Treatment Optimisation for Blood Pressure With Single-Pill Combinations in India (TOPSPIN)

Hypertension is a leading cause of morbidity and mortality globally. Although multiple drugs are frequently used to treat it, in the South Asian context, evidence is lacking on best drug combinations. This trial aims to compare efficacy of three single-pill combinations of two anti-hypertensive agents on 24-hour ambulatory systolic blood pressure among 1968 individuals with hypertension. The trial is a single-blind randomized controlled trial spread across 37 hospitals in India.

Single Pill combinations (SPCs): 1) Amlodipine + Perindopril, 2) Perindopril + Indapamide, 3) Amlodipine + Indapamide

Study Overview

• Status: Completed
• Conditions: Primary Hypertension
• Intervention / Treatment: Drug: Amlodipine + Perindopril; Drug: Perindopril + Indapamide; Drug: Amlodipine + Indapamide

Detailed Description

This is a multi-centre, individual randomized single-blind, parallel group, three-armed superiority trial to compare the efficacy of three different single-pill combinations of antihypertensive therapies (Amlodipine/Perindopril, Perindopril/Indapamide, and Amlodipine/Indapamide)on 24-hour ambulatory BP levels in Indians.

• Study Type: Interventional
• Enrollment (Actual): 1981
• Phase: Phase 4

Contacts and Locations

Study Locations

• India
  • Andhra Pradesh
    • Guntur, Andhra Pradesh, India, 522001
      • Lalitha Super Specialities Hospital
    • Visakhapatnam, Andhra Pradesh, India, 530002
      • Apollo Hospitals
  • Assam
    • Dibrugarh, Assam, India, 786002
      • Assam Medical College
    • Guwahati, Assam, India, 781033
      • Apollo-Excelcare Hospital
  • Delhi
    • New Delhi, Delhi, India, 110029
      • All India Institute of Medical Sciences
    • New Delhi, Delhi, India, 110076
      • Indraprastha Apollo Hospitals
  • Gujarat
    • Ahmedabad, Gujarat, India, 382428
      • Apollo Hospitals
    • Vadodara, Gujarat, India, 390021
      • Aman Hospital & Research Center
  • Gujrat
    • Ahmedabad, Gujrat, India, 382425
      • Rudraksha Hospital
  • Karnataka
    • Bangalore, Karnataka, India, 560092
      • Lifecare Hospital & Research Centre
    • Dharwad, Karnataka, India, 580009
      • SDM College of Medical Sciences & Hospital
    • Mangalore, Karnataka, India, 575002
      • Indiana Hospital & Heart Institute
    • Mysore, Karnataka, India, 570004
      • JSS Hospital
    • Vijayapura, Karnataka, India, 586103
      • BLDE, Shri B. M. Patil Medical College, Hospital & Research Centre
  • Kerela
    • Ernakulam, Kerela, India, 682018
      • Lisie Hospital
    • Palakkad, Kerela, India, 678013
      • Lakshmi Hospital
  • Maharashtra
    • Devran, Maharashtra, India, 415606
      • BKL Walawalkar Rural Medical College and Hospital
    • Mumbai, Maharashtra, India, 400007
      • Bhatia Hospital
    • Nagpur, Maharashtra, India, 440033
      • Sengupta Hospital & Research Institute
    • Nagpur, Maharashtra, India, 441110
      • Shalinitai Meghe Hospital and Research Center
  • Meghalaya
    • Shillong, Meghalaya, India, 793018
      • North Eastern Indira Gandhi Regional Institute of Medical Sciences
    • Shillong, Meghalaya, India, 793003
      • Nazareth Hospital
  • Odisha
    • Bhubaneshwar, Odisha, India, 751005
      • Apollo Hospitals
  • Punjab
    • Bhatinda, Punjab, India, 151001
      • All India Institute of Medical Sciences
    • Ludhiāna, Punjab, India, 141001
      • Dayanand Medical College and Hospital
    • Patiala, Punjab, India, 147001
      • Sadbhavna Medical and Heart Institute
  • Rajasthan
    • Bikaner, Rajasthan, India, 334001
      • SP Medical College
    • Jodhpur, Rajasthan, India, 342005
      • All India Institute of Medical Sciences
  • Tamil Nadu
    • Chennai, Tamil Nadu, India, 600003
      • Madras Medical College
    • Chennai, Tamil Nadu, India, 600116
      • Sri Ramchandra Institute of Higher Education and Research
    • Madurai, Tamil Nadu, India, 625020
      • Apollo Hospital
  • Telangana
    • Hyderabad, Telangana, India, 500007
      • Osmania General Hospital
    • Hyderabad, Telangana, India, 500058
      • Apollo DRDO Hospitals
    • Hyderabad, Telangana, India, 500090
      • Apollo Institute of Medical Sciences
    • Hyderabad, Telangana, India, 501401
      • Mediciti Institute of Medical Sciences

