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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT06324877




Registration number
NCT06324877
Ethics application status
Date submitted
15/03/2024
Date registered
22/03/2024
Date last updated
18/04/2024

Titles & IDs
Public title
Ataxia-telangiectasia: Treating Mitochondrial Dysfunction With Nicotinamide Riboside
Scientific title
Single Arm Open-label Clinical Trial in Ataxia-telangiectasia to Test the Effects of Nicotinamide Riboside on Ataxia Scales, Immune Function, and Neurofilament Light Chain.
Secondary ID [1] 0 0
HREC/24/QCHQ/106030
Universal Trial Number (UTN)
Trial acronym
ATNAD
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: Drugs - Nicotinamide riboside

Other: Single arm (full group) - Single arm, open-label. Dose will be via oral capsule supplementation Nicotinamide Riboside at 25mg/kg/day divided into 3 doses (max 300mgs 3 times per day). Dosing will occur via 3 equal doses 3 times a day for 12 months.


Treatment: Drugs: Nicotinamide riboside
Oral capsule Nicotinamide Riboside 25mg/kg/day divided into 3 equal doses
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Scales for assessment and rating of ataxia
Timepoint [1] 0 0
4 monthly assessment over 12 months
Primary outcome [2] 0 0
International Cooperative Ataxia Rating Scale
Timepoint [2] 0 0
4 monthly assessment over 12 months
Secondary outcome [1] 0 0
Serum analysis of neurofilament light chain
Timepoint [1] 0 0
12 months
Secondary outcome [2] 0 0
Type 1 Interferon epigenetic signature
Timepoint [2] 0 0
12 months

Eligibility
Key inclusion criteria
Participants who meet all of the following criteria are eligible for enrolment:

* 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
Participants who meet any of these criteria are not eligible for enrolment:

* 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
* 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
Not applicable
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
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Not applicable
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Not yet recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
1/05/2024
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
30/10/2025
Actual
Sample size
Target
10
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment hospital [1] 0 0
Queensland Children's Hospital - Brisbane
Recruitment postcode(s) [1] 0 0
4101 - Brisbane

Funding & Sponsors
Primary sponsor type
Other
Name
The University of Queensland
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
Study design: Single arm open-label clinical trial in ataxia-telangiectasia to test the effects of nicotinamide riboside on ataxia scales, immune function, and neurofilament light chain. Study population: 6-10 patients with Ataxia-Telangiectasia. Dose: Nicotinamide riboside 25 mg/kg/day in 3 equal divided doses.

Primary endpoint: Scales for assessment and rating of ataxia (SARA), and International Cooperative Ataxia Rating Scale (ICARS). Improvement of at least ½ standard deviation in key clinical scales which includes either; a) significant improvement in total combined scores from the SARA and ICARS scales, and /or b) significant improvements any aspects of the SARA and ICARS scales individually, especially pertaining to; Postural and gait improvements, Improved syllable speed and articulation, Improved fine motor skills.

