Intramuscular Effect of Polymerized Type I Collagen on the Cytokine Storm in COVID-19 Patients

Study Overview
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Brief Summary
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SARS-CoV-2 infection induces a hyperinflammatory syndrome, causing the acute respiratory distress syndrome, massive lung cell destruction and, as a plausible sequelae, pulmonary fibrosis in COVID-19 patients. Current focus has been on the development of novel immunosuppressant therapies, in order to control the cytokine storm in COVID-19 patients. Thus, the effect of steroids, intravenous immunoglobulin, non-steroidal immunosuppressants, selective cytokine blockade, JAK/STAT pathway inbhibition, and mesenchymal precursor cells have been evaluated. Based on the above information, we propose COLLAGEN-POLYVINYLPYRROLIDONE (Distinctive name: FibroquelMR, active substance: Collagen-polyvinylpyrrolidone, pharmaceutical form: intramuscular injectable solution, with sanitary registration No. 201M95 SSA IV and SSA code: 010 000 3999) as a potential drug for the downregulation of the cytokine storm. Polymerized type I collagen reduces the expression of IL-1β, IL-8, TNF-alpha, TGF-β1, IL-17, Cox-1, leukocyte adhesion molecules (ELAM-1, VCAM- 1 and ICAM-1), some other mediators of inflammation and increases the levels of IL-10 and the number of regulatory T cells. In addition, it promotes the mechanisms of inhibition of tissue fibrosis, without adverse effects in rheumatoid arthritis and osteoarthritis.

