Glycogen Storage Disease IIIA Clinical Trial
Official title:
Acute Nutritional Ketosis and Exercise in Glycogen Storage Disease Type IIIa
| Verified date | April 2018 |
| Source | University Medical Center Groningen |
| Contact | n/a |
| Is FDA regulated | No |
| Health authority | |
| Study type | Interventional |
The investigators will study if acute nutritional ketosis in adult GSD IIIa patients can boost muscle mitochondrial function in vivo.
| Status | Completed |
| Enrollment | 6 |
| Est. completion date | March 23, 2018 |
| Est. primary completion date | March 23, 2018 |
| Accepts healthy volunteers | No |
| Gender | All |
| Age group | 18 Years to 65 Years |
| Eligibility |
Inclusion Criteria: - GSD III confirmed with enzyme assay and/or AGL mutation analysis and GSD IIIa further specified as deficient debranching enzyme activity in muscle or clinical and/or biochemical signs of cardiac and/or skeletal muscular involvement. Exclusion Criteria: - contraindications for MRI studies (assessed by standardised questionnaire) - inability to perform bicycle exercise. - intercurrent illness which may influence exercise tolerance (anemia, musculoskeletal injury, or other undiagnosed illness under investigation). - known coronary artery disease, positive history for angina or cardiomyopathy. - insulin-dependent diabetes mellitus. - loss of, or an inability to give informed consent. - pregnancy or current breastfeeding. - any other cause which in the opinion of the investigators, may affect the participant's ability to participate in the study |
| Country | Name | City | State |
|---|---|---|---|
| Netherlands | University of Groningen, UMC Groningen | Groningen |
| Lead Sponsor | Collaborator |
|---|---|
| University Medical Center Groningen | Stichting Metakids, Stichting Stofwisselkracht, University of Oxford, University of the Faroe Islands |
Netherlands,
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
Preisler N, Laforêt P, Madsen KL, Prahm KP, Hedermann G, Vissing CR, Galbo H, Vissing J. Skeletal muscle metabolism is impaired during exercise in glycogen storage disease type III. Neurology. 2015 Apr 28;84(17):1767-71. doi: 10.1212/WNL.0000000000001518. Epub 2015 Apr 1. — View Citation
Sentner CP, Hoogeveen IJ, Weinstein DA, Santer R, Murphy E, McKiernan PJ, Steuerwald U, Beauchamp NJ, Taybert J, Laforêt P, Petit FM, Hubert A, Labrune P, Smit GPA, Derks TGJ. Glycogen storage disease type III: diagnosis, genotype, management, clinical course and outcome. J Inherit Metab Dis. 2016 Sep;39(5):697-704. doi: 10.1007/s10545-016-9932-2. Epub 2016 Apr 22. — View Citation
Verbeek RJ, Sentner CP, Smit GP, Maurits NM, Derks TG, van der Hoeven JH, Sival DA. Muscle Ultrasound in Patients with Glycogen Storage Disease Types I and III. Ultrasound Med Biol. 2016 Jan;42(1):133-42. doi: 10.1016/j.ultrasmedbio.2015.08.013. Epub 2015 Oct 3. — View Citation
| Type | Measure | Description | Time frame | Safety issue |
|---|---|---|---|---|
| Primary | Description of in vivo energy and proton balance during exercise in MR scanner with and without ketone ester drink: steady-state intramuscular levels of glycogen, Pi, PCr and pH and kinetic rate constant of metabolic recovery. | 10 minutes; during in-magnet exercise test of session II and III. | ||
| Secondary | time of individual desired workload | #minutes | through completion of the maximum exercise test (of approximately 12 minutes) during study session I. | |
| Secondary | completion of supine bicycling bout at desired workload in scanner | (yes/no; if no, #minutes) | 10 min | |
| Secondary | Muscle ultrasound density of the biceps, quadriceps, calf (gastrocnemius and/or soleus) and tibialis anterior muscles. | Will be performed during study session I by a neurologist. | Together with the muscle force examination this assessment will take 1.5 hour. | |
| Secondary | Muscle force unilateral | Will be performed during study session I by a neurologist. | Together with the muscle ultrasound this assessment will take 1.5 hour. | |
| Secondary | Subjective fatigue and muscle ache score | scale 0-10 | after each exercise bout and 24 hours after exercise | |
| Secondary | International Physical Activity Questionnaire | This questionnaire will take 10 minutes to fill out. Participants will be asked to fill out the questionnaire one week before study session II and III | ||
