Heart Failure Polypill at a Safety Net Hospital

NCT06029712 | Completed Phase 2 Results FDA Drug

• 1 other identifier: 23-39360
• Study Type: interventional
• Target: 35
• Locations: 1 country
• Sites: 1

Brief Summary

A novel four-drug regimen for heart failure with reduced ejection fraction (HFrEF) extends patients' life expectancy by an average of 6 years compared to traditional therapies, in addition to improving quality of life. Unfortunately, uptake of this complex multi-drug regimen has been low, especially among underserved communities with barriers to medication adherence. Although combination tablets have transformed access to care for conditions such as HIV and tuberculosis, no combination pill is available for HFrEF. In the proposed study, the investigators will utilize inexpensive over-encapsulation techniques to develop a novel combination pill ("polypill") for patients with HFrEF. In Aim 1, the investigators will conduct stakeholder interviews with patients, providers, and pharmacists to inform the design of a HFrEF polypill. In Aim 2, the investigators will conduct a pilot, single-center, crossover randomized clinical trial to investigate whether, compared to usual care, a HFrEF polypill increases medication adherence among 20-40 adults with HFrEF. Given the high daily pill burden among patients with HIV and HFrEF, the investigators aim to recruit a subgroup of patients with HIV (\~10-20 participants) in addition to a subgroup of patients without HIV (\~10-20 participants).

Conditions

Heart Failure With Reduced Ejection Fraction; HIV Infections

Keywords

Medication adherence; Polypill

Outcome Measures

Primary Outcomes (1)

• Measured Adherence to GDMT by Pill Count

  The primary outcome will be overall adherence to GDMT, as determined by pill count. We will first calculate the % adherence ratio for each prescribed class of GDMT (# pills missing / # pills supposed to be missing). The adherence ratio for each prescribed class of GDMT will then be averaged to derive the overall adherence ratio to GDMT. Pill count may be performed in-office or over videoconferencing.

  The outcome will be measured 1) following a month of polypill use, and 2) following a month of individual tablet use.

Secondary Outcomes (17)

• Morisky Medication Adherence-8 (MMAS-8) Questionnaire

  The outcome will be measured 1) following a month of polypill use, and 2) following a month of individual tablet use.

• Treatment Satisfaction Using the Treatment Satisfaction Questionnaire for Medication (TSQM 9)

  The outcome will be measured 1) following a month of polypill use, and 2) following a month of individual tablet use.

• Heart Failure Admission Rate

  The outcome will be measured 1) following a month of polypill use, and 2) following a month of individual tablet use.

• Kansas City Cardiomyopathy Questionnaire (KCCQ) 12

  The outcome will be measured 1) following a month of polypill use, and 2) following a month of individual tablet use.

• Adherence Ratio to Individual Components of GDMT by Pill Count

  The outcome will be measured 1) following a month of polypill use, and 2) following a month of individual tablet use.

Other Outcomes (2)

• Feasibility of Recruitment

  Completion of recruitment within 1 year of initiating recruitment

• Feasibility of Adherence to Study Protocols

  Assessed following study completion (approximately 1 year)

Study Arms (2)

GDMT delivered in a heart failure polypill

EXPERIMENTAL

The polypill intervention will be pharmacy-level over-encapsulation of heart failure medications (beta-blocker, SGLT2 inhibitor, mineralocorticoid receptor antagonist, and ACE/ARB/ARNI) into a single capsule. For patients on twice-daily sacubitril/valsartan, one dose will be included in the polypill and the second dose will be dispensed separately. The investigators will partner with a local community pharmacy with proficiency in over-encapsulation. For patients in the polypill arm, heart failure medications will be filled as usual, but rather than dispensing each medication separately, the pharmacy technician will hand-pack all once-daily heart failure medications into a small vegan capsule.

Drug: Heart failure polypill

GDMT delivered as individual tablets

ACTIVE COMPARATOR

As described above, participants who are not already prescribed a beta blocker, SGLT2i, ACE/ARB/ARNI, and MRA will be initiated on these medications prior to randomization if no contraindications exist. Participants randomized to usual care will receive their heart failure medications as individual pills. They will have the option to receive medications by mail, clinic pick-up, or pharmacy pick-up.

Drug: Control Rx

Interventions

Control Rx DRUG

GDMT delivered as individual tablets

GDMT delivered as individual tablets

Heart failure polypill DRUG

Copackaging of heart failure medications (beta blocker, SGLT2i, MRA, and ACE/ARB/ARNI) in an overencapsulated polypill. Individual tablets will be hand-packed into a single capsule at the level of the pharmacy. Specific medications and doses will be individualized to the participant.

