Mcad DeficiencyFiTtINg MCADDNCT03761693
Fasting Tolerance in MCADD-infants
A study testing Fasting test in people with Mcad Deficiency, run by University Medical Center Groningen at 1 site in Netherlands.
Trial 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… Read more about this study
- Who is it for?
- Ages 2 to 6 months
- Conditions the study is for
- Mcad Deficiency
- What is being tested?
- Fasting test
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 20 participants
- Where
- 1 siteNetherlands
- Study dates
- 15 May 2019to Jan 2024
- 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 2 to 6 months
- All sexes
- No healthy volunteers
- Child
Who may be able to join
- 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.
Who cannot join
- Any other chronic and/or genetic condition that is deemed an exclusion criterion based on the judgement of the treating metabolic paediatrician.
Trial locations and contacts
1 site in 1 country.
Netherlands1 site, 1 recruiting
- Recruiting
University Medical Center Groningen
Groningen, 9700 RB
Terry G.J. Derks, MD/PhD, +31-50-3611036, t.g.j.derks@umcg.nl
About this study
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
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.
Read the detailed description
Rationale: MCAD deficiency (MCADD; #OMIM 201450) is the most common inborn error 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 the introduction of the disorder to the NBS, newborns with novel ACADM-genotypes have been identified. Subjects can be classified as either severe/classical or mild/variant MCADD patients. Dietary management guidelines are based on expert opinion and limited experimental data summarized in one retrospective study on fasting tolerance in 35 MCADD-patients. Interestingly, data are absent from the fasting tolerance of MCADD patients between 0-6 months of age. These guidelines cause parental stress, especially regarding young patients (0-6 months). 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.
Objective: The main objective of the study is to explore the fasting tolerance in MCADD-patients of two and six months of life. Second, it is aimed to compare fasting tolerance and biochemical dynamics between subsets of MCADD patients. Third, it is aimed to identify novel diagnostic and/or prognostic biomarkers. The last objective is to elucidate the (fundamental) origin of phenotypical differences between MCADD patients.
Study design: Longitudinal, prospective investigator-initiated human pilot-study.
Study population: Otherwise healthy infants with severe MCADD and mild MCADD at the ages of two and six months of life.
Intervention: During two visits, the included infants will be fasted according to local standardized procedures at the University Medical Centre Groningen (UMCG). Fasting will take place under continuous 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. During visit 1, at two months of life, fasting will be continued for maximally eight hours. During visit 2, at six months of life, fasting will be continued for maximally twelve hours. Fasting will be ended prematurely if; (a) the blood glucose concentration drops < 3.6 mmol/L, (b) the fasting subject shows symptoms/signs of a low blood glucose concentration, and/or (c) subject's parent(s) or guardian(s) request the end of fast.
Main study parameters/endpoints: Dynamics of both traditional clinical and biochemical metabolic parameters and unbiased multi-omics (metabolomics, lipidomics, and proteomics) parameters will be studied.
Nature and extent of the burden and risks associated with participation, benefit and group relatedness: The trial is considered to be a low-risk study. The clinical research team at the UMCG has a longstanding tradition of performing supervised controlled clinical fasting test in patients with inborn errors of metabolism, for diagnostic as well as research purposes. No adverse effects are expected during fasting in otherwise healthy infants with MCADD. The study holds three moderate burdens for participants: insertion of the indwelling IV catheter, the discomfort of fasting for the subject and the parent(s) or guardian(s), and the time consumption. However, subjects and their parents(s) may directly benefit from the results of this study by reduction of stress concerning feeding, under normal, healthy circumstances and the (possible) institution of a personalized feeding regimen based on the study results by the treating pediatrician. As this project will substantiate current management guidelines and aims to identify new (prognostic) biomarkers, it may further improve the outcomes of future MCADD patients and their parent(s) or guardian(s), by reduction of (unnecessary) parental stress, treatment and follow-up.
