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Acute Nutritional Ketosis in GSD IIIa

Primary Purpose

Glycogen Storage Disease IIIA

Status
Completed
Phase
Not Applicable
Locations
Netherlands
Study Type
Interventional
Intervention
physical exercise
Sponsored by
University Medical Center Groningen
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional other trial for Glycogen Storage Disease IIIA focused on measuring glycogen storage disease type IIIa, exercise, ketone esters, magnetic resonance spectroscopy

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • University of Groningen, UMC Groningen

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Ketone-ester drink

Carbohydrate drink

Arm Description

Oral intake - physical exercise

Oral intake - physical exercise

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

time of individual desired workload
#minutes
completion of supine bicycling bout at desired workload in scanner
(yes/no; if no, #minutes)
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.
Muscle force unilateral
Will be performed during study session I by a neurologist.
Subjective fatigue and muscle ache score
scale 0-10
International Physical Activity Questionnaire
Structural muscle parameters: fat infiltration.
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.
Blood ketones level (β-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.
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.
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.
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.
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.
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.
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.
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.
Change of urine levels of myoglobin, ketones, tetraglucoside
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.
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.
Individual physical performance during exercise; VO2 and VCO2 dynamics.

Full Information

First Posted
December 22, 2016
Last Updated
April 30, 2018
Sponsor
University Medical Center Groningen
Collaborators
University of the Faroe Islands, University of Oxford, Stichting Stofwisselkracht, Stichting Metakids
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1. Study Identification

Unique Protocol Identification Number
NCT03011203
Brief Title
Acute Nutritional Ketosis in GSD IIIa
Official Title
Acute Nutritional Ketosis and Exercise in Glycogen Storage Disease Type IIIa
Study Type
Interventional

2. Study Status

Record Verification Date
April 2018
Overall Recruitment Status
Completed
Study Start Date
February 10, 2017 (Actual)
Primary Completion Date
March 23, 2018 (Actual)
Study Completion Date
March 23, 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University Medical Center Groningen
Collaborators
University of the Faroe Islands, University of Oxford, Stichting Stofwisselkracht, Stichting Metakids

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The investigators will study if acute nutritional ketosis in adult GSD IIIa patients can boost muscle mitochondrial function in vivo.
Detailed Description
Glycogen Storage Disease type IIIa (GSD IIIa) is an inborn error of carbohydrate metabolism caused by impaired glycogen debranching enzyme (GDE) activity. The ageing GSD IIIa cohort shows that muscle involvement -despite dietary management- is a common disabling phenotype in adulthood. Currently, no specific therapy has been established for muscle problems in adult GSD IIIa patients. However, it could be hypothesized that nutritional ketosis (NK) will be highly beneficial to patients. Amongst others, ketone bodies could take on the role of primary energy source in exercising muscle. Recently, acute NK in exercise was studied in humans. NK was found to enhance muscle mitochondrial function in athletes. The investigators will study if acute NK in adult GSD IIIa patients can boost muscle mitochondrial function in vivo.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Glycogen Storage Disease IIIA
Keywords
glycogen storage disease type IIIa, exercise, ketone esters, magnetic resonance spectroscopy

