PITA-HF: Feasibility, Safety, and Tolerability

NCT04159454 | Completed DMC FDA Device

• 1 other identifier: IRB00220173
• Study Type: interventional
• Target: 8
• Locations: 1 country
• Sites: 1

Brief Summary

Heart failure affects over 25 million people worldwide and nearly 7 million adults in the United States alone. Nearly 25% of patients with heart failure have worsened disease burden from dyssynchronous ventricular contraction due to abnormal electrical impulse propagation. These patients may benefit from cardiac resynchronization therapy (CRT) where contraction between the ventricles is coordinated by simultaneous electrical stimulation of the right and left ventricles. In animal models, CRT changes molecular and cellular biology by improving myofilament function, ion channel regulation, beta-receptor signaling, and overall mitochondrial energetics. In randomized clinical outcomes trials, the use of CRT further reduced the incidence of heart failure events and improved overall mortality. However, nearly 75% of patients with heart failure have synchronous ventricular contraction and therefore do not qualify for CRT. CRT profoundly alters underlying molecular and cellular biology as a result of the transition from dyssynchronous to resynchronized contraction, enhancing myocyte function and adrenergic responsiveness. The investigators previously hypothesized CRT-like benefits could be achieved in otherwise synchronous heart failure by purposely inducing dyssynchrony for several hours each day and then reversing this for the remainder of the time. The investigators termed this pacemaker induced transient dyssynchrony, or PITA, and tested its impact in a canine dilated cardiomyopathy model. Following several weeks of rapid atrial pacing to induce heart failure in the animals, the investigators compared implementing 4-weeks of PITA - consisting of dyssynchronous rapid right ventricular pacing for 6 hours each night and atrial pacing for the remaining time - to animals that always received rapid atrial pacing. The fast rate is used to generate a heart failure phenotype. PITA improved chamber dilation, increased beta-adrenergic responsiveness and contractile function, and improved myofiber structure compared to heart failure canine controls. While first tested in an intact conscious translational model, no study has yet investigated PITA in humans. This pilot research protocol tests the feasibility, safety, and tolerability of PITA in humans with dilated cardiomyopathy. The study will leverage pre-existing Medtronic (Mounds View, MN) pacemaker/defibrillators implanted in dilated cardiomyopathy patients based on current clinical guidelines. If successful, this study will allow for a larger, first-in-human study to assess indexes of left ventricular function in dilated cardiomyopathy patients with PITA.

Conditions

Heart Failure; Dilated Cardiomyopathy

Keywords

Pacing; Heart failure; Dyssynchrony

Outcome Measures

Primary Outcomes (10)

• Feasibility as assessed by percent ventricular capture through Holter monitoring

  Patients will be given 48-hour Holter monitors at Week 1, Week 4, and Week 7. The average heart rate in beats per minute (bpm) during sleep hours (midnight-6 AM) will be recorded. Percent ventricular capture will be defined as the percentage of heart rate during this time period that is above the pre-specified heart rate set for each patient during the "sleep" period. Percent will be defined from 0-100%, with the latter indicating all ventricular beats are paced from the right ventricle, and the former indicating that no ventricular beats are paced.

  Up to 7 weeks

• Safety as assessed by number of arrhythmia episodes via device interrogation

  Patients will have patient's ICD devices interrogated throughout the study as per the study protocol, and the number of sustained ventricular tachycardia (VT) episodes, non-sustained VT episodes, and ventricular fibrillation (VF) episodes will be counted and recorded. At the conclusion of each interrogation, the device counter will be reset such that the next interrogation is only reflective of the interim time period.

  Up to 3 months

• Safety as assessed by the number of hospitalizations or ER visits for arrhythmia or heart failure

  As per the study protocol, patient interviews and chart reviews will be implemented to count the number of ER visits or hospitalizations for issues related to arrhythmia or clinical heart failure decompensation.

  Up to 3 months

• Tolerability as assessed by change in Kansas City Cardiomyopathy Questionnaire (KCCQ) score

  Patients will fill out the Kansas City Cardiomyopathy Questionnaire at Weeks 0, 4, 8, and 12, and a numerical score is provided at each timepoint and compared. Scores are from 0-100, with higher scores corresponding to improved quality of life and associated with New York Heart Association Class I symptoms, and lower scores associated with poorer quality of life and association with New York Heart Association Class IV symptoms.

