Participants, interventions and outcomes
Study setting {9}
This is clinical trial in one center. The clinical site is the Central Military Hospital Luis Diaz Soto, in Havana, Cuba.
Eligibility criteria {10}
Eligibility criteria Inclusion criteria
- Patients to be enrolled must compline the following inclusion criteria:
- Positive to SARS-CoV-2, symptomatic or not, newly diagnosed as determined by RT-qPCR in oropharyngeal swab
- ≥ 19 years of age,
- Functional state according to ECOG ≤ 2 (Karnofsky ≥ 70%). Fully active; no performance restrictions. 1. Strenuous physical activity restricted; fully ambulatory and able to carry out light work. 2. Capable of all self- care but unable to carry out any work activities,
- Be willing to sign informed consent.
Exclusion criteria
- Decompensated chronic diseases at the time of inclusion (severe arterial hypertension, ischemic heart disease, diabetes mellitus, );
- Patients with a history of autoimmune diseases;
- Presence of hyper-inflammation syndrome,
- Serious coagulation disorders;
- Known hypersensitivity to any of the components of the formulation under study;
- Pregnancy or lactation,
- Obvious mental inability to issue consent and act accordingly on study.
Who will take informed consent? {26a}
- Patients will be asked for written consent to participate after having been duly informed about the characteristics of the trial, objectives, benefits and possible risks. They will have the necessary time to decide (minimum 24 hours). Likewise, they will be informed of the right to participate or not and to withdraw their consent at any time, without exposing themselves to limitations for their medical care or other retaliation.
- The investigator should obtain the patient's written consent only after making sure they understood all the information offered. The procedure will be provided by means of a standard writing; in language easily understood by the patient (it should not be technical, but practical). Neither the investigator nor the trial staff can influence the patient's decision to participate or continue in the trial. All patients who provide informed consent will be randomly allocated into one of two study groups.
Additional consent provisions for collection and use of participant data and biological specimens {26b}
The consent for collection and use of participant data and biological specimens is included in the informed consent
Interventions
Explanation for the choice of comparators {6b}
The CUBAN NATIONAL ACTION PROTOCOL FOR COVID-19Error! Bookmark not defined., taking in account the e xperience and results from Chine with the use of Kaletra and chloroquine plus IFN alpha in the treatment of COVID-19 patients, established the obligatory use of this combination for the treatment of SARS-CoV-2 patients. It was not possible to introduce a 3-arm with the sole use of kaletra and chloroquine, because the Cuban health authority prohibited the exclusion of Heberon Alpha R (IFN alpha2b) from the treatment schedule. Then, the combination of Kaletra, chloroquine and IFN alpha 2b was used as comparator.
Intervention description {11a}
Are all medications are administered by hospital staff so the patient has no responsibility for intake Intervention group
The intervention group will receive Kaletra (200/50 mg orally twice daily) and chloroquine (250 mg orally twice daily), as describedError! Bookmark not defined., and HeberFERON. HeberFERON will be administered two times per week at 3.5 MIU for 3 weeks. The use of HeberFERON does not contradict the obligatory use of Kaletra and chloroquine, and Heberon Alpha R, because it self-contains IFN alpha2b at the same concentration as used in the comparator.
Control group
The control group will use Kaletra and chloroquine, plus Heberon Alpha R administered three times per week at 3.0 MIU for 3 weeks, as described in the CUBAN NATIONAL ACTION PROTOCOL FOR COVID-19 Version 1.4.Error! Bookmark not defined..
Criteria for discontinuing or modifying allocated interventions {11b}
The allocated intervention may be discontinued by the medical staff or by the patient himself, decision. The patients may withdraw their consent at any time, without exposing themselves to limitations for their medical care or other retaliation.
In the event of serious adverse events (with proven causality) the administration of the product will be interrupted and the required measures will be taken depending on the event and the possible expedited report of the same will be considered. The occurrence of the event will be notified to the monitor within a period not exceeding 24 hours.
The person responsible for the investigation, the monitors and the team of investigators, will carry out the corresponding investigations in order to determine the component causing the undesired effect.
After recovery from the adverse event, the patient may restart treatment according to the treatment scheme has been received. If severe toxicity occurs again, treatment is permanently discontinued.
Strategies to improve adherence to interventions {11c}
Prior to the preparation of this protocol, a criteria unification workshop was held with the participation of clinical specialists and opinion leaders involved in the project, where the experimental evidence in animals and humans, as well as the elements of rationality, were presented and discussed. The analysis, discussion and mastery of the protocol will favor adherence and compliance with GCP by all researchers.
