Working…
COVID-19 is an emerging, rapidly evolving situation.
Get the latest public health information from CDC: https://www.coronavirus.gov.

Get the latest research information from NIH: https://www.nih.gov/coronavirus.
ClinicalTrials.gov
ClinicalTrials.gov Menu

Fasting Tolerance in MCADD-infants (FiTtINg MCADD)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03761693
Recruitment Status : Recruiting
First Posted : December 3, 2018
Last Update Posted : May 14, 2019
Sponsor:
Information provided by (Responsible Party):
Terry G.J. Derks, MD, PhD, University Medical Center Groningen

Brief Summary:

MCAD deficiency (MCADD; #OMIM 201450) is the most common inherited disorder of mitochondrial fatty acid oxidation. Already before the introduction of population newborn bloodspot screening (NBS), large phenotypic heterogeneity was observed between MCADD-patients, ranging between deceased patients and asymptomatic subjects. Most clinically ascertained patients were homozygous for the common c.985A>G ACADM mutation. After NBS, newborns with novel ACADM-genotypes have been identified and subjects can be classified as either severe/classical or mild/variant MCADD-patients.

Dietary management guidelines are based on expert opinion, limited experimental data summarized in one retrospective study on fasting tolerance in 35 MCADD patients. Interestingly, data are absent from fasting tolerance in MCADD patients between 0-6 months of age. These guidelines cause parental stress, especially for young patients. Moreover, the guidelines do not take into account the heterogeneity between patients, including the classification between severe versus mild MCADD-patients. The investigators question whether at least a subset of the MCADD-patients is overtreated with these guidelines.

Therefore, the investigators propose this pilot-study on fasting tolerance in 10 subjects with severe MCADD and 10 subjects with mild MCADD at the ages of two and six months. Differences between subsets of MCADD-patients will be studied longitudinally by both traditional metabolic parameters and unbiassed metabolomics, lipidomics and proteomics approach. This project will substantiate current management guidelines and aims to identify new (prognostic) biomarkers.


Condition or disease Intervention/treatment Phase
Mcad Deficiency Other: Fasting test Not Applicable

Show Show detailed description

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Diagnostic
Official Title: Fasting Tolerance in Patients With Medium-chain Acyl-CoA Dehydrogenase Deficiency (MCADD) in the First Six Months of Life: an Investigator-initiated Human Pilot-study
Estimated Study Start Date : May 15, 2019
Estimated Primary Completion Date : January 2024
Estimated Study Completion Date : January 2024


Arm Intervention/treatment
Experimental: Severe/classical MCADD

Severe MCADD will be defined by ACADM mutations associated with clinical ascertainment or residual MCAD enzyme activity < 10 %, as defined previously (Touw et al., 2012).

Interventions include fasting challenges at two and six months of age.

Other: Fasting test

The included infants will be fasted according to local standardized procedures at the University Medical Centre Groningen. Fasting will take place under hourly blood glucose monitoring and bedside supervision by an experienced, dedicated pediatric nurse, in collaboration with a metabolic pediatrician, who will be available to attend the patient instantly. Furthermore, on request of parent(s) or guardian(s), a continuous blood glucose monitoring device can be used during the study visits.

During study visit 1, at two months of life, fasting will be continued for maximally eight hours.

During study visit 2, at six months of life, fasting will be continued for maximally twelve hours.

Fasting will be ended prematurely in the following events:

  • blood glucose concentration drops < 3.6 mmol/L;
  • the child shows symptoms/signs of a low blood glucose concentration;
  • patients parent(s) or guardian(s) request end of fast.

Experimental: Mild MCADD

Mild MCADD will be defined by the remaining ACADM genotype variants and residual MCAD enzyme activity ≥ 10%.

Interventions include fasting challenges at two and six months of age.

Other: Fasting test

The included infants will be fasted according to local standardized procedures at the University Medical Centre Groningen. Fasting will take place under hourly blood glucose monitoring and bedside supervision by an experienced, dedicated pediatric nurse, in collaboration with a metabolic pediatrician, who will be available to attend the patient instantly. Furthermore, on request of parent(s) or guardian(s), a continuous blood glucose monitoring device can be used during the study visits.

During study visit 1, at two months of life, fasting will be continued for maximally eight hours.

During study visit 2, at six months of life, fasting will be continued for maximally twelve hours.

Fasting will be ended prematurely in the following events:

  • blood glucose concentration drops < 3.6 mmol/L;
  • the child shows symptoms/signs of a low blood glucose concentration;
  • patients parent(s) or guardian(s) request end of fast.




Primary Outcome Measures :
  1. Change in blood glucose concentrations [ Time Frame: Up to 8 samples will be taken during the maximally 8 hour fast (session 1), up to 12 samples will be taken during the maximally 12 hour fast (session 2). ]
    Sample #1 will be collected at baseline (8:00 AM) and hereafter hourly during the fast of session 1 and session 2.

  2. Change in plasma free fatty acid (FFA) concentrations [ Time Frame: Up to 8 samples will be taken during the maximally 8 hour fast (session 1), up to 12 samples will be taken during the maximally 12 hour fast (session 2). ]
    Sample #1 will be collected at baseline (8:00 AM) and here-after hourly during the fast of session 1 and session 2.

