Carnitine Transporter, Plasma-membrane, Deficiency ofCTDNCT02226419
Fat and Sugar Metabolism During Exercise, With and Without L-carnitine in Patients With Carnitine Transporter Deficiency
A study testing Break in L-carnitine treatment in people with Carnitine Transporter, Plasma-membrane, Deficiency of, run by Karen Lindhardt Madsen.
Trial summary
The investigators wish to investigate fat and sugar metabolism during exercise with and without L-carnitine supplementation in patients with carnitine transporter deficiency (CTD). Patients with CTD have low plasma- and muscle concentrations of carnitine, which is believed to lead to an impaired fat oxidation. Read more about this study
- Who is it for?
- Ages 18 years and olderHealthy volunteers can take part
- Conditions the study is for
- Carnitine Transporter, Plasma-membrane, Deficiency of
- What is being tested?
- Break in L-carnitine treatment
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 14 participants
- Where
- No sites listed yet
- Study dates
- Aug 2013to Aug 2014
- 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 18 years and older
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- Verified diagnosis of CTD
Who cannot join
- Other conditions or diseases that may compromise the outcome of the study
- Pregnancy or lactation
- Inability to cooperate carrying out the experiments
About this study
Official title: Fat and Carbohydrate Metabolism During Exercise, With and Without L-carnitine Supplementation in Patients With Carnitine Transporter Deficiency
The investigators wish to investigate fat and sugar metabolism during exercise with and without L-carnitine supplementation in patients with carnitine transporter deficiency (CTD).
Patients with CTD have low plasma- and muscle concentrations of carnitine, which is believed to lead to an impaired fat oxidation. Presently there is no cure available for these patients, but daily intake of L-carnitine has been shown to limit the amount of symptoms. Little is known about the metabolism during exercise and the pathophysiological mechanisms causing the symptoms.
Read more
Studying the fat and sugar metabolism in CTD patients will contribute to the understanding of the role of the carnitine transporter in the development of symptoms in these patients. Furthermore, knowledge about the fat and sugar metabolism in these patients can increase the understanding of the role of the carnitine transporter in the metabolism healthy persons.
The investigators have included 8 patients with genetically verified CTD in the study and a group of 10 age- and sex-matched controls. Subjects will perform a 1h cycling test, exercising at a moderate intensity. By measuring the expiration of carbon dioxide (CO2) and consumption of oxygen (O2), the investigators can determine the total fatty acid and carbohydrate oxidation during cycling. At the same time the investigators will measure the patients' whole body palmitate (fat) and glucose (sugar) oxidation rates using stable isotope technique.
The patient group will repeat the cycling test after 4 days without taking their usual L-carnitine treatment. During the treatment break, patients will be admitted to be continuously monitored for heart rhythm disturbances, which is a known but rarely occurring complication to untreated CTD.
Since the patients have a defect in their fat metabolism, the investigators expect to find that they have a reduced ability to burn fat, which is the major source of energy during low intensity exercise. It is therefore likely, that the CTD patients will benefit from adjustments in their daily diet, whenever they have to perform physically. By learning about the metabolism of different dietary substances, fat and sugar, these studies can help to improve the treatment in terms of dietary recommendations for CTD patients. This will have a direct impact on the daily life of the patients.
Read the detailed description
8 Patients with verified CTD have been included
- All patients have performed an incremental load exercise test to exhaustion on a cycle ergometer to determine maximal oxygen comsumption rate (VO2 max)
- One-hour exercise test: Measurement of the total fat and sugar oxidation rates during exercise using stable isotope tracers.
Subjects arrive at the laboratory after 3-9 hours 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 ) 5 days before the study, subjects must avoid eating food containing corn. Corn contains larger amounts of C13, which we use as a tracer, and can therefore disturb the measurements.
For two hours the subjects rest 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 60-70% of VO2max.
