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Efficacy and Safety of a Quadruple Ultra-low-dose Treatment for Hypertension (QUARTET USA)

Primary Purpose

Hypertension

Status

Active

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

QUARTET LDQT

Candesartan

About this trial

This is an interventional treatment trial for Hypertension focused on measuring Hypertension, Blood Pressure

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

ACCESS Martin T. Russo Family Health Center
Ashland Family Health Center

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

QUARTET LDQT

Candesartan

Arm Description

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.

Patients randomized to the comparison arm will take a once daily 8mg candesartan.

Outcomes

Primary Outcome Measures

Change in Mean Systolic Blood Pressure

Mean change (from baseline) in automated office systolic blood pressure adjusted for baseline values.

Secondary Outcome Measures

Mean Systolic Blood Pressure

Mean automated office systolic blood pressure adjusted for baseline values.

Change in Mean Diastolic Blood Pressure

Mean change (from baseline) in automated office diastolic blood pressure adjusted for baseline values.

Mean Diastolic Blood Pressure

Mean automated office diastolic blood pressure adjusted for baseline values.

Proportion of Patients With Hypertension Control

Proportion of patients with hypertension control (percent with SBP < 130 mmHg and DBP <80 mmHg).

Number of Patients Requiring Step up Treatment

Number of patients requiring step-up treatment.

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).

Medication Adherence

Medication adherence defined by objective pill counts

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.

Change in Mean Systolic Blood Pressure

Mean change (from baseline) in automated office systolic blood pressure adjusted for baseline values.

Full Information

NCT ID

NCT03640312

First Posted

August 15, 2018

Last Updated

September 20, 2023

Sponsor

Washington University School of Medicine

Collaborators

ACCESS Community Health Network, University of Sydney

1. Study Identification

Unique Protocol Identification Number

NCT03640312

Brief Title

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

Acronym

QUARTET USA

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

2. Study Status

Record Verification Date

September 2023

Overall Recruitment Status

Active, not recruiting

Study Start Date

August 30, 2019 (Actual)

Primary Completion Date

May 31, 2022 (Actual)

Study Completion Date

July 31, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Washington University School of Medicine

Collaborators

ACCESS Community Health Network, University of Sydney

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. 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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Hypertension

Keywords

Hypertension, Blood Pressure

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

62 (Actual)

8. Arms, Groups, and Interventions

Arm Title

QUARTET LDQT

Arm Type

Experimental

Arm Description

Arm Title

Candesartan

Arm Type

Active Comparator

Arm Description

Patients randomized to the comparison arm will take a once daily 8mg candesartan.

Intervention Type

Drug

Intervention Name(s)

QUARTET LDQT

Intervention Description

Ultra-low-dose combination therapy comprising four different blood pressure lowering drugs at 1/4 dosages. Taken once daily for 12 weeks.

Intervention Type

Drug

Intervention Name(s)

Candesartan

Intervention Description

Standard monotherapy of 8mg candesartan. Taken once daily for 12 weeks.

Primary Outcome Measure Information:

Title

Change in Mean Systolic Blood Pressure

Description

Mean change (from baseline) in automated office systolic blood pressure adjusted for baseline values.

Time Frame

12 weeks

Secondary Outcome Measure Information:

Title

Mean Systolic Blood Pressure

Description

Mean automated office systolic blood pressure adjusted for baseline values.

Time Frame

6 weeks

Title

Change in Mean Diastolic Blood Pressure

Description

Mean change (from baseline) in automated office diastolic blood pressure adjusted for baseline values.

Time Frame

6 weeks

Title

Mean Diastolic Blood Pressure

Description

Mean automated office diastolic blood pressure adjusted for baseline values.

Time Frame

6 weeks

Title

Proportion of Patients With Hypertension Control

Description

Proportion of patients with hypertension control (percent with SBP < 130 mmHg and DBP <80 mmHg).

Time Frame

6 and 12 weeks

Title

Number of Patients Requiring Step up Treatment

Description

Number of patients requiring step-up treatment.

Time Frame

6 weeks

Title

Proportion of Patients With Adverse Event Free Hypertension Control

Description

Proportion of patients with adverse event free hypertension control (percent with SBP < 130 mmHg and DBP <80 mmHg).

Time Frame

12 weeks

Title

Medication Adherence

Description

Medication adherence defined by objective pill counts

Time Frame

12 weeks

Title

Health-related Quality of Life

Description

Time Frame

12 weeks

Title

Change in Mean Systolic Blood Pressure

Description

Mean change (from baseline) in automated office systolic blood pressure adjusted for baseline values.

Time Frame

6 weeks

Other Pre-specified Outcome Measures:

Title

Percentage of Participants With Serious Adverse Events (SAEs)

Description

Percentage of participants with any Serious Adverse Events (SAE) according to Good Clinical Practice definition: adverse events that result in death, are life threatening, require hospitalization or prolong existing hospitalization, result in persistent disability, result in congenital anomaly or birth defect, or unimportant medical event that requires intervention to prevent any of the above.

Time Frame

12 weeks

Title

Percentage of Participants With Potentially Related Adverse Events

Description

Percentage of participants with occurrence of any potentially related adverse event (pre-specified as in study procedures). Defined as: At least possibly related to study drug.

Time Frame

12 weeks

Title

Rate of Adverse Events of Special Interest

Description

Rate of pre-specified adverse events that are known side effects of active ingredients at the participant level.

Time Frame

12 weeks

Title

Mean Change in Serum Potassium

Description

Mean change (from baseline) in continuous serum potassium.

Time Frame

12 weeks

Title

Mean Change in Serum Sodium

Description

Mean change (from baseline) in continuous serum sodium.

Time Frame

12 weeks

Title

Mean Change in Blood Urea Nitrogen

Description

Mean change (from baseline) in continuous blood urea nitrogen.

Time Frame

12 weeks

Title

Mean Change in Serum Creatinine

Description

Mean change in continuous serum creatinine.

Time Frame

12 weeks

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Mark D Huffman, PhD, MD

Organizational Affiliation

Northwestern University Feinberg School of Medicine

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

Jody D Ciolino, PhD

Organizational Affiliation

Overall Study Officials:

Official's Role

Principal Investigator

Facility Information:

Facility Name

ACCESS Martin T. Russo Family Health Center

City

Bloomingdale

State/Province

Illinois

ZIP/Postal Code

60108

Country

United States

Facility Name

Ashland Family Health Center

City

Chicago

State/Province

Illinois

ZIP/Postal Code

60609

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing Plan Description

Individual participant data will be shared through NHLBI BioLINCC.

IPD Sharing Time Frame

Data will be available within 1 year of study conclusion.

IPD Sharing Access Criteria

Access to study data will be managed through NHLBI BioLINCC

Citations:

PubMed Identifier

36116516

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.

Results Reference

derived

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

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