Ataxia-telangiectasia: Treating Mitochondrial Dysfunction With a Novel Form of Anaplerosis
NCT ID: NCT04513002
Last Updated: 2023-07-20
Study Results
Results pending
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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Recruitment Status
COMPLETED
Clinical Phase
PHASE2
Total Enrollment
30 participants
Study Classification
INTERVENTIONAL
Study Start Date
2022-03-15
Study Completion Date
2023-07-10
Brief Summary
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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.
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.
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Detailed Description
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Ataxia Telangiectasia (A-T) is a rare, genetic, progressive, life-limiting, neuro-degenerative condition affecting a variety of body systems resulting in ataxia, immune deficiency, respiratory complications and a predisposition to cancer. Currently there is no cure for A-T. Over the years, a number of small clinical trials using steroids, antioxidants and anti-inflammatory agents have had little success. The disease natural history is relentless leading to early death. A-T generates a significant disease burden for the individuals, their extended families and on health care resources. With palliative care being the only current option for families, a treatment trial for A-T meets an unmet need. The investigators preliminary data provide compelling evidence of reversible mitochondrial dysfunction and preventable cell death in A-T patient cells and the beneficial effects of heptanoate (C7), the primary metabolite of triheptanoin. C7 corrects a defect in endoplasmic reticulum (ER)-mitochondrial signalling in A-T cells and has great potential for application in treating participants. C7 has been utilised with efficacy and safety over the last 15 years for inborn errors of metabolism (IEM) such as long chain fatty acid defects (LC-FAOD).
A-T is due to a genetic defect that results in a defective serine/threonine protein kinase, known as ATM. Normally, ATM, plays a central role in protecting the genome against damage. It is increasingly evident that ATM protects cells against oxidative stress. This protein is also present outside the nucleus, where it is activated by oxidative stress through a separate mechanism from DNA damage, providing an explanation why anti-oxidants have a protective role in A-T cells in culture and in animal models. From these and other studies, it is evident that mitochondrial abnormalities characterise ATM and it has been suggested that A-T should be considered, at least in part, as a mitochondrial disease. The Investigators have added substance to that claim by showing that ATM-deficient (B3) cells are exquisitely sensitive to inhibition of glycolysis by glucose deprivation, compared to controls (HBEC). The investigators have also shown this increased sensitivity to nutrient deprivation for primary epithelial cells from patients and in immortalised patient cells. Together these data point to a reduced capacity of A-T mitochondria to support energy metabolism and provide additional evidence for a mitochondrial defect in A-T cells. The investigators have recently demonstrated that this hypersensitivity to glucose deprivation can be explained by a novel mechanism involving defective signalling between the ER and the mitochondrion. The investigators demonstrated that this was caused by defective assembly of the VDAC1-GRP75-IP3R1 calcium channel and less ER-mitochondria contact points as determined by transmission electron microscopy. This in turn resulted in reduced calcium release from the ER and less transfer to mitochondria providing further evidence for mitochondrial dysfunction in A-T cells.
The investigators selected triheptanoin, a highly purified, synthetic medium odd-chain triglyceride that is catabolized to heptanoate and can traverse the mitochondrial membrane without the carnitine carrier. Free heptanoate is then metabolized by the medium chain fatty acid oxidation enzymes to yield both acetyl CoA and propionyl CoA that act as anaplerotics to replenish the TCA cycle and enhance energy metabolism by providing NADPH and generating ATP. The investigators demonstrated that heptanoate partially corrects the extreme sensitivity to glycolysis inhibition in both the ATM-deficient cell line as well as in primary epithelial cells from a patient with A-T. Excitingly, heptanoate also corrected all of the defects in ER-mitochondrial signalling including calcium uptake into mitochondria. Based on the importance of mitochondrial dysfunction in the A-T phenotype and our results revealing correction of mitochondrial function by heptanoate, the investigators consider that triheptanoin has excellent potential in correcting many aspects of the A-T phenotype including the progressive neurodegenerative phenotype.
