E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Virus Diseases [C02] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 23.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10084268 |
E.1.2 | Term | COVID-19 |
E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate the efficacy of BEM compared with placebo in reducing all-cause hospitalization or all-cause death in COVID-19 outpatients receiving only supportive care. |
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E.2.2 | Secondary objectives of the trial |
• To evaluate the efficacy of BEM compared with placebo on: - COVID-19 related hospitalization or all-cause death through Day 29 - All-cause death through Day 29 and Day 60 - COVID-19-related complications (e.g., death, hospitalization, radiologically confirmed pneumonia, acute respiratory failure, sepsis, coagulopathy, pericarditis/myocarditis, cardiac failure) - COVID-19-related medically attended visits (hospitalization, emergency room (ER) visit, urgent care visit, physician’s office visit, or telemedicine visit) or all-cause death through Day 29 and Day 60 -COVID-19 symptom relapse • To evaluate the antiviral activity of BEM compared with placebo on viral load rebound • To evaluate the safety of BEM compared with placebo
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Willing and able to provide informed consent. 2. Positive SARS-CoV-2 diagnostic test (RT-PCR or validated rapid antigen test) conducted ≤ 5 days prior to randomization. Note: The test may be obtained locally. A documented historical record of positive result (RT-PCR or validated rapid antigen test) from test conducted ≤ 5 days prior to randomization is acceptable. 3. Mild or moderate COVID-19 with symptom onset ≤ 5 days before randomization and at least one COVID-19 related symptom present at time of screening: • Mild COVID-19: - Symptoms of mild illness with COVID-19, which could include fever, cough, sore throat, malaise, headache, muscle pain, nausea, vomiting, diarrhea, and loss of taste or smell, without shortness of breath or dyspnea - No clinical signs indicative of moderate, severe, or critical illness severity • Moderate COVID-19: - Symptoms of moderate illness with COVID-19, which could include any symptom of mild illness or shortness of breath with exertion - Clinical signs suggestive of moderate illness with COVID-19, such as respiratory rate ≥ 20 breaths per minute, heart rate ≥ 90 beats per minute; with saturation of oxygen (SpO2) > 93% on room air at sea level - No clinical signs indicative of severe or critical illness severity 4. For females of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use adequate contraception during the treatment period and for 30 days after the final dose of study drug. 5. Females of childbearing potential must have a negative pregnancy test prior to initiation of study drug. 6. Subject must be able to take oral tablet medications. 7. Subject is, in the opinion of the investigator, willing and able to comply with the study drug regimen and all other study requirements. 8. Subject must be high risk, defined below. • Age ≥80 years OR • Age ≥65 years with one of the following: - Obesity (body mass index [BMI] ≥30 kg/m2) - Diabetes mellitus - Cardiovascular disease (including congenital heart disease) or hypertension (with at least one medication recommended or prescribed) - Chronic lung disease requiring routine therapy (e.g., chronic obstructive pulmonary disease [COPD], moderate-to-severe asthma, interstitial lung disease, cystic fibrosis, pulmonary hypertension) OR • Age ≥18 years with one of the following: - Down syndrome, sickle cell disease, dementia, Parkinson’s disease, or care home residents - One of the following immunocompromising conditions or immunosuppressive treatment: o Receiving chemotherapy or other therapies for cancer o Hematologic malignancy (active or in remission) o Being within 2 years from receiving a hematopoietic stem cell or at any time following a solid organ transplant o Human immunodeficiency virus (HIV) infection untreated or with CD4+ T lymphocyte count <350 cells per cubic millimeter (mm3) within the past 6 months o Combined primary immunodeficiency disorder o Taking immunosuppressive medications (e.g., drugs to suppress rejection of transplanted organs or to treat rheumatologic and gastrointestinal conditions such as anti-tumor necrosis factor (TNF) agents, mycophenolate, or rituximab)
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E.4 | Principal exclusion criteria |
