key: cord-0301090-svo9hjen
authors: Ramos-Zaldivar, H. M.; Reyes-Perdomo, K. G.; Espinoza-Moreno, N. A.; Dox-Cruz, E. T.; Aguirre Urbina, T. C.; Rivera Caballero, A. Y.; Perdomo Dominguez, E. S.; Pena Calix, S. G.; Monterroso-Reyes, J. M.; Caballero Vampaacutesquez, E. F.; Zelaya Ortiz, T. S.; Rodriguez-Machado, H. E.; Forgas Solis, M. A.; Sebilla Silva, I.; Zavala Galeano, M. E.; Morga Alvarado, A. A.; Solis Medina, A. M. N.; Guerrero-Diaz, L. M.; Jimenez-Faraj, J. E.; Perello Santos, C. A.; Moncada Arita, W. A.; Valdiviezo Montufar, D. F.; Hernandez Sabillon, J. D.; Sorto G., M. L.; Padilla Navarro, X. X.; Palomo-Bermudez, V. A.
title: A nonrandomized phase 2 trial of oral thymic peptides in hospitalized patients with Covid-19
date: 2021-12-07
journal: nan
DOI: 10.1101/2021.12.05.21267318
sha: 0099a02e7cda00372ab23146835a4cf093ce1c15
doc_id: 301090
cord_uid: svo9hjen

Background Coronavirus disease 2019 (Covid-19) active cases continue to demand the development of safe and effective treatments. This is the first clinical trial to evaluate the safety and efficacy of oral thymic peptides. Methods We conducted a nonrandomized phase 2 trial with a historic control group to evaluate the safety and efficacy of a daily 250-mg oral dose of thymic peptides in the treatment of hospitalized Covid-19 patients. Comparison based on standard care from registry data was performed after propensity score matching. The primary outcomes were survival, time to recovery and the number of participants with treatment-related adverse events or side effects by day 20. Results A total of 44 patients were analyzed in this study, 22 in the thymic peptides group and 22 in the standard care group. There were no deaths in the intervention group, compared to 24% mortality in standard care by day 20 (log-rank P=0.02). The Kaplan-Meier analysis showed a significantly shorter time to recovery by day 20 in the thymic peptides group as compared with standard care (median, 6 days vs. 12 days; hazard ratio for recovery, 2.75 [95% confidence interval, 1.34 to 5.62]; log-rank P=0.002). No side effects or adverse events were reported. Conclusion In patients hospitalized with Covid-19, the use of thymic peptides reported no side effects, adverse events, or deaths by day 20. When compared with registry data, a significantly shorter time to recovery and mortality reduction was measured. The Catholic University of Honduras Medical Research Group (GIMUNICAH) is working on a more extensive phase 3 trial. Trial registration: ClinicalTrials.gov NCT04771013. February 25, 2021.

Coronavirus disease 2019 active cases continue to demand the development of safe and effective treatments. This is the first clinical trial to evaluate the safety and efficacy of oral thymic peptides.

We conducted a nonrandomized phase 2 trial with a historic control group to evaluate the safety and efficacy of a daily 250-mg oral dose of thymic peptides in the treatment of hospitalized Covid-19 patients. Comparison based on standard care from registry data was performed after propensity score matching. The primary outcomes were survival, time to recovery and the number of participants with treatment-related adverse events or side effects by day 20.

A total of 44 patients were analyzed in this study, 22 in the thymic peptides group and 22

in the standard care group. There were no deaths in the intervention group, compared to 24% mortality in standard care by day 20 (log-rank P=0.02). The Kaplan-Meier analysis showed a significantly shorter time to recovery by day 20 in the thymic peptides group as compared with standard care (median, 6 days vs. 12 days; hazard ratio for recovery, 2.75 [95% confidence interval, 1.34 to 5.62]; log-rank P=0.002). No side effects or adverse events were reported.

. CC-BY-NC-ND 4.0 International license It is made available under a perpetuity.