Every other minute during exercise, the heart rate is recorded and 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 until the end of exercise, blood samples are drawn through the IV-catheter in the hand vein (10-12 mL per sample) and samples of the expired breath are collected in a Douglas bag (Hans Rudolph inc.) every ten minutes. The breath is transferred into Vaccutainer-glas for analysis of 13CO2 -enrichment (10 mL). The plasma samples are anayzed for concentrations of hormones, metabolites, carnitine and acyl-carnitines.
Muscle biopsy:
On this day a muscle biopsy is taken from the vastus lateralis of the thigh to measure the intramuscular concentrations of carnitine and acylcarnitines.
- Wash-out period: For 4 days patients were admitted for telemetric cardiac monitoring while they pause their daily oral L-carnitine treatment.
- After the washout period, patients repeat the one-hour exercise test with the stable isotope tracers. Also the muscle biopsy for intramuscular carnitine and acyl-carnitine concentrations are repeated-
TRACERS In this study we will use infusions of stable isotopes incorporated into metabolites as tracers of whole body metabolism. We will use small amounts of fat (palmitate and glycerol) and sugar (glucose) labelled with stable isotopes of carbon (13C) and hydrogen (2H). The palmitate and glycerol tracers (98 % enriched, Cambrigde Isotope Laboratories, Andover, MA, USA) will be dissolved in sterile water and infused through a bacterial filter into human serum albumin. The glucose tracer (99 % enriched, Cambrigde Isotope Laboratories, Andover, MA, USA) will be dissolved and injected into a solution of 0.9% saline (NaCl) through a bacterial filter as well.
These tracers are naturally occurring in food (e.g. in corn) and in the human body. They are harmless and will be handled and given to the subjects under sterile conditions.
- Being tested
- Break in L-carnitine treatment
- Keywords
- Fatty acid oxidation disorder, Primary carnitine deficiency, Exercise, L-carnitine treatment, Stable isotopes, Carnitine transporter deficiency
- Medical subject headings
- Systemic carnitine deficiency, Motor Activity
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Break in L-carnitine treatmentDietary supplement
Also called Levocarnitine
Levocarnitine oral tablet supplement at individual doses
| Study group | Role | What they receive |
|---|---|---|
| Break in L-carnitine treatment | Experimental | Patients do not take their L-carnitine (Levocarnitine) treatment for 2-4 days until plasma carnitine and acylcarnitine have fallen. While patients abstain from taking the treatment, they are admitted for cardiac telemetry monitoring. Receives: Dietary Supplement: Break in L-carnitine treatment |
What is being measured
The primary outcome is the main question the study is designed to answer.
The whole body palmitate and carbohydrate oxidation rate in CTD patients during exercise
The whole body palmitate and carbohydrate oxidation will be assessed during 1h exercise test performed on a cycle-ergometer using stable isotope technique combined with indirect calorimetry.
Measured: With and without L-carnitine treatment
Secondary outcomes (1)
The maximal oxidative capacity (VO2max) as an indicator of exercise tolerance and performance in CTD patients
Measured: During a 15 min incremental intensity exercise test and during a 1h moderate intensity cycling test
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted27 Aug 2014 (estimated)
- Study startAug 2013
- Primary completionAug 2014
- Study completionAug 2014
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Carnitine Transporter, Plasma-membrane, Deficiency ofStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
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
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 14 participants (actual)
Sponsor and investigators
- Lead sponsor
- Karen Lindhardt Madsen
- Sponsor type
- University, hospital or other
- Collaborators
- Copenhagen University Hospital, Rigshospitalet
- Responsible party
- Sponsor-investigator, Karen Lindhardt Madsen, Copenhagen University Hospital, Rigshospitalet
- Investigators
- Karen L Madsen, MD, Principal investigator, Neuromuscular Research Unit, Rigshospitalet
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02226419
- Sponsor's protocol ID
- H-1-2012-130
- Acronym
- CTD
- Status last verified
- May 2015
- First submitted
- 5 Aug 2013
- Last updated
- 5 May 2015
- Results posted
- No
- Data monitoring committee
- No
Publications
Madsen KL, Preisler N, Rasmussen J, Hedermann G, Olesen JH, Lund AM, Vissing J. L-Carnitine Improves Skeletal Muscle Fat Oxidation in Primary Carnitine Deficiency. J Clin Endocrinol Metab. 2018 Dec 1;103(12):4580-4588. doi: 10.1210/jc.2018-00953.
