xml: <clinical_study>
    <!-- This xml conforms to an XML Schema at:
      https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
    <required_header>
      <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
      <link_text>Link to the current ClinicalTrials.gov record.</link_text>
      <url>https://clinicaltrials.gov/ct2/show/NCT06029712</url>
    </required_header>
    <id_info>
      <org_study_id>23-39360</org_study_id>
      <nct_id>NCT06029712</nct_id>
    </id_info>
    <brief_title>Heart Failure Polypill at a Safety Net Hospital</brief_title>
    <official_title>Developing a Heart Failure Polypill to Improve Outcomes at a Safety Net Hospital: A Pilot Crossover Randomized Controlled Trial</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>University of California, San Francisco</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
      <collaborator>
        <agency>UCSF CAPS-HIV Innovative Grant</agency>
        <agency_class>Other</agency_class>
      </collaborator>
      <collaborator>
        <agency>UCSF CFAR-ARI HIV Boost Award</agency>
        <agency_class>Other</agency_class>
      </collaborator>
      <collaborator>
        <agency>ACC/ABC Merck Research Fellowship Award (support for Dr. DeJong)</agency>
        <agency_class>Other</agency_class>
      </collaborator>
    </sponsors>
    <source>University of California, San Francisco</source>
    <oversight_info>
      <has_dmc>No</has_dmc>
      <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
      <is_fda_regulated_device>No</is_fda_regulated_device>
      <is_us_export>No</is_us_export>
    </oversight_info>
    <brief_summary>
      <textblock>
        A novel four-drug regimen for heart failure with reduced ejection fraction (HFrEF) extends&#xD;
        patients' life expectancy by an average of 6 years compared to traditional therapies, in&#xD;
        addition to improving quality of life. Unfortunately, uptake of this complex multi-drug&#xD;
        regimen has been low, especially among underserved communities with barriers to medication&#xD;
        adherence. Although combination tablets have transformed access to care for conditions such&#xD;
        as HIV and tuberculosis, no combination pill is available for HFrEF.&#xD;
  &#xD;
        In the proposed study, the investigators will utilize inexpensive over-encapsulation&#xD;
        techniques to develop a novel combination pill (&quot;polypill&quot;) for patients with HFrEF. In Aim&#xD;
        1, the investigators will conduct stakeholder interviews with patients, providers, and&#xD;
        pharmacists to inform the design of a HFrEF polypill. In Aim 2, the investigators will&#xD;
        conduct a pilot, single-center, crossover randomized clinical trial to investigate whether,&#xD;
        compared to usual care, a HFrEF polypill increases medication adherence among 40 adults with&#xD;
        HFrEF. Given the high daily pill burden among patients both with HIV and HFrEF, the&#xD;
        investigators aim to recruit an HIV+ subgroup (~20 participants) and an HIV- subgroup (~20&#xD;
        participants).&#xD;
      </textblock>
    </brief_summary>
    <detailed_description>
      <textblock>
        Hypothesis: Compared with usual care, a HFrEF polypill implementation strategy will increase&#xD;
        adherence to guideline-directed medical therapy (GDMT) at 4 and 8 weeks and reduce total&#xD;
        daily pill burden among patients with HFrEF, with no increase in serious adverse events.&#xD;
  &#xD;
        Rationale: HFrEF among PWH is associated with a high pill burden, which adversely impacts&#xD;
        adherence. Over-encapsulation is an inexpensive and replicable method to combine tablets into&#xD;
        a single capsule. However, the role of over-encapsulation to reduce pill burden among adults&#xD;
        with HIV and HFrEF is unknown.&#xD;
  &#xD;
        Design: Pilot phase II open-label randomized trial with a 2x2 crossover design (AB/BA)&#xD;
        Participants: Participants will be assessed for eligibility at outpatient cardiology visits&#xD;
        at Zuckerberg San Francisco General Hospital (ZSFG), leveraging the Epic-based health&#xD;
        information technology system to identify potentially eligible participants. Participants&#xD;
        will be eligible if they are ≥ 18 years old and carry a diagnosis of heart failure, with&#xD;
        echocardiographic or MRI evidence of reduced ejection fraction (≤45%). We will recruit HIV&#xD;
        positive and HIV negative patient subgroups. Patients will be excluded if they have&#xD;
        contraindications to any of the components of GDMT (for example, pregnancy, medication&#xD;
