Home-based Exercise Training in Patients With Pulmonary Arterial Hypertension: Effect on Skeletal Muscular Function and Metabolism

• ClinicalTrials.gov Identifier: NCT04241497
• Recruitment Status: Unknown
• First Posted: January 27, 2020
• Last Update Posted: January 28, 2020
• Sponsor: Laval University
• Information provided by (Responsible Party): Marius Lebret, Laval University

Tracking Information

• First Submitted Date: January 22, 2020
• First Posted Date: January 27, 2020
• Last Update Posted Date: January 28, 2020
• Estimated Study Start Date: March 2020
• Estimated Primary Completion Date: March 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 22, 2020)

Epigenetic factors influencing muscle metabolism [ Time Frame: Changes between baseline and 12 weeks of exercise rehabilitation ]

Transcriptome analysis using RNA-seq

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: January 24, 2020)

• Intramyocellular lipid accumulation [ Time Frame: Changes between baseline and 12 weeks of exercise rehabilitation ]
  H-magnetic resonance spectroscopy and Oil red O technique
• Muscular mitochondrial phosphorylation (ATP synthesis) [ Time Frame: Changes between baseline and 12 weeks of exercise rehabilitation ]
  phosphorus-31 Magnetic resonance spectroscopy saturation transfer
• Proportion of muscle fiber types [ Time Frame: Changes between baseline and 12 weeks of exercise rehabilitation ]
  Ethanol modified technique
• HbA1c [ Time Frame: Changes between baseline and 12 weeks of exercise rehabilitation ]
  Serum HbA1c
• Insulin [ Time Frame: Changes between baseline and 12 weeks of exercise rehabilitation ]
  Serum Insulin
• Glucose [ Time Frame: Changes between baseline and 12 weeks of exercise rehabilitation ]
  Serum glucose
• Apolipoprotein A1 [ Time Frame: Changes between baseline and 12 weeks of exercise rehabilitation ]
  Serum Apolipoprotein A1
• Adiponectin [ Time Frame: Changes between baseline and 12 weeks of exercise rehabilitation ]
  Serum Adiponectin
• Leptin [ Time Frame: Changes between baseline and 12 weeks of exercise rehabilitation ]
  Serum leptin
• Volitional strength quadriceps [ Time Frame: Changes between baseline and 12 weeks of exercise rehabilitation ]
  Maximal Voluntary force using isometric force meter
• Non-volitional strength of the quadriceps [ Time Frame: Changes between baseline and 12 weeks of exercise rehabilitation ]
  Maximal non-Voluntary force using isometric force meter and magnetic stimulation of the femoral neve
• Maximal exercise capacity [ Time Frame: Changes between baseline and 12 weeks of exercise rehabilitation ]
  Cardio-pulmonary exercise testing on a cycloergometer
• Functional Exercise capacity [ Time Frame: Changes between baseline and 12 weeks of exercise rehabilitation ]
  6-MWD
• Quality of life (QOL) [ Time Frame: Changes between baseline and 12 weeks of exercise rehabilitation ]
  Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) questionnaire. The CAMPHOR questionnaire contains 65 items in total, 25 relating to symptoms, 15 relating to activities, and 25 relating to QoL. It is negatively weighted; a higher score indicates worse QoL and greater functional limitation. Symptom and QoL items are both scored out of 25: "yes/true" scores 1 and "no/not true" scores 0. Activity items have three possible responses (score 0-2), giving a score out of 30. Each CAMPHOR assessment takes an average of 10 min

Original Secondary Outcome Measures (submitted: January 22, 2020)

