Fat and Sugar Metabolism During Exercise in Patients With Metabolic Myopathy

Brief Title

Fat and Sugar Metabolism During Exercise in Patients With Metabolic Myopathy

Official Title

Fat and Sugar Metabolism During Exercise in Patients With Metabolic Myopathy

Brief Summary

      This study aims to characterize the pathophysiological mechanisms of 21 different metabolic
      myopathies. The study will focus on exercise capacity and the metabolic derangement during
      exercise.
    

Detailed Description

      Patients will be compared to a group of matched healthy control subjects (matched for age,
      gender, physical activity level and BMI) for comparison of the primary and secondary outcome
      measures.

      Methods:

      Each subject will go through 3 test days.

      Test day 1:

        -  International Physical Activity Questionnaire (IPAQ). The results will be used to match
           the patients to control subjects.

        -  DEXA-scan. This is used to estimate the volume of distribution for stable isotope
           tracers.

        -  Maximal oxidative capacity test (max-test). On a cycle ergometer, subjects will exercise
           for approximately 15 minutes with increasing resistance until exhaustion. The peak
           oxidative and workload capacities will be compared to the healthy controls and will be
           used to find the workload that corresponds to 55-65 % of VO2max used in the following
           exercise tests.

        -  Blood samples. Samples will be drawn before exercise and at exhaustion and will be
           analyzed for the plasma concentrations of glucose, lactate, ammonia, creatine kinase and
           myoglobin.

      Test day 2:

      •Long exercise test #1. The purpose of this test is to measure the total fat and sugar
      oxidation rates during exercise by using stable isotope tracers.

      Subjects arrive at the laboratory after 3-9 hours of fasting. One IV-catheter is inserted in
      the cubital vein in one arm and another in a peripheral vein in the other hand. The stable
      isotope tracers will be given in the cubital vein as a constant infusion of solutions of:

        -  [U-13C]-palmitate (0.0026 mg x kg-1 x min-1, after a priming bolus of 0.085 mg x kg-1
           NaH13CO3)

        -  [1,1,2,3,3-2H5]-glycerol (0.0049 mg x kg-1 x min-1 )

        -  [6.6-2H2]-glucose (0.0728 mg x kg-1 x min-1 ) For two hours the subjects rests while
           receiving the infusions until the tracers have distributed in the body and reached a
           steady state. After the rest, the subjects exercise on the cycle-ergometer until
           exhaustion or for a maximum of 1 hour at an intensity that corresponds to 55-65% of
           VO2max.

      The heart rate is continuously measured during exercise, and every other minute the subject
      evaluates his/her degree of exertion (Rate of Perceived Exertion, RPE) on a Borg scale.

      •Blood and breath samples From 20 minutes before exercise and every ten minutes until the end
      of exercise, blood samples are drawn and samples of the expired breath are collected.The
      breath is analysed for 13CO2 -enrichment. The blood is analysed for the plasma concentrations
      of glucose, lactate, ammonia, creatine kinase and myoglobin.

      Test day 3:

      •Long exercise test #2. The purpose of this test is to investigate exercise capacity and
      performance measured as HR, VO2 and RPE during prolonged exercise. To mimic the conditions
      for the working muscles in healthy persons who have an intact metabolism, the patients are
      given an infusion of a 10% glucose solution to maintain the blood sugar while exercising.

      Subjects arrive at the laboratory after 3-9 hours fasting. After 2 hours of rest, the
      subjects exercise on the cycle-ergometer until exhaustion or for a maximum of 1 hour at an
      intensity that corresponds to 60-65% of VO2max, like they did on test day 2. This time the
      subjects are not given stable isotope tracers. 10 minutes before exercising, the subjects are
      given a bolus of glucose solution 0.2 g/kg in a cubital vein catheter and a constant infusion
      of 10% glucose solution is started (100ml/h). The infusion continues throughout the exercise
      period.

      Assessments of heart rate, Rate of Perceived Exertion and blood sampling follow the same
      protocol as on test day 1, except no breath samples are taken and no analyses of stable
      isotopes are made, since the tracers are not used on test day 3.

        -  Blood samples. From 20 minutes before exercise and every ten minutes until the end of
           exercise, blood samples are drawn. The blood is analysed for the plasma concentrations
           of glucose, lactate, ammonia, creatine kinase and myoglobin.

        -  Muscle Biopsy At the end of test day 1 the investigators will perform a voluntary muscle
           biopsy.

      Statistical Methods:

      The investigators will use a paired t-test, two-tailed testing (or the corresponding
      non-parametric test, if the assumption of normality is not met). A p-value of < 0.05 will be
      considered significant. Results will be reported with Confidence Intervals of the difference
      in means. SigmaPlot version 11.0 (or a similar statistical program) will be used for
      statistical analysis.

      No interim analyses will be made during the 4 days trial period. In the case, that a patient
      withdraws/is withdrawn, the obtained data from the completed tests will be included in the
      analyses. Raw data that is clearly and indisputably a result of an error in measurement will
      not be included (evaluated by the investigator). Missing or lost data will if possible be
      reassessed.
    


Study Type

Interventional


Primary Outcome

Total fat oxidation (rate of disappearance) during prolonged moderate intensity exercise. Measured as micro mol per kg per minute.

Secondary Outcome

 Maximal oxidative capacity (mL*kg-1*minutes-1)

Condition

Metabolism, Inborn Errors

Intervention

Sugar

Study Arms / Comparison Groups

 Sugar
Description:  The subjects exercise on the cycle-ergometer until exhaustion or for a maximum of 1 hour at an intensity that corresponds to 60-65% of VO2max.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Other

Estimated Enrollment

60

Start Date

January 2016

Completion Date

December 2020

Primary Completion Date

August 2020

Eligibility Criteria

        Inclusion Criteria:

          -  Men and women with genetically and/or biochemically verified LCHAD Deficiency

          -  Healthy controls needs to be healthy to be included, evaluated by the investigator.

        Exclusion Criteria:

          -  Competing conditions at risk of compromising the results of the study.

          -  Pregnancy or breastfeeding

          -  Cardiac or pulmonary disease contraindicating peak exercise testing or strenuous
             exercise.

          -  Inability to understand the purpose of the trial or corporate for the conduction of
             the experiments.

          -  Veins that are too difficult to puncture for blood sampling or insertion of
             intravenous catheters, evaluated by the investigator

          -  Moderate to severe muscle weakness, that prevents the subject completing 10 minutes of
             cycle-ergometry exercise at 60-70 % of VO2peak, evaluated by the investigator.

          -  Participation in other trials that may interfere with the results.

          -  Intake of medications that may interfere with the results or may compromise exercise
             performance, as evaluated by the investigators.

          -  Donation of blood within 30 days prior to conduction of the tests on test day 1.
      

Gender

All

Ages

15 Years - 80 Years

Accepts Healthy Volunteers

Accepts Healthy Volunteers

Contacts

Karen L Madsen, MD, , 

Location Countries

Denmark

Location Countries

Denmark

Administrative Informations


NCT ID

NCT02635269

Organization ID

Metabolic Myopathy

Secondary IDs

H-15015150

Responsible Party

Principal Investigator

Study Sponsor

Rigshospitalet, Denmark


Study Sponsor

Karen L Madsen, MD, Principal Investigator, Neuromuscular Research Unit


Verification Date

October 2019