A Phase 2 interventional study of Heart failure polypill and Control Rx in Heart Failure With Reduced Ejection Fraction and HIV Infections, sponsored by University of California, San Francisco. Completed at 1 site in United States. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2025-12-31.
Sponsored by University of California, San Francisco · Phase 2, Interventional, and Treatment
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).
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.
4,258 studies on the registry are indexed under HIV Infections; 240 are open to participants now.
This study's enrollment of 35 is below the median of 83 across 3,251 interventional studies indexed under HIV Infections.
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Exclusion criteria:
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
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
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 as individual tablets
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.
Time frame: The outcome will be measured 1) following a month of polypill use, and 2) following a month of individual tablet use.
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.
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)
TSQM scores range from 0 to 100, with higher scores indicating greater treatment satisfaction.
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
As a pilot trial, our study will not be powered for clinical outcomes, but key exploratory outcomes will include HFrEF admissions.
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
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.
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
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).
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)
Systolic Blood pressure at baseline and study follow-up
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
Heart rate (beats per minute)
Time frame: 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
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
Lab test
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
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.
Time frame: 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.
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
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.
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
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.
Time frame: 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)
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 required to prepare a 30-day supply of HFrEF polypill
Time frame: 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
Time frame: 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
Time frame: Assessed at weeks 4 and 8
Feasibility of Recruitment
Number of months taken to recruit 30-40 people to consent to participate in the study
Time frame: Completion of recruitment within 1 year of initiating recruitment
Feasibility of Adherence to Study Protocols
Successful completion of study related procedures for at least 20 participants (screening, randomization, drug allocation, follow-up procedures, retention, and transition to ongoing care)
Time frame: Assessed following study completion (approximately 1 year)
| Milestone | GDMT Delivered in a Heart Failure Polypill First (Individual Tablets Second) | GDMT Delivered as Individual Tablets First (Polypill Second) |
|---|---|---|
| Started | 17 | 18 |
| Completed | 14 | 13 |
| Not completed | 3 | 5 |
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.
| adherence ratio expressed in % | Individual Tablets | Polypill |
|---|---|---|
| Measured Adherence to GDMT by Pill Count | 74.6 (66.6 to 82.5) | 83.3 (75.3 to 91.3) |
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.
| Total Score | Individual Tablets | Polypill |
|---|---|---|
| Morisky Medication Adherence-8 (MMAS-8) Questionnaire | 4.1 (3.4 to 4.8) | 4.6 (3.9 to 5.4) |
TSQM scores range from 0 to 100, with higher scores indicating greater treatment satisfaction.
| Points on Global Satisfaction Score | Individual Tablets | Polypill |
|---|---|---|
| Treatment Satisfaction Using the Treatment Satisfaction Questionnaire for Medication (TSQM 9) | 69.0 (61.6 to 76.3) | 73.6 (66.3 to 81) |
As a pilot trial, our study will not be powered for clinical outcomes, but key exploratory outcomes will include HFrEF admissions.
| Participants | Individual Tablets | Polypill |
|---|---|---|
| Heart Failure Admission Rate | 0 | 1 |
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.
| Overall Summary Score | Individual Tablets | Polypill |
|---|---|---|
| Kansas City Cardiomyopathy Questionnaire (KCCQ) 12 | 67.9 (59.6 to 76.3) | 70.6 (62.2 to 78.9) |
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).
| adherence ratio expressed in % | Individual Tablets | Polypill |
|---|---|---|
| Beta Blockers | 73.8 (64.7 to 82.8) | 83.6 (74.6 to 92.7) |
| ACE/ARB/ARNI | 71.1 (61.0 to 81.1) | 80.4 (70.4 to 90.4) |
| MRA | 74.4 (66.3 to 82.5) | 83.7 (75.6 to 91.8) |
| SGLT2i | 73.4 (64.5 to 82.3) | 81.6 (72.7 to 90.4) |
Systolic Blood pressure at baseline and study follow-up
| mm Hg | Individual Tablets | Polypill |
|---|---|---|
| Blood Pressure (mmHg) | 126 (118 to 134) | 124 (116 to 132) |
Heart rate (beats per minute)
| beats per minute | Individual Tablets | Polypill |
|---|---|---|
| Heart Rate | 77 (71 to 84) | 77 (71 to 83) |
Weight at baseline and study follow-up
| kg | Individual Tablets | Polypill |
|---|---|---|
| Weight | 92.0 (82.8 to 101.1) | 93.0 (83.9 to 102.1) |
Lab test
| pg/ml | Individual Tablets | Polypill |
|---|---|---|
| NT-ProBNP | 1040.5 (448.4 to 1632.6) | 1086.5 (494.4 to 1678.7) |
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.
| Participants | Individual Tablets | Polypill |
|---|---|---|
| Serious Adverse Events | 1 | 1 |
| Any Adverse Event | 6 | 7 |
This will be calculated based on the patient's active medication list.
