Safety and Tolerability, Dose-Escalating, Double-Blind Trial of Oral Mannitol in Parkinson's Disease 03 January 2022 | doi.org/10.3389/fneur.2021....
Primary Clinical Outcome Measures (Safety and Tolerability):
Twenty-four participants initiated oral therapy (15 mannitol, 9 placebo). One participant from each of the groups terminated the study earlier than planned. Early termination of a participant receiving mannitol was due to in situ breast carcinoma discovered 3 weeks after the first visit. This severe adverse event was considered unrelated to mannitol treatment. The participant in the placebo group dropped out of the trial within a week due to nausea. This side effect was considered as related to the investigated product by the investigator.
No mannitol-related severe adverse events occurred during the study. A single severe adverse event (recurrence of prostate carcinoma), considered unrelated to the investigated product, was documented on the last visit in one patient receiving placebo. Clinically significant gastrointestinal symptoms (diarrhea, nausea, abdominal discomfort) were reported in 6/14 participants in the mannitol group who completed the study. In 5/14 participants these symptoms required dose reduction (Figure 1B). Only a single participant in the placebo group required dose reduction due to abdominal discomfort (Fisher exact P = 0.19). Overall, 64% of participants receiving mannitol tolerated well the target dose of 18 g of mannitol per day divided into two doses.
Blood tests, taken during each of the visits before dose increment, did not reveal electrolyte abnormalities, increased liver enzymes, impaired renal function, elevated non-fasting glucose level or evidence of systemic inflammation (leukocytosis or increased CRP). Blood counts and biochemistry parameters did not change during the trials and no adverse events were documented by the laboratory tests (Table 2).
Secondary Clinical Outcome Measures (Efficacy):
The study was not designed to demonstrate statistically significant differences in efficacy measures. None of the clinical measures were significantly different between the mannitol and placebo groups (Table 3). Sub-analysis, comparing the placebo group with participants who completed the trial on the maximal target dose of mannitol (18 g, n = 9), also did not reveal significant differences. Only a single participant (mannitol group), not on levodopa at screening, started levodopa therapy during the trial.
Biomarker Measures:
Blood samples taken with each increment of mannitol or placebo dose were used to measure biochemical variables that included total and pSer129 α-synuclein levels, in both lysed blood cells and in membrane pellets of lysed blood cells (6), and PI4,5P2 levels that based on recent findings are increased in PD models (8, 9). No observable or statistically significant differences were demonstrated between the groups and no intra-group longitudinal changes were observed during the trial.
Retrospective Power Calculation for Future Trials:
PD patients who buy and consume oral mannitol (not as part of controlled clinical studies) frequently report improvement of their sense of smell. In our small study no such effect was observed (in the mannitol group the median change in B-SIT score was −1, a mean change of −0.54 ± 2.22). Based on these results, a future study aiming to demonstrate an improvement of at least 1 point on the B-SIT test, with a power of 80% and a significance level of 5% in a one-sided paired t-test, would require a sample size of at least 32 subjects on mannitol.
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From S of PD. Could all the benefit of B1 be the placebo affect? I think it's time for me to switch to benfotiamine instead.
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Thumbs up for Nilotinib - Phase II Trials
