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

Phase 3

Completed

• Conditions: Type 2 diabetes mellitus without complications,

• Registration Number: CTRI/2021/12/038391
• Lead Sponsor: Glenmark Pharmaceuticals Ltd

Brief Summary

Thisstudy is a randomized, double blind, double- dummy, three arm -activecontrolled, parallel group, multi-centre trial comparing the safety andefficacy of lobeglitazone sulphate (0.5 mg) given once daily and FDC ofLobeglitazone sulfate 0.5 mg and Glimepiride 1 mg once daily. The studywill be 2-arms double-blind 16 weeks study Lobeglitazone 0.5 mg oncedaily vs.  Pioglitazone 15 mg oncedaily followed by 3-arms 12 week study of FDC of Lobeglitazone sulfate 0.5 mgand Glimepiride 1 mg once daily vs. Lobeglitazone vs. Pioglitazone. Thestudy will be conducted in subjects with T2DM who have inadequate glycemiccontrol with stable dose of metformin as monotherapy. The subjects willcontinue to receive metformin at stable doses of ≥ 1500 mg per day,throughout the study period in an open label manner.

Thestudy consists of screening period of up to 3 weeks (including 2 week runin period).

Inpart A of the study the subjects will receive double blind study treatment for16 weeks, post step 1 analysis, in part B treatment with open label studytreatment for 12 weeks.

The primary outcomemeasures will be mean change from baseline in HbA1c at week 16 for part A andweek 12 for part B. Any adverse event (AE), either clinical/laboratory, will berecorded and assessed for severity, seriousness and causality

Detailed Description

Not available

Study Timeline

• Study Start: 2021-08-12
• Study Completion: 2023-02-16
• Last Update Posted: 2023-08-21

Recruitment & Eligibility

• Status: Completed
• Sex: All
• Target Recruitment: 492

Inclusion Criteria

• 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).

Exclusion Criteria

• .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).
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• Patients with history of hereditary QT prolongation syndrome or patients having history of Torsades de pointes.
• Patients with history of abdominal surgery or intestinal obstruction.
• Patients with history of acute pancreatitis.
• Uninvestigated macroscopic haematuria at screening, during the run-in period or within 1 month before screening 19.
• 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.
• History of Intolerance, contraindication or potential allergy/hypersensitivity to any of the ingredients of study medication or any other Thiazolidinediones or Sulfonylureas 23.
• Subject is known to be seropositive for human immunodeficiency virus (HIV) based on history.
• 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.
• Employee of the clinical study site or any other individuals involved with the conduct of the study, or immediate family members of such individuals.
• Concurrent enrolment in another interventional clinical study.
• 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.

Study & Design

• Study Type: Interventional
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
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
1. Mean change in HbA1c levels in Lobeglitazone sulfate group compared to Pioglitazone group.	1. From baseline to Week-16 | 2. From baseline to Week-12

Secondary Outcome Measures

Name	Time	Method
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
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%
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 %

Trial Locations

Locations (21)

Arthur Asirvatham Hospital; 🇮🇳 Madurai, TAMIL NADU, India

Bangalore Diabetes Centre; 🇮🇳 Bangalore, KARNATAKA, India

Brij Medical Centre Pvt Ltd; 🇮🇳 Nagar, UTTAR PRADESH, India

CIMETs Inamdar Multispeciality Hospital; 🇮🇳 Pune, MAHARASHTRA, India

Diabetes Thyroid & Endocrine Centre; 🇮🇳 Jaipur, RAJASTHAN, India

Eternal Hospital, Unit of Eternal Heart Care Centre and Research Institute; 🇮🇳 Jaipur, RAJASTHAN, India

Getwell Hospital & research Institute; 🇮🇳 Nagpur, MAHARASHTRA, India

GSVM Medical College; 🇮🇳 Nagar, UTTAR PRADESH, India

Kovai Diabetes Speciality Centre & Hospital; 🇮🇳 Coimbatore, TAMIL NADU, India

Life Care Hospital & Research CentreÂ; 🇮🇳 Bangalore, KARNATAKA, India

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Arthur Asirvatham Hospital

🇮🇳Madurai, TAMIL NADU, India

Dr Arthur Joseph Asirvatham

Principal investigator

9443751977

ajasirvathamresearch@yahoo.in