The trial monitors will make quality monitoring visits at all stages of its execution, ensuring strict compliance with the provisions of the protocol.
In the case report form (CRF) there is a table to control the use of the in study drugs that signs the doctor.
Relevant concomitant care permitted or prohibited during the trial {11d}
Rules for the use of concomitant treatments.
Medicines may be used concomitantly to prevent or mitigate adverse events of probable causation with the use of Heberon Alfa R and HeberFERON.
Indications for treatment with antihistamines and / or steroids
Drugs
|
Habitual doses (adults)
|
Diphenhydramine
|
20 mg c/8 h
|
Hydrocortisone
|
100 mg c/8 h
|
Prednisolone
|
20 mg c/8 h
|
Dexamethasone
|
8 mg c/8 h
|
Chlorpheniramine
|
4 mg c/8 h
|
Promethazine
|
25 mg c/4-6 h
|
Dipirone or acetaminophen will be indicated to relieve fever, headache, and pain if necessary, depending on the doses listed below, taken from the AHCPR "Guidelines for the Management of Acute Pain"33.
Indications for treatment with antipyretics / analgesics
Drugs
|
Habitual doses (adults)
|
Dipirona
|
300-600 mg c/4-6 h
|
Paracetamol
|
500 mg a 1g c/6-8 h
|
In the event of nausea or vomiting, gravinol (1 ampoule; 50 mg) or metoclopramide (1 ampoule; 10 mg IM or I.V. every 8 hours) may be administered.
In case of need for other concomitant medication, this will be administered at the discretion of the investigator in charge of the patient. The conduct before any adverse event will be the decision of the responsible investigator and will depend on the type, magnitude and severity of the clinical manifestations in each case.
Provisions for post-trial care {30}
'Not applicable'. There is no anticipated harm and compensation for trial participation. No compensation is provided for enrolment in the trial.
Outcomes {12}
Primary outcomes
Time to 2019-nCoV RNA negativity in patients and the time until progression to severe COVID-19 within 14- 21 days of randomization.
Secondary outcomes.
- The rate of patients with non-favorable evolution as measured by clinical evaluation (fever, unproductive cough or dyspnea, and their X-ray or CT scan imaging) within 14-21 days of randomization;
- The increments of RNA and protein levels of IFN responses markers (2-5 OAS, ß-2 microglobulin), and IFN signaling factors (STAT-1 and STAT-3) within 14 days of randomization;
- Increments in the MHC-I and II and the activation of NK, T cytotoxic and memory cells within 14 days of randomization;
- Safety within 14-21 days of randomization.
Virological evaluation:
- Time to negativization of the SARS-Cov-2 RNA (absence of the virus according to the qPCR technique in real time) in positive patients after starting antiviral therapy. The percentage of patients negative to SARS-COV-2 by qPCR in nasopharyngeal exudate tissue will be calculated at 48, 72 and 96 hours after starting
Clinical evaluation:
- Time to progression to severe COVID-19. The percentage of patients who become severe after the end of the antiviral treatment under investigation (three weeks) will be
Participant timeline {13}
Sample size {14}
The sample size was estimated for the difference in the proportion of negative patients at different time (secondary outcomes), early in the disease, when the effect of external agent can exerts the highest effect, using the PASS software .Taking in account that the 100% of patients will be positive to SARS-CoV-2 and that only 15% will have the probability to became severe ill, we hope to enroll a sample size of one hundred and twenty patients for this study, based on a power of 80%, and a level of confidence set at 95%, while also considering a dropout rate of 5%.
Recruitment {15}
The source of patients is all the positive patients that are hospitalized at the study hospital positive by RT- qPCR amplification in oropharyngeal swab to SARS-CoV-2.
Assignment of interventions: allocation
Sequence generation {16a}
There will be a centralized randomization at CIGB. The randomization procedure will be carried out by the Supply Group of the Direction of Clinical Investigations at CIGB. Patients will be block randomized individually to one of two treatment arms by means of random computer-generated lists, with an allocation ratio of 1:1, with block sizes of six patients
Concealment mechanism {16b}
The allocation of treatment will be done after the patients have been included following the inclusion and exclusion criteria, and will be mediated by an email with attached allocation form that must include the following information: name and family name initials, clinical history number, age, sex, previous or current concurrent diseases, doctor name, health intuition name and province. It should be send also an electronic copy of writing consent of the patient, signed by the patient and the medial doctor responsible for the study. The allocated vials of the drug will contain etiquette with the inclusion code, the short name of the trial (ESPERANZA), and the lot, and its spired data.