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 30 years to 79 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Age 30-79 years AND
2. Sitting clinic values* of SBP ≥140 mmHg and <160 mmHg on one antihypertensive agent OR
3. Sitting clinic values* of SBP ≥150 mmHg and <180 mmHg on no antihypertensive treatment * Mean of the last 2 of 3 readings.

Exclusion Criteria:

1. Congestive heart failure (clinically defined).
2. Patients with a history of intolerance to any of the study medications for example angioedema or dry cough with Angiotensin-converting enzyme inhibitors.
3. Serum creatinine levels greater than 132.6µmol/l (1.5mg/dl)
4. 4. History of coronary heart disease (i.e., chronic stable angina, myocardial infarction or acute coronary syndrome).
5. History of a stroke or other cerebrovascular accident (i.e. transient ischaemic attack or reversible ischaemic neurological deficit).
6. Severe hepatic impairment
7. Treatment with agents causing torsades de pointes
8. Lactation
9. Contraindications to any of the investigational medicinal products as per the summaries product characteristics of drugs studied
10. Known or suspected secondary hypertension.
11. Any other concomitant illness, physical or mental impairment that could interfere with the effective conduct of the study.
12. Pregnancy or those of child-bearing age who are not taking reliable contraception.
13. History of Gout.

14. Serum potassium < 3.5mmol/L at screening.

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Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm 1; (Arm 1 compare to Arm 2 compare to Arm 3) - Treatment Period 1 (Enrollment - 2 months) - Single Pill Combination of Amlodipine 5 mg and Perindopril 4 mg once daily, orally Treatment Period 2 (2 months - 6 months) - Single Pill Combination of Amlodipine 10 mg and Perindopril 8 mg once daily, orally	Drug: Amlodipine + Perindopril; Single pill combination of dual antihypertensive agent
Experimental: Arm 2; (Arm 1 compare to Arm 2 compare to Arm 3) - Treatment Period 1 (Enrollment - 2 months) - Single Pill Combination of Perindopril 4 mg and Indapamide 1.25 mg once daily, orally Treatment Period 2 (2 months - 6 months) - Single Pill Combination of Perindopril 8 mg and Indapamide 2.5 mg once daily, orally	Drug: Perindopril + Indapamide; Single pill combination of dual antihypertensive agent
Experimental: Arm 3; (Arm 1 compare to Arm 2 compare to Arm 3) - Treatment Period 1 (Enrollment - 2 months) - Single Pill Combination of Amlodipine 5 mg and Indapamide 1.5 mg sustained release once daily, orally Treatment Period 2 (2 months - 6 months) - Single Pill Combination of Amlodipine 10 mg and Indapamide 1.5 mg sustained release once daily, orally	Drug: Amlodipine + Indapamide; Single pill combination of dual antihypertensive agent

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
24-hour ambulatory systolic Blood Pressure	To determine which of three single pill combinations of two anti-hypertensive agents is most effective in reducing 24-hour ambulatory systolic BP (ASBP) in Indian patients with hypertension.	Change in between baseline and 6 month Ambulatory Systolic Blood Pressure

