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 antiviral effects of RV521, compared to placebo, on nasopharyngeal shedding of RSV in infants hospitalised with 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: To evaluate virologic parameters derived from the RSV viral load as measured in nasopharyngeal swabs. 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: To evaluate the clinical efficacy of multiple oral doses of RV521 in infants hospitalised with RSV LRTI. Part C: Evaluate the safety and tolerability of RV521 given as a multiple dose regimen. |
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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 (Parts A, B and C) but ≤ 18 kg (Part C only). 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 Part B only 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 postnatal age 2. Known to have significant comorbidities, including genetic disorders (eg, trisomy 21); cardiopulmonary diseases (eg, haemodynamically significant congenital heart disease); significant 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. Current respiratory insufficiency likely to require imminent invasive mechanical ventilation (Part C only). 4. 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. 5. Any clinically significant electrocardiogram (ECG) abnormalities. 6. Known to be immunocompromised 7. High probability of asthma (per GINA Guidance 2020) with all of the following: a. Symptoms (cough, wheeze, heavy breathing) for > 10 days during previous upper respiratory infections b. History of > 3 episodes per year or severe episodes and/or night worsening c. Between episodes, child has cough, wheeze, or heavy breathing during play or when laughing d. Allergic sensitisation, atopic dermatitis, food allergy, or family history of asthma 8. 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. 9. Has significant oral and/or maxillofacial malformations that would limit the ability to administer IMP. 10. 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) 11. 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) 12. History of epilepsy or seizures. Subjects with a history of febrile seizures will be permitted to enroll. 13. Allergy to test medication or constituents 14. Known to be concurrently infected with COVID-19 virus (SARS-CoV-2) 15. Requires any prohibited medication/therapy during the course of the study: a. Requires inhaled, oral, or IV corticosteroid therapy during the dosing period of the study b. Has taken within 21 days before dosing, or requires during the dosing period of the study, any drug that could impact on the PK of the investigational product including potent inhibitors or potent and moderate inducers of CYP450s (as listed in Appendix 17.3), c. Has taken within 21 days before dosing, or requires during the dosing period of the study, any prescription medications, over-the-counter (OTC) medications, herbal remedies or dietary supplements containing St. John's Wort, or the consumption of grapefruit, Seville oranges, or cranberry juice-containing products as these are known to be potent inhibitors or moderate or potent inducers of CYP3A4. d. Requires the use of Heliox, Leukotriene receptor antagonist (eg, Montelukast, exogenous surfactant, or mucolytics) during the dosing period of the study. 16. 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. 17. 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 18. Currently participating in any investigational study or at the time of screening, has received an investigational product within 3 months or within 5 half-lives of the investigational product, whichever is longer. 19. 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: -Virologic parameters derived from the RSV viral load as measured in nasal swabs include but are not limited to: o Change from baseline in viral load (RT-qPCR and CBIA) at each time point o Time to below viral load quantification limit (RT-qPCR and CBIA) o Proportion of subjects with viral load below quantification limit (RT qPCR and CBIA) at each timepoint throughout the study - Correlation between plasma PK parameters and RSV viral load • Time to resolution in RSV-related symptoms • Time to improvement of RSV-related 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 • Time to normalisation of respiratory rate - Safety of RV521 compared to placebo assessed by incidences of AEs, discontinuations due to AEs, SAEs, and clinically significant changes in clinical laboratory tests |
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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 | 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 | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 30 |
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 |
Israel |
Korea, Republic of |
Malaysia |
New Zealand |
Panama |
Taiwan |
Thailand |
United States |
Latvia |
Poland |
Romania |
Belgium |
Hungary |
Ukraine |
United Kingdom |
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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 | 2 |
E.8.9.1 | In the Member State concerned months | 7 |
E.8.9.1 | In the Member State concerned days | 17 |
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 | 2 |