Heart Failure Polypill at a Safety Net Hospital

HIV Infections Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06029712
• Other study ID #: 23-39360
• Status: Recruiting
• Phase: Phase 2
• Start date: February 27, 2024
• Est. completion date: July 2024

Study information

• Verified date: March 2024
• Source: University of California, San Francisco
• Contact: Colette DeJong, MD
• Phone: (415) 443-6698
• Email: colette.dejong[@]ucsf.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 40
• Est. completion date: July 2024
• Est. primary completion date: July 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion criteria:

• 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.

Exclusion criteria:

• 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.

Related Conditions & MeSH terms

• Heart Failure
• Heart Failure With Reduced Ejection Fraction
• HIV Infections

Intervention

Drug:
• Heart failure polypill
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 Rx
GDMT delivered as individual tablets

Locations

Country	Name	City	State
United States	Zuckerberg San Francisco General Hospital	San Francisco	California

Sponsors (1)

Lead Sponsor	Collaborator
University of California, San Francisco

Country where clinical trial is conducted

United States, 

References & Publications (11)

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. — View Citation

Baldridge AS, Huffman MD, Lazar D, Abbas H, Flowers FM, Quintana A, Jackson A, Khan SS, Chopra A, Vu M, Tripathi P, Jacobson T, Sanuade OA, Kandula NR, Persell SD, Paparello JJ, Rosul LL, Mejia J, Lloyd-Jones DM, Chow CK, Ciolino JD. Efficacy and safety of a quadruple ultra-low-dose treatment for hypertension (QUARTET USA): Rationale and design for a randomized controlled trial. Am Heart J. 2022 Dec;254:183-193. doi: 10.1016/j.ahj.2022.09.004. Epub 2022 Sep 15. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

* Note: There are 11 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Measured adherence to GDMT by pill count	The primary outcome will be GDMT adherence proportion, as determined by pill count. The proportion will be calculated as (# of GDMT pills taken) / (# of GDMT pills that should have been taken since the last study visit). The polypill will be treated as 1 pill for the purposes of this calculation. Pill count may be performed in-office or over videoconferencing.	4 and 8 weeks
Secondary	Morisky Medication Adherence-8 (MMAS-8) questionnaire	MMAS-8 scores range from 0-8 and can be classified into low adherence (0-5), medium adherence (6-7), or high adherence (8).	0, 4, and 8 weeks
Secondary	Self-reported adherence to GDMT, antiretroviral therapy, and all other medications	The investigators will use a simple survey to ask patients about their adherence to each medication in the preceding 1 week and the preceding 4 weeks.	0, 4, and 8 weeks
Secondary	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.	0, 4, and 8 weeks
Secondary	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.	0, 4, and 8 weeks
Secondary	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.	0, 4, and 8 weeks
Secondary	Adherence ratio to individual components of GDMT by pill count	At study visits at 4 weeks and 8 weeks, the investigators will calculate the adherence ratio for each individual component of GDMT (beta blocker, MRA, SGLT2i, and ACE/ARB/ARNI). This will allow us to investigate whether there is differential adherence to some categories of GDMT (for example, lower adherence to beta-blockers).	0, 4, and 8 weeks
Secondary	Blood pressure (mmHg)	Blood pressure at baseline and study follow-up	0, 4, and 8 weeks
Secondary	Heart rate (beats per minute)	Heart rate at baseline and study follow-up	0, 4, and 8 weeks
Secondary	Weight (lb)	Weight at baseline and study follow-up	0, 4, and 8 weeks
Secondary	NT-ProBNP	Lab test	0, 4, and 8 weeks
Secondary	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.	0, 2, 4, 6, and 8 weeks
Secondary	Total daily pill burden of the patient	This will be calculated based on the patient's active medication list.	0, 4, and 8 weeks