| 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 determine the PK of nirmatrelvir/ritonavir in pediatric participants from birth to <18 years of age, using modeling and simulation approaches, in order to identify the appropriate dose for each pediatric age group that will achieve systemic exposures comparable to adults.
- To describe the safety and tolerability of nirmatrelvir/ritonavir in the treatment of nonhospitalized symptomatic pediatric participants with COVID-19 who are at risk of progression to severe disease. |
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| E.2.2 | Secondary objectives of the trial |
- To evaluate the change from baseline in viral load to Day 5 in pediatric participants from birth to <18 years of age with COVID-19 who are at risk of progression to severe disease.
- To evaluate the efficacy of nirmatrelvir/ritonavir for the treatment of COVID-19 in nonhospitalized symptomatic pediatric participants with COVID-19 who are at increased risk of progression to severe disease.
- To determine acceptability and palatability of formulation. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or female participants:
Cohort 1: Weight ≥40 kg
a. ≥12 to <18 years
b. ≥6 to <12 years
Cohort 2: Weight ≥20 kg to <40 kg, ≥6 to <18 years
Cohort 3: ≥2 to <6 years
Cohort 4: ≥1 month (≥28 days) to <2 years
Cohort 5: <1 month (<28 days)
- From birth (postmenstrual age of 44 weeks or greater weighing >2.6 kg at the time of screening) to <18 years of age
- Negative urine pregnancy test for female participants who are biologically capable of having children. Refer to Appendix 4 or reproductive criteria for
male (Section 10.4.1) and female (Section 10.4.2) participants.
- Female participant of childbearing potential who is willing to use a highly effective method of contraception as outlined in this protocol for at least 28 days after the last dose of study intervention if at risk of pregnancy with her partner.
Note: If the childbearing potential changes after start of the study (eg, a premenarchal female participant experiences menarche) or the risk of
pregnancy changes (eg, a female participant who was not heterosexually active becomes active), the participant must discuss this with the investigator, who should determine if a female participant must begin a highly effective method of contraception. If reproductive status is questionable, additional evaluation should be considered.
2. Until oral powder is available for use, ability to swallow tablets confirmed by participants’ parent(s)/legal guardian(s) for Cohorts 1 and 2 using the presentation of nirmatrelvir/ritonavir supplied in the study.
3. Confirmed SARS-CoV-2 infection as determined by RT-PCR or another method of diagnosis approved by a health authority in any specimen collected within 72 hours prior to enrollment and initial onset of signs/symptoms attributable to COVID-19 within 5 days prior to the day of enrollment and at least 1 of the specified signs/symptoms attributable to COVID-19 present on the day of enrollment.
Note: RT-PCR is the preferred method; however, with evolving approaches to confirmation of SARS-CoV-2 infection, other molecular or antigen tests that detect viral RNA or protein are allowed. The test result must be available to confirm eligibility. Participants may be enrolled based on positive results of a rapid SARSCoV-2 antigen test performed at screening.
4. Has at least 1 characteristic or underlying medical condition associated with an increased risk of developing severe illness from COVID-19 including:
Risk factors for severe COVID-19 disease <18 years of age:
- Overweight or Obese (BMI [kg/m2] ≥85th percentile for age and gender based on CDC growth charts, see Appendix 8)
- For children <2 years of age, sex specific weight-for-length;
- Current smoker (cigarette smoking within the past 30 days) and history of at least 100 lifetime cigarettes;
- Immunosuppressive disease (eg, bone marrow or organ transplantation or primary immune deficiencies) OR prolonged use of immune-weakening
medications:
- Has received corticosteroids at a dose known to cause immune suppression, based on the clinical judgement of the investigator, for at least 14 days, within 30 days prior to study entry
- Has received treatment with biologics (eg, infliximab, ustekinumab), immunomodulators (eg, methotrexate, 6MP, azathioprine) or cancer chemotherapy within 90 days prior to study entry
- HIV infection with CD4 cell count <200 mm3 and a viral load lower than 400 copies/mL;
- Chronic lung disease
- If asthma, requires daily prescribed therapy;
- Known diagnosis of hypertension;
- Cardiovascular disease;
- Type 1 or Type 2 diabetes mellitus;
Chronic kidney disease (Grade 2 or 3a) defined as eGFR or eCrCl between 45 to 89 mL/min AND/OR albuminuria >30 mg/g OR proteinuria ≥1+;
- Sickle cell disease;
- Neurodevelopmental disorders (eg, cerebral palsy, Down’s syndrome, ADHD, intellectual and developmental disabilities, learning disabilities, limitations with self-care of activities of daily living) or other conditions that confer medical complexity (eg, genetic or metabolic
syndromes and severe congenital anomalies, congenital malformations);
- Active cancer, other than localized skin cancer, including those requiring treatment as long as the treatment is not among the prohibited medications
that must be administered/continued during the trial period;
- Infants (<1 year of age);
- Spinal cord injury
- Any new criteria identified by the CDC as a risk factor for severe COVID-19 for pediatric participants. |
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| E.4 | Principal exclusion criteria |
1. Hospitalization:
- History of hospitalization for the medical treatment of current COVID-19 infection.
