A Single-arm, Open-Label, Phase II Clinical Study to Evaluate the Safety and Efficacy of Thymic Peptides in the Treatment of Hospitalized COVID-19 Patients in Honduras
Phase: PHASE2
Conditions: COVID-19
Sponsor: Universidad Católica de Honduras

1 
 
Universidad Católica De Honduras 
“Nuestra Señora Reina De La Paz” 
 
Campus San Pedro y San Pablo 
 
Protocol: 
Safety and Efficacy of Thymic Peptides in the Treatment of Hospitalized COVID-19 
Patients in Honduras 
 
Principal Investigators: 
Héctor Miguel Ramos Zaldívar1 
Karla Giselle Reyes Perdomo3 
Nelson Alberto Espinoza Moreno2 
   
Authors: 
Héctor M. Ramos Zaldívar, M.D., 1,2 Karla G. Reyes Perdomo, M.D.,1,3 Nelson A. 
Espinoza Moreno, M.D.,1  Ernesto Tomás Dox Cruz,1 Thania Camila Aguirre Urbina,1 
Astrid Yohaly Rivera Caballero,1 Eduardo Smelin Perdomo Dominguez,1 Sofía 
Guadalupe Peña Calix ,1 Joselin Michelle Monterroso Reyes,1 Erick Fernando Caballero 
Vásquez,1 Tarek Sai Zelaya Ortiz,1 Hilbron Eduardo Rodríguez Machado,1 Marcelo 
Andres Forgas Solis, M.D.,1 Iveth Sebilla Silva,1 Mauricio Edgardo Zavala Galeano,1 
Alejandro Antonio Morga Alvarado,1 Angie María Nicolle Solís Medina,1 Leticia M. 
Guerrero Díaz,1 Julia E. Jiménez Faraj, M.D.,4 Caroll Alejandra Perelló Santos, M.D.,5 
Wilberg A. Moncada Arita, M.D.,1 Darwing Fabricio Valdiviezo Montufar,1 Josué David 
Hernández Sabillón,1 Mónica L. Sorto G.,1 Xochilt Xiomara Padilla Navarro,1 Victoria A. 
Palomo Bermúdez, M.D.,5 Héctor Armando Alvarenga Andino, V.M.D., MsC,1 Sandra 
Patricia Reyes Guzman, M.D.,6 María Haydee Rivera Reyes, M.D.,6 Esdras Said Medina 
Paz, M.D.,6 Joselyn Rosario Alvarado Enamorado, M.D.,6 Yenny Mariel Sabillón 
Sagastume, M.D.,6 Ariadna Stephanny Mejia Rivera, M.D.,6 Claudia Michelle Posas 
Sarmiento, M.D.,6 Xenia Vanessa Jiménez Pineda, M.D.,6 Verónica Alejandra 
Hernández Puerto, M.D.,6 Josué David Portillo Landaverde, M.D.,6 Sergio Reyes 
S.,M.D.,6 Ivin Perdomo R., M.D.,6 Josué J. Rivera, M.D.,6 Wendy Cecilia Mendoza Girón, 
M.D.,6 Karla Melissa Tróchez Sabillón, M.D.,6 Paola Nohemy Katsumata Leiva, M.D.,7 
Karla Elizabeth Pineda Toro, M.D.,7 Jimena A. Montes-Gambarelli, M.D.,1 Cristhiam 
Flores, P.G.Cert.,1,8 Edison Salas-Huenuleo, Ph.D.,9 Marcelo E. Andia, M.D.10,11 
1. 
GIMUNICAH, Faculty of Medicine, Universidad Católica de Honduras. 
2. 
Doctoral Program in Medical Sciences, Faculty of Medicine, Pontificia Universidad Católica de 
Chile. 
3. 
Postgraduate Program on Breastfeeding and Nutrition in Children Under the Age of Two, Faculty 
of Sciences, Universidad Mayor, Chile. 
4. 
Hospital Civil de Guadalajara Juan I. Menchaca, México.  
5. 
Hospital del Valle, San Pedro Sula, Honduras. 
6. 
Hospital de Santa Bárbara Integrado, Santa Bárbara, Honduras. 
7. 
Triaje de Santa Bárbara, Secretaría de Salud de Honduras. 
8. 
Laboratorio de Biología Molecular de San Pedro Sula, Secretaría de Salud de Honduras. 
9. 
Advanced Integrated Technologies, (AINTECH), Santiago, Chile.  
10. Biomedical Imaging Center Radiology Department, School of Medicine, Pontificia Universidad 
Católica de Chile, Santiago, Chile. 
11. Millennium Nucleus in Cardiovascular Magnetic Resonance, Santiago, Chile. 
 
ClinicalTrials.gov Identifier: NCT04771013 
Date Version A: April 4, 2020 
Date Version B: April 8, 2021 
 

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Table of Contents 
 
PROTOCOL VERSION A ......................................................................................................... 5 
SECTION 1 – TITLE, PURPOSE AND JUSTIFICATION ............................................... 5 
1.1Title .................................................................................................................................. 5 
1.2Study Purpose ................................................................................................................. 5 
1.3Justification. .................................................................................................................... 5 
Hypothesis ............................................................................................................................ 7 
General Objective ................................................................................................................ 7 
Specific objectives ................................................................................................................ 7 
SECTION 2 - DESCRIPTION OF THE POPULATION ................................................... 7 
2.1 Number of participants ................................................................................................. 7 
2.2 Describe the population ................................................................................................ 7 
2.3 Criteria ........................................................................................................................... 8 
Inclusion Criteria ................................................................................................................ 8 
Exclusion criteria................................................................................................................. 8 
SECTION 3. PARTICIPANT RECRUITMENT ................................................................. 9 
SECTION 4 - METHODOLOGY AND PROCEDURES ................................................... 9 
4.1 Study design ................................................................................................................... 9 
Clinical characterization ..................................................................................................... 9 
Administration of thymic peptides (Unicahsina) ............................................................ 10 
Primary outcome measures .............................................................................................. 10 
Secondary Outcomes measures ........................................................................................ 10 
Other complementary analyzes ........................................................................................ 11 
Computerized axial tomography and chest radiography .............................................. 11 
Statistical Analysis Plan .................................................................................................... 12 
SECTION 5 - ANONYMITY AND CONFIDENTIALITY OF DATA ........................... 12 
SECTION 6 - POTENTIAL RISKS AND BENEFITS ...................................................... 12 
6.1 Describe potential risks and discomforts .................................................................. 12 
6.2 Describe how risks will be minimized ........................................................................ 13 
    6.3 Describe the potential benefits .................................................................................... 13 
SECTION 7 - INCENTIVES AND INDUCEMENTS TO PARTICIPATE .................... 14 
7.1 Describe any incentive/inducement to participate that will be offered to the 
participants. ....................................................................................................................... 14 
SECTION 8 - OTHER FINANCIAL CONSIDERATIONS ............................................. 14 
8.1 Describe the monetary expenses that the participants will incur. .......................... 14 
8.2 Describe the procedures for compensating research-related injuries .................... 14 

