Efficacy and safety of high-dose intramuscular vitamin D2 injection in type 2 diabetes mellitus with distal symmetric polyneuropathy combined with vitamin D insufficiency: study protocol for a multicenter, randomized, double-blinded, and placebo-controlled trial

Tao Chen; Xiaoyan Xing; Lihua Huang; Mei Tu; Xiaoli Lai; Shidi Wen; Jin Cai; Shenglong Lin; Youping Zheng; Yuehui Lin; Lijuan Xu; Yuwen Qiu; Lumin Qiu; Yuebo Xu; Peiwen Wu

doi:10.3389/fendo.2023.1202917

Efficacy and safety of high-dose intramuscular vitamin D₂ injection in type 2 diabetes mellitus with distal symmetric polyneuropathy combined with vitamin D insufficiency: study protocol for a multicenter, randomized, double-blinded, and placebo-controlled trial

Front Endocrinol (Lausanne). 2023 Jul 7:14:1202917. doi: 10.3389/fendo.2023.1202917. eCollection 2023.

Authors

Tao Chen^{1

2}, Xiaoyan Xing³, Lihua Huang⁴, Mei Tu², Xiaoli Lai², Shidi Wen², Jin Cai², Shenglong Lin⁵, Youping Zheng⁶, Yuehui Lin⁷, Lijuan Xu⁷, Yuwen Qiu⁸, Lumin Qiu⁸, Yuebo Xu⁹, Peiwen Wu¹

Affiliations

¹ Department of Endocrinology, Clinical Research Center for Metabolic Diseases of Fujian Province, the First Affiliated Hospital, Fujian Medical University, Fuzhou, China.
² Department of Endocrinology and Metabolism, Longyan First Affiliated Hospital of Fujian Medical University, Longyan, China.
³ Department of Endocrinology and Metabolism, China-Japan Friendship Hospital, Beijing, China.
⁴ Department of Tumor Radiotherapy, Longyan First Affiliated Hospital of Fujian Medical University, Longyan, China.
⁵ Department of Severe Liver Disease, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, China.
⁶ Department of Ultrasound, Longyan First Affiliated Hospital of Fujian Medical University, Longyan, China.
⁷ Department of Endocrinology and Metabolism, Longyan Traditional Chinese Medicine Affiliated Hospital of Fujian University of Traditional Chinese Medicine, Longyan, China.
⁸ Department of Endocrinology and Metabolism, Longyan Shanghang County Hospital, Longyan, China.
⁹ Department of Diabetes, Longyan Boai Hospital, Longyan, China.

Abstract

Background: Distal symmetric polyneuropathy (DSPN) is the most common chronic complication of type 2 diabetes mellitus (T2DM). DSPN may lead to more serious complications, such as diabetic foot ulcer, amputation, and reduced life expectancy. Observational studies have suggested that vitamin D deficiency may be associated with the development of DSPN in T2DM. However, interventional studies have found that low-dose vitamin D supplementation does not significantly improve neuropathy in DSPN. This study aims to evaluate the efficacy and safety of intramuscular injection of high-dose vitamin D (HDVD) in T2DM with DSPN combined with vitamin D insufficiency.

Methods and analysis: We will conduct a multicenter, randomized, double-blinded, and placebo-controlled trial in four large hospitals. All eligible participants will be randomly assigned to either the vitamin D₂ supplement or placebo control group and injected intramuscularly monthly for 3 months. Additionally, anthropometric measurements and clinical data will be collected at baseline and 3 months. Adverse events will be collected at 1, 2, and 3 months. The primary outcome measure is the change in the mean Michigan Neuropathy Screening Instrument (MNSI) score at baseline and 3 months post-intervention. We will use the gold-standard liquid chromatography-tandem mass spectrometry method to distinguish between 25(OH)D₂ and 25(OH)D₃ levels. The MNSN score before the intervention will be used as a covariate to compare the changes between both groups before and after the intervention, and the analysis of covariance will be used to analyze the change in the MNSI score after HDVD supplementation.

Discussion: Glycemic control alone does not prevent the progression of DSPN in T2DM. Some studies have suggested that vitamin D may improve DSPN; however, the exact dose, method, and duration of vitamin D supplementation are unknown. Additionally, neuropathy repair requires HDVD supplementation to sustain adequate vitamin D levels. This once-a-month intramuscular method avoids daily medication; therefore, compliance is high. This study will be the first randomized controlled trial in China to analyze the efficacy and safety of HDVD supplementation for patients with T2DM and DSPN and will provide new ideas for pharmacological research and clinical treatment of diabetic neuropathy.

Clinical trial registration: https://www.chictr.org.cn/, identifier ChiCTR2200062266.

Keywords: Michigan neuropathy screening instrument; distal symmetric polyneuropathy; high-dose vitamin D supplementation; randomized controlled trial; type 2 diabetes mellitus.

Publication types

Clinical Trial Protocol
Research Support, Non-U.S. Gov't

MeSH terms

Diabetes Mellitus, Type 2* / complications
Double-Blind Method
Humans
Multicenter Studies as Topic
Polyneuropathies* / complications
Randomized Controlled Trials as Topic
Vitamin D / therapeutic use
Vitamin D Deficiency* / complications
Vitamins / therapeutic use

Substances

Vitamin D
Vitamins

Grants and funding

This work was sponsored by the Natural Science Foundation of Fujian Province (Grant Nos.2021J011435 and 2020J01951), Fujian Provincial Health Technology Project (Grant No.2020CXA035), and Joint Funds for the Innovation of Science and Technology, Fujian Province (Grant No. 2021Y9106).