Clinical trial NCT03531554: Acute Nutritional Ketosis in VLCAD Deficiency
Official title: Acute Nutritional Ketosis in VLCAD Deficiency: Testing the Metabolic Base for Therapeutic Use
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: VLCAD Deficiency
Fatty Acid Oxidation Defects
Keywords: Fatty acid Oxidation Disorders
ketone ester
VLCAD deficiency
Lead sponsor: University Medical Center Groningen
Sponsor class: OTHER
Collaborators: name: UMC Utrecht
name: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
name: University of Oxford
name: ESN (Erfelijke Stofwisselingsziekten Nederland)
First posted: 2018-05-21
Enrollment: 5
Sex: ALL
Minimum age (years): 16
Maximum age (years): 65
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: randomized, blinded, placebo controlled, 2-way cross-over trial
Primary purpose: OTHER

Brief summary: 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.

Detailed 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Change of ATP concentration in millimolar
timeFrame: During session 2 and 3: continuous measurements from t=75 minutes until t=85 minutes
measure: Change of PCr concentration in millimolar
timeFrame: During session 2 and 3: continuous measurements from t=75 minutes until t=85 minutes
measure: Change of Pi concentration in millimolar
timeFrame: During session 2 and 3: continuous measurements from t=75 minutes until t=85 minutes
Secondary outcomes:
measure: kinetic rate constant of ATP synthesis in Hertz
timeFrame: session 2 and 3, 10 minutes each time
measure: intramuscular concentration of H+ in millimolar
timeFrame: session 2 and 3, 10 minutes each time
measure: completion of 35 minute upright bicycling bout at FATMAX
timeFrame: Session 2 and 3, 35 minutes
measure: completion of 10 minute supine bicycling bout at FATMAX in scanner
timeFrame: Session 2 and 3, 10 minutes
measure: HR in beats per minute
timeFrame: During session 1, 15 minutes During Session 2 + 3: 35 minutes
measure: VO2 in milliliter per minute per kilogram
timeFrame: During session 1, 15 minutes During Session 2 + 3: 35 minutes
measure: VCO2 in milliliter per minute per kilogram
timeFrame: During session 1, 15 minutes During Session 2 + 3: 35 minutes
measure: Changes in blood metabolites: D-betahydroxybutyrate in millimol per liter
timeFrame: Session 2 and 3, 265 minutes per session
measure: Changes in blood metabolites: glucose in millimol per liter
timeFrame: Session 2 and 3, 265 minutes per session
measure: Changes in blood metabolites: lactate in millimol per liter
timeFrame: Session 2 and 3, 265 minutes per session
measure: Changes in blood metabolites: insulin in picomol per liter
timeFrame: Session 2 and 3, 265 minutes per session
measure: Changes in blood metabolites: creatine kinase in units per liter
timeFrame: Session 2 and 3, 265 minutes per session
measure: Changes in blood metabolites: triglycerides in millimol per liter
timeFrame: Session 2 and 3, 265 minutes per session
measure: Changes in blood metabolites: LDL cholesterol in millimol per liter
timeFrame: Session 2 and 3, 265 minutes per session
measure: Changes in blood metabolites: free fatty acids in millimol per liter
timeFrame: Session 2 and 3, 265 minutes per session
measure: Changes in blood metabolites: total cholesterol in millimol per liter
timeFrame: Session 2 and 3, 265 minutes per session
measure: Changes in blood metabolites: HDL cholesterol in millimol per liter
timeFrame: Session 2 and 3, 265 minutes per session
measure: Changes in blood metabolites: acylcarnitines in micromol per liter
timeFrame: Session 2 and 3, 265 minutes per session
measure: Subjective exertion
timeFrame: During Session 2 + 3, assessed during blood sampling, 265 minutes per session
measure: height in meters
timeFrame: 1 minute during screening visit
measure: weight in kilogram
timeFrame: 1 minute during screening visit
measure: BMI in kg/m^2
timeFrame: 1 minute during screening visit
measure: optional: TCA intermediates in muscle tissue (units is ratio of metabolite peak/ internal standard) and will be expressed as fold change from baseline
timeFrame: Session 2+3: before and after exercise, 20 minutes per session
measure: optional: glycolysis intermediates in muscle tissue (units is ratio of metabolite peak/ internal standard) and will be expressed as fold change from baseline
timeFrame: Session 2+3: before and after exercise, 20 minutes per session
measure: optional: acylcarnitines in muscle tissue (units is ratio of metabolite peak/ internal standard) and will be expressed as fold change from baseline
timeFrame: Session 2+3: before and after exercise, 20 minutes per session
measure: optional: D-betahydroxybutyrate in muscle tissue (units is ratio of metabolite peak/ internal standard) and will be expressed as fold change from baseline
timeFrame: Session 2+3: before and after exercise, 20 minutes per session
measure: optional: capillary density in muscle tissue based on CD31 staining (capillaries per millimeter^2)
timeFrame: Session 2+3: before and after exercise, 20 minutes per session
measure: optional: mitochondrial density based on ATPase, COX-SDH, SDH and NADH staining (intensity per microgram per minute).
