Heart Failure With Reduced Ejection FractionPhase 2NCT06029712

Heart Failure Polypill at a Safety Net Hospital

A Phase 2 study testing Heart failure polypill in people with Heart Failure With Reduced Ejection Fraction and HIV Infections, run by University of California, San Francisco at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial summary

Who is it for?: Ages 18 years and older
Conditions the study is for: Heart Failure With Reduced Ejection Fraction, HIV Infections
What is being tested?: Heart failure polypill
Type of treatment: Pill or oral medicine
Could I receive a placebo?: No, everyone receives an active treatment
How many people: 35 participants
Where: 1 siteUnited States
Study dates: 27 Feb 2024to 29 Jan 2025
Phase: Phase 2
Are there results?: Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 18 years and older
All sexes
No healthy volunteers
Adult, Older adult

Who may be able to join

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
In addition to the inclusion criteria above, the investigators will preferentially recruit the following patient groups: people with HIV for a recruitment subgroup; patients who are less connected to cardiology care; people who are on <4 pillars of GDMT, and have difficulty with medication adherence (as evidenced by detectable HIV viral load or refill gaps in Epic); and people who do not use bubble packs and do not have daily medication support staff for med administration.

Who cannot join

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.

Show all 9Show fewer

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.

Trial locations and contacts

1 site in 1 country.

United States1 site

Zuckerberg San Francisco General Hospital
San Francisco, California, 94110

Other trials in United States

About this study

Official title: Developing a Heart Failure Polypill to Improve Outcomes at a Safety Net Hospital: A Pilot Crossover Randomized Controlled Trial

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).

Read the detailed description

Hypothesis: Compared with usual care, a HFrEF polypill implementation strategy will increase adherence to GDMT 4 weeks and reduce total daily pill burden among patients with HFrEF.

Rationale:HFrEF among PWH is associated with a high pill burden, which adversely impacts adherence. Over-encapsulation is an inexpensive and replicable method to co-package several tablets into a single capsule at the level of the pharmacy. However, the role of over-encapsulation to reduce pill burden among adults with HIV and HFrEF is unknown.

Design: Pilot phase II open-label randomized trial with a 2x2 crossover design (AB/BA)

Intervention: The intervention will be pharmacy-level over-encapsulation of once-daily heart failure medications (beta-blocker, SGLT2 inhibitor, spironolactone, and ACE/ARB/ARNI) into a single capsule. For some patients, other once-daily cardiovascular medications, such as a diuretic, may be included if capsule size allows (otherwise, these medications will continued to be filled separate to the polypill, as individual tablets). If the patient uses a twice-daily ARNI medication, the morning dose may be included in the polypill and the PM dose will continue to be dispensed separately. The investigators will partner with Daniel's Pharmacy, a local community pharmacy with proficiency in over-encapsulation and over 20 years' experience working with ZSFG to deliver adherence interventions.

Polypill Description: 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 plastic capsule. The doses will be individualized to the patient based on their physician's prescription. Thus, the polypill will be a late-stage implementation intervention to reduce pill burden, without restricting dose possibilities or interfering with medication titration.

Visit Schedule and Randomization: Patients will first attend an intake visit (week T-1), where eligibility will be reviewed, informed consent will be obtained, baseline patient questionnaires will be collected, and additional GDMT agents may be prescribed by the study clinician if clinically indicated and there are no contraindications. At the first trial visit (week 0), baseline labs will be collected and additional GDMT agents may prescribed if clinically indicated, with the goal of all participants being prescribed guideline-directed quad therapy for HFrEF prior to randomization if there are no contraindications.

During the first trial visit (week 0), half of participants will be randomized to the AB group (polypill for 4 weeks, then individual tablets for 4 weeks). The other half of participants will be randomized to the BA group (individual tablets for 4 weeks, then polypill for 4 weeks).

After randomization, participants assigned to receive the polypill up-front will be delivered 30-day supplies of the polypill via their preferred delivery method (mail, pick up at a ZSFG clinic, or pick up at Daniel's Pharmacy). Participants assigned to usual care will be mailed or pick up their existing heart failure medications as individual pills. The screening visit and first trial visit may be timed by study clinicians based on when the participant's heart failure medications will be ready for a refill according to insurance.

At trial follow-up visits at 4 and 8 weeks, participants will be assessed for outcomes and adverse events and will undergo lab monitoring as clinically indicated. Patients will be asked to bring in their pill bottles and/or MediSets or bubble packs. Medication doses may be titrated at these visits if clinically indicated. Participants in the AB and BA arms will have the same follow-up schedule, and can opt to receive refills of their medications by mail, at the pharmacy, or in clinic. Any new starts of guideline-directed heart failure medications that are included in the polypill will be continued as individual pills when the polypill group crosses over to the individual tablet condition, and/or when the trial concludes. All participants will be referred to cardiology clinic, if not already established there, for ongoing management of their heart failure therapies after the trial.

