E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Respiratory Syncytial Virus |
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E.1.1.1 | Medical condition in easily understood language |
Respiratory Syncytial Virus |
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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 | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10061603 |
E.1.2 | Term | Respiratory syncytial virus infection |
E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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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 evaluate the superiority of rilematovir compared to placebo treatment with respect to the clinical outcome on the RSV Recovery Scale (RRS). |
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E.2.2 | Secondary objectives of the trial |
-To evaluate the superiority of rilematovir compared to placebo treatment with respect to: 1) clinical resolution of RSV disease; 2)the time from first dosing to resolution of Key RSV Signs/Symptoms including supplementation free; 3)the time from discharge to resolution of Key RSV Signs/Symptoms; 4)the time from first dosing to end of oxygen supplementation; 5)the incidence of post-baseline RSV-related complications. -To evaluate the safety and tolerability of rilematovir.(6) -To evaluate the effect of rilematovir on the clinical course of RSV disease as assessed electronically by: 7)ObsRO Signs/Symptoms and ObsRO General Health Questions (GHQ); 8)ClinRO Signs/Symptoms and CLinRO GHQ. -To evaluate the effect of rilematovir on the clinical course of RSV disease (other than ClinRO and ObsRO assessments).(9) -To evaluate the antiviral effect of rilematovir as measured by RSV viral load in nasal mid-turbinate (MT) swab samples by qRT-PCR assay.(10).
*partial list due to space.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. The participant is a boy or girl ≥28 days corrected for gestational age at birth to ≤5 years old at the time of consent. Note: After this main study opens to neonate enrollment: in addition, a neonate (boy or girl) from birth at term (ie, after at least 37 weeks of gestation) to <28 days at the time of consent. 2. The participant weighs within ≥2.4 kg and ≤24.6 kg. 3. Each participant’s parent(s) (preferably both if available or as per local requirements) or their legally acceptable representative(s) has/have signed an ICF indicating that (s)he: • understands the purpose of, and procedures required for, the study, • is willing for their child to participate in the study, • is willing for their child to remain in the hospital until at least Day 2, • is willing and able to adhere to the prohibitions and restrictions with regards to - the concomitant medication, - the lifestyle consideration, - study procedures and assessments to be performed by the parent(s)/caregiver(s) as well as those by the investigator/study site personnel. 4. The participant has been diagnosed with RSV infection using a polymerase chain reaction (PCR)- or other molecular-based diagnostic assay. Note: If a participant had a positive RSV test result using a molecular-based diagnostic assay from another study for which (s)he was otherwise ineligible or from a SOC molecular-based diagnostic test within 24 hours prior to start of screening and meets all eligibility criteria for inclusion in this study, this diagnostic test result can be used for determination of eligibility. 5. The participant has an acute respiratory illness with at least 1 of the signs/symptoms listed in each of the following categories within 24 hours prior to start of screening and at screening, as evaluated by the investigator: • Upper respiratory tract infection: nasal congestion or rhinorrhea; AND • Lower respiratory tract infection: increased respiratory effort (as evidenced by subcostal, intercostal or tracheosternal retractions, grunting, head bobbing, nasal flaring, or tachypnea), wheezing, cough*, cyanosis, or apnea; AND • Systemic/general: feeding difficulties (defined as <75% intake of normal food amounts); dehydration; fever; disturbed sleep, or disturbed activity level (irritable/restless/agitated/less responsive). *Cough cannot be the only LRTI sign/symptom present, ie, another LRTI sign/symptom needs to be present for eligibility. 6. The time of onset of RSV signs/symptoms to the anticipated time of randomization must be ≤3 days. Onset of signs/symptoms is defined as the time of the day (or part of the day if time of the day cannot be specified) the parent(s)/caregiver(s) became aware of the first sign and/or symptom consistent with respiratory or systemic/general manifestation of signs/symptoms of RSV infection. The time of sign/symptom onset has to be assessed as accurately as possible. 7. The participant is hospitalized or presented to the ER/clinic and expected to be hospitalized. Note: Hospitalized refers to having at least 24 hours with an overnight stay in the hospital. 8. Participants are otherwise healthy or have (a) risk factor(s) for severe RSV disease. Participants who are immunocompromised are excluded. 9. The participant must have been assessed per local public health practice and considered not to have SARS-CoV-2 infection during this respiratory infection.