- Conditions
- Mcad Deficiency
- Being tested
- Fasting test
- Keywords
- Mcad deficiency, Phenotypic Variation, Biomarkers, Diet Therapy
- Medical subject headings
- Medium chain acyl CoA dehydrogenase deficiency
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Fasting testOther
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.
| Study group | Role | What they receive |
|---|---|---|
| Severe/classical MCADD | Experimental | 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. Receives: Other: Fasting test |
| Mild MCADD | Experimental | 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. Receives: Other: Fasting test |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change in blood glucose concentrations
Sample #1 will be collected at baseline (8:00 AM) and hereafter hourly during the fast of session 1 and session 2.
Measured: 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).
Change in plasma free fatty acid (FFA) concentrations
Sample #1 will be collected at baseline (8:00 AM) and here-after hourly during the fast of session 1 and session 2.
Measured: 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).
Change in Heart rate
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.
Measured: 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)
Change in Respiratory rate
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.
Measured: 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).
(Change in) presence of lethargy
Physical examination will be performed hourly by a nurse during the fast of session 1 and session 2.
Yes/no; if yes, #hours, minutes.
Measured: 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.
(Change in) presence of trembling
Physical examination will be performed hourly by a nurse during the fast of session 1 and session 2.
Yes/no; if yes, #hours, minutes.
Measured: 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.
Secondary outcomes (14)
Continuous glucose monitoring (CGM) data
Subcutaneous glucose concentrations will be obtained with a Dexcom G6 CGM sensor, if used.
Measured: 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).
Blood pH
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).
Measured: 3 samples will be taken during the maximally 8 hour fast (session 1) and during the maximally 12 hour fast (session 2).
Blood oxygen partial pressure
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).
Measured: 3 samples will be taken during the maximally 8 hour fast (session 1) and during the maximally 12 hour fast (session 2).
Blood carbon dioxide partial pressure
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).
Measured: 3 samples will be taken during the maximally 8 hour fast (session 1) and during the maximally 12 hour fast (session 2).
Plasma bicarbonate concentrations
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).
Measured: 3 samples will be taken during the maximally 8 hour fast (session 1) and during the maximally 12 hour fast (session 2).
Base excess
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).
Measured: 3 samples will be taken during the maximally 8 hour fast (session 1) and during the maximally 12 hour fast (session 2).
Blood oxygen saturation
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).
Measured: 3 samples will be taken during the maximally 8 hour fast (session 1) and during the 12 hour fast (session 2).
Plasma ketones concentrations (β-hydroxybutyrate, acetoacetate)
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).
Measured: 3 samples will be taken during the maximally 8 hour fast (session 1) and during the maximally 12 hour fast (session 2).
Plasma acylcarnitines concentrations
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).
Measured: 3 samples will be taken during the maximally 8 hour fast (session 1) and during the maximally 12 hour fast (session 2).
Plasma amino acid concentrations
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).
Measured: 3 samples will be taken during the maximally 8 hour fast (session 1) and during the maximally 12 hour fast (session 2).
Urine organic acids concentrations
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.
Measured: 2 samples will be collected during the maximally 8 hour fast (session 1) and during the maximally 12 hour fast (session 2).
(Untargeted) Metabolomics
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).
Measured: 3 samples will be taken during the maximally 8 hour fast (session 1) and during the maximally 12 hour fast (session 2).
Lipidomics
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).
Measured: 3 samples will be taken during the maximally 8 hour fast (session 1) and during the maximally 12 hour fast (session 2).
Proteomics
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).
Measured: 3 samples will be taken during the maximally 8 hour fast (session 1) and during the 12 hour fast (session 2).
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted3 Dec 2018
- Study start15 May 2019 (estimated)
- Primary completionJan 2024 (estimated)
- Study completionJan 2024 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (15)Papers the sponsor has linked to this study.
