Clinical Trial Results:
A Phase 2 OpenLabel Study in Infants with Respiratory Syncytial Virus Lower Respiratory Tract Infection, Followed by a Doubleblind, Placebo Controlled Part, to Evaluate the Safety, Tolerability, Pharmacokinetics and Antiviral Effect of RV521 (REVIRAL 1)
Summary


EudraCT number 
201800101015 
Trial protocol 
HU PL BE 
Global end of trial date 
05 Dec 2022

Results information


Results version number 
v1(current) 
This version publication date 
21 Jun 2023

First version publication date 
21 Jun 2023

Other versions 
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information


Trial identification


Sponsor protocol code 
C5241003


Additional study identifiers


ISRCTN number 
  
US NCT number 
NCT04225897  
WHO universal trial number (UTN) 
  
Other trial identifiers 
REVC003: Study ID  
Sponsors


Sponsor organisation name 
Pfizer Inc.


Sponsor organisation address 
235 E 42nd Street, New York, United States, NY 10017


Public contact 
Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., 001 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com


Scientific contact 
Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., 001 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com


Paediatric regulatory details


Is trial part of an agreed paediatric investigation plan (PIP) 
No


Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? 
No


Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? 
Yes


Results analysis stage


Analysis stage 
Final


Date of interim/final analysis 
27 Jan 2023


Is this the analysis of the primary completion data? 
No


Global end of trial reached? 
Yes


Global end of trial date 
05 Dec 2022


Was the trial ended prematurely? 
Yes


General information about the trial


Main objective of the trial 
Part A and Part B: 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).


Protection of trial subjects 
The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Council for Harmonisation (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.


Background therapy 
  
Evidence for comparator 
  
Actual start date of recruitment 
13 Nov 2019


Long term followup planned 
No


Independent data monitoring committee (IDMC) involvement? 
Yes


Population of trial subjects


Number of subjects enrolled per country 

Country: Number of subjects enrolled 
Hungary: 4


Country: Number of subjects enrolled 
Malaysia: 7


Country: Number of subjects enrolled 
Taiwan: 1


Country: Number of subjects enrolled 
Thailand: 9


Country: Number of subjects enrolled 
Panama: 3


Country: Number of subjects enrolled 
Spain: 27


Worldwide total number of subjects 
51


EEA total number of subjects 
31


Number of subjects enrolled per age group 

In utero 
0


Preterm newborn  gestational age < 37 wk 
0


Newborns (027 days) 
0


Infants and toddlers (28 days23 months) 
43


Children (211 years) 
8


Adolescents (1217 years) 
0


Adults (1864 years) 
0


From 65 to 84 years 
0


85 years and over 
0



Recruitment


Recruitment details 
  
Preassignment


Screening details 
This study was planned to be conducted in 3 parts: Part A, B and optional part C. Part C was not conducted as part of a reassessment of the clinical development plan for RV521 (sisunatovir); hence, data is not reported for Part C in any section of the results. A total of 51 subjects were enrolled in the study (Part A=19 and Part B=32).  
Period 1


Period 1 title 
Part A (Screening Visit to Day 7)


Is this the baseline period? 
Yes  
Allocation method 
Not applicable


Blinding used 
Not blinded  
Arms


Are arms mutually exclusive 
Yes


Arm title

Cohort 1: RV521 1.0 mg/kg  
Arm description 
Infants aged >=6 months to <=36 months hospitalised with RSV LRTI received a single dose of 1.0 milligram per kilogram (mg/kg) of RV521 orally on Day 1.  
Arm type 
Experimental  
Investigational medicinal product name 
RV521


Investigational medicinal product code 

Other name 
Sisunatovir


Pharmaceutical forms 
Capsule


Routes of administration 
Oral use


Dosage and administration details 
Subjects were administered RV521 1.0 mg/kg dispersed in a defined volume of permitted suspending diluent via the oral route on Day 1.


Arm title

Cohort 1: RV521 2.0 mg/kg  
Arm description 
Infants aged >=6 months to <=36 months hospitalised with RSV LRTI received a single dose of 2.0 mg/kg of RV521 orally on Day 1.  
Arm type 
Experimental  
Investigational medicinal product name 
RV521


Investigational medicinal product code 

Other name 
Sisunatovir


Pharmaceutical forms 
Capsule


Routes of administration 
Oral use


Dosage and administration details 
Subjects were administered RV521 2.0 mg/kg dispersed in a defined volume of permitted suspending diluent via the oral route on Day 1.


Arm title

Cohort 1: RV521 2.5 mg/kg  
Arm description 
Infants aged >=6 months to <=36 months hospitalised with RSV LRTI received a single dose of 2.5 mg/kg of RV521 orally on Day 1.  
Arm type 
Experimental  
Investigational medicinal product name 
RV521


Investigational medicinal product code 

Other name 
Sisunatovir


Pharmaceutical forms 
Capsule


Routes of administration 
Oral use


Dosage and administration details 
Subjects were administered RV521 2.5 mg/kg dispersed in a defined volume of permitted suspending diluent via the oral route on Day 1.


Arm title

Cohort 2: RV521 2.0 mg/kg  
Arm description 
Infants aged >=1 month to <6 months hospitalised with RSV LRTI received a single dose of 2 mg/kg of RV521 orally on Day 1.  
Arm type 
Experimental  
Investigational medicinal product name 
RV521


Investigational medicinal product code 

Other name 
Sisunatovir


Pharmaceutical forms 
Capsule


Routes of administration 
Oral use


Dosage and administration details 
Subjects were administered RV521 2.0 mg/kg dispersed in a defined volume of permitted suspending diluent via the oral route on Day 1.




Notes [1]  The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same. Justification: Total 51 subjects were enrolled (Part A=19 and Part B=32). 

Period 2


Period 2 title 
Part B (Screening Visit to Day 12)


Is this the baseline period? 
No  
Allocation method 
Randomised  controlled


Blinding used 
Double blind  
Roles blinded 
Investigator, Subject  
Arms


Are arms mutually exclusive 
No


Arm title

Cohort 3: Placebo  
Arm description 
Infants aged >=6 months to <=36 months hospitalised with RSV LRTI received placebo every 12 hours twice daily (BID) orally for 5 days.  
Arm type 
Placebo  
Investigational medicinal product name 
Placebo


Investigational medicinal product code 

Other name 

Pharmaceutical forms 
Capsule


Routes of administration 
Oral use


Dosage and administration details 
Subjects were administered placebo dispersed in a defined volume of permitted suspending diluent via the oral route. Subjects received BID of placebo separated by 12 hours orally for 5 days.


Arm title

Cohort 3: RSV1 2.5 mg/kg  
Arm description 
Infants aged >=6 months to <=36 months hospitalised with RSV LRTI received RV521 2.5 mg/kg every 12 hours (BID) orally for 5 days.  
Arm type 
Experimental  
Investigational medicinal product name 
RV521


Investigational medicinal product code 

Other name 
Sisunatovir


Pharmaceutical forms 
Capsule


Routes of administration 
Oral use


Dosage and administration details 
Subjects were administered RV521 2.5 mg/kg dispersed in a defined volume of permitted suspending diluent via the oral route. Subjects received BID of RV521 separated by 12 hours orally for 5 days.


Arm title

Cohort 3: RV521 3.5 mg/kg  
Arm description 
Infants aged >=6 months to <=36 months hospitalised with RSV LRTI received RV521 3.5 mg/kg every 12 hours (BID) orally for 5 days.  
Arm type 
Experimental  
Investigational medicinal product name 
RV521


Investigational medicinal product code 

Other name 
Sisunatovir


Pharmaceutical forms 
Capsule


Routes of administration 
Oral use


Dosage and administration details 
Subjects were administered RV521 3.5 mg/kg dispersed in a defined volume of permitted suspending diluent via the oral route. Subjects received BID of RV521 separated by 12 hours orally for 5 days.


Arm title

Cohort 3: RV521 5 mg/kg  
Arm description 
Infants aged >=6 months to <=36 months hospitalised with RSV LRTI received RV521 5 mg/kg every 12 hours (BID) orally for 5 days.  
Arm type 
Experimental  
Investigational medicinal product name 
RV521


Investigational medicinal product code 

Other name 
Sisunatovir


Pharmaceutical forms 
Capsule


Routes of administration 
Oral use


Dosage and administration details 
Subjects were administered RV521 5 mg/kg dispersed in a defined volume of permitted suspending diluent via the oral route. Subjects received BID of RV521 separated by 12 hours orally for 5 days.


Arm title

Cohort 4: Placebo  
Arm description 
Infants aged >=1 month to <6 months hospitalised with RSV LRTI received placebo every 12 hours (BID) orally for 5 days.  
Arm type 
Placebo  
Investigational medicinal product name 
Placebo


Investigational medicinal product code 

Other name 

Pharmaceutical forms 
Capsule


Routes of administration 
Oral use


Dosage and administration details 
Subjects were administered placebo dispersed in a defined volume of permitted suspending diluent via the oral route. Subjects received BID of placebo separated by 12 hours orally for 5 days.


Arm title

Cohort 4: RV521 2.5 mg/kg  
Arm description 
Infants aged >=1 month to <6 months hospitalised with RSV LRTI received RV521 2.5 mg/kg every 12 hours (BID) orally for 5 days.  
Arm type 
Experimental  
Investigational medicinal product name 
RV521


Investigational medicinal product code 

Other name 
Sisunatovir


Pharmaceutical forms 
Capsule


Routes of administration 
Oral use


Dosage and administration details 
Subjects were administered RV521 2.5 mg/kg dispersed in a defined volume of permitted suspending diluent via the oral route. Subjects received BID of RV521 separated by 12 hours orally for 5 days.


