REVIRAL 1: A Study in Infants With RSV LRTI to Evaluate RV521
Study Details
Study Description
Brief Summary
This is a multicentre, 3-part study to evaluate safety, tolerability, PK, PD, and antiviral effect of single and multiple dosing of RV521 in infants hospitalised due to Respiratory Syncytial Virus (RSV) lower respiratory tract infection (LRTI). Due to the adaptive study design, the number of enrolled subjects may vary depending on the obtained PK and safety profiles.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
Detailed Description
This is a multicentre, 3-part study to evaluate safety, tolerability, PK, PD, and antiviral effect of single and multiple dosing of RV521 in infants hospitalised due to RSV LRTI.
The clinical study consists of 3 parts, the third part (Part C) is optional:
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Part A is an open-label, multicentre, single dose study in infants hospitalised with RSV LRTI (Cohorts 1 & 2)
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Part B is a randomised, double-blind, placebo-controlled, multicentre multiple dose study in infants hospitalised with RSV LRTI (Cohorts 3, 4 & 5)
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Part C is a randomised 1:1, double-blind, placebo-controlled, multicentre, multiple-dose study in infants hospitalised with RSV LRTI I The number of subjects enrolled in Parts A and B of the study will depend on the safety and PK data from the group of subjects enrolled in specified age cohorts and the subsequent recommendation of the Data Safety Monitoring Committee (DSMC).
The DSMC may recommend a dose adjustment (either a reduction or an escalation) and/or regimen adjustment (Part B only) for subsequent subjects because of the observation of an unexpected safety/tolerability profile and/or differences between the observed and predicted exposure resulting from a specified dose of RV521.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: RV521 sisunatovir is formulated as a dry powder blend of RV521 drug substance with mannitol as excipient. The RV521 dry powder blend will be supplied in capsules containing 10, 20, or 50 mg RV521. The Investigational Medicinal Product (IMP) will be dispersed in a defined volume of suspending diluent prior to oral administration on a mg/kg basis. Instructions for opening the capsule(s) and dispersing the contents in a fixed volume of suspending diluent prior to administration will be provided in the Pharmacy Manual. The proposed dosing regimen for Part A is a single open label dose of RV521. Part B and C is RV521 or placebo administered BID, 12 hours apart, for a period of 5 consecutive days with a total of 10 doses. However, this is subject to the recommendation of the DSMC. |
Drug: RV521
RV521 is an RSV F protein inhibitor administered orally
Other Names:
|
| Placebo Comparator: Placebo The placebo capsules administered in Part B and C will contain mannitol and microcrystalline cellulose (vehicle). The placebo dry powder will be dispersed in suspending diluent and given orally BID. Instructions for opening the capsule(s) and dispersing the contents in a fixed volume of suspending diluent prior to administration will be provided in the Pharmacy Manual. |
Drug: Placebo
vehicle administered orally
|
Outcome Measures
Primary Outcome Measures
- To evaluate the safety and tolerability of single (Part A) and multiple (Part B) oral doses of RV521 in infants hospitalised with RSV LRTI by assessing incidence of AEs, TEAEs, SAEs, and withdrawals due to TEAEs. [48 hours post dose 1 (Part A) and 48 hours post dose 10 (Part B)]
Summary tables of AEs will be based on TEAEs, defined as events starting, or worsening, after the first dose of IMP.
- To evaluate the safety and tolerability of single (Part A) and multiple (Part B) oral doses of RV521 in infants hospitalised with RSV LRTI by assessing changes in physical examinations. [48 hours post dose 1 (Part A) and 48 hours post dose 10 (Part B)]
Results at each visit will be summarised using the statistics: n (number of observations), mean, SD, median, minimum and maximum.
- To evaluate the safety and tolerability of single (Part A) and multiple (Part B) oral doses of RV521 in infants hospitalised with RSV LRTI by assessing systolic BP (vital sign parameters) and changes from baseline [48 hours post dose 1 (Part A) and 48 hours post dose 10 (Part B)]
Baseline characteristics will be summarized descriptively by treatment. Quantitative variables will be summarized used the statistics n, mean, standard deviation, median, minimum and maximum.
