Phase 1 NR-SAFE Trial Highlight’s Safety Profile of High Dose Nicotinamide Riboside in Parkinson Disease

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According to a recent study, investigators found no reports of moderate or severe adverse events with a high dose of nicotinamide riboside therapy in patients with Parkinson disease.

Charalampos Tzoulis, PhD, MD, the director for the K.G. Jebsen Center for Parkinson’s Disease at Haukeland University Hospital and professor of neurology at University of Bergen in Norway

Charalampos Tzoulis, PhD, MD

A recent single-center, randomized, placebo-controlled, double-blind, phase 1 study, NR-SAFE (NCT05344404), published in Nature Communications, met its primary outcome with findings that use of high dose nicotinamide riboside (NR) was safe, with no association with adverse events (AEs) among patients with Parkinson disease (PD) over a 4-week treatment period. These results support extending the dose range of NR in phase 2 clinical trials to 3000 mg per day, with appropriate safety monitoring, for patients with PD.1

In the study, 42 AEs were observed among 20 patients with PD, 25 of which were in the NR group (n = 10) and 17 in the placebo group (n = 10). At least 1 AE was reported in 90% of the NR group (n = 9) and 80% in the placebo group (n = 8). All AEs reported were reported as mild, with no significant between-group difference observed in the frequency of AEs. In the NR group, the most common AEs observed were extrapyramidal disorder (events, n = 3; patients, n = 3), headache (n = 3; n= 3), tremor (n = 2; n = 3) muscle cramp (n = n = 2; n = 1), fatigue (n = 2; n = 2), nausea (n = 2; n = 2) and dyspepsia (n = 2; n = 2). Notably, all cases of dyspepsia and nausea in the NR group were resolved at the end of the follow up period.

Clinical Takeaways

  • Recent trial supports 1500 mg nicotinamide riboside (NR) twice daily in Parkinson disease (PD), signaling safety for extending to 3000 mg daily in a phase 2 trial.
  • Study suggests direct initiation of NR therapy up to 3000 mg daily, with significant motor function improvement in patients with PD.
  • NR elevates NAD+, causing mild homocysteine increase; trial's 4-week span hints at NR potential, requiring more research for long-term safety in PD and other disorders.

“In our opinion, adequate dose experimentation in clinical trials will be paramount, in order to adequately explore and exploit potential dose-dependent beneficial effects in PD, as well as the multitude of other neurological and non-neurological diseases, for which NR is currently being tested. Furthermore, our results suggest that NR doses up to 3000 mg daily do not need to be gradually increased and can be initiated directly in NR-naïve individuals,” senior author Charalampos Tzoulis, PhD, MD, the director for the K.G. Jebsen Center for Parkinson’s Disease at Haukeland University Hospital and professor of neurology at University of Bergen in Norway, and colleagues wrote.1

READ MORE: Study Reveals Core Recommendations to Improve Palliative Care in Parkinson Disease

In this phase 1 trial, investigators evaluated the safety of high-dose NR therapy on individuals with PD (women, n =5; men, n = 15) who were randomized 1:1 to either NR 1500 mg twice daily (n = 10) or placebo (n = 10) for 4 weeks (number of blocks: 2, block size 4, allocation: 1:1). Conducted at the department of neurology in Haukeland University Hospital between April 29, 2022, and July 1, 2022, the primary outcome of the trial was safety, defined as the frequency of moderate and severe AEs. The secondary outcomes were tolerability defined as frequency of mild AEs, change in the whole blood and urine NAD metabolome, and change in the clinical severity of PD, measured by Movement Disorder Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS).2

Investigators noted that NR therapy was significantly associated with clinical improvement of motor function since the MDS-UPDRS change in the NR-group was significantly higher compared with the placebo (t-test, p = 0.024). However, the authors noted that this change was also associated with shorter interval times since the last levodopa dose in the NR group (−49 [±71.92] min) and longer times in the placebo group (+28.33 [±105.58] min).

Additional findings showed that treatment with NR greatly augmented the blood NAD metabolome with up to 5-fold increase in blood NAD+ levels (P = 0.056). While clinical routine blood assays showed a mild, but significant increase in serum homocysteine levels in the NR group (Δ = +1.66 ± 0.63 µmol/L; p = 5.4 ×10−4), this was not apparent for theplacebo group (Δ = −0.73 ± 1.7 µmol/L; p = 0.869). Notably, investigators observed that the integrity of the methyl donor pool remained intact with the increase of serum homocysteine levels in the NR group.

All told, the findings were not informative regarding long-term safety of 3000 mg NR daily because the study tested this approach for a 4-week period. The results are less generalizable for women with PD since the women to men ratio in the study was lower than that observed in the general PD population.3 The trial was also not designed to address clinical efficacy of NR in PD and the findings are not generalizable for other neurodegenerative disorders. In addition, the authors noted that it is unlikely that separate safety trials with NR therapy are needed for other conditions, provided adequate safety monitoring is included in the study.

REFERENCES
1. Berven H, Kverneng S, Sheard E, et al. NR-SAFE: a randomized, double-blind safety trial of high dose nicotinamide riboside in Parkinson's disease. Nat Commun. 2023;14(1):7793. Published 2023 Nov 28. doi:10.1038/s41467-023-43514-6
2. Goetz CG, Tilley BC, Shaftman SR, et al. Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS): scale presentation and clinimetric testing results. Mov Disord. 2008;23(15):2129-2170. doi:10.1002/mds.22340
3. GBD 2016 Neurology Collaborators. Global, regional, and national burden of neurological disorders, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 2019;18(5):459-480. doi:10.1016/S1474-4422(18)30499-X
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