The Effect of Combination Therapy of Oral MB and PRP-FG in Patients With Non-healing Diabetic Foot Ulcer

The Effect of Combination Therapy of Oral Methylene Blue and Platelet-rich Plasma-fibrin Glue in Patients With Non-healing Diabetic Foot Ulcer: a Pilot Study

The aim of this study is to evaluate the chance of non-healing diabetic foot ulcers repair by improving the condition of lack of oxygen or hypoxia in the wound area caused by diabetes using methylene blue along with the use of platelet-rich plasma-fibrin glue as an effective treatment for wound healing.

Study Overview

• Status: Recruiting
• Conditions: Diabetic Foot Ulcers; Diabetic Wound
• Intervention / Treatment: Drug: Methylene Blue; Other: Milk (control); Drug: Methylene Blue and Platelet-Rich Plasma-Fibrin Glue; Other: Milk and Platelet-Rich Plasma-Fibrin Glue (control)

Detailed Description

The current study assesses the effects of methylene blue along with the use of platelet-rich plasma-fibrin glue on wound healing in patients with nonhealing diabetic foot ulcers (non-healing DFU). This randomized controlled trial is performed on 20 patients with non-healing DFU. Patients were treated with PRP-FG dressing plus 200 ml of oral methylene blue dissolved in milk(intervention group) or PRP-FG dressing plus placebo (200 ml of milk) (control group) for 4 weeks.

• Study Type: Interventional
• Enrollment (Estimated): 20
• Phase: Early Phase 1

Contacts and Locations

• Study Contact: Name: Daryoush Hamidi Alamdari, Ph.D; Phone Number: +98 51 3882 8574; Email: hamidiad@mums.ac.ir
• Study Contact Backup: Name: Elaheh Emadi, Ph.D; Phone Number: +98 9355850931; Email: EmadiE4001@mums.ac.ir

Study Locations

• Iran, Islamic Republic of
  • Razavi Khorasan
    • Mashhad, Razavi Khorasan, Iran, Islamic Republic of, 99191-91778
      • Recruiting
      • Mashhad University of Medical Sciences
      • Contact: Daryoush Hamidi Alamdari, Ph.D; Phone Number: 98 51 3882 8574; Email: hamidiad@mums.ac.ir
      • Contact: Elaheh Emadi, Ph.D; Phone Number: 98 9355850931; Email: EmadiE4001@mums.ac.ir

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Having a Diabetic ulcer grade II and IV based on Wagner's classification on the sole, medial, or lateral part of the foot (including all surfaces of the toes)
• Having a single ulcer on the feet and extremities (toes, soles, heels) with no significant reduction in ulcer size (<20%) despite the use of best treatment methods for at least four weeks
• If there is more than one non-healing wound, choose the largest wound
• The size of the wound surface (length × width) between 2 cm2 and 20 cm2
• No smoking, alcohol, and drug addiction based on the patient's self-report
• Not taking drugs that may interfere with wound healing, such as Corticosteroids, immunosuppressants, and cytotoxic agents
• Not having a concurrent chronic disease that may cause problems in wound healing, such as cancers, vasculitis, no history of known severe kidney, liver, and heart disease, such as liver cirrhosis, active hepatitis, dialysis, etc.
• Not taking antidepressants
• Insensitivity to milk lactose
• Not having Glucose 6-phosphate dehydrogenase (G6PD) deficiency
• Confirmed, informed, signed consent form
• Ankle Brachial Index (ABI) higher than or equal to 0.7

Exclusion Criteria:

• Do not be treated with methylene blue
• The confirmed presence of osteomyelitis, or if there is suspicion of osteomyelitis
• The subject is pregnant or intends to become pregnant during the test period
• The patient is known to have mental, developmental, physical, and emotional disorders
• The occurrence of certain medical conditions
• The presence of a wound with a clear and severe infection, which is characterized by significant purulent secretions or extensive cellulitis, or gangrene requiring amputation
• Evidence of venous, ischemic, neurotrophic ulcers (numbness, tingling, lack of Achilles tendon reflex) and traumatic wounds in the patient
• Failure to refer the patient more than two times to the mentioned center for follow-up and dressing change
• Hypersensitivity reaction to methylene blue
• Platelet count less than 100,000
• The patient's lack of consent to continue cooperation