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SECTION 9 - INFORMED CONSENT .......................................................................... 14 
REFERENCES ................................................................................................................. 15 
PROTOCOL VERSION B ....................................................................................................... 18 
SECTION 1 – TITLE, PURPOSE AND JUSTIFICATION ............................................. 18 
1.1Title ................................................................................................................................ 18 
1.2 Study Purpose. ............................................................................................................. 18 
1.3 Justification.. ................................................................................................................ 18 
Hypothesis .......................................................................................................................... 20 
General Objective .............................................................................................................. 20 
Specific objectives .............................................................................................................. 20 
SECTION 2 - DESCRIPTION OF THE POPULATION ................................................. 20 
2.1 Number of participants. .............................................................................................. 20 
2.2 Describe the population .............................................................................................. 20 
2.3 Criteria ......................................................................................................................... 21 
Inclusion Criteria .............................................................................................................. 21 
Exclusion criteria............................................................................................................... 21 
SECTION 3. PARTICIPANT RECRUITMENT ............................................................... 21 
SECTION 4 - METHODOLOGY AND PROCEDURES ................................................. 22 
4.1 Study design ................................................................................................................. 22 
Clinical characterization ................................................................................................... 22 
Administration of thymic peptides (Unicahsina) ............................................................ 23 
Primary outcome measures .............................................................................................. 23 
Secondary Outcomes measures ........................................................................................ 23 
Other complementary analyzes ........................................................................................ 24 
Computerized axial tomography and chest radiography .............................................. 24 
Statistical Analysis Plan .................................................................................................... 25 
SECTION 5 - ANONYMITY AND CONFIDENTIALITY OF DATA ........................... 25 
SECTION 6 - POTENTIAL RISKS AND BENEFITS ...................................................... 25 
6.1 Describe potential risks and discomforts .................................................................. 25 
6.2 Describe how risks will be minimized ........................................................................ 26 
6.3 Describe the potential benefits ................................................................................... 26 
SECTION 7 - INCENTIVES AND INDUCEMENTS TO PARTICIPATE .................... 26 
7.1 Describe any incentive/inducement to participate that will be offered to the 
participants ........................................................................................................................ 27 
SECTION 8 - OTHER FINANCIAL CONSIDERATIONS ............................................. 27 
8.1 Describe the monetary expenses that the participants will incur. .......................... 27 
8.2 Describe the procedures for compensating research-related injuries .................... 27 

4 
 
SECTION 9 - INFORMED CONSENT .......................................................................... 27 
REFERENCES ................................................................................................................. 28 
SUMMARY OF CHANGES .................................................................................................... 31 
 
 
 
 

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PROTOCOL 
VERSION A 
 
SECTION 1 – TITLE, PURPOSE AND JUSTIFICATION 
1.1 Title. Safety and Efficacy of Thymic Peptides in the Treatment of Hospitalized 
COVID-19 Patients in Honduras. 
 
1.2 Study Purpose. To determine if thymic peptides (Unicahsina) are a new therapeutic 
option for the treatment of patients infected by COVID-19 in order to improve their 
clinical prognosis. 
 
1.3 Justification. Coronaviruses are important pathogens in humans and animals, 
causing respiratory tract and lung parenchymal infections. In late 2019, a novel 
coronavirus was identified as the cause of a series of pneumonia cases in Wuhan, a 
city in Hubei province in China (1). The infection spread rapidly, leading to an 
epidemic throughout China, followed by an increasing number of cases in other 
countries, affecting all continents except Antarctica (1). WHO declared COVID-19 a 
pandemic on March 11, 2020 (2). The virus is currently referred to as Severe Acute 
Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and the disease caused by the 
virus is known as COVID-19. 
 
At the time of writing this protocol, more than 5,584,091 cases of COVID-19 have 
been reported worldwide (3). This is largely due to the ease with which this virus is 
transmitted. The primary mechanism of spread is person-to-person transmission, 
which occurs primarily by respiratory droplets (1). Transmission of SARS-CoV-2 
via fomites is plausible as it has been shown to remain viable on surfaces for hours 
and even several days (4). 
 
The coronavirus that causes COVID-19 is a betacoronavirus of the same subgenus as 
SARS-CoV (5). The incubation period is estimated to be 14 days after exposure, with 
most cases occurring between 4 and 5 days (6-8). The disease is mild in 81% of cases, 
severe in 14% and critical in 5% (9). The overall mortality rate is 2.3% (9). The 
clinical course is characterized by fever (99%), fatigue (70%), dry cough (59%), 
anorexia (40%), myalgia (35%), dyspnea (31%) and sputum (27%) (10). Pneumonia 
appears to be the most serious manifestation of infection, characterized mainly by 
fever, cough, dyspnea and a bilateral pulmonary infiltrate (visible on imaging) (7, 10-
12). 
 
Global statistics show that mortality due to COVID-19 increases significantly with 
age. Pediatric patients under 9 years of age present mild cases with practically zero 
mortality (13). Between 9 and 39 years of age, statistics indicate a mortality of 
approximately 0.2% (13). In the age range between 40 and 69 years, the rate oscillates 
between 1.3 and 3.6% (13). Above 70 years of age, deaths due to COVID-19 increase 
exponentially, reaching 8% of cases (13). Patients over 80 years of age are the highest 
risk group with a mortality rate of 14.8% (13). 
 
This remarkable statistical difference in morbidity and mortality is consistent with a 
biological process that has so far been scarcely addressed: involution of the thymus. 

6 
 
This retrosternal gland is part of the primary lymphoid organs, playing an important 
role in the maturation and differentiation of T cells to CD4+ and CD8+ subtypes, in 
addition to secretion of cytokines that mediate the immune response (14). Involution 
follows a characteristic pattern in which there is a progressive loss of function from 
the first year of life (15). Between 35 and 45 years of age this process accelerates, 
losing up to 30% of its function in a decade (15). Finally, after the age of 65 it 
regresses and is replaced in its totality by adipose tissue (15). 
 
Ferman-Cano et al. suggest that the relative protection observed in the infant 
population with COVID-19 could be explained by the influence of the thymus. Based 
on this background and the evident relationship between the age ranges in which 
thymus involution occurs and the exponential increase in mortality, we propose that 
at older ages there is a greater deficiency of thymic factors, whose replacement 
represents a therapeutic mechanism to be explored. In this context, thymic peptides 
stand out as potent candidates given their immunogenic properties and proven safety. 
 
Thymomodulin is a set of low molecular weight peptides of less than 10,000 Daltons, 
derived from the acid lysis of calf thymus (16). It has been shown that modulates the 
maturation and function of T lymphocytes and favors the expression of B cell surface 
markers (16,17). In vitro, thymomodulin has been shown to possess a myelopoiesis-
inducing effect in the bone marrow, stimulating granulocyte and macrophage 
colonies (18). In addition, in murine studies it has been shown to produce an increase 
in serum thymic hormone (19). 
 
In clinical studies, thymomodulin has proved to reduce the number of recurrent 
respiratory infections in children (20). This improvement is associated with a higher 
CD3 + and CD4 + cell count, increased neutrophilic function and salivary IgA levels 
(21, 22). It also has multiple reports on its safety and efficacy in patients with immune 
imbalance, in pathologies such as chronic bronchitis (23-25), bronchial 
hyperresponsiveness (26), asthma (27-29), food allergy (30, 31), atopic dermatitis, 
immunosuppression by chemo or radiotherapy for neoplasms (32, 33), initial phases 
of AIDS (34-36) and senectitude thymic involution (19,37,38). 
 