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
24-hour ambulatory diastolic blood pressure	To determine which of three single pill combinations of two antihypertensive agents is most effective in reducing 24-hour ambulatory diastolic blood pressure at 6 months adjusted for baseline ADBP	Change in between baseline and 6 month Ambulatory Diastolic Blood Pressure
Clinic Blood Pressure	To determine which of three single pill combinations of two antihypertensive agents is most effective in reducing Clinic SBP and diastolic blood pressure (DBP) at two, four and six months adjusted for baseline values	Comparison of Clinic blood pressure measured at baseline 2 month , 4 month and 6 month
Daytime and nighttime Blood Pressure	To determine which of three single pill combinations of two antihypertensive agents is most effective in reducing Daytime and nighttime blood pressure (BP) a t six months adjusted for baseline values	Change in between baseline and 6 month ASBP and ADBP
BP variability measured by ABPM and within-visit clinic BPs	To determine which of three single pill combinations of two antihypertensive agents is most effective in reducing 3.2.4. BP variability measured by ASBP and within-visit clinic BP	Fluctuations in Ambulatory blood pressures as measured at baseline and 6 month and fluctuation in Clinic BP as measured at baseline, 2 month, 4 month and 6 month
Proportion of patients who achieve BP control	To determine which of the three single pill combinations of two antihypertensive agents is most effective in increasing the proportion of patients who achieve BP control defined as BP: <140/90 mmHg and <130/80mmHg at any of their clinic visits and maintained at the 6-month clinic visit.	BP control measured in Clinic BP as measured at baseline, 2 month, 4 month and 6 month and ABP measured at baseline and 6 month
Proportion of patients classified as "responders"	Proportion of patients classified as "responders" defined as those who had a reduction of SBP ≥20mmHg and DBP ≥10 mmHg at any of their clinic visits and maintained at the 6-month clinic visit.	Clinic BP as measured at baseline, 2 month, 4 month and 6 month
Micro- and macro-albuminuria	To determine the effect of three single pill combinations of two antihypertensive agents on Micro- and macro-albuminuria.	Change in serum albumin measured at baseline and 6 month
Fasting blood glucose	To determine the effect of three single pill combinations of two antihypertensive agents on Fasting blood glucose.	Change in fasting blood glucose measured at baseline and 6 month
Fasting lipid profile	To determine the effect of three single pill combinations of two antihypertensive agents on fasting lipid profile.	Change in serum lipid profile measured at baseline and 6 month
Serum sodium	To determine the effect of three single pill combinations of two antihypertensive agents on serum sodium	Change in serum sodium measured at baseline and 6 month
Serum potassium	To determine the effect of three single pill combinations of two antihypertensive agents on serum potassium	Change in serum potassium measured at baseline and 6 month
Serum urea	To determine the effect of three single pill combinations of two antihypertensive agents on serum urea	Change in serum urea measured at baseline and 6 month
Serum creatinine	To determine the effect of three single pill combinations of two antihypertensive agents on serum creatinine	Change in serum creatinine measured at baseline and 6 month
eGFR	To determine the effect of three single pill combinations of two antihypertensive agents on eGFR	Change in eGFR measured at baseline and 6 month
Adverse events causing trial withdrawal	To determine the effect of three single pill combinations of two antihypertensive agents on adverse events causing trial withdrawal	adverse events causing withdrawal at 2 month, 4 month and 6 month
renin and aldosterone	To determine whether baseline plasma renin and/or aldosterone predicts any differential BP effects of the three single-pill combinations under investigation.	Change in plasme renin and/or aldosterone measured at baseline and 6 month

Collaborators and Investigators

• Sponsor: Centre for Chronic Disease Control, India
• Collaborators: All India Institute of Medical Sciences, New Delhi; Imperial College London
• Investigators: Principal Investigator: Dorairaj Prabhakaran, DM Cardiology, Centre for Chronic Disease Control, New Delhi

Study record dates

Study Major Dates

• Study Start (Actual): August 30, 2022
• Primary Completion (Actual): August 30, 2024
• Study Completion (Actual): September 22, 2024

Study Registration Dates

• First Submitted: December 10, 2022
• First Submitted That Met QC Criteria: January 12, 2023
• First Posted (Actual): January 13, 2023

Study Record Updates

• Last Update Posted (Actual): October 8, 2024
• Last Update Submitted That Met QC Criteria: October 4, 2024
• Last Verified: October 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Hypertension; Essential Hypertension; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Vasodilator Agents; Enzyme Inhibitors; Protease Inhibitors; Natriuretic Agents; Membrane Transport Modulators; Diuretics; Calcium-Regulating Hormones and Agents; Calcium Channel Blockers; Angiotensin-Converting Enzyme Inhibitors; Sodium Chloride Symporter Inhibitors; Amlodipine; Perindopril; Indapamide; Indapamide, perindopril drug combination
• Other Study ID Numbers: CCDC-2022-001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: De-identified data collected for the study will be shared with bonafide researchers with a valid research question. Request may be addressed to Prof. Prabhakaran - dprabhakaran@ccdcindia.org
• IPD Sharing Time Frame: 01-09-2025 till 30-09-2030
• IPD Sharing Access Criteria: Only bonafide researchers with a valid research question shall be provided data. Interested researchers shall write to Prof. Prabhakaran (dprabhakaran@ccdcindia.org) with a concept note and necessary approvals as applicable.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ANALYTIC_CODE; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No