timeFrame: Session 2+3: before and after exercise, 20 minutes per session
measure: optional: mitochondrial density based on as citrate synthase activity expressed as absorbance/s/mg.
timeFrame: Session 2+3: before and after exercise, 20 minutes per session
measure: optional: parameters for metabolism and mitochondrial function in muscle (AMPK, PPAR gamma, PGC1a, and GLUT4). All expressed as protein content as % of control.
timeFrame: Session 2+3: before and after exercise, 20 minutes per session
measure: optional: lipid accumulation based on Oil-Red-O staining (intensity of staining, and percentage positive-stained cells).
timeFrame: Session 2+3: before and after exercise, 20 minutes per session
measure: optional: muscle fiber type composition based on myosin heavy chain profiling. Type I, IIa, IIx fibres will be expressed as % of total fibres.
timeFrame: Session 2+3: before and after exercise, 20 minutes per session
measure: optional: muscle fiber type composition based on ATPase staining (intensity/ug/min). Type I, IIa, IIx fibres will be expressed as % of total fibres.
timeFrame: Session 2+3: before and after exercise, 20 minutes per session
measure: optional: glycogen content of muscle based on Periodic acid-Schiff (PAS) staining (intensity per millimeter^2)
timeFrame: Session 2+3: before and after exercise, 20 minutes per session
measure: optional: glycogen content of muscle measured as glucose released after enzymatic digestion with amyloglucosidase expressed as micromol per gram wet muscle weight.
timeFrame: Session 2+3: before and after exercise, 20 minutes per session
Other outcomes:
Locations:
city: Amsterdam
country: Netherlands
facility: Academic Medical Center
state: Noord-Holland
city: Groningen
country: Netherlands
facility: Dept of Neuroscience/ Neuroimaging Center
Study officials:
affiliation: Dept of Neuroscience/ Neuroimaging Center Groningen
name: Jeroen AL Jeneson, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Cox PJ, Kirk T, Ashmore T, Willerton K, Evans R, Smith A, Murray AJ, Stubbs B, West J, McLure SW, King MT, Dodd MS, Holloway C, Neubauer S, Drawer S, Veech RL, Griffin JL, Clarke K. Nutritional Ketosis Alters Fuel Preference and Thereby Endurance Performance in Athletes. Cell Metab. 2016 Aug 9;24(2):256-68. doi: 10.1016/j.cmet.2016.07.010. Epub 2016 Jul 27.
citation: Diekman EF, Visser G, Schmitz JP, Nievelstein RA, de Sain-van der Velden M, Wardrop M, Van der Pol WL, Houten SM, van Riel NA, Takken T, Jeneson JA. Altered Energetics of Exercise Explain Risk of Rhabdomyolysis in Very Long-Chain Acyl-CoA Dehydrogenase Deficiency. PLoS One. 2016 Feb 16;11(2):e0147818. doi: 10.1371/journal.pone.0147818. eCollection 2016.
citation: Bleeker JC, Visser G, Clarke K, Ferdinandusse S, de Haan FH, Houtkooper RH, IJlst L, Kok IL, Langeveld M, van der Pol WL, de Sain-van der Velden MGM, Sibeijn-Kuiper A, Takken T, Wanders RJA, van Weeghel M, Wijburg FA, van der Woude LH, Wust RCI, Cox PJ, Jeneson JAL. Nutritional ketosis improves exercise metabolism in patients with very long-chain acyl-CoA dehydrogenase deficiency. J Inherit Metab Dis. 2020 Jul;43(4):787-799. doi: 10.1002/jimd.12217. Epub 2020 Feb 5.