Arm title

Cohort 5: Placebo  
Arm description 
Infants aged >=1 month to <6 months hospitalised with RSV LRTI received placebo every 12 hours (BID) orally for 5 days.  
Arm type 
Placebo  
Investigational medicinal product name 
Placebo


Investigational medicinal product code 

Other name 

Pharmaceutical forms 
Capsule


Routes of administration 
Oral use


Dosage and administration details 
Subjects were administered placebo dispersed in a defined volume of permitted suspending diluent via the oral route. Subjects received BID of placebo separated by 12 hours orally for 5 days.


Arm title

Cohort 5: RV521 2.5 mg/kg  
Arm description 
Infants aged >=1 month to <6 months hospitalised with RSV LRTI received RV521 2.5 mg/kg every 12 hours (BID) orally for 5 days.  
Arm type 
Experimental  
Investigational medicinal product name 
RV521


Investigational medicinal product code 

Other name 
Sisunatovir


Pharmaceutical forms 
Capsule


Routes of administration 
Oral use


Dosage and administration details 
Subjects were administered RV521 2.5 mg/kg dispersed in a defined volume of permitted suspending diluent via the oral route. Subjects received BID of RV521 separated by 12 hours orally for 5 days.





Baseline characteristics reporting groups


Reporting group title 
Cohort 1: RV521 1.0 mg/kg


Reporting group description 
Infants aged >=6 months to <=36 months hospitalised with RSV LRTI received a single dose of 1.0 milligram per kilogram (mg/kg) of RV521 orally on Day 1.  
Reporting group title 
Cohort 1: RV521 2.0 mg/kg


Reporting group description 
Infants aged >=6 months to <=36 months hospitalised with RSV LRTI received a single dose of 2.0 mg/kg of RV521 orally on Day 1.  
Reporting group title 
Cohort 1: RV521 2.5 mg/kg


Reporting group description 
Infants aged >=6 months to <=36 months hospitalised with RSV LRTI received a single dose of 2.5 mg/kg of RV521 orally on Day 1.  
Reporting group title 
Cohort 2: RV521 2.0 mg/kg


Reporting group description 
Infants aged >=1 month to <6 months hospitalised with RSV LRTI received a single dose of 2 mg/kg of RV521 orally on Day 1.  


Subject analysis sets


Subject analysis set title 
Cohort 3: Placebo


Subject analysis set type 
Safety analysis  
Subject analysis set description 
Infants aged >=6 months to <=36 months hospitalised with RSV LRTI received placebo every 12 hours (BID) orally for 5 days.


Subject analysis set title 
Cohort 3: RSV1 2.5 mg/kg


Subject analysis set type 
Safety analysis  
Subject analysis set description 
Infants aged >=6 months to <=36 months hospitalised with RSV LRTI received RV521 2.5 mg/kg every 12 hours (BID) orally for 5 days.


Subject analysis set title 
Cohort 3: RV521 3.5 mg/kg


Subject analysis set type 
Safety analysis  
Subject analysis set description 
Infants aged >=6 months to <=36 months hospitalised with RSV LRTI received RV521 3.5 mg/kg every 12 hours (BID) orally for 5 days.


Subject analysis set title 
Cohort 3: RV521 5 mg/kg


Subject analysis set type 
Safety analysis  
Subject analysis set description 
Infants aged >=6 months to <=36 months hospitalised with RSV LRTI received RV521 5 mg/kg every 12 hours (BID) orally for 5 days.


Subject analysis set title 
Cohort 4: Placebo


Subject analysis set type 
Safety analysis  
Subject analysis set description 
Infants aged >=1 month to <6 months hospitalised with RSV LRTI received placebo every 12 hours (BID) orally for 5 days.


Subject analysis set title 
Cohort 4: RV521 2.5 mg/kg


Subject analysis set type 
Safety analysis  
Subject analysis set description 
Infants aged >=1 month to <6 months hospitalised with RSV LRTI received RV521 2.5 mg/kg every 12 hours (BID) orally for 5 days.


Subject analysis set title 
Cohort 5: Placebo


Subject analysis set type 
Safety analysis  
Subject analysis set description 
Infants aged >=1 month to <6 months hospitalised with RSV LRTI received placebo every 12 hours (BID) orally for 5 days.


Subject analysis set title 
Cohort 5: RV521 2.5 mg/kg


Subject analysis set type 
Safety analysis  
Subject analysis set description 
Infants aged >=1 month to <6 months hospitalised with RSV LRTI received RV521 2.5 mg/kg every 12 hours (BID) orally for 5 days.


Subject analysis set title 
Cohort 4 and 5 combined: RV521 2.5 mg/kg


Subject analysis set type 
Subgroup analysis  
Subject analysis set description 
Infants aged >=1 month to <6 months hospitalised with RSV LRTI received BID of RV521 2.5 mg/kg separated by 12 hours orally for 5 days. Subjects from Cohort 4 and 5 were included.


Subject analysis set title 
Cohort 4 and 5 combined: Placebo


Subject analysis set type 
Subgroup analysis  
Subject analysis set description 
Infants aged >=1 month to <6 months hospitalised with RSV LRTI received BID of placebo separated by 12 hours orally for 5 days. Subjects from Cohorts 4 and 5 were included.





End points reporting groups


Reporting group title 
Cohort 1: RV521 1.0 mg/kg


Reporting group description 
Infants aged >=6 months to <=36 months hospitalised with RSV LRTI received a single dose of 1.0 milligram per kilogram (mg/kg) of RV521 orally on Day 1.  
Reporting group title 
Cohort 1: RV521 2.0 mg/kg


Reporting group description 
Infants aged >=6 months to <=36 months hospitalised with RSV LRTI received a single dose of 2.0 mg/kg of RV521 orally on Day 1.  
Reporting group title 
Cohort 1: RV521 2.5 mg/kg


Reporting group description 
Infants aged >=6 months to <=36 months hospitalised with RSV LRTI received a single dose of 2.5 mg/kg of RV521 orally on Day 1.  
Reporting group title 
Cohort 2: RV521 2.0 mg/kg


Reporting group description 
Infants aged >=1 month to <6 months hospitalised with RSV LRTI received a single dose of 2 mg/kg of RV521 orally on Day 1.  
Reporting group title 
Cohort 3: Placebo


Reporting group description 
Infants aged >=6 months to <=36 months hospitalised with RSV LRTI received placebo every 12 hours twice daily (BID) orally for 5 days.  
Reporting group title 
Cohort 3: RSV1 2.5 mg/kg


Reporting group description 
Infants aged >=6 months to <=36 months hospitalised with RSV LRTI received RV521 2.5 mg/kg every 12 hours (BID) orally for 5 days.  
Reporting group title 
Cohort 3: RV521 3.5 mg/kg


Reporting group description 
Infants aged >=6 months to <=36 months hospitalised with RSV LRTI received RV521 3.5 mg/kg every 12 hours (BID) orally for 5 days.  
Reporting group title 
Cohort 3: RV521 5 mg/kg


Reporting group description 
Infants aged >=6 months to <=36 months hospitalised with RSV LRTI received RV521 5 mg/kg every 12 hours (BID) orally for 5 days.  
Reporting group title 
Cohort 4: Placebo


Reporting group description 
Infants aged >=1 month to <6 months hospitalised with RSV LRTI received placebo every 12 hours (BID) orally for 5 days.  
Reporting group title 
Cohort 4: RV521 2.5 mg/kg


Reporting group description 
Infants aged >=1 month to <6 months hospitalised with RSV LRTI received RV521 2.5 mg/kg every 12 hours (BID) orally for 5 days.  
Reporting group title 
Cohort 5: Placebo


Reporting group description 
Infants aged >=1 month to <6 months hospitalised with RSV LRTI received placebo every 12 hours (BID) orally for 5 days.  
Reporting group title 
Cohort 5: RV521 2.5 mg/kg


Reporting group description 
Infants aged >=1 month to <6 months hospitalised with RSV LRTI received RV521 2.5 mg/kg every 12 hours (BID) orally for 5 days.  
Subject analysis set title 
Cohort 3: Placebo


Subject analysis set type 
Safety analysis  
Subject analysis set description 
Infants aged >=6 months to <=36 months hospitalised with RSV LRTI received placebo every 12 hours (BID) orally for 5 days.


Subject analysis set title 
Cohort 3: RSV1 2.5 mg/kg


Subject analysis set type 
Safety analysis  
Subject analysis set description 
Infants aged >=6 months to <=36 months hospitalised with RSV LRTI received RV521 2.5 mg/kg every 12 hours (BID) orally for 5 days.


Subject analysis set title 
Cohort 3: RV521 3.5 mg/kg


Subject analysis set type 
Safety analysis  
Subject analysis set description 
Infants aged >=6 months to <=36 months hospitalised with RSV LRTI received RV521 3.5 mg/kg every 12 hours (BID) orally for 5 days.


Subject analysis set title 
Cohort 3: RV521 5 mg/kg


Subject analysis set type 
Safety analysis  
Subject analysis set description 
Infants aged >=6 months to <=36 months hospitalised with RSV LRTI received RV521 5 mg/kg every 12 hours (BID) orally for 5 days.