Secondary endpoints: Serum analysis of neurofilament light chain (Nfl), Type 1 Interferon (INFs) epigenetic signature
Trial website
https://clinicaltrials.gov/study/NCT06324877
Trial related presentations / publications
Veenhuis SJG, van Os NJH, Janssen AJWM, van Gerven MHJC, Coene KLM, Engelke UFH, Wevers RA, Tinnevelt GH, Ter Heine R, van de Warrenburg BPC, Weemaes CMR, Roeleveld N, Willemsen MAAP. Nicotinamide Riboside Improves Ataxia Scores and Immunoglobulin Levels in Ataxia Telangiectasia. Mov Disord. 2021 Dec;36(12):2951-2957. doi: 10.1002/mds.28788. Epub 2021 Sep 13.
Fang EF, Kassahun H, Croteau DL, Scheibye-Knudsen M, Marosi K, Lu H, Shamanna RA, Kalyanasundaram S, Bollineni RC, Wilson MA, Iser WB, Wollman BN, Morevati M, Li J, Kerr JS, Lu Q, Waltz TB, Tian J, Sinclair DA, Mattson MP, Nilsen H, Bohr VA. NAD+ Replenishment Improves Lifespan and Healthspan in Ataxia Telangiectasia Models via Mitophagy and DNA Repair. Cell Metab. 2016 Oct 11;24(4):566-581. doi: 10.1016/j.cmet.2016.09.004.
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.
Woelke S, Pommerening H, Kieslich M, Schubert R, Zielen S. Growth hormone treatment in patients with ataxia telangiectasia. Growth Factors. 2017 Jun;35(2-3):125-130. doi: 10.1080/08977194.2017.1367681.
Chessa L, Leuzzi V, Plebani A, Soresina A, Micheli R, D'Agnano D, Venturi T, Molinaro A, Fazzi E, Marini M, Ferremi Leali P, Quinti I, Cavaliere FM, Girelli G, Pietrogrande MC, Finocchi A, Tabolli S, Abeni D, Magnani M. Intra-erythrocyte infusion of dexamethasone reduces neurological symptoms in ataxia teleangiectasia patients: results of a phase 2 trial. Orphanet J Rare Dis. 2014 Jan 9;9:5. doi: 10.1186/1750-1172-9-5.
Nissenkorn A, Borgohain R, Micheli R, Leuzzi V, Hegde AU, Mridula KR, Molinaro A, D'Agnano D, Yareeda S, Ben-Zeev B. Development of global rating instruments for pediatric patients with ataxia telangiectasia. Eur J Paediatr Neurol. 2016 Jan;20(1):140-6. doi: 10.1016/j.ejpn.2015.09.002. Epub 2015 Sep 25.
Airhart SE, Shireman LM, Risler LJ, Anderson GD, Nagana Gowda GA, Raftery D, Tian R, Shen DD, O'Brien KD. An open-label, non-randomized study of the pharmacokinetics of the nutritional supplement nicotinamide riboside (NR) and its effects on blood NAD+ levels in healthy volunteers. PLoS One. 2017 Dec 6;12(12):e0186459. doi: 10.1371/journal.pone.0186459. eCollection 2017.
Chen P, Peng C, Luff J, Spring K, Watters D, Bottle S, Furuya S, Lavin MF. Oxidative stress is responsible for deficient survival and dendritogenesis in purkinje neurons from ataxia-telangiectasia mutated mutant mice. J Neurosci. 2003 Dec 10;23(36):11453-60. doi: 10.1523/JNEUROSCI.23-36-11453.2003.
Paap BK, Roeske S, Durr A, Schols L, Ashizawa T, Boesch S, Bunn LM, Delatycki MB, Giunti P, Lehericy S, Mariotti C, Melegh J, Pandolfo M, Tallaksen CME, Timmann D, Tsuji S, Schulz JB, van de Warrenburg BP, Klockgether T. Standardized Assessment of Hereditary Ataxia Patients in Clinical Studies. Mov Disord Clin Pract. 2016 Feb 11;3(3):230-240. doi: 10.1002/mdc3.12315. eCollection 2016 May-Jun.
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.
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.
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.
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.
Lautrup S, Sinclair DA, Mattson MP, Fang EF. NAD+ in Brain Aging and Neurodegenerative Disorders. Cell Metab. 2019 Oct 1;30(4):630-655. doi: 10.1016/j.cmet.2019.09.001.
Zapata-Perez R, Wanders RJA, van Karnebeek CDM, Houtkooper RH. NAD+ homeostasis in human health and disease. EMBO Mol Med. 2021 Jul 7;13(7):e13943. doi: 10.15252/emmm.202113943. Epub 2021 May 27.