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Factorial Assignment
• Masking: Double

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Methylene Blue; The first intervention group (group A) includes diabetic patients with chronic foot ulcers who, despite common treatments, will be undergone oral methylene blue intervention (70 mg in 200 ml of milk) for 4 weeks.	Drug: Methylene Blue; The first intervention group includes diabetic patients with chronic foot ulcers who, despite common treatments, will be undergone oral methylene blue intervention for 4 weeks.; Other Names: Methylthioninium chloride
Experimental: Milk (control); Patients with non-healing Diabetic Foot Ulcers only will receive 200 ml of milk for 4 weeks.	Other: Milk (control); Group B will receive 200 ml of milk for 4 weeks.; Other Names: Placebo
Experimental: Methylene Blue and Platelet-Rich Plasma-Fibrin Glue; Patients with non-healing Diabetic Foot Ulcers will treat with PRP-Fibrin-Glue plus oral methylene blue (70 mg in 200 ml of milk) for 4 weeks.	Drug: Methylene Blue and Platelet-Rich Plasma-Fibrin Glue; Group C will be undergone synergistic 4-week treatment with oral methylene blue and fibrin glue.; Other Names: Methylthioninium chloride and PRP-Fibrin Glue
Experimental: Milk and Platelet-Rich Plasma-Fibrin Glue (control); Patients with non-healing Diabetic Foot Ulcers will be treated with PRP-Fibrin-Glue and 200 ml of milk for 4 weeks.	Other: Milk and Platelet-Rich Plasma-Fibrin Glue (control); Group D will be treated only with fibrin glue and 200 ml of milk for 4 weeks.; Other Names: Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The healing rate of the ulcer	Measurement of wound area with a ruler	4 weeks
Wound Size	Wound size will be measured with a ruler for length, and width as well as with digital imaging. Wound size will be assessed in digital images taken of the wound.	4 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
TcPO2 at baseline and after the intervention	Transcutaneous oxygen tension (TcpO2) provides information about blood perfusion in the tissue immediately below the skin. (blood pressure, measured in millimeters of mercury (mmHg))	4 weeks
Oxygen saturation at baseline and after the intervention	Blood must contain a normal concentration of hemoglobin. that hemoglobin must be >95 % saturated with oxygen in arterial blood (sO2(a) >95 %)	4 weeks
Blood pressure (systolic and diastolic)	The pressure of the blood in the circulatory system	4 weeks
The resting systolic toe pressure (TP) at baseline and after the intervention	The toe cuff with the sphygmomanometer is slowly inflated until the waveform flattens (generally between 150-200 mmHg), then is inflated a further 20 mmHg. The cuff is slowly released at a rate of 2-5mmHg per second. The first regular cyclical waveform is considered the toe systolic pressure.	4 weeks
Serum IL-1β levels at baseline and after the intervention	Analysis of serum interleukin-1β levels	4 weeks
Serum MCP-1 levels at baseline and after the intervention	Analysis of serum monocyte chemoattractant protein-1 (MCP-1) levels	4 weeks
Serum TNF-α levels at baseline and after the intervention	Analysis of serum tumor necrosis factor α (TNFα) levels	4 weeks
Serum IL-6 levels at baseline and after the intervention	Analysis of serum interleukin-6 (IL-6) levels	4 weeks
Serum HIF-1α levels at baseline and after the intervention	Analysis of serum hypoxia-inducible factor 1-alpha (HIF-1α) levels	4 weeks
Serum FBS levels at baseline and after the intervention	Analysis of serum fasting blood sugar (FBS ) levels	4 weeks
Serum Insulin levels at baseline and after the intervention	Analysis of Insulin levels	4 weeks
Lipid Profile at baseline and after the intervention	Serum Triglyceride, Cholesterol, HDL, LDL, VLDL	4 weeks
Serum Urea at baseline and after the intervention	In a quantitative laboratory method	4 weeks
Serum Creatinine at baseline and after the intervention	In a quantitative laboratory method	4 weeks
Serum total bilirubin at baseline and after the intervention	In a quantitative laboratory method	4 weeks
Serum Vitamin D levels at baseline and after the intervention	In a quantitative laboratory method	4 weeks
HbA1c at baseline and after the intervention	Glycated hemoglobin	4 weeks
Serum Albumin (Alb) levels at baseline and after the intervention	In a quantitative laboratory method	4 weeks
Uric Acid levels at baseline and after the intervention	In a quantitative laboratory method	4 weeks
Serum Homocysteine levels at baseline and after the intervention	In a quantitative laboratory method	4 weeks
Serum ALT (alanine transaminase) levels at baseline and after the intervention	In a quantitative laboratory method	4 weeks
Serum AST (Aspartate Transferase) levels at baseline and after the intervention	In a quantitative laboratory method	4 weeks
Serum ALP (alkaline phosphatase) levels at baseline and after the intervention	In a quantitative laboratory method	4 weeks
Serum Met Hemoglobin levels at baseline and after the intervention	In a quantitative laboratory method	4 weeks
Serum Hemoglobin (Hgb, Hb) levels at baseline and after the intervention	In a quantitative laboratory method	4 weeks
Serum white blood cells (WBCs) levels at baseline and after the intervention	In a quantitative laboratory method	4 weeks
Serum total Lymphocyte levels at baseline and after the intervention	In a quantitative laboratory method	4 weeks
Platelet count at baseline and after the intervention	In a quantitative laboratory method	4 weeks
Nitric oxide blood at baseline and after the intervention	In a quantitative laboratory method	4 weeks
Serum lactate dehydrogenase (LDH) levels at baseline and after the intervention	In a quantitative laboratory method	4 weeks
Serum Erythrocyte Sedimentation Rate (ESR) levels at baseline and after the intervention	In a quantitative laboratory method	4 weeks
Serum C-Reactive Protein (CRP) levels at baseline and after the intervention	In a quantitative laboratory method	4 weeks
Neutrophils count at baseline and after the intervention	In a quantitative laboratory method	4 weeks