Subject analysis set title 
Cohort 4: Placebo


Subject analysis set type 
Safety analysis  
Subject analysis set description 
Infants aged >=1 month to <6 months hospitalised with RSV LRTI received placebo every 12 hours (BID) orally for 5 days.


Subject analysis set title 
Cohort 4: RV521 2.5 mg/kg


Subject analysis set type 
Safety analysis  
Subject analysis set description 
Infants aged >=1 month to <6 months hospitalised with RSV LRTI received RV521 2.5 mg/kg every 12 hours (BID) orally for 5 days.


Subject analysis set title 
Cohort 5: Placebo


Subject analysis set type 
Safety analysis  
Subject analysis set description 
Infants aged >=1 month to <6 months hospitalised with RSV LRTI received placebo every 12 hours (BID) orally for 5 days.


Subject analysis set title 
Cohort 5: RV521 2.5 mg/kg


Subject analysis set type 
Safety analysis  
Subject analysis set description 
Infants aged >=1 month to <6 months hospitalised with RSV LRTI received RV521 2.5 mg/kg every 12 hours (BID) orally for 5 days.


Subject analysis set title 
Cohort 4 and 5 combined: RV521 2.5 mg/kg


Subject analysis set type 
Subgroup analysis  
Subject analysis set description 
Infants aged >=1 month to <6 months hospitalised with RSV LRTI received BID of RV521 2.5 mg/kg separated by 12 hours orally for 5 days. Subjects from Cohort 4 and 5 were included.


Subject analysis set title 
Cohort 4 and 5 combined: Placebo


Subject analysis set type 
Subgroup analysis  
Subject analysis set description 
Infants aged >=1 month to <6 months hospitalised with RSV LRTI received BID of placebo separated by 12 hours orally for 5 days. Subjects from Cohorts 4 and 5 were included.



End point title 
Part A: Number of Subjects With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs) and Withdrawals due to TEAEs ^{[1]}  
End point description 
An adverse event (AE) was defined as any untoward medical occurrence in a clinical study subject administered a medicinal product which did not necessarily have a causal relationship with the investigational medicinal product (IMP). TEAEs were defined as AEs which started, or worsened, after the first dose of IMP. An SAE was any untoward medical occurrence or effect that, at any dose, resulted in death; was life threatening; required or prolonged inpatient hospitalisation; resulted in persistent or significant disability/incapacity or other important medical event. Safety population included all subjects who received at least 1 dose of IMP.


End point type 
Primary


End point timeframe 
From start of IMP on Day 1 up to Day 7


Notes [1]  No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only descriptive analysis was planned. 



No statistical analyses for this end point 


End point title 
Part B: Number of Subjects With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs) and Withdrawals due to TEAEs ^{[2]}  
End point description 
An AE was defined as any untoward medical occurrence in a clinical study subject administered a medicinal product which did not necessarily have a causal relationship with the IMP. TEAEs were defined as AEs which started, or worsened, after the first dose of IMP. An SAE was any untoward medical occurrence or effect that, at any dose, resulted in death; was life threatening; required or prolonged inpatient hospitalisation; resulted in persistent or significant disability/incapacity or other important medical event. Safety population included all subjects who received at least 1 dose of IMP.


End point type 
Primary


End point timeframe 
From start of IMP on Day 1 up to Day 12


Notes [2]  No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: The endpoint is specific to Part B; hence, only arms for Part B are included. 



No statistical analyses for this end point 


End point title 
Part A: Number of Subjects With Abnormal Clinically Significant Physical Examination Results at Baseline ^{[3]}  
End point description 
Physical examination included general appearance; head, eyes, ears, nose and throat (HEENT); dermatologic; cardiovascular; respiratory; gastrointestinal; and neurological examination. Clinical significance of results were determined by the investigator. Safety population included all subjects who received at least 1 dose of IMP. Here, 'n' signifies number of subjects evaluable for the specified categories.


End point type 
Primary


End point timeframe 
Baseline (predose on Day 1)


Notes [3]  No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only descriptive analysis was planned. 



No statistical analyses for this end point 


End point title 
Part A: Number of Subjects With Abnormal Clinically Significant Physical Examination Results Anytime Between 18 to 24 Hours Postdose ^{[4]}  
End point description 
Physical examination included general appearance; HEENT; dermatologic; cardiovascular; respiratory; gastrointestinal; and neurological examination. Clinical significance of results were determined by the investigator. Safety population included all subjects who received at least 1 dose of IMP. Here, 'Number of Subjects Analysed' signifies number of subjects evaluable for this endpoint and 'n' signifies number of subjects evaluable for the specified categories.


End point type 
Primary


End point timeframe 
Anytime between 18 to 24 hours postdose on Day 1


Notes [4]  No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only descriptive analysis was planned. 



No statistical analyses for this end point 


End point title 
Part A: Number of Subjects With Abnormal Clinically Significant Physical Examination Results at 48 Hours Postdose ^{[5]}  
End point description 
Physical examination included general appearance; HEENT; dermatologic; cardiovascular; respiratory; gastrointestinal; and neurological examination. Clinical significance of results were determined by the investigator. Safety population included all subjects who received at least 1 dose of IMP. Here, 'Number of Subjects Analysed' signifies number of subjects evaluable for this endpoint and 'n' signifies number of subjects evaluable for the specified categories.


End point type 
Primary


End point timeframe 
At 48 hours postdose on Day 1


Notes [5]  No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only descriptive analysis was planned. 



No statistical analyses for this end point 


End point title 
Part B: Number of Subjects With Abnormal Clinically Significant Physical Examination Results at Baseline ^{[6]}  
End point description 
Physical examination included general appearance; dermatologic; cardiovascular; respiratory; gastrointestinal; and neurological examination. Clinical significance of results were determined by the investigator. Safety population included all subjects who received at least 1 dose of IMP. Here, 'Number of Subjects Analysed' signifies number of subjects evaluable for this endpoint and 'n' signifies number of subjects evaluable for the specified categories.


End point type 
Primary


End point timeframe 
Baseline (predose on Day 1)


Notes [6]  No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: The endpoint is specific to Part B; hence, only arms for Part B are included. 



No statistical analyses for this end point 


End point title 
Part B: Number of Subjects With Abnormal Clinically Significant Physical Examination Results Anytime Between 40 to 48 Hours Postdose 10 ^{[7]}  
End point description 
Physical examination included general appearance; HEENT; dermatologic; cardiovascular; respiratory; gastrointestinal; and neurological examination. Clinical significance of results were determined by the investigator. Safety population included all subjects who received at least 1 dose of IMP. Here, 'Number of Subjects Analysed' signifies number of subjects evaluable for this endpoint.


End point type 
Primary


End point timeframe 
Anytime between 40 to 48 hours postdose 10 on Day 5


Notes [7]  No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: The endpoint is specific to Part B; hence, only arms for Part B are included. 



Notes [8]  No subjects were evaluable 

No statistical analyses for this end point 


End point title 
Part A: Number of Subjects With Abnormal Clinically Significant Vital Signs per Investigator’s Interpretation at Baseline ^{[9]}  
End point description 
Vital signs included body temperature, systolic and diastolic blood pressure, respiratory rate, heart rate and pulse oximetry. Number of subjects with abnormal clinically significant vital signs per investigators interpretation are reported in this outcome measure. Safety population included all subjects who received at least 1 dose of IMP.


End point type 
Primary


End point timeframe 
Baseline (predose on Day 1)


Notes [9]  No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only descriptive analysis was planned. 



No statistical analyses for this end point 


End point title 
Part A: Number of Subjects With Abnormal Clinically Significant Vital Signs per Investigator’s Interpretation Anytime Between 4 to 5 Hours PostDose ^{[10]}  
End point description 
Vital signs included body temperature, systolic and diastolic blood pressure, respiratory rate, heart rate and pulse oximetry. Number of subjects with abnormal clinically significant vital signs per investigators interpretation are reported in this outcome measure. Safety population included all subjects who received at least 1 dose of IMP.


End point type 
Primary


End point timeframe 
Anytime between 4 to 5 hours postdose on Day 1


Notes [10]  No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only descriptive analysis was planned. 



No statistical analyses for this end point 


End point title 
Part A: Number of Subjects With Abnormal Clinically Significant Vital Signs per Investigator’s Interpretation at 12 Hours PostDose ^{[11]}  
End point description 
Vital signs included body temperature, systolic and diastolic blood pressure, respiratory rate, heart rate and pulse oximetry. Number of subjects with abnormal clinically significant vital signs per investigators interpretation are reported in this outcome measure. Safety population included all subjects who received at least 1 dose of IMP. Here, 'Number of Subjects Analysed' signifies number of subjects evaluable for this endpoint.


End point type 
Primary


End point timeframe 
12 hours postdose on Day 1


Notes [11]  No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only descriptive analysis was planned. 



No statistical analyses for this end point 


End point title 
Part A: Number of Subjects With Abnormal Clinically Significant Vital Signs per Investigator’s Interpretation Anytime Between 18 to 24 Hours PostDose ^{[12]}  
End point description 
Vital signs included body temperature, systolic and diastolic blood pressure, respiratory rate, heart rate and pulse oximetry. Number of subjects with abnormal clinically significant vital signs per investigators interpretation are reported in this outcome measure. Safety population included all subjects who received at least 1 dose of IMP. Here, 'Number of Subjects Analysed' signifies number of subjects evaluable for this endpoint.