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E.4 | Principal exclusion criteria |
1. The participant had major surgery within the 28 days prior to randomization or planned major surgery through the course of the study (eg, bidirectional Glenn procedure). 2. The participant has a neuromuscular disease that affects swallowing or the thoracic muscles, an evolving developmental disorder, major congenital anomalies or known cytogenetic or metabolic disorders other than the ones allowed above (see inclusion criterion #8). 3. The participant is considered by the investigator to be immunocompromised, whether due to underlying medical condition (eg, known human immunodeficiency virus [HIV] infection, malignancy or genetic disorder other than immunoglobulin A deficiency) or medical therapy (eg, immunomodulators other than corticosteroids for the treatment of comorbidities, chemotherapy, radiation, stem cell or solid organ transplant). 4. The participant has a known or clinically suspected acute or chronically active hepatitis B or C infection (based on participant’s medical history or on participant’s examination) or history of active maternal hepatitis B or C infection around birth, unless the participant has tested negative for hepatitis B and C infection. 5. The participant has had either: a) Confirmed SARS-CoV-2 infection (test positive) during the four weeks prior to randomization, OR b) Close contact with a person with COVID-19 (test confirmed or suspected SARS CoV-2 infection) within 14 days prior to randomization. 6. The participant is being treated with extracorporeal membrane oxygenation. 7. Confirmed QTcF interval >450 msec per the machine read parameter result at screening. Presence of an abnormal QTcF interval should be confirmed by repeat ECG recording during screening. 8. Presence of repetitive ventricular premature contractions (>10/min), second or third degree heart block, or complete or incomplete left bundle branch block, or complete right bundle branch block per the machine read ECG result at screening. Presence of any of the above abnormalities should be confirmed by repeat ECG recording during screening. 9. Other clinically significant abnormal ECG findings not consistent with the present risk factor for severe RSV disease (if applicable) in the study population, as judged by the investigator based on the machine read ECG results at screening.
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint is RRS as assessed on the first day when at least 50% of the participants across treatment arms are discharged from the hospital (the day for the RRS evaluation will be determined based on blinded data at the first interim analysis by an independent statistician). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
First day when at least 50% of the participants across treatment arms are discharged from the hospital. |
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E.5.2 | Secondary end point(s) |
1) Proportion of participants clinically resolved from RSV disease based on Clinician Rated Outcome (ClinRO) Signs/Symptoms as assessed on the same day as the primary endpoint. 2) Time from first study dose to resolution of Key RSV Signs/Symptoms (absent or mild) based on parent’s/caregiver’s Observer Rated Outcome (ObsRO) Signs/Symptoms and supplementation free (oxygen and feeding/hydration) for at least 24 hours. 3) Time from discharge to resolution of Key RSV Signs/Symptoms based on ObsRO Signs/Symptoms (only including participants who did not reach resolution before first discharge). 4) Time from first dosing to end of oxygen supplementation (only including participants who were receiving oxygen supplementation at the time of first dosing). 5) Incidence in post-baseline RSV-related complications. 6) Safety and tolerability, as assessed by adverse events (AEs), clinical laboratory testing, electrocardiograms (ECGs), vital signs throughout the study. 7) A) The following endpoints will be based on the ObsRO Signs/Symptoms: time to resolution of signs/symptoms (absent or mild) of RSV disease; actual values and changes from baseline in scores. B) The following endpoint will be based on the ObsRO GHQ: time to improvement. 8) a) The following endpoints will be based on the ClinRO Signs/Symptoms: - time to resolution of signs/symptoms (absent or mild) of RSV disease; - actual values and changes from baseline in scores; - proportion of participants clinically resolved from RSV disease based on ClinRO Signs/Symptoms as assessed each day from Day 2 to 8. b) The following endpoint will be based on the ClilnRO GHQ: general impression of change. 9) See list below: - RRS as assessed each day separately from Days 2 to 8. - Time to hospital discharge from start of dosing. - Time to readiness for hospital discharge (as evaluated by the investigator). - Proportion of participants requiring intensive care unit (ICU) stay. - Duration of requiring ICU stay. - Proportion of participants requiring rehospitalization for respiratory/other reasons. - Time to end of oxygen supplementation. - Proportion of participants requiring oxygen supplementation. - Duration of oxygen supplementation. - Time to end of supplemental feeding/hydration. - Proportion of participants requiring hydration and/or feeding by intravenous (IV) administration or nasogastric tube. - Duration of supplemental feeding/hydration. - Time to end of supplementation (oxygen and/or feeding/hydration). - Number and type of medical encounters. - Incidence of antibiotic treatment episodes. - Incidence of systemic or inhaled corticosteroids and bronchodilators use.
NOTE: partial list due to character constraints in section E.5.2.1
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Numbers below correspond to numbers in E.5.2: 1)First day when at least 50% of the participants across treatment arms are discharged from the hospital 2)Time from first study dose to resolution of Key RSV Signs/Symptoms 3)Time from discharge to resolution of Key RSV Signs/Symptoms 4)Time from first dosing to end of oxygen supplementation 5)post baseline 6)Throughout the study 7a)time to resolution of signs/symptoms and actual values/changes from baseline 7b)time to improvement 8a)time to resolution of signs/symptoms (absent or mild) of RSV disease; actual values and changes from baseline in scores; proportion of participants clinically resolved from Day 2 to 8 8b)when questionnaire is administered 9)Multiple, see E.5.2 #9
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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 | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
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) | No |
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 | 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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 75 |
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 |
Australia |
Brazil |
Canada |
Chile |
China |
Colombia |
India |
Israel |
Japan |
Korea, Republic of |
Malaysia |
Mexico |
Panama |
Philippines |
Russian Federation |
South Africa |
Taiwan |
Thailand |
Turkey |
Ukraine |
United States |
Belgium |
Bulgaria |
Estonia |
Germany |
Hungary |
Italy |
Latvia |
Poland |
Slovakia |
Spain |
Sweden |
Czechia |
Argentina |
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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 | 3 |
E.8.9.1 | In the Member State concerned months | 3 |
E.8.9.1 | In the Member State concerned days | 8 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 3 |
E.8.9.2 | In all countries concerned by the trial days | 8 |