• Intramyocellular lipid accumulation [ Time Frame: Changes between baseline and 12 weeks of exercise rehabilitation ]
  H-magnetic resonance spectroscopy and Oil red O technique
• Muscular mitochondrial phosphorylation (ATP synthesis) [ Time Frame: Changes between baseline and 12 weeks of exercise rehabilitation ]
  phosphorus-31 Magnetic resonance spectroscopy saturation transfer
• Proportion of muscle fiber types [ Time Frame: Changes between baseline and 12 weeks of exercise rehabilitation ]
  Ethanol modified technique
• HbA1c [ Time Frame: Changes between baseline and 12 weeks of exercise rehabilitation ]
  Serum HbA1c
• Insulin [ Time Frame: Changes between baseline and 12 weeks of exercise rehabilitation ]
  Serum Insulin
• Glucose [ Time Frame: Changes between baseline and 12 weeks of exercise rehabilitation ]
  Serum glucose
• Apolipoprotein A1 [ Time Frame: Changes between baseline and 12 weeks of exercise rehabilitation ]
  Serum Apolipoprotein A1
• Adiponectin [ Time Frame: Changes between baseline and 12 weeks of exercise rehabilitation ]
  Serum Adiponectin
• Leptin [ Time Frame: Changes between baseline and 12 weeks of exercise rehabilitation ]
  Serum leptin
• Volitional strength quadriceps [ Time Frame: Changes between baseline and 12 weeks of exercise rehabilitation ]
  Maximal Voluntary force using isometric force meter
• Non-volitional strength of the quadriceps [ Time Frame: Changes between baseline and 12 weeks of exercise rehabilitation ]
  Maximal non-Voluntary force using isometric force meter and magnetic stimulation of the femoral neve
• Maximal exercise capacity [ Time Frame: Changes between baseline and 12 weeks of exercise rehabilitation ]
  Cardio-pulmonary exercise testing on a cycloergometer
• Functional Exercise capacity [ Time Frame: Changes between baseline and 12 weeks of exercise rehabilitation ]
  6-MWD
• Quality of life (QOL) [ Time Frame: Changes between baseline and 12 weeks of exercise rehabilitation ]
  CAMPHOR questionnaire

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Home-based Exercise Training in Patients With Pulmonary Arterial Hypertension: Effect on Skeletal Muscular Function and Metabolism
• Official Title: Home-based Exercise Training in Patients With Pulmonary Arterial Hypertension: Effect on Skeletal Muscular Function and Metabolism

Brief Summary

Pulmonary Arterial Hypertension has gone from a disease that causes rapid death to a more chronic condition. Yet, improved survival is associated with major challenges for clinicians as most patients remain with poor quality of life and limited exercise capacity. The effects of exercise training on exercise capacity have been largely evaluated and showed an improvement in 6-minutes walking distance (6MWD), peak V'O2. It is also known that exercise program improves quality of life. Maximal volitional and nonvolitional strength of the quadriceps are reduced in patients with Pulmonary Arterial Hypertension and correlated to exercise capacity. Moreover, on the cellular level, alterations are observed in both the respiratory as well as the peripheral muscles. Muscle fiber size has been reported to be decreased in some studies or conversely unaltered in human and animal models. Reduction in type I fibers and a more anaerobic energy metabolism has also been reported, but not in all studies. Likewise, a loss in capillary density in quadriceps of patients with Pulmonary Arterial Hypertension and rats has been reported, but could not be confirmed in other studies. While the impact of exercise training on clinical outcomes such as exercise capacity or quality of life is well known, this data highlight the fact that the underlying causes of peripheral muscle weakness as well as the mechanisms underlying the clinical improvements observed with exercise programs are not completely understood. Improvement of muscle cell metabolism in part via the enhancement of oxidative cellular metabolism and decrease in intracellular lipid accumulation may play a role in improving muscle function and exercise capacity.

In this study, we intend to evaluate the impact of a 12 weeks home-based rehabilitation program on peripheral muscle function and metabolism, focusing on lipid infiltration, oxidative metabolism and epigenetic factors that can be involved in metabolic syndrome, in patients with Pulmonary Arterial Hypertension.

Detailed Description

The 12 weeks home-based rehabilitation program is detailed as follows:

• 1st sessions at the hospital, in the presence of a physiotherapist/kinesiologist
• 3 weeks of supervised home-based rehabilitation (using a telemonitoring system) 3 times a weeks
• 9 weeks of unsupervised home-based rehabilitation (one phone call a week)

Patients will be evaluated at baseline and at endpoint (12 weeks)

• Study Type: Interventional
• Study Phase: Not Applicable
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Pulmonary Arterial Hypertension
• Exercise Training
• Home-based Rehabilitation
• Exercise Capacity
• Muscle Metabolism
• Muscle Function
• Lipid Infiltration
• Oxidative Metabolism

Intervention

Behavioral: Home-based rehabilitation

1 supervised exercise session at the hospital; 3 weeks of supervised home-based exercise training (3x/week); 9 weeks of unsupervised home-based exercise training (3x/week)