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The copyright holder for this this version posted December 7, 2021. ; https://doi.org/10.1101/2021.12.05.21267318 doi: medRxiv preprint

In patients hospitalized with Covid-19, the use of thymic peptides reported no side effects, adverse events, or deaths by day 20. When compared with registry data, a significantly shorter time to recovery and mortality reduction was measured. The Catholic University of Honduras Medical Research Group (GIMUNICAH) is working on a more extensive phase 3 trial. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted December 7, 2021. ; https://doi.org/10.1101/2021.12.05.21267318 doi: medRxiv preprint

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), responsible for the coronavirus disease 2019 (Covid- 19) global pandemic, continues to spread rapidly with increasing daily hospitalizations and deaths worldwide. 1 Even though vaccine platforms are expected to significantly reduce the burden of disease, 2 the amount of active Covid-19 cases continue to demand the development of effective treatments. Emerging viral variants 3,4 and vaccination hesitancy 5,6 may extend or aggravate the problem, particularly in developing countries where access to vaccines is already limited. 7 The glucocorticoid dexamethasone, alone or in combination with tocilizumab, is the only treatment that has shown a reduction in mortality in large randomized controlled trials, 8 a benefit circumscribed to patients requiring oxygen supplementation. 9 Results from corticosteroids suggest that immune regulation is key in Covid-19 management.

Nevertheless, immunosuppression alone might be improved by more complex regulatory mechanisms.

One such theorized approach by the Catholic University of Honduras Medical Research Group (GIMUNICAH), and previously discussed by others, 10-16 is through thymic regulation. Evidence supporting this hypothesis is gradually emerging, and the virtual absence of side effects 10 confers thymic peptides a particularly advantageous potential in the management of vulnerable groups most affected by Covid-19.

A mechanistic model by Palmer et al. showed that the risk of Covid-19 hospitalization rises exponentially with age and inversely proportional to T-cell production and thymus degeneration. 17 In an observational study conducted on ICU patients, enlargement of . CC-BY-NC-ND 4.0 International license It is made available under a perpetuity.

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The copyright holder for this this version posted December 7, 2021. ; https://doi.org/10.1101/2021.12.05.21267318 doi: medRxiv preprint the thymus during infection was associated with lower mortality rates. 18 Further research on ex vivo treatment with thymosin alpha 1 (Tα1) of blood from Covid-19 patients has revealed mitigation of cytokine expression and inhibited lymphocyte activation in a CD8+ T-cell subset. 19 Finally, retrospective studies of subcutaneous Tα1 and a prospective randomized controlled trial on intramuscular thymic peptides in Covid-19 patients have shown reduction in mortality rates and improvement of the T cell system with normalization of IL-6 levels, respectively. [20] [21] [22] The pathogenesis of Covid-19 is thought to be driven by SARS-COV-2 replication in the early stages of disease, while a dysregulated immune/inflammatory response appears to promote tissue damage in later phases. 8 Therefore, the use of thymic peptides might improve immunomodulation and clinical outcomes in the complex management of COVID-19 of moderate to severe cases. We report a nonrandomized phase 2 clinical trial with historic controls from Hospital Santa Bárbara Integrado (HSBI) to evaluate the safety and efficacy of oral thymic peptides in the treatment of hospitalized Covid-19 patients in Honduras.

We conducted a nonrandomized, open-label, phase 2 clinical study to evaluate the safety and efficacy of thymic peptides in the treatment of hospitalized Covid-19 patients in Honduras. All patients were enrolled from HSBI in consecutive sampling. A participant-level comparison based on a control group by propensity score matching from registry data was performed. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint 23 defined as a patient with or without risk factors that presents with warning signs (shortness of breath, tachypnea), and altered inflammatory parameters. Patients were required to present with at least one of the following: oxygen saturation level below 94%; complete blood count showing lymphopenia, neutrophilia, or both; positive C-reactive protein; chest radiography or computed tomography scan with ground-glass opacities. All patients were hospitalized with oxygen by mask or nasal prongs, which corresponds to a score of 5 according to the World Health Organization (WHO) clinical progression scale. 24 Pregnant and breast-feeding women, as well as organ transplant recipients, were not eligible. For the comparison group, registry data from June 2020 to February 2021 was considered, as standardization of Stage IIB therapeutic management to its current guideline in Honduras occurred on May 2020. 23