End point type 
Primary


End point timeframe 
Anytime between 18 to 24 hours postdose on Day 1


Notes [12]  No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only descriptive analysis was planned. 



No statistical analyses for this end point 


End point title 
Part A: Number of Subjects With Abnormal Clinically Significant Vital Signs per Investigator’s Interpretation at 48 Hours PostDose ^{[13]}  
End point description 
Vital signs included body temperature, systolic and diastolic blood pressure, respiratory rate, heart rate and pulse oximetry. Number of subjects with abnormal clinically significant vital signs per investigators interpretation are reported in this outcome measure. Safety population included all subjects who received at least 1 dose of IMP. Here, 'Number of Subjects Analysed' signifies number of subjects evaluable for this endpoint.


End point type 
Primary


End point timeframe 
48 hours postdose on Day 1


Notes [13]  No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only descriptive analysis was planned. 



No statistical analyses for this end point 


End point title 
Part B: Number of Subjects With Abnormal Vital Signs per Investigator’s Interpretation at Baseline ^{[14]}  
End point description 
Vital signs included body temperature, systolic and diastolic blood pressure, respiratory rate, heart rate and pulse oximetry. Number of subjects with abnormal clinically significant vital signs per investigators interpretation are reported in this outcome measure. Safety population included all subjects who received at least 1 dose of IMP.


End point type 
Primary


End point timeframe 
Baseline (predose on Day 1)


Notes [14]  No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: The endpoint is specific to Part B; hence, only arms for Part B are included. 



No statistical analyses for this end point 


End point title 
Part B: Number of Subjects With Abnormal Clinically Significant Vital Signs per Investigator’s Interpretation Anytime Between 4 to 5 Hours PostDose 1 ^{[15]}  
End point description 
Vital signs included body temperature, systolic and diastolic blood pressure, respiratory rate, heart rate and pulse oximetry. Number of subjects with abnormal clinically significant vital signs per investigators interpretation are reported in this outcome measure. Safety population included all subjects who received at least 1 dose of IMP.


End point type 
Primary


End point timeframe 
Anytime between 4 to 5 hours postdose 1 (Day 1)


Notes [15]  No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: The endpoint is specific to Part B; hence, only arms for Part B are included. 



No statistical analyses for this end point 


End point title 
Part B: Number of Subjects With Abnormal Clinically Significant Vital Signs per Investigator’s Interpretation At Predose 2 ^{[16]}  
End point description 
Vital signs included body temperature, systolic and diastolic blood pressure, respiratory rate, heart rate and pulse oximetry. Number of subjects with abnormal clinically significant vital signs per investigators interpretation are reported in this outcome measure. Safety population included all subjects who received at least 1 dose of IMP. Here, 'Number of Subjects Analysed' signifies number of subjects evaluable for this endpoint.


End point type 
Primary


End point timeframe 
Predose 2 (Day 1)


Notes [16]  No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: The endpoint is specific to Part B; hence, only arms for Part B are included. 



No statistical analyses for this end point 


End point title 
Part B: Number of Subjects With Abnormal Clinically Significant Vital Signs per Investigator’s Interpretation at Predose 3 ^{[17]}  
End point description 
Vital signs included body temperature, systolic and diastolic blood pressure, respiratory rate, heart rate and pulse oximetry. Number of subjects with abnormal clinically significant vital signs per investigators interpretation are reported in this outcome measure. Safety population included all subjects who received at least 1 dose of IMP. Here, 'Number of Subjects Analysed' signifies number of subjects evaluable for this endpoint.


End point type 
Primary


End point timeframe 
Predose 3 (Day 2)


Notes [17]  No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: The endpoint is specific to Part B; hence, only arms for Part B are included. 



No statistical analyses for this end point 


End point title 
Part B: Number of Subjects With Abnormal Clinically Significant Vital Signs per Investigator’s Interpretation at Predose 4 ^{[18]}  
End point description 
Vital signs included body temperature, systolic and diastolic blood pressure, respiratory rate, heart rate and pulse oximetry. Number of subjects with abnormal clinically significant vital signs per investigators interpretation are reported in this outcome measure. Safety population included all subjects who received at least 1 dose of IMP. Here, 'Number of Subjects Analysed' signifies number of subjects evaluable for this endpoint.


End point type 
Primary


End point timeframe 
Predose 4 (Day 2)


Notes [18]  No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: The endpoint is specific to Part B; hence, only arms for Part B are included. 



No statistical analyses for this end point 


End point title 
Part B: Number of Subjects With Abnormal Clinically Significant Vital Signs per Investigator’s Interpretation at Predose 5 ^{[19]}  
End point description 
Vital signs included body temperature, systolic and diastolic blood pressure, respiratory rate, heart rate and pulse oximetry. Number of subjects with abnormal clinically significant vital signs per investigators interpretation are reported in this outcome measure. Safety population included all subjects who received at least 1 dose of IMP. Here, 'Number of Subjects Analysed' signifies number of subjects evaluable for this endpoint.


End point type 
Primary


End point timeframe 
Predose 5 (Day 3)


Notes [19]  No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: The endpoint is specific to Part B; hence, only arms for Part B are included. 



No statistical analyses for this end point 


End point title 
Part B: Number of Subjects With Abnormal Clinically Significant Vital Signs per Investigator’s Interpretation at Predose 6 ^{[20]}  
End point description 
Vital signs included body temperature, systolic and diastolic blood pressure, respiratory rate, heart rate and pulse oximetry. Number of subjects with abnormal clinically significant vital signs per investigators interpretation are reported in this outcome measure. Safety population included all subjects who received at least 1 dose of IMP. Here, 'Number of Subjects Analysed' signifies number of subjects evaluable for this endpoint.


End point type 
Primary


End point timeframe 
Predose 6 (Day 3)


Notes [20]  No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: The endpoint is specific to Part B; hence, only arms for Part B are included. 



No statistical analyses for this end point 


End point title 
Part B: Number of Subjects With Abnormal Clinically Significant Vital Signs per Investigator’s Interpretation Anytime Between 4 to 5 Hours PostDose 6 ^{[21]}  
End point description 
Vital signs included body temperature, systolic and diastolic blood pressure, respiratory rate, heart rate and pulse oximetry. Number of subjects with abnormal clinically significant vital signs per investigators interpretation are reported in this outcome measure. Safety population included all subjects who received at least 1 dose of IMP. Here, 'Number of Subjects Analysed' signifies number of subjects evaluable for this endpoint.


End point type 
Primary


End point timeframe 
Anytime between 4 to 5 hours postdose 6 (Day 3)


Notes [21]  No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: The endpoint is specific to Part B; hence, only arms for Part B are included. 



No statistical analyses for this end point 


End point title 
Part B: Number of Subjects With Abnormal Clinically Significant Vital Signs per Investigator’s Interpretation at Predose 7 ^{[22]}  
End point description 
Vital signs included body temperature, systolic and diastolic blood pressure, respiratory rate, heart rate and pulse oximetry. Number of subjects with abnormal clinically significant vital signs per investigators interpretation are reported in this outcome measure. Safety population included all subjects who received at least 1 dose of IMP. Here, 'Number of Subjects Analysed' signifies number of subjects evaluable for this endpoint.


End point type 
Primary


End point timeframe 
Predose 7 (Day 4)


Notes [22]  No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: The endpoint is specific to Part B; hence, only arms for Part B are included. 



No statistical analyses for this end point 


End point title 
Part B: Number of Subjects With Abnormal Clinically Significant Vital Signs per Investigator’s Interpretation at Predose 8 ^{[23]}  
End point description 
Vital signs included body temperature, systolic and diastolic blood pressure, respiratory rate, heart rate and pulse oximetry. Number of subjects with abnormal clinically significant vital signs per investigators interpretation are reported in this outcome measure. Safety population included all subjects who received at least 1 dose of IMP. Here, 'Number of Subjects Analysed' signifies number of subjects evaluable for this endpoint.


End point type 
Primary


End point timeframe 
Predose 8 (Day 4)


Notes [23]  No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: The endpoint is specific to Part B; hence, only arms for Part B are included. 



No statistical analyses for this end point 


End point title 
Part B: Number of Subjects With Abnormal Clinically Significant Vital Signs per Investigator’s Interpretation at Predose 9 ^{[24]}  
End point description 
Vital signs included body temperature, systolic and diastolic blood pressure, respiratory rate, heart rate and pulse oximetry. Number of subjects with abnormal clinically significant vital signs per investigators interpretation are reported in this outcome measure. Safety population included all subjects who received at least 1 dose of IMP. Here, 'Number of Subjects Analysed' signifies number of subjects evaluable for this endpoint.


End point type 
Primary


End point timeframe 
Predose 9 (Day 5)


Notes [24]  No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: The endpoint is specific to Part B; hence, only arms for Part B are included. 



No statistical analyses for this end point 


End point title 
Part B: Number of Subjects With Abnormal Clinically Significant Vital Signs per Investigator’s Interpretation at Predose 10 ^{[25]}  
End point description 
Vital signs included body temperature, systolic and diastolic blood pressure, respiratory rate, heart rate and pulse oximetry. Number of subjects with abnormal clinically significant vital signs per investigators interpretation are reported in this outcome measure. Safety population included all subjects who received at least 1 dose of IMP. Here, 'Number of Subjects Analysed' signifies number of subjects evaluable for this endpoint.


