E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Respiratory Syncytial Virus Infection |
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E.1.1.1 | Medical condition in easily understood language |
Respiratory Syncytial Virus Infection |
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E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
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 safety and tolerability of single (Part A) and multiple (Part B) oral doses of RV521 in infants hospitalised with Respiratory Syncytial Virus (RSV) lower respiratory tract infection (LRTI) Part C: Evaluate the effect of RV521, compared to placebo, on the clinical course of RSV LRTI |
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E.2.2 | Secondary objectives of the trial |
To characterise the pharmacokinetics (PK) of single (Part A) and multiple (Part B) oral doses of RV521 in infants hospitalised with RSV LRTI. To evaluate the antiviral effects of RV521 in infants hospitalised with RSV LRTI. Part B: To evaluate the antiviral effects of RV521 in infants hospitalised with RSV LRTI Part B: Evaluate the effect of RV521 compared to placebo on the clinical course of RSV infection Part C: Evaluate the safety of RV521 given as a multiple dose regimen Part C: Effect of RV521, compared to placebo, on nasopharyngeal shedding of RSV Part C: To evaluate the PK and PK-PD relationship through correlation of RV521 plasma levels with changes in viral load after repeated oral dosing Part C: Comparison between RV521 and placebo on the development of viral mutations associated with in vitro resistance |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Male or female ≥ 1 month and ≤ 36 months of age 2. Weight ≥ 3.5 kg 3. Clinical diagnosis of LRTI defined by a. Evidence of respiratory infection by one or both of the following with or without fever: i. Rhinitis/coryza ii. Cough AND b. Evidence of LRTI by the presence of one or more of the following: i. Increased respiratory rate PLUS other evidence of lower respiratory tract disease (eg, laboratory or radiographic evidence). ii. Increased respiratory effort as evidenced by one or more of the following: 1. Grunting with expiration 2. Nasal flaring 3. Retraction: intercostal or subcostal iii. Wheezing: audible or on chest auscultation 4. A positive RSV diagnostic test (RSV infection confirmed either according to routine site practice [polymerase chain reaction or diagnostic quick test], or using a [Sponsor-provided] commercial kit. 5. Hospitalised because of RSV LRTI (bronchiolitis or bronchopneumonia) 6. For Part B, symptoms of LRTI must be present for no more than 1 week before the Screening Visit, with the first day of symptoms counting as Day 1. 7. For Part C, symptoms of LRTI must be present for no more than 5 days prior to the Screening Visit, with the first day of symptoms counting as Day 1. 8. Expected to remain in hospital for a minimum of 3 days (administration of 6 doses for both Parts B and C) 9. The parent(s)/legal guardian(s) of the subject have provided written informed consent for the subject to participate 10. The parent(s)/legal guardian(s) are able and willing to comply with the study protocol |
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E.4 | Principal exclusion criteria |
1. Premature (gestational age less than 37 weeks) AND <1 year of post-natal age 2. Known to have significant comorbidities, including genetic disorders (eg, trisomy 21); cardiopulmonary diseases (eg, haemodynamically significant congenital heart disease); pulmonary disease (eg, bronchopulmonary dysplasia, cystic fibrosis); history of surgery for diaphragmatic hernia; any hereditary or acquired metabolic diseases; haematological 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 study drug or evaluate the safety or clinical response to IMP. 3. Malformation of the gastrointestinal tract including unresolved pyloric stenosis, history of necrotising enterocolitis, short bowel, or other significant condition that would alter drug absorption or increase the risk of diarrhoea. 4. Any clinically significant ECG abnormalities. 5. Known to be immunocompromised 6. High risk of having developing asthma. Features that indicate a high likelihood of asthma in a young child include: a. Symptoms (cough, wheeze, heavy breathing) for > 10 days during upper respiratory infections b. > 3 wheezing episodes per year (during the previous 12 months) or severe episodes and/or night wheezing c. Between episodes, child has cough, wheeze, or heavy breathing during play or when laughing d. Atopy or family history of asthma in a first degree relative 7. Suspected of having a clinically significant bacterial infection as indicated by symptoms or laboratory findings consistent with a bacterial infection including but not limited to: elevated white blood cell count, elevated C-reactive protein, chest X-ray consistent with bacterial pneumonia, unstable vital signs, hypotension, or evidence of shock or poor perfusion. 8. Has significant oral and/or maxillofacial malformations that would limit the ability to administer IMP. 9. History of renal failure including renal anomalies likely to be associated with renal insufficiency (eg, clinical conditions of renal dysplasia, polycystic renal disease, renal agenesis) 10. Clinical evidence of hepatic decompensation (eg, hepatic disorder with associated coagulopathy or associated encephalopathy) or significantly elevated liver enzymes (aspartate aminotransferase [AST] and/or alanine aminotransferase [ALT] >3 × the upper limit of normal) 11. History of epilepsy or seizures, including febrile seizures 12. Allergy to test medication or constituents 13. Requires any prohibited medication/therapy as listed in the body of the protocol. a. Receiving treatment with inhaled, oral, or IV corticosteroids and requires continued corticosteroid therapy b. Has taken within 21 days before dosing, any drug that could impact by any mechanism of action on the PK of the investigational product including any substrates, inducers, inhibitors of CYP3A4 and/or P-glycoprotein (P-gp); or the use of prescription medications, over-the-counter (OTC) medications, herbal remedies or dietary supplements containing St. John’s Wort, or the consumption of drugs or other substances (eg, grapefruit, Seville oranges, or cranberry juice-containing products) known to be potent inhibitors or inducers of CYP P450s. c. Requires the use of Heliox, Leukotriene receptor antagonist (eg, Montelukast, exogenous surfactant, mucolytics or Hypertonic saline [allowed in the Part A of the study]). 