Thymic peptides were isolated from 25 thymus glands of 6-to 10-month-old calves bred in an organic production system (free of antibiotics, antiparasitic drugs, anabolic steroids, or other hormonal treatment), through acid lysis with a modified protocol from GIMUNICAH, prepared by the Universidad Católica de Honduras. The entire cervical and thoracic thymus glands portions were utilized, obtaining 100g of lyophilized is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted December 7, 2021. ; https://doi.org/10.1101/2021.12.05.21267318 doi: medRxiv preprint product. Crystalized stevia was used as sweetener. The amino acidic composition of the calf thymus lysate, as determined by reversed-phase high-performance liquid chromatography after hydrolysis, is detailed in Table S1 . Thymic peptides were administered orally once a day by trained physicians either one hour before or two hours after a meal, in a 250-mg dose, dissolved in 50 mL of water, until hospital discharge or death within a 20-day period.

Patients were evaluated daily during their hospitalization, from day 1 through 20.

Clinical status was assessed on an eight-category ordinal scale (defined below). Adverse events ≥ Grade 3, as defined by the Common Terminology Criteria for Adverse Events Version 5.0 (CTCAE v5.0), were analyzed. The occurrence of side effects was assessed weekly through the General Assessment of Side Effects (GASE) form. Patients who agreed to follow-ups by phone communication were monitored for adverse events or side effects up to two weeks after discharge.

The primary outcome measures included time to recovery and the number of participants with treatment-related adverse events and side effects. The first was measured in days to clinical recovery, defined as the first day, during the 20 days after enrollment, on which a patient met the criteria for category 1, 2, or 3 on an eightcategory ordinal scale (as described by Beigel et al.) . 25 The categories are as follows: 1, not hospitalized and no limitations of activities; 2, not hospitalized, with limitation of activities, home oxygen requirement, or both; 3, hospitalized, not requiring supplemental oxygen and no longer requiring ongoing medical care; 4, hospitalized, not . CC-BY-NC-ND 4.0 International license It is made available under a perpetuity.

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The copyright holder for this this version posted December 7, 2021. ; https://doi.org/10.1101/2021.12.05.21267318 doi: medRxiv preprint requiring supplemental oxygen but requiring ongoing medical care (related to or other medical conditions); 5, hospitalized, requiring any supplemental oxygen; 6, hospitalized, requiring noninvasive ventilation or use of high-flow oxygen devices; 7, hospitalized, receiving invasive mechanical ventilation or extracorporeal membrane oxygenation; and 8, death. The time to recovery assessment was modified from the first protocol version to better adhere to WHO recommendations on clinical progression

outcomes. An amendment submission was presented to the IRB on April 4, 2021, and it was approved April 8, 2021. Adverse events ≥ Grade 3 were registered using the CTCAE v5.0 and side effects were evaluated as defined by the GASE.

The secondary outcome measure was overall survival, defined as the time from the start of treatment until death due to any reason in the 20-day period. Although hospital average length of stay was removed as a secondary outcome for considering it a less reliable metric, it was analyzed as a complementary analysis using the Kaplan-Meier method.

For the comparison group, propensity score matching using IBM SPSS ver.25 (IBM Co., Armonk, NY, USA) was performed based on registry data from HSBI. Heatmap and dimensional reduction techniques using principal component analysis were applied to determine the two groups global comparison.

Analyses on time to recovery, mortality, length of stay, and time to supplemental oxygen withdrawal were estimated using the Kaplan-Meier method. Cumulative is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted December 7, 2021. ; https://doi.org/10.1101/2021.12.05.21267318 doi: medRxiv preprint incidence curves were compared between the two groups with the log-rank test. The

Cox proportional-hazard model was used to estimate the hazard ratio and 95% confidence interval. For time to recovery, data for patients who died or did not recover were censored at day 20. For mortality, patients who did not die were censored at day 20. For length of stay, patients who were not discharged at day 20 and patients who died were censored at day 20. For supplemental oxygen withdrawal, patients who still required oxygen therapy after day 20 and patients who died were censored at day 20.

