TRC150094, a Novel Mitochondrial Modulator, Reduces Cardio-Metabolic Risk as an Add-On Treatment: a Phase-2, 24-Week, Multi-Center, Randomized, Double-Blind, Clinical Trial

Abstract

Background

TRC150094, a novel mitochondrial modulator, reduces insulin resistance and is expected to improve the trinity of dysglycemia, dyslipidemia, and hypertension. In this multi-dose phase-2 study, we evaluated the safety and efficacy of TRC150094 in diabetic subjects with dyslipidemia receiving standard of care.

Methods

A randomized, multicenter, double-blind, placebo-controlled, parallel-group, Phase 2 study was conducted in 225 subjects from July 2013 to August 2015. The key inclusion criteria were body mass index of 23–35 kg/m², age between 30 and 65 years, fasting glucose of ≥126 or glycated hemoglobin (HbA1c) of ≥6.4% stabilized on treatment with ≤2 oral hypoglycemic agents, apolipoprotein-B (apo-B) ≥100 mg/dL, serum triglyceride (TG) ≥150 mg/dL, systolic blood pressure (SBP) ≥130 mmHg, and diastolic blood pressure (DBP) ≥85 mmHg with/without antihypertensive treatment. The subjects were randomly assigned to one of three TRC150094 doses (25, 50, or 75 mg) or placebo for 24 weeks. The outcomes assessed included fasting plasma glucose (FPG), insulin, mean arterial blood pressure (MAP), and apoB. In addition, safety and tolerability were assessed.

Results

A reduction for dose up to 50 mg was noted for FPG in the range of 13.9 to 21.7 mg/dL (p < 0.05 for TRC150094 25 and 50 mg), fasting insulin reduction in the range 2.7 to 6.0 mU/L (all doses, p > 0.05), and improved HOMA-IR (−2.0 to −2.5) (all doses, p > 0.05) compared to placebo after 24 weeks of treatment. Furthermore, a significant reduction in MAP in the range 3.1 to 4.2 mmHg (p < 0.05 for TRC150094 25 and 75 mg) was noted. In addition, TRC150094 treatment was weight neutral, had a favorable effect on lowering atherogenic lipid fractions, including non-HDL cholesterol (−6.8 mg/dL at 50 mg dose). Adverse events were mild to moderate in nature and not dose-related. One adverse event not related to treatment led to the discontinuation of the study. Overall, TRC150094 was safe and well tolerated for up to 24 weeks.

Conclusion

In this study, TRC150094 treatment in the dose range of 25 to 50 mg showed improvement in various components of CMBCD, ie, dysglycemia, dyslipidemia, and hypertension.

Trial Registration

This study was registered in the Clinical Trial Registry of India. Trial registration number: CTRI/2013/03/003444. Date of registration: 4th March 2013.

Keywords:

• cardiometabolic-based chronic disease
• mitochondrial modulator
• type 2 diabetes
• non-HDL cholesterol
• hypertension
• dyslipidemia

Abbreviations

ABP, ambulatory blood pressure; ACE, angiotensin converting enzyme; AE, adverse event; AMPK, adenosine monophosphate kinase; ANCOVA, analysis of covariance; ANOVA, analysis of variance; ARB, angiotensin receptor blocker; AUC, area under curve; BMI, body mass index; BP, blood pressure; CCB, calcium channel blocker; CMBCD, cardiometabolic based chronic disease; CMD, cardiometabolic disease; CTRI, clinical trial registry of India; CVD, cardiovascular disease; DBP, diastolic blood pressure; DCGI, drug controller general of India; DSCF, Dwass-Steel-Critchlow-Fligner; DSMB, data safety monitoring board; ECG, electrocardiogram; ETC, electron transport chain; FPG, fasting plasma glucose; GCP, good clinical practice; GGT, gamma-glutamyl transaminase; HBA1c, glycated hemoglobin; HDL, high density lipoprotein-cholesterol; HIV, human immunodeficiency virus; HOMA-IR, homeostasis model assessment insulin resistance; ICH, International council for Harmonization; IEC, institutional ethics committee; IR, insulin resistance; IRB, institutional review board; mITT, modified intention to treat; LDL, Low density lipoprotein-cholesterol; LOCF, last observation carried forward; MAP, mean arterial pressure; MRI, magnetic resonance imaging; MRS, magnetic resonance spectroscopy; RP, retinyl palmitate; SAD, single ascending dose; SAE, serious adverse event; SBP, systolic blood pressure; SD, standard deviation; SoC, standard of care; T2D, type 2 diabetes mellitus; TC, total cholesterol; TEAE, treatment emergent adverse event; TG, triglyceride; TSH, thyrotropin stimulating hormone; URTI, upper respiratory tract infection; UTI, urinary tract infection; WC, waist circumference.

Data Sharing Statement

Data will be available from the corresponding author upon request.

Ethics Approval and Consent to Participate

The study was initiated after obtaining the approval of the Drug Controller General of India (DCGI; F.No.12-196/09 DC, Dec 21, 2012), Independent/Institutional Ethics Committee (IEC) of each site. All subjects provided written informed consent before study procedures were commenced.

Consent for Publication

All authors have read and approved the final manuscript for submission.

Acknowledgments

The authors would like to acknowledge SIRO Clinpharm Pvt. Ltd. (CRO), Dr. Suchit Kumbhare, Dr. Amarinder Singh, and Dr. Vipin Bulani (Torrent Pharmaceuticals) for editorial assistance and administrative support. The authors also acknowledge CAMRRI trial collaborators (a list of participating investigators and institutions follows).

CAMRRI trial collaborators: list of participating investigator(s) and institution(s)

Author Contributions

All authors contributed significantly to the conception, study design, acquisition of data, or analysis and interpretation of data; participated in drafting or revising the article critically; agreed to submit to the current journal; gave final approval of the version to be published; and agreed to be accountable for all aspects of the work.

Disclosure

Deepa Joshi, Prashant GJ, Shohini Ghosh, Anookh Mohanan and Chaitanya Dutt report being employees of Torrent Pharmaceuticals Ltd, Dr Shohini Ghosh reports grants from Biotechnology Industry Research Assistance Council (BIRAC)/Dept. of Biotechnology (DBT), during the conduct of the study. Dr Anookh Mohanan reports grants from Biotechnology Industry Research Assistance Council (BIRAC) of Department of Biotechnology (DBT), Government of India (received financial support (partial) from BIRAC (DBT) in the form of soft loan (major) and grant (minor) for this trial), during the conduct of the study. Dr Shashank Joshi reports advisory for Torrent, during the conduct of the study; speaker for Eli Lilly, Abbott, Boehringer Ingelheim, MSD, Novo Nordisk, PHFI, Micro Labs, and Bayer Zydus, advisory for Astra Zeneca, USV, Marico, Sanofi, Zydus Cadila, Twin Health, and Franco Indian, and speaker and advisory for Roche Diabetes Care, outside the submitted work. Professor Subhankar Chowdhury reports personal fees from Healtheon, Intas Pharmaceutical, and Novo Nordisk, outside the submitted work. Dr Chaitanya Dutt reports grants from Biotechnology Industry Research Assistance Council (BIRAC) of Department of Biotechnology (DBT), Government of India, during the conduct of the study (BIRAC/DBT has partially funded this study with a mix of soft loan and grant); and in addition has a patents IN254907, US8143424 B2, EP2061766B1, and WO2008/149379A2 issued not licensed to any third party. The authors report no other potential conflicts of interest in this work.

Additional information

Funding

This study was funded by Torrent Pharmaceuticals Ltd.