- Other trials for Mcad DeficiencyStudies 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
- Diagnosis
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 20 participants (estimated)
Sponsor and investigators
- Lead sponsor
- University Medical Center Groningen
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Terry G.J. Derks, MD, PhD, University Medical Center Groningen
- Investigators
- Terry Derks, MD, PhD, Principal investigator, Consultant pediatrician metabolic diseases
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03761693
- Sponsor's protocol ID
- NL201800774
- Acronym
- FiTtINg MCADD
- Status last verified
- May 2019
- First submitted
- 21 Nov 2018
- Last updated
- 14 May 2019
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Derks TG, van Spronsen FJ, Rake JP, van der Hilst CS, Span MM, Smit GP. Safe and unsafe duration of fasting for children with MCAD deficiency. Eur J Pediatr. 2007 Jan;166(1):5-11. doi: 10.1007/s00431-006-0186-0. Epub 2006 Jun 21.
PubMed 16788829Touw CM, Smit GP, de Vries M, de Klerk JB, Bosch AM, Visser G, Mulder MF, Rubio-Gozalbo ME, Elvers B, Niezen-Koning KE, Wanders RJ, Waterham HR, Reijngoud DJ, Derks TG. Risk stratification by residual enzyme activity after newborn screening for medium-chain acyl-CoA dehyrogenase deficiency: data from a cohort study. Orphanet J Rare Dis. 2012 May 25;7:30. doi: 10.1186/1750-1172-7-30.
PubMed 22630369Fletcher JM, Pitt JJ. Fasting medium chain acyl-coenzyme A dehydrogenase--deficient children can make ketones. Metabolism. 2001 Feb;50(2):161-5. doi: 10.1053/meta.2001.20177.
PubMed 11229423Heales SJ, Thompson GN, Massoud AF, Rahman S, Halliday D, Leonard JV. Production and disposal of medium-chain fatty acids in children with medium-chain acyl-CoA dehydrogenase deficiency. J Inherit Metab Dis. 1994;17(1):74-80. doi: 10.1007/BF00735398.
PubMed 8051939Jakobs C, Kneer J, Martin D, Boulloche J, Brivet M, Poll-The BT, Saudubray JM. In vivo stable isotope studies in three patients affected with mitochondrial fatty acid oxidation disorders: limited diagnostic use of 1-13C fatty acid breath test using bolus technique. Eur J Pediatr. 1997 Aug;156 Suppl 1:S78-82.
PubMed 9266222Walter JH. Tolerance to fast: rational and practical evaluation in children with hypoketonaemia. J Inherit Metab Dis. 2009 Apr;32(2):214-7. doi: 10.1007/s10545-009-1087-y. Epub 2009 Mar 4.
PubMed 19255872Bonnefont JP, Specola NB, Vassault A, Lombes A, Ogier H, de Klerk JB, Munnich A, Coude M, Paturneau-Jouas M, Saudubray JM. The fasting test in paediatrics: application to the diagnosis of pathological hypo- and hyperketotic states. Eur J Pediatr. 1990 Dec;150(2):80-5. doi: 10.1007/BF02072043.
PubMed 2279514Derks TG, Duran M, Waterham HR, Reijngoud DJ, Ten Kate LP, Smit GP. The difference between observed and expected prevalence of MCAD deficiency in The Netherlands: a genetic epidemiological study. Eur J Hum Genet. 2005 Aug;13(8):947-52. doi: 10.1038/sj.ejhg.5201428.
PubMed 15870827Derks TG, Reijngoud DJ, Waterham HR, Gerver WJ, van den Berg MP, Sauer PJ, Smit GP. The natural history of medium-chain acyl CoA dehydrogenase deficiency in the Netherlands: clinical presentation and outcome. J Pediatr. 2006 May;148(5):665-670. doi: 10.1016/j.jpeds.2005.12.028.
PubMed 16737882Derks TG, Boer TS, van Assen A, Bos T, Ruiter J, Waterham HR, Niezen-Koning KE, Wanders RJ, Rondeel JM, Loeber JG, Ten Kate LP, Smit GP, Reijngoud DJ. Neonatal screening for medium-chain acyl-CoA dehydrogenase (MCAD) deficiency in The Netherlands: the importance of enzyme analysis to ascertain true MCAD deficiency. J Inherit Metab Dis. 2008 Feb;31(1):88-96. doi: 10.1007/s10545-007-0492-3. Epub 2008 Jan 14.