| pills per day | Individual Tablets | Polypill |
|---|---|---|
| Total Daily Pill Burden of the Patient | 10 (9 to 12) | 7 (5 to 8) |
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.
| Participants | Individual Tablets | Polypill |
|---|---|---|
| Beta Blocker | 30 | 30 |
| ACE/ARB/ARNI | 28 | 28 |
| MRA | 30 | 29 |
| SGLT2i | 29 | 29 |
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.
| Score on a 5-point scale | All Participants Who Completed the Study (Both Intervention Periods) |
|---|---|
| HFrEF Polypill Patient Satisfaction Exit Survey | 4.75 (4 to 5) |
Participation in a semi-structured exit interview using a RE-AIM framework (Reach, Effectiveness, Adoption, Implementation, Maintenance)
| Participants | All Participants Who Completed the Study (Both Intervention Periods) |
|---|---|
| Number of Participants Completing a Qualitative Exit Interview | 27 |
Time required to prepare a 30-day supply of HFrEF polypill
| minutes | Manufacturing Set |
|---|---|
| Implementation Outcome: Time Required to Manufacture the HFrEF Polypill at Our Community Pharmacy Partner | 27 ± 4 |
Cost of manufacturing a 30-day supply of HFrEF polypill
| Dollars | Manufacturing Set |
|---|---|
| Implementation Outcome: Cost of HFrEF Polypill Manufacturing at Our Community Pharmacy Partner | 60 ± 0 |
Number of days off GDMT due to a clinical event (e.g. hospitalization) or due to logistical / pharmacy issues
| Participants | Individual Tablets | Polypill |
|---|---|---|
| 0 days | 27 | 23 |
| 1-3 days | 1 | 3 |
| 4-7 days | 0 | 1 |
| 8+days | 1 | 0 |
Number of months taken to recruit 30-40 people to consent to participate in the study
| months | Consented |
|---|---|
| Feasibility of Recruitment | 6 |
Successful completion of study related procedures for at least 20 participants (screening, randomization, drug allocation, follow-up procedures, retention, and transition to ongoing care)
| Participants | Consented |
|---|---|
| Feasibility of Adherence to Study Protocols | 27 |
Collected over Adverse event data were collected from the time of starting the intervention period to the end of the intervention period.. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Individual Tablets | 0/31 (0%) | 1/31 (3.2%) | 5/31 (16.1%) |
| Polypill | 0/30 (0%) | 1/30 (3.3%) | 6/30 (20%) |
| Event | Individual Tablets | Polypill |
|---|---|---|
| Heart Failure HospitalizationCardiac disorders | 0/31 | 1/30 |
| Non-Heart Failure HospitalizationGeneral disorders | 1/31 | 0/30 |
| Event | Individual Tablets | Polypill |
|---|---|---|
| Non-HF Emergency Department or Urgent Care VisitGeneral disorders | 1/31 | 4/30 |
| Dizziness or HypotensionGeneral disorders | 2/31 | 3/30 |
| Acute Kidney InjuryRenal and urinary disorders | 1/31 | 2/30 |
| GDMT Medication Discontinuation or Downtriation due IntoleranceGeneral disorders | 1/31 | 2/30 |
| HyperkalemiaRenal and urinary disorders | 1/31 | 1/30 |
| Age, Continuous(years) | GDMT Delivered in a Heart Failure Polypill First (Individual Tablets Second) | GDMT Delivered as Individual Tablets First (Polypill Second) | Total |
|---|---|---|---|
| Median | 55 (52 to 60) | 50.5 (42 to 61) | 54 (46 to 61) |
| Sex: Female, Male(Participants) | GDMT Delivered in a Heart Failure Polypill First (Individual Tablets Second) | GDMT Delivered as Individual Tablets First (Polypill Second) | Total |
|---|---|---|---|
| Female | 2 | 7 | 9 |
| Male | 15 | 11 | 26 |
| Race (NIH/OMB)(Participants) | GDMT Delivered in a Heart Failure Polypill First (Individual Tablets Second) | GDMT Delivered as Individual Tablets First (Polypill Second) | Total |
|---|---|---|---|
| American Indian or Alaska Native | 1 | 0 | 1 |
| Asian | 1 | 1 | 2 |
| Native Hawaiian or Other Pacific Islander | 1 | 1 | 2 |
| Black or African American | 11 | 7 | 18 |
| White | 3 | 7 | 10 |
| More than one race | 0 | 0 | 0 |
| Unknown or Not Reported | 0 | 2 | 2 |
| Ethnicity (NIH/OMB)(Participants) | GDMT Delivered in a Heart Failure Polypill First (Individual Tablets Second) | GDMT Delivered as Individual Tablets First (Polypill Second) | Total |
|---|---|---|---|
| Hispanic or Latino | 2 | 4 | 6 |
| Not Hispanic or Latino | 15 | 14 | 29 |
| Unknown or Not Reported | 0 | 0 | 0 |
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Plan to share: Yes
Supporting information: Study protocol, Icf
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University of California, San Francisco