PubMed 30219858
Study at a glance
From the registry record, last updated by the sponsor on 5 May 2015. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Fat and Carbohydrate Metabolism During Exercise, With and Without L-carnitine Supplementation in Patients With Carnitine Transporter Deficiency
- ClinicalTrials.gov ID
- NCT02226419
- Acronym / sponsor ID
- CTD / H-1-2012-130
- Keywords
- Fatty acid oxidation disorder, Primary carnitine deficiency, Exercise, L-carnitine treatment, Stable isotopes, Carnitine transporter deficiency
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 14 participants (actual)
- Lead sponsor
- Karen Lindhardt MadsenUniversity, hospital or other
- Collaborators
- Copenhagen University Hospital, Rigshospitalet
- Study start
- Aug 2013
- Primary completion
- Aug 2014 (actual)
- Study completion
- Aug 2014 (actual)
- First posted
- 27 Aug 2014 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The investigators wish to investigate fat and sugar metabolism during exercise with and without L-carnitine supplementation in patients with carnitine transporter deficiency (CTD).
Patients with CTD have low plasma- and muscle concentrations of carnitine, which is believed to lead to an impaired fat oxidation. Presently there is no cure available for these patients, but daily intake of L-carnitine has been shown to limit the amount of symptoms. Little is known about the metabolism during exercise and the pathophysiological mechanisms causing the symptoms.
Studying the fat and sugar metabolism in CTD patients will contribute to the understanding of the role of the carnitine transporter in the development of symptoms in these patients. Furthermore, knowledge about the fat and sugar metabolism in these patients can increase the understanding of the role of the carnitine transporter in the metabolism healthy persons.
The investigators have included 8 patients with genetically verified CTD in the study and a group of 10 age- and sex-matched controls. Subjects will perform a 1h cycling test, exercising at a moderate intensity. By measuring the expiration of carbon dioxide (CO2) and consumption of oxygen (O2), the investigators can determine the total fatty acid and carbohydrate oxidation during cycling. At the same time the investigators will measure the patients' whole body palmitate (fat) and glucose (sugar) oxidation rates using stable isotope technique.
The patient group will repeat the cycling test after 4 days without taking their usual L-carnitine treatment. During the treatment break, patients will be admitted to be continuously monitored for heart rhythm disturbances, which is a known but rarely occurring complication to untreated CTD.
Since the patients have a defect in their fat metabolism, the investigators expect to find that they have a reduced ability to burn fat, which is the major source of energy during low intensity exercise. It is therefore likely, that the CTD patients will benefit from adjustments in their daily diet, whenever they have to perform physically. By learning about the metabolism of different dietary substances, fat and sugar, these studies can help to improve the treatment in terms of dietary recommendations for CTD patients. This will have a direct impact on the daily life of the patients.
Detailed description
8 Patients with verified CTD have been included
- All patients have performed an incremental load exercise test to exhaustion on a cycle ergometer to determine maximal oxygen comsumption rate (VO2 max)
- One-hour exercise test: Measurement of the total fat and sugar oxidation rates during exercise using stable isotope tracers.
Subjects arrive at the laboratory after 3-9 hours 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 ) 5 days before the study, subjects must avoid eating food containing corn. Corn contains larger amounts of C13, which we use as a tracer, and can therefore disturb the measurements.
For two hours the subjects rest 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 60-70% of VO2max.
