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

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ClinicalTrials.gov Identifier: NCT03640312
Recruitment Status : Recruiting
First Posted : August 21, 2018
Last Update Posted : August 22, 2019
Sponsor:
Collaborators:
ACCESS Community Health Network
University of Sydney
Information provided by (Responsible Party):
Mark Huffman, Northwestern University

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
Hypertension Drug: QUARTET LDQT Drug: Candesartan 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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 365 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
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)
Estimated Study Start Date : August 30, 2019
Estimated Primary Completion Date : November 30, 2021
Estimated Study Completion Date : December 30, 2021

Resource links provided by the National Library of Medicine


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.




Primary Outcome Measures :
  1. Change in Mean Systolic Blood Pressure [ Time Frame: 12 weeks ]
    Mean change (from baseline) in automated office systolic blood pressure adjusted for baseline values.


Secondary Outcome Measures :
  1. Mean Systolic Blood Pressure [ Time Frame: 12 weeks ]
    Mean automated office systolic blood pressure adjusted for baseline values.

  2. Mean 24-Hour Blood Pressure [ Time Frame: 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.

  3. Mean Daytime Blood Pressure [ Time Frame: 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.

  4. Mean Nighttime Blood Pressure [ Time Frame: 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.

  5. Proportion of dippers [ Time Frame: 24 hours at 12 week follow up ]
    Proportion of dippers assessed through 24-hour ambulatory blood pressure adjusted for baseline values.

  6. Change in Mean Systolic Blood Pressure [ Time Frame: 6 weeks ]
    Mean change (from baseline) in automated office systolic blood pressure adjusted for baseline values.

  7. Mean Systolic Blood Pressure [ Time Frame: 6 weeks ]
    Mean automated office systolic blood pressure adjusted for baseline values.

  8. Change in Mean Diastolic Blood Pressure [ Time Frame: 6 and 12 weeks ]
    Mean change (from baseline) in automated office diastolic blood pressure adjusted for baseline values.

  9. Mean Diastolic Blood Pressure [ Time Frame: 6 and 12 weeks ]
    Mean automated office diastolic blood pressure adjusted for baseline values.

  10. Proportion of patients with hypertension control [ Time Frame: 6 and 12 weeks ]
    Proportion of patients with hypertension control (percent with SBP < 130 mmHg and DBP <80 mmHg).

  11. Proportion of patients requiring step up treatment [ Time Frame: 6 and 12 weeks ]
    Proportion of patients requiring step-up treatment (ever, and at each study time point).

  12. Proportion of patients with adverse event free hypertension control [ Time Frame: 12 weeks ]
    Proportion of patients with adverse event free hypertension control (percent with SBP < 130 mmHg and DBP <80 mmHg).

  13. Medication Adherence [ Time Frame: 6 and 12 weeks ]
    Medication adherence defined by objective pill counts

  14. Health-related quality of life [ Time Frame: 12 weeks ]
    Mean change (from baseline) in health-related quality of life using PROMIS Global Health instrument.


Other Outcome Measures:
  1. Percentage of Participants with Severe adverse events [ Time Frame: 12 weeks ]
    Percentage of participants with any severe adverse event (SAE) according to GCP definition.

  2. Percentage of Participants with Side effects [ Time Frame: 12 weeks ]
    Percentage of participants with occurrence of any potentially relevant side effect (pre-specified as in study procedures).

  3. Rate of relevant side effects [ Time Frame: 12 weeks ]
    Rate of relevant side effects (pre-specified as in study procedures) at the participant level.

  4. Mean Change in Serum Potassium [ Time Frame: 12 weeks ]
    Mean change (from baseline) in continuous serum potassium.

  5. Mean Change in Serum Sodium [ Time Frame: 12 weeks ]
    Mean change (from baseline) in continuous serum sodium.

  6. Mean Change in Blood Urea Nitrogen [ Time Frame: 12 weeks ]
    Mean change (from baseline) in continuous blood urea nitrogen.

