Phase 1b Randomized, Double-Blind, Placebo-Controlled Study of Sisunatovir in Pediatric Patients with RSV Lower Respiratory Tract Infection

Trial ID: 2023-504425-39-00
Protocol: C5241009
Sponsor: Pfizer Inc.

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Diseases & Conditions

Respiratory syncytial virus infection

Objectives

The primary objective of this study is to evaluate the **safety** and **tolerability** of sisunatovir compared to placebo in pediatric participants with Respiratory Syncytial Virus (RSV) Lower Respiratory Tract Infection (LRTI). This is clinically relevant as it aims to determine the potential adverse effects and overall acceptability of sisunatovir in a vulnerable population, which is crucial for ensuring patient safety and guiding future therapeutic use.

Secondary objectives include:

Characterizing the pharmacokinetics (PK) of sisunatovir in participants with RSV-LRTI. Understanding the PK profile is essential for optimizing dosing regimens and ensuring effective drug delivery.

Participants

The clinical trial involves a total of **92 participants** diagnosed with **Respiratory Syncytial Virus (RSV) Infection**. The study population includes both male and female subjects, ranging in age from 1 day to 60 months, with a weight between 2.5 kg and 23 kg. Participants were selected based on a positive RSV diagnostic test, with results available in the source document, confirming eligibility. The trial focuses on evaluating the safety and tolerability of sisunatovir compared to placebo in participants with RSV-LRTI. The study population includes a vulnerable group, as it involves young children. Key lifestyle considerations such as diet and physical activity are not specified, and the general health status of participants is not detailed beyond the presence of RSV infection. The selection criteria required evidence of lower respiratory tract infection (LRTI) and specific respiratory symptoms, with the duration of RSV-related signs and symptoms varying based on the age of the participants.

Plans and Procedures

The clinical trial is designed as a **randomized**, **double-blind**, sponsor-open, placebo-controlled, multi-center, dose-finding study. It aims to evaluate the safety, tolerability, and pharmacokinetics of **sisunatovir** in pediatric participants up to 60 months of age with **Respiratory Syncytial Virus (RSV) Lower Respiratory Tract Infection (LRTI)**. The trial is categorized as a Phase 1b study and is not considered low intervention. The estimated recruitment start date is December 15, 2023, with an anticipated end date of September 2, 2024.

Participants will be involved in the study for a duration that includes an initial screening visit, multiple follow-up visits, and an end-of-study visit. The inclusion visit will confirm eligibility based on criteria such as age, weight, and a positive RSV diagnostic test. Participants must exhibit evidence of LRTI, such as increased respiratory rate, low SpO2, increased respiratory effort, or specific auscultation findings. Follow-up visits will monitor the incidence of treatment-emergent adverse events (TEAEs), adverse events (AEs), serious adverse events (SAEs), and clinically significant laboratory values, ECG parameters, and vital signs. Plasma concentrations of sisunatovir at steady state will also be assessed as a secondary endpoint.

The expected length of participant involvement will vary depending on the individual response to treatment and the occurrence of any adverse events. Conditions that may lead to early termination from the study include the incidence of significant adverse events or any other safety concerns as determined by the investigator. The trial will utilize a placebo for sisunatovir 50 mg capsule as a comparator, with both the active drug and placebo administered in a hard capsule form via the oral route. The study is sponsored by Pfizer Inc., and the investigational medicinal product is identified by the sponsor product code PF-07923568.

Treatment

The clinical trial involves the administration of **Sisunatovir**, an investigational medication, to evaluate its safety, tolerability, and pharmacokinetics in pediatric participants with **Respiratory Syncytial Virus (RSV) Lower Respiratory Tract Infection (LRTI)**. **Sisunatovir** is provided in the form of a hard capsule, with each capsule containing the active substance **sisunatovir**. The medication is administered orally. The specific dosage and frequency of administration are determined based on the study protocol, which aims to identify the optimal dosing regimen for this population. The investigational product is manufactured by Pfizer Inc., and it is not a pediatric formulation.

In addition to the experimental treatment, a **placebo** is used as a comparator in this double-blind, placebo-controlled study. The placebo is designed to match the **sisunatovir** 50 mg capsule in appearance but does not contain the active substance. The placebo is also administered orally, following the same schedule as the investigational drug, to maintain the study's blinding integrity. The use of a placebo allows for a controlled comparison to assess the true effects of **sisunatovir** on the study's primary and secondary endpoints.

Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the protocol. This monitoring is crucial for the accurate assessment of the investigational drug's safety and efficacy. The study is conducted under rigorous conditions to maintain the integrity of the data collected and to ensure the safety of all participants involved.

Efficacy

Efficacy in this clinical trial will be assessed through both primary and secondary endpoints. The primary endpoints include the incidence of treatment-emergent adverse events (TEAEs), adverse events (AEs) and serious adverse events (SAEs) leading to discontinuations, as well as the incidence of clinically significant abnormal laboratory values, electrocardiogram (ECG) parameters, and vital signs. These parameters will be systematically measured and collected throughout the trial to evaluate the safety and tolerability of **sisunatovir** compared to placebo in pediatric participants with Respiratory Syncytial Virus (RSV) Lower Respiratory Tract Infection (LRTI).