GDMT delivered in a heart failure polypill

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Adults age 18+ with heart failure (current or prior NYHA stage II-IV)
• Ejection fraction \<50% on the most recent echocardiogram or MRI
• Last eGFR \> 30
• Able to conveniently obtain medications through one of 3 available mechanisms (mail, pick up at a ZSFG clinic, or pick up at Daniel's pharmacy)
• Working phone number for telephone visits

You may not qualify if:

• Patients who are not fluent in English (due to constraints of the small pilot trial)
• Patients who are incarcerated
• Patients who cannot provide informed consent
• Patients with a ventricular assist device (VAD) or patients with an MI, unstable angina, stroke, or TIA within 12 weeks prior to enrollment
• Women who are pregnant, breastfeeding 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 medical condition which in the opinion of the study team could interfere with the safe conduct of the study including outcome assessment.
• 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 physician believes it is not appropriate for participant to take part in the study.
• Unable to complete study procedures and/or plan to move out of the study area in the next 2 months.

Sponsors & Collaborators

• University of California, San Francisco: lead

Study Sites (1)

Zuckerberg San Francisco General Hospital

San Francisco, California, 94110, United States

Location

Related Publications (12)

• Pandey A, Keshvani N, Wang TJ. Should Polypills Be Used for Heart Failure With Reduced Ejection Fraction? Circulation. 2022 Jul 26;146(4):276-278. doi: 10.1161/CIRCULATIONAHA.122.059661. Epub 2022 Jul 25. No abstract available.

  PMID: 35877830 BACKGROUND

• Gnanenthiran SR, Agarwal A, Patel A. Frontiers of cardiovascular polypills: From atherosclerosis and beyond. Trends Cardiovasc Med. 2023 Apr;33(3):182-189. doi: 10.1016/j.tcm.2021.12.013. Epub 2021 Dec 30.

  PMID: 34973412 BACKGROUND

• Mastromarino V, Casenghi M, Testa M, Gabriele E, Coluccia R, Rubattu S, Volpe M. Polypharmacy in heart failure patients. Curr Heart Fail Rep. 2014 Jun;11(2):212-9. doi: 10.1007/s11897-014-0186-8.

  PMID: 24493574 BACKGROUND

• Castellano JM, Pocock SJ, Bhatt DL, Quesada AJ, Owen R, Fernandez-Ortiz A, Sanchez PL, Marin Ortuno F, Vazquez Rodriguez JM, Domingo-Fernandez A, Lozano I, Roncaglioni MC, Baviera M, Foresta A, Ojeda-Fernandez L, Colivicchi F, Di Fusco SA, Doehner W, Meyer A, Schiele F, Ecarnot F, Linhart A, Lubanda JC, Barczi G, Merkely B, Ponikowski P, Kasprzak M, Fernandez Alvira JM, Andres V, Bueno H, Collier T, Van de Werf F, Perel P, Rodriguez-Manero M, Alonso Garcia A, Proietti M, Schoos MM, Simon T, Fernandez Ferro J, Lopez N, Beghi E, Bejot Y, Vivas D, Cordero A, Ibanez B, Fuster V; SECURE Investigators. Polypill Strategy in Secondary Cardiovascular Prevention. N Engl J Med. 2022 Sep 15;387(11):967-977. doi: 10.1056/NEJMoa2208275. Epub 2022 Aug 26.

  PMID: 36018037 BACKGROUND

• Mohd Salleh NA, Richardson L, Kerr T, Shoveller J, Montaner J, Kamarulzaman A, Milloy MJ. A Longitudinal Analysis of Daily Pill Burden and Likelihood of Optimal Adherence to Antiretroviral Therapy Among People Living With HIV Who Use Drugs. J Addict Med. 2018 Jul/Aug;12(4):308-314. doi: 10.1097/ADM.0000000000000403.

  PMID: 29521670 BACKGROUND

• 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.

  PMID: 36116516 BACKGROUND

• Chow CK, Thakkar J, Bennett A, Hillis G, Burke M, Usherwood T, Vo K, Rogers K, Atkins E, Webster R, Chou M, Dehbi HM, Salam A, Patel A, Neal B, Peiris D, Krum H, Chalmers J, Nelson M, Reid CM, Woodward M, Hilmer S, Thom S, Rodgers A. Quarter-dose quadruple combination therapy for initial treatment of hypertension: placebo-controlled, crossover, randomised trial and systematic review. Lancet. 2017 Mar 11;389(10073):1035-1042. doi: 10.1016/S0140-6736(17)30260-X. Epub 2017 Feb 10.