        allergy, or history of hyperkalemia). After obtaining informed consent at an initial&#xD;
        screening visit, eligible participants will be randomized to the AB group or BA group using a&#xD;
        random number generator via REDcap.&#xD;
  &#xD;
        Intervention: The intervention will be pharmacy-level over-encapsulation of once-daily heart&#xD;
        failure medications (beta blocker, SGLT2 inhibitor, and mineralocorticoid receptor&#xD;
        antagonist) into a single capsule. For some patients, a diuretic and once-daily ACE inhibitor&#xD;
        or angiotensin receptor blocker may also be included if capsule size allows. Any twice-daily&#xD;
        HFrEF medications, such as sacubitril/valsartan, will be omitted from the polypill and will&#xD;
        continue to be filled individually. the investigators will partner with a community pharmacy&#xD;
        with proficiency in over-encapsulation and over 20 years' experience working with ZSFG to&#xD;
        deliver adherence interventions.&#xD;
  &#xD;
        For patients in the polypill arm, heart failure medications will be filled as usual, but&#xD;
        rather than dispensing each medication separately, the pharmacy technician will hand-pack all&#xD;
        once-daily heart failure medications into a small capsule. The doses will be individualized&#xD;
        to the patient based on their physician's prescription. Thus, the polypill will be a&#xD;
        late-stage implementation intervention to reduce pill burden, without restricting dose&#xD;
        possibilities or interfering with medication titration.&#xD;
  &#xD;
        Prior to randomization, participants who are not already prescribed a beta blocker, SGLT2&#xD;
        inhibitor (SGLT2i), and mineralocorticoid receptor antagonist (MRA) will be initiated on&#xD;
        these medications at starting doses if no contraindications exist. Half of the participants&#xD;
        will then be randomized to the AB group (polypill for 2 months, then usual care for 2&#xD;
        months). The other half of participants will be randomized to the BA group (usual care for 2&#xD;
        months, then polypill for 2 months). After randomization, participants assigned to receive&#xD;
        the polypill up-front will be delivered 30-day supplies of the polypill via their preferred&#xD;
        delivery method (mail, pick up at a ZSFG clinic, or pick up at the pharmacy). Participants&#xD;
        assigned to usual care will be mailed or pick up their existing heart failure medications as&#xD;
        individual pills.&#xD;
  &#xD;
        At trial follow-up visits at 4, 8, 12, and 16 weeks, participants will be assessed for&#xD;
        outcomes and adverse events and will undergo lab monitoring. Medication doses may be titrated&#xD;
        at these visits if clinically indicated. Participants in the AB and BA arms will have the&#xD;
        same follow-up schedule, and can opt to receive refills of their medications by mail or in&#xD;
        clinic. Participants will receive gift certificates for each visit, with an additional gift&#xD;
        certificate if blood draws are needed. Bus tokens or other transportation vouchers will also&#xD;
        be provided. At the conclusion of the study, the investigators will perform semi-structured&#xD;
        exit interviews with participants, clinicians, and pharmacists. The investigators will use&#xD;
        prepared interview guides, and will offer gift cards for participation in a 30-60 minute exit&#xD;
        interview. Investigators will elicit stakeholders' experiences with the polypill, barriers&#xD;
        encountered, preferences for trade-offs between pill size and number of pills, perceptions&#xD;
        about taking polypills vs. the individual components, and experience working with the&#xD;
        pharmacy for medication delivery.&#xD;
  &#xD;
        Outcomes: The primary outcome will be adherence to overall and individual components of GDMT&#xD;
        at 4, 8, 12, and 16 weeks, as measured by pill count. Specifically, investigators will&#xD;
        calculate the adherence ratio (number of pills missing divided by the number of days between&#xD;
        the 2 visits). Secondary outcomes will include adherence ratio to other medications,&#xD;
        self-report of GDMT adherence using the MMAS-8 questionnaire, treatment satisfaction using&#xD;
        the Treatment Satisfaction Questionnaire for Medication, and documented episodes of&#xD;
        treatment-related adverse effects (e.g. allergy, hyperkalemia, bradycardia). Investigators&#xD;
