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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT04513002




Registration number
NCT04513002
Ethics application status
Date submitted
26/07/2020
Date registered
14/08/2020
Date last updated
20/07/2023

Titles & IDs
Public title
Ataxia-telangiectasia: Treating Mitochondrial Dysfunction With a Novel Form of Anaplerosis
Scientific title
A Phase 2A/2B Placebo-controlled Randomised Clinical Trial to Test the Ability of Triheptanoin to Protect Primary Airway Epithelial Cells Obtained From Participants With Ataxia-telangiectasia Against Death Induced by Glucose Deprivation
Secondary ID [1] 0 0
A-T2020/01
Universal Trial Number (UTN)
Trial acronym
A-TC7
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Ataxia Telangiectasia 0 0
Condition category
Condition code
Neurological 0 0 0 0
Other neurological disorders
Neurological 0 0 0 0
Neurodegenerative diseases
Human Genetics and Inherited Disorders 0 0 0 0
Other human genetics and inherited disorders
Cardiovascular 0 0 0 0
Diseases of the vasculature and circulation including the lymphatic system

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Other - Triheptanoin

Other: Group 1: Triheptanoin and no Placebo - Parallel group, placebo-controlled, dose-escalation each 2 months for 12 months. Dose based on percent (%) of calculated caloric intake.

Thirty participants will be randomised in blocks on a 1:1:1 ratio into one of three groups.

Group 1: 10%, 20%, 35%, 35%, 35% (no placebo). Group 2: placebo, 10%, 20%, 35%, 35% Group 3: placebo, placebo, 10%, 20%, 35%

Other: Group 2: Placebo and Triheptanoin - Parallel group, placebo-controlled, dose-escalation each 2 months for 12 months. Dose based on percent (%) of calculated caloric intake.

Thirty participants will be randomised in blocks on a 1:1:1 ratio into one of three groups.

Group 1: 10%, 20%, 35%, 35%, 35% (no placebo). Group 2: placebo, 10%, 20%, 35%, 35% Group 3: placebo, placebo, 10%, 20%, 35%

Other: Group 3: Placebo, Placebo and Triheptanoin - Parallel group, placebo-controlled, dose-escalation each 2 months for 12 months. Dose based on percent (%) of calculated caloric intake.

Thirty participants will be randomised in blocks on a 1:1:1 ratio into one of three groups.

Group 1: 10%, 20%, 35%, 35%, 35% (no placebo). Group 2: placebo, 10%, 20%, 35%, 35% Group 3: placebo, placebo, 10%, 20%, 35%