End point type 
Primary


End point timeframe 
Predose 10 (Day 5)


Notes [25]  No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: The endpoint is specific to Part B; hence, only arms for Part B are included. 



No statistical analyses for this end point 


End point title 
Part B: Number of Subjects With Abnormal Clinically Significant Vital Signs per Investigator’s Interpretation Anytime Between 40 to 48 Hours PostDose 10 ^{[26]}  
End point description 
Vital signs included body temperature, systolic and diastolic blood pressure, respiratory rate, heart rate and pulse oximetry. Number of subjects with abnormal clinically significant vital signs per investigators interpretation are reported in this outcome measure. Safety population included all subjects who received at least 1 dose of IMP. Here, 'Number of Subjects Analysed' signifies number of subjects evaluable for this endpoint.


End point type 
Primary


End point timeframe 
Anytime between 40 to 48 hours postdose 10 on Day 5


Notes [26]  No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: The endpoint is specific to Part B; hence, only arms for Part B are included. 



Notes [27]  No subjects were evaluable 

No statistical analyses for this end point 


End point title 
Part A: Number of Subjects With Abnormal Hematology Results at Baseline ^{[28]}  
End point description 
Haematology parameters included basophils, eosinophils, lymphocytes, monocytes, neutrophils, haemoglobin (Hb), haematocrit (HCT), white blood cell count (WBC), red blood cell count (RBC), platelet count, mean cell volume (MCV), mean cell haemoglobin (MCH), and MCH concentration (MCHC). Institutional laboratory normal ranges were used. Safety population included all subjects who received at least 1 dose of IMP. Here, 'Number of Subjects Analysed' signifies number of subjects evaluable for this endpoint and 'n' signifies number of subjects evaluable for the specified categories.


End point type 
Primary


End point timeframe 
Baseline (predose on Day 1)


Notes [28]  No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only descriptive analysis was planned. 



No statistical analyses for this end point 


End point title 
Part A: Number of Subjects With Abnormal Hematology Results at 48 Hours PostDose ^{[29]}  
End point description 
Haematology parameters included basophils, eosinophils, lymphocytes, monocytes, neutrophils, Hb, HCT, WBC, RBC, platelet count, MCV, MCH and MCHC. Institutional laboratory normal ranges were used. Safety population included all subjects who received at least 1 dose of IMP. Here, 'Number of Subjects Analysed' signifies number of subjects evaluable for this endpoint and 'n' signifies number of subjects evaluable for the specified categories.


End point type 
Primary


End point timeframe 
48 hours postdose on Day 1


Notes [29]  No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only descriptive analysis was planned. 



No statistical analyses for this end point 


End point title 
Part B: Number of Subjects With Abnormal Hematology Results at Baseline ^{[30]}  
End point description 
Haematology parameters included basophils, eosinophils, lymphocytes, monocytes, neutrophils, Hb, HCT, WBC, RBC, platelet count, MCV, MCH and MCHC. Institutional laboratory normal ranges were used. Safety population included all subjects who received at least 1 dose of IMP. Here, 'Number of Subjects Analysed' signifies number of subjects evaluable for this endpoint and 'n' signifies number of subjects evaluable for the specified categories.


End point type 
Primary


End point timeframe 
Baseline (predose on Day 1)


Notes [30]  No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: The endpoint is specific to Part B; hence, only arms for Part B are included. 



Notes [31]  No subjects were evaluable 

No statistical analyses for this end point 


End point title 
Part B: Number of Subjects With Abnormal Hematology Results Anytime Between 40 to 48 Hours Postdose 10 ^{[32]}  
End point description 
Haematology parameters included basophils, eosinophils, lymphocytes, monocytes, neutrophils, Hb, HCT, WBC, RBC, platelet count, MCV, MCH and MCHC. Institutional laboratory normal ranges were used. Safety population included all subjects who received at least 1 dose of IMP. Here, 'Number of Subjects Analysed' signifies number of subjects evaluable for this endpoint and 'n' signifies number of subjects evaluable for the specified categories.


End point type 
Primary


End point timeframe 
Anytime between 40 to 48 hours postdose 10 on Day 5


Notes [32]  No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: The endpoint is specific to Part B; hence, only arms for Part B are included. 



Notes [33]  No subjects were evaluable 

No statistical analyses for this end point 


End point title 
Part A: Number of Subjects With Abnormal Clinical Chemistry Results at Baseline ^{[34]}  
End point description 
Clinical chemistry parameters included creatinine, urea (or blood urea nitrogen), aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma glutamyltransferase (GGT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), total bilirubin, albumin, total protein, sodium, potassium, chloride, glucose, and calcium. Institutional laboratory normal ranges were used. Safety population included all subjects who received at least 1 dose of IMP. Here, 'n' signifies number of subjects evaluable for the specified categories.


End point type 
Primary


End point timeframe 
Baseline (predose on Day 1)


Notes [34]  No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only descriptive analysis was planned. 



No statistical analyses for this end point 


End point title 
Part A: Number of Subjects With Abnormal Clinical Chemistry Results at 48 Hours PostDose ^{[35]}  
End point description 
Clinical chemistry parameters included creatinine, urea, AST, ALT, GGT, ALP, LDH, total bilirubin, albumin, total protein, sodium, potassium, chloride, glucose, and calcium. Institutional laboratory normal ranges were used. Safety population included all subjects who received at least 1 dose of IMP. Here, 'n' signifies number of subjects evaluable for the specified categories.


End point type 
Primary


End point timeframe 
48 hours postdose on Day 1


Notes [35]  No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only descriptive analysis was planned. 



No statistical analyses for this end point 


End point title 
Part B: Number of Subjects With Abnormal Clinical Chemistry Results at Baseline ^{[36]}  
End point description 
Clinical chemistry parameters included creatinine, urea, AST, ALT, GGT, ALP, LDH, total bilirubin, albumin, total protein, sodium, potassium, chloride, glucose, and calcium. Institutional laboratory normal ranges were used. Safety population included all subjects who received at least 1 dose of IMP. Here, 'n' signifies number of subjects evaluable for the specified categories. 99999 indicates data was not available as no subjects were evaluable.


End point type 
Primary


End point timeframe 
Baseline (predose on Day 1)


Notes [36]  No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: The endpoint is specific to Part B; hence, only arms for Part B are included. 



No statistical analyses for this end point 


End point title 
Part B: Number of Subjects With Abnormal Clinical Chemistry Results Anytime Between 40 to 48 Hours Postdose 10 ^{[37]}  
End point description 
Clinical chemistry parameters included creatinine, urea, AST, ALT, GGT, ALP, LDH, total bilirubin, albumin, total protein, sodium, potassium, chloride, glucose, and calcium. Institutional laboratory normal ranges were used. Safety population included all subjects who received at least 1 dose of IMP. Here, 'Number of Subjects Analysed' signifies number of subjects evaluable for this endpoint and 'n' signifies number of subjects evaluable for the specified categories.


End point type 
Primary


End point timeframe 
Anytime between 40 to 48 hours postdose 10 on Day 5


Notes [37]  No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: The endpoint is specific to Part B; hence, only arms for Part B are included. 



Notes [38]  No subjects were evaluable 

No statistical analyses for this end point 


End point title 
Part A: Number of Subjects With Abnormal Urinalysis Results at Baseline ^{[39]}  
End point description 
Following urine parameters were analysed: epithelial cells (normal range: 0 to 5 cells per high power field [hpf]), erythrocytes (0 to 2 per hpf), granular casts (0 per low power field [lpf]), hyaline casts (0 to 1 per lpf), leukocytes (0 to 5 per hpf), RBC casts (0 per lpf), WBC casts (0 per lpf), waxy casts (0 per lpf) and pH (5 to 8). Safety population included all subjects who received at least 1 dose of IMP. Here, 'Number of Subjects Analysed' signifies number of subjects evaluable for this endpoint and 'n' signifies number of subjects evaluable for the specified categories.


End point type 
Primary


End point timeframe 
Baseline (predose on Day 1)


Notes [39]  No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only descriptive analysis was planned. 



No statistical analyses for this end point 


End point title 
Part A: Number of Subjects With Abnormal Urinalysis Results at 48 Hours Postdose ^{[40]}  
End point description 
Following urine parameters were analysed: epithelial cells (normal range: 0 to 5 cells per hpf), erythrocytes (0 to 2 per hpf), granular casts (0 per lpf), hyaline casts (0 to 1 per lpf), leukocytes (0 to 5 per hpf), RBC casts (0 per lpf), WBC casts (0 per lpf), waxy casts (0 per lpf) and pH (5 to 8). Safety population included all subjects who received at least 1 dose of IMP. Here, 'Number of Subjects Analysed' signifies number of subjects evaluable for this endpoint and 'n' signifies number of subjects evaluable for the specified categories.


End point type 
Primary


End point timeframe 
48 hours postdose on Day 1


Notes [40]  No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only descriptive analysis was planned. 



