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

Study Overview
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Brief Summary
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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 15 hospitals in India. Single Pill combinations (SPCs): 1) Amlodipine + Perindopril, 2) Perindopril + Indapamide, 3) Amlodipine + Indapamide

Detailed Description
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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.

Official Title
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Treatment Optimisation for Blood Pressure With Single-Pill Combinations in India

Conditions
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Primary Hypertension

Intervention / Treatment
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* Drug: Amlodipine + Perindopril
* Drug: Perindopril + Indapamide
* Drug: Amlodipine + Indapamide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 30-79 years AND Sitting clinic values* of SBP ≥140 mmHg and <160 mmHg on one antihypertensive agent OR Sitting clinic values* of SBP ≥150 mmHg and <180 mmHg on no antihypertensive treatment * Mean of the last 2 of 3 readings. Exclusion Criteria: Congestive heart failure (clinically defined). Patients with a history of intolerance to any of the study medications for example angioedema or dry cough with Angiotensin-converting enzyme inhibitors. Serum creatinine levels greater than 132.6µmol/l (1.5mg/dl) 4. History of coronary heart disease (i.e., chronic stable angina, myocardial infarction or acute coronary syndrome). History of a stroke or other cerebrovascular accident (i.e. transient ischaemic attack or reversible ischaemic neurological deficit). Severe hepatic impairment Treatment with agents causing torsades de pointes Lactation Contraindications to any of the investigational medicinal products as per the summaries product characteristics of drugs studied Known or suspected secondary hypertension. Any other concomitant illness, physical or mental impairment that could interfere with the effective conduct of the study. Pregnancy or those of child-bearing age who are not taking reliable contraception. History of Gout. Serum potassium < 3.5mmol/L at screening. -

Ages Eligible for Study
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Minimum Age: 30 Years
Maximum Age: 79 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1<br>(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<br>* Single pill combination of dual antihypertensive agent<br>|
| Experimental: Arm 2<br>(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<br>* Single pill combination of dual antihypertensive agent<br>|
| Experimental: Arm 3<br>(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<br>* Single pill combination of dual antihypertensive agent<br>|

What is the study measuring?
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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 |