In geriatric patients, studies prove safety at high doses (19), an increase in the number 
of lymphocytes, monocytes, IgA, IgG and IgM levels (37-40). Likewise, 
thymomodulin increases the production of free radicals due to alveolar macrophages 
(23). It is noteworthy to mention that it can even prevent and emend leukopenia in 
patients undergoing chemotherapy and radiotherapy (41), which has been proven in 
patients with breast and genitourinary tract cancer (42).       
 
In studies of acute and chronic toxicity, it has been shown that thymomodulin does 
not possess teratogenic or embryotoxic effects (43). For this reason, it has a high 
potential for use during pregnancy. 
 
Given the fact that the population most at risk of presenting severe disease and a 
higher mortality rate due to COVID-19 are immunosuppressed patients, older adults 
and/or those with comorbidities, effective therapeutic options with high safety 
profiles are needed.  Currently there are no treatments available that meet these 
requirements for disease management. Treatment options include protocols using 
chloroquine or hydroxychloroquine. The evidence in favor of its use remains 

7 
 
controversial, since a number of adverse effects have been documented that could 
affect the most vulnerable population. They are contraindicated in patients with 
retinopathy (44), neuromyopathy and heart disease due to the possible increase in the 
QT interval (45). 
 
Scientific evidence proves the absence of short or long-term adverse effects of 
thymomodulin, obtaining significant results in the treatment of patients with 
immunological vulnerability in various respiratory pathologies (23). Taking this into 
account, it can be considered a promising alternative to combat the COVID-19 
pandemic. The following sections will discuss the methodology of the clinical trial 
that will be used to evaluate its efficacy as a therapeutic option.  
 
Hypothesis 
 
Oral administration of thymic peptides (Unicahsina) is a safe and effective therapy 
for the management of patients with COVID-19 respiratory onsets. 
 
General Objective 
 
To demonstrate the therapeutic efficacy and safety of thymic peptides (Unicahsina) 
in patients with COVID-19 respiratory disease.  
 
Specific objectives 
 
1. To evaluate the safety of thymic peptides (Unicahsina) by monitoring adverse 
events using the Common Terminology Criteria for Adverse Events Version 5.0 
(CTCAE v5.0) and side effects using the General Assessment of Side Effects 
(GASE).  
2. Determine the time required until the participants’ response, according to clinical 
stability parameters.  
3. Determine the median number of days of hospitalization in patients diagnosed 
with COVID-19 and treated with thymic peptides (Unicahsina).  
4. To perform survival analysis in patients diagnosed with COVID-19 and treated 
with thymic peptides (Unicahsina). 
 
SECTION 2 - DESCRIPTION OF THE POPULATION 
 
2.1 Number of participants: 20 participants.  
 
2.2 Describe the population: 
 
Patients with diagnosis of COVID-19 confirmed by RT-qPCR testing, viral antigen 
detection or antibody detection plus associated symptomatology. The study will be 
performed in patients over 20 years of age without distinction of sex, race, religion, 
or socioeconomic status. Since the population under 20 years of age presents mostly 
mild or asymptomatic symptoms, with a mortality rate between 0% and 0.2%, it was 
decided to exclude this age range. 
 

8 
 
This research will involve elderly patients and those with comorbidities. The current 
COVID-19 pandemic has shown that this group of patients has the highest mortality 
rate, exposing the need to discover safe and effective therapies. Therefore, and given 
the innocuous profile that thymic peptides possess, we consider their use in this 
population.   
 
Should any of the participants decide to withdraw from the study voluntarily or 
request self-discharge, another patient will be added to the study until 20 patients 
have reached conclusion either by medical discharge or death within a 20-day 
hospitalization follow-up. Patient data will be used up to the date of voluntary 
withdrawal or self-discharge.  
 
2.3 Criteria 
 
Inclusion Criteria: 
 
1. Confirmed case of COVID-19 by viral nucleic acid (RNA) detection, viral 
antigen detection, or detection of antibodies to the virus. 
 
2. Participants that require hospitalization under Honduran Ministry of Health 
Guidelines for Clinical Management of COVID-19 Adult Patients: Stage IIb, 
defined as a patient with or without risk factors that presents with warning signs 
(shortness of breath, tachypnea), and altered inflammatory parameters. 
 
3. Participants that present with at least one of the following: oxygen saturation 
level below 94 percent; complete blood count showing lymphopenia, 
neutrophilia, or both; positive C-reactive protein; chest radiography or CT scan 
with ground-glass opacities. 
 
4. Male or female at least 21 years old. 
 
Exclusion criteria  
 
1. COVID-19 patients that do not require hospitalization under Honduran Ministry 
of Health Guidelines for Clinical Management of COVID-19 Adult Patients: 
phase IA (asymptomatic), phase IB (mild symptoms without risk factors), or 
phase IC (mild symptoms with risk factors). 
 
2. Participants currently in other clinical trials evaluating experimental drugs. 
 
3. Known history of allergic reactions to thymic peptides or calf thymus acid lysate 
derivatives. 
 
4. Organ transplant recipients. 
 
5. Women who are pregnant or breast feeding. 
 
 
 

9 
 
SECTION 3. PARTICIPANT RECRUITMENT  
 
Patients who meet the inclusion criteria and are hospitalized in Honduran facilities 
designated for the care of patients with COVID-19, will be recruited. Patients over 
20 years of age capable of giving their consent will be included.  In case that the 
patient is unable to authorize participation, authorization will be requested from his 
legal representative. 
 
Prior to their incorporation into the study, patients will be approached by the 
specialist or health personnel present on behalf of the Medical Research Group of the 
Catholic University of Honduras. In addition, there will be auxiliary methods with 
electronic devices that will allow telemedicine to be carried out between the principal 
investigators of the study and the potential participants. This last procedure will be 
carried out with encrypted methods that guarantee the confidentiality and anonymity 
of the patients. The purpose and procedures of the investigation will be explained, as 
well as clarifying any doubts that may arise. Once consent has been obtained, the 
clinical data registration will begin, and the application of the protocol will be 
coordinated with the treating physicians. 
 
SECTION 4 - METHODOLOGY AND PROCEDURES 
 
4.1 Study design 
This is a single-arm, open-label, phase II clinical trial to evaluate the safety and 
efficacy of thymic peptides in the treatment of hospitalized COVID-19 patients in 
Honduras, at the Hospital de Santa Bárbara Integrado. A participant-level 
comparison will be made based on registry data of the Hospital de Santa Bárbara 
Integrado, after propensity score matching. 
 
In total, 20 patients will be recruited from the designated hospital for COVID-19 
patient care, including those who have signed informed consent and who meet the 
inclusion criteria. For the generation of the comparison group through data from 
clinical records, it will be carried out by authorization from the Hospital de Santa 
Bárbara Integrado, given its retrospective nature, without experimental intervention. 
 
Clinical characterization 
 
Once the protocol is started, the information corresponding to the general data, signs, 
symptoms, physical examination and laboratory values of each patient will be 
recorded daily in the data collection instrument. The record will be made on paper, 
which will be digitized and sent under encryption to the principal investigators every 
day. 
 
As a quantitative method, the following laboratory findings will be considered to 
evaluate clinical progress, according to the requirement and availability of the 
hospital: 
● Complete blood count 
● C-reactive protein 
● D-dimer 
● Ferritin 

10 
 
● Procalcitonin 
● Lactate 
● AST 
● ALT 
● BUN 
● Creatinine 
 
Administration of thymic peptides (Unicahsina) 
Thymic peptides (Unicahsina) will be administered in an oral dose of 250 mg per 
day. In the intubated patient, the administration will be done through a nasogastric 
tube. The presentation of thymic peptides (Unicahsina) will be in lyophilized form, 
which will be diluted in 50 ml of drinking water prior to administration. It should be 
administered on an empty stomach one hour before or two hours after a meal. If the 
patient is discharged, or if they need to be referred to an ICU, all the information will 
be gathered up to that moment and the administration of Unicahsina will be stopped. 
 