        will also capture feasibility metrics in conjunction with the study's pharmacy partner,&#xD;
        including production time and costs for polypill packaging. As a pilot trial, this study will&#xD;
        not be powered for clinical outcomes, but key exploratory outcomes will include HFrEF&#xD;
        admissions and change in health-related quality of life measured by the Kansas City&#xD;
        Cardiomyopathy Questionnaire. The exit interviews will be transcribed, coded, and analyzed&#xD;
        using the Consolidated Framework for Implementation Research (CFIR) for evaluation of an&#xD;
        implementation project.&#xD;
  &#xD;
        Data management, sample size, and statistical analyses: In the FOCUS trial of an&#xD;
        over-encapsulated polypill for hypertension, patients randomized to a polypill were 24% more&#xD;
        likely to be adherent compared to those receiving separate pills (50.8% adherence in polypill&#xD;
        group vs. 41% adherence in usual care, p = 0.019; OR, 1.24; 95% CI, 1.06-1.47). Considering a&#xD;
        power of 80% and alpha of 5%, using a two-treatment crossover trial design, a minimum sample&#xD;
        size of 20 participants total (10 per arm) will be necessary to identify a 20% absolute&#xD;
        change in adherence ratio among patients prescribed the polypill vs. usual care, assuming a&#xD;
        standard deviation of 30% in the change in adherence ratio over time. Assuming that up to 50%&#xD;
        of patients will not complete the run-in period, it is estimated that 40 patients (20 per&#xD;
        arm) should be recruited. A sample size of 20 participants in each arm is comparable to other&#xD;
        pilot studies of cardiovascular polypills.45 Demographic data for participants will be&#xD;
        described in each group and compared using a Student's T-test (continuous variables) or&#xD;
        Fisher's exact test (categorical variables). Investigators will use mixed model multilevel&#xD;
        linear regression analyses to determine the effect of a polypill vs. usual care on GDMT&#xD;
        adherence. Analyses will be performed according to an intention-to-treat principle, using&#xD;
        Stata, version 17. The threshold for statistical significance will be P &lt; 0.05.&#xD;
      </textblock>
    </detailed_description>
    <overall_status>Not yet recruiting</overall_status>
    <start_date type="Anticipated">November 2023</start_date>
    <completion_date type="Anticipated">June 2024</completion_date>
    <primary_completion_date type="Anticipated">June 2024</primary_completion_date>
    <phase>Phase 2</phase>
    <study_type>Interventional</study_type>
    <has_expanded_access>No</has_expanded_access>
    <study_design_info>
      <allocation>Randomized</allocation>
      <intervention_model>Crossover Assignment</intervention_model>
      <primary_purpose>Treatment</primary_purpose>
      <masking>None (Open Label)</masking>
    </study_design_info>
    <primary_outcome>
      <measure>Measured adherence to GDMT by pill count</measure>
      <time_frame>Change in adherence from 8 to 16 weeks</time_frame>
      <description>The primary outcome will be adherence to overall and individual components of GDMT at 4, 8, 12, and 16 weeks, as measured by pill count. Specifically, we will calculate the adherence ratio (number of pills missing divided by the number of days between the 2 visits).</description>
    </primary_outcome>
    <secondary_outcome>
      <measure>Self-reported adherence to GDMT using the Morisky Medication Adherence-8 (MMAS-8) questionnaire</measure>
      <time_frame>Change in adherence from 8 to 16 weeks</time_frame>
      <description>MMAS-8 scores range from 0-8 and can be classified into low adherence (0-5), medium adherence (6-7), or high adherence (8).</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Measured adherence to other medications, using pill count</measure>
      <time_frame>Change in adherence from 8 to 16 weeks</time_frame>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Treatment satisfaction using the Treatment Satisfaction Questionnaire for Medication (TSQM)</measure>
      <time_frame>8 and 16 weeks</time_frame>
      <description>TSQM scores range from 0 to 100, with higher scores indicating greater treatment satisfaction.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Heart failure admission rate</measure>
      <time_frame>Baseline, 8 weeks, and 16 weeks</time_frame>
      <description>As a pilot trial, our study will not be powered for clinical outcomes, but key exploratory outcomes will include HFrEF admissions.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Kansas City Cardiomyopathy Questionnaire (KCCQ)</measure>