Conditions: Heart Failure With Reduced Ejection Fraction, HIV Infections
Being tested: Heart failure polypill, Control Rx
Keywords: Medication adherence, Polypill
Medical subject headings: HIV Infections, Medication Adherence

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

Heart failure polypillDrug
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.
Control RxDrug
GDMT delivered as individual tablets

Study groups in NCT06029712
Study group	Role	What they receive
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. Receives: 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. Receives: Drug: Control Rx

What is being measured

The primary outcome is the main question the study is designed to answer.

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.
Measured: 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 MMAS-8 scale consists of 8 items. Each of the first 7 items has 2 possible responses (yes/no), while the 8th item is answered with a 5-point Likert scale. The possible total medication adherence score ranges between 0 and 8, and the higher the score, the better the adherence level. A total score < 6 is considered low adherence, while a total score of ≥ 6 but < 8 indicates moderate adherence, and a score of 8 indicates high adherence.
Measured: 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)
TSQM scores range from 0 to 100, with higher scores indicating greater treatment satisfaction.
Measured: 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
As a pilot trial, our study will not be powered for clinical outcomes, but key exploratory outcomes will include HFrEF admissions.
Measured: 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
Exploratory clinical outcomes will include change in health-related quality of life as measured by the Kansas City Cardiomyopathy Questionnaire. KCCQ scores range from 0 to 100, with higher scores indicating higher quality of life.
Measured: 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 investigators will calculate the adherence ratio for each individual component of GDMT (beta blocker, MRA, SGLT2i, and ACE/ARB/ARNI). This will be calculated as the (# pills missing) / (# pills supposed to be missing based on time elapsed between visits). This will allow us to investigate whether there is differential adherence to some categories of GDMT (for example, lower adherence to beta-blockers).
Measured: The outcome will be measured 1) following a month of polypill use, and 2) following a month of individual tablet use.
Blood Pressure (mmHg)
Systolic Blood pressure at baseline and study follow-up
Measured: The outcome will be measured 1) following a month of polypill use, and 2) following a month of individual tablet use.
Heart Rate
Heart rate (beats per minute)
Measured: The outcome will be measured 1) following a month of polypill use, and 2) following a month of individual tablet use.
Weight
Weight at baseline and study follow-up
Measured: The outcome will be measured 1) following a month of polypill use, and 2) following a month of individual tablet use.
NT-ProBNP
Lab test
Measured: The outcome will be measured 1) following a month of polypill use, and 2) following a month of individual tablet use.
Adverse Events
The investigators will document adverse events throughout the study period, for example, hyperkalemia, dizziness, or other medication-related side effects. The investigators will ask participants about adverse events at in-person visits (0, 4, and 8 weeks) and at telephone calls at approximately 2 and 6 weeks.
Measured: 0, 2, 4, 6, and 8 weeks
Total Daily Pill Burden of the Patient
This will be calculated based on the patient's active medication list.
Measured: The outcome will be measured 1) following a month of polypill use, and 2) following a month of individual tablet use.
Number of GDMT Pillars Prescribed
The number of GDMT pillars prescribed to the patient (BB, MRA, SGLT2i, and either ACEi, ARB, or ARNI) will be calculated at baseline and week 4.
Measured: The outcome will be measured 1) at the start of the polypill intervention, and 2) at the start of the individual tablet intervention.
HFrEF Polypill Patient Satisfaction Exit Survey
A Likert scale-style exit survey will be administered asking participants to compare their experience with the HFrEF polypill vs. individual tablets. 4 questions will comprise an Acceptability of Intervention Measure (AIM): 1) the polypill met my approval; 2) the polypill was appealing to me; 3) I liked the polypill; and 4) I welcomed the polypill as a treatment option for my heart failure. Each question includes a 5-point Likert scale, from 1 (strongly disagree) to 5 (strongly agree). Participants' responses to the 4 AIM questions will be averaged to comprise an AIM summary score.
Measured: After study completion
Number of Participants Completing a Qualitative Exit Interview
Participation in a semi-structured exit interview using a RE-AIM framework (Reach, Effectiveness, Adoption, Implementation, Maintenance)
Measured: After study completion (between 8 and 12 weeks)
Implementation Outcome: Time Required to Manufacture the HFrEF Polypill at Our Community Pharmacy Partner
Time required to prepare a 30-day supply of HFrEF polypill
Measured: Assessed at week 0 or week 4
Implementation Outcome: Cost of HFrEF Polypill Manufacturing at Our Community Pharmacy Partner
Cost of manufacturing a 30-day supply of HFrEF polypill
Measured: Assessed at week 0 or week 4
Number of Days Off of GDMT
Number of days off GDMT due to a clinical event (e.g. hospitalization) or due to logistical / pharmacy issues
Measured: Assessed at weeks 4 and 8