Subramanian GN, Yeo AJ, Gatei MH, Coman DJ, Lavin MF. Metabolic Stress and Mitochondrial Dysfunction in Ataxia-Telangiectasia. Antioxidants (Basel). 2022 Mar 28;11(4):653. doi: 10.3390/antiox11040653.
Stern N, Hochman A, Zemach N, Weizman N, Hammel I, Shiloh Y, Rotman G, Barzilai A. Accumulation of DNA damage and reduced levels of nicotine adenine dinucleotide in the brains of Atm-deficient mice. J Biol Chem. 2002 Jan 4;277(1):602-8. doi: 10.1074/jbc.M106798200. Epub 2001 Oct 25.
Yang B, Dan X, Hou Y, Lee JH, Wechter N, Krishnamurthy S, Kimura R, Babbar M, Demarest T, McDevitt R, Zhang S, Zhang Y, Mattson MP, Croteau DL, Bohr VA. NAD+ supplementation prevents STING-induced senescence in ataxia telangiectasia by improving mitophagy. Aging Cell. 2021 Apr;20(4):e13329. doi: 10.1111/acel.13329. Epub 2021 Mar 18.
Aguado J, Chaggar HK, Gomez-Inclan C, Shaker MR, Leeson HC, Mackay-Sim A, Wolvetang EJ. Inhibition of the cGAS-STING pathway ameliorates the premature senescence hallmarks of Ataxia-Telangiectasia brain organoids. Aging Cell. 2021 Sep;20(9):e13468. doi: 10.1111/acel.13468. Epub 2021 Aug 30.
Presterud R, Deng WH, Wennerstrom AB, Burgers T, Gajera B, Mattsson K, Solberg A, Fang EF, Nieminen AI, Stray-Pedersen A, Nilsen H. Long-Term Nicotinamide Riboside Use Improves Coordination and Eye Movements in Ataxia Telangiectasia. Mov Disord. 2024 Feb;39(2):360-369. doi: 10.1002/mds.29645. Epub 2023 Oct 29.
van Os NJH, Jansen AFM, van Deuren M, Haraldsson A, van Driel NTM, Etzioni A, van der Flier M, Haaxma CA, Morio T, Rawat A, Schoenaker MHD, Soresina A, Taylor AMR, van de Warrenburg BPC, Weemaes CMR, Roeleveld N, Willemsen MAAP. Ataxia-telangiectasia: Immunodeficiency and survival. Clin Immunol. 2017 May;178:45-55. doi: 10.1016/j.clim.2017.01.009. Epub 2017 Jan 24.
Kim J, Gupta R, Blanco LP, Yang S, Shteinfer-Kuzmine A, Wang K, Zhu J, Yoon HE, Wang X, Kerkhofs M, Kang H, Brown AL, Park SJ, Xu X, Zandee van Rilland E, Kim MK, Cohen JI, Kaplan MJ, Shoshan-Barmatz V, Chung JH. VDAC oligomers form mitochondrial pores to release mtDNA fragments and promote lupus-like disease. Science. 2019 Dec 20;366(6472):1531-1536. doi: 10.1126/science.aav4011. Epub 2019 Dec 19.
Gul E, Sayar EH, Gungor B, Eroglu FK, Surucu N, Keles S, Guner SN, Findik S, Alpdundar E, Ayanoglu IC, Kayaoglu B, Geckin BN, Sanli HA, Kahraman T, Yakicier C, Muftuoglu M, Oguz B, Cagdas Ayvaz DN, Gursel I, Ozen S, Reisli I, Gursel M. Type I IFN-related NETosis in ataxia telangiectasia and Artemis deficiency. J Allergy Clin Immunol. 2018 Jul;142(1):246-257. doi: 10.1016/j.jaci.2017.10.030. Epub 2017 Nov 16.
Siddoo-Atwal C, Haas AL, Rosin MP. Elevation of interferon beta-inducible proteins in ataxia telangiectasia cells. Cancer Res. 1996 Feb 1;56(3):443-7.
Hartlova A, Erttmann SF, Raffi FA, Schmalz AM, Resch U, Anugula S, Lienenklaus S, Nilsson LM, Kroger A, Nilsson JA, Ek T, Weiss S, Gekara NO. DNA damage primes the type I interferon system via the cytosolic DNA sensor STING to promote anti-microbial innate immunity. Immunity. 2015 Feb 17;42(2):332-343. doi: 10.1016/j.immuni.2015.01.012.
Song X, Ma F, Herrup K. Accumulation of Cytoplasmic DNA Due to ATM Deficiency Activates the Microglial Viral Response System with Neurotoxic Consequences. J Neurosci. 2019 Aug 7;39(32):6378-6394. doi: 10.1523/JNEUROSCI.0774-19.2019. Epub 2019 Jun 12.
Paul BD, Snyder SH, Bohr VA. Signaling by cGAS-STING in Neurodegeneration, Neuroinflammation, and Aging. Trends Neurosci. 2021 Feb;44(2):83-96. doi: 10.1016/j.tins.2020.10.008. Epub 2020 Nov 10.
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
David Coman, MBBS FRACP
Address 0 0
Country 0 0
Phone 0 0
+610730681111
Fax 0 0
Email 0 0
[email protected]
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/study/NCT06324877