Working…
COVID-19 is an emerging, rapidly evolving situation.
Get the latest public health information from CDC: https://www.coronavirus.gov.

Get the latest research information from NIH: https://www.nih.gov/coronavirus.
ClinicalTrials.gov
ClinicalTrials.gov Menu

PITA-HF: Feasibility, Safety, and Tolerability

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04159454
Recruitment Status : Not yet recruiting
First Posted : November 12, 2019
Last Update Posted : June 18, 2020
Sponsor:
Collaborator:
Medtronic
Information provided by (Responsible Party):
Johns Hopkins University

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.

Condition or disease Intervention/treatment Phase
Heart Failure Dilated Cardiomyopathy Device: PITA Not Applicable

Show Show detailed description

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 8 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description: 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.
Masking: None (Open Label)
Masking Description: 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.
Primary Purpose: Device Feasibility
Official Title: Pacemaker Induced Transient Dyssynchrony for Treating Heart Failure (PITA-HF): Feasibility, Safety, and Tolerability
Estimated Study Start Date : August 2020
Estimated Primary Completion Date : October 2020
Estimated Study Completion Date : October 2020


Arm Intervention/treatment
Experimental: PITA Participants
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
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.




Primary Outcome Measures :
  1. Feasibility as assessed by percent ventricular capture through Holter monitoring [ Time Frame: Up to 7 weeks ]
    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.

  2. Safety as assessed by number of arrhythmia episodes via device interrogation [ Time Frame: Up to 3 months ]
    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.

  3. Safety as assessed by the number of hospitalizations or ER visits for arrhythmia or heart failure [ Time Frame: Up to 3 months ]
    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.

  4. Tolerability as assessed by change in Kansas City Cardiomyopathy Questionnaire (KCCQ) score [ Time Frame: Baseline, Week 4, Week 8 and Week 12 ]
    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.

  5. Tolerability as assessed by change in distance during 6-minute walk test [ Time Frame: Baseline and Week 8 ]
    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.

  6. Safety as assessed by number of tachytherapies delivered by ICDs [ Time Frame: Up to 3 months ]
    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.

  7. Tolerability as assessed by change in Global Well-Being score on a Visual Analog Scale [ Time Frame: Baseline, Week 4, Week 8 and Week 12 ]
    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.

  8. Tolerability as assessed by change in Subjective Dyspnea score on a Visual Analog Scale [ Time Frame: Baseline, Week 4, Week 8 and Week 12 ]
    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.

  9. Tolerability as assessed by change in Frailty Index [ Time Frame: Baseline, Week 4, Week 8 and Week 12 ]
    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).

  10. Tolerability as assessed by change in Sleep Quality [ Time Frame: Baseline, Week 1, Week 4, Week 5, Week 8 and Week 12 ]
    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.


Secondary Outcome Measures :
  1. Presence of dyssynchrony on echocardiography [ Time Frame: Baseline, Week 8 ]

    Dyssynchrony will be determined by differences in right and left ventricle contraction and regional wall contraction differences in the left ventricle using echocardiography. It will be reported as present or not per participant.

    Echocardiograms will be obtained at Weeks 0 and 8. To assess interventricular dyssynchrony, onset of QRS complex to peak pulmonic valve inflow or peak aortic valve inflow >40 ms or aortic pre-ejection delay >140 ms is considered significant. To assess intraventricular or LV mechanical dyssynchrony, M-mode in the parasternal long axis will be used to assess septal to posterior wall motion delay, with values >130 ms considered significant. Furthermore, time to onset or time to peak systolic velocity of 4 opposing walls >65 ms is considered significant, and will be obtained from parasternal short axis views of the LV via tissue doppler.


  2. Change in N-terminal pro b-type natriuretic peptide (NT pro-BNP) values [ Time Frame: Baseline, Week 4 and Week 12 ]
    NT pro-BNP values (pg/mL) will be obtained at Weeks 0, 4, and 12 and be compared. Values less than 125 pg/mL are considered normal.

