COVID-19 Treatment Using Methylene Blue and Photodynamic Therapy

The Clinical Trial of Methylene Blue Application Combined With Photodynamic Therapy for Treatment of SARS-CoV-2 Infected Patients

According to the epidemiological situation worldwide and the number of vaccinations made, there is little success in the fight against COVID-19. For many reasons, methylene blue is a promising drug for an active treatment against SARS-CoV-2 infected patients. Since methylene blue can work as a photosensitizer, photodynamic therapy as an antiviral treatment has great potential in the treatment of COVID-19. This clinical study investigated the effectiveness of SARS-CoV-2 infected people treatment using methylene blue and the following photodynamic therapy on the base of the L.L. Levshin Institute of Cluster Oncology (Department of Infectious Diseases №13) of I.M. Sechenov First Moscow State Medical University.

Study Overview

• Status: Completed
• Conditions: SARS-CoV-2
• Intervention / Treatment: Drug: Methylene Blue and Photodynamic Therapy

Detailed Description

This is a randomized, parallel, single masking clinical study 60 participants aged 18-90 with one positive COVID-19 quantitative Polymerase Chain Reaction test and any severity of pneumonia (checked by computer tomography scans) were recruited. The experimental and control samples included 30 participants. Randomization was performed using the Random Number Table generated in STATISTICA Advanced 13.3. The physiological parameters including oxygen saturation, severity of pneumonia using computer tomography scans, heart rate, symptoms, and physical examination were collected. Participants in the experimental sample received methylthioninium chloride, Methylene Blue (SamaraMedProm, Russia, Registration number: MP-001834, 13.09.2012) orally in concentration 1 mg/kg in addition to the current therapy of the participant (e.g., azithromycin, hydroxychloroquine, aminodihydrophthalazinedione sodium, levofloxacin, etc.), if any. After 3 hours, photodynamic therapy of the participant's chest by a 650 nm laser source (UFPh-675-01-BIOSPEC, BIOSPEC, Russia, Registration number: 2009/04648, 26.03.2009) with 18 J/cm^2 energy dose was performed for 50 minutes. If the participant is in a critical state, inhalation by 0.2 mg Methylene Blue 10 ml water solution and following photodynamic therapy of pharynx and nasal cavity using 650 nm laser source with 36 J/cm^2 energy dose during 10 minutes were performed. Participants in the control sample received only standard medical supportive therapy (e.g., azithromycin, hydroxychloroquine, aminodihydrophthalazinedione sodium, levofloxacin, etc.). All next steps were performed for p participants from the experimental sample: 12 and 24 hours after photodynamic therapy, blood saturation were measured. 2 days after - participants will take a quantitative polymerase chain reaction test. 14 days after - computer tomography Aquilion One 640 (Canon Medical Systems Corporation, Registration Certificate FSZ 2008/01304, 02.07.2018) scans were performed. The participant's status scale (EQ-5D-3L, SHOCS-COVID score, validated) was checked on day 84. On 24 and 84 days all participants were checked whether they are alive or not by phone call. For participants in the control sample continuous check of blood saturation, quantitative Polymerase Chain Reaction tests after 2 and 14 days of treatment, and computer tomography scans were performed. The primary outcome of this study is to calculate the percentage of participants with negative quantitative Polymerase Chain Reaction test on SARS-CoV-2 by 2 days after methylene blue administration and photodynamic therapy. Experimental and control samples were comparable in gender, age, and severity of the disease. Z-test was used to analyze results on quantitative Polymerase Chain Reaction tests within control and experimental samples. For each sample paired Student t-test was used to analyze individual saturation changes. Wilcoxon criterion was used for data on severity of pneumonia and status scale.

• Study Type: Interventional
• Enrollment (Actual): 60
• Phase: Phase 1

Contacts and Locations

Study Locations

• Russian Federation
  • Moscow, Russian Federation
    • I.M. Sechenov First Moscow State Medical University (Sechenov University)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 90 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• signed informed consent
• age: 18-90 years
• positive quantitative Polymerase Chain Reaction test on SARS-CoV-2 infection
• negative pregnancy test in women
• any severity of pneumonia (computer tomography scans)

Non-inclusion Criteria:

• documented refusal to participate in the study
• treatment with a serotonergic drug
• connection to artificial lung ventilation with or without sedation
• history of G-6-Phosphatase deficiency
• pregnancy and breastfeeding
• medical records of cirrhosis
• active chronic hepatitis

Exclusion Criteria:

• myocardial infarction, developed after the patient was included in the study, but before the intervention
• bleeding, developed after the patient was included in the study, but before the intervention
• connection to artificial lung ventilation developed after the patient was included in the study, but before the intervention

