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 | 23.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10084460 |
E.1.2 | Term | COVID-19 treatment |
E.1.2 | System Organ Class | 10042613 - Surgical and medical procedures |
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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 compare the effect of nirmatrelvir/ritonavir to placebo/ritonavir on viral RNA level in NP swabs in participants with mild-to-moderate COVID-19. |
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E.2.2 | Secondary objectives of the trial |
- To compare the effect of nirmatrelvir/ritonavir to placebo/ritonavir on the duration of viral shedding. - To compare the effect of nirmatrelvir/ritonavir to placebo/ritonavir on the duration and severity of signs and symptoms in participants with mild-to-moderate COVID-19. - To describe the safety and tolerability of nirmatrelvir/ritonavir in participants with mild-to-moderate COVID-19. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Participants aged 12 years or older and weighing ≥40 kg at screening. 2. Participants must have written documentation with patient-reported 100% compliance (ie, completed a 5 day course of nirmatrelvir/ritonavir). They must have symptom alleviation or resolution in COVID-19 signs/symptoms followed by a worsening (rebound) of signs/symptoms after completing an initial 5-day course of nirmatrelvir/ritonavir based on the judgement of both the participant and investigator. 3. The onset of rebound in COVID-19 symptoms must occur within 2 weeks (14 days) after the completion of the initial 5-day course of nirmatrelvir/ritonavir. 4. Onset of rebound in signs/symptoms attributable to COVID-19 within 48 hours prior to randomization and ≥1 sign/symptom attributable to COVID-19 present on the day of randomization. 5. SARS-CoV-2 infection as determined by rapid antigen testing in any specimen collected within 24 hours prior to randomization and collected within 2 weeks (14 days) after the completion of the initial 5-day treatment course of nirmatrelvir/ritonavir. 6. Has at least 1 characteristic or underlying medical condition associated with an increased risk of developing severe illness from COVID-19. |
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E.4 | Principal exclusion criteria |
1. Current need for hospitalization, hospitalized for the index COVID-19 infection, or anticipated need for hospitalization within 24h after randomization in the clinical opinion of the site investigator. 2. History of severe chronic liver disease (eg, jaundice, ascites, hepatic encephalopathy, history of bleeding esophageal or gastric varices). No laboratory testing is needed. 3. History of hypersensitivity or other contraindication to any of the components of the study interventions, as determined by the investigator. 4. Suspected or confirmed concurrent active systemic infection other than COVID-19 that may interfere with the evaluation of response to the study intervention. 5. Receiving dialysis or eGFR <30 mL/min/1.73m2 (for adults) or eCrCl <30 mL/min (for adolescents) at screening using creatinine point of care device. 6. Oxygen saturation of <92% on room air obtained at rest within 24 hours prior to randomization. 7. Immunocompromised. 8. Other medical or psychiatric condition including recent (within the past year) or active suicidal ideation/behavior or laboratory abnormality that may increase the risk of study participation or, in the investigator’s judgment, make the participant inappropriate for the study. 9. Current use of any prohibited concomitant medication(s). 10. COVID-19 vaccination within 14 days prior to study entry or anticipated COVID-19 vaccination through Day 34. 11. Receiving other COVID-19 specific treatments within 30 days of randomization and through Day 34, excluding the initial course of nirmatrelvir/ritonavir as well as blinded study medication. 12. Prior participation in this trial. 13. Current or previous administration with an investigational product (drug or vaccine) within 30 days (or as determined by the local requirement) or 5 half-lives preceding the first dose of study intervention used in this study (whichever is longer). 14. Females who are pregnant up to 14 weeks gestation. Pregnancy ≥14 weeks is not exclusionary. 15. Investigator site staff directly involved in the conduct of the study and their family members, site staff otherwise supervised by the investigator, and sponsor and sponsor delegate employees directly involved in the conduct of the study and their family members. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The difference in mean change of SARS-CoV-2 RNA level in NP swabs from baseline to Day 5 between nirmatrelvir/ritonavir and placebo/ritonavir group in patients with a rebound in COVID-19 symptoms and a positive rapid antigen test within 2 weeks following completion of an initial 5- day treatment course, who have a positive viral RNA NP swab test result at baseline. This will be estimated without regard to study treatment discontinuation and without regard to prohibited therapies. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The difference in mean change of SARS-CoV-2 RNA level in NP swabs from baseline to Day 5 between nirmatrelvir/ritonavir and placebo/ritonavir group in patients with a rebound in COVID-19 symptoms and a positive rapid antigen test within 2 weeks following completion of an initial 5-day treatment course ,who have a positive viral RNA NP swab test result at baseline. This will be estimated without regard to study treatment discontinuation and without regard to prohibited therapies. |
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E.5.2 | Secondary end point(s) |
- Time to 2 consecutive negative rapid antigen test results obtained at least 24 (-2) h apart through Day 28. - Time (days) to sustained alleviation of all targeted signs and symptoms through Day 28 where sustained alleviation is defined as the first of 2 consecutive days when any symptoms scored as moderate or severe at baseline are scored as mild or absent and any symptoms scored as mild or absent at baseline are scored as absent. - Incidence of TEAEs. Incidence of SAEs and AEs leading to discontinuation. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
The hazard ratio for time to 2 consecutive negative rapid antigen test results obtained at least 24 (-2) h apart through Day 28 between nirmatrelvir/ritonavir and placebo/ritonavir group in patients with rebound in COVID-19 symptoms and a positive rapid antigen test within 2 weeks following completion of an initial 5-day treatment course, who have a positive viral RNA NP swab test result at baseline. This will be estimated without regard to study treatment discontinuation and without regard to prohibited therapies. |
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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 | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
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 | Yes |
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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
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 | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
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 | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 13 |
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 |
Taiwan |
Canada |
Germany |
Greece |
Italy |
United Kingdom |
United States |
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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 | |
E.8.9.1 | In the Member State concerned months | 14 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial months | 14 |