An interventional study of Nicotinamide riboside in Ataxia Telangiectasia, sponsored by The University of Queensland. Not yet recruiting at 1 site in Australia. Per ClinicalTrials.gov, last updated 2024-04-18.
Sponsored by The University of Queensland · Not applicable, Interventional, and Health services research
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
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. Our group previously demonstrated 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 patients. 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.
We 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). We have also shown this increased sensitivity to nutrient deprivation for primary epithelial cells from patients and in immortalised patient cells. We 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. We have recently completed a Phase 2A/B clinical trial exploring the efficacy and tolerability of C7 in AT patients (https://classic.clinicaltrials.gov/NCT04513002).
Nicotinamide adenine dinucleotide (NAD+) is an essential cofactor for many cellular enzymes, including those involved in mitochondrial biogenesis and maintenance. Nicotinamide adenine dinucleotide exists in two forms, including an oxidized (NAD+) and a reduced (NADH) form, and plays a key role in intermediary metabolism, as obligatory partner in numerous oxidation/reduction reactions. The cellular pool of NAD+ and NADH is tightly regulated through a careful balance between its biosynthesis and its breakdown by NAD+-consuming enzymes. NAD+ deficiency plays a role in disease mechanisms underlying DNA repair disorders. Mitochondrial damage and NAD+ depletion are key features in ataxia telangiectasia.
ATM-deficient mice have neuronal NAD+ deficiency, in particular in the cerebellum.
Fang et al. have demonstrated that mitochondrial dysfunction in ATM deficiency is linked to NAD+/SIRT1 inhibition. NAD+ replenishment significantly extends lifespan and improves health span in both ATM worms and mice through mitophagy and DNA repair. Treatments that replenish intracellular NAD+ reduce the severity of A-T neuropathology, normalize neuromuscular function, delay memory loss, and extend lifespan in both animal models. Mechanistically, treatments that increase intracellular NAD+ also stimulate neuronal DNA repair and improve mitochondrial quality via mitophagy.
Immune deficiency is common in AT, with most patients have humoral and cellular immune defects comprising immunoglobulin-A deficiency, immunoglobulin-G2 and immunoglobulin-G deficiency, and lymphopenia with low numbers of total and naive CD4 T cells. About 10% of patients with classic ataxia-telangiectasia present with hypogammaglobulinaemia with normal or raised immunoglobulin-M levels and follow a severe disease course. Recognition of foreign or misplaced nucleic acids is one of the principal modes by which the immune system detects pathogenic entities. When cytosolic DNA is sensed, a signal is relayed via the cGAS-STING pathway.
ATM deficient cells display elevated levels of INF- induced proteins, a feature also reported in sera of A-T patients. A double knockout of ATM and STING genes in mice attenuated autoinflammatory phenotypes, which was further decreased when the cGAS gene is also deleted in these mice. Inhibition of the cGAS-STING pathway ameliorates the premature senescence phenotype in AT brain organoids. Similar inflammatory manifestations are seen in patients with STING-associated vasculopathy in infancy which is an autosomal dominant type 1 interferonopathy.
Two groups have explored Nicotinamide Riboside (NR) supplementation in small groups of A-T patients via single arm, open label access, proof-of-concept clinical trials. Both have demonstrated improvements in validated ataxia scales. Improvements in immunoglobulin-G (IgG) levels were observed, no alterations were noted in NFlc. Improvements were lost in the wash out period. NR was well tolerated with no reported adverse events.
This is a 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.
Dose will be via oral capsule supplementation 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.
Primary efficacy endpoint: 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 include: Serum analysis of neurofilament light chain (Nfl). Type 1 Interferon (INFs) epigenetic signature specifically the cGAS-STING pathway.
Safety endpoints: Treatment-related adverse events, Routine haematology and biochemical analyses, Paediatric Epilepsy Side Effects Questionnaire (PESQ), Regular clinical assessments.
42 studies on the registry are indexed under Ataxia Telangiectasia; 7 are open to participants now.
This study's planned enrollment of 10 is below the median of 30 across 28 interventional studies indexed under Ataxia Telangiectasia.
Browse Ataxia Telangiectasia studies →The University of Queensland is the lead sponsor of 91 studies on the registry; 24 are open to participants now.
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Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.
Participants who meet all of the following criteria are eligible for enrolment:
Exclusion Criteria:
Participants who meet any of these criteria are not eligible for enrolment:
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
A drug or device being studied in a clinical trial.
It may be new, or already approved and being studied for another use, dose or form. Criteria often leave out people who took part in another study of one within a recent period, commonly 30 days or five half-lives.
Ways of preventing pregnancy. “Highly effective” methods fail less than 1% of the time a year when used correctly — for example an IUD or an implant.
Criteria usually say which methods count and how long to keep using them after the last dose, sometimes for male participants too. Some studies accept a partner’s vasectomy if it was confirmed successful and that person is the participant’s only sexual partner.
