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Clinical Trial Details — Status: Completed

Administrative data

NCT number NCT03531554
Other study ID # METC2014.492;ABR51222.042.14
Secondary ID
Status Completed
Phase N/A
First received
Last updated
Start date April 1, 2016
Est. completion date April 1, 2017

Study information

Verified date May 2018
Source University Medical Center Groningen
Contact n/a
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial 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.


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.


Recruitment information / eligibility

Status Completed
Enrollment 5
Est. completion date April 1, 2017
Est. primary completion date March 31, 2017
Accepts healthy volunteers No
Gender All
Age group 16 Years to 65 Years
Eligibility 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.

Study Design


Intervention

Dietary Supplement:
ketone ester drink
395 mg of ketone ester/kg
Behavioral:
exercise
35 min cycling test on an upright bicycle, followed by 10 minutes of supine cycling inside a MR scanner.
Procedure:
muscle biopsy
biopsy from the quadriceps muscle prior to and immediately after upright bicycling
Diagnostic Test:
Magnetic Resonance Imaging
1H MR images and 31P MR spectra were acquired from the upper leg prior to-, during and after exercise

Locations

Country Name City State
Netherlands Academic Medical Center Amsterdam Noord-Holland
Netherlands Dept of Neuroscience/ Neuroimaging Center Groningen

Sponsors (5)

Lead Sponsor Collaborator
University Medical Center Groningen Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA), ESN (Erfelijke Stofwisselingsziekten Nederland), UMC Utrecht, University of Oxford

Country where clinical trial is conducted

Netherlands, 

References & Publications (2)

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. — View 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. — View Citation