Study Arms

Experimental: Patients with Pulmonary Arterial Hypertension

12 weeks home-based rehabilitation

Intervention: Behavioral: Home-based rehabilitation

Publications *

• Grunig E, Lichtblau M, Ehlken N, Ghofrani HA, Reichenberger F, Staehler G, Halank M, Fischer C, Seyfarth HJ, Klose H, Meyer A, Sorichter S, Wilkens H, Rosenkranz S, Opitz C, Leuchte H, Karger G, Speich R, Nagel C. Safety and efficacy of exercise training in various forms of pulmonary hypertension. Eur Respir J. 2012 Jul;40(1):84-92. doi: 10.1183/09031936.00123711. Epub 2012 Feb 9.
• Ehlken N, Lichtblau M, Klose H, Weidenhammer J, Fischer C, Nechwatal R, Uiker S, Halank M, Olsson K, Seeger W, Gall H, Rosenkranz S, Wilkens H, Mertens D, Seyfarth HJ, Opitz C, Ulrich S, Egenlauf B, Grunig E. Exercise training improves peak oxygen consumption and haemodynamics in patients with severe pulmonary arterial hypertension and inoperable chronic thrombo-embolic pulmonary hypertension: a prospective, randomized, controlled trial. Eur Heart J. 2016 Jan 1;37(1):35-44. doi: 10.1093/eurheartj/ehv337. Epub 2015 Jul 31.
• Grunig E, Eichstaedt C, Barbera JA, Benjamin N, Blanco I, Bossone E, Cittadini A, Coghlan G, Corris P, D'Alto M, D'Andrea A, Delcroix M, de Man F, Gaine S, Ghio S, Gibbs S, Gumbiene L, Howard LS, Johnson M, Jureviciene E, Kiely DG, Kovacs G, MacKenzie A, Marra AM, McCaffrey N, McCaughey P, Naeije R, Olschewski H, Pepke-Zaba J, Reis A, Santos M, Saxer S, Tulloh RM, Ulrich S, Vonk Noordegraaf A, Peacock AJ. ERS statement on exercise training and rehabilitation in patients with severe chronic pulmonary hypertension. Eur Respir J. 2019 Feb 28;53(2):1800332. doi: 10.1183/13993003.00332-2018. Print 2019 Feb.
• Potus F, Malenfant S, Graydon C, Mainguy V, Tremblay E, Breuils-Bonnet S, Ribeiro F, Porlier A, Maltais F, Bonnet S, Provencher S. Impaired angiogenesis and peripheral muscle microcirculation loss contribute to exercise intolerance in pulmonary arterial hypertension. Am J Respir Crit Care Med. 2014 Aug 1;190(3):318-28. doi: 10.1164/rccm.201402-0383OC.
• Malenfant S, Brassard P, Paquette M, Le Blanc O, Chouinard A, Nadeau V, Allan PD, Tzeng YC, Simard S, Bonnet S, Provencher S. Compromised Cerebrovascular Regulation and Cerebral Oxygenation in Pulmonary Arterial Hypertension. J Am Heart Assoc. 2017 Oct 12;6(10):e006126. doi: 10.1161/JAHA.117.006126.
• Malenfant S, Potus F, Fournier F, Breuils-Bonnet S, Pflieger A, Bourassa S, Tremblay E, Nehme B, Droit A, Bonnet S, Provencher S. Skeletal muscle proteomic signature and metabolic impairment in pulmonary hypertension. J Mol Med (Berl). 2015 May;93(5):573-84. doi: 10.1007/s00109-014-1244-0. Epub 2014 Dec 30.

Recruitment Information

• Recruitment Status: Unknown status
• Estimated Enrollment (submitted: January 22, 2020): 10
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: March 2021
• Estimated Primary Completion Date: March 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Men or women > 18 years old
• Pulmonary Arterial Hypertension group 1: idiopathic, genetics, drug or toxin-induced, associated with connective tissue, HIV, portal hypertension, congenital heart disease.
• Diagnosis performed by right heart catheterization with Pulmonary Arterial Pressure⩾ 20 mmHg, pulmonary artery occlusion pressure <15 and pulmonary vascular resistance >3 Wood units
• New York Heart Association II or III and a 6-Minute Walk Test < 500m
• Patient stable without therapeutic modification within the last 3 months
• Patient having wireless internet at home
• Consciously informed and written by the patient

Exclusion Criteria:

• Syncope within the last 6 month
• Metabolic comorbidity (eg Diabetes)
• Musculoskeletal impairment that does not allow physical exercise
• Patient unable or with contraindications to perform a cardio pulmonary exercise testing
• Patient with pulmonary veno-occlusive disease
• Presence of a permanent pacemaker or other contraindication to MRI
• Pregnant or breastfeeding woman
• Age <18 years

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 100 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Canada

Administrative Information

• NCT Number: NCT04241497
• Other Study ID Numbers: HTAP A DOM
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

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

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Marius Lebret, Laval University
• Original Responsible Party: Same as current
• Current Study Sponsor: Laval University
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Laval University
• Verification Date: January 2020