      <time_frame>Baseline, 8 weeks, and 16 weeks</time_frame>
      <description>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.</description>
    </secondary_outcome>
    <number_of_arms>2</number_of_arms>
    <enrollment type="Anticipated">40</enrollment>
    <condition>Heart Failure With Reduced Ejection Fraction</condition>
    <condition>HIV Infections</condition>
    <arm_group>
      <arm_group_label>GDMT delivered in a heart failure polypill</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>The polypill intervention will be pharmacy-level over-encapsulation of once-daily heart failure medications (beta-blocker, SGLT2 inhibitor, and spironolactone) into a single capsule. Any twice-daily HFrEF medications, such as sacubitril/valsartan, will be omitted from the polypill and will continue to be filled individually. We 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 plastic capsule.</description>
    </arm_group>
    <arm_group>
      <arm_group_label>GDMT delivered as individual tablets</arm_group_label>
      <arm_group_type>Active Comparator</arm_group_type>
      <description>As described above, participants who are not already prescribed a beta blocker, SGLT2i, 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.</description>
    </arm_group>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Heart failure polypill</intervention_name>
      <description>Copackaging of once-daily heart failure medications (beta blocker, SGLT2i, and MRA) 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.</description>
      <arm_group_label>GDMT delivered in a heart failure polypill</arm_group_label>
    </intervention>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Control Rx</intervention_name>
      <description>GDMT delivered as individual tablets</description>
      <arm_group_label>GDMT delivered as individual tablets</arm_group_label>
    </intervention>
    <eligibility>
      <criteria>
        <textblock>
          Inclusion Criteria:&#xD;
  &#xD;
            -  Age &gt; 18 years old&#xD;
  &#xD;
            -  Previously diagnosed with heart failure with reduced ejection fraction ( &lt;40% by&#xD;
               echocardiogram or cardiac MRI)&#xD;
  &#xD;
            -  With or without a prior diagnosis of HIV (HIV+ and HIV- subgroups)&#xD;
  &#xD;
            -  Able to conveniently obtain medications through one of 3 available mechanisms (mail,&#xD;
               pick up at a ZSFG clinic, or pick up at our pharmacy partner)&#xD;
  &#xD;
          Exclusion Criteria:&#xD;
  &#xD;
            -  Patients who are not fluent in English. These patients are excluded from this small&#xD;
               pilot trial for feasibility reasons (i.e. access to medical interpreters)&#xD;
  &#xD;
            -  Patients who have dementia or lack capacity&#xD;
  &#xD;
            -  Patients who are incarcerated&#xD;
  &#xD;
            -  Patients who cannot provide informed consent&#xD;
  &#xD;
            -  Patients with contraindications to any of the components of GDMT (for example,&#xD;
               pregnancy or breastfeeding, medication allergy, CKD with eGFR &lt; 30, or history of&#xD;
               hyperkalemia)&#xD;
        </textblock>
      </criteria>
      <gender>All</gender>
      <minimum_age>18 Years</minimum_age>
      <maximum_age>N/A</maximum_age>
      <healthy_volunteers>No</healthy_volunteers>
    </eligibility>
    <overall_official>
      <last_name>Colette DeJong, MD</last_name>
      <role>Principal Investigator</role>
      <affiliation>University of California, San Francisco</affiliation>
    </overall_official>
    <overall_official>
      <last_name>Priscilla Hsue, MD</last_name>
      <role>Principal Investigator</role>
      <affiliation>University of California, San Francisco</affiliation>
    </overall_official>
    <overall_contact>
      <last_name>Colette DeJong, MD</last_name>
      <phone>(415) 443-6698</phone>
      <email>colette.dejong@ucsf.edu</email>
    </overall_contact>
    <location>
      <facility>
        <name>Zuckerberg San Francisco General Hospital</name>
        <address>
          <city>San Francisco</city>
          <state>California</state>
          <zip>94110</zip>
          <country>United States</country>
        </address>
      </facility>
      <contact>
        <last_name>Colette DeJong</last_name>
        <email>colette.dejong@ucsf.edu</email>
      </contact>
      <investigator>
        <last_name>Colette DeJong, MD</last_name>
        <role>Principal Investigator</role>
      </investigator>
      <investigator>
