CDSCO Panel suggests revising phase III CT protocol of Zydus Healthcare's Empagliflozin plus Metoprolol Succinate FDC

New Delhi: Considering the bioequivalence (BE) study report presented by Zydus Healthcare for the fixed dose combination of empagliflozin plus metoprolol succinate, the Subject Expert Committee (SEC) functional under the Central Drug Standard Control Organization (CDSCO) has suggested few modifications in the Phase III clinical trial protocol and opined the firm to submit the revised Phase III CT protocol to the CDSCO for further review.

This came after Zydus Healthcare presented their proposal along with the BE study report and Phase III clinical trial protocol of the fixed-dose combination (FDC) Empagliflozin 10 mg/10 mg plus Metoprolol Succinate IP 23.75 mg eq. to Metoprolol Tartrate (ER) 25 mg/ Metoprolol Succinate IP 47.50 mg eq. to Metoprolol Tartrate (ER) 50 mg uncoated bilayered tablet before the committee.

Empagliflozin is in a class of medications called sodium-glucose co-transporter 2 (SGLT2) inhibitors. It lowers blood sugar by causing the kidneys to get rid of more glucose in the urine. Empagliflozin can also be used to treat heart failure. 

Empagliflozin exerts cardiovascular benefits—specifically in the prevention of heart failure—independent of its blood glucose-lowering effects, though the exact mechanism of this benefit is not precisely understood. Several theories have been posited, including the potential inhibition of Na+/H+ exchanger (NHE) 1 in the myocardium and NHE3 in the proximal tubule, reduction of pre-load via diuretic/natriuretic effects and reduction of blood pressure, prevention of cardiac fibrosis via suppression of pro-fibrotic markers, and reduction of pro-inflammatory adipokines.

Metoprolol is in a class of medications called beta blockers. It works by relaxing blood vessels and slowing heart rate to improve blood flow and decrease blood pressure. Metoprolol is also used in combination with other medications to treat heart failure. Metoprolol succinate extended-release tablet is indicated for the treatment of hypertension. It may be used alone or in combination with other antihypertensive agents. Metoprolol succinate extended-release tablet is indicated in the long-term treatment of angina pectoris.

Last year, the Medical Dialogues Team reported that Zydus Healthcare had got approval from the Subject Expert Committee (SEC) functional under the Central Drug Standard Control Organisation (CDSCO) to conduct the bioequivalence (BE) study of the fixed-dose combination (FDC) Empagliflozin 10 mg/10 mg plus Metoprolol Succinate IP 23.75 mg eq. to Metoprolol Tartrate (ER) 25 mg/ Metoprolol Succinate IP 47.50 mg eq. to Metoprolol Tartrate (ER) 50 mg uncoated bilayered tablet.

At the recent SEC meeting for Cardiovascular held on 13th February 2025, the expert panel reviewed the proposal along with the BE study report and Phase III clinical trial protocol.

After detailed deliberation, the committee considered the BE study report. As regard the Phase III clinical trial protocol, the following modifications are suggested:

1. Empagliflozin should be taken as a separate reference arm.

2. BNP (B-type natriuretic peptide) level measurement should be excluded and instead pro-BNP level should be used accordingly to age and co-morbidity with cut-off value.

3. All LV strain imaging echocardiogram assessment/evaluation should be done at the core laboratory by qualified and independent observer.

4. In Primary endpoint criteria 5% improvement in LV (Left ventricular) ejection fraction cannot be the only criteria.

5. In Exclusion criteria clinically uncontrolled systemic diseases,uncontrolled respiratory disease, uncontrolled psychiatric disease, uncontrolled endocrine disease should be defined.

Accordingly, the expert panel suggested that the firm should submit the revised Phase III CT protocol to the CDSCO for further review by the committee.

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