- To evaluate the safety and tolerability of single (Part A) and multiple (Part B) oral doses of RV521 in infants hospitalised with RSV LRTI by assessing diastolic BP (vital sign parameters) and changes from baseline [48 hours post dose 1 (Part A) and 48 hours post dose 10 (Part B)]
Baseline characteristics will be summarized descriptively by treatment. Quantitative variables will be summarized used the statistics n, mean, standard deviation, median, minimum and maximum.
- To evaluate the safety and tolerability of single (Part A) and multiple (Part B) oral doses of RV521 in infants hospitalised with RSV LRTI by assessing body temperature (vital sign parameters) and changes from baseline [48 hours post dose 1 (Part A) and 48 hours post dose 10 (Part B)]
Baseline characteristics will be summarized descriptively by treatment. Quantitative variables will be summarized used the statistics n, mean, standard deviation, median, minimum and maximum.
- To evaluate the safety and tolerability of single (Part A) and multiple (Part B) oral doses of RV521 in infants hospitalised with RSV LRTI by assessing respiration rate (vital sign parameters) and changes from baseline [48 hours post dose 1 (Part A) and 48 hours post dose 10 (Part B)]
Baseline characteristics will be summarized descriptively by treatment. Quantitative variables will be summarized used the statistics n, mean, standard deviation, median, minimum and maximum.
- To evaluate the safety and tolerability of single (Part A) and multiple (Part B) oral doses of RV521 in infants hospitalised with RSV LRTI by assessing heart rate (vital sign parameters) and changes from baseline [48 hours post dose 1 (Part A) and 48 hours post dose 10 (Part B)]
Baseline characteristics will be summarized descriptively by treatment. Quantitative variables will be summarized used the statistics n, mean, standard deviation, median, minimum and maximum.
- To evaluate the safety and tolerability of single (Part A) and multiple (Part B) oral doses of RV521 in infants hospitalised with RSV LRTI by assessing pulse oximetry (vital sign parameters) and changes from baseline [48 hours post dose 1 (Part A) and 48 hours post dose 10 (Part B)]
Baseline characteristics will be summarized descriptively by treatment. Quantitative variables will be summarized used the statistics n, mean, standard deviation, median, minimum and maximum.
- Number of participants with changes in haematology/clinical chemistry/urinalysis laboratory values (laboratory tests read by a central lab) from baseline in Part A and Part B. [48 hours post dose 1 (Part A) and 48 hours post dose 10 (Part B)]
Results at each visit will be summarised using the statistics n, mean, standard deviation, median, minimum and maximum. Also, change from baseline will also be summarised by post baseline visits.
- Number of participants with changes in ECG measurements from baseline in Part A and Part B [48 hours post dose 1 (Part A) and 48 hours post dose 10 (Part B)]
Parameters collected will be: Ventricular Heart Rate (bpm) PR Interval (msec) QRS Interval (msec) QT Interval (msec) QTcB Interval (msec) Results at each visit will be summarised using the statistics: n (number of observations), mean, SD, median, minimum and maximum.
- Part C: Evaluate the effect of RV521, compared to placebo, on the clinical course of RSV LRTI using the RSV Clinical Scoring System and the Adapted Version of ReSVinet Scale to show time to resolution of symptoms. [up to 48 hours post dose 10]
Overall time to resolution of RSV-related signs and symptoms will be calculated from the time of randomization to the time that they are no longer present (absent or severity =0), and will be summarized and analysed as Time to Improvement.
- Part C: Evaluate the effect (efficacy) of RV521, compared to placebo, on the clinical course of RSV LRTI using the RSV Clinical Scoring System and the Adapted Version of ReSVinet Scale to assess time to change of symptoms. [up to 48 hours post dose 10]
Time to change in symptoms will be calculated for RSV-related signs and symptoms that are classified as moderate or severe during the course of the study and will be defined as the time from randomization until no longer present (absent or severity=0) or mild (scores ≤ 5).
- Part C: Evaluate the effect (efficacy) of RV521, compared to placebo, on the clinical course of RSV LRTI using the RSV Clinical Scoring System and the Adapted Version of ReSVinet Scale to assess change in severity of symptoms [up to 48 hours post dose 10]
Change in severity of symptoms by RV521, compared to placebo, will be measured by a composite score over time.
- Part C: Evaluate the effect (efficacy) of RV521, compared to placebo, on the clinical course of RSV LRTI using the RSV Clinical Scoring System and the Adapted Version of ReSVinet Scale to assess use of supplemental oxygen. [up to 48 hours post dose 10]
Duration and maximum level of O2 provided will be assessed.