- Current need for hospitalization or anticipated need for hospitalization for the treatment of COVID-19 within 48 hours after enrollment in the clinical opinion of the site investigator.
Note: Children hospitalized for quarantine only or who are in the hospital to receive treatment for other conditions may be eligible provided that all study procedures can be completed.
2. Suspected or confirmed concurrent active systemic infection other than COVID-19 that may interfere with the evaluation of response to the study intervention.
3. History of hypersensitivity or other contraindication to any of the components of the study intervention, as determined by the investigator.
4. 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.
5. Known medical history of active liver disease (other than nonalcoholic hepatic steatosis), including chronic or active hepatitis B or C infection, primary biliary cirrhosis, Child Pugh Class B or C or acute liver failure.
6. Current or expected use of any prohibited medication(s) or those and that are highly dependent on CYP3A4 for clearance, and for which elevated plasma concentrations may be associated with serious and/or life-threatening events during treatment and for 4 days after the last dose of nirmatrelvir/ritonavir.
7. Concomitant use of any medications or substances that are strong inducers of CYP3A4 are prohibited within 28 days prior to first dose of nirmatrelvir/ritonavir and during study treatment.
8. Use of monoclonal antibody treatment, antiviral treatment (eg, molnupiravir) or convalescent COVID-19 plasma for treatment of COVID-19 at any time during the course of the study and expectation to receive SARS-CoV-2 vaccine prior to Day 34 of the study.
9. Participating in another interventional clinical study with an investigational compound or device, including those for COVID-19 therapeutics, through the longterm follow-up visit.
10. 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) or known prior participation in this trial or other trial involving nirmatrelvir/ritonavir.
11. Known history of any of the following abnormality in clinical laboratory tests (within past 6 months of the screening visit):
- Total bilirubin ≥2 X ULN (except for Gilbert’s syndrome);
12. Receiving dialysis or have known moderate to severe renal impairment (CKD Grade 3b to 5) ie, eGFR or eCrCl (estimated creatinine clearance of <45 mL/min/1.73 m2) within 6 months of the screening visit using the age-appropriate calculation:
- If participant <1 month of age, use the Bedside Schwartz Equation;
- If participant ≥1 month to <2 years of age, use the Bedside Schwartz Equation;
- If participant ≥2 years to <12 years of age, use the Modified Schwartz Equation;
- If participant is ≥12 years to <18 years of age and is either receiving dialysis or has known moderate to severe renal impairment (CKD Grade 3b to 5) (estimated creatinine clearance of <45 mL/min/ 1.73 m2) within 6 months of the screening visit use the Cockcroft-Gault Formula.
Note: If the investigator suspects the participant may have any of the above laboratory values, confirmatory tests should be performed at screening to confirm eligibility before the first dose of study intervention. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
- PK parameters including Cmax and AUC0-tau ( and if the data permit t1/2, Ctrough) of nirmatrelvir and ritonavir. In adolescents (≥12 years to <18 years of age), robust PK sampling will be performed. A sparser approach will be incorporated for younger participants as PK samples are more difficult to obtain.
- Incidence of TEAEs, SAEs, AEs leading to discontinuations, and vital sign measurements. |
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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) |
- SARS-CoV-2 viral RNA measured via RT-PCR in nasopharyngeal or nasal swabs over time.
- Proportion of participants with COVID-19 related hospitalization or death from any cause through Day 28
- Acceptability and palatability assessments of nirmatrelvir/ritonavir (filmcoated tablets and oral powder) |
|
| 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) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| 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 | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| 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 | 10 |
| 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 |
| Mexico |
| South Africa |
| United Kingdom |
| United States |
| Bulgaria |
| Hungary |
|
| 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
|
The end of the study is defined as the date of the last visit of the last participant in the study globally.
A participant is considered to have completed the study if he/she has completed all periods of the study, including the last visit. |
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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 | 4 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | 15 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
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