Detailed Description
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This is a single center, double-blind, placebo-controlled, randomized clinical trial that compares PTIC with placebo in adult outpatients with confirmed COVID-19. The study was approved by the institutional review board at Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán (INCMNSZ, reference no. IRE 3412-20-21-1) and was conducted in compliance with the Declaration of Helsinki (World Medical Association. World Medical Association Declaration of Helsinki. JAMA. 2013;310(20):2191-2194.), the Good Clinical Practice guidelines, and local regulatory requirements. All participants will provide written informed consent. Trial candidates will be identified in a prospective database of patients that go to a medical appointment at the hospital and be discharged home with a diagnosis of COVID-19 and symptomatic treatment. Diagnosis will base on suggestive symptoms (fever, headache, cough or dyspnea, plus another symptom such as malaise, myalgias, arthralgias, rhinorrhea, throat pain, conjunctivitis, vomiting or diarrhea) and positive real-time reverse-transcription polymerase chain (RT-PCR). Staff will reach candidates via telephone calls and inform them about the purpose of the study. Once in the hospital study site, and after verifying inclusion (suggestive symptoms and PCR) and exclusion criteria, patients will sign the informed consent before being randomly allocated to either PTIC or matching placebo. Exclusion criteria includes hypersensitivity to PTIC or any of its excipients, COVID-19 patients that require hospitalization, all pregnant or breast-feeding patients, patients with chronic kidney disease as determined by calculating an estimated glomerular filtration rate (eGFR), or need for hemodialysis or hemofiltration, decompensated cirrhosis, congestive heart failure (New York Heart Association class III or IV), patients with cerebrovascular disease, autoimmune disease, cancer, multiorgan failure or immunocompromised (solid organ transplant recipient or donor, bone marrow transplant recipient, AIDS, or taking immunosuppressant biologic drugs or corticosteroids). During the first day of enrollment, candidates will receive the study supplies that consist of the study medication or placebo, a pulse oximeter, and a symptom questionnaire booklet. Patients will be instructed on how to administer the study medication, how to use the oxygen monitor and how to complete the questionnaires. Also, staff will administer the first dose of study medication or placebo on site. Phone contact will make daily during the first 3 days of the trial to address participants' questions, address any medication-related issues, and encourage completion of questionnaires. Additional phone calls will be conducted on a case-by-case basis when participant's survey data indicated values outside of expected ranges. For participants that will have a worsening disease course (89% or lower while breathing ambient air), study staff will recommend to attend at emergency department. If the patient will require hospitalization and treatment with dexamethasone, then patient will be eliminated from the study. Patients will be evaluated by staff on day 8, 15 and 97 (1, 7 and 90 days after last dose of medication or placebo, respectively). Participants The study will include non-hospitalized adults with COVID-19 whose symptoms start within the previous 7 days counted from the first dose of study medication. Individuals will ask to provide personal information (date of birth, type of job, educational level, previous contact with infected individuals, and date of symptom onset), preexisting conditions (systemic hypertension, diabetes mellitus, cardiovascular disease, cerebrovascular disease, hypertriglyceridemia, dyslipidemia) and symptoms. Real-time reverse-transcription polymerase chain Naso/oropharyngeal swab samples will obtain and send in a universal transport medium for viruses. Nucleic acid extraction will do using the NucliSens easy-MAG system (bioMérieux, Boxtel, Netherlands). RT-PCR will carry out in the Applied Biosystems 7500 thermocycler (Applied Biosystems, Foster City, CA, USA) using primers and conditions described elsewhere; the cycle threshold value for positivity will 38 (Corman VM, 2020). Study sample According to a study completed previously in Mexico City (Valencia CA, 2008), the mean oxygen saturation readings of a selected elderly sample without cardiopulmonary comorbidities was 95.3 ± 1.7%. Since a notorious drop in such readings was not to be expected (due to the non-severe nature of disease in our sample of outpatients), it was arbitrarily decided that a difference of 2 percentage points (beyond the preceding standard deviation cutoff points) between groups would be clinically significant in this pilot study. In this regard, total sample size assuming alpha=0.05 and power=0.80 was 32. However, to increase the power to detect meaningful differences in frequency of cough between groups (a potential indicator of lung disease), it was decided to include 45 patients per group (based on a baseline frequency of 60% (Wang DA, 2020) and a reduction of symptom frequency by half with the experimental intervention, keeping alpha and power values fixed). Randomization Patients will be randomized in a 1:1 fashion to PTIC or matching placebo. Randomization schedules will prepare in Excel, which displayed randomization assignment to the laboratory manager, who will prepare the study materials, including the study drug or placebo. All outcome assessors, investigators, and research staff who will be in contact with participants will blind to participant treatment assignment. Intervention Participants will receive an intramuscular dose of either PTIC (1.5 ml, equivalent to 12.5 mg of collagen) every 12 h for 3 days and then every 24 h for 4 days, or matching placebo. Only acetaminophen or acetylsalicylic acid will allow as concomitant therapy. Data collection Personal data, contact and exposure history, clinical presentation, chest computed (CT) tomography, laboratory tests, previous treatment and outcome data will collect both prospectively and from inpatient medical records. Laboratory data collected from each patient from study days 1 (baseline), 8 (1-day post-treatment), 15 (7 days post-treatment) and 97 (90 days post-treatment) will include complete blood count, coagulation profile, serum biochemical tests (including renal and liver function tests, electrolytes, lactate dehydrogenase, D dimer and creatine kinase), serum ferritin, and biomarkers of infection, such as procalcitonin. Chest CT scans will be done in all patients at baseline.

Official Title
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Effect of Collagen-Polyvinylpyrrolidone for the Treatment of Hyperinflammation and the Pulmonary Fibrosis in COVID-19 Patients. Double Blind Placebo-controlled Pilot Trial

Conditions
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Covid19, Cytokine Storm, Regulation of Inflammatory Response, Pulmonary Fibrosis

