Efficacy and safety of the combined metabolic medication, containing inosine, nicotinamide, riboflavin and succinic acid, for the treatment of diabetic neuropathy: a multicenter randomized, double-blind, placebo-controlled parallel group clinical trial (CYLINDER)

Tatiana Kharitonova, Yury G Shvarts, Andrey F Verbovoy, Natalia S Orlova, Valentina P Puzyreva, Igor A Strokov, Tatiana Kharitonova, Yury G Shvarts, Andrey F Verbovoy, Natalia S Orlova, Valentina P Puzyreva, Igor A Strokov

Abstract

Introduction: Antioxidants may have positive impact on diabetic polyneuropathy (DPN), presumably due to alleviation of oxidative stress. We aimed to evaluate the efficacy and safety of combination of antioxidants: succinic acid, inosine, nicotinamide, and riboflavin (SINR) in the treatment of DPN.

Research design and methods: In a double-blind, placebo-controlled clinical trial, men and women aged 45-74 years with type 2 diabetes and symptomatic DPN, with initial Total Symptom Score (TSS) ˃5, were randomized into experimental (n=109) or placebo (n=107) group. Patients received study medication/placebo intravenously for 10 days, followed by oral administration for 75 days. Statistical significance was defined as a two-tailed p<0.05.

Results: In SINR group, mean TSS change after 12 weeks was -2.65 (±1.46) vs -1.73 (±1.51) in the placebo group (p<0.0001; t-test). Reduction of symptoms in the SINR group was achieved regardless of hemoglobin A1c levels, but better results were observed in patients with initial TSS <7.5. The analysis of TSS subscores revealed statistically significant between-group differences by dynamics of the intensity of paresthesia and of numbness starting from day 11 (p=0.035 and p=0.001, respectively; mixed model); by day 57, statistically significant between-group differences were detected also by dynamics of burning intensity (p=0.005; mixed model). Study limitations are small effect size, moderate proportion of patients with severe DPN symptoms, subjective assessment of outcomes, exclusion of participants who received injectable glucose-lowering medications other than insulins, and patients with uncontrolled and type 1 diabetes.

Conclusions: The combination of SINR effectively alleviates DPN symptoms in patients with type 2 diabetes.

Trial registration number: ClinicalTrials.gov Registry (NCT04649203; Unique Protocol ID: CTF-III-DM-2019).

Keywords: Diabetes Complications; Diabetes Mellitus, Type 2; Diabetic Neuropathies.

Conflict of interest statement

Competing interests: TK was an employee of POLYSAN Scientific & Technological Pharmaceutical Company when this research was conducted. IAS was a scientific advisor for this study and was compensated by POLYSAN Scientific & Technological Pharmaceutical Company for his work on this research. YGS, AFV, NSO, and VPP were compensated by POLYSAN Scientific & Technological Pharmaceutical Company for their work on this research.

© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1
Figure 1
A schematic illustration of the study procedures.
Figure 2
Figure 2
Allocation of study subjects and trial profile. ITT, full analysis set; PP, per protocol.
Figure 3
Figure 3
Baseline level and the sequential changes of the Total Symptom Score and its individual components in experimental and placebo groups, based on ITT population. (A) Paresthesia intensity; (B) Numbness intensity; (C) Burning intensity; (D) Shooting pain intensity; (E) Total score (TSS); #p

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