Ataxia-telangiectasia: Treating Mitochondrial Dysfunction With a Novel Form of Anaplerosis

NCT04513002 | Completed Phase 2 DMC

• 1 other identifier: A-T2020/01
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

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.

Conditions

Ataxia Telangiectasia

Keywords

Ataxia Telangiectasia; Anaplerosis

Outcome Measures

Primary Outcomes (7)

• Nasal epithelial cell survival under conditions of glucose deprivation.

  Submerged epithelial cultures will be established at each visit to the clinic and assays described above carried out within 2 weeks to determine effects of triheptanoin treatment on cell death, mitochondrial function and signalling. The primary outcome variable will be percent cell death induced by glucose deprivation in cell culture.

  Day 1, baseline measurement

• Nasal epithelial cell survival under conditions of glucose deprivation.

  Submerged epithelial cultures will be established at each visit to the clinic and assays described above carried out within 2 weeks to determine effects of triheptanoin treatment on cell death, mitochondrial function and signalling. The primary outcome variable will be percent cell death induced by glucose deprivation in cell culture.

  Day 60, assessment of effects/changes from Day 1 baseline measurement

• Nasal epithelial cell survival under conditions of glucose deprivation.

  Submerged epithelial cultures will be established at each visit to the clinic and assays described above carried out within 2 weeks to determine effects of triheptanoin treatment on cell death, mitochondrial function and signalling. The primary outcome variable will be percent cell death induced by glucose deprivation in cell culture.

  Day 120, assessment of effects/changes from Day 60 baseline measurement

• Nasal epithelial cell survival under conditions of glucose deprivation.

  Submerged epithelial cultures will be established at each visit to the clinic and assays described above carried out within 2 weeks to determine effects of triheptanoin treatment on cell death, mitochondrial function and signalling. The primary outcome variable will be percent cell death induced by glucose deprivation in cell culture.

  Day 180, assessment of effects/changes from Day 120 baseline measurement

• Nasal epithelial cell survival under conditions of glucose deprivation.

  Submerged epithelial cultures will be established at each visit to the clinic and assays described above carried out within 2 weeks to determine effects of triheptanoin treatment on cell death, mitochondrial function and signalling. The primary outcome variable will be percent cell death induced by glucose deprivation in cell culture.

  Day 240, assessment of effects/changes from Day 180 baseline measurement

• Nasal epithelial cell survival under conditions of glucose deprivation.

  Submerged epithelial cultures will be established at each visit to the clinic and assays described above carried out within 2 weeks to determine effects of triheptanoin treatment on cell death, mitochondrial function and signalling. The primary outcome variable will be percent cell death induced by glucose deprivation in cell culture.

  Day 300, assessment of effects/changes from Day 240 baseline measurement

• Nasal epithelial cell survival under conditions of glucose deprivation.

  Submerged epithelial cultures will be established at each visit to the clinic and assays described above carried out within 2 weeks to determine effects of triheptanoin treatment on cell death, mitochondrial function and signalling. The primary outcome variable will be percent cell death induced by glucose deprivation in cell culture.

  Day 360, assessment of effects/changes from Day 300 baseline measurement

Secondary Outcomes (12)

• Scales for assessment and rating of ataxia

  Day 1, Day 120, Day 240, Day 360

• International Cooperative Ataxia Rating Scale

  Day 1, Day 120, Day 240, Day 360

• Speech Pathology Assessments

  Day 1, Day 120, Day 240, Day 360

• Ophthalmology assessments

  Day 1, Day 120, Day 240, Day 360

• MRI lung imaging

  Performed at Day 1 and Day 360 in suitable participants

Other Outcomes (9)

• Survival and inflammatory phenotype of airway epithelial cells, macrophages and in serum

  Day 1, Day 60, Day 120, Day 180, Day 240, Day 300, Day 360

• Serum metabolomic biomarker

  Day 1, Day 60, Day 120, Day 180, Day 240, Day 300, Day 360

• Air Displacement Plethysmography

  Day 1, Day 60, Day 120, Day 180, Day 240, Day 300, Day 360

Study Arms (3)

Group 1: Triheptanoin and no Placebo

OTHER

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%

Dietary Supplement: Triheptanoin

Group 2: Placebo and Triheptanoin

OTHER

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%

Dietary Supplement: Triheptanoin

Group 3: Placebo, Placebo and Triheptanoin

OTHER

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%

Dietary Supplement: Triheptanoin

Interventions

Triheptanoin DIETARY_SUPPLEMENT

Triheptanoin is a highly purified, synthetic medium odd-chain triglyceride that is catabolized to heptanoate.

