E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
|
E.1.1.1 | Medical condition in easily understood language |
|
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 |
|
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 effect of nirmatrelvir/ritonavir compared to placebo/ritonavir on SARS-CoV-2 viral RNA levels in NP swabs in hospitalized participants ≥12 years of age with severe COVID-19 who are immunocompromised or at increased risk for severe COVID 19 outcomes |
|
E.2.2 | Secondary objectives of the trial |
•To evaluate the effect of nirmatrelvir/ritonavir compared to placebo/ritonavir treatment on clinical outcomes when added to background usual care, for the treatment of severe COVID 19 in hospitalized participants ≥12 years of age who are immunocompromised or at increased risk for severe COVID 19 outcomes. •To evaluate the effect of nirmatrelvir/ritonavir compared to placebo/ritonavir on SARS-CoV 2 viral RNA levels in NP swabs in hospitalized participants ≥12 years of age with severe COVID-19 who are immunocompromised or at increased risk for severe COVID 19 outcomes. •To describe the safety and tolerability of nirmatrelvir/ritonavir relative to placebo/ritonavir for the treatment of severe COVID-19 in hospitalized participants ≥12 years of age who are immunocompromised or at increased risk for severe COVID 19 outcomes.
|
|
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. -Refer to Appendix 4 for reproductive criteria and contraception requirements for male (Section 10.4.1) and female (Section 10.4.2) participants. 2. Meeting 1 of the 2 categories of COVID-19 risk: (see Appendix 9, Section 10.9.2). -Category A: Immunocompromised -Category B: Non-Immunocompromised, but with ≥2 risk factors -Onset of signs/symptoms attributable to COVID-19 ≤10 days prior to the day of randomization for non-immunocompromised participants (Category B). 3.Confirmed SARS-CoV-2 infection as determined by RT-PCR or acceptable test method performed by a health care provider (See Appendix 9, Section 10.9.3) in any specimen collected within 48 hours prior to randomization. 4.Hospitalized for inpatient care for the treatment of clinical manifestations of severe COVID-19 (see Appendix 9, Section 10.9.4). Requirement for oxygen supplementation (via nasal cannula, mask, NIV or high flow oxygen) to maintain SpO2 ≥94% at the time of Screening and Randomization. Participants with chronic lung disease requiring home oxygen therapy are eligible if they require a higher than usual oxygen flow rate to maintain their target oxygen saturation. 5.Requirement for oxygen supplementation (via nasal cannula, mask, NIV or high flow oxygen) to maintain SpO2 ≥94% at the time of Screening and Randomization. Participants with chronic lung disease requiring home oxygen therapy are eligible if they require a higher than usual oxygen flow rate to maintain their target oxygen saturation. |
|
E.4 | Principal exclusion criteria |
1.Critical illness, defined by ≥1 of the following: a.Requirement for mechanical ventilation or ECMO at randomization, or likely to require IMV or ECMO within 12 hours of randomization in the judgment of the investigator, or clinical need for mechanical ventilation or ECMO, even if not able to be administered due to resource limitation at the time of randomization. b.Multi-organ dysfunction/failure. c.Hemodynamically unstable, eg. septic shock, cardiac failure or requiring vasopressors. d.Participant not expected to survive 24 hours from time of randomization 2.History of severe chronic liver disease (see Appendix 9, Section 10.9.5). 3.Receiving dialysis of any kind or severe renal impairment defined as eGFR in adults <30 mL/min/1.73 m2 or eCrCl in adolescents aged 12 to 17 years <30 mL/min (see Section 10.7.1 for the recommended formulas). 4.Confirmed concurrent active systemic infection other than COVID-19 that may interfere with the evaluation of response to the study intervention. 5.History of hypersensitivity or other contraindication to any of the components of the study intervention, as determined by the investigator. 6.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 patient inappropriate for the study. 7.Use of nirmatrelvir/ritonavir as an outpatient to treat the current COVID 19 related illness ≤7 days of randomization. 8.Current use of any prohibited concomitant medication(s). (See Section 6.9 and Appendix 8). 9.Inability to closely monitor concentrations of immunosuppressant medications (ie, Calcineurin inhibitors and mTOR inhibitors) and adjust their doses for nirmatrelvir/ritonavir DDI during active treatment, and for at least 5 days after the last dose of study intervention. 1.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). 11.Known prior participation in this trial.
|
|
E.5 End points |
E.5.1 | Primary end point(s) |
•Change from baseline in SARS CoV-2 RNA level in NP swabs at Day 5. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
•The difference between nirmatrelvir and placebo in mean change from baseline in SARS CoV-2 RNA level in NP swabs 5 days after the start of treatment, regardless of intercurrent events, in the population of hospitalized patients ≥12 years of age with severe COVID-19 who are immunocompromised or at increased risk for severe COVID 19 outcomes. |
|
E.5.2 | Secondary end point(s) |
•Time to sustained clinical recovery, defined as the first day during the 30 days after randomization in which a participant attains a score of 1, 2, or 3 on the 8-point ordinal scale (ie, remains alive and is either not hospitalized or is hospitalized but no longer requires ongoing inpatient medical care for COVID 19) for at least 7 consecutive days. •Proportion of participants with death from any cause or initiation of invasive mechanical ventilation or ECMO from baseline (Day 1) through Day 30. •Proportion of participants with SARS-CoV-2 RNA <LLOQ (defined as <2.0 log10 copies/mL) in NP swabs on Day 15. •Proportion of participants with sustained NP swab SARS CoV 2 RNA <LLOQ (defined as <2.0 log10 copies/mL) from Day 15 through Day 45. •Incidence of TEAEs. •Incidence of SAEs and AEs leading to discontinuations.
|
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
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 | 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) | 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 | 18 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 50 |
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 |
Australia |
Brazil |
India |
Mexico |
Puerto Rico |
United States |
France |
Bulgaria |
Spain |
Slovakia |
|
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
|
|
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 | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial months | 12 |
E.8.9.2 | In all countries concerned by the trial days | 0 |