PubMed 18188679Lamers KJ, Doesburg WH, Gabreels FJ, Lemmens WA, Romsom AC, Wevers RA, Renier WO. The concentration of blood components related to fuel metabolism during prolonged fasting in children. Clin Chim Acta. 1985 Oct 31;152(1-2):155-63. doi: 10.1016/0009-8981(85)90186-x.
PubMed 4053396Chang IJ, Lam C, Vockley J. Medium-Chain Acyl-Coenzyme A Dehydrogenase Deficiency. 2000 Apr 20 [updated 2024 Sep 26]. In: Adam MP, Bick S, Mirzaa GM, Wallace SE, Amemiya A, editors. GeneReviews(R) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. Available from http://www.ncbi.nlm.nih.gov/books/NBK1424/
PubMed 20301597Touw CM, Smit GP, Niezen-Koning KE, Bosgraaf-de Boer C, Gerding A, Reijngoud DJ, Derks TG. In vitro and in vivo consequences of variant medium-chain acyl-CoA dehydrogenase genotypes. Orphanet J Rare Dis. 2013 Mar 20;8:43. doi: 10.1186/1750-1172-8-43.
PubMed 23509891van der Hilst CS, Derks TG, Reijngoud DJ, Smit GP, TenVergert EM. Cost-effectiveness of neonatal screening for medium chain acyl-CoA dehydrogenase deficiency: the homogeneous population of The Netherlands. J Pediatr. 2007 Aug;151(2):115-20, 120.e1-3. doi: 10.1016/j.jpeds.2007.03.013.
PubMed 17643759van Veen MR, van Hasselt PM, de Sain-van der Velden MG, Verhoeven N, Hofstede FC, de Koning TJ, Visser G. Metabolic profiles in children during fasting. Pediatrics. 2011 Apr;127(4):e1021-7. doi: 10.1542/peds.2010-1706. Epub 2011 Mar 21.
PubMed 21422093
Study at a glance
From the registry record, last updated by the sponsor on 14 May 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT03761693
- Acronym / sponsor ID
- FiTtINg MCADD / NL201800774
- Conditions
- Mcad Deficiency
- Keywords
- Mcad deficiency, Phenotypic Variation, Biomarkers, Diet Therapy
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 20 participants (estimated)
- Lead sponsor
- University Medical Center GroningenUniversity, hospital or other
- Study start
- 15 May 2019 (estimated)
- Primary completion
- Jan 2024 (estimated)
- Study completion
- Jan 2024 (estimated)
- First posted
- 3 Dec 2018 (actual)
- 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.
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.
Detailed description
Rationale: MCAD deficiency (MCADD; #OMIM 201450) is the most common inborn error 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 the introduction of the disorder to the NBS, newborns with novel ACADM-genotypes have been identified. Subjects can be classified as either severe/classical or mild/variant MCADD patients. Dietary management guidelines are based on expert opinion and limited experimental data summarized in one retrospective study on fasting tolerance in 35 MCADD-patients. Interestingly, data are absent from the fasting tolerance of MCADD patients between 0-6 months of age. These guidelines cause parental stress, especially regarding young patients (0-6 months). 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.
Objective: The main objective of the study is to explore the fasting tolerance in MCADD-patients of two and six months of life. Second, it is aimed to compare fasting tolerance and biochemical dynamics between subsets of MCADD patients. Third, it is aimed to identify novel diagnostic and/or prognostic biomarkers. The last objective is to elucidate the (fundamental) origin of phenotypical differences between MCADD patients.
Study design: Longitudinal, prospective investigator-initiated human pilot-study.
Study population: Otherwise healthy infants with severe MCADD and mild MCADD at the ages of two and six months of life.