7. Study Design

Primary Purpose
Other
Study Phase
Not Applicable
Interventional Study Model
Crossover Assignment
Masking
ParticipantOutcomes Assessor
Allocation
Randomized
Enrollment
6 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Ketone-ester drink
Arm Type
Experimental
Arm Description
Oral intake - physical exercise
Arm Title
Carbohydrate drink
Arm Type
Active Comparator
Arm Description
Oral intake - physical exercise
Intervention Type
Other
Intervention Name(s)
physical exercise
Intervention Description
In session II and III participants will perform an exercise test on a bicycle inside and outside the MR scanner.
Primary Outcome Measure Information:
Title
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.
Time Frame
10 minutes; during in-magnet exercise test of session II and III.
Secondary Outcome Measure Information:
Title
time of individual desired workload
Description
#minutes
Time Frame
through completion of the maximum exercise test (of approximately 12 minutes) during study session I.
Title
completion of supine bicycling bout at desired workload in scanner
Description
(yes/no; if no, #minutes)
Time Frame
10 min
Title
Muscle ultrasound density of the biceps, quadriceps, calf (gastrocnemius and/or soleus) and tibialis anterior muscles.
Description
Will be performed during study session I by a neurologist.
Time Frame
Together with the muscle force examination this assessment will take 1.5 hour.
Title
Muscle force unilateral
Description
Will be performed during study session I by a neurologist.
Time Frame
Together with the muscle ultrasound this assessment will take 1.5 hour.
Title
Subjective fatigue and muscle ache score
Description
scale 0-10
Time Frame
after each exercise bout and 24 hours after exercise
Title
International Physical Activity Questionnaire
Time Frame
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
Title
Structural muscle parameters: fat infiltration.
Time Frame
During the in-magnet exercise test of 10 minutes during session II and III
Title
Change in blood glucose levels
Description
#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.
Time Frame
Up to 7 samples will be taken during the 25 minutes exercise test (session II and III).
Title
Blood ketones level (β-hydroxybutyrate, acetoacetate).
Description
#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.
Time Frame
Up to 7 samples will be taken during the 25 minutes exercise test (session II and III).
Title
Change of blood pH
Description
#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.
Time Frame
Up to 7 samples will be taken during the 25 minutes exercise test (session II and III).
Title
Blood levels of free fatty acids
Description
#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.
Time Frame
Up to 7 samples will be taken during the 25 minutes exercise test (session II and III).
Title
Blood levels of insulin
Description
#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.
Time Frame
Up to 7 samples will be taken during the 25 minutes exercise test (session II and III).
Title
Blood levels of creatine kinase
Description
#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.
Time Frame
Up to 7 samples will be taken during the 25 minutes exercise test (session II and III).
Title
Blood levels of ammonia
Description
#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.
Time Frame
Up to 7 samples will be taken during the 25 minutes exercise test (session II and III).
Title
Blood levels of NT-proBNP
Description
#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.
Time Frame
Up to 7 samples will be taken during the 25 minutes exercise test (session II and III).
Title
Blood levels of lactate
Description
#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.
Time Frame
Up to 7 samples will be taken during the 25 minutes exercise test (session II and III).
Title
Change of urine levels of myoglobin, ketones, tetraglucoside
Time Frame
Urine will be collected through study session II and III. A study session will take place from 8 am till 2 pm.
Title
optional: muscle metabolic profile (according to Cox et. al. 2016] of a muscle biopsy.
Description
optional, on a patient-voluntary basis. If consent has been given a total of 4 muscle biopsies will be performed.
Time Frame
This procedure takes 30 minutes each time and will be performed prior to and immediately post-exercise during study session II and III.
Title
optional: individual phenotypic muscle properties (fiber type, mitochondrial density, capillary density
Description
optional, on a patient-voluntary basis. If consent has been given a total of 4 muscle biopsies will be performed.
Time Frame
This procedure takes 30 minutes each time and will be performed prior to and immediately post-exercise during study session II and III.
Title
Individual physical performance during exercise; VO2 and VCO2 dynamics.
Time Frame
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.

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
T.G.J. Derks, MD PhD
Organizational Affiliation
University Medical Center Groningen
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Groningen, UMC Groningen
City
Groningen
Country
Netherlands

12. IPD Sharing Statement

Plan to Share IPD
Undecided
Citations:
PubMed Identifier
27475046
Citation
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.
Results Reference
background
PubMed Identifier
26881790
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.
Results Reference
background
PubMed Identifier
27106217
Citation
Sentner CP, Hoogeveen IJ, Weinstein DA, Santer R, Murphy E, McKiernan PJ, Steuerwald U, Beauchamp NJ, Taybert J, Laforet 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.
Results Reference
background
PubMed Identifier
26437929
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.
Results Reference
background
PubMed Identifier
25832663
Citation
Preisler N, Laforet 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.
Results Reference
background
PubMed Identifier
33448466
Citation
Hoogeveen IJ, de Boer F, Boonstra WF, van der Schaaf CJ, Steuerwald U, Sibeijn-Kuiper AJ, Vegter RJK, van der Hoeven JH, Heiner-Fokkema MR, Clarke KC, Cox PJ, Derks TGJ, Jeneson JAL. Effects of acute nutritional ketosis during exercise in adults with glycogen storage disease type IIIa are phenotype-specific: An investigator-initiated, randomized, crossover study. J Inherit Metab Dis. 2021 Jan;44(1):226-239. doi: 10.1002/jimd.12302. Epub 2020 Sep 7.
Results Reference
derived

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Acute Nutritional Ketosis in GSD IIIa

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