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| Name | Class |
|---|---|
| UMC Utrecht | OTHER |
| Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA) | OTHER |
| University of Oxford | OTHER |
| ESN (Erfelijke Stofwisselingsziekten Nederland) |
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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.
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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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| ketone ester drink | Experimental | Oral intake of ketone ester drink muscle biopsy exercise muscle biopsy Magnetic Resonance imaging |
|
| carbohydrate drink | Placebo Comparator | Oral intake of isocaloric carbohydrate drinkmuscle biopsy exercise muscle biopsy Magnetic Resonance imaging |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| ketone ester drink | Dietary Supplement | 395 mg of ketone ester/kg |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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 |
| 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 |
| 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 |
| Measure | Description | Time Frame |
|---|---|---|
| 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 |
| intramuscular concentration of H+ in millimolar | steady-state in vivo intramuscular concentration of H+ during rest and exercise |
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Inclusion Criteria:
- Confirmed VLCADD by genetic profiling
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Jeroen AL Jeneson, PhD | Dept of Neuroscience/ Neuroimaging Center Groningen | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Academic Medical Center | Amsterdam | North Holland | 1105 AZ | Netherlands | ||
| Dept of Neuroscience/ Neuroimaging Center |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 27475046 | Background | 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. | |
| 26881790 |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Feb 15, 2017 | Oct 20, 2017 | Prot_000.pdf |
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| ID | Term |
|---|---|
| C536353 | VLCAD deficiency |
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| ID | Term |
|---|---|
| D015444 | Exercise |
| D008279 | Magnetic Resonance Imaging |
| D049268 | Positron-Emission Tomography |
| ID | Term |
|---|---|
| D009043 | Motor Activity |
| D009068 | Movement |
| D009142 | Musculoskeletal Physiological Phenomena |
| D055687 | Musculoskeletal and Neural Physiological Phenomena |
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| UNKNOWN |
randomized, blinded, placebo controlled, 2-way cross-over trial
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Double (Participant, Outcomes Assessor)
| 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 |
|
|
| session 2 and 3, 10 minutes each time |
| completion of 35 minute upright bicycling bout at FATMAX | (yes/no; if no, #minutes) | Session 2 and 3, 35 minutes |
| completion of 10 minute supine bicycling bout at FATMAX in scanner | (yes/no; if no, #minutes) | Session 2 and 3, 10 minutes |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| height in meters | height of patient | 1 minute during screening visit |
| weight in kilogram | weight of patient to dose intervention and normalize outcome parameters | 1 minute during screening visit |
| BMI in kg/m^2 | weight and height will be combined to report BMI in kg/m^2 | 1 minute during screening visit |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| Groningen |
| 9700RB |
| Netherlands |
| 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. |
| 31955429 | Derived | 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. |
| D014054 | Tomography |
| D003952 | Diagnostic Imaging |
| D019937 | Diagnostic Techniques and Procedures |
| D003933 | Diagnosis |
| D014055 | Tomography, Emission-Computed |
| D007090 | Image Interpretation, Computer-Assisted |
| D007089 | Image Enhancement |
| D010781 | Photography |
| D011877 | Radionuclide Imaging |
| D003947 | Diagnostic Techniques, Radioisotope |