Differences in base drug treatments among groups were analyzed using the Chi-square test or the Fisher's exact test when appropriate. Safety analysis findings are descriptive in nature and not based on formal statistical hypothesis testing. The number of patients that presented adverse events in the prospectively treated group which were ≥ Grade 3 according to CTCAE v5.0, and the number that manifested side effects according to GASE, were considered. All P values are two-sided, and all analyses were performed according to the intention-to-treat principle.

Written informed consent prior to inclusion in the study was obtained from all participants or a legal representative if they were unable to provide it. Research was is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted December 7, 2021. ; https://doi.org/10.1101/2021.12.05.21267318 doi: medRxiv preprint but authorized a historic control group. Treatment approval for the clinical trial was given until 20 patients in the group receiving oral thymic peptides reached conclusion either by medical discharge or death within a 20-day hospitalization follow-up. Data collection approval was granted for safety data follow-up of discharged patients, which occurred by phone communication for up to two more weeks.

The Universidad Católica de Honduras had no role in the design or conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

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is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint Between February 10, 2021, and April 12, 2021, a total of 31 patients were prospectively assessed for eligibility for the intervention group (Fig. 1 is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint For the comparison group, 462 patient records from the Covid-19 hospital ward at HSBI were assessed for eligibility (Fig. 1) (Table   S2 ). 26 The lowest match tolerance (MT = 0.4) was used in SPSS ver.25 that allowed for 22 paired patients. The characteristics of the resulting sample of 44 patients for the intention-to-treat analysis are shown in Table 1 . There was a significant (P=0.01) difference in the percentage of diabetic patients between the thymic peptides group (50%) and the standard care group (13.6%), but there were no significant differences between the groups in any other baseline characteristic. Dimensionality reduction by principal component analysis (PCA) demonstrates the overlapping of both groups, and heatmap analysis shows a homogeneous behavior on baseline characteristics (Fig. 2) .

Together, these results indicate that groups were globally similar on severity indices after matching. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint c. There was a significant (P=0.01) difference in the percentage of diabetic patients between the thymic peptides group and the standard care group, but there were no significant differences between the groups in any other baseline characteristic. d. Liver damage was defined as elevated liver enzymes, and kidney damage as elevated creatinine level.

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panel A. PCA considered the following variables: confirmatory covid test, number of comorbidities, sex, WHO clinical progression score, need for oxygen therapy, age distribution, heart rate distribution, systolic blood pressure distribution, respiratory rate distribution, oxygen saturation distribution, temperature distribution, and presence of diabetes, hypertension, obesity, overweight, chronic obstructive pulmonary disease, heart failure, organ damage, and dyspnea. Hierarchical heat map cluster of baseline patient characteristics and outcomes is shown in panel B. AgeClass indicates age distribution, TempClass temperature distribution, COPD Chronic obstructive pulmonary disease, HRClass heart rate distribution, No.Comorb number of comorbidities, O2SatClass oxygen saturation distribution, RespRateClass respiratory rate distribution, O2Omitted time to oxygen withdrawal by day 20, DaysHosp time to discharge by day 20.

The median number of days between symptom onset and hospitalization/enrollment was 11.5 (interquartile range, 9 to 13) in the intervention group, and 10 (interquartile range, 9 to 14) in the standard care group. In the thymic peptides and standard care groups, 15 (68.2%) and 13 (59.1%) were men, respectively, and the mean (±SD) age was 52±16 years and 57±17 years, respectively. All patients were mestizo. Most patients had one or more comorbidities (75%), mainly hypertension (36.4%) and diabetes (31.8%). Of note, 61.4% of patients in both groups had elevated liver enzymes or creatinine levels at admission. All patients were WHO clinical progression score 5 at hospitalization/enrollment, and most (86.4%) had an oxygen saturation of ≤91%. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

