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NCT Number: NCT03531554

Acute Nutritional Ketosis in VLCAD Deficiency

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.

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Key information

Conditions

VLCAD Deficiency Fatty Acid Oxidation Defects

Age range

16 year–65 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Not applicable

Primary location

Academic Medical Center, Amsterdam, North Holland, Netherlands

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About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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.

Treatment and study plan

ketone ester drink

Dietary Supplement

395 mg of ketone ester/kg

Other names: deltaG (R)

Exercise

Behavioral

35 min cycling test on an upright bicycle, followed by 10 minutes of supine cycling inside a MR scanner.

Muscle biopsy

Procedure

biopsy from the quadriceps muscle prior to and immediately after upright bicycling

Magnetic Resonance Imaging

Diagnostic Test

1H MR images and 31P MR spectra were acquired from the upper leg prior to-, during and after exercise

Other names: Magnetic Resonance Spectroscopy

Primary outcomes

  1. Change of ATP concentration in millimolar

    Time frame: During session 2 and 3: continuous measurements from t=75 minutes until t=85 minutes

    steady-state in vivo intramuscular concentration of ATP metabolites during rest and exercise.

  2. Change of PCr concentration in millimolar

    Time frame: During session 2 and 3: continuous measurements from t=75 minutes until t=85 minutes

    steady-state in vivo intramuscular concentration of ATP metabolites during rest and exercise.

  3. Change of Pi concentration in millimolar

    Time frame: During session 2 and 3: continuous measurements from t=75 minutes until t=85 minutes

    steady-state in vivo intramuscular concentration of ATP metabolites during rest and exercise.

Secondary outcomes

  1. kinetic rate constant of ATP synthesis in Hertz

    Time frame: session 2 and 3, 10 minutes each time

    rate constant of Pi and PCr recovery post-exercise

  2. intramuscular concentration of H+ in millimolar

    Time frame: session 2 and 3, 10 minutes each time

    steady-state in vivo intramuscular concentration of H+ during rest and exercise

  3. completion of 35 minute upright bicycling bout at FATMAX

    Time frame: Session 2 and 3, 35 minutes

    (yes/no; if no, #minutes)

  4. completion of 10 minute supine bicycling bout at FATMAX in scanner

    Time frame: Session 2 and 3, 10 minutes

    (yes/no; if no, #minutes)

  5. HR in beats per minute

    Time frame: During session 1, 15 minutes During Session 2 + 3: 35 minutes

    heart rate, VO2 and VCO2 dynamics. During session 2+3 breath sampling will be done for 2 minutes per timepoint, simultaneously with blood sampling.

  6. VO2 in milliliter per minute per kilogram

    Time frame: During session 1, 15 minutes During Session 2 + 3: 35 minutes

    heart rate, VO2 and VCO2 dynamics. During session 2+3 breath sampling will be done for 2 minutes per timepoint, simultaneously with blood sampling.

  7. VCO2 in milliliter per minute per kilogram

    Time frame: During session 1, 15 minutes During Session 2 + 3: 35 minutes

    VCO2 dynamics during session 2+3 breath sampling for 2 minutes per timepoint, simultaneously with blood sampling.

  8. Changes in blood metabolites: D-betahydroxybutyrate in millimol per liter

    Time frame: Session 2 and 3, 265 minutes per session

    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

  9. Changes in blood metabolites: glucose in millimol per liter

    Time frame: Session 2 and 3, 265 minutes per session

    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

  10. Changes in blood metabolites: lactate in millimol per liter

    Time frame: Session 2 and 3, 265 minutes per session

    Samples are taken at baseline, 30 minutes, 60 minutes, 85 minutes and 265 min after ingestion of the testdrink

  11. Changes in blood metabolites: insulin in picomol per liter

    Time frame: Session 2 and 3, 265 minutes per session

    Samples are taken at baseline, 30 minutes, 60 minutes, 85 minutes and 265 min after ingestion of the testdrink

  12. Changes in blood metabolites: creatine kinase in units per liter

    Time frame: Session 2 and 3, 265 minutes per session

    Samples are taken at baseline, 30 minutes, 60 minutes, 85 minutes and 265 min after ingestion of the testdrink

  13. Changes in blood metabolites: triglycerides in millimol per liter

    Time frame: Session 2 and 3, 265 minutes per session

    Samples are taken at baseline, 30 minutes, 60 minutes, 85 minutes and 265 min after ingestion of the testdrink

  14. Changes in blood metabolites: LDL cholesterol in millimol per liter

    Time frame: Session 2 and 3, 265 minutes per session

    Samples are taken at baseline, 30 minutes, 60 minutes, 85 minutes and 265 min after ingestion of the testdrink

  15. Changes in blood metabolites: free fatty acids in millimol per liter

    Time frame: Session 2 and 3, 265 minutes per session

    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

  16. Changes in blood metabolites: total cholesterol in millimol per liter

    Time frame: Session 2 and 3, 265 minutes per session

    Samples are taken at baseline, 30 minutes, 60 minutes, 85 minutes and 265 min after ingestion of the testdrink

  17. Changes in blood metabolites: HDL cholesterol in millimol per liter

    Time frame: Session 2 and 3, 265 minutes per session

    Samples are taken at baseline, 30 minutes, 60 minutes, 85 minutes and 265 min after ingestion of the testdrink

  18. Changes in blood metabolites: acylcarnitines in micromol per liter

    Time frame: Session 2 and 3, 265 minutes per session

    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

  19. Subjective exertion

    Time frame: During Session 2 + 3, assessed during blood sampling, 265 minutes per session

    Measured with Borg score (range from 6 (rest) to 20 (extreme exertion)).