Triheptanoin has been used for over 15 years to treat LC-FAOD, with demonstrated improvements in cardiac function and reductions in rhabdomyolysis episodes. Triheptanoin and heptanoate are known to protect against cell death in experimental conditions largely characterised by oxidative stress, such as stroke and motor neurone disease, adult polyglucosan body disease, alternating hemiplegia of childhood, Glucose-1 transporter deficiency, and mouse models and humans with epilepsy. Heptanoate protects cultured neurons against H2O2-induced cell death. Collectively these studies demonstrate that triheptanoin is well tolerated and is effective in treating a range of neurological conditions associated with neuronal energy deficiency.
Seamless Phase II to Phase III go/no-go criteria Interim monitoring for the intervention program in the A-T2020/01 trial will occur at the times of the two interim analyses (first, when the study cohort has completed the initial 2 months treatment, and second, after 6 months treatment when Group One has completed 2 months of the 35% dose). A blinded report will be presented to the iDSMB containing pertinent descriptive statistics of the groups, a standard between-group comparison for the primary and secondary outcomes, and a Bayesian estimation of the (posterior) probability that each of the three intervention groups is superior for the primary outcomes. The information to be presented to the iDSMB will be agreed with the iDSMB prior to the first iDSMB meeting, and will be updated at the time of the iDSMB meetings. Data will be presented to the iDSMB in a blind fashion, but the iDSMB can request unblinded data to confirm or ratify any reported interim results. The iDSMB may however make a recommendation about stopping current interventions if they show poor promise or futility.
The primary endpoints for interim iDSMB reports are the percent cell death induced by glucose deprivation in cell culture, and reversal/correction of their abnormal mitochondrial profile in primary epithelial cells resulting in cell death over the treatment period.
Secondary scales clinical neurological assessments assist formulating the go/no-go criteria and will include: SARA and ICARS. SARA is a validated cerebellar ataxia tool, measuring gait, stance, sitting, speech, finger-chase test, finger nose-test, fast alternating movements and heel-shin test. It has eight categories with accumulative score ranging from 0 (no ataxia) to 40 (most severe ataxia); Gait (0-8 points), Stance (0-6 points), Sitting (0-4 points), Speech disturbance (0-6 points), Finger chase (0-4 points), Nose-finger test (0-4 points), Fast alternating hand movement (0-4 points), Heel-shin slide (0-4 points). ICARS is a scale recorded out of 100 with 19 items and 4 subscales and has been used in A-T. Disorders rated as subscales within the ICARS are: Postural and gait disturbances, (7 items, 0-34 points) Limb Ataxia (7 items, 0-52 points), Dysarthria (2 items, 0-8 points), and Oculomotor disorders (3 items, 0-6 points). Minimum Score: 0 Maximum score: 100.
go/no-go triggers
go triggers Seamless progress from Phase II to Phase III will be triggered under the following pre-set parameters;
* If clinically or statistically significant improvement in the primary study outcome is observed in combination with a measured improvement of at least ½ standard deviation in key clinical scales which includes either;
* significant improvement in total combined scores from the SARA and ICARS scales.
* And/or significant improvements any aspects of the SARA and ICARS scales individually, especially pertaining to; Postural and gait improvements, Speech disturbance, Improved fine motor skills, Fine motor disturbance, Kinetic functions
No-go triggers Seamless progress from Phase II to Phase III will not occur under the following pre-set parameters;
* Adverse events
* If no clinically significant improvement in the primary study outcome is observed
* If a clinically significant improvement in the primary study outcome occurs without any improvements in key secondary scales specifically the SARA and ICARS.