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

27 Feb 202429 Jan 2025

First posted8 Sep 2023
Study start27 Feb 2024
Primary completion17 Sep 2024
Study completion29 Jan 2025

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
Publications (12)Papers the sponsor has linked to this study.
Other trials for Heart Failure With Reduced Ejection FractionStudies of the same condition, open and under way.
More trials run by University of California, San FranciscoThe sponsor's other registered studies.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 2
Primary purpose: Treatment
Allocation: Randomised
Intervention model: Crossover
Masking: None (open label)
Enrolment: 35 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT06029712
Sponsor's protocol ID: 23-39360
Status last verified: Dec 2025
First submitted: 1 Sep 2023
Last updated: 31 Dec 2025
Results posted: Yes, on ClinicalTrials.gov
Data monitoring committee: No
FDA-regulated drug: Yes
FDA-regulated device: No
Individual data sharing: Yes

Publications

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.
PubMed 35877830
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.
PubMed 34973412
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.
PubMed 24493574
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.
PubMed 36018037
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.
PubMed 29521670
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.
PubMed 36116516
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.
PubMed 28190578
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.
PubMed 28263370
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.
PubMed 34612082
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.
PubMed 31532959
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.
PubMed 25193393
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.
PubMed 40118491

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

See locations

RecruitingPhase 4
The Effects of Ferric Derisomaltose in Patients With Acute Heart Failure and Iron Deficiency on Exercise Capacity and Quality of Life(COREVIVE-HFrEF)
Heart Failure With Reduced Ejection Fraction, Iron Deficiency
Active, not recruiting
Assessment of Combined CCM and ICD Device in HFrEF
Heart Failure, Heart Failure With Reduced Ejection Fraction
Not yet recruiting
RELIEVE-HFrEF TRIAL: REducing Lung congestIon Symptoms Using the v-wavE Shunt in adVancEd Heart Failure With Reduced EF
Heart Failure and Reduced Ejection Fraction, Heart Failure Chronic
Recruiting
Endovascular Ablation of the Right Greater Splanchnic Nerve in Subjects With Reduced Ejection Fraction
Heart Failure With Reduced Ejection Fraction (HFrEF)
RecruitingObservational study
Descriptive Study of Circulating Gene or Protein Inflammatory Biomarkers and Bioimpedance Parameters in a Population of Patients Hospitalized for Decompensated Heart Failure With Preserved or Mildly Reduced Cardiac Function
Inflammation Biomarkers, Heart Failure

All Heart Failure With Reduced Ejection Fraction trials

Study at a glance

From the registry record, last updated by the sponsor on 31 Dec 2025. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: Developing a Heart Failure Polypill to Improve Outcomes at a Safety Net Hospital: A Pilot Crossover Randomized Controlled Trial
ClinicalTrials.gov ID: NCT06029712
Acronym / sponsor ID: 23-39360
Conditions: Heart Failure With Reduced Ejection Fraction, HIV Infections
Keywords: Medication adherence, Polypill
Phase: Phase 2
Study type: Interventional
Recruitment status: Completed
Enrolment: 35 participants (actual)
Lead sponsor: University of California, San FranciscoUniversity, hospital or other
Study start: 27 Feb 2024 (actual)
Primary completion: 17 Sep 2024 (actual)
Study completion: 29 Jan 2025 (actual)
First posted: 8 Sep 2023 (actual)
Results: Posted 31 Dec 2025

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Detailed description

Hypothesis: Compared with usual care, a HFrEF polypill implementation strategy will increase adherence to GDMT 4 weeks and reduce total daily pill burden among patients with HFrEF.

Design: Pilot phase II open-label randomized trial with a 2x2 crossover design (AB/BA)

Study design

Primary purpose: Treatment
Allocation: Randomised
Intervention model: Crossover
Masking: None (open label)
Number of arms: 2

Arm	Type	Receives
GDMT delivered in a heart failure polypill	Experimental	Drug: Heart failure polypillThe 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.
GDMT delivered as individual tablets	Active comparator	Drug: Control RxAs 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.