Collaborators and Investigators

• Sponsor: Mashhad University of Medical Sciences
• Investigators: Principal Investigator: Daryoush Hamidi Alamdari, Ph.D, Mashhad University of Medical Sciences, Mashhad, Iran

Study record dates

Study Major Dates

• Study Start (Actual): April 30, 2023
• Primary Completion (Actual): August 21, 2023
• Study Completion (Estimated): September 21, 2024

Study Registration Dates

• First Submitted: March 6, 2023
• First Submitted That Met QC Criteria: April 30, 2023
• First Posted (Actual): May 9, 2023

Study Record Updates

• Last Update Posted (Actual): October 4, 2023
• Last Update Submitted That Met QC Criteria: October 3, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: DFU; Methylene blue; Platelet-Rich Plasma-Fibrin Glue; Non-healing Diabetic Foot Ulcers
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Skin Diseases; Endocrine System Diseases; Diabetic Angiopathies; Leg Ulcer; Skin Ulcer; Diabetes Complications; Diabetes Mellitus; Diabetic Neuropathies; Foot Diseases; Diabetic Foot; Foot Ulcer; Ulcer; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Hemostatics; Coagulants; Fibrin Tissue Adhesive; Methylene Blue
• Other Study ID Numbers: IRCT20191228045924N3

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: All data related to the project after the unidentifiable people will be shared.
• IPD Sharing Time Frame: Access to data is allowed 6 months after the publication of results.
• IPD Sharing Access Criteria: The investigator's data will be available to university staff and academic institutions.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No