Low-doses Melphalan Inhalation in Patients With COVID-19 (CoronavIrus Disease 2019) Pneumonia (MICOV)

Single-center, Prospective, Open-label, Comparator Study, Blind for Central Accessor to Access the Efficacy, Safety, and Tolerability of Inhalations of Low-doses of Melphalan in Patients With Pneumonia With Confirmed or Suspected COVID-19

This single-center, prospective, open-label, comparator study, blind for central accessor evaluates the efficacy, safety of inhalations of low-doses of melphalan in patients with pneumonia with confirmed or suspected COVID-19. All patients will receive 0,1 mg of melphalan in 7-10 daily inhalations 1 time per day.

Study Overview

• Status: Unknown
• Conditions: COVID-19; Viral Pneumonia
• Intervention / Treatment: Drug: Melphalan; Other: Standard of care

Detailed Description

It was previously shown that in ultra-low (more than 100 times lower than conventional therapeutic) doses inhalations of alkylating drug (melphalan) are effective in severe steroid-resistant bronchial asthma, a form of the disease often characterised by neutrophilic type of inflammation. The exacerbation frequency reduced after the treatment, steroid-sparing effect was shown, morphological signs of bronchial epithelial regeneration were revealed and quality of life of asthmatic patients, treated with ultra-low doses of melphalan, improved. In preclinical studies and studies with volunteers, it was found that inhalations of ultra-low doses of melphalan do not have cytotoxic properties, but have local and systemic anti-inflammatory effects and decrease the activation of lymphocytes due to blockade of heavy β-chain of the interleukin (IL)-2 surface receptor. In addition, in ultra-low concentrations, alkylating agents are able to disrupt the cell signalling through the receptor for tumor necrosis factor (TNF), thereby exerting a protective effect from the cytotoxic activity of TNF-α, which leads to the anti-inflammatory response.

Taking into account, that severe cases of COVID are characterised with hyperergic inflammatory response (and in some cases even with the development of "cytokine storm") it can be assumed that the inhalation use of low-doses of melphalan due to its anti-inflammatory properties can be effective treatment for patients with COVID-associated pneumonia.

• Study Type: Interventional
• Enrollment (Anticipated): 60
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Evgeny Sinitsyn; Phone Number: +79269490744; Email: sinymlad@list.ru
• Study Contact Backup: Name: Kiril A Zykov, Prof; Phone Number: +79257729462; Email: kirillaz@inbox.ru

Study Locations

• Russian Federation
  • Moscow, Russian Federation, 115682
    • Recruiting
    • Kirill Zykov
    • Contact: Evgeny Sinitsyn; Phone Number: +79269490744; Email: sinymlad@list.ru
    • Contact: Kirill Zykov, Prof; Phone Number: +79257729462; Email: kirillaz@inbox.ru
    • Sub-Investigator: Anna Rvacheva, PhD
    • Sub-Investigator: Evgeny Sinitsyn, MD
  • Moscow, Russian Federation, 125430
    • Recruiting
    • Clinical Hospital
    • Contact: Evgeny Sinitsyn; Phone Number: +79269490744; Email: sinymlad@list.ru
    • Contact: Kirill Zykov, MD; Phone Number: +79257729462; Email: kirillaz@inbox.ru

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Age ≥18 years
2. A patient must have confirmed the diagnosis of bi-lateral moderate / severe pneumonia ( viral or viral-bacterial with confirmed of suspected COVID-19).
3. Presence new infiltrates or increase already available infiltrates of pulmonary infiltrates on lung CT within 48 hours before baseline.
4. A patient has as minimum one of the following symptoms:

fever >38 degrees Celsius, cough, dyspnea, SaO2 (arterial oxygen saturation) <95% (with room air)

Exclusion Criteria:

1. Informed consent is withdrawn by the patient.
2. The patient doesn't follow the instructions of the research staff regarding the requirements of the research protocol.
3. Unable to contact the patient.
4. The researcher believes that participation in the study is not in the interests of the patient and / or further participation in the study is unsafe for the patient's health.
5. There is a violation of the criteria for inclusion and / or non-inclusion in the study.
6. The patient has developed an adverse event, which, according to the researcher, makes further participation in the study unsafe for the patient.
7. The licensing authority or ethics committee, for any reason, decides to discontinue the entire study or close this research center.
8. A female patient becomes pregnant, is planning a pregnancy, or is breastfeeding while participating in this study.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Melphalan inhalations; Inhalations with Melphalan 0,1 mg dissolved in 2 ml sodium chloride (NaCl) 0,9% 1 per day for 7-10 consequent days	Drug: Melphalan; Inhalations with low doses of Melphalan for 7-10 consequent days; Other Names: Alkeran
Other: Standard of care group; Patients assigned to the standard of care group will not receive any additional therapy.	Other: Standard of care; the patients will receive only SOC (standard of care) treatment