  3. Change in Heart rate [ Time Frame: Up to 8 frequencies will be noted during the maximally 8 hour fast (session 1), up to 12 frequencies will be noted during the maximally 12 hour fast (session 2) ]
    Heart rate per minute will be noted at baseline (8:00 AM) and here-after hourly during the fast of session 1 and session 2.

  4. Change in Respiratory rate [ Time Frame: Up to 8 frequencies will be noted during the maximally 8 hour fast (session 1), up to 12 frequencies will be noted during the maximally 12 hour fast (session 2). ]
    Respiratory rate per minute will be noted at baseline (8:00 AM) and here-after hourly during the fast of session 1 and session 2.

  5. (Change in) presence of lethargy [ Time Frame: Up to 8 physical examinations will be performed during the maximally 8 hour fast (session 1), up to 12 physical examinations will be performed during the maximally 12 hour fast (session 2). Physical examinations will take 5 minutes. ]

    Physical examination will be performed hourly by a nurse during the fast of session 1 and session 2.

    Yes/no; if yes, #hours, minutes.


  6. (Change in) presence of trembling [ Time Frame: Up to 8 physical examinations will be performed during the maximally 8 hour fast (session 1), up to 12 physical examinations will be performed during the maximally 12 hour fast (session 2). Physical examinations will take 5 minutes. ]

    Physical examination will be performed hourly by a nurse during the fast of session 1 and session 2.

    Yes/no; if yes, #hours, minutes.



Secondary Outcome Measures :
  1. Continuous glucose monitoring (CGM) data [ Time Frame: Blood glucose concentrations will be sensored every 5 minutes, during the maximally 8 hour fast (session 1). Blood glucose concentrations will be sensored every 5 minutes, during the 12 hour fast (session 2). ]
    Subcutaneous glucose concentrations will be obtained with a Dexcom G6 CGM sensor, if used.

  2. Blood pH [ Time Frame: 3 samples will be taken during the maximally 8 hour fast (session 1) and during the maximally 12 hour fast (session 2). ]
    Sample #1 will be collected at baseline (start fast, 8:00 AM), sample #2 will be collected 2 hours after the start of the fast (10:00 AM), sample #3 will be taken at the end of the fast after maximally 8 hours (16:00, session 1) or 12 hours (20:00, session 2), or earlier if necessary (#hours, minutes).

  3. Blood oxygen partial pressure [ Time Frame: 3 samples will be taken during the maximally 8 hour fast (session 1) and during the maximally 12 hour fast (session 2). ]
    Sample #1 will be collected at baseline (start fast, 8:00 AM), sample #2 will be collected 2 hours after the start of the fast (10:00 AM), sample #3 will be taken at the end of the fast after maximally 8 hours (16:00, session 1) or 12 hours (20:00, session 2), or earlier if necessary (#hours, minutes).

  4. Blood carbon dioxide partial pressure [ Time Frame: 3 samples will be taken during the maximally 8 hour fast (session 1) and during the maximally 12 hour fast (session 2). ]
    Sample #1 will be collected at baseline (start fast, 8:00 AM), sample #2 will be collected 2 hours after the start of the fast (10:00 AM), sample #3 will be taken at the end of the fast after maximally 8 hours (16:00, session 1) or 12 hours (20:00, session 2), or earlier if necessary (#hours, minutes).

  5. Plasma bicarbonate concentrations [ Time Frame: 3 samples will be taken during the maximally 8 hour fast (session 1) and during the maximally 12 hour fast (session 2). ]
    Sample #1 will be collected at baseline (start fast, 8:00 AM), sample #2 will be collected 2 hours after the start of the fast (10:00 AM), sample #3 will be taken at the end of the fast after maximally 8 hours (16:00, session 1) or 12 hours (20:00, session 2), or earlier if necessary (#hours, minutes).

  6. Base excess [ Time Frame: 3 samples will be taken during the maximally 8 hour fast (session 1) and during the maximally 12 hour fast (session 2). ]
    Sample #1 will be collected at baseline (start fast, 8:00 AM), sample #2 will be collected 2 hours after the start of the fast (10:00 AM), sample #3 will be taken at the end of the fast after maximally 8 hours (16:00, session 1) or 12 hours (20:00, session 2), or earlier if necessary (#hours, minutes).

  7. Blood oxygen saturation [ Time Frame: 3 samples will be taken during the maximally 8 hour fast (session 1) and during the 12 hour fast (session 2). ]
    Sample #1 will be collected at baseline (start fast, 8:00 AM), sample #2 will be collected 2 hours after the start of the fast (10:00 AM), sample #3 will be taken at the end of the fast after maximally 8 hours (16:00, session 1) or 12 hours (20:00, session 2), or earlier if necessary (#hours, minutes).