Treatment: Other: Triheptanoin
Triheptanoin is a highly purified, synthetic medium odd-chain triglyceride that is catabolized to heptanoate.
Intervention code [1] 0 0
Treatment: Other
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Nasal epithelial cell survival under conditions of glucose deprivation.
Timepoint [1] 0 0
Day 1, baseline measurement
Primary outcome [2] 0 0
Nasal epithelial cell survival under conditions of glucose deprivation.
Timepoint [2] 0 0
Day 60, assessment of effects/changes from Day 1 baseline measurement
Primary outcome [3] 0 0
Nasal epithelial cell survival under conditions of glucose deprivation.
Timepoint [3] 0 0
Day 120, assessment of effects/changes from Day 60 baseline measurement
Primary outcome [4] 0 0
Nasal epithelial cell survival under conditions of glucose deprivation.
Timepoint [4] 0 0
Day 180, assessment of effects/changes from Day 120 baseline measurement
Primary outcome [5] 0 0
Nasal epithelial cell survival under conditions of glucose deprivation.
Timepoint [5] 0 0
Day 240, assessment of effects/changes from Day 180 baseline measurement
Primary outcome [6] 0 0
Nasal epithelial cell survival under conditions of glucose deprivation.
Timepoint [6] 0 0
Day 300, assessment of effects/changes from Day 240 baseline measurement
Primary outcome [7] 0 0
Nasal epithelial cell survival under conditions of glucose deprivation.
Timepoint [7] 0 0
Day 360, assessment of effects/changes from Day 300 baseline measurement
Secondary outcome [1] 0 0
Scales for assessment and rating of ataxia
Timepoint [1] 0 0
Day 1, Day 120, Day 240, Day 360
Secondary outcome [2] 0 0
International Cooperative Ataxia Rating Scale
Timepoint [2] 0 0
Day 1, Day 120, Day 240, Day 360
Secondary outcome [3] 0 0
Speech Pathology Assessments
Timepoint [3] 0 0
Day 1, Day 120, Day 240, Day 360
Secondary outcome [4] 0 0
Ophthalmology assessments
Timepoint [4] 0 0
Day 1, Day 120, Day 240, Day 360
Secondary outcome [5] 0 0
MRI lung imaging
Timepoint [5] 0 0
Performed at Day 1 and Day 360 in suitable participants
Secondary outcome [6] 0 0
Spirometry Vital capacity (litres)
Timepoint [6] 0 0
Day 1, Day 120, Day 240, Day 360
Secondary outcome [7] 0 0
Spirometry Forced vital capacity (litres)
Timepoint [7] 0 0
Day 1, Day 120, Day 240, Day 360
Secondary outcome [8] 0 0
Spirometry Forced expiratory volume in one second (litres)
Timepoint [8] 0 0
Day 1, Day 120, Day 240, Day 360
Secondary outcome [9] 0 0
Spirometry Peak expiratory flow (L.min-1)
Timepoint [9] 0 0
Day 1, Day 120, Day 240, Day 360
Secondary outcome [10] 0 0
Upper respiratory microbiome
Timepoint [10] 0 0
Day 1, Day 60, Day 120, Day 180, Day 240, Day 300, Day 360
Secondary outcome [11] 0 0
Faecal microbiome
Timepoint [11] 0 0
Day 1, Day 60, Day 120, Day 180, Day 240, Day 300, Day 360
Secondary outcome [12] 0 0
Intestinal permeability
Timepoint [12] 0 0
Day 1, Day 60, Day 120, Day 180, Day 240, Day 300, Day 360

Eligibility
Key inclusion criteria
* Patients of either sex, of any age, with a confirmed diagnosis of A-T,
* Patients who are able to undertake the study procedures,
* Families who are able to comply with the protocol for its duration and who provide informed patient assent and consent signed and dated by parent/legal guardian or adult participant according to local regulations.
Minimum age
No limit
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
* Patients whose parents/legal guardians are not able to provide consent
* Patients who have been in another randomised clinical intervention trial where the use of investigational medicinal product within 3 months or 5 half-lives, whichever is longer, before study enrolment
* Taking off label mediations or nutritional supplements that the PI consider would impact participant's safe participation.
* Patients who are pregnant and/or lactating, planning a pregnancy during the study. Contraception must be used for sexually active male and female participants
* Intestinal Malabsorption secondary to Pancreatic Insufficiency
* Liver enzymes (alanine aminotransferase [ALT]/aspartate aminotransferase [AST]) or total bilirubin > 2 x the upper limit of normal at the time of screening.
* Renal insufficiency as defined by estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73m2 at the screening visit.
* Any comorbid medical condition that in the assessment of the PI that would impact participant's safe participation (e.g. active cancer requiring treatment)
* Evidence of dysphagia that places subject at risk of aspiration if orally fed.

Study design
Purpose of the study
Other
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
15/03/2022
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
10/07/2023
Sample size
Target
Accrual to date
Final
30
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment hospital [1] 0 0
Queensland Children's Hospital - Brisbane
Recruitment postcode(s) [1] 0 0
4001 - Brisbane

Funding & Sponsors
Primary sponsor type
Other
Name
The University of Queensland
Address
Country
Other collaborator category [1] 0 0
Other
Name [1] 0 0
National Health and Medical Research Council, Australia
Address [1] 0 0
Country [1] 0 0

Ethics approval
Ethics application status

Summary
Brief summary
Study design: Parallel group, placebo-controlled, dose-escalation each 2 months for 12 months. Dose based on percent (%) of calculated caloric intake. Thirty participants will be randomised in blocks on a 1:1:1 ratio into one of three groups stratified by age (\< 5 years, 5-10 years, \> 10 years of age). Group 1: 10%, 20%, 35%, 35%, 35% (no placebo). Group 2: placebo, 10%, 20%, 35%, 35% Group 3: placebo, placebo, 10%, 20%, 35%.