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Although highly controversial among the Honduran scientific community, guidelines approved by the Honduran Ministry of Health for the treatment of Covid-19 include the use of ivermectin, azithromycin, zinc, hydroxychloroquine or chloroquine, acetaminophen, ibuprofen, and oral disinfectants (sodium hypochlorite, hypochlorous acid, hydrogen peroxide, among others) for the initial phases of disease progression. 23 On top of these, therapeutic options for patients presenting with pulmonary compromise before or during hospitalization for phase IIb include colchicine, dexamethasone or methylprednisolone, and anticoagulation (rivaroxaban, apixaban, heparin, or enoxaparin). 23 Data for therapies used before hospitalization/enrollment was missing for 14 (31. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted December 7, 2021. ; https://doi.org/10.1101/2021.12.05.21267318 doi: medRxiv preprint peptides group compared to standard of care (95.5% vs. 40.9%, P<0.001). It is important to note that one patient received hydroxychloroquine in the intervention group, but as continuation of her rheumatoid arthritis chronic management, not as Covid-19 treatment.

Heatmap clusters showed differences between group behavior in time to recovery (Fig.   2 ). The median time to recovery in the thymic peptides group was 6 days, as compared with 12 days of standard care (Table S3 ). The Kaplan-Meier analysis revealed a significantly shorter time to recovery in the intervention group (log-rank test of P=0.002) (Fig. 3) . The hazard ratio for recovery was 2.75, with a 95% confidence interval (CI) of 1.34 to 5.62. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted December 7, 2021. ; https://doi.org/10.1101/2021.12.05.21267318 doi: medRxiv preprint Fig. 3 Kaplan-Meier estimates of time to recovery by day 20. The Kaplan-Meier method was used to estimate the cumulative proportion of patients and the log-rank test was used to compare the two groups. The Cox proportional-hazard model was used to estimate the hazard ratio and 95% confidence interval. Vertical dashes indicate censored data.

The GASE instrument was evaluated weekly by physicians of the Covid-19 ward for every patient in the thymic peptides group. No side effect related to thymic peptides was reported during the 20-day follow-up hospitalization period. Adverse events ≥ Grade 3 as defined by the CTCAE v5.0 were monitored daily for every patient. No adverse event was reported during the 20-day follow-up hospitalization period. After the 20-day intervention cutoff, side effects or adverse events were monitored for up to two more weeks. Discharged patients were interviewed to the cellphone number reported in the patient's file. However, 11 patients were lost to follow-up after medical discharge. For patients monitored, no side effects or adverse events related to thymic peptides were reported.

Heatmap clusters also showed differences between group behavior in mortality (Fig. 2) .

There were no deaths in the thymic peptides group by day 20. In contrast, the Kaplan-Meier estimate of mortality for the standard care group by day 20 was 24% (Fig. 4) .

This difference was statistically significant (log-rank P=0.02). The log-rank statistic was used alone because the Cox proportional-hazard model results in a degenerate estimation for the group with no events. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint 

Kaplan-Meier analysis showed a median time to oxygen therapy withdrawal of 4 days in the thymic peptides group, as compared with 10 days in standard care (hazard ratio, 2.3; 95% CI, 1.13 to 4.67; log-rank P=0.01) (Fig. S1 and Table S4 ). Finally, patients in the intervention group had a shorter length of in-hospital stay (median, 6 days, as compared with 12 days; hazard ratio for discharge, 2.34; 95% CI, 1. 16-4.75 ; log-rank P=0.01) (Fig. S2 and Table S5 ). These differences in the previous outcomes can be visualized in the heatmap hierarchical clusters (Fig. 2) . is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

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This nonrandomized phase 2 clinical trial of thymic peptides for the treatment of hospitalized Covid-19 patients reported no side effects, adverse events, or deaths by the 20-day cutoff point. In addition, when compared with registry patient data after PSM, a significantly shorter time to recovery (median, 6 days vs. 12 days; hazard ratio for recovery, 2.75 [95% CI, 1.34 to 5.62]) and mortality reduction (log-rank P=0.02) was observed. This is the first clinical trial of oral thymic peptides in the management of Covid-19 patients.