Notes [41]  No subjects were evaluable 

No statistical analyses for this end point 


End point title 
Part B: Number of Subjects With Abnormal Urinalysis Results at Baseline ^{[42]}  
End point description 
Following urine parameters were analysed: epithelial cells (normal range: 0 to 5 cells per hpf), erythrocytes (0 to 2 per hpf), granular casts (0 per lpf), hyaline casts (0 to 1 per lpf), leukocytes (0 to 5 per hpf), RBC casts (0 per lpf), WBC casts (0 per lpf), waxy casts (0 per lpf) and pH (5 to 8). Safety population included all subjects who received at least 1 dose of IMP. Here, 'Number of Subjects Analysed' signifies number of subjects evaluable for this endpoint and ‘n’ signifies number of subjects evaluable for the specified categories.


End point type 
Primary


End point timeframe 
Baseline (predose on Day 1)


Notes [42]  No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: The endpoint is specific to Part B; hence, only arms for Part B are included. 



No statistical analyses for this end point 


End point title 
Part B: Number of Subjects With Abnormal Urinalysis Results Anytime Between 40 to 48 Hours PostDose 10 ^{[43]}  
End point description 
Following urine parameters were analysed: epithelial cells (normal range: 0 to 5 cells per hpf), erythrocytes (0 to 2 per hpf), granular casts (0 per lpf), hyaline casts (0 to 1 per lpf), leukocytes (0 to 5 per hpf), RBC casts (0 per lpf), WBC casts (0 per lpf), waxy casts (0 per lpf) and pH (5 to 8). Safety population included all subjects who received at least 1 dose of IMP. Here, 'Number of Subjects Analysed' signifies number of subjects evaluable for this endpoint and ‘n’ signifies number of subjects evaluable for the specified categories.


End point type 
Primary


End point timeframe 
Anytime between 40 to 48 hours postdose 10 on Day 5


Notes [43]  No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: The endpoint is specific to Part B; hence, only arms for Part B are included. 



Notes [44]  No subjects were evaluable [45]  No subjects were evaluable 

No statistical analyses for this end point 


End point title 
Part A: Number of Subjects With Abnormal Clinically Significant Electrocardiogram (ECG) Results per Investigator’s Interpretation at Baseline ^{[46]}  
End point description 
A 12lead ECG was performed for assessment of following ECG parameters: ventricular heart rate, PR interval, QRS interval, QT interval and QT interval corrected by Bazzett's formula (QTcB) interval. Number of subjects with abnormal clinically significant results for any ECG parameter per investigators interpretation are reported in this outcome measure. Safety population included all subjects who received at least 1 dose of IMP.


End point type 
Primary


End point timeframe 
Baseline (predose on Day 1)


Notes [46]  No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only descriptive analysis was planned. 



No statistical analyses for this end point 


End point title 
Part A: Number of Subjects With Abnormal Clinically Significant Electrocardiogram (ECG) Results per Investigator’s Interpretation Anytime Between 4 to 5 Hours PostDose ^{[47]}  
End point description 
A 12lead ECG was performed for assessment of following ECG parameters: ventricular heart rate, PR interval, QRS interval, QT interval and QTcB interval. Number of subjects with abnormal clinically significant results for any ECG parameter per investigators interpretation are reported in this outcome measure. Safety population included all subjects who received at least 1 dose of IMP.


End point type 
Primary


End point timeframe 
Anytime between 4 to 5 hours postdose on Day 1


Notes [47]  No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only descriptive analysis was planned. 



No statistical analyses for this end point 


End point title 
Part A: Number of Subjects With Abnormal Clinically Significant Electrocardiogram (ECG) Results per Investigator’s Interpretation Anytime Between 18 to 24 Hours Postdose ^{[48]}  
End point description 
A 12lead ECG was performed for assessment of following ECG parameters: ventricular heart rate, PR interval, QRS interval, QT interval and QTcB interval. Number of subjects with abnormal clinically significant results for any ECG parameter per investigators interpretation are reported in this outcome measure. Safety population included all subjects who received at least 1 dose of IMP. Here, 'Number of Subjects Analysed' signifies number of subjects evaluable for this endpoint.


End point type 
Primary


End point timeframe 
Anytime between 18 to 24 hours postdose on Day 1


Notes [48]  No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only descriptive analysis was planned. 



No statistical analyses for this end point 


End point title 
Part B: Number of Subjects With Abnormal Clinically Significant Electrocardiogram (ECG) Results per Investigator’s Interpretation at Baseline ^{[49]}  
End point description 
A 12lead ECG was performed for assessment of following ECG parameters: ventricular heart rate, PR interval, QRS interval, QT interval and QTcB interval. Number of subjects with abnormal clinically significant results for any ECG parameter per investigators interpretation are reported in this outcome measure. Safety population included all subjects who received at least 1 dose of IMP.


End point type 
Primary


End point timeframe 
Baseline (predose on Day 1)


Notes [49]  No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: The endpoint is specific to Part B; hence, only arms for Part B are included. 



No statistical analyses for this end point 


End point title 
Part A: Number of Subjects With Abnormal Clinically Significant Electrocardiogram (ECG) Results per Investigator’s Interpretation at 48 Hours Postdose ^{[50]}  
End point description 
A 12lead ECG was performed for assessment of following ECG parameters: ventricular heart rate, PR interval, QRS interval, QT interval and QTcB interval. Number of subjects with abnormal clinically significant results for any ECG parameter per investigators interpretation are reported in this outcome measure. Safety population included all subjects who received at least 1 dose of IMP. Here, 'Number of Subjects Analysed' signifies number of subjects evaluable for this endpoint.


End point type 
Primary


End point timeframe 
48 hours postdose on Day 1


Notes [50]  No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only descriptive analysis was planned. 



No statistical analyses for this end point 


End point title 
Part B: Number of Subjects With Abnormal Clinically Significant Electrocardiogram (ECG) Results per Investigator’s Interpretation Anytime Between 4 to 5 Hours PostDose 1 ^{[51]}  
End point description 
A 12lead ECG was performed for assessment of following ECG parameters: ventricular heart rate, PR interval, QRS interval, QT interval and QTcB interval. Number of subjects with abnormal clinically significant results for any ECG parameter per investigators interpretation are reported in this outcome measure. Safety population included all subjects who received at least 1 dose of IMP. Here, 'Number of Subjects Analysed' signifies number of subjects evaluable for this endpoint.


End point type 
Primary


End point timeframe 
Anytime between 4 to 5 hours postdose 1 on Day 1


Notes [51]  No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: The endpoint is specific to Part B; hence, only arms for Part B are included. 



No statistical analyses for this end point 


End point title 
Part B: Number of Subjects With Abnormal Clinically Significant Electrocardiogram (ECG) Results per Investigator’s Interpretation at Predose 3 ^{[52]}  
End point description 
A 12lead ECG was performed for assessment of following ECG parameters: ventricular heart rate, PR interval, QRS interval, QT interval and QTcB interval. Number of subjects with abnormal clinically significant results for any ECG parameter per investigators interpretation are reported in this outcome measure. Safety population included all subjects who received at least 1 dose of IMP. Here, 'Number of Subjects Analysed' signifies number of subjects evaluable for this endpoint.


End point type 
Primary


End point timeframe 
Predose 3 (Day 2)


Notes [52]  No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: The endpoint is specific to Part B; hence, only arms for Part B are included. 



No statistical analyses for this end point 


End point title 
Part B: Number of Subjects With Abnormal Clinically Significant Electrocardiogram (ECG) Results per Investigator’s Interpretation at Predose 5 ^{[53]}  
End point description 
A 12lead ECG was performed for assessment of following ECG parameters: ventricular heart rate, PR interval, QRS interval, QT interval and QTcB interval. Number of subjects with abnormal clinically significant results for any ECG parameter per investigators interpretation are reported in this outcome measure. Safety population included all subjects who received at least 1 dose of IMP. Here, 'Number of Subjects Analysed' signifies number of subjects evaluable for this endpoint.


End point type 
Primary


End point timeframe 
Predose 5 (Day 3)


Notes [53]  No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: The endpoint is specific to Part B; hence, only arms for Part B are included. 



No statistical analyses for this end point 


End point title 
Part B: Number of Subjects With Abnormal Clinically Significant Electrocardiogram (ECG) Results per Investigator’s Interpretation Anytime Between 4 to 5 Hours PostDose 6 ^{[54]}  
End point description 
A 12lead ECG was performed for assessment of following ECG parameters: ventricular heart rate, PR interval, QRS interval, QT interval and QTcB interval. Number of subjects with abnormal clinically significant results for any ECG parameter per investigators interpretation are reported in this outcome measure. Safety population included all subjects who received at least 1 dose of IMP. Here, 'Number of Subjects Analysed' signifies number of subjects evaluable for this endpoint.


End point type 
Primary


End point timeframe 
Anytime between 4 to 5 hours postdose 6 (Day 3)


Notes [54]  No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: The endpoint is specific to Part B; hence, only arms for Part B are included. 



No statistical analyses for this end point 


End point title 
Part B: Number of Subjects With Abnormal Clinically Significant Electrocardiogram (ECG) Results per Investigator’s Interpretation at Predose 10 ^{[55]}  
End point description 
A 12lead ECG was performed for assessment of following ECG parameters: ventricular heart rate, PR interval, QRS interval, QT interval and QTcB interval. Number of subjects with abnormal clinically significant results for any ECG parameter per investigators interpretation are reported in this outcome measure. Safety population included all subjects who received at least 1 dose of IMP. Here, 'Number of Subjects Analysed' signifies number of subjects evaluable for this endpoint.


End point type 
Primary


End point timeframe 
Predose (Day 5)


Notes [55]  No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: The endpoint is specific to Part B; hence, only arms for Part B are included. 