Primary outcome measures 
 
1) Time to participant recovery (Time Frame: During hospitalization for up to 20 
days.) 
 
Measured in days to clinical response that will be defined as clinical stability 
(temperature, ≤37.8°C; heart rate, ≤100 beats per min; systolic blood pressure, ≥90 
mm Hg; respiratory rate, ≤24 breaths per min; oxygen saturation, ≥90 percent; normal 
mental status; no receipt of supplemental oxygen by face mask or mechanical 
ventilation) with improvement in at least one symptom (anosmia, dysgeusia, cough, 
shortness of breath, cyanosis, conjunctivitis, pharyngitis, sputum production, 
rhinorrhea, myalgia, otalgia, odynophagia, fatigue, diarrhea, hemoptysis, vomit) and 
with no symptom worsening that is sustained for at least 24 h. 
 
2) Number of participants with treatment related adverse events as assessed by the 
Common Terminology Criteria for Adverse Events Version 5.0 (CTCAE v5.0) 
(Time Frame: Up to 20 days) 
 
Number of participants who experience adverse events ≥ Grade 3, as defined by the 
CTCAE v5.0. 
 
3) Number of participants with treatment related side effects as assessed by the 
General Assessment of Side Effects (GASE) (Time Frame: Up to 20 days) 
 
Number of participants who experience severe side effects as defined by the GASE. 
 
Secondary Outcomes measures 
 
1) Hospital average length of stay (ALOS) as measured by the mean participants' 
inpatient days (Time Frame: Up to 20 days) 
 
The average length of stay will be calculated by dividing the sum of inpatient days 
by the number of participant admissions. 
 

11 
 
2) Overall survival defined as the time from the start of treatment until death due to 
any reason [ Time Frame: Up to 20 days] 
 
Time for overall survival will be measured in days. 
 
 
Other complementary analyzes 
 
Computerized axial tomography and chest radiography 
 
A Computerized tomography without contrast will be performed, with the patient in 
the supine position and the image acquisition will be carried out at the end of 
inspiration. The following parameters will be requested to obtain axial images: 1.25 
mm thick, 1.25 mm interval, 120 kVp. If it is possible, chest radiographs will be 
requested in posteroanterior projection. However, in patients whose clinical 
condition warrants it, anteroposterior radiography will be considered. The images 
will be obtained at the moment of maximum inspiration, either with instruction to the 
patient or by controlling the ventilator console in the case of intubated patients. 
 
The tomographic or radiographic findings will be interpreted using the scoring 
system previously described by Cai et al (46). After the analysis by the assigned 
radiologist of the hospital center, the data generated by CT or X-ray will be submitted 
to two independent radiologist physicians, both blinded to the corresponding group 
of participants and the corresponding clinic. These specialists will assign a 
Pulmonary Score 1 (SP1) according to the findings they observe, based on three 
categories:  
1 = Normal attenuation  
2 = Ground-glass opacity  
3 = Consolidation 
 
Each lung will be divided into 3 zones with limits defined as follows: 
 
Upper zone: area above the level of the carina.  
Middle zone: area between the level of the carina and the inferior pulmonary vein. 
Inferior zone: area below the level of the inferior pulmonary vein. 
 
In this way, a total of 6 pulmonary areas will be delimited, each of which will receive 
a score according to the following scale of distribution of compromised lung 
parenchyma or Pulmonary Score 2 (SP2):  
 
0 = Normal  
1 = 1% to 25% involvement 
2 = 25% to 50% involvement 
3 = 50% to 75% involvement 
4 = More than 75% involvement 
 
The scores of each lung area will be summed to obtain the Total Affectation (AT) 
grade. Finally, AT will be multiplied by SP1 to obtain the Total Cumulative Scale 
(ETA), which comprises a range from 0 to 72. A change of "Improvement" on CT or 
chest X-ray will be defined as an ETA lower than the previous value obtained at the 

12 
 
start of treatment or from the previous imaging studies. A "worsening" change will 
be defined as an ETA greater than the previous value obtained at the start of treatment 
or previous imaging studies. The stability of the picture will be defined as "Constant" 
when the ETA is equal to the previous value obtained at the beginning of treatment 
or from previous imaging studies. 
 
Statistical Analysis Plan 
 
All quantitative data will be described using parameters such as the mean ± standard 
deviation, or as the median (minimum and maximum). Qualitative data will be 
described by the number of cases (proportion%). Patient characteristics will be 
compared using the chi-square test or Fisher's exact test for categorical data. For 
continuous variable data, the Wilcoxon test or Student's t test will be employed. The 
analysis of time to a particular event will be carried out using the Kaplan-Meier 
method, and the analysis of differences between groups will be calculated with the 
log-rank test. The Cox proportional-hazard model will be used to estimate the hazard 
ratio and 95% confidence interval (CI). Propensity score matching methodology will 
be used to generate the comparison group from the clinical records. A p-value less 
than 0.05 will be required to establish significance. All analyses will be performed 
using SPSS and GraphPad Prism software. 
 
SECTION 5 - ANONYMITY AND CONFIDENTIALITY OF DATA 
 
The data will be obtained from the healthcare center assigned to treat positive cases 
of COVID-19, through the clinical record designed as an instrument for this study. 
The laboratory and imaging test reports, as well as the clinical records, will be 
digitized and sent to the principal investigators using the SOPHOS encryption 
software. This last part will ensure the confidentiality of each patient's data between 
devices while transferred. Access will be given to the Dirección General de 
Vigilancia del Marco Normativo de la Secretaría de Salud de Honduras (General 
Directorate for Regulatory Framework Surveillance of the Ministry of Health of 
Honduras) for the monitoring of the study. The hospital will have a password-
protected electronic device. The access will be limited exclusively to medical doctors 
assigned for the study. 
 
The physical documents will be attached to the patient clinical file at the end of the 
hospitalization.  
 
For the data produced by CT or chest x-ray, the HOROS software will be used to 
visualize and anonymized DICOM files before sending them to radiologists. The 
confidentiality in transferring this information will be ensured by using the SOPHOS 
software. 
 
SECTION 6 - POTENTIAL RISKS AND BENEFITS 
 
6.1 Describe potential risks and discomforts 
 
The administration of oral thymic peptides (Unicahsina) constitutes a minimal risk 
intervention since its use has not reported any toxic or mutagenic effects even at high 

13 
 
concentrations (16). It has multiple reports on its safety and efficacy in patients with 
immune imbalance, pathologies such as chronic bronchitis (23-25), bronchial 
hyperreactivity (26), asthma (27-29), food allergy (30, 31), atopic dermatitis, 
immunosuppression by chemo or radiotherapy for neoplasms (32, 33), initial phases 
of AIDS (34-37) and thymic involution of agedness (19, 38). No additional risks are 
expected from the application of this treatment. However, the possibility of unknown 
adverse effects in patients with COVID-19 cannot be ruled out.   
    
