Exercise Intolerance Study in Long Chain Fatty Acid Oxidation Disorders (EXCITE LcFAOD)

• ClinicalTrials.gov Identifier: NCT05924555
• Recruitment Status: Not yet recruiting
• First Posted: June 29, 2023
• Last Update Posted: June 29, 2023
• Sponsor: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
• Collaborator: Stichting Stofwisselkracht
• Information provided by (Responsible Party): Dr. Mirjam Langeveld, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Study Description

Brief Summary:

In this study, the exercise tolerance in patients with long-chain fatty acid oxidation disorders (LcFAOD) will be compared to that of healthy volunteers who are carefully matched in terms of age, sex, BMI and physical activity score. The study aims to assess exercise capacity using cardiopulmonary exercise (CPX) tests and activity monitoring over a 7-day period. The hypothesis of the study is that LcFAOD patients will exhibit greater oxygen debt during short periods of exercise compared to healthy individuals. These findings will contribute to a better understanding of exercise intolerance in LcFAOD patients and may guide the development of targeted interventions, such as exercise training programs and enable the analysis of effectiveness of (new) treatments.

Condition or disease	Intervention/treatment
Long-chain Fatty Acid Oxidation Disorders \(LC-FAOD\)	Other: Intermittent cardiopulmonary exercise test; Other: Incremental cardiopulmonary exercise test; Other: Echography of upper leg; Other: Hand grip strength with hand dynamometer; Other: Fill in questionnaires regarding physical activity

Detailed Description:

Background:Long-chain fatty acid oxidation disorders (LcFAOD) are a group of autosomal recessive disorders that impair the utilization of long-chain fatty acids as an energy source. Exercise intolerance is a commonly reported symptom in adult patients with LcFAOD, but its severity varies significantly among individuals. In addition, little is currently known about the natural progression of exercise intolerance in this group of patients, and reliable outcome measures to assess treatment efficacy remain scarce. In this study, we will evaluate the exercise capacity in LcFAOD patients using intermittent CPX, and determine whether this yields outcome parameters that can be used to determine the course of exercise intolerance over the patients lifetime and evaluate treatment effectiveness.

Hypothesis: Exercise intolerance in LcFAOD patients will be reflected in differences in VO2/VCO2 and heart rate kinetics during short periods of exercise compared to healthy subjects.

Primary Objective: 1. Objectify and quantify exercise intolerance in LcFAOD patients. 2. Determine the relationship between the measured exercise intolerance and patient-reported symptoms, daily life functioning, as well as known markers of disease severity.

Secondary Objective(s): 3. Determine the aetiology of exercise intolerance in LcFAODs. 4. Determine whether the intermittent exercise protocol can be used to establish the course of exercise intolerance and provide clinical outcome measure for future intervention studies.

Methods: Participants will be asked to wear an activity monitor (Activ8) for a period of 7 days. The participants will also perform two cardiopulmonary exercise (CPX) tests (one intermittent and one incremental). During the CPX tests gas exchange, ventilation, blood pressure and cardiac output will be measured and exhaustion level monitored. Blood samples will be taken before the first and after the second CPX test. The grip strength (Maximal Voluntary Contraction) and the leg muscle size (echography) will be assessed. Body composition (using BIA) will be assessed.

Approximately a year later all procedures, including the wearing of the activity monitor, will be repeated in all patients. Some participants will be asked to perform the two exercise tests again within two weeks of their first visit. This way reproducibility of the intermittent exercise protocol can be tested.

Study Design

• Study Type: Observational
• Estimated Enrollment: 50 participants
• Observational Model: Case-Control
• Time Perspective: Prospective
• Official Title: Exercise Intolerance Study in Long Chain Fatty Acid Oxidation Disorders
• Estimated Study Start Date: August 1, 2023
• Estimated Primary Completion Date: August 1, 2028
• Estimated Study Completion Date: August 1, 2028

Groups and Cohorts

Group/Cohort	Intervention/treatment
LcFAOD-patients; Patients with long-chain Fatty Acid Oxidation including CPT2-, CACT-, VLCAD-, LCHAD-, or MTP-deficiency	Other: Intermittent cardiopulmonary exercise test; Exercise test with step-change from rest to a relatively low constant workload.; Other: Incremental cardiopulmonary exercise test; Exercise test with incremental workload until maximal workload.; Other: Echography of upper leg; Determine upper leg muscle size; Other: Hand grip strength with hand dynamometer; Determine muscle strength; Other: Fill in questionnaires regarding physical activity; SQUASH, mMRC, questionnaire designed to report myopathic symptoms in LcFAOD patients.
Healthy controls; Controls are matched based on Age, Sex, BMI and comparable activity score assessed using the SQUASH questionnaire	Other: Intermittent cardiopulmonary exercise test; Exercise test with step-change from rest to a relatively low constant workload.; Other: Incremental cardiopulmonary exercise test; Exercise test with incremental workload until maximal workload.; Other: Echography of upper leg; Determine upper leg muscle size; Other: Hand grip strength with hand dynamometer; Determine muscle strength; Other: Fill in questionnaires regarding physical activity; SQUASH, mMRC, questionnaire designed to report myopathic symptoms in LcFAOD patients.

