within 5 half-lives of the previous study drug.
30. Pregnant or breastfeeding women
31. Subjects with a history of substance abuse or dependence that in the opinion of the Investigator is considered to interfere with the subject’s participation in the study
Method of Generating Random Sequence
Stratified randomization
Method of Concealment
Centralized
Blinding/Masking
Participant, Investigator, Outcome Assessor and Date-entry Operator Blinded
Primary Outcome
Outcome
TimePoints
1. Mean change in HbA1c levels in Lobeglitazone sulfate group compared to Pioglitazone group.
2. Mean change in HbA1c levels in FDC of Lobeglitazone sulfate and Glimepiride group compared to Lobeglitazone sulfate group
1. From baseline to Week-16
2. From baseline to Week-12
Secondary Outcome
Outcome
TimePoints
Mean change in HbA1c levels in Lobeglitazone sulfate arm compared to Pioglitazone arm
From baseline to week 12
Mean change from baseline in fasting plasma glucose (FPG) levels in Lobeglitazone sulfate arm compared to Pioglitazone arm
From baseline to week-16
Mean change from baseline in post-prandial plasma glucose (PPG) at week 16 in Lobeglitazone sulfate arm compared to Pioglitazone arm
From baseline to Week-16
Mean change from baseline in fasting plasma glucose (FPG) levels at week 12 FDC of Lobeglitazone sulfate and Glimepiride arm compared to Lobeglitazone sulfate arm
From Baseline to Week 12
Mean change from baseline in postprandial plasma glucose (PPG) at week 12 in FDC of Lobeglitazone sulfate and Glimepiride arm compared to Lobeglitazone sulfate arm
From Baseline to Week 12
Proportion of subjects requiring rescue medication for hyperglycemia during study treatment in Lobeglitazone sulfate arm compared to Pioglitazone arm
During study treatment
Proportion of subjects requiring rescue medication for hyperglycaemia during study treatment in FDC of Lobeglitazone sulfate and Glimepiride arm compared to Lobeglitazone sulfate arm
During study treatment
Change from baseline in fasting insulin, HOMA-IR and HOMA-β at week 16 in Lobeglitazone sulfate arm compared to Pioglitazone arm
From baseline to Week 16
Change from baseline in fasting insulin, HOMA-IR and HOMA-β at week-12 in FDC of Lobeglitazone sulfate and Glimepiride arm compared to Lobeglitazone sulfate arm
From baseline to Week-12
Proportion of subjects achieving a therapeutic glycaemic response, at Week-16 in Lobeglitazone sulfate arm compared to Pioglitazone arm, defined as:
- HbA1c responders: ≥0.7% reduction from baseline in HbA1c or a target HbA1c of less than less than 7 %
- FPG responders: ≥30 mg/dL reduction from baseline in FPG or a target FPG of less than 126 mg/dL
At Week-16
Proportion of subjects achieving a therapeutic glycaemic response, at week 12 in FDC of Lobeglitazone sulfate and Glimepiride arm compared to Lobeglitazone sulfate arm defined as:
- HbA1c responders: ≥0.7% reduction from baseline in HbA1c or a target HbA1c of less than 7%
- FPG responders: ≥ 30 mg/dL reduction from baseline in FPG or a target FPG of less than 126 mg/dL
At Week-12
Target Sample Size
Total Sample Size="492" Sample Size from India="492" Final Enrollment numbers achieved (Total)= "492" Final Enrollment numbers achieved (India)="492"
Individual Participant Data (IPD) Sharing Statement
Will individual participant data (IPD) be shared publicly (including data dictionaries)?
Response - NO
Brief Summary
This
study is a randomized, double blind, double- dummy, three arm -active
controlled, parallel group, multi-centre trial comparing the safety and
efficacy of lobeglitazone sulphate (0.5 mg) given once daily and FDC of
Lobeglitazone sulfate 0.5 mg and Glimepiride 1 mg once daily. The study
will be 2-arms double-blind 16 weeks study Lobeglitazone 0.5 mg once
daily vs. Pioglitazone 15 mg once
daily followed by 3-arms 12 week study of FDC of Lobeglitazone sulfate 0.5 mg
and Glimepiride 1 mg once daily vs. Lobeglitazone vs. Pioglitazone. The
study will be conducted in subjects with T2DM who have inadequate glycemic
control with stable dose of metformin as monotherapy. The subjects will
continue to receive metformin at stable doses of ≥ 1500 mg per day,
throughout the study period in an open label manner.
The
study consists of screening period of up to 3 weeks (including 2 week run
in period).
In
part A of the study the subjects will receive double blind study treatment for
16 weeks, post step 1 analysis, in part B treatment with open label study
treatment for 12 weeks.
The primary outcome
measures will be mean change from baseline in HbA1c at week 16 for part A and
week 12 for part B. Any adverse event (AE), either clinical/laboratory, will be
recorded and assessed for severity, seriousness and causality