14. Has received 1 or more doses of palivizumab at any time before Screening or received treatment with antiviral therapy for RSV (eg, ribavirin or intravenous [IV] immunoglobulin) within 3 months before the Screening Visit. NOTE: Subjects eligible for palivizumab treatment or other RSV prophylaxis cannot be included in the study. 15. The subject’s parent(s) or legal guardian(s) is a study team member (ie, has direct involvement in this study or other studies under the direction of the Investigator or the study centre) or is a family member of either the Investigator or other team members 16. Currently participating in any investigational study or has participated in an investigational study within 3 months before the Screening Visit 17. Any other reason which in the opinion of the Investigator makes the participant unsuitable for a clinical trial |
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E.5 End points |
E.5.1 | Primary end point(s) |
Safety and tolerability parameters to be assessed will include, but are not limited to: Adverse events (AEs), treatment-emergent AEs (TEAEs), serious AEs (SAEs), and withdrawals due to TEAEs Physical examinations Vital sign parameters (ie, systolic and diastolic blood pressure [BP], temperature, respiration rate [RR], heart rate [HR], and pulse oximetry), and changes from baseline in these parameters at predefined time points Laboratory tests (haematology, chemistry, and urinalysis test results) and changes from baseline in these parameters, at predefined time points Electrocardiogram (ECG) measurements and changes from baseline in these parameters at predefined time points
Part C: Time to resolution of symptoms Time to improvement of symptoms Reduction in severity of symptoms by RV521, compared to placebo, measured by a composite score over time Use of supplemental oxygen, including, but not limited to, duration and maximum level of O2 provided
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
From baseline, evaluations will be made throughout the course of the study, including following discharge from hospital |
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E.5.2 | Secondary end point(s) |
Secondary endpoints related to PK will include but are not limited to: Time to maximum plasma concentration (tmax) Maximum observed plasma concentration(Cmax) Area under the plasma concentration time curve from time zero to 12 hours (AUC0-12) Area under the plasma concentration time curve from time zero to last measurable plasma concentration (AUC0-t) Terminal half-life (t1/2) Area under the plasma concentration time curve from time zero to infinity (AUC0-∞) Predicted plasma clearance Apparent volume of distribution of the drug after extravascular administration (V/F) Trough concentration at the end of first dosing interval (C12) (data permitting) In addition for Part B: Accumulation ratio, percent fluctuation Area under the plasma concentration time curve from time zero to the end of last dosing interval (AUC0-tau) Average plasma concentration over dosing interval (Cave) Minimum observed plasma concentration (Cmin) Plasma trough concentration (Ctrough) Any other relevant parameters
Secondary endpoints related to assessment of antiviral activity and efficacy in Part B include but are not limited to: RSV viral load measured in nasopharyngeal swabs by quantitative reverse transcription polymerase chain reaction (RT-qPCR) RSV viral load measured in nasopharyngeal swabs by cell-based infectivity assay (CBIA)
Secondary endpoints related to assessment of the effect of RV521 compared to placebo on the clinical course of RSV infection: Time to resolution of symptoms Time to improvement evaluated by reduction in severity of symptoms Reduction in severity of symptoms by RV521, compared to placebo, measured by a composite score over time
Secondary endpoints of Part C: Safety of RV521 compared to placebo assessed by incidences of AEs, discontinuations due to AEs, SAEs, and clinically significant changes in clinical laboratory tests Comparison between RV521 and placebo for changes in viral load over time as for Part B Correlation between plasma PK parameters and RSV viral load Incidence of viral genome mutations associated with resistance to the antiviral effect of RV521
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
From baseline, evaluations will be made throughout the course of the study, including following discharge from hospital |
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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 | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
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 | 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 | Yes |
E.8.1.7.1 | Other trial design description |
In Part A the trial is Open Label. In Part B and C the trial is double-blinded. |
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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 | 3 |
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 | 24 |
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 |
Chile |
Costa Rica |
Hungary |
Latvia |
Malaysia |
New Zealand |
Panama |
Philippines |
Poland |
Spain |
Taiwan |
Thailand |
Ukraine |
United States |
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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 | 1 |
E.8.9.1 | In the Member State concerned months | 3 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 3 |