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Acute Nutritional Ketosis in VLCAD Deficiency

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ClinicalTrials.gov Identifier: NCT03531554
Recruitment Status : Completed
First Posted : May 21, 2018
Last Update Posted : May 21, 2018
Sponsor:
Collaborators:
UMC Utrecht
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
University of Oxford
ESN (Erfelijke Stofwisselingsziekten Nederland)
Information provided by (Responsible Party):
dr. J.A.L. Jeneson, University Medical Center Groningen

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.

Condition or disease Intervention/treatment Phase
VLCAD Deficiency Fatty Acid Oxidation Defects Dietary Supplement: ketone ester drink Behavioral: exercise Procedure: muscle biopsy Diagnostic Test: Magnetic Resonance Imaging Not Applicable

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.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 5 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description: randomized, blinded, placebo controlled, 2-way cross-over trial
Masking: Double (Participant, Outcomes Assessor)
Masking Description: Double (Participant, Outcomes Assessor)
Primary Purpose: Other
Official Title: Acute Nutritional Ketosis in VLCAD Deficiency: Testing the Metabolic Base for Therapeutic Use
Actual Study Start Date : April 1, 2016
Actual Primary Completion Date : March 31, 2017
Actual Study Completion Date : April 1, 2017


Arm Intervention/treatment
Experimental: ketone ester drink
Oral intake of ketone ester drink muscle biopsy exercise muscle biopsy Magnetic Resonance imaging
Dietary Supplement: ketone ester drink
395 mg of ketone ester/kg
Other Name: deltaG (R)

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
Other Name: Magnetic Resonance Spectroscopy

Placebo Comparator: carbohydrate drink
Oral intake of isocaloric carbohydrate drinkmuscle biopsy exercise muscle biopsy Magnetic Resonance imaging
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
Other Name: Magnetic Resonance Spectroscopy




Primary Outcome Measures :
  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 Outcome Measures :
  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.



Information from the National Library of Medicine

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Ages Eligible for Study:   16 Years to 65 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03531554


Locations
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Netherlands
Academic Medical Center
Amsterdam, Noord-Holland, Netherlands, 1105 AZ
Dept of Neuroscience/ Neuroimaging Center
Groningen, Netherlands, 9700RB
Sponsors and Collaborators
University Medical Center Groningen
UMC Utrecht
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
University of Oxford
ESN (Erfelijke Stofwisselingsziekten Nederland)
Investigators
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Principal Investigator: Jeroen AL Jeneson, PhD Dept of Neuroscience/ Neuroimaging Center Groningen
  Study Documents (Full-Text)

Documents provided by dr. J.A.L. Jeneson, University Medical Center Groningen:
Study Protocol  [PDF] February 15, 2017


Publications:
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Responsible Party: dr. J.A.L. Jeneson, Principal Investigator, University Medical Center Groningen
ClinicalTrials.gov Identifier: NCT03531554     History of Changes
Other Study ID Numbers: METC2014.492;ABR51222.042.14
First Posted: May 21, 2018    Key Record Dates
Last Update Posted: May 21, 2018
Last Verified: May 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by dr. J.A.L. Jeneson, University Medical Center Groningen:
Fatty acid Oxidation Disorders
ketone ester
VLCAD deficiency
Additional relevant MeSH terms:
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Muscular Diseases
Lipid Metabolism, Inborn Errors
Mitochondrial Diseases
Metabolic Diseases
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Lipid Metabolism Disorders
Musculoskeletal Diseases
Neuromuscular Diseases
Nervous System Diseases