A-T is due to a genetic defect that results in a defective serine/threonine protein kinase, known as ATM. Normally, ATM, plays a central role in protecting the genome against damage. It is increasingly evident that ATM protects cells against oxidative stress. This protein is also present outside the nucleus, where it is activated by oxidative stress through a separate mechanism from DNA damage, providing an explanation why anti-oxidants have a protective role in A-T cells in culture and in animal models. From these and other studies, it is evident that mitochondrial abnormalities characterise ATM and it has been suggested that A-T should be considered, at least in part, as a mitochondrial disease. The Investigators have added substance to that claim by showing that ATM-deficient (B3) cells are exquisitely sensitive to inhibition of glycolysis by glucose deprivation, compared to controls (HBEC). The investigators have also shown this increased sensitivity to nutrient deprivation for primary epithelial cells from patients and in immortalised patient cells. Together these data point to a reduced capacity of A-T mitochondria to support energy metabolism and provide additional evidence for a mitochondrial defect in A-T cells. The investigators have recently demonstrated that this hypersensitivity to glucose deprivation can be explained by a novel mechanism involving defective signalling between the ER and the mitochondrion. The investigators demonstrated that this was caused by defective assembly of the VDAC1-GRP75-IP3R1 calcium channel and less ER-mitochondria contact points as determined by transmission electron microscopy. This in turn resulted in reduced calcium release from the ER and less transfer to mitochondria providing further evidence for mitochondrial dysfunction in A-T cells.
The investigators selected triheptanoin, a highly purified, synthetic medium odd-chain triglyceride that is catabolized to heptanoate and can traverse the mitochondrial membrane without the carnitine carrier. Free heptanoate is then metabolized by the medium chain fatty acid oxidation enzymes to yield both acetyl CoA and propionyl CoA that act as anaplerotics to replenish the TCA cycle and enhance energy metabolism by providing NADPH and generating ATP. The investigators demonstrated that heptanoate partially corrects the extreme sensitivity to glycolysis inhibition in both the ATM-deficient cell line as well as in primary epithelial cells from a patient with A-T. Excitingly, heptanoate also corrected all of the defects in ER-mitochondrial signalling including calcium uptake into mitochondria. Based on the importance of mitochondrial dysfunction in the A-T phenotype and our results revealing correction of mitochondrial function by heptanoate, the investigators consider that triheptanoin has excellent potential in correcting many aspects of the A-T phenotype including the progressive neurodegenerative phenotype.
Triheptanoin has been used for over 15 years to treat LC-FAOD, with demonstrated improvements in cardiac function and reductions in rhabdomyolysis episodes. Triheptanoin and heptanoate are known to protect against cell death in experimental conditions largely characterised by oxidative stress, such as stroke and motor neurone disease, adult polyglucosan body disease, alternating hemiplegia of childhood, Glucose-1 transporter deficiency, and mouse models and humans with epilepsy. Heptanoate protects cultured neurons against H2O2-induced cell death. Collectively these studies demonstrate that triheptanoin is well tolerated and is effective in treating a range of neurological conditions associated with neuronal energy deficiency.
Seamless Phase II to Phase III go/no-go criteria Interim monitoring for the intervention program in the A-T2020/01 trial will occur at the times of the two interim analyses (first, when the study cohort has completed the initial 2 months treatment, and second, after 6 months treatment when Group One has completed 2 months of the 35% dose). A blinded report will be presented to the iDSMB containing pertinent descriptive statistics of the groups, a standard between-group comparison for the primary and secondary outcomes, and a Bayesian estimation of the (posterior) probability that each of the three intervention groups is superior for the primary outcomes. The information to be presented to the iDSMB will be agreed with the iDSMB prior to the first iDSMB meeting, and will be updated at the time of the iDSMB meetings. Data will be presented to the iDSMB in a blind fashion, but the iDSMB can request unblinded data to confirm or ratify any reported interim results. The iDSMB may however make a recommendation about stopping current interventions if they show poor promise or futility.
The primary endpoints for interim iDSMB reports are the percent cell death induced by glucose deprivation in cell culture, and reversal/correction of their abnormal mitochondrial profile in primary epithelial cells resulting in cell death over the treatment period.