CT or chest x-rays carry minimal risks. Imaging procedures will not involve the 
administration of contrast media, so no allergic reactions or renal damage is expected. 
Even though exposure to CT of the thorax can increase the risk of cancer, this 
represents an increment of only 0.7% (47). No pregnant women will be included in 
this study.  
 
The administration of thymic peptides (Unicahsina) will be orally, diluting the 
lyophilized product in water for ingestion. In case of impaired consciousness, 
difficulty swallowing, or if the medical doctors consider the necessity of intubation, 
a nasogastric tube will be placed for the continuation of treatment. This process 
carries the following risks: displacement of the tube, electrolyte dysregulation, 
hyperglycemia, diarrhea, constipation, vomit, tube obstruction, and pulmonary 
aspiration (48). However, to minimize risks, this procedure will be performed by 
trained healthcare personnel.    
 
Samples for RT-qPCR will be taken using a nasal swab. This technique carries 
minimal risks that include pharyngeal reflex, mild nose bleeding, discomfort, and 
cough (49, 50). 
 
No psychological, sociological, or legal risks are expected in this study.  
 
6.2 Describe how risks will be minimized  
 
Monitoring of possible adverse reactions or side effects will occur after the 
administration of the drug. In case reactions that compromise the health of the 
participant appear, the drug will be suspended. If discomfort occurs when 
swallowing, a way will be sought to facilitate ingestion, fractionating the doses of the 
drug or its volume.  
 
In case the placement of a nasogastric tube is required for the administration of the 
drug, it will be placed by trained personnel. 
 
6.3 Describe the potential benefits  
 
The administration of thymic peptides (Unicahsina) exerts an immunomodulatory 
effect, which will enhance the response of T, B and Natural Killer (NK) lymphocytes 
(51). This response is expected to help stop or mitigate the progression of alveolar 
destruction induced by the inflammatory reaction in the infection by Sars-Cov-2. The 
objective is to prevent progression to a more severe form of the disease, and 
consequently to reduce the mortality rate. 
 

14 
 
SECTION 7 - INCENTIVES AND INDUCEMENTS TO PARTICIPATE 
 
7.1 Describe any incentive/inducement to participate that will be offered to the 
participants. 
 
No incentives or inducements will be offered to participate in this study. 
 
SECTION 8 - OTHER FINANCIAL CONSIDERATIONS 
 
8.1 Describe the monetary expenses that the participants will incur.   
 
The participants will not incur in any monetary expenses directly related with the 
study. The doses of the thymic peptides (Unicahsina), as well as the RT-qPCR tests, 
antigen or antibody test, CT scan and chest radiographs that are required as additional 
controls to those requested as a protocol by the Ministry of Health of Honduras will 
be financed by the State of Honduras, the Universidad Católica de Honduras and the 
Grupo de Investigacion Medica de la Universidad Católica de Honduras 
(GIMUNICAH). 
 
8.2 Describe the procedures for compensating research-related injuries 
 
Study-related injuries are not expected. However, for the minimal risks of a slight 
nasal bleeding originating after sampling for RT-qPCR or some complication in the 
placement of a nasogastric tube in intubated patients, immediate management of the 
lesion will be performed, and all expenses related to this will be covered by the State 
of Honduras. In the event of a hypersensitivity reaction to thymic peptides 
(Unicahsina), timely management will be given and the necessary medication 
expenses for the specific event will be covered by the State of Honduras. 
 
SECTION 9 - INFORMED CONSENT 
 
The informed consent process will start from the recruitment of the participants. Once 
the potential study participants have been identified, we will proceed to report on the 
objective and the methodology that will be used to answer the research questions. 
During the discussion of the consent form, it will be ensured that the participant has 
the necessary time to fully understand all the interventions to which he/she will be 
exposed. The participants will be allowed to ask the questions that are necessary to 
clear any doubts. It will be emphasized that the decision to be part of the study is 
absolutely voluntary, in addition to the fact that participant can withdraw at any time 
without incurring in any penalty. If the participant agrees, he/she will be asked for a 
signature or fingerprint. The participant will receive a copy of the form.  
 
During the duration of the research, the participant will continue to be informed about 
their clinical evolution, new risks, changes in procedures, dose modification, 
extension, or completion of the study (prior authorization by the Ethics Committee). 
In addition, the ability of the patient to consent and reaffirm their willingness to 
remain in the study will be continuously evaluated. 
 
 

15 
 
 
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18 
 
 
PROTOCOL 
VERSION B 
 
SECTION 1 – TITLE, PURPOSE AND JUSTIFICATION 
1.1 Title. Safety and Efficacy of Thymic Peptides in the Treatment of Hospitalized 
COVID-19 Patients in Honduras. 
 
1.2 Study Purpose. To determine if thymic peptides (Unicahsina) are a new therapeutic 
option for the treatment of patients infected by COVID-19 in order to improve their 
clinical prognosis. 
 
1.3 Justification. Coronaviruses are important pathogens in humans and animals, 
causing respiratory tract and lung parenchymal infections. In late 2019, a novel 
coronavirus was identified as the cause of a series of pneumonia cases in Wuhan, a 
city in Hubei province in China (1). The infection spread rapidly, leading to an 
epidemic throughout China, followed by an increasing number of cases in other 
countries, affecting all continents except Antarctica (1). WHO declared COVID-19 a 
pandemic on March 11, 2020 (2). The virus is currently referred to as Severe Acute 
Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and the disease caused by the 
virus is known as COVID-19. 
 
At the time of writing this protocol, more than 5,584,091 cases of COVID-19 have 
been reported worldwide (3). This is largely due to the ease with which this virus is 
transmitted. The primary mechanism of spread is person-to-person transmission, 
which occurs primarily by respiratory droplets (1). Transmission of SARS-CoV-2 
via fomites is plausible as it has been shown to remain viable on surfaces for hours 
and even several days (4). 
 
The coronavirus that causes COVID-19 is a betacoronavirus of the same subgenus as 
SARS-CoV (5). The incubation period is estimated to be 14 days after exposure, with 
most cases occurring between 4 and 5 days (6-8). The disease is mild in 81% of cases, 
severe in 14% and critical in 5% (9). The overall mortality rate is 2.3% (9). The 
clinical course is characterized by fever (99%), fatigue (70%), dry cough (59%), 
anorexia (40%), myalgia (35%), dyspnea (31%) and sputum (27%) (10). Pneumonia 
appears to be the most serious manifestation of infection, characterized mainly by 
fever, cough, dyspnea and a bilateral pulmonary infiltrate (visible on imaging) (7, 10-
12). 
 
Global statistics show that mortality due to COVID-19 increases significantly with 
age. Pediatric patients under 9 years of age present mild cases with practically zero 
mortality (13). Between 9 and 39 years of age, statistics indicate a mortality of 
approximately 0.2% (13). In the age range between 40 and 69 years, the rate oscillates 
between 1.3 and 3.6% (13). Above 70 years of age, deaths due to COVID-19 increase 
exponentially, reaching 8% of cases (13). Patients over 80 years of age are the highest 
risk group with a mortality rate of 14.8% (13). 
 

19 
 
This remarkable statistical difference in morbidity and mortality is consistent with a 
biological process that has so far been scarcely addressed: involution of the thymus. 
This retrosternal gland is part of the primary lymphoid organs, playing an important 
role in the maturation and differentiation of T cells to CD4+ and CD8+ subtypes, in 
addition to secretion of cytokines that mediate the immune response (14). Involution 
follows a characteristic pattern in which there is a progressive loss of function from 
the first year of life (15). Between 35 and 45 years of age this process accelerates, 
losing up to 30% of its function in a decade (15). Finally, after the age of 65 it 
regresses and is replaced in its totality by adipose tissue (15). 
 