Who may qualify

Ages: 18 years and older
Sex: All
Healthy volunteers: Not accepted
Age groups: Adult, Older adult

Key inclusion criteria (6 listed)

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

Key exclusion criteria (9 listed)

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).

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
Heart failure polypillCopackaging 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.	Drug	GDMT delivered in a heart failure polypill
Control RxGDMT delivered as individual tablets	Drug	GDMT delivered as individual tablets

Primary outcome

Measured Adherence to GDMT by Pill Count
Time frame: The outcome will be measured 1) following a month of polypill use, and 2) following a month of individual tablet use.
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.

17 secondary outcomes

Morisky Medication Adherence-8 (MMAS-8) Questionnaire
Time frame: 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)
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: The outcome will be measured 1) following a month of polypill use, and 2) following a month of individual tablet use.
Blood Pressure (mmHg)
Time frame: The outcome will be measured 1) following a month of polypill use, and 2) following a month of individual tablet use.
Heart Rate
Time frame: The outcome will be measured 1) following a month of polypill use, and 2) following a month of individual tablet use.
Weight
Time frame: The outcome will be measured 1) following a month of polypill use, and 2) following a month of individual tablet use.
NT-ProBNP
Time frame: The outcome will be measured 1) following a month of polypill use, and 2) following a month of individual tablet use.
Adverse Events
Time frame: 0, 2, 4, 6, and 8 weeks
Total Daily Pill Burden of the Patient
Time frame: The outcome will be measured 1) following a month of polypill use, and 2) following a month of individual tablet use.
Number of GDMT Pillars Prescribed
Time frame: The outcome will be measured 1) at the start of the polypill intervention, and 2) at the start of the individual tablet intervention.
HFrEF Polypill Patient Satisfaction Exit Survey
Time frame: After study completion
Number of Participants Completing a Qualitative Exit Interview
Time frame: After study completion (between 8 and 12 weeks)
Implementation Outcome: Time Required to Manufacture the HFrEF Polypill at Our Community Pharmacy Partner
Time frame: Assessed at week 0 or week 4
Implementation Outcome: Cost of HFrEF Polypill Manufacturing at Our Community Pharmacy Partner
Time frame: Assessed at week 0 or week 4
Number of Days Off of GDMT
Time frame: Assessed at weeks 4 and 8

Results and safety

Results posted to the registry on 31 Dec 2025, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
GDMT Delivered in a Heart Failure Polypill First (Individual Tablets Second)	17	14
GDMT Delivered as Individual Tablets First (Polypill Second)	18	13

Primary outcome: Measured Adherence to GDMT by Pill Count

Time frame: The outcome will be measured 1) following a month of polypill use, and 2) following a month of individual tablet use.. Mean (95% Confidence Interval). Unit: adherence ratio expressed in %

Measure	Individual Tablets n = 27	Polypill n = 27
Value	74.6 (66.6 to 82.5)	83.3 (75.3 to 91.3)

Population analysed: As part of the crossover analysis, the individual tablet periods were combined from both assignment groups (individual tablets first and polypill first), and the polypill periods were combined.

17 secondary outcomes are reported in the full results.

Adverse events

Time frame: Adverse event data were collected from the time of starting the intervention period to the end of the intervention period.. Other adverse events reported at 0% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
Individual Tablets	1 of 31 (3.2%)	5 of 31 (16.1%)	0 of 31
Polypill	1 of 30 (3.3%)	6 of 30 (20%)	0 of 30

Limitations and caveats (from the sponsor): 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.

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 31 Dec 2025.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Background: PubMed 35877830Pandey 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.
Background: PubMed 34973412Gnanenthiran 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.
Background: PubMed 24493574Mastromarino 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.
Background: PubMed 36018037Castellano 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.
Background: PubMed 29521670Mohd 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.
Background: PubMed 36116516Baldridge 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.
Background: PubMed 28190578Chow 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.
Background: PubMed 28263370Bahiru 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.
Background: PubMed 34612082Vijay 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.
Background: PubMed 31532959Munoz 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.
Background: PubMed 25193393Castellano 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.
Derived from this study: PubMed 40118491DeJong 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.
Individual participant dataSharing planned: Yes

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Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

Colette DeJong, MD principal investigator

University of California, San Francisco

Priscilla Hsue, MD principal investigator

University of California, San Francisco

1 site in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 6 inclusion and 9 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 31 Dec 2025. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 31 Dec 2025). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Measured Adherence to GDMT by Pill Count (time frame: The outcome will be measured 1) following a month of polypill use, and 2) following a month of individual tablet use.). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT06029712, which also lists 12 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 31 Dec 2025.