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

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ClinicalTrials.gov Identifier: NCT04380376
Recruitment Status : Recruiting
First Posted : May 8, 2020
Last Update Posted : May 12, 2020
Sponsor:
Collaborators:
Medsi Clinic #1, Moscow
Moscow State University of Medicine and Dentistry
Information provided by (Responsible Party):
Kirill Zykov, Federal State Budgetary Institution, Pulmonology Scientific Research Institute

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.

Condition or disease Intervention/treatment Phase
COVID-19 Viral Pneumonia Drug: Melphalan Other: Standard of care Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 60 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Prospective, Single-center, Open-Label, Central Assessor Blinded, Comparative Study
Masking: Single (Outcomes Assessor)
Masking Description: An independent central blinded assessor will be blinded to study treatment and will review the clinical response assessments. In case of a discrepancy with the Investigator's assignment of clinical response, the adjudication committee's assessment will prevail.
Primary Purpose: Treatment
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
Actual Study Start Date : April 30, 2020
Estimated Primary Completion Date : October 30, 2020
Estimated Study Completion Date : October 30, 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Pneumonia

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 Name: Alkeran

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




Primary Outcome Measures :
  1. The changes of COVID Ordinal Outcomes Scale [ Time Frame: baseline vs Day 14, day 28 ]

    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)

    1. Death
    2. Hospitalized with Invasive mechanical ventilation plus additional organ support - ECMO / pressors / RRT
    3. Hospitalized with intubation and mechanical ventilation
    4. Hospitalized on non-invasive ventilation or high flow oxygen.
    5. Hospitalized on a mask or nasal prongs.
    6. Hospitalized no oxygen therapy.
    7. Ambulatory, with limitation of activities.
    8. Ambulatory, no limitation of activities. I. No clinical or virological evidence of infection.

  2. Percentage of the patients with Clinical Recovery [ Time Frame: baseline vs day 7, day 14, day 28 ]

    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.

  3. The changes of the Borg's scale [ Time Frame: Baseline vs day 7, day 14, day 28 ]
    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.


Secondary Outcome Measures :
  1. CRP level [ Time Frame: baseline, day 7, Day 14, Day 28 ]
    Change in C-reactive protein (CRP) level from baseline in mg/ml. A lower level of CRP means a better clinical result.

  2. Lymphocyte count [ Time Frame: baseline, day 7, Day 14, Day 28 ]
    Change in blood absolute lymphocyte count from baseline. A higher number of lymphocytes means a better clinical result.

  3. D-dimer [ Time Frame: baseline, day 7, Day 14, Day 28 ]
    Change in blood D-dimer level from baseline. A lower level of D-dimer means a better clinical result.

  4. IL-6 [ Time Frame: baseline, day 7, Day 14, Day 28 ]
    Change in peripheral blood IL-6 level from baseline. A lower level of IL-6 means a better clinical result.

  5. Percentage of patients without artificial lung ventilation [ Time Frame: baseline, day 7, Day 14, Day 28 ]
    Percentage of patients without artificial lung ventilation during the study. A lower percentage of patients means a better clinical result.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04380376


Contacts
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Contact: Kiril A Zykov, Prof +79257729462 kirillaz@inbox.ru
Contact: Evgeny Sinitsyn +79269490744 sinymlad@list.ru

Locations
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Russian Federation
Kirill Zykov Recruiting
Moscow, Russian Federation, 115682
Contact: Evgeny Sinitsyn    +79269490744    sinymlad@list.ru   
Contact: Kirill Zykov, Prof    +79257729462    kirillaz@inbox.ru   
Sub-Investigator: Evgeny Sinitsyn, MD         
Sub-Investigator: Anna Rvacheva, PhD         
Clinical hospital Recruiting
Moscow, Russian Federation, 125430
Contact: Kirill Zykov, MD    +79257729462    kirillaz@inbox.ru   
Contact: Evgeny Sinitsyn    +79269490744    sinymlad@list.ru   
Sponsors and Collaborators
Federal State Budgetary Institution, Pulmonology Scientific Research Institute
Medsi Clinic #1, Moscow
Moscow State University of Medicine and Dentistry
Investigators
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Principal Investigator: Kirill A Zykov, Prof Federal State Budgetary Institution, Pulmonology Scientific Research Institute
Publications:
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Responsible Party: Kirill Zykov, Deputy director for Science and Innovations, Federal State Budgetary Institution, Pulmonology Scientific Research Institute
ClinicalTrials.gov Identifier: NCT04380376    
Other Study ID Numbers: PSRI05-20
First Posted: May 8, 2020    Key Record Dates
Last Update Posted: May 12, 2020
Last Verified: May 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Kirill Zykov, Federal State Budgetary Institution, Pulmonology Scientific Research Institute:
COVID
treatment
inhalation
alkylating drug
pneumonia
Additional relevant MeSH terms:
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Pneumonia, Viral
Pneumonia
Respiratory Aspiration
Lung Diseases
Respiratory Tract Diseases
Respiratory Tract Infections
Respiration Disorders
Pathologic Processes
Virus Diseases
Melphalan
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs