Study setting {9}
The study will be conducted at the facilities of the Hospital General de México “Dr. Eduardo Liceaga”, located near downtown Mexico City, Mexico.
Eligibility criteria {10}
Screening: criteria: Upon admission, screening criteria will be applied in the Emergency service to select the candidates
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Adult patients (18-70)
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Within 12 days of the appearance of symptoms
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Severe non-critical clinical stage at admission
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At least one of the following risk factors: DM, obesity (BMI>30), hypertension history or age >65
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Respiratory rate 25-34/min AND absence of other clinical signs of respiratory distress (nasal flaring, intercostal pulling, thoracoabdominal dissociation, hypoxic encephalopathy
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Respiratory rate 25-34/min
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Thorax USG with LUS >23
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O2 saturation 90-81% (Unassisted)
Inclusion criteria: These will confirm the selected subjects for enrollment.
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Positive for SARS-CoV-2 confirmed by PCR
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PaFi 250-100
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LDH (Lactate dehydrogenase) >350
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>50% pulmonary infiltration as determined by thoracic imaging
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FiO2 requirement >60% to maintain oxygenation goals
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Normal hepatic function, defined as a maximum of a fivefold increase of transaminases.
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Signed informed consent.
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Women in fertile capability must accept the use of a contraceptive method for 90 days after treatment completion.
Exclusion criteria
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Pregnant or lactating women
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Participating in another clinical trial
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Clinical evidence of an infectious disease different from COVID-19 at the time of admission
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Glasgow coma score <13
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Clinical signs of respiratory distress (nasal flaring, intercostal pulling, thoracoabdominal dissociation, hypoxic encephalopathy AND persisting Glasgow score ≤ 13
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Glomerular filtration rate <60ml/min/1.73m2 and known history of pre-existing chronic kidney disease (Chronic kidney disease stage 3,4,5)
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Coronary disease (acute or chronic)
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Previous history of allergies to MVC or FPV
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Autoimmune disorders
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History of any previous transplant
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Under treatment with psychotropic drugs of any kind.
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Cancer of any kind
Elimination criteria
Who will take informed consent? {26a}
All candidates must read and sign an Informed Consent Form (ICF) before enrollment. The ICF will be obtained by certified researchers, physicians and nurses of the Hospital staff participating in this study (APG, MLHM, EOMH, and MLH). A model of the ICF can be provided upon request.
Additional consent provisions for collection and use of participant data and biological specimens {26b}
Not applicable since there are no additional samples to be collected.
Interventions
Explanation for the choice of comparators {6b}
Comparison between groups was based upon treatment with MVC or FPV or both or none.
Intervention description {11a}
*ARM A: Active Comparator: Currently used therapy (CT) only. Treatment currently used at Hospital General de México "Dr. Eduardo Liceaga" for non-critical COVID patients: Enoxaparin, dexamethasone, and antibiotics if associated bacteremia is present.
*ARM B:Experimental: Maraviroc+CT. Maraviroc tablets. 300 mg bid, given orally for a 10 day period AND CT (Enoxaparin, dexamethasone, and antibiotics if associated bacteremia is present, as per currently used at Hospital General de México "Dr. Eduardo Liceaga").
*ARM C: Experimental: Favipiravir+CT. Favipiravir tablets 200 mg. given orally for a 7 day period. 1600 mg bid on day 1 and 600 mg tid days 2-7 AND CT (Enoxaparin, dexamethasone, and antibiotics if associated bacteremia is present, as per currently used at Hospital General de México "Dr. Eduardo Liceaga").
*ARM D: Experimental: Maraviroc+Favipiravir+CT. Maraviroc tablets. 300 mg bid, given orally for a 10 day period AND Favipiravir tablets 200 mg. given orally for the first 7 days. 1600 mg bid on day 1 and 600 mg tid days 2-7 AND CT (Enoxaparin, dexamethasone, and antibiotics if associated bacteremia is present, as per currently used at Hospital General de México "Dr. Eduardo Liceaga"").
Criteria for discontinuing or modifying allocated interventions {11b}
If patients progress to critical condition, tablets will be crushed and administered using a nasogastric tube. The treatment will be discontinued in the occurrence of treatment-related adverse effects ruled so by a physician.
Strategies to improve adherence to interventions {11c}
Not applicable since all participants are inpatients.
Relevant concomitant care permitted or prohibited during the trial {11d}
Not applicable since all participants are inpatients, and such care will be provided by nursery staff if needed.
Provisions for post-trial care {30}
Not applicable since patients are discharged upon improvement
Outcomes {12}
Primary:
Secondary:
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Percentage of patients free of mechanically-assisted ventilation [Time frame: day 5] Clinical relevance: Evaluation of the efficacy of the treatment to prevent complications and death at day 5
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Time of improvement in at least 2 categories in the WHO 7-category ordinal scale (44) [Time frame: day 15] Clinical relevance: Evaluation of the efficacy of the treatment to improve the patients’ condition and prognosis.
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Evaluation of the response to treatment of the hyperinflammatory condition by analysis of the change rate in percentage of lymphocytes, monocytes and neutrophils, as well as proinflammatory chemokine and cytokine levels [Time frame: day 10-0]
Participant timeline {13}
The following diagram depicts the arms and interventions of the study
STUDY PERIOD
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Enrollment
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Allocation
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Post-allocation
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Screening period
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Treatment period
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Follow-up period
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Close out
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EVENT
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-D2
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D0
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D1
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D2
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D3
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D4
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D5
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D6
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D7
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D8
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D9
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D10
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D15
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D28
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D180
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Informed consent
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X
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Screening criteria
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X
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Inclusion criteria
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X
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Allocation
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X
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INTERVENTION
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Arm A: Current Therapy (CT)
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X
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X
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X
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X
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X
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X
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X
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X
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X
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X
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Arm B: MVC + CT
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X
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X
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X
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X
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X
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X
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X
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X
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X
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X
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Arm C: FVP + CT
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X
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X
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X
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X
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X
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X
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X
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X
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X
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X
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Arm D: MVC + FVP + CT
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X
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X
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X
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X
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X
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X
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X
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X
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X
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X
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ASSESSMENTS
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Variables
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Hematic biometry
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X
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Electrocardiogram
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X
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X
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Viral Load
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X
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X
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X
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X
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Chemokines
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X
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X
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Cytokines
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X
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X
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X
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Chest x-ray
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X
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X
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Disease progress
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X
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X
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Days free of mechanical ventilation
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X
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X
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X
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Sample size {14}
The calculation was performed to compare survival curves using EPIDAT 4.2, based upon the current casuistry observed at the Infectology service of the Hospital General de México, with a mechanical ventilation free survival rate in severe cases of 65% and a maximum expected value of 80%, with a confidence level of 80%. For a 4-arm study, the following is obtained:
Sample size and power for survival curves comparison:
Groups: 4
Estimated losses: 15%
Confidence level: 80.0%
Survival probability (%)
Group 1: 65
Group 2: 75
Group 3: 75
Group 4: 80
Power (%) Total
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80.0 98
Therefore, 25 patients were allocated by group; 100 total.
Recruitment {15}
Participants will be recruited from the adult COVID-19 population of patients admitted to the Hospital.
Assignment of interventions: allocation
Sequence generation {16a}
The allocation order will be generated randomly by EPIDAT 4.2 to assign the subjects to the A, B, C or D arms. Each patient’s medical record number will serve for identification of the assigned treatment.
Concealment mechanism {16b}
Not applicable since this is not a blinded study.
Implementation {16c}
The allocation and enrollment of patients will be performed by certified researchers and nurses from the Hospital who are members of the staff of the study. (MLHM, ARCM, APG)
Assignment of interventions: Blinding
Who will be blinded {17a}
Not applicable since this is not a blinded study
Procedure for unblinding if needed {17b}
Not applicable since this is not a blinded study
Data collection and management
Plans for assessment and collection of outcomes {18a}
Data will be collected from the patients in printed forms by the nursery staff and then captured in a specially designed Excel data collection tool (Project EXCELEN-19 currently being conducted in the Hospital) by the study staff (LMPN), or their authorized surrogates. Double capture will be applied. Laboratory results will be uploaded to the patients database and incorporated to each participant’s information.
Plans to promote participant retention and complete follow-up {18b}
After discharge, patients will be contacted by the study staff (LMPN, MMSM, MLH) or their authorized surrogates to ask them about their general health and some specific issues addressed to evaluate their pulmonary condition and the appearance of possible respiratory sequels.
Data management {19}
Data will be captured in a specially designed Excel data collection tool (Project EXCELEN-19 currently being conducted in the Hospital) by the study staff (LMPN), or their authorized surrogates. Double capture will be applied. Data will be stored in a Hospital’s server with restricted access rights.
Confidentiality {27}
Participant’s names will be collected only at admission, and will not be used for the study. A consecutive ID number and the patient unique file number (assigned by the Hospital database) will be used instead.
Plans for collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis in this trial/future use {33}
The following diagram describes the planned collection of samples
Blood samples will be collected by certified nursery personnel. Samples will be processed in three different ways:
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Fresh samples immediately processed in laboratory.
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Serum collection and freezing at -80°C. Samples will be analyzed by flow cytometry at a later time
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Obtaining and preservation of leukocytes in DMSO at -80°C. Samples will be analyzed by flow cytometry at a later time.
Saliva and nasopharyngeal exudate samples will be collected by certified nursery personnel and frozen at -80°C. Samples will be analyzed for viral load at a later time.
Statistical methods
Statistical methods for primary and secondary outcomes {20a}
The primary endpoint (Percentage of patients free of mechanically assisted ventilation [time frame: day 28]) will be compared between the 4 arms using a Cochran-Mantel-Haenszel test stratified in time.
The secondary endpoints will be compared between arms as follows:
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Percentage of patients free of mechanically assisted ventilation [Time frame: day 5]: Cochran-Mantel-Haenszel test stratified in time.
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Time of improvement in at least 2 categories in the WHO 7-category ordinal scale (44) [Time frame: day 15]: Kruskal-Wallis test.
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Change rate in expression of proinflammatory cytokines and chemokines in different leukocyte subpopulations [Time frame: day 10-1]: One-way ANOVA will be used to compare change rate of each cytokine/chemokine. Additionally, a Principal Component Analysis (PCA) will be performed for cluster identification and their role in the response to treatment.
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Change rate in the patterns of activation, trafficking and exhaustion in peripheral blood lymphocytes, monocytes and neutrophils [Time frame: day 10-1]: Data will be analyzed for subpopulations, percentages and mean fluorescence intensities for each molecule
Data will be controlled by confounding factors (BMI, sex, hypertension and diabetes). A Cox regression survival analysis adjusted by age, BMI, sex and comorbidities will be performed to estimate the relative risk of each of the following variables: Discharge by improvement or death, days of hospital stay and days free of ventilatory support.
Interim analyses {21b}
An interim analysis will be carried out when data from 50 patients had been processed. If such analysis has a minimum of 50% power, a group analysis will be performed, and the results will be published.
Methods for additional analyses (e.g. subgroup analyses) {20b}
Not Applicable since there are no subgroups
Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c}
We are foreseeing no issues with non-adherence, because all the subjects are inpatients. To prevent inconsistencies or biases from missing data due to interruption of treatment, the modified intention to treat (mITT) will be calculated, based on the criterion of at least one dose taken and at least one measurement after basal of the endpoints.
Plans to give access to the full protocol, participant level-data and statistical code {31c}
Access will be given on the basis of inter institutional exchanges upon request, for collaborative research purposes.
Oversight and monitoring
Composition of the coordinating centre and trial steering committee {5d}
The study will be monitored by the Committees of Ethics, Research and Biosafety of the Hospital General de México “Dr. Eduardo Liceaga” The Ethics Committee has a valid registration in the National Commission of Bioethics.
Composition of the data monitoring committee, its role and reporting structure {21a}
The Quality Manager, and a MD from the Clinical Pharmacology service, along with their authorized surrogates, will form the Data Monitoring Committee. They will review the data and will check for consistency and completeness of the records.
Adverse event reporting and harms {22}
All adverse events will be immediately recorded and reported to the MDs who serve as Officials (MLHM, EOMH). They will assess if the AE is related to the medication under study, and if the participation of the patient should be terminated for safety reasons.
Frequency and plans for auditing trial conduct {23}
Auditing will be a mixture of internal and external monitoring. Internal will be an in-house quality control, while external will assure international quality standards. Both will be performed on a regular basis during the protocol. Internal monitoring will be performed by in-house personnel, whereas external will be carried out by a third independent party
Plans for communicating important protocol amendments to relevant parties (e.g. trial participants, ethical committees) {25}
Every relevant change to the protocol is of mandatory notification to the Committees of Ethics, Research and Biosecurity of the Hospital in the form of an amendment, which will be evaluated for approval.
Dissemination plans {31a}
The results will be available for the participants upon request. Publication in a peer-reviewed journal is being prepared. The process to register the protocol in the National Commission of National Institutes and High Specialty Hospitals (CCINSHAE for its acronym in Spanish) is already being completed.