Notes [56]  No subjects were evaluable [57]  No subjects were evaluable 

No statistical analyses for this end point 


End point title 
Part B: Number of Subjects With Abnormal Clinically Significant Electrocardiogram (ECG) Results per Investigator’s Interpretation at Predose 8 ^{[58]}  
End point description 
A 12lead ECG was performed for assessment of following ECG parameters: ventricular heart rate, PR interval, QRS interval, QT interval and QTcB interval. Number of subjects with abnormal clinically significant results for any ECG parameter per investigators interpretation are reported in this outcome measure. Safety population included all subjects who received at least 1 dose of IMP. Here, 'Number of Subjects Analysed' signifies number of subjects evaluable for this endpoint.


End point type 
Primary


End point timeframe 
Predose 8 (Day 4)


Notes [58]  No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: The endpoint is specific to Part B; hence, only arms for Part B are included. 



No statistical analyses for this end point 


End point title 
Part B: Number of Subjects With Abnormal Clinically Significant Electrocardiogram (ECG) Results per Investigator’s Interpretation Anytime Between 40 to 48 Hours PostDose 10 ^{[59]}  
End point description 
A 12lead ECG was performed for assessment of following ECG parameters: ventricular heart rate, PR interval, QRS interval, QT interval and QTcB interval. Number of subjects with abnormal clinically significant results for any ECG parameter per investigators interpretation are reported in this outcome measure. Safety population included all subjects who received at least 1 dose of IMP. Here, 'Number of Subjects Analysed' signifies number of subjects evaluable for this endpoint.


End point type 
Primary


End point timeframe 
Anytime between 40 to 48 hours postdose 10 on Day 5


Notes [59]  No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: The endpoint is specific to Part B; hence, only arms for Part B are included. 



Notes [60]  No subjects were evaluable 

No statistical analyses for this end point 


End point title 
Part A: Time to Maximum Plasma Concentration (tmax)  
End point description 
PK population included all subjects who received IMP and had at least 1 postdose PK concentration measurement.


End point type 
Secondary


End point timeframe 
Anytime between 4 to 5 hours, anytime between 6 to 8 hours, 12 hours, 18 to 24 hours and 48 hours postdose on Day 1




No statistical analyses for this end point 


End point title 
Part B: Time to Maximum Plasma Concentration (tmax)  
End point description 
PK population included all subjects who received IMP and had at least 1 postdose PK concentration measurement. Here, 'n' signifies number of subjects evaluable for the specified categories.


End point type 
Secondary


End point timeframe 
Day 1 Dose 1 (anytime between 4 to 5 hours postdose, 12 hours postdose), Day 3 Dose 6 (predose, anytime between 4 to 5 hours postdose, 12 hours postdose)




No statistical analyses for this end point 


End point title 
Part A: Maximum Observed Plasma Concentration (Cmax)  
End point description 
PK population included all subjects who received IMP and had at least 1 postdose PK concentration measurement.


End point type 
Secondary


End point timeframe 
Anytime between 4 to 5 hours, anytime between 6 to 8 hours, 12 hours, 18 to 24 hours and 48 hours postdose on Day 1




No statistical analyses for this end point 


End point title 
Part B: Maximum Observed Plasma Concentration (Cmax)  
End point description 
PK population included all subjects who received IMP and had at least 1 postdose PK concentration measurement. Here, 'n' signifies number of subjects evaluable for the specified categories.


End point type 
Secondary


End point timeframe 
Day 1 Dose 1 (anytime between 4 to 5 hours postdose, 12 hours postdose), Day 3 Dose 6 (predose, anytime between 4 to 5 hours postdose, 12 hours postdose)




No statistical analyses for this end point 


End point title 
Part A: Area Under the Plasma Concentration Time Curve From Time Zero to 12 Hours (AUC012)  
End point description 
AUC(0 to 12) was calculated using the linear trapezoidal method. No sampling was done at 0 hour. PK population included all subjects who received IMP and had at least 1 postdose PK concentration measurement. Here, 'Number of Subjects Analysed' signifies number of subjects evaluable for this endpoint.


End point type 
Secondary


End point timeframe 
0 hour, anytime between 4 to 5 hours, anytime between 6 to 8 hours, 12 hours postdose on Day 1




No statistical analyses for this end point 


End point title 
Part B: Area Under the Plasma Concentration Time Curve From Time Zero to 12 Hours (AUC012)  
End point description 
AUC(0 to 12) was calculated using the linear trapezoidal method. No sampling was done at 0 hour on Day 1. PK population included all subjects who received IMP and had at least 1 postdose PK concentration measurement. Here, 'Number of Subjects Analysed' signifies number of subjects evaluable for this endpoint and 'n' signifies number of subjects evaluable for the specified categories. 99999 indicates data could not be calculated due to insufficient number of subjects.


End point type 
Secondary


End point timeframe 
Day 1 Dose 1 (0 hour, anytime between 4 to 5 hours postdose, 12 hours postdose), Day 3 Dose 6 (predose, anytime between 4 to 5 hours postdose, 12 hours postdose)




No statistical analyses for this end point 


End point title 
Part A: Area Under the Plasma ConcentrationTime Curve From Time 0 to the Last Measurable Concentration (AUC[0 to t])  
End point description 
Area under the plasma concentrationtime curve from time 0 to the last measurable concentration was determined using the linear trapezoidal method. No sampling was done at 0 hour. PK population included all subjects who received IMP and had at least 1 postdose PK concentration measurement. Here, 'Number of Subjects Analysed' signifies number of subjects evaluable for this endpoint. 99999 signifies data could not be calculated due to insufficient subjects.


End point type 
Secondary


End point timeframe 
0 hour, anytime between 4 to 5 hours, anytime between 6 to 8 hours, 12 hours, 18 to 24 hours and 48 hours postdose on Day 1




No statistical analyses for this end point 


End point title 
Part B: Area Under the Plasma ConcentrationTime Curve From Time 0 to the Last Measurable Concentration (AUC[0 to t])  
End point description 
Area under the plasma concentrationtime curve from time 0 to the last measurable concentration was determined using the linear trapezoidal method. No sampling was done at 0 hour on Day 1. PK population included all subjects who received IMP and had at least 1 postdose PK concentration measurement. Here, 'Number of Subjects Analysed' signifies number of subjects evaluable for this endpoint.


End point type 
Secondary


End point timeframe 
Day 1 Dose 1 (0 hour, anytime between 4 to 5 hours postdose, 12 hours postdose), Day 3 Dose 6 (predose, anytime between 4 to 5 hours postdose, 12 hours postdose)




No statistical analyses for this end point 


End point title 
Part B: Terminal Halflife (t1/2)  
End point description 
T1/2 was calculated as loge (2) divided by kel, where kel is the terminal phase rate constant calculated by a linear regression of the loglinear concentrationtime curve. PK population included all subjects who received IMP and had at least 1 postdose PK concentration measurement. Here, 'Number of Subjects Analysed' signifies number of subjects evaluable for this endpoint.


End point type 
Secondary


End point timeframe 
Day 1 Dose 1 (anytime between 4 to 5 hours postdose, 12 hours postdose), Day 3 Dose 6 (predose, anytime between 4 to 5 hours postdose, 12 hours postdose)




Notes [61]  No subjects were evaluable [62]  No subjects were evaluable [63]  No subjects were evaluable [64]  No subjects were evaluable [65]  No subjects were evaluable 

No statistical analyses for this end point 


End point title 
Part A: Terminal Halflife (t1/2)  
End point description 
T1/2 was calculated as loge (2) divided by kel, where kel is the terminal phase rate constant calculated by a linear regression of the loglinear concentrationtime curve. PK population included all subjects who received IMP and had at least 1 postdose PK concentration measurement. Here, 'Number of Subjects Analysed' signifies number of subjects evaluable for this endpoint.


End point type 
Secondary


End point timeframe 
Anytime between 4 to 5 hours, anytime between 6 to 8 hours, 12 hours, 18 to 24 hours and 48 hours postdose on Day 1




Notes [66]  No subjects were evaluable [67]  No subjects were evaluable [68]  No subjects were evaluable 

No statistical analyses for this end point 


End point title 
Part A: Area Under the Plasma Concentration Time Curve From Time Zero to Infinity (AUC0 to inf)  
End point description 
AUCinf was determined as AUC(0 to t) + (Clast/kel), where Clast was the plasma concentration at the last quantifiable timepoint estimated from the loglinear regression analysis and kel was the terminal phase rate. No sampling was done at 0 hour. PK population included all subjects who received IMP and had at least 1 postdose PK concentration measurement. Here, 'Number of Subjects Analysed' signifies number of subjects evaluable for this endpoint.


End point type 
Secondary


End point timeframe 
0 hour, anytime between 4 to 5 hours, anytime between 6 to 8 hours, 12 hours, 18 to 24 hours and 48 hours postdose on Day 1




Notes [69]  No subjects were evaluable [70]  No subjects were evaluable [71]  No subjects were evaluable 

No statistical analyses for this end point 


End point title 
Part B: Area Under the Plasma Concentration Time Curve From Time Zero to Infinity (AUC0 to inf)  
End point description 
AUCinf was determined as AUC(0 to t) + (Clast/kel), where Clast was the plasma concentration at the last quantifiable timepoint estimated from the loglinear regression analysis and kel was the terminal phase rate. No sampling was done at 0 hour on Day 1. PK population included all subjects who received IMP and had at least 1 postdose PK concentration measurement. Here, 'Number of Subjects Analysed' signifies number of subjects evaluable for this endpoint.