Ferman-Cano et al. suggest that the relative protection observed in the infant 
population with COVID-19 could be explained by the influence of the thymus. Based 
on this background and the evident relationship between the age ranges in which 
thymus involution occurs and the exponential increase in mortality, we propose that 
at older ages there is a greater deficiency of thymic factors, whose replacement 
represents a therapeutic mechanism to be explored. In this context, thymic peptides 
stand out as potent candidates given their immunogenic properties and proven safety. 
 
Thymomodulin is a set of low molecular weight peptides of less than 10,000 Daltons, 
derived from the acid lysis of calf thymus (16). It has been shown that modulates the 
maturation and function of T lymphocytes and favors the expression of B cell surface 
markers (16,17). In vitro, thymomodulin has been shown to possess a myelopoiesis-
inducing effect in the bone marrow, stimulating granulocyte and macrophage 
colonies (18). In addition, in murine studies it has been shown to produce an increase 
in serum thymic hormone (19). 
 
In clinical studies, thymomodulin has proved to reduce the number of recurrent 
respiratory infections in children (20). This improvement is associated with a higher 
CD3 + and CD4 + cell count, increased neutrophilic function and salivary IgA levels 
(21, 22). It also has multiple reports on its safety and efficacy in patients with immune 
imbalance, in pathologies such as chronic bronchitis (23-25), bronchial 
hyperresponsiveness (26), asthma (27-29), food allergy (30, 31), atopic dermatitis, 
immunosuppression by chemo or radiotherapy for neoplasms (32, 33), initial phases 
of AIDS (34-36) and senectitude thymic involution (19,37,38). 
 
In geriatric patients, studies prove safety at high doses (19), an increase in the number 
of lymphocytes, monocytes, IgA, IgG and IgM levels (37-40). Likewise, 
thymomodulin increases the production of free radicals due to alveolar macrophages 
(23). It is noteworthy to mention that it can even prevent and emend leukopenia in 
patients undergoing chemotherapy and radiotherapy (41), which has been proven in 
patients with breast and genitourinary tract cancer (42).       
 
In studies of acute and chronic toxicity, it has been shown that thymomodulin does 
not possess teratogenic or embryotoxic effects (43). For this reason, it has a high 
potential for use during pregnancy. 
 
Given the fact that the population most at risk of presenting severe disease and a 
higher mortality rate due to COVID-19 are immunosuppressed patients, older adults 
and/or those with comorbidities, effective therapeutic options with high safety 
profiles are needed.  Currently there are no treatments available that meet these 

20 
 
requirements for disease management. Treatment options include protocols using 
chloroquine or hydroxychloroquine. The evidence in favor of its use remains 
controversial, since a number of adverse effects have been documented that could 
affect the most vulnerable population. They are contraindicated in patients with 
retinopathy (44), neuromyopathy and heart disease due to the possible increase in the 
QT interval (45). 
 
Scientific evidence proves the absence of short or long-term adverse effects of 
thymomodulin, obtaining significant results in the treatment of patients with 
immunological vulnerability in various respiratory pathologies (23). Taking this into 
account, it can be considered a promising alternative to combat the COVID-19 
pandemic. The following sections will discuss the methodology of the clinical trial 
that will be used to evaluate its efficacy as a therapeutic option.  
 
Hypothesis 
 
Oral administration of thymic peptides (Unicahsina) is a safe and effective therapy 
for the management of patients with COVID-19 respiratory onsets. 
 
General Objective 
 
To demonstrate the therapeutic efficacy and safety of thymic peptides (Unicahsina) 
in patients with COVID-19 respiratory disease.  
 
Specific objectives 
 
1. To evaluate the safety of thymic peptides (Unicahsina) by monitoring adverse 
events using the Common Terminology Criteria for Adverse Events Version 5.0 
(CTCAE v5.0) and side effects using the General Assessment of Side Effects 
(GASE).  
2. Determine the time to participant recovery, according to a clinical ordinal 
progression scale.  
3. To perform survival analysis in patients diagnosed with COVID-19 and treated 
with thymic peptides (Unicahsina). 
 
SECTION 2 - DESCRIPTION OF THE POPULATION 
 
2.1 Number of participants: 20 participants.  
 
2.2 Describe the population: 
 
Patients with diagnosis of COVID-19 confirmed by RT-qPCR testing, viral antigen 
detection or antibody detection plus associated symptomatology. The study will be 
performed in patients over 20 years of age without distinction of sex, race, religion, 
or socioeconomic status. Since the population under 20 years of age presents mostly 
mild or asymptomatic symptoms, with a mortality rate between 0% and 0.2%, it was 
decided to exclude this age range. 
 

21 
 
This research will involve elderly patients and those with comorbidities. The current 
COVID-19 pandemic has shown that this group of patients has the highest mortality 
rate, exposing the need to discover safe and effective therapies. Therefore, and given 
the innocuous profile that thymic peptides possess, we consider their use in this 
population.   
 
Should any of the participants decide to withdraw from the study voluntarily or 
request self-discharge, another patient will be added to the study until 20 patients 
have reached conclusion either by medical discharge or death within a 20-day 
hospitalization follow-up. Patient data will be used up to the date of voluntary 
withdrawal or self-discharge.  
 
2.3 Criteria 
 
Inclusion Criteria: 
 
1. Confirmed case of COVID-19 by viral nucleic acid (RNA) detection, viral 
antigen detection, or detection of antibodies to the virus. 
 
2. Participants that require hospitalization under Honduran Ministry of Health 
Guidelines for Clinical Management of COVID-19 Adult Patients: Stage IIb, 
defined as a patient with or without risk factors that presents with warning signs 
(shortness of breath, tachypnea), and altered inflammatory parameters. 
 
3. Participants that present with at least one of the following: oxygen saturation 
level below 94 percent; complete blood count showing lymphopenia, 
neutrophilia, or both; positive C-reactive protein; chest radiography or CT scan 
with ground-glass opacities. 
 
4. Male or female at least 21 years old. 
 
Exclusion criteria  
 
1. COVID-19 patients that do not require hospitalization under Honduran Ministry 
of Health Guidelines for Clinical Management of COVID-19 Adult Patients: 
phase IA (asymptomatic), phase IB (mild symptoms without risk factors), or 
phase IC (mild symptoms with risk factors). 
 
2. Participants currently in other clinical trials evaluating experimental drugs. 
 
3. Known history of allergic reactions to thymic peptides or calf thymus acid lysate 
derivatives. 
 
4. Organ transplant recipients. 
 
5. Women who are pregnant or breast feeding. 
 
SECTION 3. PARTICIPANT RECRUITMENT  
 

22 
 
Patients who meet the inclusion criteria and are hospitalized in Honduran facilities 
designated for the care of patients with COVID-19, will be recruited. Patients over 
20 years of age capable of giving their consent will be included.  In case that the 
patient is unable to authorize participation, authorization will be requested from his 
legal representative. 
 