Intervention / Treatment
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* Drug: Collagen-Polyvinylpyrrolidone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: According to the sample size calculation (Cohen's d calculation, using a 50% decrease in IP-10 as the expected effect size), 90 COVID-19 patients will be recruited (symptoms: cough, expectoration, odynophagia, dyspnea with or without fever; radiographic findings by imaging study: inflammatory infiltrates), of both sexes, older than 18 years. Participants will be enrolled, even when they do not have a laboratory-confirmed SARS-CoV-2 infection as determined by a positive reverse transcription, polymerase-chain-reaction (RT-PCR) assay result. Patients will be included if they have progressive disease consistent with ongoing SARS-CoV -2 infection. Patients with laboratory predictors of mild to severe disease (D-dimer> 1000 ng/ml; total lymphocytes <800 cells/µl, creatine phosphokinase> 2 times upper limit of the normal range; elevated troponins and ferritin> 300 µg/L) will be included. Only those patients who are negative to the intradermal reaction of polymerized type I collagen (subcutaneous application of 0.2 ml of the drug on the forearm, evaluation at 24-48h) will be included. Patients with mild to severe disease, peripheral oxygen saturation (SpO2) <92% on room air, or requiring supplemental oxygen, or mechanical ventilation will be recruited. There will be no limit to the duration of symptoms prior to enrollment. Only those patients who are not participating in another protocol and who are not receiving biological therapy and whose standardized therapy is suggested will be included (AmoxiClav or ceftriaxone, or azithromycin, clarithromycin or doxycycline, ivermectin, low molecular weight anticoagulants, paracetamol). All patients who agree to participate in the protocol and from whom written informed consent is obtained will be included. Exclusion Criteria: All patients positive for intradermal reaction to polymerized type I collagen (allergy to study producto) will be excluded. All pregnant or breast-feeding patients, patients with chronic kidney disease as determined by calculating an estimated glomerular filtration rate (eGFR), or need for hemodialysis or hemofiltration, patients with cerebrovascular disease, autoimmune disease, cancer, multiorgan failure or immunodeficiencies (HIV, transplant patients, hematological diseases, patients with chemotherapy) will be excluded.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Double Blind Placebo-controlled Clinical Trial
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Active comparator or polymerized type I collagen<br>1.5 mL of polymerized type I collagen every 12 h for 3 days and then every 24 h for 4 days (in total 10 injections in 7 days) | Drug: Collagen-Polyvinylpyrrolidone<br>* 1.5 mL of polymerized-type I collagen or placebo, every 12 h for 3 days and then every 24 h for 4 days (in total 10 injections in 7 days)<br>* Other names: polymerized type I collagen;|
| Placebo Comparator: Placebo comparator o placebo<br>1.5 mL of placebo, every 12 h for 3 days and then every 24 h for 4 days (in total 10 injections in 7 days) | Drug: Collagen-Polyvinylpyrrolidone<br>* 1.5 mL of polymerized-type I collagen or placebo, every 12 h for 3 days and then every 24 h for 4 days (in total 10 injections in 7 days)<br>* Other names: polymerized type I collagen;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical primary Outcome measure | It will be considered as primary outcome if the patients meet the first criterion, or 2 of the remaining 3: No oxygen required to maintain oxygen saturation more than 92%, Decrease in severity category from Table 1 by at least 1 level, or Reduction in the time of symptoms, by at least 30% compared to placebo and baseline, or recovery of at least 30% the number of lymphocytes compared to placebo and baseline. | 14 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Immunological secondary outcome measure | It will be considered as secondary outcome if the patients meet the first criterion, or 2 of the remaining 3: significant decrease in serum IP-10 (at least 30% compared to placebo and baseline), since this chemokine is directly associated with the progression and severity of COVID-19, significant decrease in serum pro-inflammatory cytokines (TNF-a, IL-1β, IL-7, at least 30% compared to placebo and baseline), significant decrease in the percentage of circulating effector T cells (at least 30% compared to placebo and baseline), or significant improvement from computerized axial tomography at re-examination. This improvement is defined as: a decrease of at least 40% in parenchymal attenuation, the appearance of ground glass, nodular opacities, thickening of interlobular septa and / or thickening of bronchial walls. | 3 months |