Implementation {16c}
The information of the treatment group (A or B) will only be known after the patient is included. At the time of inclusion (after the selection criteria have been verified and written informed consent has been obtained), the clinical investigator will give the information to the CIGB monitors (who will visit the hospital daily and remain at their posts command). After collecting the general patient information to include (initials, date and time), will assign the inclusion number and the corresponding treatment (consecutive, according to a random list in their possession).
Assignment of interventions: Blinding
Who will be blinded {17a}
This is an open label RCT so patients, doctors are aware of treatment allocation and outcome assessment is not blinded. The virological data analysis will be conducted blind by external laboratory personal and the clinical data analysis by external statistic committee.
Procedure for unblinding if needed {17b}
The design is open label with only data analysts being blinded, so unblinding will not occur
Data collection and management
Plans for assessment and collection of outcomes {18a}
For the conduction of the trial following the Good Clinical Practice, the Steering Committee and any other personal related to the trail execution (laboratory technician, nurses, and pharmacist) will participate in a workshop to receive specific technical information about the products for clinical interventions during the investigation and information and training in procedures for assessment and collection of outcomes, ensuring compliance with the study procedures,
The design, execution of the trial, the clinical and analytical determinations, as well as the analysis of the data will be carried by suitably qualified personnel.
Doctors and nurses were aware of the possible adverse effects of IFNs and their management, both those expected immediately after applying the product (local to the injection site) and hours later (flu-like symptoms).
Routine blood examinations will be performed included whole blood counts, coagulation profiles, serum biochemical tests (including renal and liver function, electrolytes, and coagulation), C-reactive protein (CRP) and ferritin levels.
These determinations will be done using reagents of the required quality and validated techniques. In the case of hematological determinations, several equipment will be used (BC 3200 Hematological Complex, BC 5800 Hematological Complex, as well as a Coagulograph). For blood chemistry determinations, the Midray BS -400 equipment will be used. The reagents to be used for each determination are the following: Gluc, AU, Chol, TRIG, Prot, Fosf, Album, CA, BT, BD, TGO, TGP, FALC, GGT, AML, CPK, CKMB, CREAT, HDLc,
LDLc, Urea, FE, FERRIT, PCR, HS. All the analytical techniques will include the necessary controls to ensure the reliability of the determinations, in accordance with the procedures of each of them.
All the analytical techniques used included the necessary controls to ensure the reliability of the determinations, in accordance with the procedures for each of them..
All patients will be evaluated by a chest X-ray after randomization and before the administration of first dose of the IFNs, and weekly determinations, on days two and four of each week.
Imaging studies will be carried out using the official validate data form. The imaging evaluations are integrated into the XAVIA PACS Medical Image Transmission and Storage System (PACS) for the storage, acquisition, visualization and manipulation of medical images of diagnostic modalities. It is complemented by the Radiological Information System (RIS) XAVIA RIS, which allows closing the work flow and facilitating the tools for managing the information of patients who are treated.
Throat swab specimens will be transported to a BSL2 certified laboratory at the CIGB for SARS-CoV-2 viral nucleic acid detection by RT-qPCR, using the QIAamp Viral RNA Mini kit (Qiagen,USA), as per the manufacturer’s instructions.
Demographic, clinical, laboratory, treatments and outcome characteristics of patients will be extracted from medical record, registered in the case report forms (CRFs) and then entered in duplicate (independently by two operators) for the subsequent process of automatic comparison and cleaning of the database.
The blood determinations data will be kept in the GALEN LAB software, which is an information system for diagnostic means, aimed at managing them, facilitating the request for examinations, recording and evaluation of the results obtained, as well as the generation of statistical information. This software is designed to be used by diagnostic technicians, physicians, and administrative personnel who need to optimize their work and increase their efficiency. It guarantees a strict control of the information, differentiating for each one, the available options according to their responsibility. It is a useful tool, for a possible evaluation by a committee of experts outside the investigation if it is considered necessary
Plans to promote participant retention and complete follow-up {18b}
There is no any patient retention plan due to the complex pandemic situation. Patients that discontinued the treatment will be asked to finish the planned laboratory and clinical evaluations up to day 14 at home. The medical staff from the trial will design a technician and specialist in internal medicine to obtain blood samples for routine haematological and biochemical determinations from the patient as planed in the procedures at home, and will ask for any adverse events.
Data management {19}
For the purposes of this study, a data entry system will be generated at OpenClinica, which is a free software platform for protocol configuration and CRF design, which allows the electronic capture, storage and management of data.
