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Abstract
Objective: This exploratory Phase 2 clinical trial is the first determining safety and efficacy of oral D-methionine (D-met) in reducing cisplatin-induced ototoxicity.
Design: Randomised parallel double-blind placebo-controlled exploratory Phase 2 study.
Study samples: Fifty adult cancer patients received oral D-met or placebo before each cisplatin dose. Physical examination, blood collection and audiometry occurred at baseline and subsequent visits plus post-treatment audiometry. After attrition, final analysis included 27 patients.
Results: Significant treatment group by ear and time (baseline vs. post-treatment) interactions occurred at 10 kHz and 11.2 kHz. Placebo and D-met groups differed in threshold shift for left ear at 11.2 kHz (mean difference = 22.97 dB [9.59, 36.35]). Averaging across ears, placebo group showed significant threshold shifts from baseline to post-treatment at 10 kHz (mean shift= −13.65 dB [−21.32,−5.98]), 11.2 kHz (−16.15 dB [−25.19,−7.12]), and 12.5 kHz (−11.46 dB [−19.18,−3.74]) but not 8 kHz (−8.65 dB [−17.86, 0.55]). The D-met group showed no significant threshold shifts (8 kHz: −1.25 dB [−7.75, 5.25]; 10 kHz:−3.93 dB [−8.89, 1.03]; 11.2 kHz:−4.82 dB [−11.21, 1.57]; 12.5 kHz:−3.68 dB [−11.57, 4.21]). Side effects did not significantly differ between groups.
Conclusion: Oral D-met reduces cisplatin-induced ototoxicity in humans.
Acknowledgments
The authors thank Ravi Nayar, and Sudhir Borgonha for their assistance with patient recruitment and data collection and Larry Hughes, and Steve Verhulst with preliminary data analysis. The authors thank Nicole Cosenza and Jill Anderson for assisting in manuscript preparation.
Disclosure statement
At the time of data collection, patents issued to Kathleen Campbell through SIU School of Medicine were active and licensed to Molecular Therapeutics. At the time of this manuscript submission these patents are expired and no longer licensed to Molecular Therapeutics. Consequently, none of the authors have any current conflict of interest.
Author contributions
KC, PS, BDR: Conception and design; RN, PS, DH: Collection and assembly of data; SV, KC: Data analysis and interpretation