        <last_name>Priscilla Hsue, MD</last_name>
        <role>Principal Investigator</role>
      </investigator>
      <investigator>
        <last_name>Matthew Durstenfeld, MD, MAS</last_name>
        <role>Sub-Investigator</role>
      </investigator>
      <investigator>
        <last_name>Wayne Steward, PhD, MPH</last_name>
        <role>Sub-Investigator</role>
      </investigator>
      <investigator>
        <last_name>Elise Riley, PhD</last_name>
        <role>Sub-Investigator</role>
      </investigator>
      <investigator>
        <last_name>Matthew Hickey, MD</last_name>
        <role>Sub-Investigator</role>
      </investigator>
      <investigator>
        <last_name>Jonathan Davis, MD</last_name>
        <role>Sub-Investigator</role>
      </investigator>
      <investigator>
        <last_name>Christina Wang, PharmD</last_name>
        <role>Sub-Investigator</role>
      </investigator>
      <investigator>
        <last_name>Janet Grochowski, PharmD</last_name>
        <role>Sub-Investigator</role>
      </investigator>
    </location>
    <location_countries>
      <country>United States</country>
    </location_countries>
    <reference>
      <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.</citation>
      <PMID>35877830</PMID>
    </reference>
    <reference>
      <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.</citation>
      <PMID>34973412</PMID>
    </reference>
    <reference>
      <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.</citation>
      <PMID>24493574</PMID>
    </reference>
    <reference>
      <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.</citation>
      <PMID>36018037</PMID>
    </reference>
    <reference>
      <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.</citation>
      <PMID>29521670</PMID>
    </reference>
    <reference>
      <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.</citation>
      <PMID>36116516</PMID>
    </reference>
    <reference>
      <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.</citation>
      <PMID>28190578</PMID>
    </reference>
    <reference>
      <citation>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.</citation>
      <PMID>28263370</PMID>
    </reference>
    <reference>
      <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.</citation>
      <PMID>34612082</PMID>
    </reference>
    <reference>
      <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.</citation>
      <PMID>31532959</PMID>
    </reference>
    <reference>
      <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.</citation>
      <PMID>25193393</PMID>
    </reference>
    <verification_date>September 2023</verification_date>
    <study_first_submitted>September 1, 2023</study_first_submitted>
    <study_first_submitted_qc>September 1, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">September 8, 2023</study_first_posted>
    <last_update_submitted>September 1, 2023</last_update_submitted>
    <last_update_submitted_qc>September 1, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">September 8, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Sponsor</responsible_party_type>
    </responsible_party>
    <keyword>Medication adherence</keyword>
    <keyword>Polypill</keyword>
    <condition_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Heart Failure</mesh_term>
    </condition_browse>
    <patient_data>
      <sharing_ipd>Yes</sharing_ipd>
      <ipd_info_type>Study Protocol</ipd_info_type>
      <ipd_info_type>Informed Consent Form (ICF)</ipd_info_type>
    </patient_data>
    <!-- Results have not yet been posted for this study                                          -->
  </clinical_study>
  
  
text: download date: ClinicalTrials.gov processed this data on September 20, 2023
  link text: Link to the current ClinicalTrials.gov record.
  url: https://clinicaltrials.gov/ct2/show/NCT06029712
  org study id: 23-39360
  nct id: NCT06029712
  lead sponsor: 
  collaborator: 
  collaborator: 
  collaborator: 
  has dmc: No
  is fda regulated drug: Yes
  is fda regulated device: No
  is us export: No
  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 40 adults with
        HFrEF. Given the high daily pill burden among patients both with HIV and HFrEF, the
        investigators aim to recruit an HIV+ subgroup (~20 participants) and an HIV- subgroup (~20
        participants).
  Hypothesis: Compared with usual care, a HFrEF polypill implementation strategy will increase
        adherence to guideline-directed medical therapy (GDMT) at 4 and 8 weeks and reduce total
        daily pill burden among patients with HFrEF, with no increase in serious adverse events.