Primary endpoint: The percent cell death induced by glucose deprivation in cell culture. Secondary endpoints include: Scales for assessment and rating of ataxia, International Cooperative Ataxia Rating Scale, Ataxia Telangiectasia Neurological Examination Scale Toolkit, speech and language assessment, EyeSeeCam assessment, MRI lung imaging, Lung function, Upper respiratory microbiome, Faecal microbiome, Survival and inflammatory phenotype of airway epithelial cells, macrophages and in serum, Metabolomic biomarker discovery in serum and measurement of neuroflament light chain.
Trial website
https://clinicaltrials.gov/study/NCT04513002
Trial related presentations / publications
Guo Z, Kozlov S, Lavin MF, Person MD, Paull TT. ATM activation by oxidative stress. Science. 2010 Oct 22;330(6003):517-21. doi: 10.1126/science.1192912.
Zannolli R, Buoni S, Betti G, Salvucci S, Plebani A, Soresina A, Pietrogrande MC, Martino S, Leuzzi V, Finocchi A, Micheli R, Rossi LN, Brusco A, Misiani F, Fois A, Hayek J, Kelly C, Chessa L. A randomized trial of oral betamethasone to reduce ataxia symptoms in ataxia telangiectasia. Mov Disord. 2012 Sep 1;27(10):1312-6. doi: 10.1002/mds.25126. Epub 2012 Aug 23.
Gueven N, Luff J, Peng C, Hosokawa K, Bottle SE, Lavin MF. Dramatic extension of tumor latency and correction of neurobehavioral phenotype in Atm-mutant mice with a nitroxide antioxidant. Free Radic Biol Med. 2006 Sep 15;41(6):992-1000. doi: 10.1016/j.freeradbiomed.2006.06.018. Epub 2006 Jul 4.
Valentin-Vega YA, Maclean KH, Tait-Mulder J, Milasta S, Steeves M, Dorsey FC, Cleveland JL, Green DR, Kastan MB. Mitochondrial dysfunction in ataxia-telangiectasia. Blood. 2012 Feb 9;119(6):1490-500. doi: 10.1182/blood-2011-08-373639. Epub 2011 Dec 5.
Gillingham MB, Heitner SB, Martin J, Rose S, Goldstein A, El-Gharbawy AH, Deward S, Lasarev MR, Pollaro J, DeLany JP, Burchill LJ, Goodpaster B, Shoemaker J, Matern D, Harding CO, Vockley J. Triheptanoin versus trioctanoin for long-chain fatty acid oxidation disorders: a double blinded, randomized controlled trial. J Inherit Metab Dis. 2017 Nov;40(6):831-843. doi: 10.1007/s10545-017-0085-8. Epub 2017 Sep 4.
Roe CR, Brunengraber H. Anaplerotic treatment of long-chain fat oxidation disorders with triheptanoin: Review of 15 years Experience. Mol Genet Metab. 2015 Dec;116(4):260-8. doi: 10.1016/j.ymgme.2015.10.005. Epub 2015 Oct 24.
Roe CR, Mochel F. Anaplerotic diet therapy in inherited metabolic disease: therapeutic potential. J Inherit Metab Dis. 2006 Apr-Jun;29(2-3):332-40. doi: 10.1007/s10545-006-0290-3.
Schiffmann R, Wallace ME, Rinaldi D, Ledoux I, Luton MP, Coleman S, Akman HO, Martin K, Hogrel JY, Blankenship D, Turner J, Mochel F. A double-blind, placebo-controlled trial of triheptanoin in adult polyglucosan body disease and open-label, long-term outcome. J Inherit Metab Dis. 2018 Sep;41(5):877-883. doi: 10.1007/s10545-017-0103-x. Epub 2017 Nov 6.