1. Female subject is pregnant or breastfeeding. 2. Clinical signs or symptoms indicative of severe or critical COVID-19 illness, including any of the following: shortness of breath at rest, respiratory rate ≥ 30 breaths per minute, heart rate ≥ 125 beats per minute, SpO2 ≤ 93% on room air at sea level, partial pressure of oxygen/ fraction of inspired oxygen (PaO2/FiO2) <300, shock (defined by systolic blood pressure < 90 mm Hg or diastolic blood pressure < 60 mm Hg or requiring vasopressors), multi-organ dysfunction/failure, respiratory distress, respiratory failure; requirement of endotracheal intubation, mechanical ventilation, oxygen delivered by high-flow nasal cannula, noninvasive positive pressure ventilation, extracorporeal membrane oxygenation (ECMO). 3. Admitted to a hospital within 90 days prior to randomization due to COVID-19 or is hospitalized (inpatient) at randomization due to COVID-19. Note: If local policy requires COVID-19 isolation or internment in a hospital or similar facility, but subjects otherwise meet criteria, this exclusion may not apply. 4. In the opinion of the investigator, is likely to experience imminent deterioration and require hospitalization within 24 hours. 5. Use of other investigational drugs within 30 days prior to planned dosing, or plans to enroll in another clinical trial of an investigational agent while participating in the present study, except for unblinded protocols that don’t include direct acting antivirals for COVID-19 (e.g., open-label oncological regimen variations or biologic studies). Note: Prior to enrolling subjects that are on other open-label studies, it is the site’s responsibility to ensure that the study criteria for that study allow for enrollment into this study. 6. Initiation or planned initiation of remdesivir for treatment of the current SARS-CoV-2 infection. 7. Requirement of any prohibited medications, as described in Section 5.7 of protocol, including either hydroxychloroquine or amiodarone within 3 months prior to screening. Note: Subjects who had already initiated any COVID-19 drug with antiviral effects intended to treat symptomatic SARS-CoV-2 infection (≥ 24 hours prior to randomization) will be excluded. During screening (or within 24 hours prior to or after randomization), locally available COVID-19 drugs with antiviral effects (including but not limited to Paxlovid, molnupiravir, favipiravir, mAbs) will be permitted, as long as there are no concerns for DDIs (e.g., remdesivir would not be permitted). 8. Other known active viral or bacterial infection at the time of screening, such as influenza (i.e., as verified by a locally available rapid flu test at screening_ and respiratory syncytial virus (RSV). Note: This exclusion does not apply to subjects with stable chronic viral infections, such as chronic HCV or HIV providing other eligibility criteria are met. 9. Receiving dialysis or have known moderate to severe renal impairment [i.e. estimated glomerular filtration rate (eGFR) <45 mL/min/1.73 m2 within 6 months of the screening visit, using the serum creatinine-based CKD-EPI formula]. Note: If the investigator suspects the subject may have eGFR <45 mL/min/1.73 m2, a confirmatory test should be performed at screening to confirm eligibility before the first dose of study drug. 10. History of severe hepatic impairment (Child-Pugh Class C) 11. Known allergy or hypersensitivity to components of study drug. 12. Malabsorption syndrome or other condition that would interfere with enteral absorption. 13. Any clinically significant medical condition or known laboratory abnormality that, in the opinion of the investigator, could jeopardize the safety of the subject or impact subject compliance or safety/efficacy observations in the study.
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint is the proportion of subjects in the supportive-care-only population who are hospitalized for any cause or died due to any cause through Day 29 |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
• Proportion of subjects in the supportive-care-only population with COVID-19-related hospitalization or who died due to any cause through Day 29 • Proportion of subjects in the overall study population, the supportive-care-only population, and the combination antiviral population who died due to any cause through Day 29 and Day 60 • Proportion of subjects in the supportive-care-only population with COVID-19-related complications (e.g., death, hospitalization, radiologically confirmed pneumonia, acute respiratory failure, sepsis, coagulopathy, pericarditis/myocarditis, cardiac failure) • Proportion of subjects in the supportive-care-only population with COVID-19-related medically attended visits (hospitalization, emergency room (ER) visit, urgent care visit, physician’s office visit, or telemedicine visit) or who died due to any cause through Day 29 and Day 60 • Proportion of subjects with COVID-19 symptom relapse in each population through Day 29 • Proportion of subjects in each population with viral load rebound through Day 29
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Various timepoints as described, primarily through day 29 and up to day 60
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
Add-on to standard of care |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 57 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Argentina |
Brazil |
Canada |
Colombia |
Egypt |
Ghana |
India |
Japan |
Kenya |
Mexico |
Morocco |
Pakistan |
Philippines |
South Africa |
Tunisia |
United States |
Latvia |
Sweden |
Netherlands |
Romania |
Spain |
Germany |
Turkey |
United Kingdom |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 3 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 3 |