Intervention: During two visits, the included infants will be fasted according to local standardized procedures at the University Medical Centre Groningen (UMCG). Fasting will take place under continuous 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. During visit 1, at two months of life, fasting will be continued for maximally eight hours. During visit 2, at six months of life, fasting will be continued for maximally twelve hours. Fasting will be ended prematurely if; (a) the blood glucose concentration drops < 3.6 mmol/L, (b) the fasting subject shows symptoms/signs of a low blood glucose concentration, and/or (c) subject's parent(s) or guardian(s) request the end of fast.
Main study parameters/endpoints: Dynamics of both traditional clinical and biochemical metabolic parameters and unbiased multi-omics (metabolomics, lipidomics, and proteomics) parameters will be studied.
Nature and extent of the burden and risks associated with participation, benefit and group relatedness: The trial is considered to be a low-risk study. The clinical research team at the UMCG has a longstanding tradition of performing supervised controlled clinical fasting test in patients with inborn errors of metabolism, for diagnostic as well as research purposes. No adverse effects are expected during fasting in otherwise healthy infants with MCADD. The study holds three moderate burdens for participants: insertion of the indwelling IV catheter, the discomfort of fasting for the subject and the parent(s) or guardian(s), and the time consumption. However, subjects and their parents(s) may directly benefit from the results of this study by reduction of stress concerning feeding, under normal, healthy circumstances and the (possible) institution of a personalized feeding regimen based on the study results by the treating pediatrician. As this project will substantiate current management guidelines and aims to identify new (prognostic) biomarkers, it may further improve the outcomes of future MCADD patients and their parent(s) or guardian(s), by reduction of (unnecessary) parental stress, treatment and follow-up.
Study design
- Primary purpose
- Diagnosis
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Severe/classical MCADD | Experimental | Other: Fasting testSevere 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. |
| Mild MCADD | Experimental | Other: Fasting testMild 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. |
Who may qualify
- Ages
- 2 to 6 months
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child
Key inclusion criteria (2 listed)
- 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.
Key exclusion criteria (1 listed)
- Any other chronic and/or genetic condition that is deemed an exclusion criterion based on the judgement of the treating metabolic paediatrician.
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 |
|---|---|---|
| Fasting testThe 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. | Other | Mild MCADD, Severe/classical MCADD |
Primary outcome
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.
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.
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.
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.
(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.
(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.
14 secondary outcomes
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
(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).
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).
Proteomics
Time frame: 3 samples will be taken during the maximally 8 hour fast (session 1) and during the 12 hour fast (session 2).
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 14 May 2019.
- Background: PubMed 16788829Derks TG, van Spronsen FJ, Rake JP, van der Hilst CS, Span MM, Smit GP. Safe and unsafe duration of fasting for children with MCAD deficiency. Eur J Pediatr. 2007 Jan;166(1):5-11. doi: 10.1007/s00431-006-0186-0. Epub 2006 Jun 21.
- Background: PubMed 22630369Touw CM, Smit GP, de Vries M, de Klerk JB, Bosch AM, Visser G, Mulder MF, Rubio-Gozalbo ME, Elvers B, Niezen-Koning KE, Wanders RJ, Waterham HR, Reijngoud DJ, Derks TG. Risk stratification by residual enzyme activity after newborn screening for medium-chain acyl-CoA dehyrogenase deficiency: data from a cohort study. Orphanet J Rare Dis. 2012 May 25;7:30. doi: 10.1186/1750-1172-7-30.
- Background: PubMed 11229423Fletcher JM, Pitt JJ. Fasting medium chain acyl-coenzyme A dehydrogenase--deficient children can make ketones. Metabolism. 2001 Feb;50(2):161-5. doi: 10.1053/meta.2001.20177.
- Background: PubMed 8051939Heales SJ, Thompson GN, Massoud AF, Rahman S, Halliday D, Leonard JV. Production and disposal of medium-chain fatty acids in children with medium-chain acyl-CoA dehydrogenase deficiency. J Inherit Metab Dis. 1994;17(1):74-80. doi: 10.1007/BF00735398.
