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

Study Overview
=================
Brief Summary
-----------------
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.

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.

Official Title
-----------------
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

Conditions
-----------------
COVID-19, Viral Pneumonia

Intervention / Treatment
-----------------
* Drug: Melphalan
* Other: Standard of care


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age ≥18 years A patient must have confirmed the diagnosis of bi-lateral moderate / severe pneumonia ( viral or viral-bacterial with confirmed of suspected COVID-19). Presence new infiltrates or increase already available infiltrates of pulmonary infiltrates on lung CT within 48 hours before baseline. 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: Informed consent is withdrawn by the patient. The patient doesn't follow the instructions of the research staff regarding the requirements of the research protocol. Unable to contact the patient. 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. There is a violation of the criteria for inclusion and / or non-inclusion in the study. The patient has developed an adverse event, which, according to the researcher, makes further participation in the study unsafe for the patient. The licensing authority or ethics committee, for any reason, decides to discontinue the entire study or close this research center. A female patient becomes pregnant, is planning a pregnancy, or is breastfeeding while participating in this study.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Prospective, Single-center, Open-Label, Central Assessor Blinded, Comparative Study
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Melphalan inhalations<br>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<br>* Inhalations with low doses of Melphalan for 7-10 consequent days<br>* Other names: Alkeran;|
| Other: Standard of care group<br>Patients assigned to the standard of care group will not receive any additional therapy. | Other: Standard of care<br>* the patients will receive only SOC (standard of care) treatment<br>|

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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
COVID, treatment, inhalation, alkylating drug, pneumonia