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The changes of COVID Ordinal Outcomes Scale	The number of patients with the clinical improvement is defined as an improvement of two points (from the status at baseline) on an ordinal scale of clinical improvement on day 28 or discharge from hospital ( whatever occurs earlier); Death; Hospitalized with Invasive mechanical ventilation plus additional organ support - ECMO / pressors / RRT; Hospitalized with intubation and mechanical ventilation; Hospitalized on non-invasive ventilation or high flow oxygen.; Hospitalized on a mask or nasal prongs.; Hospitalized no oxygen therapy.; Ambulatory, with limitation of activities.; Ambulatory, no limitation of activities. I. No clinical or virological evidence of infection.	baseline vs Day 14, day 28
Percentage of the patients with Clinical Recovery	Percentage of the patients with clinical recovery which is defined as a normalisation of fever, respiratory rate, and oxygen saturation, and improvement of cough, sustained for at least 72 hours, or live hospital discharge, whichever comes first. Normalization and improvement criteria: Fever - <37°C,; Respiratory rate - ≤24/minute on room air,; Oxygen saturation - >94% on room air,; Cough - mild or absent on a patient reported scale of severe, moderate, mild, absent.	baseline vs day 7, day 14, day 28
The changes of the Borg's scale	The evaluation of changes in modified Borg dyspnea scale. From 0 to 10 units.A lower score means a better clinical result (0 is the absence of dyspnea, and 10 - is maximal dyspnea). Minimal clinically important difference is 1 unit.	Baseline vs day 7, day 14, day 28

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
CRP level	Change in C-reactive protein (CRP) level from baseline in mg/ml. A lower level of CRP means a better clinical result.	baseline, day 7, Day 14, Day 28
Lymphocyte count	Change in blood absolute lymphocyte count from baseline. A higher number of lymphocytes means a better clinical result.	baseline, day 7, Day 14, Day 28
D-dimer	Change in blood D-dimer level from baseline. A lower level of D-dimer means a better clinical result.	baseline, day 7, Day 14, Day 28
IL-6	Change in peripheral blood IL-6 level from baseline. A lower level of IL-6 means a better clinical result.	baseline, day 7, Day 14, Day 28
Percentage of patients without artificial lung ventilation	Percentage of patients without artificial lung ventilation during the study. A lower percentage of patients means a better clinical result.	baseline, day 7, Day 14, Day 28

Collaborators and Investigators

• Sponsor: Federal State Budgetary Institution, Pulmonology Scientific Research Institute
• Collaborators: Moscow State University of Medicine and Dentistry; Medsi Clinic #1, Moscow

Publications and helpful links

General Publications

• Pukhalsky AL, Shmarina GV. Stimulatory and protective effects of alkylating agents applied in ultra-low concentrations. Pharmacology. 2001;62(3):129-32. doi: 10.1159/000056084.
• Pukhalsky A, Shmarina G, Alioshkin V, Sabelnikov A. Alkylating drugs applied in non-cytotoxic doses as a novel compounds targeting inflammatory signal pathway. Biochem Pharmacol. 2006 Nov 30;72(11):1432-8. doi: 10.1016/j.bcp.2006.03.008. Epub 2006 Mar 14.
• Pukhal'skii AL, Shmarina GV, Zykov KA, Aleshkin VA. [Effect of steroid therapy on the clinical course of bronchial asthma]. Vestn Ross Akad Med Nauk. 2009;(6):3-9. Russian.

Study record dates

Study Major Dates

• Study Start (Actual): April 30, 2020
• Primary Completion (Anticipated): October 30, 2020
• Study Completion (Anticipated): October 30, 2020

Study Registration Dates

• First Submitted: May 6, 2020
• First Submitted That Met QC Criteria: May 6, 2020
• First Posted (Actual): May 8, 2020

Study Record Updates

• Last Update Posted (Actual): May 12, 2020
• Last Update Submitted That Met QC Criteria: May 10, 2020
• Last Verified: May 1, 2020

More Information

Terms related to this study

• Keywords: treatment; COVID; pneumonia; inhalation; alkylating drug
• Additional Relevant MeSH Terms: Pathologic Processes; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Respiration Disorders; Lung Diseases; COVID-19; Respiratory Aspiration; Pneumonia; Pneumonia, Viral; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Melphalan
• Other Study ID Numbers: PSRI05-20

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

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