  8. Plasma ketones concentrations (β-hydroxybutyrate, acetoacetate) [ Time Frame: 3 samples will be taken during the maximally 8 hour fast (session 1) and during the maximally 12 hour fast (session 2). ]
    Sample #1 will be collected at baseline (start fast, 8:00 AM), sample #2 will be collected 2 hours after the start of the fast (10:00 AM), sample #3 will be taken at the end of the fast after maximally 8 hours (16:00, session 1) or 12 hours (20:00, session 2), or earlier if necessary (hours, minutes).

  9. Plasma acylcarnitines concentrations [ Time Frame: 3 samples will be taken during the maximally 8 hour fast (session 1) and during the maximally 12 hour fast (session 2). ]
    Sample #1 will be collected at baseline (start fast, 8:00 AM), sample #2 will be collected 2 hours after the start of the fast (10:00 AM), sample #3 will be taken at the end of the fast after maximally 8 hours (16:00, session 1) or 12 hours (20:00, session 2), or earlier if necessary (hours, minutes).

  10. Plasma amino acid concentrations [ Time Frame: 3 samples will be taken during the maximally 8 hour fast (session 1) and during the maximally 12 hour fast (session 2). ]
    Sample #1 will be collected at baseline (start fast, 8:00 AM), sample #2 will be collected 2 hours after the start of the fast (10:00 AM), sample #3 will be taken at the end of the fast after maximally 8 hours (16:00, session 1) or 12 hours (20:00, session 2), or earlier if necessary (#hours, minutes).

  11. Urine organic acids concentrations [ Time Frame: 2 samples will be collected during the maximally 8 hour fast (session 1) and during the maximally 12 hour fast (session 2). ]
    During session 1, sample #1 will be collected during the first 6 hours of the maximally 8 hours fast. Sample #2 will be collected during the last 2 hours of the maximally 8 hour fast. During session 2, sample #1 will be collected during the first 10 hours of the maximally 12 hour fast. Sample 2 will be collected during the last 2 hours of the maximally 12 hour fast.

  12. (Untargeted) Metabolomics [ Time Frame: 3 samples will be taken during the maximally 8 hour fast (session 1) and during the maximally 12 hour fast (session 2). ]
    Sample #1 will be collected at baseline (start fast, 8:00 AM), sample #2 will be collected 2 hours after the start of the fast (10:00 AM), sample #3 will be taken at the end of the fast after maximally 8 hours (16:00, session 1) or 12 hours (20:00, session 2), or earlier if necessary (#hours, minutes).

  13. Lipidomics [ Time Frame: 3 samples will be taken during the maximally 8 hour fast (session 1) and during the maximally 12 hour fast (session 2). ]
    Sample #1 will be collected at baseline (start fast, 8:00 AM), sample #2 will be collected 2 hours after the start of the fast (10:00 AM), sample #3 will be taken at the end of the fast after maximally 8 hours (16:00, session 1) or 12 hours (20:00, session 2), or earlier if necessary (#hours, minutes).

  14. Proteomics [ Time Frame: 3 samples will be taken during the maximally 8 hour fast (session 1) and during the 12 hour fast (session 2). ]
    Sample #1 will be collected at baseline (start fast, 8:00 AM), sample #2 will be collected 2 hours after the start of the fast (10:00 AM), sample #3 will be taken at the end of the fast after maximally 8 hours (16:00, session 1) or 12 hours (20:00, session 2), or earlier if necessary (#hours, minutes).



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   2 Months to 6 Months   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • A child must be at least younger than 6 months of life at inclusion. In case of prematurity, the child will be included and treated according to the adjusted age.
  • Established MCADD diagnosis. The diagnosis should be confirmed by a combination of (a) NBS outcome (b) MCAD enzyme activity measured with phenylpropionyl-CoA as a substrate, ideally in lymphocytes (considered to be the golden standard) and (c) ACADM gene mutation-analysis.

Exclusion Criteria:

  • Any other chronic and/or genetic condition that is deemed an exclusion criterion based on the judgement of the treating metabolic paediatrician.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03761693


Contacts
Layout table for location contacts
Contact: Terry Derks, MD, PhD +31-50-3614147 t.g.j.derks@umcg.nl
Contact: Emmalie Jager, Bsc +31-6-20066931 e.a.jager@umcg.nl

Locations
Layout table for location information
Netherlands
University Medical Center Groningen Recruiting
Groningen, Netherlands, 9700 RB
Contact: Terry G.J. Derks, MD/PhD    +31-50-3611036    t.g.j.derks@umcg.nl   
Sponsors and Collaborators
University Medical Center Groningen
Investigators
Layout table for investigator information
Principal Investigator: Terry Derks, MD, PhD Consultant pediatrician metabolic diseases
Publications:

Layout table for additonal information
Responsible Party: Terry G.J. Derks, MD, PhD, Principal Investigator, University Medical Center Groningen
ClinicalTrials.gov Identifier: NCT03761693    
Other Study ID Numbers: NL201800774
First Posted: December 3, 2018    Key Record Dates
Last Update Posted: May 14, 2019
Last Verified: May 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Terry G.J. Derks, MD, PhD, University Medical Center Groningen:
Mcad deficiency
Phenotypic Variation
Biomarkers
Diet Therapy