Outcome

Type Measure Description Time frame Safety issue
Primary Change of ATP concentration in millimolar steady-state in vivo intramuscular concentration of ATP metabolites during rest and exercise. During session 2 and 3: continuous measurements from t=75 minutes until t=85 minutes
Primary Change of PCr concentration in millimolar steady-state in vivo intramuscular concentration of ATP metabolites during rest and exercise. During session 2 and 3: continuous measurements from t=75 minutes until t=85 minutes
Primary Change of Pi concentration in millimolar steady-state in vivo intramuscular concentration of ATP metabolites during rest and exercise. During session 2 and 3: continuous measurements from t=75 minutes until t=85 minutes
Secondary kinetic rate constant of ATP synthesis in Hertz rate constant of Pi and PCr recovery post-exercise session 2 and 3, 10 minutes each time
Secondary intramuscular concentration of H+ in millimolar steady-state in vivo intramuscular concentration of H+ during rest and exercise session 2 and 3, 10 minutes each time
Secondary completion of 35 minute upright bicycling bout at FATMAX (yes/no; if no, #minutes) Session 2 and 3, 35 minutes
Secondary completion of 10 minute supine bicycling bout at FATMAX in scanner (yes/no; if no, #minutes) Session 2 and 3, 10 minutes
Secondary HR in beats per minute heart rate, VO2 and VCO2 dynamics. During session 2+3 breath sampling will be done for 2 minutes per timepoint, simultaneously with blood sampling. During session 1, 15 minutes During Session 2 + 3: 35 minutes
Secondary VO2 in milliliter per minute per kilogram heart rate, VO2 and VCO2 dynamics. During session 2+3 breath sampling will be done for 2 minutes per timepoint, simultaneously with blood sampling. During session 1, 15 minutes During Session 2 + 3: 35 minutes
Secondary VCO2 in milliliter per minute per kilogram VCO2 dynamics during session 2+3 breath sampling for 2 minutes per timepoint, simultaneously with blood sampling. During session 1, 15 minutes During Session 2 + 3: 35 minutes
Secondary Changes in blood metabolites: D-betahydroxybutyrate in millimol per liter Samples are taken at baseline, 30 minutes, 40 minutes, 50 minutes, 60 minutes, 75 minutes, 85 minutes and 265 minutes after ingestion of the testdrink Session 2 and 3, 265 minutes per session
Secondary Changes in blood metabolites: glucose in millimol per liter Samples are taken at baseline, 30 minutes, 40 minutes, 50 minutes, 60 minutes, 75 minutes, 85 minutes and 265 min after ingestion of the testdrink Session 2 and 3, 265 minutes per session
Secondary Changes in blood metabolites: lactate in millimol per liter Samples are taken at baseline, 30 minutes, 60 minutes, 85 minutes and 265 min after ingestion of the testdrink Session 2 and 3, 265 minutes per session
Secondary Changes in blood metabolites: insulin in picomol per liter Samples are taken at baseline, 30 minutes, 60 minutes, 85 minutes and 265 min after ingestion of the testdrink Session 2 and 3, 265 minutes per session
Secondary Changes in blood metabolites: creatine kinase in units per liter Samples are taken at baseline, 30 minutes, 60 minutes, 85 minutes and 265 min after ingestion of the testdrink Session 2 and 3, 265 minutes per session
Secondary Changes in blood metabolites: triglycerides in millimol per liter Samples are taken at baseline, 30 minutes, 60 minutes, 85 minutes and 265 min after ingestion of the testdrink Session 2 and 3, 265 minutes per session
Secondary Changes in blood metabolites: LDL cholesterol in millimol per liter Samples are taken at baseline, 30 minutes, 60 minutes, 85 minutes and 265 min after ingestion of the testdrink Session 2 and 3, 265 minutes per session
Secondary Changes in blood metabolites: free fatty acids in millimol per liter Samples are taken at baseline, 30 minutes, 40 minutes, 50 minutes, 60 minutes, 75 minutes, 85 minutes and 265 min after ingestion of the test drink Session 2 and 3, 265 minutes per session
Secondary Changes in blood metabolites: total cholesterol in millimol per liter Samples are taken at baseline, 30 minutes, 60 minutes, 85 minutes and 265 min after ingestion of the testdrink Session 2 and 3, 265 minutes per session
Secondary Changes in blood metabolites: HDL cholesterol in millimol per liter Samples are taken at baseline, 30 minutes, 60 minutes, 85 minutes and 265 min after ingestion of the testdrink Session 2 and 3, 265 minutes per session
Secondary Changes in blood metabolites: acylcarnitines in micromol per liter Samples are taken at baseline, 30 minutes, 40 minutes, 50 minutes, 60 minutes, 75 minutes, 85 minutes and 265 min after ingestion of the test drink Session 2 and 3, 265 minutes per session
Secondary Subjective exertion Measured with Borg score (range from 6 (rest) to 20 (extreme exertion)). During Session 2 + 3, assessed during blood sampling, 265 minutes per session
Secondary height in meters height of patient 1 minute during screening visit
Secondary weight in kilogram weight of patient to dose intervention and normalize outcome parameters 1 minute during screening visit
Secondary BMI in kg/m^2 weight and height will be combined to report BMI in kg/m^2 1 minute during screening visit
Secondary optional: TCA intermediates in muscle tissue (units is ratio of metabolite peak/ internal standard) and will be expressed as fold change from baseline metabolomics (mass spectrometry) of muscle tissue on a voluntary basis Session 2+3: before and after exercise, 20 minutes per session
Secondary optional: glycolysis intermediates in muscle tissue (units is ratio of metabolite peak/ internal standard) and will be expressed as fold change from baseline metabolomics (mass spectrometry) of muscle tissue on a voluntary basis Session 2+3: before and after exercise, 20 minutes per session
Secondary optional: acylcarnitines in muscle tissue (units is ratio of metabolite peak/ internal standard) and will be expressed as fold change from baseline metabolomics (mass spectrometry) of muscle tissue on a voluntary basis Session 2+3: before and after exercise, 20 minutes per session
Secondary optional: D-betahydroxybutyrate in muscle tissue (units is ratio of metabolite peak/ internal standard) and will be expressed as fold change from baseline metabolomics (mass spectrometry) of muscle tissue on a voluntary basis Session 2+3: before and after exercise, 20 minutes per session
Secondary optional: capillary density in muscle tissue based on CD31 staining (capillaries per millimeter^2) individual phenotypic muscle properties on a voluntary basis. Immunohistochemistry. Session 2+3: before and after exercise, 20 minutes per session
Secondary optional: mitochondrial density based on ATPase, COX-SDH, SDH and NADH staining (intensity per microgram per minute). individual phenotypic muscle properties on a voluntary basis. Immunohistochemistry. Session 2+3: before and after exercise, 20 minutes per session
Secondary optional: mitochondrial density based on as citrate synthase activity expressed as absorbance/s/mg. individual phenotypic muscle properties on a voluntary basis. Session 2+3: before and after exercise, 20 minutes per session
Secondary optional: parameters for metabolism and mitochondrial function in muscle (AMPK, PPAR gamma, PGC1a, and GLUT4). All expressed as protein content as % of control. individual phenotypic muscle properties on a voluntary basis. Westernblots. Session 2+3: before and after exercise, 20 minutes per session
Secondary optional: lipid accumulation based on Oil-Red-O staining (intensity of staining, and percentage positive-stained cells). individual phenotypic muscle properties on a voluntary basis. Immunohistochemistry. Session 2+3: before and after exercise, 20 minutes per session
Secondary optional: muscle fiber type composition based on myosin heavy chain profiling. Type I, IIa, IIx fibres will be expressed as % of total fibres. individual phenotypic muscle properties on a voluntary basis. Session 2+3: before and after exercise, 20 minutes per session
Secondary optional: muscle fiber type composition based on ATPase staining (intensity/ug/min). Type I, IIa, IIx fibres will be expressed as % of total fibres. individual phenotypic muscle properties on a voluntary basis. Immunohistochemistry. Session 2+3: before and after exercise, 20 minutes per session
Secondary optional: glycogen content of muscle based on Periodic acid-Schiff (PAS) staining (intensity per millimeter^2) individual phenotypic muscle properties on a voluntary basis. Immunohistochemistry. Session 2+3: before and after exercise, 20 minutes per session
Secondary optional: glycogen content of muscle measured as glucose released after enzymatic digestion with amyloglucosidase expressed as micromol per gram wet muscle weight. individual phenotypic muscle properties on a voluntary basis. Session 2+3: before and after exercise, 20 minutes per session
See also
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