Prior to their incorporation into the study, patients will be approached by the 
specialist or health personnel present on behalf of the Medical Research Group of the 
Catholic University of Honduras. In addition, there will be auxiliary methods with 
electronic devices that will allow telemedicine to be carried out between the principal 
investigators of the study and the potential participants. This last procedure will be 
carried out with encrypted methods that guarantee the confidentiality and anonymity 
of the patients. The purpose and procedures of the investigation will be explained, as 
well as clarifying any doubts that may arise. Once consent has been obtained, the 
clinical data registration will begin, and the application of the protocol will be 
coordinated with the treating physicians. 
 
SECTION 4 - METHODOLOGY AND PROCEDURES 
 
4.1 Study design 
This is a single-arm, open-label, phase II clinical trial to evaluate the safety and 
efficacy of thymic peptides in the treatment of hospitalized COVID-19 patients in 
Honduras, at the Hospital de Santa Bárbara Integrado. A participant-level 
comparison will be made based on registry data of the Hospital de Santa Bárbara 
Integrado, after propensity score matching. 
 
In total, 20 patients will be recruited from the designated hospital for COVID-19 
patient care, including those who have signed informed consent and who meet the 
inclusion criteria. For the generation of the comparison group through data from 
clinical records, it will be carried out by authorization from the Hospital de Santa 
Bárbara Integrado, given its retrospective nature, without experimental intervention. 
 
Clinical characterization 
 
Once the protocol is started, the information corresponding to the general data, signs, 
symptoms, physical examination and laboratory values of each patient will be 
recorded daily in the data collection instrument. The record will be made on paper, 
which will be digitized and sent under encryption to the principal investigators every 
day. 
 
As a quantitative method, the following laboratory findings will be considered to 
evaluate clinical progress, according to the requirement and availability of the 
hospital: 
● Complete blood count 
● C-reactive protein 
● D-dimer 
● Ferritin 
● Procalcitonin 
● Lactate 
● AST 

23 
 
● ALT 
● BUN 
● Creatinine 
 
Administration of thymic peptides (Unicahsina) 
Thymic peptides (Unicahsina) will be administered in an oral dose of 250 mg per 
day. In the intubated patient, the administration will be done through a nasogastric 
tube. The presentation of thymic peptides (Unicahsina) will be in lyophilized form, 
which will be diluted in 50 ml of drinking water prior to administration. It should be 
administered on an empty stomach one hour before or two hours after a meal. If the 
patient is discharged, or if they need to be referred to an ICU, all the information will 
be gathered up to that moment and the administration of Unicahsina will be stopped. 
 
Primary outcome measures 
 
1) Time to participant recovery [Time Frame: During hospitalization for up to 20 
days.] 
 
Measured in days to clinical recovery that will be 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 
the eight-category ordinal scale. 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 requiring supplemental 
oxygen but requiring ongoing medical care (related to Covid-19 or to 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 
(ECMO); and 8, death. 
 
2) Number of participants with treatment related adverse events as assessed by the 
Common Terminology Criteria for Adverse Events Version 5.0 (CTCAE v5.0) [ 
Time Frame: Up to 20 days] 
 
Number of participants who experience adverse events ≥ Grade 3, as defined by the 
CTCAE v5.0. 
 
3) Number of participants with treatment related side effects as assessed by the 
General Assessment of Side Effects (GASE) [ Time Frame: Up to 20 days] 
 
Number of participants who experience severe side effects as defined by the GASE. 
 
Secondary Outcomes measures 
 
1) Overall survival defined as the time from the start of treatment until death due to 
any reason [ Time Frame: Up to 20 days] 
 
Time for overall survival will be measured in days. 
 
 

24 
 
Other complementary analyzes 
 
Computerized axial tomography and chest radiography 
 
A Computerized tomography without contrast will be performed, with the patient in 
the supine position and the image acquisition will be carried out at the end of 
inspiration. The following parameters will be requested to obtain axial images: 1.25 
mm thick, 1.25 mm interval, 120 kVp. If it is possible, chest radiographs will be 
requested in posteroanterior projection. However, in patients whose clinical 
condition warrants it, anteroposterior radiography will be considered. The images 
will be obtained at the moment of maximum inspiration, either with instruction to the 
patient or by controlling the ventilator console in the case of intubated patients. 
 
The tomographic or radiographic findings will be interpreted using the scoring 
system previously described by Cai et al (46). After the analysis by the assigned 
radiologist of the hospital center, the data generated by CT or X-ray will be submitted 
to two independent radiologist physicians, both blinded to the corresponding group 
of participants and the corresponding clinic. These specialists will assign a 
Pulmonary Score 1 (SP1) according to the findings they observe, based on three 
categories:  
1 = Normal attenuation  
2 = Ground-glass opacity  
3 = Consolidation 
 
Each lung will be divided into 3 zones with limits defined as follows: 
 
Upper zone: area above the level of the carina.  
Middle zone: area between the level of the carina and the inferior pulmonary vein. 
Inferior zone: area below the level of the inferior pulmonary vein. 
 
In this way, a total of 6 pulmonary areas will be delimited, each of which will receive 
a score according to the following scale of distribution of compromised lung 
parenchyma or Pulmonary Score 2 (SP2):  
 
0 = Normal  
1 = 1% to 25% involvement 
2 = 25% to 50% involvement 
3 = 50% to 75% involvement 
4 = More than 75% involvement 
 
The scores of each lung area will be summed to obtain the Total Affectation (AT) 
grade. Finally, AT will be multiplied by SP1 to obtain the Total Cumulative Scale 
(ETA), which comprises a range from 0 to 72. A change of "Improvement" on CT or 
chest X-ray will be defined as an ETA lower than the previous value obtained at the 
start of treatment or from the previous imaging studies. A "worsening" change will 
be defined as an ETA greater than the previous value obtained at the start of treatment 
or previous imaging studies. The stability of the picture will be defined as "Constant" 
when the ETA is equal to the previous value obtained at the beginning of treatment 
or from previous imaging studies. 
 

25 
 
Statistical Analysis Plan 
 
All quantitative data will be described using parameters such as the mean ± standard 
deviation, or as the median (minimum and maximum). Qualitative data will be 
described by the number of cases (proportion%). Patient characteristics will be 
compared using the chi-square test or Fisher's exact test for categorical data. For 
continuous variable data, the Wilcoxon test or Student's t test will be employed. The 
analysis of time to a particular event will be carried out using the Kaplan-Meier 
method, and the analysis of differences between groups will be calculated with the 
log-rank test. The Cox proportional-hazard model will be used to estimate the hazard 
ratio and 95% confidence interval (CI). Propensity score matching methodology will 
be used to generate the comparison group from the clinical records. A p-value less 
than 0.05 will be required to establish significance. All analyses will be performed 
using SPSS and GraphPad Prism software. 
 
SECTION 5 - ANONYMITY AND CONFIDENTIALITY OF DATA 
 
The data will be obtained from the healthcare center assigned to treat positive cases 
of COVID-19, through the clinical record designed as an instrument for this study. 
The laboratory and imaging test reports, as well as the clinical records, will be 
digitized and sent to the principal investigators using the SOPHOS encryption 
software. This last part will ensure the confidentiality of each patient's data between 
devices while transferred. Access will be given to the Dirección General de 
Vigilancia del Marco Normativo de la Secretaría de Salud de Honduras (General 
Directorate for Regulatory Framework Surveillance of the Ministry of Health of 
Honduras) for the monitoring of the study. The hospital will have a password-
protected electronic device. The access will be limited exclusively to medical doctors 
assigned for the study. 
 
The physical documents will be attached to the patient clinical file at the end of the 
hospitalization.  
 
