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High-intensity Interval Training in Heart Failure Patients With Preserved Ejection Fraction (HIT-HF)

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ClinicalTrials.gov Identifier: NCT03184311
Recruitment Status : Not yet recruiting
First Posted : June 12, 2017
Last Update Posted : June 12, 2017
Sponsor:
Collaborator:
Clinical Trial Unit, University Hospital Basel, Switzerland
Information provided by (Responsible Party):
Thomas Dieterle, Cantonal Hosptal, Baselland

Brief Summary:
This study investigates the effects of a 12-week high-intensity interval training (HIT) on exercise tolerance, functional status and quality of life in patients with chronic heart failure with preserved ejection fraction (HFpEF), in comparison to a control group continuing to undergo usual care.

Condition or disease Intervention/treatment Phase
Heart Failure With Normal Ejection Fraction Other: High-intensity interval training (HIT) Other: Usual care Not Applicable

Detailed Description:

Heart failure (HF) with preserved ejection fraction (HFpEF) occurs in about 50% of all HF patients. Remodeling and fibrosis stimulated by inflammation appear to be main factors for the progression of HFpEF. Furthermore, iron deficiency (ID) has been recognized to be a common comorbidity in HFpEF. The lack of prognostic treatment options in HFpEF urgently calls for new therapeutic approaches. While beneficial effects of exercise training and iron substitution have been demonstrated in HF with reduced ejection fraction, they have not yet been evaluated in HFpEF. Therefore, the aim of this study is to investigate the effects of high-intensity interval training (HIT) in HFpEF patients with optimally adjusted iron values.

The proposed study will be a prospective, single-blind, randomized controlled trial in a primary care setting including 98 patients with stable HFpEF. Patients will undergo 3 study visits (a screening visit, a baseline visit and a post-intervention visit) including measurements of disease-specific biomarkers (using blood samples), cardiac and arterial vessel structure and function (using electrocardiogram, echocardiography and pulse wave velocity), exercise tolerance (using spiroergometry), habitual physical activity (using accelerometry) and QoL. After the screening visit, patients with a functional or absolute ID will undergo iron substitution until sufficient iron levels are reached (up to max. 12 weeks), in order to ensure comparable baseline conditions for the training intervention. The study examinations will be repeated after 12 weeks in both, initially iron deficient and non-iron deficient patients (baseline visit). Patients will then be randomized to either the intervention or control group, stratified by initial iron-deficiency status. The intervention group (n=49) will attend a supervised 12-week HIT on a bicycle ergometer, while the control group (n=49) will be advised to continue usual care and follow health recommendations for patients with chronic HF. After 12 weeks, the study measurements will be repeated in all patients (intervention and control group) in order to monitor the effects of the intervention (post-intervention visit). At 6 months, 1, 2 and 3 years after the last study visit, telephone interviews will be performed to assess medical outcomes and QoL.

Outlook: This study is expected to add important knowledge about the potential utility of a novel treatment strategy in HFpEF patients, which may help to improve both, QoL and functional status. Moreover, the analysed biomarkers might be able to provide further insight into prognosis and pathogenesis of HFpEF.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 98 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
  • Intervention group: 12-week high-intensity interval training on a bicycle ergometer.
  • Control group: usual care, health recommendations for patients with chronic heart failure.
Masking: Single (Outcomes Assessor)
Masking Description: Study personnel involved in the study measurements will be blinded to whether patients are allocated to the intervention or control group. Furthermore, the statistician will be blinded to treatment allocation. To ensure blinding, the study measurements will be performed in different rooms and by different staff than those involved in the training intervention. It is not possible to blind participating patients and investigators performing the randomization and training sessions.
Primary Purpose: Treatment
Official Title: High-intensity Interval Training as Treatment Strategy for Heart Failure Patients With Preserved Ejection Fraction: A Prospective, Single-blind, Randomized Controlled Trial
Estimated Study Start Date : October 1, 2017
Estimated Primary Completion Date : March 31, 2020
Estimated Study Completion Date : March 31, 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Heart Failure

Arm Intervention/treatment
Experimental: High-intensity interval training (HIT)
A 12-week HIT will be performed 3 times per week on a bicycle ergometer according to the protocol of Wisløff et al. In the first 4 weeks of the program, all sessions will consist of moderate continuous training (MCT) at 60-80% of peak heart rate (HRpeak) for 40 minutes in order that patients get used to exercising. For weeks 4-12, the following HIT protocol is intended: Patients will warm up for 10 minutes at moderate intensity (60-70% of HRpeak, Borg 11-13) before cycling four 4-minute intervals at high intensity (85-95% of HRpeak, Borg 15-17). Each interval will be separated by a 3-minute active pause at 60-70% of HRpeak (Borg 11-13). The training session will end with a 5-minute cool-down at moderate intensity (60-70% of HRpeak). Total exercise time will be 40 minutes.
Other: High-intensity interval training (HIT)
Supervised 12-week HIT 3 times per week on a bicycle ergometer.