The data entry will be carried out in duplicate (independently by two operators) for the subsequent process of automatic comparison and correction of the bases, necessary for statistical analysis with accurate information from the trial. For debugging errors, the data that does not match the one registered in the original CRF will be corroborated to avoid confusion. The comparison will be repeated until no differences are found between the databases. This process will guarantee the cleanliness of the data included in the databases that will later be used in the statistical analysis. This activity will be recorded, so that it can be traced to national and foreign inspections and / or audits.
Confidentiality {27}
The protocol's medical specialists, the promoter, the monitors and auditors appointed by the promoter will guarantee that the personal data of the subjects included in the protocol are treated in accordance with the provisions established in Law 15/1999 on data protection personal nature and the regulations that develop it. Likewise, the anonymity of the subjects included and the protection of their identity will be maintained; no personal data of the subjects of the protocol will be transferred, except in those circumstances allowed by law.
Monitors and auditors appointed by the promoter may access clinical information and documentation on the subjects included, in order to verify the accuracy and reliability of the data, but must not collect the personal identification data of the subjects. Access to this data should also be provided to the inspectors of the competent health authorities.
The results of the clinical trial, as well as all the work and reports carried out and all the industrial property rights derived from it, are the exclusive property of the promoter. The latter is committed to disseminating them, once the protocol is finished and whether they are negative or positive, in public access media.
The publication of the results, by the medical specialists of the hospital institutions, in scientific magazines or books and the oral presentations or posters at scientific events, workshops or meetings, must be carried out in agreement with the promoting center.
Plans for collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis in this trial/future use {33}
The promoter center will be in charge of transmitting, operationally, the procedure for the extraction, identification and conservation of the biological samples that will be transferred to the CIGB according to procedures 4.40.121.01 and 4.40.122.01 in force at the Direction of Clinical Research at CIGB.The transfer of samples from the healthcare unit will be the responsibility of the promoter center, which will guarantee the transportation, specialized personnel and resources necessary to carry out these operations with the maximum quality and compliance with GCP, as established by the procedures. in force (4.40.120.01 and 4.40.123.07) and their biosafety protocols.
Statistical methods
Statistical methods for primary and secondary outcomes {20a}
The statistical analysis will be done as intention to treat (patients that will receive at least one doses of the in study drugs) and per protocol (patients that will receive at least four doses of HeberFERON or six doses of Heberon Alpha R). We will compare the study endpoints between the two arms using time-to-event methods with the Cox proportional-hazards model. The different categorical variables will be analyzed using the one- way analysis of variance. To describe the efficacy and safety of the IFN regimens, Kaplan-Meier estimates and a multivariate Cox proportional hazards model will be used to compare severity of patients and adverse events among the two arms during the study period at week four. A p-value of <0.05 will be deemed to confer statistical significance.
Interim analyses {21b}
The promotor did not considered to undertake interim analyses for this RCT because of the expected high rate of inclusion and the necessity to rapid ending of the trial to have results to define clinical decision for the best treatment of patient in the pandemic situation that permit to have a high rate of discharges in the lowest time as possible.
The promotor did not expect any harm that will justifies the anticipated stop of the trial based in the safety of IFNs in this short time and low does intervention schedules.
Methods for additional analyses (e.g. subgroup analyses) {20b}
No additional analyses were planed
Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c}
All the patients that receive at least one doses of the in study interventions will be evaluated by intention treat independent of the non-adherence to the protocol. The missing data will be considered as part of the statistically analysis for demographic data. In the case of virological evaluations, the analyses will be take in account only the evaluated samples, the missing data will be non-considered
In the case of virological determination when two first consecutive samples (24 hour and 72 hours) will be negative by RT-qPCR, the thirst sample (96 hours) will be no evaluated, and the patient will be declared negative.
Plans to give access to the full protocol, participant level-data and statistical code
{31c}
The datasets analysed during the current study are available from the corresponding author on reasonable request.
Oversight and monitoring
Composition of the coordinating centre and trial steering committee {5d}
Steering Committee
The Steering Committee, led by the principal investigator, will be responsible for overseeing the conduction of the trial, providing training for new sites, ensuring compliance with the study procedures, addressing challenges that occur at all sites, reviewing serious adverse events and formulating the statistical analysis plan.
For clinical trials at CIGB, the function of coordinating centre is playing by the Direction of Clinical Research that is the responsible for design, endpoint adjudication, data management, statistical analysis and final report for the clinical trial.
Monitors from the Clinical Research Direction at CIGB, Havana, Cuba.
- Iván Campa Legrá. MSc. Monitor
- Yaquelin Duncan Roberts, MD, MSc. Monitor
- Claudia Martínez Lic. Monitor
Data managing.