  Baseline, Week 4, Week 8 and Week 12

• Tolerability as assessed by change in distance during 6-minute walk test

  Distance (feet) during 6 minute-walk test will be obtained and recorded at Weeks 0 and 8. Larger distances are associated with improved functional status/capacity. Typical distances covered in healthy individuals range from 1300-2300 ft.

  Baseline and Week 8

• Safety as assessed by number of tachytherapies delivered by ICDs

  Patients will have patient's ICD devices interrogated throughout the study as per the study protocol, and the number of tachytherapies delivered (ATP or ICD shocks) will be counted and recorded. At the conclusion of each interrogation, the device counter will be reset such that the next interrogation is only reflective of the interim time period.

  Up to 3 months

• Tolerability as assessed by change in Global Well-Being score on a Visual Analog Scale

  Patients will fill out the Global Well-Being score at Weeks 0, 4, 8, and 12, and a numerical score is provided at each timepoint and compared. The scale is from 0-100, with higher numbers corresponding to improved well-being, and lower numbers corresponding to lower well-being.

  Baseline, Week 4, Week 8 and Week 12

• Tolerability as assessed by change in Subjective Dyspnea score on a Visual Analog Scale

  Patients will fill out the Subjective Dyspnea score at Weeks 0, 4, 8, and 12, and a numerical score is provided at each timepoint and compared. The score is from 0-100, with higher scores indicating improved subjective dyspnea, and lower scores indicating worsened subjective dyspnea.

  Baseline, Week 4, Week 8 and Week 12

• Tolerability as assessed by change in Frailty Index

  The Frailty Index will be assessed by the Johns Hopkins Older Americans Independence Center Online Frailty Assessment Tool. Patients will by assessed by the Frailty Index at Weeks 0, 4, 8, and 12, and a numerical score is provided at each timepoint and compared. The score is from 0-5, indicating frail (score 3-5), pre-frail (score 1 or 2) or robust (score 0).

  Baseline, Week 4, Week 8 and Week 12

• Tolerability as assessed by change in Sleep Quality

  Sleep Quality will be assessed by Pittsburgh Sleep Quality Index (PSQI). Patients will fill out the Pittsburgh Sleep Quality Index at Weeks 0, 1, 4, 5, 8, and 12, and a numerical score is provided at each timepoint and compared. Scores range from 0-21, with lower scores corresponding to healthier sleep habits and improved sleep quality, and higher scores corresponding to worsened sleep quality.

  Baseline, Week 1, Week 4, Week 5, Week 8 and Week 12

Secondary Outcomes (6)

• Presence of dyssynchrony on echocardiography

  Baseline, Week 8

• Change in N-terminal pro b-type natriuretic peptide (NT pro-BNP) values

  Baseline, Week 4 and Week 12

• Change in troponin values (ng/mL)

  Baseline, Week 4 and Week 12

• Change in sodium values (mEq/L)

  Baseline, Week 4 and Week 12

• Change in serum creatinine values (mg/dL)

  Baseline, Week 4 and Week 12

Other Outcomes (2)

• Change in left ventricular (LV) chamber dimensions

  Baseline, Week 8

• Change in left ventricular (LV) ejection fraction

  Baseline, Week 8

Study Arms (1)

PITA Participants

EXPERIMENTAL

All patients in the study are part of the "PITA" arm, where PITA will be on for Weeks 0-8, and off from Weeks 8-12.

Device: PITA

Interventions

PITA DEVICE

Patients will have PITA turned on to patients' existing Medtronic devices, such that patients will be RV-paced from midnight to 6 AM each night at a rate \~10 beats per minute (BPM) above patients' baseline heart rates during this time period as determined by Holter monitors.

PITA Participants

Eligibility Criteria

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

You may qualify if:

• Patient ≥18 years of age
• Ejection fraction of \<40% by noninvasive testing (TTE, nuclear stress, cardiac MRI) within 6 months of study enrollment
• Presence of Medtronic device (single chamber ICD or dual chamber ICD) with Sleep Function feature (Models: Evera, Maximo II, Virtuoso II, Secura, Protecta)
• Low pacing burden, defined as \<5% RV pacing in the prior month as determined by baseline device interrogation (prior to Week 0)
• Narrow QRS complex (\<100 milliseconds) on baseline ECG without any pacing or with atrial pacing only
• No evidence of incomplete bundle branch block or intraventricular conduction delay, defined as QRS 100-120 milliseconds with: a. S wave in V1 with broad R waves in I, aVL, and V6 b. RSR' in v1 with terminal S waves in I, aVL, and V6 c. not meeting patterns in a or b but with QRS complex 100-120 milliseconds
• No indications for CRT-D upgrade at time of enrollment
• Followed by a physician for treatment of heart failure
• Currently receiving guideline-directed medical therapy for HFrEF
• No changes in diuretic over the past 30 days
• Willingness to provide informed consent
• Negative pregnancy test in a female of child bearing potential

