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

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Long-chain Fatty Acid Oxidation Disorders \(LC-FAOD\)
• Intervention / Treatment: 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 Type: Observational
• Enrollment (Estimated): 50

Contacts and Locations

• Study Contact: Name: Khya Snelder, BSc; Phone Number: +31 20 5666791; Email: c.k.snelder@amsterdamumc.nl

Study Locations

• Netherlands
  • Noord-Holland
    • Amsterdam, Noord-Holland, Netherlands, 1105 AZ
      • Amsterdam UMC, location AMC

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• 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).

Description

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

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

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.

What is the study measuring?

Primary Outcome Measures

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

Collaborators and Investigators

• Sponsor: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
• Collaborators: Stichting Stofwisselkracht
• Investigators: Principal Investigator: Mirjam Langeveld, MD PhD, Amsterdam UMC, location AMC

Study record dates

Study Major Dates

• Study Start (Estimated): August 1, 2023
• Primary Completion (Estimated): August 1, 2028
• Study Completion (Estimated): August 1, 2028

Study Registration Dates

• First Submitted: June 21, 2023
• First Submitted That Met QC Criteria: June 21, 2023
• First Posted (Actual): June 29, 2023

Study Record Updates

• Last Update Posted (Actual): June 29, 2023
• Last Update Submitted That Met QC Criteria: June 21, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Keywords: Cardiopulmonary exercise test; Exercise intolerance; Long-chain Fatty Acid Oxidation disorders
• Other Study ID Numbers: NL83869.018.23

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No