Efficacy and Safety of a Quadruple Ultra-low-dose Treatment for Hypertension

Study Overview
=================
Brief Summary
-----------------
To investigate, in a double-blind randomized controlled trial, whether initiating treatment with ultra-low-dose quadruple-combination therapy (LDQT) will lower office blood pressure more effectively, and with fewer side effects, compared to initiating standard dose monotherapy as per current guidelines in patients with hypertension. Primary hypothesis: A combination pill comprising four types of blood pressure lowering medications, each at one-quarter standard doses, will lower office blood pressure more effectively than initiating patients with standard dose monotherapy as per contemporary clinical practice guideline recommendations.

Detailed Description
-----------------
This trial will investigate whether initiating treatment with ultra-low-dose quadruple-combination therapy (LDQT; including candesartan 2 mg, amlodipine 1.25 mg, indapamide 0.625 mg, and bisoprolol 2.5 mg) will lower automated office blood pressure and 24-hour ambulatory blood pressure at 12 weeks more effectively, and with no increase in side effects, compared to initiating standard dose monotherapy (candesartan 8 mg) in adults with raised blood pressure (SBP>130 mmHg or DBP>80 mmHg) and without cardiovascular disease. Our preliminary data from a short-term (4-week) crossover trial of 18 participants suggest that LDQT lowers office blood pressure by 22/13 mmHg on average compared with placebo with no difference in serious adverse events. Effects on 24-hour ambulatory blood pressure were similar. The investigators will perform this phase II, single site, randomized controlled trial in a network of federally qualified health centers in Chicago because this population bears a disproportionate burden of blood pressure related diseases, and the investigators have previously successfully conducted clinical studies in this population. While the investigators hypothesize this intervention will be easily implemented and efficacious for all patients and clinicians, the investigators will explore variation in treatment effect by potential moderating variables, including age, sex, race/ethnicity, and health literacy level. Beyond examining efficacy, the investigators also plan to assess feasibility of implementing this intervention in a clinical setting by simultaneously evaluating implementation outcomes of acceptability, preferences, and lessons of LDQT among patients and clinicians.

Official Title
-----------------
A Double Blind Randomized Controlled Trial to Assess the Efficacy and Safety of a Quadruple Ultra-low-dose Treatment for Hypertension (QUARTET USA)

Conditions
-----------------
Hypertension

Intervention / Treatment
-----------------
* Drug: QUARTET LDQT
* Drug: Candesartan


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Adults (≥18 years) Spanish or English speaker. Previous documentation within the past 24 months of hypertension or high blood pressure (SBP 130-179 mmHg or DBP 80-109 mmHg) from general practitioner, pharmacist or health care professional (e.g., medical assistant, physician or nurse). Either: 1) Untreated (automated) clinic SBP 140-179 or DBP 90-109 mmHg in the last 12 weeks, OR 2) Monotherapy with clinic SBP 130-159 or DBP 85-99 mmHg in the last 12 weeks. Either: 1) Treatment naïve, OR 2) Currently not on treatment (not take in last 4 weeks), OR 3) Currently taking 1 BP lowering drug (ACE, ARB, CCB, thiazide- or thiazide-like diuretic, BB, MRA, alpha blocker) at any dose. Research grade blood pressure measurement (baseline mean) SBP>= 115 mmHg and DBP >= 60 mmHg Exclusion Criteria: Known contraindication to candesartan, amlodipine, indapamide or bisoprolol. Previous diagnosis of coronary artery disease, stroke, or heart failure. Presence of significant proteinuria (based on 3+ proteinuria via spot urinalysis or >300mg/dL of proteinuria based on random urinary albumin-to-creatinine ratio testing of 300 mg/g) Evidence of secondary cause of hypertension e.g., renal artery stenosis; significant renal impairment (eGFR <50 ml/min/1.73 m2), raised serum potassium (above lab normal limit of 5.5 mEq/L). Women who are pregnant, breast feeding or of childbearing potential and are not using and do not plan to continue using medically acceptable form of contraception throughout the study (pharmacological or barrier methods). Concomitant illness, physical impairment or mental condition which in the opinion of the study team / primary care physician could interfere with the conduct of the study including outcome assessments. Participation in a concurrent interventional medical investigation or pharmacologic clinical trial. Patients in observational, natural history or epidemiological studies not involving an intervention are eligible. Participant's responsible primary care or other responsible physician believes it is not appropriate for participant to switch current monotherapy. Inability or unwillingness to provide written informed consent. Unable to complete study procedures.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: QUARTET LDQT<br>Patients randomized to the intervention arm will take a once daily ultra-low-dose quadruple combination therapy (QUARTET LDQT). The LDQT is an overencapsulated combination pill comprising four types of blood pressure lowering medications each at ¼ standard doses. QUARTET includes candesartan 2mg, amlodipine besylate 1.25mg, indapamide 0.625mg, and bisoprolol 2.5mg. The individual components are currently approved and marketed within the United States. | Drug: QUARTET LDQT<br>* Ultra-low-dose combination therapy comprising four different blood pressure lowering drugs at 1/4 dosages. Taken once daily for 12 weeks.<br>|
| Active Comparator: Candesartan<br>Patients randomized to the comparison arm will take a once daily 8mg candesartan. | Drug: Candesartan<br>* Standard monotherapy of 8mg candesartan. Taken once daily for 12 weeks.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Mean Systolic Blood Pressure | Mean change (from baseline) in automated office systolic blood pressure adjusted for baseline values. | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Systolic Blood Pressure | Mean automated office systolic blood pressure adjusted for baseline values. | 6 weeks | 
| Change in Mean Diastolic Blood Pressure | Mean change (from baseline) in automated office diastolic blood pressure adjusted for baseline values. | 6 weeks | 
| Mean Diastolic Blood Pressure | Mean automated office diastolic blood pressure adjusted for baseline values. | 6 weeks | 
| Proportion of Patients With Hypertension Control | Proportion of patients with hypertension control (percent with SBP < 130 mmHg and DBP <80 mmHg). | 6 and 12 weeks | 
| Number of Patients Requiring Step up Treatment | Number of patients requiring step-up treatment. | 6 weeks | 
| Proportion of Patients With Adverse Event Free Hypertension Control | Proportion of patients with adverse event free hypertension control (percent with SBP < 130 mmHg and DBP <80 mmHg). | 12 weeks | 
| Medication Adherence | Medication adherence defined by objective pill counts | 12 weeks | 
| Health-related Quality of Life | Mean change (from baseline) in health-related quality of life using Patient-Reported Outcomes Measurement Information System (PROMIS) Global Health instrument. PROMIS Global Health is a gauge of general health-care related quality of life. Possible PROMIS Global Physical Health and Global Mental Health scores range from 0-20, with 20 indicating best possible state of health. Raw scores are converted to T-scores to compare to a standardized population. A PROMIS T-score of 50 represents the mean of the population (SD = 10). Higher values here also indicate better health. A positive change in T score, as reported in this outcome measure, would represent an improvement in Global Physical Health or Global Mental Health at 12 weeks compared to baseline. | 12 weeks | 
| Change in Mean Systolic Blood Pressure | Mean change (from baseline) in automated office systolic blood pressure adjusted for baseline values. | 6 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Hypertension, Blood Pressure