High-Dose Vitamin D3 for Diabetic Foot Ulcer Healing: Randomized Controlled Trial

Not Applicable

Completed

• Conditions: Diabetic Foot Ulcer; Vitamin D Deficiency; Wound Healing Disorder

• Registration Number: NCT07139964
• Lead Sponsor: Universitas Sriwijaya

Brief Summary

This randomized, double-blind, placebo-controlled clinical trial aims to evaluate the effectiveness of high-dose vitamin D3 supplementation in improving diabetic foot ulcer (DFU) healing. DFUs are common, serious complications of diabetes, often associated with delayed wound healing due to persistent inflammation, impaired angiogenesis, and imbalances between matrix metalloproteinase-9 (MMP-9) and its tissue inhibitor (TIMP-1). Vitamin D deficiency is prevalent among DFU patients and is linked to impaired fibroblast function, poor angiogenesis, and increased inflammation.

Participants with DFUs and serum vitamin D levels \<30 ng/mL will be randomized to receive either 10,000 IU oral vitamin D3 daily or placebo for 28 days, in addition to standard DFU care. Primary outcomes include changes in tissue MMP-9/TIMP-1 expression ratio and wound healing progression. The study will provide evidence on whether high-dose vitamin D3 can serve as a safe, effective adjunctive therapy in DFU management.

Detailed Description

Diabetic foot ulcers are a prevalent and serious complication of uncontrolled diabetes, with a significant proportion leading to infection, amputation, and mortality. Delayed wound healing in DFUs is often driven by prolonged inflammation, persistent infection, impaired angiogenesis, and an imbalance between extracellular matrix (ECM) degradation by MMP-9 and inhibition by TIMP-1. Elevated MMP-9 levels disrupt keratinocyte migration, collagen deposition, and epithelial regeneration, while reduced TIMP-1 further compromises healing.

Vitamin D plays a regulatory role in immune modulation, inflammation control, fibroblast activity, and angiogenesis. Observational and interventional studies have shown that vitamin D deficiency is common in DFU patients and is associated with slower healing. Supplementation has been linked to improved wound healing, reduced inflammatory markers, and better microcirculation. Vitamin D may also modulate MMP-9 and TIMP-1 expression, thereby restoring ECM balance.

This study is a double-blind, placebo-controlled, randomized controlled trial conducted at Dr. Mohammad Hoesin General Hospital, Palembang. Eligible participants are adults with DFUs, low serum vitamin D (\<30 ng/mL), and no exclusion criteria such as advanced kidney disease, severe liver disease, osteomyelitis, or sepsis. Participants will be randomized into two groups:

Intervention group: Oral vitamin D3, 10,000 IU daily for 28 days Control group: Placebo daily for 28 days Both groups will receive standard DFU care. Compliance will be monitored with the MMAS-8 scale. Primary outcomes are changes in tissue MMP-9 and TIMP-1 expression (assessed by immunohistochemistry) and wound healing parameters. Secondary outcomes include changes in serum vitamin D levels and correlation between vitamin D status and wound healing outcomes.

The study aims to determine whether high-dose vitamin D3 supplementation reduces the MMP-9/TIMP-1 ratio and accelerates wound healing, potentially supporting its use as a standard adjunctive therapy for DFUs.

Study Timeline

• Study Start: 2024-07-01
• Primary Completion: 2025-01-31
• Study Completion: 2025-07-31
• Status Verified: 2025-08
• Study First Submitted: 2025-08-15
• Study First Submitted QC: 2025-08-21
• Last Update Submitted: 2025-08-21
• Study First Posted: 2025-08-24
• Last Update Posted: 2025-08-24

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 24

Inclusion Criteria

Diagnosis of diabetic foot ulcer (DFU) Serum 25-hydroxyvitamin D level < 30 ng/mL Willingness and ability to provide written informed consent Ability to comply with study procedures and follow-up visits

Exclusion Criteria

Currently undergoing cancer treatment Pregnant or breastfeeding Current use of vitamin D supplementation History of autoimmune disease Chronic kidney disease with estimated GFR < 30 mL/min/1.73 m² Abnormal liver function tests (AST or ALT ≥ 3× upper normal limit) Ankle-brachial index (ABI) < 0.4 Presence of osteomyelitis Proven sepsis Allergy to vitamin D3 Amputation prior to randomization Withdrawal of consent during the study

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Primary Outcome Measures

Name	Time	Method
Change in tissue MMP-9/TIMP-1 expression ratio from baseline to Day 28	Baseline (Day 0) and after completion of intervention (Day 28)	Ratio of matrix metalloproteinase-9 (MMP-9) to tissue inhibitor of metalloproteinase-1 (TIMP-1) expression in wound tissue, measured using immunohistochemistry from surgical biopsy samples.

Secondary Outcome Measures

Name	Time	Method
Change in wound size from baseline to Day 28	Baseline (Day 0) and Day 28	Measurement of ulcer area using standardized planimetry software from digital photographs.
Change in serum vitamin D3 concentration from baseline to Day 28	Baseline (Day 0) and Day 28	Serum 25-hydroxyvitamin D3 level measured by chemiluminescent immunoassay.
Change in tissue MMP-9 expression from baseline to Day 28	Baseline (Day 0) and Day 28	Immunohistochemical staining score of matrix metalloproteinase-9 in wound biopsy specimens.
Change in tissue TIMP-1 expression from baseline to Day 28	Baseline (Day 0) and Day 28	Immunohistochemical staining score of tissue inhibitor of metalloproteinase-1 in wound biopsy specimens.
Correlation between serum vitamin D3 level and wound healing outcomes	Baseline (Day 0) to Day 28	Pearson or Spearman correlation between serum 25-hydroxyvitamin D3 concentration and percentage reduction in ulcer size.

Trial Locations

Locations (1)

Dr. Mohammad Hoesin General Hospital; 🇮🇩 Palembang, South Sumatra, Indonesia