Clinical trial NCT03640312: Efficacy and Safety of a Quadruple Ultra-low-dose Treatment for Hypertension
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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Hypertension
Keywords: Hypertension
Blood Pressure
Lead sponsor: Washington University School of Medicine
Sponsor class: OTHER
Collaborators: name: ACCESS Community Health Network
name: University of Sydney
First posted: 2018-08-21
Enrollment: 62
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Change in Mean Systolic Blood Pressure
timeFrame: 12 weeks
Secondary outcomes:
measure: Mean Systolic Blood Pressure
timeFrame: 6 weeks
measure: Change in Mean Diastolic Blood Pressure
timeFrame: 6 weeks
measure: Mean Diastolic Blood Pressure
timeFrame: 6 weeks
measure: Proportion of Patients With Hypertension Control
timeFrame: 6 and 12 weeks
measure: Number of Patients Requiring Step up Treatment
timeFrame: 6 weeks
measure: Proportion of Patients With Adverse Event Free Hypertension Control
timeFrame: 12 weeks
measure: Medication Adherence
timeFrame: 12 weeks
measure: Health-related Quality of Life
timeFrame: 12 weeks
measure: Change in Mean Systolic Blood Pressure
timeFrame: 6 weeks
Other outcomes:
measure: Percentage of Participants With Serious Adverse Events (SAEs)
timeFrame: 12 weeks
measure: Percentage of Participants With Potentially Related Adverse Events
timeFrame: 12 weeks
measure: Rate of Adverse Events of Special Interest
timeFrame: 12 weeks
measure: Mean Change in Serum Potassium
timeFrame: 12 weeks
measure: Mean Change in Serum Sodium
timeFrame: 12 weeks
measure: Mean Change in Blood Urea Nitrogen
timeFrame: 12 weeks
measure: Mean Change in Serum Creatinine
timeFrame: 12 weeks
Locations:
city: Bloomingdale
country: United States
facility: ACCESS Martin T. Russo Family Health Center
state: Illinois
city: Chicago
country: United States
facility: Ashland Family Health Center
state: Illinois
Study officials:
affiliation: Northwestern University Feinberg School of Medicine
name: Mark D Huffman, PhD, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Overall Study Officials:
name: Jody D Ciolino, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Baldridge AS, Huffman MD, Lazar D, Abbas H, Flowers FM, Quintana A, Jackson A, Khan SS, Chopra A, Vu M, Tripathi P, Jacobson T, Sanuade OA, Kandula NR, Persell SD, Paparello JJ, Rosul LL, Mejia J, Lloyd-Jones DM, Chow CK, Ciolino JD. Efficacy and safety of a quadruple ultra-low-dose treatment for hypertension (QUARTET USA): Rationale and design for a randomized controlled trial. Am Heart J. 2022 Dec;254:183-193. doi: 10.1016/j.ahj.2022.09.004. Epub 2022 Sep 15.