Acute Nutritional Ketosis in VLCAD Deficiency

University Medical Center Groningen (UMCG)

Status: Completed

Conditions: Fatty Acid Oxidation Defects; VLCAD Deficiency

Treatments: Dietary Supplement: ketone ester drink; Procedure: muscle biopsy; Behavioral: exercise; Diagnostic Test: Magnetic Resonance Imaging

Study type: Interventional

Funder types: Other

Identifiers

NCT03531554

METC2014.492 ABR51222.042.14;

Details and patient eligibility

About

To test if a ketone-ester based drink can boost muscle mitochondrial function in vivo in patients with VLCADD in order to establish a rational basis for therapeutic use in this disorder.

Full description

Exertional rhabdomyolysis is a common symptom in very long-chain acylCoA dehydrogenase deficient (VLCADD) patients. Failing muscle ATP homeostasis, due to impaired fatty acid oxidation, is the most likely cause. Therefore, supplementation with an alternative energy substrate to boost ATP homeostasis, such as an exogenous ketone ester (KE) drink, could be a therapeutic option. Previous results suggest that KE is preferentially oxidized in the tricyclic acid (TCA) cycle and improves physical endurance in athletes. Our primary objective is to test if KE boosts muscular ATP homeostasis in VLCADD patients to establish a rational basis for therapeutic use.

VLCADD patients will be included in a randomized, blinded, placebo controlled, 2-way cross-over trial. Prior to each test, patients receive a KE drink or an isocaloric carbohydrate equivalent, and completed a 35 min cycling test on an upright bicycle, followed by 10 minutes of supine cycling inside a MR scanner. The protocol will be repeated after at least one week with the opposite drink.

Enrollment: 5 patients

Sex: All

Ages: 16 to 65 years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Confirmed VLCADD by genetic profiling

Exclusion criteria

• contraindications for MRI studies (assessed by standardised questionnaire as previously used in METC 08-267/K; see UMCG section F METC documents)
• inability to perform bicycle exercise.
• recent episode of rhabdomyolysis, or treatment for acute renal failure in the past 2 months.
• intercurrent illness which may influence exercise tolerance (anaemia, musculoskeletal injury, or other undiagnosed illness under investigation).
• known coronary artery disease, positive history for angina, or changes on ECG suggestive of previous ischaemia without a negative stress test.
• insulin-dependent diabetes mellitus.
• loss of, or an inability to give informed consent.
• pregnancy or current breastfeeding, or females not taking the oral contraceptive pill (this is due to the variability in hormonal patterns and substrate levels with different parts of the menstrual cycle).
• any other cause which in the opinion of the investigators, may affect the volunteers ability to participate in the study.

Trial design

Primary purpose: Other

Allocation: Randomized

Interventional model: Crossover Assignment

Masking: Double Blind

---

5 participants in 2 patient groups, including a placebo group

ketone ester drink

Experimental group

Description:

Oral intake of ketone ester drink muscle biopsy exercise muscle biopsy Magnetic Resonance imaging

Treatment:

Procedure: muscle biopsy

Diagnostic Test: Magnetic Resonance Imaging

Dietary Supplement: ketone ester drink

Behavioral: exercise

carbohydrate drink

Placebo Comparator group

Description:

Oral intake of isocaloric carbohydrate drinkmuscle biopsy exercise muscle biopsy Magnetic Resonance imaging

Treatment:

Procedure: muscle biopsy

Diagnostic Test: Magnetic Resonance Imaging

Behavioral: exercise