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Methylene Blue and Photodynamic Therapy; Methylene Blue 1 mg/kg water solution. Participants have orally received Methylene Blue solution of 1 mg/kg concentration one time in addition to the current therapy of the participant (e.g., azithromycin, hydroxychloroquine, aminodihydrophthalazinedione sodium, levofloxacin, etc.), if any. After 3 hours of Methylene Blue administration irradiation of chest using 650 nm laser source with 18 J/cm^2 energy dose was performed.	Drug: Methylene Blue and Photodynamic Therapy; Treatment group. Methylene blue (SamaraMedProm, Russia, Registration number: MP-001834, 13.09.2012) 1 mg/kg concentration orally one time were added to the current therapy of the participant (e.g., azithromycin, hydroxychloroquine, aminodihydrophthalazinedione sodium, levofloxacin, etc.), if any, and irradiation of the participant's chest was performed by 650 nm laser source (UFPh-675-01-BIOSPEC, BIOSPEC, Russia, Registration number: 2009/04648, 26.03.2009) with 18 J/cm^2 energy dose. For critically ill participants: Inhalation by 0.2 mg methylene blue (SamaraMedProm, Russia, Registration number: MP-001834, 13.09.2012) 10 ml water solution and irradiation of pharynx and nasal cavity by 650 nm laser source (UFPh-675-01-BIOSPEC, BIOSPEC, Russia, Registration number: 2009/04648, 26.03.2009) with 36 J/cm^2 energy dose were performed.; Other Names: Methylene Blue (SamaraMedProm, Russia, Registration number: MP-001834, 13.09.2012), 650 nm laser source (UFPh-675-01-BIOSPEC, BIOSPEC, Russia, Registration number: 2009/04648, 26.03.2009)
No Intervention: Control group; COVID-19 positive participants treated with standard medical supportive therapy (e.g. azithromycin, hydroxychloroquine, aminodihydrophthalazinedione sodium, levofloxacin, etc.).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The percentage of participants with negative quantitative Polymerase Chain Reaction test on SARS-CoV-2 on day 2 after methylene blue administration and photodynamic therapy	The percentage of participants with negative quantitative Polymerase Chain Reaction test was reported. Quantitative Polymerase Chain Reaction test was performed not earlier than 3-4 hours after the last meal, excluding the use of medicines for topical application (drops, sprays, etc.) before taking the test.	Day 2

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Comparison of oxygen saturation dynamics measured by pulse oximeter before and after treatment	The saturation dynamics after photodynamic therapy in 12 and 24 hours were reported	12 and 24 hours after photodynamic therapy
The percentage of participants with positive dynamics in severity of pneumonia (e.g., from CT-4 to CT-2)	The percentage of participants that have a positive trend in severity of pneumonia (computer tomography scans) after treatment (e.g., from CT-4 to CT-2) was reported	Day 14
The percentage of participants having positive dynamics in patient status scale (EQ-5D-3L, SHOCS-COVID score) after treatment	The percentage of participants that have positive dynamics in patient status scale (EQ-5D-3L, SHOCS-COVID score) was calculated	Day 84
The percentage of participants alive at day 28	The percentage of participants still alive at day 28 of samples collection was reported	Day 28
The percentage of participants alive at day 84	The percentage of participants still alive at day 84 of samples collection was reported	Day 84

Collaborators and Investigators

• Sponsor: I.M. Sechenov First Moscow State Medical University
• Collaborators: Prokhorov General Physics Institute of the Russian Academy of Sciences (GPI RAS)
• Investigators: Study Director: Igor V. Reshetov, Prof., I.M. Sechenov First Moscow State Medical University (Sechenov University); Principal Investigator: Artem A. Shiryaev, Ph.D., I.M. Sechenov First Moscow State Medical University (Sechenov University); Study Chair: Victor B. Loschenov, Prof., Prokhorov General Physics Institute of the Russian Academy of Sciences

Publications and helpful links

General Publications

• Strakhovskaya, M. G., Meerovich, G. A., Kuskov, A. N., Gonchukov, S. A., & Loschenov, V. B. (2020, September 1). Photoinactivation of coronaviruses: Going along the optical spectrum. Laser Physics Letters. IOP Publishing Ltd. https://doi.org/10.1088/1612-202X/abab14

Study record dates

Study Major Dates

• Study Start (Actual): April 24, 2020
• Primary Completion (Actual): May 20, 2020
• Study Completion (Actual): July 30, 2020

Study Registration Dates

• First Submitted: June 15, 2021
• First Submitted That Met QC Criteria: June 21, 2021
• First Posted (Actual): June 22, 2021

Study Record Updates

• Last Update Posted (Actual): June 22, 2021
• Last Update Submitted That Met QC Criteria: June 21, 2021
• Last Verified: June 1, 2021

More Information

Terms related to this study

• Keywords: COVID-19; photodynamic therapy; methylene blue
• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Methylene Blue
• Other Study ID Numbers: 2206

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: The Local Ethics Committee of I.M. Sechenov First Moscow State Medical University did not give permission to provide individual participant data.

Drug and device information, study documents

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