| Secondary | Structural muscle parameters: fat infiltration. | During the in-magnet exercise test of 10 minutes during session II and III | ||
| Secondary | Change in blood glucose levels | #1 and #2 at baseline, #3 after 10 min, #4 after 15 minutes, #5 at the start of bicycle exercise test inside scanner, #6 after 10 minutes of in-magnet exercise and #7 three hours post-exercise inside scanner. | Up to 7 samples will be taken during the 25 minutes exercise test (session II and III). | |
| Secondary | Blood ketones level (ß-hydroxybutyrate, acetoacetate). | #1 and #2 at baseline, #3 after 10 min, #4 after 15 minutes, #5 at the start of bicycle exercise test inside scanner, #6 after 10 minutes of in-magnet exercise and #7 three hours post-exercise inside scanner. | Up to 7 samples will be taken during the 25 minutes exercise test (session II and III). | |
| Secondary | Change of blood pH | #1 and #2 at baseline, #3 after 10 min, #4 after 15 minutes, #5 at the start of bicycle exercise test inside scanner, #6 after 10 minutes of in-magnet exercise and #7 three hours post-exercise inside scanner. | Up to 7 samples will be taken during the 25 minutes exercise test (session II and III). | |
| Secondary | Blood levels of free fatty acids | #1 and #2 at baseline, #3 after 10 min, #4 after 15 minutes, #5 at the start of bicycle exercise test inside scanner, #6 after 10 minutes of in-magnet exercise and #7 three hours post-exercise inside scanner. | Up to 7 samples will be taken during the 25 minutes exercise test (session II and III). | |
| Secondary | Blood levels of insulin | #1 and #2 at baseline, #3 after 10 min, #4 after 15 minutes, #5 at the start of bicycle exercise test inside scanner, #6 after 10 minutes of in-magnet exercise and #7 three hours post-exercise inside scanner. | Up to 7 samples will be taken during the 25 minutes exercise test (session II and III). | |
| Secondary | Blood levels of creatine kinase | #1 and #2 at baseline, #3 after 10 min, #4 after 15 minutes, #5 at the start of bicycle exercise test inside scanner, #6 after 10 minutes of in-magnet exercise and #7 three hours post-exercise inside scanner. | Up to 7 samples will be taken during the 25 minutes exercise test (session II and III). | |
| Secondary | Blood levels of ammonia | #1 and #2 at baseline, #3 after 10 min, #4 after 15 minutes, #5 at the start of bicycle exercise test inside scanner, #6 after 10 minutes of in-magnet exercise and #7 three hours post-exercise inside scanner. | Up to 7 samples will be taken during the 25 minutes exercise test (session II and III). | |
| Secondary | Blood levels of NT-proBNP | #1 and #2 at baseline, #3 after 10 min, #4 after 15 minutes, #5 at the start of bicycle exercise test inside scanner, #6 after 10 minutes of in-magnet exercise and #7 three hours post-exercise inside scanner. | Up to 7 samples will be taken during the 25 minutes exercise test (session II and III). | |
| Secondary | Blood levels of lactate | #1 and #2 at baseline, #3 after 10 min, #4 after 15 minutes, #5 at the start of bicycle exercise test inside scanner, #6 after 10 minutes of in-magnet exercise and #7 three hours post-exercise inside scanner. | Up to 7 samples will be taken during the 25 minutes exercise test (session II and III). | |
| Secondary | Change of urine levels of myoglobin, ketones, tetraglucoside | Urine will be collected through study session II and III. A study session will take place from 8 am till 2 pm. | ||
| Secondary | optional: muscle metabolic profile (according to Cox et. al. 2016] of a muscle biopsy. | optional, on a patient-voluntary basis. If consent has been given a total of 4 muscle biopsies will be performed. | This procedure takes 30 minutes each time and will be performed prior to and immediately post-exercise during study session II and III. | |
| Secondary | optional: individual phenotypic muscle properties (fiber type, mitochondrial density, capillary density | optional, on a patient-voluntary basis. If consent has been given a total of 4 muscle biopsies will be performed. | This procedure takes 30 minutes each time and will be performed prior to and immediately post-exercise during study session II and III. | |
| Secondary | Individual physical performance during exercise; VO2 and VCO2 dynamics. | During session I; the maximum exercise test of approximately 12 minutes and during the exercise tests of 15 minutes outside the MR scanner at session II and III. |