  7. Mean Change in Serum Creatinine [ Time Frame: 12 weeks ]
    Mean change in continuous serum creatinine.

  8. Mean Daytime Blood Pressure Load [ Time Frame: 24 hours at 12 week follow up ]
    Mean daytime blood pressure load assessed through 24-hour ambulatory blood pressure.

  9. Mean Nightime Blood Pressure Load [ Time Frame: 24 hours at 12 week follow up ]
    Mean nighttime blood pressure load assessed through 24-hour ambulatory blood pressure.

  10. Percentage of Participants with Morning Surge [ Time Frame: 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.

  11. Coefficient of Variability of Blood Pressure [ Time Frame: 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.

  12. Day-night Blood Pressure Variability [ Time Frame: 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.

  13. Average Real Blood Pressure Variability [ Time Frame: 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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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).
  • Treatment naïve, or currently not on treatment (not taken in last 4 weeks), or taking only one BP lowering drug (ACE-I, ARB, CCB, BB, aldosterone antagonist, alpha-blocker).
  • Eligible for monotherapy based on 2017 AHA Guidelines for Hypertension through either one of the following measurements within the last 12 weeks: 1) Second measure of office SBP 130-149 mmHg or DBP 80-99 mmHg documented by study staff with attended automatic office BP device OR, 2) Recorded daytime average SBP 130-149 mmHg or DBP 80-99 mmHg on 24-hour ambulatory BP monitoring.
  • Individuals with Stage 1 hypertension must also have an ASCVD risk score ≥ 10%. If ASCVD risk score cannot be calculated (adults younger than 40 or over 75 years), then individuals with Stage 1 hypertension are not eligible to participate in the trial. Individuals with Stage 2 hypertension are eligible regardless of age and ASCVD risk score.

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, including 24-hour ABPM.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03640312


Contacts
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Contact: Abigail S Baldridge, MS 3125033911 abigail.baldridge@northwestern.edu

Locations
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United States, Illinois
ACCESS Martin T. Russo Family Health Center Recruiting
Bloomingdale, Illinois, United States, 60108
Contact: Edgar Pizarro, MPH       edgar.pizarro@achn.net   
Contact: Hiba Abbas, RN       hiba.abbas@access.net   
Principal Investigator: Jairo A Mejia, MD         
Sub-Investigator: Charity Alikpala, DO         
Sponsors and Collaborators
Northwestern University
ACCESS Community Health Network
University of Sydney
Investigators
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Principal Investigator: Mark D Huffman, PhD, MD Northwestern University Feinberg School of Medicine
Principal Investigator: Jody D Ciolino, PhD Overall Study Officials:

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Responsible Party: Mark Huffman, Director, Institute for Global Health - Center for Global Cardiovascular Health, Northwestern University
ClinicalTrials.gov Identifier: NCT03640312     History of Changes
Other Study ID Numbers: STU00205834
First Posted: August 21, 2018    Key Record Dates
Last Update Posted: August 22, 2019
Last Verified: August 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: IPD data will be shared through NHLBI BioLINCC.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (CSR)
Analytic Code
Time Frame: Data will be available within 1 year of study conclusion.
Access Criteria: Access to study data will be managed through NHLBI BioLINCC

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Mark Huffman, Northwestern University:
Hypertension
Blood Pressure

Additional relevant MeSH terms:
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Hypertension
Vascular Diseases
Cardiovascular Diseases
Candesartan
Candesartan cilexetil
Ethinyl estradiol, levonorgestrel drug combination
Antihypertensive Agents
Angiotensin II Type 1 Receptor Blockers
Angiotensin Receptor Antagonists
Molecular Mechanisms of Pharmacological Action
Contraceptives, Oral, Combined
Contraceptives, Oral
Contraceptive Agents, Female
Contraceptive Agents
Reproductive Control Agents
Physiological Effects of Drugs