Hainque E, Caillet S, Leroy S, Flamand-Roze C, Adanyeguh I, Charbonnier-Beaupel F, Retail M, Le Toullec B, Atencio M, Rivaud-Pechoux S, Brochard V, Habarou F, Ottolenghi C, Cormier F, Meneret A, Ruiz M, Doulazmi M, Roubergue A, Corvol JC, Vidailhet M, Mochel F, Roze E. A randomized, controlled, double-blind, crossover trial of triheptanoin in alternating hemiplegia of childhood. Orphanet J Rare Dis. 2017 Oct 2;12(1):160. doi: 10.1186/s13023-017-0713-2.
Hainque E, Gras D, Meneret A, Atencio M, Luton MP, Barbier M, Doulazmi M, Habarou F, Ottolenghi C, Roze E, Mochel F. Long-term follow-up in an open-label trial of triheptanoin in GLUT1 deficiency syndrome: a sustained dramatic effect. J Neurol Neurosurg Psychiatry. 2019 Nov;90(11):1291-1293. doi: 10.1136/jnnp-2018-320283. Epub 2019 Apr 4. No abstract available.
Hadera MG, Smeland OB, McDonald TS, Tan KN, Sonnewald U, Borges K. Triheptanoin partially restores levels of tricarboxylic acid cycle intermediates in the mouse pilocarpine model of epilepsy. J Neurochem. 2014 Apr;129(1):107-19. doi: 10.1111/jnc.12610. Epub 2013 Dec 2.
Hadera MG, McDonald T, Smeland OB, Meisingset TW, Eloqayli H, Jaradat S, Borges K, Sonnewald U. Modification of Astrocyte Metabolism as an Approach to the Treatment of Epilepsy: Triheptanoin and Acetyl-L-Carnitine. Neurochem Res. 2016 Feb;41(1-2):86-95. doi: 10.1007/s11064-015-1728-5. Epub 2015 Oct 3.
Yeo AJ, Henningham A, Fantino E, Galbraith S, Krause L, Wainwright CE, Sly PD, Lavin MF. Increased susceptibility of airway epithelial cells from ataxia-telangiectasia to S. pneumoniae infection due to oxidative damage and impaired innate immunity. Sci Rep. 2019 Feb 22;9(1):2627. doi: 10.1038/s41598-019-38901-3. Erratum In: Sci Rep. 2020 Jul 24;10(1):12742. doi: 10.1038/s41598-020-69649-w.
McGrath-Morrow SA, Collaco JM, Detrick B, Lederman HM. Serum Interleukin-6 Levels and Pulmonary Function in Ataxia-Telangiectasia. J Pediatr. 2016 Apr;171:256-61.e1. doi: 10.1016/j.jpeds.2016.01.002. Epub 2016 Feb 2.
McGrath-Morrow SA, Ndeh R, Collaco JM, Rothblum-Oviatt C, Wright J, O'Reilly MA, Singer BD, Lederman HM. Inflammation and transcriptional responses of peripheral blood mononuclear cells in classic ataxia telangiectasia. PLoS One. 2018 Dec 26;13(12):e0209496. doi: 10.1371/journal.pone.0209496. eCollection 2018.
Ross LJ, Capra S, Baguley B, Sinclair K, Munro K, Lewindon P, Lavin M. Nutritional status of patients with ataxia-telangiectasia: A case for early and ongoing nutrition support and intervention. J Paediatr Child Health. 2015 Aug;51(8):802-7. doi: 10.1111/jpc.12828. Epub 2015 Feb 6.
Morita DA, Glauser TA, Modi AC. Development and validation of the Pediatric Epilepsy Side Effects Questionnaire. Neurology. 2012 Sep 18;79(12):1252-8. doi: 10.1212/WNL.0b013e3182635b87. Epub 2012 Aug 8.
Yeo AJ, Chong KL, Gatei M, Zou D, Stewart R, Withey S, Wolvetang E, Parton RG, Brown AD, Kastan MB, Coman D, Lavin MF. Impaired endoplasmic reticulum-mitochondrial signaling in ataxia-telangiectasia. iScience. 2020 Dec 23;24(1):101972. doi: 10.1016/j.isci.2020.101972. eCollection 2021 Jan 22.
Public notes

Contacts
Principal investigator
Name 0 0
David Coman, MBBS FRACP
Address 0 0
Queensland Children's Hospital
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/study/NCT04513002