QUARTET USA: Efficacy and Safety of a Quadruple Ultra-low-dose Treatment for Hypertension
Study Details
Study Description
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: QUARTET LDQT 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
Ultra-low-dose combination therapy comprising four different blood pressure lowering drugs at 1/4 dosages. Taken once daily for 12 weeks.
|
| Active Comparator: Candesartan Patients randomized to the comparison arm will take a once daily 8mg candesartan. |
Drug: Candesartan
Standard monotherapy of 8mg candesartan. Taken once daily for 12 weeks.
|
Outcome Measures
Primary Outcome Measures
- Change in Mean Systolic Blood Pressure [12 weeks]
Mean change (from baseline) in automated office systolic blood pressure adjusted for baseline values.
Secondary Outcome Measures
- Mean Systolic Blood Pressure [6 weeks]
Mean automated office systolic blood pressure adjusted for baseline values.
- Change in Mean Diastolic Blood Pressure [6 and 12 weeks]
Mean change (from baseline) in automated office diastolic blood pressure adjusted for baseline values.
- Mean Diastolic Blood Pressure [6 and 12 weeks]
Mean automated office diastolic blood pressure adjusted for baseline values.
- Proportion of patients with hypertension control [6 and 12 weeks]
Proportion of patients with hypertension control (percent with SBP < 130 mmHg and DBP <80 mmHg).
- Proportion of patients requiring step up treatment [6 and 12 weeks]
Proportion of patients requiring step-up treatment (ever, and at each study time point).
- Proportion of patients with adverse event free hypertension control [12 weeks]
Proportion of patients with adverse event free hypertension control (percent with SBP < 130 mmHg and DBP <80 mmHg).
- Medication Adherence [6 and 12 weeks]
Medication adherence defined by objective pill counts
- Health-related quality of life [12 weeks]
Mean change (from baseline) in health-related quality of life using PROMIS Global Health instrument.
- Change in Mean Systolic Blood Pressure [6 weeks]
Mean change (from baseline) in automated office systolic blood pressure adjusted for baseline values.
Other Outcome Measures
- Percentage of Participants with Severe adverse events [12 weeks]
Percentage of participants with any severe adverse event (SAE) according to Good Clinical Practice definition.
- Percentage of Participants with Side effects [12 weeks]
Percentage of participants with occurrence of any potentially relevant side effect (pre-specified as in study procedures).
- Rate of relevant side effects [12 weeks]
Rate of relevant side effects (pre-specified as in study procedures) at the participant level.
- Mean Change in Serum Potassium [12 weeks]
Mean change (from baseline) in continuous serum potassium.
- Mean Change in Serum Sodium [12 weeks]
Mean change (from baseline) in continuous serum sodium.
- Mean Change in Blood Urea Nitrogen [12 weeks]
Mean change (from baseline) in continuous blood urea nitrogen.
- Mean Change in Serum Creatinine [12 weeks]
Mean change in continuous serum creatinine.
- Mean Daytime Blood Pressure Load [24 hours at 12 week follow up]
Mean daytime blood pressure load assessed through 24-hour ambulatory blood pressure (ABPM).
- Mean Nightime Blood Pressure Load [24 hours at 12 week follow up]
Mean nighttime blood pressure load assessed through 24-hour ambulatory blood pressure.
- Percentage of Participants with Morning Surge [24 hours at 12 week follow up]
Percentage of participants with morning surge, calculated as the difference between the mean SBP during the morning hours and nighttime trough SBP, assessed through 24-hour ambulatory blood pressure.
- Coefficient of Variability of Blood Pressure [24 hours at 12 week follow up]
Coefficient of variability of blood pressure, defined as the ratio of the 24-hour standard deviation of BP / mean 24-hour value, assessed through 24-hour ambulatory blood pressure.
- Day-night Blood Pressure Variability [24 hours at 12 week follow up]
Day-night variability (SDdn), which uses the SD for daytime measurements and, separately for nighttime measurements, to calculate a weighted mean of these SDs, assessed through 24-hour ambulatory blood pressure.
- Average Real Blood Pressure Variability [24 hours at 12 week follow up]
Average real variability (ARV), calculated as the average absolute difference between consecutive readings over the 24-hour ABPM period, assessed through 24-hour ambulatory blood pressure.
- Mean Systolic Blood Pressure [12 weeks]
Mean automated office systolic blood pressure adjusted for baseline values.
- Mean 24-Hour Blood Pressure [24 hours at 12 week follow up]
Mean 24-hour systolic and diastolic blood pressure assessed through 24-hour ambulatory blood pressure adjusted for baseline values.
- Mean Daytime Blood Pressure [24 hours at 12 week follow up]
Mean daytime (0600 to 2200) systolic and diastolic blood pressure assessed through 24-hour ambulatory blood pressure adjusted for baseline values.
- Mean Nighttime Blood Pressure [24 hours at 12 week follow up]
Mean daytime (2200 to 0600) systolic and diastolic blood pressure assessed through 24-hour ambulatory blood pressure adjusted for baseline values.
- Proportion of dippers [24 hours at 12 week follow up]
Proportion of dippers assessed through 24-hour ambulatory blood pressure adjusted for baseline values.
Eligibility Criteria
Criteria
Inclusion Criteria:
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Adults (≥18 years)
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Spanish or English speaker.
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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).
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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.
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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.
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Research grade blood pressure measurement (baseline mean) SBP>= 115 mmHg and DBP >= 60 mmHg
Exclusion Criteria:
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Known contraindication to candesartan, amlodipine, indapamide or bisoprolol.
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Previous diagnosis of coronary artery disease, stroke, or heart failure.
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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)
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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).
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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).
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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.
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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.
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Participant's responsible primary care or other responsible physician believes it is not appropriate for participant to switch current monotherapy.
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Inability or unwillingness to provide written informed consent.
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Unable to complete study procedures.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | ACCESS Martin T. Russo Family Health Center | Bloomingdale | Illinois | United States | 60108 |
| 2 | Ashland Family Health Center | Chicago | Illinois | United States | 60609 |
Sponsors and Collaborators
- Washington University School of Medicine
- ACCESS Community Health Network
- University of Sydney
Investigators
- Principal Investigator: Mark D Huffman, PhD, MD, Northwestern University Feinberg School of Medicine
- Principal Investigator: Jody D Ciolino, PhD, Overall Study Officials:
Study Documents (Full-Text)
More Information
Publications
None provided.- STU00205834