- Background: PubMed 9266222Jakobs C, Kneer J, Martin D, Boulloche J, Brivet M, Poll-The BT, Saudubray JM. In vivo stable isotope studies in three patients affected with mitochondrial fatty acid oxidation disorders: limited diagnostic use of 1-13C fatty acid breath test using bolus technique. Eur J Pediatr. 1997 Aug;156 Suppl 1:S78-82.
- Background: PubMed 19255872Walter JH. Tolerance to fast: rational and practical evaluation in children with hypoketonaemia. J Inherit Metab Dis. 2009 Apr;32(2):214-7. doi: 10.1007/s10545-009-1087-y. Epub 2009 Mar 4.
- Background: PubMed 2279514Bonnefont JP, Specola NB, Vassault A, Lombes A, Ogier H, de Klerk JB, Munnich A, Coude M, Paturneau-Jouas M, Saudubray JM. The fasting test in paediatrics: application to the diagnosis of pathological hypo- and hyperketotic states. Eur J Pediatr. 1990 Dec;150(2):80-5. doi: 10.1007/BF02072043.
- Background: PubMed 15870827Derks TG, Duran M, Waterham HR, Reijngoud DJ, Ten Kate LP, Smit GP. The difference between observed and expected prevalence of MCAD deficiency in The Netherlands: a genetic epidemiological study. Eur J Hum Genet. 2005 Aug;13(8):947-52. doi: 10.1038/sj.ejhg.5201428.
- Background: PubMed 16737882Derks TG, Reijngoud DJ, Waterham HR, Gerver WJ, van den Berg MP, Sauer PJ, Smit GP. The natural history of medium-chain acyl CoA dehydrogenase deficiency in the Netherlands: clinical presentation and outcome. J Pediatr. 2006 May;148(5):665-670. doi: 10.1016/j.jpeds.2005.12.028.
- Background: PubMed 18188679Derks TG, Boer TS, van Assen A, Bos T, Ruiter J, Waterham HR, Niezen-Koning KE, Wanders RJ, Rondeel JM, Loeber JG, Ten Kate LP, Smit GP, Reijngoud DJ. Neonatal screening for medium-chain acyl-CoA dehydrogenase (MCAD) deficiency in The Netherlands: the importance of enzyme analysis to ascertain true MCAD deficiency. J Inherit Metab Dis. 2008 Feb;31(1):88-96. doi: 10.1007/s10545-007-0492-3. Epub 2008 Jan 14.
- Background: PubMed 4053396Lamers KJ, Doesburg WH, Gabreels FJ, Lemmens WA, Romsom AC, Wevers RA, Renier WO. The concentration of blood components related to fuel metabolism during prolonged fasting in children. Clin Chim Acta. 1985 Oct 31;152(1-2):155-63. doi: 10.1016/0009-8981(85)90186-x.
- Background: PubMed 20301597Chang IJ, Lam C, Vockley J. Medium-Chain Acyl-Coenzyme A Dehydrogenase Deficiency. 2000 Apr 20 [updated 2024 Sep 26]. In: Adam MP, Bick S, Mirzaa GM, Wallace SE, Amemiya A, editors. GeneReviews(R) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. Available from http://www.ncbi.nlm.nih.gov/books/NBK1424/
- Individual participant dataSharing planned: No
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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.
Terry Derks, MD, PhD principal investigator
Consultant pediatrician metabolic diseases
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Fasting test in people with Mcad Deficiency, run by University Medical Center Groningen at 1 site in Netherlands.
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 2 inclusion and 1 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: status not confirmed, as of the sponsor's last update on 14 May 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.
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?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Terry Derks, MD, PhD (+31-50-3614147, t.g.j.derks@umcg.nl), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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).). The study lists 6 primary outcomes in all. 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 NCT03761693, which also lists 15 linked publications.
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 14 May 2019.