Clinical trial NCT04380376: Low-doses Melphalan Inhalation in Patients With COVID-19 (CoronavIrus Disease 2019) 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
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: COVID-19
Viral Pneumonia
Keywords: COVID
treatment
inhalation
alkylating drug
pneumonia
Lead sponsor: Federal State Budgetary Institution, Pulmonology Scientific Research Institute
Sponsor class: OTHER_GOV
Collaborators: name: Medsi Clinic #1, Moscow
name: Moscow State University of Medicine and Dentistry
First posted: 2020-05-08
Enrollment: 60
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Prospective, Single-center, Open-Label, Central Assessor Blinded, Comparative Study
Primary purpose: TREATMENT

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.

Eligibility 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.

Primary outcomes:
measure: The changes of COVID Ordinal Outcomes Scale
timeFrame: baseline vs Day 14, day 28
measure: Percentage of the patients with Clinical Recovery
timeFrame: baseline vs day 7, day 14, day 28
measure: The changes of the Borg's scale
timeFrame: Baseline vs day 7, day 14, day 28
Secondary outcomes:
measure: CRP level
timeFrame: baseline, day 7, Day 14, Day 28
measure: Lymphocyte count
timeFrame: baseline, day 7, Day 14, Day 28
measure: D-dimer
timeFrame: baseline, day 7, Day 14, Day 28
measure: IL-6
timeFrame: baseline, day 7, Day 14, Day 28
measure: Percentage of patients without artificial lung ventilation
timeFrame: baseline, day 7, Day 14, Day 28
Other outcomes:
Locations:
city: Moscow
country: Russian Federation
facility: Kirill Zykov
city: Moscow
country: Russian Federation
facility: Clinical hospital
Study officials:
affiliation: Federal State Budgetary Institution, Pulmonology Scientific Research Institute
name: Kirill A Zykov, Prof
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.