Secondary Outcome Measures
- To characterise the pharmacokinetics (PK) of single (Part A) and multiple (Part B) oral doses of RV521 in infants hospitalised with RSV LRTI by assessing time to maximum plasma concentration (tmax). [48 hours post dose 1 (Part A)]
Pharmacokinetic analysis will include listings and summaries of PK concentrations by time point, derived PK, parameters and analysis of relationship with dose and body weight.
- To characterise the pharmacokinetics (PK) of single (Part A) and multiple (Part B) oral doses of RV521 in infants hospitalised with RSV LRTI by assessing maximum observed plasma concentration (Cmax). [48 hours post dose 1 (Part A)]
Pharmacokinetic analysis will include listings and summaries of PK concentrations by time point, derived PK, parameters and analysis of relationship with dose and body weight.
- To characterise the pharmacokinetics (PK) of single (Part A) and multiple (Part B) oral doses of RV521 in infants hospitalised with RSV LRTI by assessing area under the plasma concentration time curve from time zero to 12 hours (AUC0-12). [48 hours post dose 1 (Part A)]
Pharmacokinetic analysis will include listings and summaries of PK concentrations by time point, derived PK, parameters and analysis of relationship with dose and body weight.
- To characterise the PK of single (Part A) and multiple (Part B) oral doses of RV521 in infants hospitalised with RSV LRTI by assessing the area under the plasma concentration time curve from time zero to last measurable plasma concentration (AUC0 t). [48 hours post dose 1 (Part A)]
Pharmacokinetic analysis will include listings and summaries of PK concentrations by time point, derived PK, parameters and analysis of relationship with dose and body weight.
- To characterise the pharmacokinetics (PK) of single (Part A) and multiple (Part B) oral doses of RV521 in infants hospitalised with RSV LRTI by assessing terminal half-life (t1/2). [48 hours post dose 1 (Part A)]
Pharmacokinetic analysis will include listings and summaries of PK concentrations by time point, derived PK, parameters and analysis of relationship with dose and body weight.
- To characterise the pharmacokinetics (PK) of single (Part A) and multiple (Part B) oral doses of RV521 in infants hospitalised with RSV LRTI by assessing area under the plasma concentration time curve from time zero to infinity (AUC0-∞). [48 hours post dose 1 (Part A)]
Pharmacokinetic analysis will include listings and summaries of PK concentrations by time point, derived PK, parameters and analysis of relationship with dose and body weight.
- To characterise the pharmacokinetics (PK) of single (Part A) and multiple (Part B) oral doses of RV521 in infants hospitalised with RSV LRTI by assessing predicted plasma clearance. [48 hours post dose 1 (Part A)]
Pharmacokinetic analysis will include listings and summaries of PK concentrations by time point, derived PK, parameters and analysis of relationship with dose and body weight.
- To characterise the pharmacokinetics (PK) of single (Part A) and multiple (Part B) oral doses of RV521 in infants hospitalised with RSV LRTI by assessing apparent volume of distribution of the drug after extravascular administration (V/F). [48 hours post dose 1 (Part A)]
Pharmacokinetic analysis will include listings and summaries of PK concentrations by time point, derived PK, parameters and analysis of relationship with dose and body weight.
- To characterise the pharmacokinetics (PK) of single (Part A) and multiple (Part B) oral doses of RV521 in infants hospitalised with RSV LRTI by assessing trough concentration at the end of first dosing interval (C12) (data permitting). [48 hours post dose 1 (Part A)]
Pharmacokinetic analysis will include listings and summaries of PK concentrations by time point, derived PK, parameters and analysis of relationship with dose and body weight.
- To characterise the pharmacokinetics (PK) of multiple (Part B) oral doses of RV521 in infants hospitalised with RSV LRTI by assessing accumulation ratio, percent fluctuation. [48 hours post dose 10]
Pharmacokinetic analysis will include listings and summaries of PK concentrations by time point, derived PK, parameters and analysis of relationship with dose and body weight.
- To characterise the pharmacokinetics (PK) of multiple (Part B) oral doses of RV521 in infants hospitalised with RSV LRTI by assessing the area under the plasma concentration time curve from time zero to the end of last dosing interval (AUC0-tau). [48 hours post dose 10]
Pharmacokinetic analysis will include listings and summaries of PK concentrations by time point, derived PK, parameters and analysis of relationship with dose and body weight.