  3. Change in troponin values (ng/mL) [ Time Frame: Baseline, Week 4 and Week 12 ]
    Troponin values (ng/mL) will be obtained at Weeks 0, 4, and 12 and be compared. Values less than 0.04 ng/mL are considered normal.

  4. Change in sodium values (mEq/L) [ Time Frame: Baseline, Week 4 and Week 12 ]
    Changes in sodium volume (mEq/L) will be obtained at Weeks 0, 4, and 12 and be compared. Values 135-145 mEq/L are considered normal.

  5. Change in serum creatinine values (mg/dL) [ Time Frame: Baseline, Week 4 and Week 12 ]
    Serum creatinine values (mg/dL) will be obtained at Weeks 0, 4, and 12 and be compared. Values less than 1.2 mg/dL are considered normal.

  6. Change in serum blood urea nitrogen (BUN) values [ Time Frame: Baseline, Week 4 and Week 12 ]
    Serum BUN values (mg/dL) will be obtained at Weeks 0, 4, and 12 and be compared. Values 7 to 20 mg/dL are considered normal.


Other Outcome Measures:
  1. Change in left ventricular (LV) chamber dimensions [ Time Frame: Baseline, Week 8 ]
    Change in LV chamber dimensions (systolic and diastolic dimension in centimeters) as measured via the parasternal long-axis view as part of standard echocardiography at Week 0 and Week 8. Diastolic dimensions less than 6 cm and systolic dimensions less than 4 cm are considered normal.

  2. Change in left ventricular (LV) ejection fraction [ Time Frame: Baseline, Week 8 ]
    Changes in LV ejection fraction (as a percentage) measured via method of discs via the 4-chamber apical echocardiogram view and the 2-chamber echocardiogram view at Week 0 and Week 8. Ejection fractions of 52-65% are considered normal.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 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

Exclusion Criteria:

  • 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
  • Actively listed for any other organ transplantation or undergoing evaluation for any other organ transplantation
  • Planned surgical intervention in the next 1 year
  • History of persistent, permanent, or long-standing atrial fibrillation
  • Terminal illness (other than HF) with expected survival of less than 1 year
  • Other end-organ, permanent dysfunction including severe chronic obstructive pulmonary disease (COPD) by Gold's criteria or severe pulmonary disease requiring oxygen, cirrhosis of any cause, renal failure on dialysis, chronic untreatable infectious disease, underlying malignancy undergoing active treatment (chemotherapy, radiation therapy, planned surgical resection of tumor), uncontrolled endocrinologic disorder (thyroid dysfunction, adrenal disease, etc.) requiring ongoing medication titration
  • Previous symptomatic intolerance to right ventricular pacing
  • Enrollment or planned enrollment in another randomized clinical trial
  • Inability to comply with planned study procedures
  • Pregnancy or nursing mothers, or women planning on becoming pregnant
  • Irreversible neurologic function with inability to provide own consent
  • Prisoners

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04159454


Contacts
Layout table for location contacts
Contact: Kavita Sharma, MD 410-955-7670 ksharma8@jhmi.edu

Sponsors and Collaborators
Johns Hopkins University
Medtronic
Investigators
Layout table for investigator information
Principal Investigator: Kavita Sharma, MD Johns Hopkins University
Publications:
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. Erratum in: Circulation. 2020 Jan 14;141(2):e33.

Layout table for additonal information
Responsible Party: Johns Hopkins University
ClinicalTrials.gov Identifier: NCT04159454    
Other Study ID Numbers: IRB00220173
First Posted: November 12, 2019    Key Record Dates
Last Update Posted: June 18, 2020
Last Verified: June 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Johns Hopkins University:
Pacing
Heart failure
Dyssynchrony
Additional relevant MeSH terms:
Layout table for MeSH terms
Heart Failure
Cardiomyopathies
Cardiomyopathy, Dilated
Heart Diseases
Cardiovascular Diseases
Cardiomegaly