Secondary scales clinical neurological assessments assist formulating the go/no-go criteria and will include: SARA and ICARS. SARA is a validated cerebellar ataxia tool, measuring gait, stance, sitting, speech, finger-chase test, finger nose-test, fast alternating movements and heel-shin test. It has eight categories with accumulative score ranging from 0 (no ataxia) to 40 (most severe ataxia); Gait (0-8 points), Stance (0-6 points), Sitting (0-4 points), Speech disturbance (0-6 points), Finger chase (0-4 points), Nose-finger test (0-4 points), Fast alternating hand movement (0-4 points), Heel-shin slide (0-4 points). ICARS is a scale recorded out of 100 with 19 items and 4 subscales and has been used in A-T. Disorders rated as subscales within the ICARS are: Postural and gait disturbances, (7 items, 0-34 points) Limb Ataxia (7 items, 0-52 points), Dysarthria (2 items, 0-8 points), and Oculomotor disorders (3 items, 0-6 points). Minimum Score: 0 Maximum score: 100.
go/no-go triggers
go triggers Seamless progress from Phase II to Phase III will be triggered under the following pre-set parameters;
* If clinically or statistically significant improvement in the primary study outcome is observed in combination with a measured improvement of at least ½ standard deviation in key clinical scales which includes either;
* significant improvement in total combined scores from the SARA and ICARS scales.
* And/or significant improvements any aspects of the SARA and ICARS scales individually, especially pertaining to; Postural and gait improvements, Speech disturbance, Improved fine motor skills, Fine motor disturbance, Kinetic functions
No-go triggers Seamless progress from Phase II to Phase III will not occur under the following pre-set parameters;
* Adverse events
* If no clinically significant improvement in the primary study outcome is observed
* If a clinically significant improvement in the primary study outcome occurs without any improvements in key secondary scales specifically the SARA and ICARS.
Conditions
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Ataxia Telangiectasia
Study Design
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Allocation Method
RANDOMIZED
Intervention Model
PARALLEL
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.
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.
Primary Study Purpose
HEALTH_SERVICES_RESEARCH
Blinding Strategy
QUADRUPLE
Participants
Caregivers
Investigators
Outcome Assessors
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).
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).
Study Groups
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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%
Group Type
OTHER
Triheptanoin
Intervention Type
DIETARY_SUPPLEMENT
Triheptanoin is a highly purified, synthetic medium odd-chain triglyceride that is catabolized to heptanoate.
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%
Group Type
OTHER
Triheptanoin
Intervention Type
DIETARY_SUPPLEMENT
Triheptanoin is a highly purified, synthetic medium odd-chain triglyceride that is catabolized to heptanoate.
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%
Group Type
OTHER
Triheptanoin
Intervention Type
DIETARY_SUPPLEMENT
Triheptanoin is a highly purified, synthetic medium odd-chain triglyceride that is catabolized to heptanoate.
Interventions
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Triheptanoin
Triheptanoin is a highly purified, synthetic medium odd-chain triglyceride that is catabolized to heptanoate.
Intervention Type
DIETARY_SUPPLEMENT
Eligibility Criteria
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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.
* 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.
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.
* 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.
Eligible Sex
ALL
Accepts Healthy Volunteers
No
Sponsors
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National Health and Medical Research Council, Australia
OTHER
Sponsor Role
collaborator
The University of Queensland
OTHER
Sponsor Role
lead
Responsible Party
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Responsibility Role
SPONSOR
Principal Investigators
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David Coman, MBBS FRACP
Role: PRINCIPAL_INVESTIGATOR
Queensland Children's Hospital
Locations
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Queensland Children's Hospital
Brisbane, Queensland, Australia
Site Status
Countries
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Australia
References
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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.
Reference Type
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.
Reference Type
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.
Reference Type
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.
Reference Type
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.
Reference Type
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.
Reference Type
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.
Reference Type
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.
Reference Type
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.
Reference Type
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.
Reference Type
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.
Reference Type
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.
Reference Type
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.
Reference Type
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.
Reference Type
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.
Reference Type
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.
Reference Type
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.
Reference Type
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.
Reference Type
RESULT
Other Identifiers
Review additional registry numbers or institutional identifiers associated with this trial.
A-T2020/01
Identifier Type: -
Identifier Source: org_study_id
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