- To characterise the pharmacokinetics (PK) of multiple (Part B) oral doses of RV521 in infants hospitalised with RSV LRTI by assessing average plasma concentration over dosing interval (Cave). [48 hours post dose 10]
Pharmacokinetic analysis will include listings and summaries of PK concentrations by time point, derived PK, parameters and analysis of relationship with dose and body weight.
- To characterise the pharmacokinetics (PK) of multiple (Part B) oral doses of RV521 in infants hospitalised with RSV LRTI by assessing minimum observed plasma concentration (Cmin). [48 hours post dose 10]
Pharmacokinetic analysis will include listings and summaries of PK concentrations by time point, derived PK, parameters and analysis of relationship with dose and body weight.
- To characterise the pharmacokinetics (PK) of multiple (Part B) oral doses of RV521 in infants hospitalised with RSV LRTI by assessing plasma trough concentration (Ctrough). [48 hours post dose 10]
Pharmacokinetic analysis will include listings and summaries of PK concentrations by time point, derived PK, parameters and analysis of relationship with dose and body weight.
- Part B: To evaluate the antiviral effects of RV521 in infants hospitalised with RSV LRTI by RSV viral load measured in nasopharyngeal swabs by RT qPCR. [up to 48 hours post dose 10]
Pharmacodynamics analysis will include listing of results of viral load with summary statistics by dose level and time point.
- Part B: To evaluate the antiviral effects of RV521 in infants hospitalised with RSV LRTI by RSV viral load measured in nasopharyngeal swabs by CBIA. [up to 48 hours post dose 10]
Pharmacodynamics analysis will include listing of results of viral load with summary statistics by dose level and time point.
- Part B: Evaluate the effect of RV521 compared to placebo on the clinical course of RSV LRTI using the RSV Clinical Scoring System and the Adapted Version of ReSVinet Scale to assess time to resolution of symptoms. [48 hours post dose 10]
Overall Time to Resolution of RSV-related signs and symptoms will be calculated from the time of randomization to the time that they are no longer present (absent or severity =0), and will be summarized and analysed as for Time to Improvement.
- Part B: Evaluate the effect of RV521 compared to placebo on the clinical course of RSV LRTI using the RSV Clinical Scoring System and the Adapted Version of ReSVinet Scale to assess time to improvement evaluated by change in severity of symptoms. [48 hours post dose 10]
Time to improvement will be calculated for RSV-related signs and symptoms that are classified as moderate or severe during the course of the study and will be defined as the time from randomization until no longer present (absent or severity=0) or mild (scores ≤ 5).
- Part B: Evaluate the effect of RV521 compared to placebo on the clinical course of RSV LRTI using the RSV Clinical Scoring System and the Adapted Version of ReSVinet Scale to assess change in severity of symptoms. [48 hours post dose 10]
Change in severity of symptoms by RV521, compared to placebo, will be measured by a composite score over time.
Eligibility Criteria
Criteria
Inclusion Criteria:
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Male or female ≥ 1 month and ≤ 36 months of age
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Weight ≥ 3.5 kg
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Clinical diagnosis of LRTI
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A positive RSV diagnostic test
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Hospitalised because of RSV LRTI
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Symptoms of LRTI must be present for no more than 1 week (Part B) and no more than 5 days (Part C) before the Screening Visit
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Expected to remain in hospital for a minimum of 3 days
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The parent(s)/legal guardian(s) of the subject have provided written informed consent for the subject to participate and are able and willing to comply with the study protocol
Exclusion Criteria:
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Premature (gestational age less than 37 weeks) AND <1 year of post-natal age
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Known to have significant comorbidities that would limit the ability to administer study drug or evaluate the safety or clinical response to study drug.
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Any clinically significant ECG abnormalities.
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Known to be immunocompromised.
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High risk of having developing asthma.
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Suspected of having a clinically significant bacterial infection.
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History of renal failure.