Two enzymes measured in a routine blood test of the liver. Higher levels can mean the liver is under strain or damaged. SGPT and SGOT are older names for ALT and AST.
Criteria usually give a limit as a multiple of the upper limit of normal (ULN), often higher when cancer has spread to the liver.
A yellow substance made when red blood cells are broken down, which the liver clears. A high level can mean a problem with the liver or the bile ducts.
Criteria often allow more for people with Gilbert’s syndrome, a harmless inherited condition that raises bilirubin.
The top of the normal range for a blood test, as set by the laboratory that runs it. Each lab prints its own range next to your result.
“≤ 2.5 × ULN” means the result can be up to two and a half times that top value.
GFR (glomerular filtration rate) is how much blood the kidneys filter each minute. It is usually estimated from a blood test — eGFR, by formulas such as CKD-EPI or MDRD — and some studies ask for it to be measured directly instead. Usually given in mL/min/1.73 m².
Check the method, the units and the minimum the study states. A value of 90 or above is in the normal-or-high range, but kidney damage can show in other tests too.
Investigational drug or device
A drug or device being studied in a clinical trial.
It may be new, or already approved and being studied for another use, dose or form. Criteria often leave out people who took part in another study of one within a recent period, commonly 30 days or five half-lives.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Contraception
Ways of preventing pregnancy. “Highly effective” methods fail less than 1% of the time a year when used correctly — for example an IUD or an implant.
Criteria usually say which methods count and how long to keep using them after the last dose, sometimes for male participants too. Some studies accept a partner’s vasectomy if it was confirmed successful and that person is the participant’s only sexual partner.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
ALT and AST (liver enzymes)
Two enzymes measured in a routine blood test of the liver. Higher levels can mean the liver is under strain or damaged. SGPT and SGOT are older names for ALT and AST.
Criteria usually give a limit as a multiple of the upper limit of normal (ULN), often higher when cancer has spread to the liver.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Bilirubin
A yellow substance made when red blood cells are broken down, which the liver clears. A high level can mean a problem with the liver or the bile ducts.
Criteria often allow more for people with Gilbert’s syndrome, a harmless inherited condition that raises bilirubin.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
ULN (upper limit of normal)
The top of the normal range for a blood test, as set by the laboratory that runs it. Each lab prints its own range next to your result.
“≤ 2.5 × ULN” means the result can be up to two and a half times that top value.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
GFR and eGFR (kidney filtering)
GFR (glomerular filtration rate) is how much blood the kidneys filter each minute. It is usually estimated from a blood test — eGFR, by formulas such as CKD-EPI or MDRD — and some studies ask for it to be measured directly instead. Usually given in mL/min/1.73 m².
Check the method, the units and the minimum the study states. A value of 90 or above is in the normal-or-high range, but kidney damage can show in other tests too.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
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.
Drug: Nicotinamide riboside
Oral capsule Nicotinamide Riboside 25mg/kg/day divided into 3 equal doses
Scales for assessment and rating of ataxia
Scales for assessment and rating of ataxia is a validated cerebellar ataxia tool, measuring gait (scale 0-8), stance (scale 0-6), sitting (scale 0-4), speech (scale 0-6), finger-chase test scale 0-4), finger nose-test (scale 0-4), fast alternating movements (scale 0-4) and heel-shin test (scale 0-4). 0 indicates normal function, escalating numbers in the scale domains indicate increased difficultly with the measured tasks.
Time frame: 4 monthly assessment over 12 months
International Cooperative Ataxia Rating Scale
International Cooperative Ataxia Rating Scale is a scale recorded out of 100 with 19 items and 4 sub-scales and has been used in A-T. 0 indicates normal function, escalating numbers in the scale domains indicate increased difficulty with the measured tasks.
Time frame: 4 monthly assessment over 12 months
Serum analysis of neurofilament light chain
Neurofilament light chain (Nfl) will be quantified using the single-molecule (Simoa) array method and the Simoa NF-light assay (Quanterix, MA, US) on an HD-1platform (GBIO). Levels of neurofilament light chain will be correlated with clinical endpoints.
Time frame: 12 months
Type 1 Interferon epigenetic signature
An IFN signature will be investigated by measuring six IFN-stimulated genes (ISGs) by quantitative PCR (QPCR).
Time frame: 12 months
Quality of Life Measures
Paediatric Side Effect Questionnaire is a 19-item measure consisting of five sub-scales: cognitive (six items), motor (four items), behavioural (three items), general neurological (four items), and weight (two items) side effects. The investigators will add five items for gastrointestinal side effects to the questionnaire, including gastrointestinal pain, acid reflux, vomiting, diarrhoea, and constipation. The scale will be recorded from 0 to 96. 0 indicates normal function, escalating numbers in the scale domains indicate increased difficultly with the measured task.
Time frame: 4 monthly assessment over 12 months
Plan to share: No
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Studies of the drug tested here: Nicotinamide-beta-riboside
The University of Queensland