Group 1: Triheptanoin and no Placebo; Group 2: Placebo and Triheptanoin; Group 3: Placebo, Placebo and Triheptanoin

Eligibility Criteria

• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• The University of Queensland: lead
• National Health and Medical Research Council, Australia: collaborator

Study Sites (1)

Queensland Children's Hospital

Brisbane, Queensland, 4001, Australia

Location

Related Publications (18)

• 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.

  PMID: 20966255 BACKGROUND

• 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.

  PMID: 22927201 RESULT

• 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.

  PMID: 16934683 RESULT

• 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.

  PMID: 22144182 RESULT

• 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.

  PMID: 28871440 RESULT

• 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.

  PMID: 26547562 RESULT

• 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.

  PMID: 16763896 RESULT

• 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.

  PMID: 29110179 RESULT

• 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.

  PMID: 28969699 RESULT

• 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.

  PMID: 30948626 RESULT

• 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.

  PMID: 24236946 RESULT

• 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.

  PMID: 26433381 RESULT

• 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.

  PMID: 30796268 RESULT

• 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.

  PMID: 26851119 RESULT

• 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.

  PMID: 30586396 RESULT

• 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.

  PMID: 25656498 RESULT

• 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.

  PMID: 22875082 RESULT

• 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.

  PMID: 33437944 RESULT

MeSH Terms

Conditions

Ataxia Telangiectasia

Interventions

triheptanoin

Condition Hierarchy (Ancestors)

Spinocerebellar Ataxias; Cerebellar Ataxia; Cerebellar Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocutaneous Syndromes; Ataxia; Dyskinesias; Neurologic Manifestations; Telangiectasis; Vascular Diseases; Cardiovascular Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Primary Immunodeficiency Diseases; DNA Repair-Deficiency Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Immunologic Deficiency Syndromes; Immune System Diseases

Study Officials

• David Coman, MBBS FRACP

  Queensland Children's Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Once all required screening assessments are completed and eligibility is confirmed, participants will be registered with the Sponsor. Upon approval of registration, participants will be assigned a unique participant number that will remain consistent for the duration of the study. Participants will be randomised (RandoWeb) into one of the following three groups on a 1:1 ratio: 1. Group 1: 10%, 20%, 35%, 35%, 35%,35%. 2. Group 2: placebo, 10%, 20%, 35%, 35%,35%. 3. Group 3; placebo, placebo, 10%, 20%, 35%,35%. Our study pharmacist will ensure the groups are blinded in terms of dose increases, volumes, colour and taste of liquid dispensed in triheptanoin and placebo (medium chain triglyceride oil).
• Purpose: HEALTH SERVICES RESEARCH
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 1. Primary objective A combined phase 2A/B trial will be undertaken to determine optimal dose, demonstrate tolerability, and to examine efficacy and safety of triheptanoin in participants with A-T. 2. Secondary objectives * Determine to what extent the beneficial effects of triheptanoin on epithelial cells in culture translate to clinical efficacy in patients with A-T. Clinical endpoints will include ataxia rating; MRI imaging; lung function; eye movement changes and speech assessment. * Provide validation of our primary and secondary endpoints to plan a phase 3 trial and form the basis of future trials.

Study Record Dates

• First Submitted: July 26, 2020
• First Posted: August 14, 2020
• Study Start: March 15, 2022
• Primary Completion: March 17, 2023
• Study Completion: July 10, 2023
• Last Updated: July 20, 2023

Record last verified: 2021-11

Data Sharing

• IPD Sharing: Will not share

Locations

AU (1)