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Clinical evidence of hepatic decompensation
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History of epilepsy or seizures, including febrile seizures
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Allergy to test medication or constituents
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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.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Reviral Site 3001 | Buenos Aires | Argentina | 8000 | |
| 2 | Reviral Site 3004 | Buenos Aires | Argentina | 8000 | |
| 3 | Reviral Site 3003 | Buenos Aires | Argentina | CP1425 | |
| 4 | Reviral Site 3005 | Ciudad Autonoma de Buenos Aires | Argentina | C1431FWO | |
| 5 | Reviral Site 3002 | San Miguel De Tucumán | Argentina | T4000 | |
| 6 | Reviral Site 3104 | Puerto Montt | Region De Los Lagos | Chile | 5480000 |
| 7 | Reviral Site 3106 | Los Ángeles | Chile | 4440000 | |
| 8 | Reviral Site 3101 | Osorno | Chile | 5311523 | |
| 9 | Reviral Site 3103 | Santiago | Chile | 8330024 | |
| 10 | Reviral Site 3102 | Santiago | Chile | ||
| 11 | Reviral site 3302 | Escazú | San Jose | Costa Rica | 10203 |
| 12 | Reviral Site 3301 | San José | Costa Rica | 10108 | |
| 13 | Reviral Site 3303 | San José | Costa Rica | ||
| 14 | Reviral Site 3304 | San José | Costa Rica | ||
| 15 | Reviral Site 1002 | Szeged | Csongrad | Hungary | 6720 |
| 16 | Reviral Site 1003 | Budapest | Hungary | 1094 | |
| 17 | Reviral Site 1001 | Budapest | Hungary | 1125 | |
| 18 | Reviral Site 2001 | Kota Bharu | Kelantan | Malaysia | 15586 |
| 19 | Reviral Site 2004 | Ipoh | Perak | Malaysia | 30450 |
| 20 | Reviral Site 2002 | Seberang Jaya | Pulau Pinang | Malaysia | 13700 |
| 21 | Reviral Site 2003 | Kuala Terengganu | Terengganu | Malaysia | 20400 |
| 22 | Reviral Site 2102 | Wellington | New Zealand | 6021 | |
| 23 | Reviral Site 3203 | Chiriquí | San Pablo Viejo | Panama | |
| 24 | Reviral Site 3201 | Panama City | Panama | ||
| 25 | Reviral Site 3202 | Panama City | Panama | ||
| 26 | Reviral Site 2202 | Manila | National Capital Region | Philippines | 1000 |
| 27 | Reviral Site 2204 | Manila | National Capital Region | Philippines | 1000 |
| 28 | Reviral Site 2201 | Quezon City | National Capital Region | Philippines | 1101 |
| 29 | Reviral Site 2205 | Quezon City | National Capital Region | Philippines | 1101 |
| 30 | Reviral Site 1204 | Rzeszów | Podkarpackie | Poland | 35-210 |
| 31 | Reviral Site 1205 | Łódź | Woj. Lodzkie | Poland | 93-338 |
| 32 | Reviral Site 1201 | Warsaw | Woj. Mazowieckie | Poland | 02-091 |
| 33 | Reviral Site 1206 | Poznań | Woj. Wielkopolskie | Poland | 60-693 |
| 34 | Reviral Site 1203 | Kraków | Woj.Malopolskie | Poland | 30663 |
| 35 | Reviral site 1305 | Barcelona | Spain | 8950 | |
| 36 | Reviral site 1308 | Madrid | Spain | 28041 | |
| 37 | Reviral site 1301 | Madrid | Spain | 28046 | |
| 38 | Reviral site 1306 | Santiago De Compostela | Spain | 15706 | |
| 39 | Reviral Site 2302 | Hualien City | Taiwan | 97002 | |
| 40 | Reviral Site 2303 | Kaohsiung City | Taiwan | 81362 | |
| 41 | Reviral Site 2304 | Tainan City | Taiwan | 710 | |
| 42 | Reviral Site 2405 | Bangkok | Thailand | 10330 | |
| 43 | Reviral Site 2401 | Bangkok | Thailand | 10700 | |
| 44 | Reviral Site 2403 | Chiang Mai | Thailand | 50200 | |
| 45 | Reviral Site 2402 | Khon Kaen | Thailand | 40002 | |
| 46 | Reviral Site 2404 | Phitsanulok | Thailand | 65000 |
Sponsors and Collaborators
- ReViral Ltd
Investigators
- Study Director: Brett Haumann, MD, ReViral Ltd
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- REVC003