AzTrials
AzTrials

VLCAD DeficiencyNCT03531554

Acute Nutritional Ketosis in VLCAD Deficiency

A study testing ketone ester drink, exercise and muscle biopsy in people with VLCAD Deficiency and Fatty Acid Oxidation Defects, run by University Medical Center Groningen at 2 sites in Netherlands.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

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. Read more about this study

Who is it for?
Ages 16 to 65 years
What is being tested?
ketone ester drink, exercise and muscle biopsy
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
5 participants
Where
2 sitesNetherlands
Study dates
1 Apr 2016to 1 Apr 2017
Phase
Interventional
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 16 to 65 years
  • All sexes
  • No healthy volunteers
  • Child, Adult, Older adult

Who may be able to join

  • Confirmed VLCADD by genetic profiling

Who cannot join

  • 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.
Show all 9Show fewer
  • 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.

Trial locations and contacts

2 sites in 1 country.

Netherlands2 sites

  • Academic Medical Center

    Amsterdam, North Holland, 1105 AZ

  • Dept of Neuroscience/ Neuroimaging Center

    Groningen, 9700RB

Other trials in Netherlands

About this study

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

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.

Read the 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.

Being tested
ketone ester drink, exercise, muscle biopsy, Magnetic Resonance Imaging
Keywords
Fatty acid Oxidation Disorders, ketone ester, VLCAD deficiency
Medical subject headings
VLCAD deficiency

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • ketone ester drinkDietary supplement

    Also called deltaG (R)

    395 mg of ketone ester/kg

  • exerciseBehavioural

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

  • muscle biopsyProcedure or surgery

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

  • Magnetic Resonance ImagingDiagnostic test

    Also called Magnetic Resonance Spectroscopy

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

Study groups in NCT03531554
Study groupRoleWhat they receive
ketone ester drinkExperimentalOral intake of ketone ester drink muscle biopsy exercise muscle biopsy Magnetic Resonance imaging
Receives: Dietary Supplement: ketone ester drink; Behavioral: exercise; Procedure: muscle biopsy; Diagnostic Test: Magnetic Resonance Imaging
carbohydrate drinkPlacebo comparatorOral intake of isocaloric carbohydrate drinkmuscle biopsy exercise muscle biopsy Magnetic Resonance imaging
Receives: Behavioral: exercise; Procedure: muscle biopsy; Diagnostic Test: Magnetic Resonance Imaging

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Change of ATP concentration in millimolar

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

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

  2. Change of PCr concentration in millimolar

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

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

  3. Change of Pi concentration in millimolar

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

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

Secondary outcomes (35)

  1. kinetic rate constant of ATP synthesis in Hertz

    rate constant of Pi and PCr recovery post-exercise

    Measured: session 2 and 3, 10 minutes each time

  2. intramuscular concentration of H+ in millimolar

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

    Measured: session 2 and 3, 10 minutes each time

  3. completion of 35 minute upright bicycling bout at FATMAX

    (yes/no; if no, #minutes)

    Measured: Session 2 and 3, 35 minutes

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

    (yes/no; if no, #minutes)

    Measured: Session 2 and 3, 10 minutes

  5. 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.

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

  6. 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.

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

  7. VCO2 in milliliter per minute per kilogram

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

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

  8. 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

    Measured: Session 2 and 3, 265 minutes per session

  9. 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

    Measured: Session 2 and 3, 265 minutes per session

  10. 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

    Measured: Session 2 and 3, 265 minutes per session

  11. 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

    Measured: Session 2 and 3, 265 minutes per session

  12. 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

    Measured: Session 2 and 3, 265 minutes per session

  13. 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

    Measured: Session 2 and 3, 265 minutes per session

  14. 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

    Measured: Session 2 and 3, 265 minutes per session

  15. 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

    Measured: Session 2 and 3, 265 minutes per session

  16. 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

    Measured: Session 2 and 3, 265 minutes per session

  17. 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

    Measured: Session 2 and 3, 265 minutes per session

  18. 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

    Measured: Session 2 and 3, 265 minutes per session

  19. Subjective exertion

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

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

  20. height in meters

    height of patient

    Measured: 1 minute during screening visit

  21. weight in kilogram

    weight of patient to dose intervention and normalize outcome parameters

    Measured: 1 minute during screening visit

  22. BMI in kg/m^2

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

    Measured: 1 minute during screening visit

  23. 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

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

  24. 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

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

  25. 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

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

  26. 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

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

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

    individual phenotypic muscle properties on a voluntary basis. Immunohistochemistry.

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

  28. 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.

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

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

    individual phenotypic muscle properties on a voluntary basis.

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

  30. 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.

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

  31. 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.

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

  32. 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.

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

  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.

    individual phenotypic muscle properties on a voluntary basis. Immunohistochemistry.

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

  34. 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.

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

  35. 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.

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

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted21 May 2018
  2. Study start1 Apr 2016
  3. Primary completion31 Mar 2017
  4. Study completion1 Apr 2017

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase N/A
Primary purpose
Other
Allocation
Randomised
Intervention model
Crossover
Model description
randomized, blinded, placebo controlled, 2-way cross-over trial
Masking
Double blind
Who is masked
Participant, Outcomes assessor
Enrolment
5 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03531554
Sponsor's protocol ID
METC2014.492;ABR51222.042.14
Status last verified
May 2018
First submitted
17 Oct 2017
Last updated
21 May 2018
Results posted
No
Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
Undecided

Publications

  • 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.

    PubMed 27475046

  • 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.

    PubMed 26881790

  • 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.

    PubMed 31955429

Questions about this trial

What is this clinical trial studying?

A study testing ketone ester drink, exercise and muscle biopsy in people with VLCAD Deficiency and Fatty Acid Oxidation Defects, run by University Medical Center Groningen at 2 sites in Netherlands.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 1 inclusion and 9 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 21 May 2018. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 2 sites in Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Change of ATP concentration in millimolar (time frame: During session 2 and 3: continuous measurements from t=75 minutes until t=85 minutes). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03531554, which also lists 3 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 21 May 2018.

AzTrials uses cookies for analytics and advertising. You can accept or reject them; the site works either way. Privacy Policy.

Free account

Log in to keep searching

You’ve used your 3 free searches. AzTrials is free: log in or create a free account to keep searching clinical trials and save the ones you want to follow.

Create a free accountLog in