Placebo Comparator: Usual care
Patients in the control group will continue to undergo usual care and be advised to follow health recommendations for patients with chronic heart failure according to an information leaflet of the Swiss Heart Foundation.
Other: Usual care
Usual care, no supervised training sessions.




Primary Outcome Measures :
  1. Change in peak oxygen uptake (VO2peak) due to training [ Time Frame: Baseline and 12 weeks ]
    VO2peak will be measured by spiroergometry at the baseline and post-intervention visit: an incremental symptom-limited exercise test on an electronically operated bicycle ergometer (eBike, General Electric Company, Fairfield, Connecticut, USA) using a fixed ramp protocol (start at 10 watts, increase of 10 watts/minute) will be conducted. The test will be performed in an air-conditioned laboratory in the early afternoon under non-fasting conditions. After a 2-minute warm-up at 10 watts, patients will be instructed to pedal at a constant rate of 60 rpm to exhaustion or until signs of ischemia or serious cardiac arrhythmias appear. The exercise bout will be followed by a cool-down at 25 watts for 10 minutes or until HR is dropping down below 100 beats/minute. VO2peak will be defined as the highest value reached during exercise.


Secondary Outcome Measures :
  1. Change in peak oxygen uptake (VO2peak) due to iron substitution [ Time Frame: -12 weeks and baseline (before and after iron substitution) ]
    VO2peak will be measured by spiroergometry at the baseline and post-intervention visit: an incremental symptom-limited exercise test on an electronically operated bicycle ergometer (eBike, General Electric Company, Fairfield, Connecticut, USA) using a fixed ramp protocol (start at 10 watts, increase of 10 watts/minute) will be conducted. The test will be performed in an air-conditioned laboratory in the early afternoon under non-fasting conditions. After a 2-minute warm-up at 10 watts, patients will be instructed to pedal at a constant rate of 60 rpm to exhaustion or until signs of ischemia or serious cardiac arrhythmias appear. The exercise bout will be followed by a cool-down at 25 watts for 10 minutes or until HR is dropping down below 100 beats/minute. VO2peak will be defined as the highest value reached during exercise.

  2. Change in disease-specific biomarkers [ Time Frame: Baseline and 12 weeks ]
    For measuring N-terminal prohormone of brain natriuretic peptide (NT-proBNP), Renin, Angiotensin-II (AT-2), Urocortin-2 (UCN-2), Osteopontin, Soluble ST2 (sST2), Galectin-3, Growth differentiation factor 15 (GDF-15), Copeptin, Big-Endothelin-1, Placental growth factor/Soluble Fms-like tyrosine-kinase 1 (PlGF/sFlt-1), High-sensitivity C-reactive protein (Hs-CRP), Interleukin 6 (IL-6) and Insulin-like growth factor-binding protein 7 (IGF-BP7), blood samples will be taken (in total 40 ml of blood) and immediately centrifuged, and the serum will be transferred to a separate tube, which will be frozen at approximately -80°C and stored in the central laboratory at the Cantonal Hospital Baselland in Liestal until the last patient will have completed the study procedures.

  3. Change in echocardiographic parameters of the left ventricular systolic and diastolic function [ Time Frame: Baseline and 12 weeks ]
    An echocardiography will be performed using a Full HD Color Doppler Ultrasound Scanner UF-890AG (Fukuda Denshi, Tokyo, Japan) by experienced echocardiographers blinded to the assignment of the patient to the intervention or control group, and independently analysed by cardiologists of the KSBL Liestal.

  4. Change in arteriovenous oxygen difference (Da-vO2) [ Time Frame: Baseline and 12 weeks ]
    Da-vO2 will be calculated using the Fick Principle: Peak Da-vO2 = VO2peak / peak cardiac output. VO2peak will be measured by spiroergometry, while peak cardiac output will be determined using the Full HD Color Doppler Ultrasound Scanner UF-890AG (Fukuda Denshi, Tokyo, Japan).

  5. Change in pulse wave velocity (PWV) [ Time Frame: Baseline and 12 weeks ]
    PWV will be measured at the same time as the echocardiographic parameters with the VaSera VS-2000 Vascular Screening System (Fukuda Denshi Co. Ltd, Tokyo, Japan) and evaluated by experienced blinded members of the study team.

  6. Change in daily physical activity [ Time Frame: Baseline and 12 weeks ]
    The number of daily steps, physical activity level and time spent at different walking speeds will be measured by the AiperMotion 440 PC (Aipermon GmbH, Munich, Germany), a three-axis accelerometer that is attached to the belt on the left hip, on 7 consecutive days for at least 12 hours a day with the exception of the time spent for showering, bathing and sleeping. For recording daily activities and non-wearing periods, patients will be asked to keep a diary.

  7. Change in NYHA functional class [ Time Frame: Baseline and 12 weeks ]
    NYHA functional class will be determined according to the New York Heart Association classification.

