Inosine 5'‐Monophosphate to Raise Serum Uric Acid Level in Multiple System Atrophy (IMPROVE‐MSA study)

Abstract

The aim of this trial was to investigate the safety, tolerability, and capability of serum uric acid (UA) elevation of inosine 5'‐monophosphate (IMP) in multiple system atrophy (MSA). The IMPROVE‐MSA trial was a randomized, double‐blind, placebo‐controlled trial in patients with MSA with no history of hyperuricemia‐related disorders. The participants were assigned to placebo (n = 25) or IMP (n = 30) in a 1 to 1 ratio, and then followed up for 24 weeks. The primary end points included safety, tolerability, and alteration of the serum UA level during the follow‐up period. The secondary end points were changes in scores of the unified MSA rating scale (UMSARS) and the Mini‐Mental Status Examination (MMSE) and Montreal Cognitive Assessment (MoCA). The total number of adverse events (AEs) and serious AEs was comparable between the active and placebo groups. Serum UA level (mg/dL) was significantly increased from baseline (active vs. placebo, 4.57 vs. 4.58; P = 0.98) to study end point (6.96 vs. 4.43; P < 0.001) in the active group compared with the placebo group (time × group interaction; P < 0.001). The change in UMSARS scores did not differ between the active and placebo groups. However, the active group showed better alterations in MoCA scores with nominal significance (P < 0.001) and tendency for better alterations in MMSE scores (P = 0.09) than the placebo group. Our data demonstrated that IMP treatment was generally safe and well‐tolerated in patients with MSA. A further trial with a long‐term follow‐up is required to examine whether UA elevation will slow clinical progression in early MSA.

Nocebo effect in multiple system atrophy: systematic review and meta-analysis of placebo-controlled clinical trials

“…1. After the application of our search strategy, we found that eleven RCTs [9][10][11][12][13][14][15][16][17][18][19] published between 1996 and 2021, that met our selection criteria. The included RCTs have a JADAD score of 4 or greater.…”

“…Only eight of the studies [10,11,[14][15][16][17][18][19] reported in detail the exact number of patients experiencing at least one AE in the study groups. The pooled estimate of the percentage of placebo treated patients with at least one AE was 64.2% (95% CI = 43.2-82.6%), compared to 72.4% (95% CI = 53.4-88.0%) for active drug treated patients.…”

Inosine: A bioactive metabolite with multimodal actions in human diseases

“…However, another recent clinical trial showed that inosine treatment does not modify progression of early Parkinson’s disease ( Schwarzschild et al, 2021 ). In a clinical trial for use of IMP in multiple system atrophy (MSA), IMP raised serum levels of uric acids, and was considered to be tolerable and safe during a 24-week treatment ( Jung Lee et al, 2021 ), although a more long-term follow-up study is warranted.…”