  
        Rationale: HFrEF among PWH is associated with a high pill burden, which adversely impacts
        adherence. Over-encapsulation is an inexpensive and replicable method to combine tablets into
        a single capsule. 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)
        Participants: Participants will be assessed for eligibility at outpatient cardiology visits
        at Zuckerberg San Francisco General Hospital (ZSFG), leveraging the Epic-based health
        information technology system to identify potentially eligible participants. Participants
        will be eligible if they are ≥ 18 years old and carry a diagnosis of heart failure, with
        echocardiographic or MRI evidence of reduced ejection fraction (≤45%). We will recruit HIV
        positive and HIV negative patient subgroups. Patients will be excluded if they have
        contraindications to any of the components of GDMT (for example, pregnancy, medication
        allergy, or history of hyperkalemia). After obtaining informed consent at an initial
        screening visit, eligible participants will be randomized to the AB group or BA group using a
        random number generator via REDcap.
  
        Intervention: The intervention will be pharmacy-level over-encapsulation of once-daily heart
        failure medications (beta blocker, SGLT2 inhibitor, and mineralocorticoid receptor
        antagonist) into a single capsule. For some patients, a diuretic and once-daily ACE inhibitor
        or angiotensin receptor blocker may also be included if capsule size allows. Any twice-daily
        HFrEF medications, such as sacubitril/valsartan, will be omitted from the polypill and will
        continue to be filled individually. the investigators will partner with a community pharmacy
        with proficiency in over-encapsulation and over 20 years' experience working with ZSFG to
        deliver adherence interventions.
  
        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 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.
  
        Prior to randomization, participants who are not already prescribed a beta blocker, SGLT2
        inhibitor (SGLT2i), and mineralocorticoid receptor antagonist (MRA) will be initiated on
        these medications at starting doses if no contraindications exist. Half of the participants
        will then be randomized to the AB group (polypill for 2 months, then usual care for 2
        months). The other half of participants will be randomized to the BA group (usual care for 2
        months, then polypill for 2 months). 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 the pharmacy). Participants
        assigned to usual care will be mailed or pick up their existing heart failure medications as
        individual pills.
  
        At trial follow-up visits at 4, 8, 12, and 16 weeks, participants will be assessed for
        outcomes and adverse events and will undergo lab monitoring. 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 or in
        clinic. Participants will receive gift certificates for each visit, with an additional gift
        certificate if blood draws are needed. Bus tokens or other transportation vouchers will also
        be provided. At the conclusion of the study, the investigators will perform semi-structured
        exit interviews with participants, clinicians, and pharmacists. The investigators will use
        prepared interview guides, and will offer gift cards for participation in a 30-60 minute exit
        interview. Investigators will elicit stakeholders' experiences with the polypill, barriers
        encountered, preferences for trade-offs between pill size and number of pills, perceptions
        about taking polypills vs. the individual components, and experience working with the
        pharmacy for medication delivery.
  
        Outcomes: The primary outcome will be adherence to overall and individual components of GDMT
        at 4, 8, 12, and 16 weeks, as measured by pill count. Specifically, investigators will
        calculate the adherence ratio (number of pills missing divided by the number of days between
        the 2 visits). Secondary outcomes will include adherence ratio to other medications,
        self-report of GDMT adherence using the MMAS-8 questionnaire, treatment satisfaction using
        the Treatment Satisfaction Questionnaire for Medication, and documented episodes of
        treatment-related adverse effects (e.g. allergy, hyperkalemia, bradycardia). Investigators
        will also capture feasibility metrics in conjunction with the study's pharmacy partner,
        including production time and costs for polypill packaging. As a pilot trial, this study will
        not be powered for clinical outcomes, but key exploratory outcomes will include HFrEF
        admissions and change in health-related quality of life measured by the Kansas City
        Cardiomyopathy Questionnaire. The exit interviews will be transcribed, coded, and analyzed
        using the Consolidated Framework for Implementation Research (CFIR) for evaluation of an
        implementation project.