You may not qualify if:

• Age \<18 years
• Ejection fraction \>40% by noninvasive testing in the preceding 12 months
• Acute coronary syndrome within 4 weeks as defined by electrocardiographic (ECG) ST-segment depression or prominent T-wave inversion and/or positive biomarkers of necrosis (e.g., troponin) in the absence of ST-segment elevation and in an appropriate clinical setting (chest discomfort or anginal equivalent)
• Hospital admission for acute decompensated heart failure in the prior 30 days
• Non-Medtronic implanted device or Medtronic device lacking Sleep Function, or Medtronic pacemaker without ICD
• High pacing burden defined as \>5% right ventricular pacing in the preceding month based on interrogation
• Meets indication for CRT-D upgrade at the time of enrollment
• Not currently on guideline-directed therapy or non-compliant with medical therapy, assessed through patient interview and review of medical charts
• Non-compliant with medical visits defined as \>3 missed clinical visits in the prior year
• NYHA Class IV symptoms at time of enrollment
• Hemodynamically significant arrhythmias including supraventricular tachycardias not responsive to rate control therapies or resulting in hemodynamic instability, sustained ventricular tachycardia (defined as \>30 seconds of VT), or defibrillator shock within 4 weeks
• Cardiac arrest within the prior 6 months
• Coronary artery bypass graft (CABG) or percutaneous coronary intervention (PCI) within the prior 3 months, or recent coronary angiogram with plans for CABG or PCI (unrevascularized disease)
• Presence of durable mechanical hemodynamic support (left ventricular assist device)
• Actively listed for cardiac transplantation, prior history of cardiac transplantation or undergoing evaluation for cardiac transplantation

Sponsors & Collaborators

• Johns Hopkins University: lead
• Medtronic: collaborator

Study Sites (1)

Johns Hopkins Hospital

Baltimore, Maryland, 21287, United States

Location

Related Publications (18)

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• Benjamin EJ, Muntner P, Alonso A, Bittencourt MS, Callaway CW, Carson AP, Chamberlain AM, Chang AR, Cheng S, Das SR, Delling FN, Djousse L, Elkind MSV, Ferguson JF, Fornage M, Jordan LC, Khan SS, Kissela BM, Knutson KL, Kwan TW, Lackland DT, Lewis TT, Lichtman JH, Longenecker CT, Loop MS, Lutsey PL, Martin SS, Matsushita K, Moran AE, Mussolino ME, O'Flaherty M, Pandey A, Perak AM, Rosamond WD, Roth GA, Sampson UKA, Satou GM, Schroeder EB, Shah SH, Spartano NL, Stokes A, Tirschwell DL, Tsao CW, Turakhia MP, VanWagner LB, Wilkins JT, Wong SS, Virani SS; American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee. Heart Disease and Stroke Statistics-2019 Update: A Report From the American Heart Association. Circulation. 2019 Mar 5;139(10):e56-e528. doi: 10.1161/CIR.0000000000000659. No abstract available.

  PMID: 30700139 BACKGROUND

• Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Colvin MM, Drazner MH, Filippatos GS, Fonarow GC, Givertz MM, Hollenberg SM, Lindenfeld J, Masoudi FA, McBride PE, Peterson PN, Stevenson LW, Westlake C. 2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. Circulation. 2017 Aug 8;136(6):e137-e161. doi: 10.1161/CIR.0000000000000509. Epub 2017 Apr 28. No abstract available.

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• Shen L, Jhund PS, McMurray JJV. Declining Risk of Sudden Death in Heart Failure. N Engl J Med. 2017 Nov 2;377(18):1794-5. doi: 10.1056/NEJMc1711901. No abstract available.

  PMID: 29091558 BACKGROUND

• Moss AJ, Hall WJ, Cannom DS, Klein H, Brown MW, Daubert JP, Estes NA 3rd, Foster E, Greenberg H, Higgins SL, Pfeffer MA, Solomon SD, Wilber D, Zareba W; MADIT-CRT Trial Investigators. Cardiac-resynchronization therapy for the prevention of heart-failure events. N Engl J Med. 2009 Oct 1;361(14):1329-38. doi: 10.1056/NEJMoa0906431. Epub 2009 Sep 1.

