Effect of polymerized type I collagen in hyperinflammation of adult outpatients with symptomatic COVID-19: a double blind, randomised, placebo-controlled clinical trial

ABSTRACT BACKGROUND Currently, therapeutic options for ambulatory COVID-19 patients are limited. OBJECTIVE To evaluate the safety, efficacy and effect of the intramuscular administration of polymerized type I collagen (PTIC) on hyperinflammation, oxygen saturation and symptom improvement in adult outpatients with symptomatic COVID-19. DESIGN Double-blind, randomised, placebo-controlled clinical trial of PTIC vs placebo. SETTING Single Third-level hospital in Mexico City (Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán) PARTICIPANTS Eighty-nine adult participants with a confirmed COVID-19 diagnosis and symptom onset within the 7 days preceding recruitment were included from August 31, 2020 to November 7, 2020 and followed for 12 weeks. Final date of follow-up was February 4, 2021. INTERVENTIONS Patients were randomly assigned to receive either 1.5 ml of PTIC intramuscularly every 12 h for 3 days and then every 24 h for 4 days (n=45), or matching placebo (n=44). MAIN OUTCOMES AND MEASURES The primary outcome was a mean reduction of at least 50% in the level of IP-10 compared to baseline. The secondary outcomes were mean oxygen saturation ≥92% while breathing ambient air and duration of symptoms. RESULTS Of 89 patients who were randomised, 87 (97.8%) were included in an intention-to-treat analysis; 37 (41.6%) were male and mean age was 48.5±14.0 years. The IP-10 levels decreased 75% in the PTIC group and 40% in the placebo group vs baseline. The comparison between treatment vs placebo was also statistically significant ( P= 0.0047). The IL-8 (44%, P= 0.045), M-CSF (25%, P= 0.041) and IL-1Ra (36%, P= 0.05) levels were also decreased in the PTIC group vs baseline. Mean oxygen saturation ≥92% was achieved by 40/44 (90%), 41/42 (98%) and 40/40 (100%) of participants that received PTIC at 8, 15 and 97 days of follow-up vs 29/43 (67%), 31/39 (80%) and 33/37 (89%) of patients treated with placebo ( P =0.001). The unadjusted accelerated failure time model showed that patients treated with PTIC achieved the primary outcome 2.70-fold faster ( P <0.0001) than placebo. In terms of risk, the group of patients treated with PTIC had a 63% lower risk of having a mean oxygen saturation <92% vs placebo ( P <0.0001). Symptom duration in patients treated with PTIC was reduced by 6.1±3.2 days vs placebo. No differences in adverse effects were observed between the groups at 8, 15 and 97 days of follow-up. CONCLUSIONS In this study, treatment with PTIC down-regulated IP-10, IL-8, M-CSF and IL-Ra levels, which could explain the PTIC effect on the higher proportion of patients with mean oxygen saturation readings ≥92% and a shorter duration of symptoms as compared to patients treated with placebo. Although results are encouraging, larger randomised trials are needed. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT04517162