Outcome Measures

Primary Outcome Measures :

1. 1. Differences in V'O2/ V'CO2/heart rate kinetics during the intermittent exercise test between LcFAOD patients and healthy control subjects [ Time Frame: At rest (baseline) and during the intermittent CPX test (30 min) ]
2. Anaerobic threshold (ml/kg/min) [ Time Frame: During maximum exercise (max 30 min). ]
   Pulmonary involvement/Cardiac dysfunction/Skeletal muscle alterations
3. Ventilation reserve (L) [ Time Frame: During maximum exercise (max 30 min). ]
   Pulmonary involvement/Skeletal muscle alterations
4. CO2 ventilation equivalent (L/L) [ Time Frame: During maximum exercise (max 30 min). ]
   Pulmonary involvement/Cardiac dysfunction
5. Cardiac Output (L/min) [ Time Frame: During maximum exercise (max 30 min). ]
   Cardiac dysfunction
6. Heart rate reserve (per minute) [ Time Frame: During maximum exercise (max 30 min). ]
   Cardiac dysfunction
7. Muscle size on echography (cm) [ Time Frame: Baseline ]
   Skeletal muscle alterations
8. Muscle strength via resistance test (kg) [ Time Frame: Baseline ]
   Skeletal muscle alterations

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes
• Sampling Method: Non-Probability Sample

Study Population

All adult patients with long chain fatty acid oxidation disorders are under follow-up are eligible to participate in the study. Each patients will be compared to a matched healthy control subject (one healthy subject can serve as a control for more than one LcFAOD patient). Matching will be done by age (± 3 years), sex, BMI (± 2 kg/m2) and a comparable activity score assessed using a questionnaire (the Short Questionnaire to Asses Health enhancing physical activity (SQUASH).

Criteria

Inclusion Criteria:

• LC-FAOD patients:
• Men and women (age ≥18 years) with a confirmed diagnosis of carnitine palmitoyltransferase 2 (CPT2) deficiency, Carnitine-acylcarnitine translocase (CACT) deficiency, Mitochondrial Trifunctional protein (MTP) deficiency, Very-long-chain acyl-CoA dehydrogenase (VLCAD) deficiency or Long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency.

Healthy control subjects:

- Healthy men and women age ≥ 18 years

Exclusion Criteria:

LcFAOD patients:

• Pregnancy
• Recent acute myocardial infarction (<6 months prior to inclusion)
• Uncontrolled arrhythmia/severe conduction disorder causing hemodynamic compromise
• Implantable pacemaker or other cardiac device with complete ventricular pacing
• Uncontrolled heart failure with hemodynamic compromise
• Uncontrolled hypertension (Systolic Blood Pressure >150 mmHg and Diastolic Blood Pressure >100 mmHg on repeated measurements)
• Active infection, anemia, severe renal dysfunction (estimated Glomerular filtration rate < 30 ml/min/1,73m2), or other chronic disease likely to significantly impact exercise performance
• History of severe asthma or chronic obstructive pulmonary disease
• Active use of medication likely to affect exercise tolerance

Healthy controls:

• All abovementioned exclusion criteria for LcFOAD patients
• History of smoking - History of asthma, chronic obstructive pulmonary disease, heart failure, heart surgery, heart rhythm disorders or congenital heart diseases
• Chronic illness (including orthopedic, endocrinological, hematological, malignant, gastrointestinal, neurological, muscle or inflammatory disorders) likely to significantly impact on exercise performance
• > 6 alcohol units per day or > 14 alcohol units per week

Contacts and Locations

Contacts

Contact: Khya Snelder, BSc; 20 5666791 ext +31; c.k.snelder@amsterdamumc.nl

Locations

Netherlands

Amsterdam UMC, location AMC

Amsterdam, Noord-Holland, Netherlands, 1105 AZ

Sponsors and Collaborators

Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Stichting Stofwisselkracht

Investigators

• Principal Investigator: Mirjam Langeveld, MD PhD; Amsterdam UMC, location AMC

More Information

• Responsible Party: Dr. Mirjam Langeveld, MD PhD, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
• ClinicalTrials.gov Identifier: NCT05924555
• Other Study ID Numbers: NL83869.018.23
• First Posted: June 29, 2023
• Last Update Posted: June 29, 2023
• Last Verified: June 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

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

Keywords provided by Dr. Mirjam Langeveld, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA):

Long-chain Fatty Acid Oxidation disorders; Exercise intolerance; Cardiopulmonary exercise test