The secondary endpoint focuses on the pharmacokinetics of **sisunatovir**, specifically the plasma concentrations at steady state, which will be measured on Day 3 or later. This will provide additional insights into the drug's behavior in the body and its potential therapeutic effects. The trial is designed as a Phase 1b, randomized, double-blind, sponsor-open, placebo-controlled, multi-center, dose-finding study, ensuring a robust evaluation of the investigational product's efficacy and safety profile.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Participants 1 day to ≤60 months of age and weight ≥2.5 kg to ≤23 kg
A positive RSV diagnostic test with result available in source document to confirm eligibility either according to routine site practice or Investigator sites may use RSV POC test kits that are provided for this study. RSV diagnostic test, antigen or molecular test is acceptable, and should be collected within 48 hours of randomization. Note: Participants ≤30 days old with RSV diagnostic test collected within 72 hours is acceptable for eligibility.
Evidence of LRTI by the presence of ≥1 from any of the following 4 categories (a through d): a.Increased respiratory rate for age: •<2 months: ≥60 bpm •≥2 to <12 months: ≥50 bpm •≥12 to ≤60 months: ≥40 bpm b.SpO2 < 95% on room air c.Increased respiratory effort as evidenced by ≥1 of the following: •Grunting with expiration •Nasal flaring •Retractions d.One or more of the following exam findings on auscultation: •Wheezing •Rhonchi •Rales or crackles
For participants >30 days old, RSV-related signs and/or symptoms must be present for ≤5 days at time of randomization. For participants 1 day to 30 days old, RSV related signs and/or symptoms must be present within ≤7 days at time of randomization.

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Exclusion Criteria

Any medical, developmental, or behavioral condition (including history of self-harmful behaviors) or laboratory abnormality that may increase the risk of study participation or, in the investigator’s judgment, make the participant inappropriate for the study.
Suspected or confirmed clinically significant moderate or severe bacterial infection (eg, bacterial pneumonia, bacteremia), that may interfere with the evaluation of response to the study intervention at investigator discretion. Participants with mild, localized infections such as otitis media or UTI can be included.
Evidence of severe respiratory failure requiring invasive mechanical ventilation or ECMO. Note: Participants requiring non-invasive ventilation, including high flow nasal cannula (HFNC), remain eligible for the study
Known to have significant comorbidities, including genetic disorders (eg, trisomy 21); cardiopulmonary diseases (eg, hemodynamically significant congenital heart disease); significant pulmonary disease (eg, bronchopulmonary dysplasia, cystic fibrosis); history of renal failure including renal anomalies likely to be associated with renal insufficiency (eg, renal dysplasia, polycystic renal disease, renal agenesis); history of surgery for diaphragmatic hernia; any hereditary or acquired metabolic diseases, hematological or other malignancy; or is known to be HIV positive; or has evidence of severe neurologic impairment or developmental delay that would limit the ability to administer IMP or evaluate the safety or clinical response to IMP.
Immunosuppressive disease (eg, bone marrow or organ transplantation or primary immune deficiencies) OR prolonged use of immune-weakening medications. • Has received corticosteroids equivalent to prednisone ≥2mg/kg daily for at least 14 consecutive days within 30 days prior to study start. Inhaled/nebulized or topical (skin, eyes or ears) corticosteroids are permitted, except those prohibited (see Section 6.9). • Has received treatment with biologics (eg, infliximab, ustekinumab), immunomodulators (eg, methotrexate, 6MP, azathioprine) or cancer chemotherapy within 90 days prior to study start.
Malformation of the gastrointestinal tract including unresolved pyloric stenosis, history of necrotizing enterocolitis, short bowel, or other significant condition that would alter drug absorption or increase the risk of diarrhea.
Has significant oral and/or maxillofacial malformations that would limit the ability to administer IMP.
Allergy to test medication or constituents.
Current use of any prohibited concomitant medication(s) or participants unwilling or unable to use a required concomitant medication(s). Refer to Section 6.9 • Has taken within 5 half-lives plus 14 days before dosing, or requires during the dosing period of the study, any drug that could impact the PK of the investigational product, including any prescription medications, OTC medications, herbal remedies or dietary supplements containing St. John’s Wort or the consumption of grapefruit, Seville orange, or cranberry juice-containing products as these are known to be potent inhibitors or moderate or potent inducers of CYP3A4.
Premature infants (gestational age less than 35 weeks) AND <1 year of post-natal age. Note: Infants 35- and 36-week gestational age are permitted if they weigh at least 2.5 kg and are at least 2 months post-natal age.
Neonates (1 to 30 days old) with intrauterine growth restriction defined by having 3 or more of the following: • Birth weight <10th percentile on population-based or customized growth charts • Head circumference <10th percentile • Length <10th percentile • Prenatal diagnosis of fetal growth restriction • Maternal pregnancy information associated with fetal growth restriction (eg, hypertension, pre-eclampsia)
Any clinically significant ECG abnormality in a participant's medical history, or in the pre-dose ECG that per investigator judgement may affect participant safety or interpretation of study results. Note: If sinus tachycardia is present, and not worse than expected due to underlying disease, participant may be considered if it does not interfere with evaluation of response to study intervention, at investigator discretion.
Participant history or risk factors for QT prolongation or torsades de pointes (eg, organic heart disease, hypokalemia, hypomagnesaemia, congenital long QT syndrome) or congenital deafness. Family history of long QT syndrome or sudden unexplained death.
Known history of hepatic disease, concern for active acute or chronic viral hepatitis, or acute hepatic failure.
Participants >30 days only: Known history of AST, ALT or T bili abnormalities >2 x ULN within 6 months of screening. Laboratory assessments not required at screening for participants >30 days unless deemed necessary by the investigator to confirm normal hepatic function.
History of epilepsy or seizures. Participants with a history of febrile seizures will be permitted to enroll.
Expected to receive an antiviral for another viral infection (eg, influenza or COVID-19) within 10 days of screening.