  
        Data management, sample size, and statistical analyses: In the FOCUS trial of an
        over-encapsulated polypill for hypertension, patients randomized to a polypill were 24% more
        likely to be adherent compared to those receiving separate pills (50.8% adherence in polypill
        group vs. 41% adherence in usual care, p = 0.019; OR, 1.24; 95% CI, 1.06-1.47). Considering a
        power of 80% and alpha of 5%, using a two-treatment crossover trial design, a minimum sample
        size of 20 participants total (10 per arm) will be necessary to identify a 20% absolute
        change in adherence ratio among patients prescribed the polypill vs. usual care, assuming a
        standard deviation of 30% in the change in adherence ratio over time. Assuming that up to 50%
        of patients will not complete the run-in period, it is estimated that 40 patients (20 per
        arm) should be recruited. A sample size of 20 participants in each arm is comparable to other
        pilot studies of cardiovascular polypills.45 Demographic data for participants will be
        described in each group and compared using a Student's T-test (continuous variables) or
        Fisher's exact test (categorical variables). Investigators will use mixed model multilevel
        linear regression analyses to determine the effect of a polypill vs. usual care on GDMT
        adherence. Analyses will be performed according to an intention-to-treat principle, using
        Stata, version 17. The threshold for statistical significance will be P < 0.05.
  allocation: Randomized
  intervention model: Crossover Assignment
  primary purpose: Treatment
  masking: None (Open Label)
  measure: Measured adherence to GDMT by pill count
  time frame: Change in adherence from 8 to 16 weeks
  description: The primary outcome will be adherence to overall and individual components of GDMT at 4, 8, 12, and 16 weeks, as measured by pill count. Specifically, we will calculate the adherence ratio (number of pills missing divided by the number of days between the 2 visits).
  measure: Self-reported adherence to GDMT using the Morisky Medication Adherence-8 (MMAS-8) questionnaire
  time frame: Change in adherence from 8 to 16 weeks
  description: MMAS-8 scores range from 0-8 and can be classified into low adherence (0-5), medium adherence (6-7), or high adherence (8).
  measure: Measured adherence to other medications, using pill count
  time frame: Change in adherence from 8 to 16 weeks
  measure: Treatment satisfaction using the Treatment Satisfaction Questionnaire for Medication (TSQM)
  time frame: 8 and 16 weeks
  description: TSQM scores range from 0 to 100, with higher scores indicating greater treatment satisfaction.
  measure: Heart failure admission rate
  time frame: Baseline, 8 weeks, and 16 weeks
  description: As a pilot trial, our study will not be powered for clinical outcomes, but key exploratory outcomes will include HFrEF admissions.
  measure: Kansas City Cardiomyopathy Questionnaire (KCCQ)
  time frame: Baseline, 8 weeks, and 16 weeks
  description: 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.
  arm group label: GDMT delivered in a heart failure polypill
  arm group type: Experimental
  description: The polypill intervention will be pharmacy-level over-encapsulation of once-daily heart failure medications (beta-blocker, SGLT2 inhibitor, and spironolactone) into a single capsule. Any twice-daily HFrEF medications, such as sacubitril/valsartan, will be omitted from the polypill and will continue to be filled individually. We 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 plastic capsule.
  arm group label: GDMT delivered as individual tablets
  arm group type: Active Comparator
  description: As described above, participants who are not already prescribed a beta blocker, SGLT2i, 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.
  intervention type: Drug
  intervention name: Heart failure polypill
  description: Copackaging of once-daily heart failure medications (beta blocker, SGLT2i, and MRA) 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.
  arm group label: GDMT delivered in a heart failure polypill
  intervention type: Drug
  intervention name: Control Rx
  description: GDMT delivered as individual tablets
  arm group label: GDMT delivered as individual tablets
  criteria: 
  gender: All
  minimum age: 18 Years
  maximum age: N/A
  healthy volunteers: No
  last name: Colette DeJong, MD
  role: Principal Investigator
  affiliation: University of California, San Francisco
  last name: Priscilla Hsue, MD
  role: Principal Investigator
  affiliation: University of California, San Francisco
  last name: Colette DeJong, MD
  phone: (415) 443-6698
  email: colette.dejong@ucsf.edu
  facility: 
  contact: 
  investigator: 
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  country: United States
  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.
  PMID: 35877830
  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.
  PMID: 34973412
  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.
  PMID: 24493574
  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.
  PMID: 36018037
  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.
  PMID: 29521670
  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.
  PMID: 36116516
  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.
  PMID: 28190578
  citation: 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
  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.
  PMID: 34612082
  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.
  PMID: 31532959
  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.
  PMID: 25193393
  responsible party type: Sponsor
  mesh term: Heart Failure
  sharing ipd: Yes
  ipd info type: Study Protocol
  ipd info type: Informed Consent Form (ICF)