  PMID: 28190578 BACKGROUND

• Bahiru E, de Cates AN, Farr MR, Jarvis MC, Palla M, Rees K, Ebrahim S, Huffman MD. Fixed-dose combination therapy for the prevention of atherosclerotic cardiovascular diseases. Cochrane Database Syst Rev. 2017 Mar 6;3(3):CD009868. doi: 10.1002/14651858.CD009868.pub3.

  PMID: 28263370 BACKGROUND

• Vijay A, Mohanan PP, Kondal D, Baldridge A, Davies D, Devarajan R, Unni G, Abdullakutty J, Natesan S, Joseph J, Jayagopal PB, Joseph S, Gopinath R, Prabhakaran D, Huffman MD, Agarwal A. Polypill Eligibility for Patients with Heart Failure With Reduced Ejection Fraction in South India: A Secondary Analysis of a Prospective, Interrupted Time Series Study. J Am Heart Assoc. 2021 Oct 19;10(20):e021676. doi: 10.1161/JAHA.121.021676. Epub 2021 Oct 6. No abstract available.

  PMID: 34612082 BACKGROUND

• Munoz D, Uzoije P, Reynolds C, Miller R, Walkley D, Pappalardo S, Tousey P, Munro H, Gonzales H, Song W, White C, Blot WJ, Wang TJ. Polypill for Cardiovascular Disease Prevention in an Underserved Population. N Engl J Med. 2019 Sep 19;381(12):1114-1123. doi: 10.1056/NEJMoa1815359.

  PMID: 31532959 BACKGROUND

• Castellano JM, Sanz G, Penalvo JL, Bansilal S, Fernandez-Ortiz A, Alvarez L, Guzman L, Linares JC, Garcia F, D'Aniello F, Arnaiz JA, Varea S, Martinez F, Lorenzatti A, Imaz I, Sanchez-Gomez LM, Roncaglioni MC, Baviera M, Smith SC Jr, Taubert K, Pocock S, Brotons C, Farkouh ME, Fuster V. A polypill strategy to improve adherence: results from the FOCUS project. J Am Coll Cardiol. 2014 Nov 18-25;64(20):2071-82. doi: 10.1016/j.jacc.2014.08.021. Epub 2014 Sep 1.

  PMID: 25193393 BACKGROUND

• DeJong C, Durstenfeld MS, Davis JD, Wang CS, Riley ED, Huffman MD, Hickey MD, Shade SB, Chen JC, Kazi DS, Grochowski J, Steward WT, Zier LS, Moreau N, Sandhu AT, Heidenreich PA, Agarwal A, Hsue PY. Delivering guideline-directed medical therapy for heart failure with reduced ejection fraction as an over-encapsulated polypill: rationale and protocol for the COMBO-HF-X pilot crossover randomised clinical trial. BMJ Open. 2025 Mar 21;15(3):e093663. doi: 10.1136/bmjopen-2024-093663.

  PMID: 40118491 DERIVED

MeSH Terms

Conditions

HIV Infections; Medication Adherence

Interventions

Tin Fluorides

Condition Hierarchy (Ancestors)

Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases; Patient Compliance; Patient Acceptance of Health Care; Treatment Adherence and Compliance; Health Behavior; Behavior

Intervention Hierarchy (Ancestors)

Fluorides; Hydrofluoric Acid; Fluorine Compounds; Inorganic Chemicals; Tin Compounds; Cariostatic Agents; Biomedical and Dental Materials; Manufactured Materials; Technology, Industry, and Agriculture

Limitations and Caveats

This study is a single-center, short-term pilot study in a safety-net setting with a meaningful dropout rate and high missingness of complete pill count data; blinding participants or investigators to the polypill vs individual tablets condition was not possible. Drug level monitoring was beyond the budget for this study. Finally, as a feasibility study, we included a number of secondary outcomes and did not correct for multiple comparisons.

Results Point of Contact

• Title: Colette DeJong
• Organization: Stanford University

cdejong@stanford.edu

650-229-2482

Study Officials

• Colette DeJong, MD

  University of California, San Francisco

  PRINCIPAL INVESTIGATOR

• Priscilla Hsue, MD

  University of California, San Francisco

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 1, 2023
• First Posted: September 8, 2023
• Study Start: February 27, 2024
• Primary Completion: September 17, 2024
• Study Completion: January 29, 2025
• Last Updated: December 31, 2025
• Results First Posted: December 31, 2025

Record last verified: 2025-12

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, ICF

Locations

US (1)