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| Name | Class |
|---|---|
| Medsi Clinic #1, Moscow | OTHER |
| Moscow State University of Medicine and Dentistry | OTHER |
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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.
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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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Melphalan inhalations | Experimental | Inhalations with Melphalan 0,1 mg dissolved in 2 ml sodium chloride (NaCl) 0,9% 1 per day for 7-10 consequent days |
|
| Standard of care group | Other | Patients assigned to the standard of care group will not receive any additional therapy. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Melphalan | Drug | Inhalations with low doses of Melphalan for 7-10 consequent days |
|
| 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)
| 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:
| 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 |
| 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. |
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Inclusion Criteria:
fever >38 degrees Celsius, cough, dyspnea, SaO2 (arterial oxygen saturation) <95% (with room air)
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Kiril A Zykov, Prof | Contact | +79257729462 | kirillaz@inbox.ru | |
| Evgeny Sinitsyn | Contact | +79269490744 | sinymlad@list.ru |
| Name | Affiliation | Role |
|---|---|---|
| Kirill A Zykov, Prof | Federal State Budgetary Institution, Pulmonology Scientific Research Institute | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Kirill Zykov | Recruiting | Moscow | 115682 | Russia |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 11287812 | Background | 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. | |
| 19645099 | Background | 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. |
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| ID | Term |
|---|---|
| D000086382 | COVID-19 |
| D011024 | Pneumonia, Viral |
| D053120 | Respiratory Aspiration |
| D011014 | Pneumonia |
| ID | Term |
|---|---|
| D012141 | Respiratory Tract Infections |
| D007239 | Infections |
| D014777 | Virus Diseases |
| D018352 | Coronavirus Infections |
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| ID | Term |
|---|---|
| D008558 | Melphalan |
| D059039 | Standard of Care |
| ID | Term |
|---|---|
| D009588 | Nitrogen Mustard Compounds |
| D009150 | Mustard Compounds |
| D006846 | Hydrocarbons, Halogenated |
| D006838 | Hydrocarbons |
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Prospective, Single-center, Open-Label, Central Assessor Blinded, Comparative Study
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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.
| Standard of care | Other | the patients will receive only SOC (standard of care) treatment |
|
| 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 |
| Clinical hospital | Recruiting | Moscow | 125430 | Russia |
|
| 16620792 | Background | 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. |
| D003333 |
| Coronaviridae Infections |
| D030341 | Nidovirales Infections |
| D012327 | RNA Virus Infections |
| D008171 | Lung Diseases |
| D012140 | Respiratory Tract Diseases |
| D012120 | Respiration Disorders |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D009930 |
| Organic Chemicals |
| D010649 | Phenylalanine |
| D024322 | Amino Acids, Aromatic |
| D000598 | Amino Acids, Cyclic |
| D000596 | Amino Acids |
| D000602 | Amino Acids, Peptides, and Proteins |
| D019984 | Quality Indicators, Health Care |
| D011787 | Quality of Health Care |
| D006298 | Health Services Administration |
| D017530 | Health Care Quality, Access, and Evaluation |