Only one other prospective study has evaluated an administration form of thymic peptides in hospitalized Covid-19 patients. Khavinson et al. analyzed the addition of intramuscular thymic peptides to standard therapy. They found an accelerated reduction of pro-inflammatory markers, as well as improvement in T cell system indicators. 22 No deaths were reported in any of the groups. 22 However, safety data and time to recovery were not described.

Retrospective evidence on thymic peptides in Covid-19 therapy can be found for subcutaneous Tα1 alone. Consistent with our trial, a study by Wu et al. found a significant decrease in 28-day mortality of the Tα1 group relative to the non-thymosin control (7.8% vs. 14.7%, P = 0.016). 20 Prolonged hospital length of stay and disease duration were described; although this corresponded to critical type patients. 20 is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted December 7, 2021. ; https://doi.org/10.1101/2021.12.05.21267318 doi: medRxiv preprint 60.6%, P < 0.001), but after adjusting by baseline confounders, the difference became non-significant (51.0% vs. 52.9%). 27 No safety data was described in this study either.

The results with Tα1 are suggestive of the benefits that this immunomodulatory approach can add to Covid-19 therapy. However, peptides combination rather than isolated pharmacological agents might enhance the clinical response through synergism.

A recent preclinical study of recombinant human thymosin beta-4 in mice found a significantly increased survival rate by inhibiting viral replication, modulating the immune response, and promoting tissue repair. 28 Thymulin is another nonapeptide secreted by thymic epithelial cells with essential regulatory activities. It has been shown to suppress p38, a MAPK family member implicated in glucocorticoid resistance, and inhibit NF-kB activation, with crucial pathogenic effects in lung disease. 29 Limitations of our study include its small sample size and the lack of a prospectively randomized control group. However, valuable information was acquired through PSM of registry data that accounts for standard care results in a group of patients globally similar in baseline characteristics of possible severity confounders. Also, poor socioeconomic conditions could have influenced the low remote cellphone follow-up response rate after discharge (55%) by lack of patient access to internet or a service plan. A phase 3 trial by the GIMUNICAH group is underway to address the need for confirmatory analyses in a larger population. This was a single-center study that included only mestizo population, which might have impacted its universal validity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

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In conclusion, given that a dysregulated immune/inflammatory response promotes tissue damage in later phases of COVID-19, 8 the use of thymic peptides should be further examined and considered to improve immunomodulation and clinical outcomes in the complex management of the disease. The daily oral dose of 250 mg of thymic peptides proved to be safe in a hospitalized Covid-19 group of patients in Honduras, reporting no deaths by day 20. When compared with registry data after PSM, shorter times to oxygen therapy withdrawal, recovery, and length of stay, as well as reduction in mortality were identified. Trials with larger populations are required to confirm these findings. The GIMUNICAH group is already working on a more extensive Phase 3 clinical trial of oral thymic peptides in Covid-19 patients. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

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The copyright holder for this this version posted December 7, 2021. ; https://doi.org/10.1101/2021.12.05.21267318 doi: medRxiv preprint Study supervision: Ramos-Zaldívar, Reyes-Perdomo, Espinoza-Moreno, Reyes Guzman, Rivera Reyes.

All authors had full access to the full data in the study and accept responsibility to submit for publication. Beginning 3 months and ending 5 years following article publication. Email addresses hramos@unicah.edu; hmramos@uc.cl Access Criteria: Investigators whose proposed use of the data has been approved by an independent review committee ("learned intermediary") identified for this purpose.

For individual participant data meta-analysis. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

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Acquisition, analysis, or interpretation of data: All authors

Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: Ramos-Zaldívar

We thank all the patients and their families who participated in this trial. We also acknowledge the contributions of the following nursing staff at Hospital Santa Bárbara