For the data produced by CT or chest x-ray, the HOROS software will be used to 
visualize and anonymized DICOM files before sending them to radiologists. The 
confidentiality in transferring this information will be ensured by using the SOPHOS 
software. 
 
SECTION 6 - POTENTIAL RISKS AND BENEFITS 
 
6.1 Describe potential risks and discomforts 
 
The administration of oral thymic peptides (Unicahsina) constitutes a minimal risk 
intervention since its use has not reported any toxic or mutagenic effects even at high 
concentrations (16). It has multiple reports on its safety and efficacy in patients with 
immune imbalance, pathologies such as chronic bronchitis (23-25), bronchial 
hyperreactivity (26), asthma (27-29), food allergy (30, 31), atopic dermatitis, 
immunosuppression by chemo or radiotherapy for neoplasms (32, 33), initial phases 
of AIDS (34-37) and thymic involution of agedness (19, 38). No additional risks are 

26 
 
expected from the application of this treatment. However, the possibility of unknown 
adverse effects in patients with COVID-19 cannot be ruled out.   
    
CT or chest x-rays carry minimal risks. Imaging procedures will not involve the 
administration of contrast media, so no allergic reactions or renal damage is expected. 
Even though exposure to CT of the thorax can increase the risk of cancer, this 
represents an increment of only 0.7% (47). No pregnant women will be included in 
this study.  
 
The administration of thymic peptides (Unicahsina) will be orally, diluting the 
lyophilized product in water for ingestion. In case of impaired consciousness, 
difficulty swallowing, or if the medical doctors consider the necessity of intubation, 
a nasogastric tube will be placed for the continuation of treatment. This process 
carries the following risks: displacement of the tube, electrolyte dysregulation, 
hyperglycemia, diarrhea, constipation, vomit, tube obstruction, and pulmonary 
aspiration (48). However, to minimize risks, this procedure will be performed by 
trained healthcare personnel.    
 
Samples for RT-qPCR will be taken using a nasal swab. This technique carries 
minimal risks that include pharyngeal reflex, mild nose bleeding, discomfort, and 
cough (49, 50). 
 
No psychological, sociological, or legal risks are expected in this study.  
 
6.2 Describe how risks will be minimized  
 
Monitoring of possible adverse reactions or side effects will occur after the 
administration of the drug. In case reactions that compromise the health of the 
participant appear, the drug will be suspended. If discomfort occurs when 
swallowing, a way will be sought to facilitate ingestion, fractionating the doses of the 
drug or its volume.  
 
In case the placement of a nasogastric tube is required for the administration of the 
drug, it will be placed by trained personnel. 
 
6.3 Describe the potential benefits  
 
The administration of thymic peptides (Unicahsina) exerts an immunomodulatory 
effect, which will enhance the response of T, B and Natural Killer (NK) lymphocytes 
(51). This response is expected to help stop or mitigate the progression of alveolar 
destruction induced by the inflammatory reaction in the infection by Sars-Cov-2. The 
objective is to prevent progression to a more severe form of the disease, and 
consequently to reduce the mortality rate. 
 
 
 
 
SECTION 7 - INCENTIVES AND INDUCEMENTS TO PARTICIPATE 
 

27 
 
7.1 Describe any incentive/inducement to participate that will be offered to the 
participants. 
 
No incentives or inducements will be offered to participate in this study. 
 
SECTION 8 - OTHER FINANCIAL CONSIDERATIONS 
 
8.1 Describe the monetary expenses that the participants will incur.   
 
The participants will not incur in any monetary expenses directly related with the 
study. The doses of the thymic peptides (Unicahsina), as well as the RT-qPCR tests, 
antigen or antibody test, CT scan and chest radiographs that are required as additional 
controls to those requested as a protocol by the Ministry of Health of Honduras will 
be financed by the State of Honduras, the Universidad Católica de Honduras and the 
Grupo de Investigacion Medica de la Universidad Católica de Honduras 
(GIMUNICAH). 
 
8.2 Describe the procedures for compensating research-related injuries 
 
Study-related injuries are not expected. However, for the minimal risks of a slight 
nasal bleeding originating after sampling for RT-qPCR or some complication in the 
placement of a nasogastric tube in intubated patients, immediate management of the 
lesion will be performed, and all expenses related to this will be covered by the State 
of Honduras. In the event of a hypersensitivity reaction to thymic peptides 
(Unicahsina), timely management will be given and the necessary medication 
expenses for the specific event will be covered by the State of Honduras. 
 
SECTION 9 - INFORMED CONSENT 
 
The informed consent process will start from the recruitment of the participants. Once 
the potential study participants have been identified, we will proceed to report on the 
objective and the methodology that will be used to answer the research questions. 
During the discussion of the consent form, it will be ensured that the participant has 
the necessary time to fully understand all the interventions to which he/she will be 
exposed. The participants will be allowed to ask the questions that are necessary to 
clear any doubts. It will be emphasized that the decision to be part of the study is 
absolutely voluntary, in addition to the fact that participant can withdraw at any time 
without incurring in any penalty. If the participant agrees, he/she will be asked for a 
signature or fingerprint. The participant will receive a copy of the form.  
 
During the duration of the research, the participant will continue to be informed about 
their clinical evolution, new risks, changes in procedures, dose modification, 
extension, or completion of the study (prior authorization by the Ethics Committee). 
In addition, the ability of the patient to consent and reaffirm their willingness to 
remain in the study will be continuously evaluated. 
 
 

28 
 
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31 
 
SUMMARY OF CHANGES 
 
Change 
Reason 
Original: 
 
Time to Participant Response [Time Frame: 
During hospitalization for up to 20 days.] 
 
Measured in days to clinical response that 
will be defined as clinical stability 
(temperature, ≤37.8°C; heart rate, ≤100 
beats per min; systolic blood pressure, ≥90 
mm Hg; respiratory rate, ≤24 breaths per 
min; oxygen saturation, ≥90 percent; normal 
mental status; no receipt of supplemental 
oxygen by face mask or mechanical 
ventilation) with improvement in at least 
one symptom (anosmia, dysgeusia, cough, 
shortness of breath, cyanosis, conjunctivitis, 
pharyngitis, sputum production, rhinorrhea, 
myalgia, otalgia, odynophagia, fatigue, 
diarrhea, hemoptysis, vomit) and with no 
symptom worsening that is sustained for at 
least 24 h. 
 
Final: 
 
Time to Participant Recovery [ Time Frame: 
During hospitalization for up to 20 days.] 
 
Measured in days to clinical recovery that 
will be 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 the 
eight-category ordinal scale. 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 requiring supplemental 
oxygen but requiring ongoing medical care 
(related to Covid-19 or to 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 
(ECMO); and 8, death. 
 
 
The time to recovery assessment was 
modified from the first protocol version to 
better adhere to World Health Organization 
(WHO) recommendations on clinical 
progression outcomes. 

32 
 
 
 
Original: 
 
Hospital Average Length of Stay (ALOS) as 
Measured by the Mean Participants' 
Inpatient Days [ Time Frame: Up to 20 days] 
The average length of stay will be calculated 
by dividing the sum of inpatient days by the 
number of participant admissions. 
 
Final: 
 
Only overall survival as secondary outcome 
 
Hospital average length of stay was removed 
as a secondary outcome in the last version of 
the protocol for considering it a less reliable 
metric. However, it was analyzed as a 
complementary analysis using the Kaplan-
Meier method.