- Marel Alonso Valdés. Ing. Informatics at Clinical Research Direction
Statically analysis
- José C. Cortiñas Porras. Lic. Mathematics at Clinical Research Direction
Supervisors
- Iraldo Bello Rivero, MSc, PhD. Project Manager at Clinical Research Direction
- Francisco Hernández Bernal. Methodological Assessor at Clinical Research Direction
- Verena Muzio Gonzalez. MD, PhD. Director of Clinical Research Direction
- Laboratory of Genomic and Immunological determinations. Biomedical Research Direction (BRD) at CIGB, Havana,
- Dania M. Vázquez Blomquist, PhD. Genomic evaluations at BRD
- Monica Bequet Romero. PhD. Immunological evaluations at BRD
- Gilda Lemos Perez. MSc. Immunoenzymatic evaluations at BRD
- Gerardo Guillen Nieto. Methodological and Scientific Assessor. Director of Biomedical Research Direction.
Composition of the data monitoring committee, its role and reporting structure {21a}
Monitors from the Clinical Research Direction at CIGB, Havana, Cuba
- Iván Campa Legrá. MSc. Monitor
- Yaquelin Duncan Roberts, MD, MSc. Monitor
- Claudia Martínez Lic. Monitor
The trial monitors will carry out quality monitoring visits at all stages of its execution, ensuring strict compliance with the provisions of the protocol.
The flow of primary protocol information to and from health institution will be guaranteed by the CIGB.
The research product (HeberFERON), CRF and other models will be delivered / collected by the CIGB, directly by the study monitors. The monitors, in the quality monitoring visits, will collect the CRFs of those patients who concluded their participation in the trial. The Supply Group at CIGB is responsible for the adequate supply of medicines and medical supplies, as well as the collection of the product under investigation (dispensed and not dispensed).
The investigator should have a report of the number of patients included, the detected adverse events, the study departures and the causes of these, as well as any other relevant information during the course of the trial, for when they are requested during the quality monitoring visits.
Adverse event reporting and harms {22}
All the information related to the occurrence of adverse events presented in the patients included in the clinical trial will be recorded and described, as explicitly as possible, by the investigators in the Adverse Event Form of the CRF. The type, duration, intensity, severity, causality and the behavior followed will be described, specifying the frequency and dose of the treatment necessary to alleviate them.
The occurrence of the event will be notified to the sponsor monitor within a period not exceeding 24 hours. This must within the first 24 hours of occurrence. The information may be communicated by phone, fax, email or in person. The person responsible for the investigation, the monitors and the team of investigators, will carry out the corresponding investigations in order to determine the component causing the undesired effect.
Notification of adverse events
It will consist of two stages: the immediate notification of all serious adverse events and the reporting of serious and unexpected adverse events in relation to causation, which will be independent of each other.
The Responsible Investigator will notify the CER and the Sponsor will inform CECMED in the following terms.
In the event of a Serious and Unexpected adverse event that causes death or endangers the life of the patient, it will be reported to the CER, CECMED as soon as possible and never after 7 calendar days from the first moment in which the occurrence of the reaction is known.
Immediate notification will be made to the national regulatory agency in Cuba, Center for State Control of the Quality of Medicines (CECMED), within the first 72 hours after the Promoter becomes aware of the serious (serious) and unexpected adverse event and will be mandatory. This model will be filled in duplicated..
Frequency and plans for auditing trial conduct {23}
Project Management Group will meet to review trial conduct weekly during the first month and every 15 day in the second or thirst month. Quality monitoring and control will be carried out by the monitors, quality control managers, consultants and specialists responsible for the trial. These visits will also serve to discuss any aspect of the protocol that the researcher suggests.
Execution check visits will be made daily from the beginning of the study. The first Quality Control visit will be made immediately after the first patient is included.
Plans for communicating important protocol amendments to relevant parties (e.g. trial participants, ethical committees) {25}
Protocol amendments during the study will be notified to the sponsor, to the promotor and to the clinical sites, to trail participants and ethic committee. A copy of the revised protocol will be sent to the promotor and to the Investigator Site File. Any deviations from the Protocol will be fully documented using a breach report form. The protocol will be updated in the clinical trial registry.
As responsibility of the clinician’s investigators they must to have an archive with the documents coming from the trail execution, as any communication with the promotor, monitor, quality assurance personal, ethic committee, a copy of the protocol and all the amendments to it during the study.
Dissemination plans {31a}
The final results of the study will be presented in a final report workshop with the participation of all the clinician’s investigators and other technical personal involved in the trial executions and supervisors, as well as monitor and other specialist involved from the promotor. The personal eel involved direct achievements of the results (clinical, virological, clinical laboratory, and others) will have the right to communicate the respective results in conferences, national and international meeting, always with the consent of the promotor