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• Kirk JA, Kass DA. Cellular and Molecular Aspects of Dyssynchrony and Resynchronization. Heart Fail Clin. 2017 Jan;13(1):29-41. doi: 10.1016/j.hfc.2016.07.003.

  PMID: 27886930 BACKGROUND

• Chakir K, Depry C, Dimaano VL, Zhu WZ, Vanderheyden M, Bartunek J, Abraham TP, Tomaselli GF, Liu SB, Xiang YK, Zhang M, Takimoto E, Dulin N, Xiao RP, Zhang J, Kass DA. Galphas-biased beta2-adrenergic receptor signaling from restoring synchronous contraction in the failing heart. Sci Transl Med. 2011 Sep 14;3(100):100ra88. doi: 10.1126/scitranslmed.3001909.

  PMID: 21918105 BACKGROUND

• Abraham WT, Fisher WG, Smith AL, Delurgio DB, Leon AR, Loh E, Kocovic DZ, Packer M, Clavell AL, Hayes DL, Ellestad M, Trupp RJ, Underwood J, Pickering F, Truex C, McAtee P, Messenger J; MIRACLE Study Group. Multicenter InSync Randomized Clinical Evaluation. Cardiac resynchronization in chronic heart failure. N Engl J Med. 2002 Jun 13;346(24):1845-53. doi: 10.1056/NEJMoa013168.

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• Bristow MR, Saxon LA, Boehmer J, Krueger S, Kass DA, De Marco T, Carson P, DiCarlo L, DeMets D, White BG, DeVries DW, Feldman AM; Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) Investigators. Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med. 2004 May 20;350(21):2140-50. doi: 10.1056/NEJMoa032423.

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• Epstein AE, DiMarco JP, Ellenbogen KA, Estes NA 3rd, Freedman RA, Gettes LS, Gillinov AM, Gregoratos G, Hammill SC, Hayes DL, Hlatky MA, Newby LK, Page RL, Schoenfeld MH, Silka MJ, Stevenson LW, Sweeney MO; American College of Cardiology Foundation; American Heart Association Task Force on Practice Guidelines; Heart Rhythm Society. 2012 ACCF/AHA/HRS focused update incorporated into the ACCF/AHA/HRS 2008 guidelines for device-based therapy of cardiac rhythm abnormalities: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. Circulation. 2013 Jan 22;127(3):e283-352. doi: 10.1161/CIR.0b013e318276ce9b. Epub 2012 Dec 19. No abstract available.

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MeSH Terms

Conditions

Heart Failure; Cardiomyopathy, Dilated

Condition Hierarchy (Ancestors)

Heart Diseases; Cardiovascular Diseases; Cardiomegaly; Cardiomyopathies; Laminopathies; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Study Officials

• Kavita Sharma, MD

  Johns Hopkins University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NA
• Masking: NONE
• Masking Details: This is a feasibility, safety, and tolerability pilot trial that is double-blinded. To the extent that is possible, the outcome variable collection and analysis will be fully blinded. Only the device nurse responsible for programming ICDs and investigators responsible for performing physical examinations will know specifics of patient protocol (ie which patients will have PITA and when) and will be unblinded; all other investigators and patients will be blinded. Subjects meeting inclusion criteria and not any exclusion criteria (see below) will have PITA on for Weeks 0-8 and PITA off for Weeks 8-12. This design provides assessment of feasibility, tolerability and safety of PITA over a 2 month timepoint and the decay effect of PITA for an additional month once turned off.
• Purpose: DEVICE FEASIBILITY
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: The investigators will inform all subjects initially that 50% of the subjects will have PITA on for the first 8 weeks, and 50% will have PITA on for the last 4 weeks. However, all patients will follow the same protocol consisting of PITA on for Weeks 0-8, and PITA off for Weeks 8-12. Because this is a feasibility, safety, and tolerability trial, there is no need for a placebo or non-treatment group. Each patient serves as his or own control with a period of PITA on and PITA off. This data will help inform the investigators' next studies which will include control groups.

Study Record Dates

• First Submitted: November 7, 2019
• First Posted: November 12, 2019
• Study Start: November 20, 2020
• Primary Completion: February 1, 2023
• Study Completion: February 1, 2023
• Last Updated: February 14, 2023

Record last verified: 2022-12

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)