Every other minute during exercise, the heart rate is recorded and 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 until the end of exercise, blood samples are drawn through the IV-catheter in the hand vein (10-12 mL per sample) and samples of the expired breath are collected in a Douglas bag (Hans Rudolph inc.) every ten minutes. The breath is transferred into Vaccutainer-glas for analysis of 13CO2 -enrichment (10 mL). The plasma samples are anayzed for concentrations of hormones, metabolites, carnitine and acyl-carnitines.
Muscle biopsy:
On this day a muscle biopsy is taken from the vastus lateralis of the thigh to measure the intramuscular concentrations of carnitine and acylcarnitines.
- Wash-out period: For 4 days patients were admitted for telemetric cardiac monitoring while they pause their daily oral L-carnitine treatment.
- After the washout period, patients repeat the one-hour exercise test with the stable isotope tracers. Also the muscle biopsy for intramuscular carnitine and acyl-carnitine concentrations are repeated-
TRACERS In this study we will use infusions of stable isotopes incorporated into metabolites as tracers of whole body metabolism. We will use small amounts of fat (palmitate and glycerol) and sugar (glucose) labelled with stable isotopes of carbon (13C) and hydrogen (2H). The palmitate and glycerol tracers (98 % enriched, Cambrigde Isotope Laboratories, Andover, MA, USA) will be dissolved in sterile water and infused through a bacterial filter into human serum albumin. The glucose tracer (99 % enriched, Cambrigde Isotope Laboratories, Andover, MA, USA) will be dissolved and injected into a solution of 0.9% saline (NaCl) through a bacterial filter as well.
These tracers are naturally occurring in food (e.g. in corn) and in the human body. They are harmless and will be handled and given to the subjects under sterile conditions.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Break in L-carnitine treatment | Experimental | Dietary Supplement: Break in L-carnitine treatmentPatients do not take their L-carnitine (Levocarnitine) treatment for 2-4 days until plasma carnitine and acylcarnitine have fallen. While patients abstain from taking the treatment, they are admitted for cardiac telemetry monitoring. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (1 listed)
- Verified diagnosis of CTD
Key exclusion criteria (3 listed)
- Other conditions or diseases that may compromise the outcome of the study
- Pregnancy or lactation
- Inability to cooperate carrying out the experiments
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Break in L-carnitine treatmentAlso: LevocarnitineLevocarnitine oral tablet supplement at individual doses | Dietary supplement | Break in L-carnitine treatment |
Primary outcome
The whole body palmitate and carbohydrate oxidation rate in CTD patients during exercise
Time frame: With and without L-carnitine treatment
The whole body palmitate and carbohydrate oxidation will be assessed during 1h exercise test performed on a cycle-ergometer using stable isotope technique combined with indirect calorimetry.
1 secondary outcome
The maximal oxidative capacity (VO2max) as an indicator of exercise tolerance and performance in CTD patients
Time frame: During a 15 min incremental intensity exercise test and during a 1h moderate intensity cycling test
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 5 May 2015.
- Derived from this study: PubMed 30219858Madsen KL, Preisler N, Rasmussen J, Hedermann G, Olesen JH, Lund AM, Vissing J. L-Carnitine Improves Skeletal Muscle Fat Oxidation in Primary Carnitine Deficiency. J Clin Endocrinol Metab. 2018 Dec 1;103(12):4580-4588. doi: 10.1210/jc.2018-00953.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Karen L Madsen, MD principal investigator
Neuromuscular Research Unit, Rigshospitalet
Questions about this trial
What is this clinical trial studying?
A study testing Break in L-carnitine treatment in people with Carnitine Transporter, Plasma-membrane, Deficiency of, run by Karen Lindhardt Madsen.
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 3 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 5 May 2015. Status can change between updates, so confirm with the study contact before making plans.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. 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?
The whole body palmitate and carbohydrate oxidation rate in CTD patients during exercise (time frame: With and without L-carnitine treatment). 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 NCT02226419, which also lists 1 linked publication.
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 5 May 2015.