  20. height in meters

    Time frame: 1 minute during screening visit

    height of patient

  21. weight in kilogram

    Time frame: 1 minute during screening visit

    weight of patient to dose intervention and normalize outcome parameters

  22. BMI in kg/m^2

    Time frame: 1 minute during screening visit

    weight and height will be combined to report BMI in kg/m^2

  23. optional: TCA intermediates in muscle tissue (units is ratio of metabolite peak/ internal standard) and will be expressed as fold change from baseline

    Time frame: Session 2+3: before and after exercise, 20 minutes per session

    metabolomics (mass spectrometry) of muscle tissue on a voluntary basis

  24. optional: glycolysis intermediates in muscle tissue (units is ratio of metabolite peak/ internal standard) and will be expressed as fold change from baseline

    Time frame: Session 2+3: before and after exercise, 20 minutes per session

    metabolomics (mass spectrometry) of muscle tissue on a voluntary basis

  25. optional: acylcarnitines in muscle tissue (units is ratio of metabolite peak/ internal standard) and will be expressed as fold change from baseline

    Time frame: Session 2+3: before and after exercise, 20 minutes per session

    metabolomics (mass spectrometry) of muscle tissue on a voluntary basis

  26. optional: D-betahydroxybutyrate in muscle tissue (units is ratio of metabolite peak/ internal standard) and will be expressed as fold change from baseline

    Time frame: Session 2+3: before and after exercise, 20 minutes per session

    metabolomics (mass spectrometry) of muscle tissue on a voluntary basis

  27. optional: capillary density in muscle tissue based on CD31 staining (capillaries per millimeter^2)

    Time frame: Session 2+3: before and after exercise, 20 minutes per session

    individual phenotypic muscle properties on a voluntary basis. Immunohistochemistry.

  28. optional: mitochondrial density based on ATPase, COX-SDH, SDH and NADH staining (intensity per microgram per minute).

    Time frame: Session 2+3: before and after exercise, 20 minutes per session

    individual phenotypic muscle properties on a voluntary basis. Immunohistochemistry.

  29. optional: mitochondrial density based on as citrate synthase activity expressed as absorbance/s/mg.

    Time frame: Session 2+3: before and after exercise, 20 minutes per session

    individual phenotypic muscle properties on a voluntary basis.

  30. optional: parameters for metabolism and mitochondrial function in muscle (AMPK, PPAR gamma, PGC1a, and GLUT4). All expressed as protein content as % of control.

    Time frame: Session 2+3: before and after exercise, 20 minutes per session

    individual phenotypic muscle properties on a voluntary basis. Westernblots.

  31. optional: lipid accumulation based on Oil-Red-O staining (intensity of staining, and percentage positive-stained cells).

    Time frame: Session 2+3: before and after exercise, 20 minutes per session

    individual phenotypic muscle properties on a voluntary basis. Immunohistochemistry.

  32. optional: muscle fiber type composition based on myosin heavy chain profiling. Type I, IIa, IIx fibres will be expressed as % of total fibres.

    Time frame: Session 2+3: before and after exercise, 20 minutes per session

    individual phenotypic muscle properties on a voluntary basis.

  33. optional: muscle fiber type composition based on ATPase staining (intensity/ug/min). Type I, IIa, IIx fibres will be expressed as % of total fibres.

    Time frame: Session 2+3: before and after exercise, 20 minutes per session

    individual phenotypic muscle properties on a voluntary basis. Immunohistochemistry.

  34. optional: glycogen content of muscle based on Periodic acid-Schiff (PAS) staining (intensity per millimeter^2)

    Time frame: Session 2+3: before and after exercise, 20 minutes per session

    individual phenotypic muscle properties on a voluntary basis. Immunohistochemistry.

  35. optional: glycogen content of muscle measured as glucose released after enzymatic digestion with amyloglucosidase expressed as micromol per gram wet muscle weight.

    Time frame: Session 2+3: before and after exercise, 20 minutes per session

    individual phenotypic muscle properties on a voluntary basis.

Sponsors and collaborators

Lead sponsor

University Medical Center Groningen

Other

Collaborators

  • Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
  • ESN (Erfelijke Stofwisselingsziekten Nederland)
  • UMC Utrecht
  • University of Oxford

Registry information

Official study title

Acute Nutritional Ketosis in VLCAD Deficiency: Testing the Metabolic Base for Therapeutic Use

Important dates

Study start
2016
Primary completion
2017
Study completion
2017
First posted
May 21, 2018
Registry last updated
May 21, 2018

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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