  8. Change in quality of life (QoL): The 36-Item Short Form Health Survey (SF-36) [ Time Frame: Baseline and 12 weeks ]
    The SF-36 consists of 36 items, which are formatted as binary questions or as semantic 6-point differential scales. It refers to the past 4 weeks and includes 9 content areas concerning vitality, general health perception, physical functioning, social functioning, role limitations (emotional/physical problems), pain, mental health and health change.

  9. Change QoL: The Kansas City Cardiomyopathy Questionnaire (KCCQ) [ Time Frame: Baseline and 12 weeks ]
    The KCCQ consists of 15 items concerning overall symptoms, emotional, social and mental status within the past 2 weeks.

  10. Change in QoL: The Minnesota Living With Heart Failure Questionnaire (MLWHFQ) [ Time Frame: Baseline and 12 weeks ]
    The MLWHFQ refers to the past 4 weeks and includes 21 questions on a 6-point scale with a maximum of 105 points (<24 good QoL, >45 poor QoL).

  11. Change in body composition: Body Mass Index (BMI) [ Time Frame: Baseline and 12 weeks ]
    BMI will be calculated from measured height in meters and weight in kilograms. Weight and height will be combined to report BMI in kg/m^2.

  12. Change in body composition: Waist-to-Hip-Ratio (WHR) [ Time Frame: Baseline and 12 weeks ]
    WHR will be calculated from measured waist circumference (WC) and hip circumference (HC) in centimetres. WC will be divided by HC to report WHR.



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

Inclusion Criteria:

  • Informed consent as documented by the patient's signature
  • NYHA functional classes II-III
  • Signs and symptoms of chronic HF:

    • Dyspnea, paroxysmal nocturnal dyspnea
    • Reduced exercise capacity, extended recovery after exercising
    • Fatigue
    • Peripheral edema (lower leg, ankle)
  • EF (Ejection fraction) >50%
  • Structural or functional changes in echocardiography:

    • LAVI (left atrial volume index) >34 ml/m2 OR
    • LVMI (left ventricular mass index) >115 g/m2 (men), >95 g/m2 (women) OR
    • E/E' (ratio between mitral peak velocity of early filling (E) to early diastolic mitral annular velocity (E')) >13 AND mean E' septal and lateral wall <9 cm/s
  • NT-proBNP >125 pg/ml
  • At least 4 weeks on stable medical treatment or without signs and symptoms of cardiac decompensation
  • Trainable: Ventilatory threshold >50% of predicted VO2max AND VO2peak >10 ml/kg/min at the screening visit

Exclusion Criteria:

  • Planned cardiac interventions in the following 6 months
  • Unstable angina pectoris
  • Paroxysmal atrial fibrillation
  • Severe uncorrected valvular heart disease
  • Uncontrolled brady- or tachyarrhythmia and hypertonic blood pressure
  • Clinically significant concomitant disease states (e.g. advanced renal failure, hepatic dysfunction, insulin-dependent diabetes, COPD (chronic obstructive pulmonary disease) in grades III-IV, on-going cancer treatment)
  • Significant musculoskeletal disease limiting exercise tolerance
  • Active infection
  • Immunosuppressive medical therapy
  • Earlier hypersensitivity to parenteral iron preparation
  • Anemia and iron deficiency due to active and/or chronic bleeding
  • Blood transfusion within the previous 30 days
  • Vulnerable persons (age <18 years, pregnant and breastfeeding women)
  • Known or suspected non-compliance, drug or alcohol abuse
  • Inability to follow the study procedures due to insufficient language skills, psychological disorders, dementia, etc.
  • Participation in another intervention study
  • Life-expectancy <6 months

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): NCT03184311


Contacts
Contact: Thomas Dieterle, MD +41 61 925 32 30 thomas.dieterle@ksbl.ch
Contact: Stefanie Brighenti-Zogg, PhD +41 61 925 37 57 stefanie.brighenti@ksbl.ch

Sponsors and Collaborators
Cantonal Hosptal, Baselland
Clinical Trial Unit, University Hospital Basel, Switzerland
Investigators
Principal Investigator: Thomas Dieterle, MD University Department of Internal Medicine, Cantonal Hospital Baselland

Responsible Party: Thomas Dieterle, PD Dr. med., Cantonal Hosptal, Baselland
ClinicalTrials.gov Identifier: NCT03184311     History of Changes
Other Study ID Numbers: 2017-00227
First Posted: June 12, 2017    Key Record Dates
Last Update Posted: June 12, 2017
Last Verified: June 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Patient-level anonymised datasets can be requested after completion of all planned analyses and publications from the study centre (anticipated by the end of 2020). Public access to the study protocol will be granted by publishing it in a scientific journal. Blood sample results will be shared on the Swiss Biobanking Platform.

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Thomas Dieterle, Cantonal Hosptal, Baselland:
Iron deficiency
Therapy response prediction
Exercise tolerance

Additional relevant MeSH terms:
Heart Failure
Heart Diseases
Cardiovascular Diseases