A Phase 2/3 Safety, Pharmacokinetics, and Efficacy Study ofNirmatrelvir/Ritonavir in Pediatric, Nonhospitalized Symptomatic Participants With COVID-19 Who Are at Risk of Progression to Severe Disease

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Pfizer Inc.

Participant type

Pediatric, Patients

Age range

0-17 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Virus Diseases [C02]

Trial duration

13 Jul 2023 → ongoing

Decision date (initial)

2024-05-14

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Pfizer Inc.

External identifiers

EU CT number

2023-509773-23-00

EudraCT number

2022-000075-39

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy, Pharmacokinetic

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.

Secondary objectives 3

1. 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.
2. 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.
3. To determine acceptability and palatability of formulation

Conditions and MedDRA coding

SARS-CoV-2 Infection

Regulatory references

EMA paediatric investigation plan (PIP)

EMEA-003081-PIP01-21

Plan to share IPD

Yes

IPD plan description

Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 4

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. 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 SARS-CoV-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 o 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: o 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 o Has received treatment with biologics (eg, infliximab, ustekinumab), immunomodulators (eg, methotrexate, 6MP, azathioprine) or cancer chemotherapy within 90 days prior to study entry o HIV infection with CD4 cell count <200 mm3 and a viral load lower than 400 copies/mL; • Chronic lung disease o If asthma, requires daily prescribed therapy; • Known diagnosis of hypertension; • Cardiovascular disease; • Type 1 or Type 2 diabetes mellitus; • Chronic kidney disease defined as eGFR between 45 to 89 mL/min/1.73m2 or eCrCl between 45 to 89 mL/min; • 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.

Exclusion criteria 15

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 clinical study with an investigational compound or device, including those for COVID-19 therapeutics, through the long-term 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 ie, eGFR <45 mL/min/1.73 m2 or eCrCl <45 mL/min) within 6 months of the screening visit using the age-appropriate calculation o If participant <1 month of age, use the Bedside Schwartz Equation; o If participant ≥1 month to <2 years of age, use the Bedside Schwartz Equation; o If participant ≥2 years to <12 years of age, use the Modified Schwartz Equation; o If participant is ≥12 years to <18 years of age and is either receiving dialysis or has known moderate to severe renal impairment (estimated creatinine clearance of <45 mL/min) 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.
13. Females who are pregnant or breastfeeding
14. Participants who are direct descendants (child or grandchild) of investigational site staff members or Pfizer/BioNTech employees directly involved in the conduct of the study, site staff otherwise supervised by the investigator, and their respective family members.
15. Investigator site staff or Pfizer employees directly involved in the conduct of the study, site staff otherwise supervised by the investigator, and their respective family members.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Plasma nirmatrelvir PK parameters including Cmax, AUC0-tau, t1/2, and Ctrough.
2. Incidence of TEAEs, SAEs, AEs leading to discontinuations, and vital sign measurements

Secondary endpoints 3

1. SARS-CoV-2 viral RNA measured via RT-PCR in nasopharyngeal or nasal swabs over time
2. Proportion of participants with COVID-19 related hospitalization or death from any cause through Day 28
3. Acceptability and palatability assessments of nirmatrelvir/ritonavir (filmcoated tablets and oral powder)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Pfizer Inc.

Sponsor organisation

Pfizer Inc.

Address

66 Hudson Boulevard East

City

New York

Postcode

10001-2189

Country

United States

Scientific contact point

Organisation

Pfizer Inc.

Contact name

Clinical Medical Lead

Public contact point

Organisation

Pfizer Inc.

Contact name

Clinical Medical Lead

Third parties 6

Locations

2 EU/EEA countries · 5 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Temporary halts 4 · Art. 38 CTR

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 38 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

4 submissions — initial application plus substantial / non-substantial modifications