End point type 
Secondary


End point timeframe 
Day 1 Dose 1 (0 hour, anytime between 4 to 5 hours postdose, 12 hours postdose), Day 3 Dose 6 (predose, anytime between 4 to 5 hours postdose, 12 hours postdose)




Notes [72]  No subjects were evaluable [73]  No subjects were evaluable [74]  No subjects were evaluable [75]  No subjects were evaluable [76]  No subjects were evaluable 

No statistical analyses for this end point 


End point title 
Part A: Trough Concentration at the end of First Dosing Interval (C12)  
End point description 
PK Population included all subjects who received IMP and had at least 1 postdose PK concentration measurement. Here, 'Number of Subjects Analysed' signifies number of subjects evaluable for this endpoint.


End point type 
Secondary


End point timeframe 
At 12 hours postdose on Day 1




Notes [77]  No subjects were evaluable [78]  No subjects were evaluable [79]  No subjects were evaluable [80]  No subjects were evaluable 

No statistical analyses for this end point 


End point title 
Part B: Trough Concentration at the end of First Dosing Interval (C12)  
End point description 
PK Population included all subjects who received IMP and had at least 1 postdose PK concentration measurement. Here, 'Number of Subjects Analysed' signifies number of subjects evaluable for this endpoint.


End point type 
Secondary


End point timeframe 
At 12 hours postdose 6




No statistical analyses for this end point 


End point title 
Part A: Predicted Plasma Clearance  
End point description 
Clearance was calculated as Dose divided by AUC(0 to inf). PK population included all subjects who received IMP and had at least 1 postdose PK concentration measurement. Here, 'Number of Subjects Analysed' signifies number of subjects evaluable for this endpoint.


End point type 
Secondary


End point timeframe 
Anytime between 4 to 5 hours, anytime between 6 to 8 hours, 12 hours, 18 to 24 hours and 48 hours postdose on Day 1




Notes [81]  No subjects were evaluable [82]  No subjects were evaluable [83]  No subjects were evaluable 

No statistical analyses for this end point 


End point title 
Part B: Predicted Plasma Clearance  
End point description 
Clearance was calculated as Dose divided by AUC(0 to inf). PK population included all subjects who received IMP and had at least 1 postdose PK concentration measurement. Here, 'Number of Subjects Analysed' signifies number of subjects evaluable for this endpoint.


End point type 
Secondary


End point timeframe 
Day 1 Dose 1 (anytime between 4 to 5 hours postdose, 12 hours postdose), Day 3 Dose 6 (predose, anytime between 4 to 5 hours postdose, 12 hours postdose)




Notes [84]  No subjects were evaluable [85]  No subjects were evaluable [86]  No subjects were evaluable [87]  No subjects were evaluable [88]  No subjects were evaluable 

No statistical analyses for this end point 


End point title 
Part A: Apparent Volume of Distribution of the Drug After Extravascular Administration  
End point description 
Apparent volume of distribution was estimated as Dose/Kel*AUC(0 to inf), where Kel=apparent firstorder terminal elimination rate constant. PK population included all subjects who received IMP and had at least 1 postdose PK concentration measurement. Here, 'Number of Subjects Analysed' signifies number of subjects evaluable for this endpoint.


End point type 
Secondary


End point timeframe 
Anytime between 4 to 5 hours, anytime between 6 to 8 hours, 12 hours, 18 to 24 hours and 48 hours postdose on Day 1




Notes [89]  No subjects were evaluable [90]  No subjects were evaluable [91]  No subjects were evaluable 

No statistical analyses for this end point 


End point title 
Part B: Apparent Volume of Distribution of the Drug After Extravascular Administration  
End point description 
Apparent volume of distribution was estimated as Dose/Kel*AUC(0 to inf), where Kel=apparent firstorder terminal elimination rate constant. PK population included all subjects who received IMP and had at least 1 postdose PK concentration measurement. Here, 'Number of Subjects Analysed' signifies number of subjects evaluable for this endpoint.


End point type 
Secondary


End point timeframe 
Day 1 Dose 1 (anytime between 4 to 5 hours postdose, 12 hours postdose), Day 3 Dose 6 (predose, anytime between 4 to 5 hours postdose, 12 hours postdose)




Notes [92]  No subjects were evaluable [93]  No subjects were evaluable [94]  No subjects were evaluable [95]  No subjects were evaluable [96]  No subjects were evaluable 

No statistical analyses for this end point 


End point title 
Part B: Accumulation Ratio  
End point description 
Accumulation ratio was calculated as ratio of the area under the curve (AUC) during a single dosing interval under steady state conditions to the AUC during a dosing interval after one singe dose. PK population included all subjects who received IMP and had at least 1 postdose PK concentration measurement.


End point type 
Secondary


End point timeframe 
Day 1 Dose 1 (anytime between 4 to 5 hours postdose, 12 hours postdose), Day 3 Dose 6 (predose, anytime between 4 to 5 hours postdose, 12 hours postdose)




Notes [97]  No subjects were evaluable [98]  No subjects were evaluable [99]  No subjects were evaluable [100]  No subjects were evaluable [101]  No subjects were evaluable 

No statistical analyses for this end point 


End point title 
Part B: Percentage Fluctuation  
End point description 
Percentage fluctuation was calculated as 100*(CmaxCmin)/Cavg, where Cmin=minimum plasma concentration and Cmax measured over dosing interval. PK population included all subjects who received IMP and had at least 1 postdose PK concentration measurement. Here, 'Number of Subjects Analysed' signifies number of subjects evaluable for this endpoint. 99999 indicates data could not be calculated due to insufficient number of subjects.


End point type 
Secondary


End point timeframe 
Day 3 Dose 6 (predose, anytime between 4 to 5 hours postdose, 12 hours postdose)




Notes [102]  No subjects were evaluable 

No statistical analyses for this end point 


End point title 
Part B: Area Under the Plasma Concentration Time Curve From Time Zero to the end of Last Dosing Interval (AUC0tau)  
End point description 
AUC(0 to tau) was determined using the linear trapezoidal method. No sampling was done at 0 hour. PK population included all subjects who received IMP and had at least 1 postdose PK concentration measurement. Here, 'Number of Subjects Analysed' signifies number of subjects evaluable for this endpoint. 99999 indicates data could not be calculated due to insufficient number of subjects.


End point type 
Secondary


End point timeframe 
Day 3 Dose 6 (predose, anytime between 4 to 5 hours postdose, 12 hours postdose)




Notes [103]  No subjects were evaluable 

No statistical analyses for this end point 


End point title 
Part B: Average Plasma Concentration Over Dosing Interval (Cavg)  
End point description 
Cavg was estimated as AUC(0 to tau)/tau, where tau=dosing interval (12 hours). PK population included all subjects who received IMP and had at least 1 postdose PK concentration measurement. Here, 'Number of Subjects Analysed' signifies number of subjects evaluable for this endpoint. 99999 indicates data could not be calculated due to insufficient number of subjects.


End point type 
Secondary


End point timeframe 
Day 3 Dose 6 (predose, anytime between 4 to 5 hours postdose, 12 hours postdose)




Notes [104]  No subjects were evaluable 

No statistical analyses for this end point 


End point title 
Part B: Minimum Observed Plasma Concentration  
End point description 
PK population included all subjects who received IMP and had at least 1 postdose PK concentration measurement. Here, 'Number of Subjects Analysed' signifies number of subjects evaluable for this endpoint.


End point type 
Secondary


End point timeframe 
Day 1 Dose 1 (anytime between 4 to 5 hours postdose, 12 hours postdose), Day 3 Dose 6 (predose, anytime between 4 to 5 hours postdose, 12 hours postdose)




Notes [105]  No subjects were evaluable [106]  No subjects were evaluable [107]  No subjects were evaluable [108]  No subjects were evaluable [109]  No subjects were evaluable 

No statistical analyses for this end point 


End point title 
Part B: Plasma Trough Concentration  
End point description 
PK population included all subjects who received IMP and had at least 1 postdose PK concentration measurement. Here, 'Number of Subjects Analysed' signifies number of subjects evaluable for this endpoint.


End point type 
Secondary


End point timeframe 
Day 1 Dose 1 (anytime between 4 to 5 hours postdose, 12 hours postdose), Day 3 Dose 6 (predose, anytime between 4 to 5 hours postdose, 12 hours postdose)




Notes [110]  No subjects were evaluable [111]  No subjects were evaluable [112]  No subjects were evaluable [113]  No subjects were evaluable [114]  No subjects were evaluable 

No statistical analyses for this end point 


End point title 
Part B: Percent Change From Baseline in Logarithm to Base10 (Log10) Total RSV Viral Load by Quantitative Reverse Transcription Polymerase Chain Reaction (RTqPCR)  
End point description 
Percent change from baseline in log10 total RSV viral load was analysed using a mixed effects analysis of covariance (ANCOVA) model. The model was fitted to the subjects treated at the final doses selected for Cohort 5 as preplanned in statistical analysis plan. Modified Intent to Treat (mITT) population included all subjects who received at least 1 dose of IMP (RV521 or placebo) and had a pretreatment positive RSV nasopharyngeal swab confirmed by the central laboratory and agreed by the project team during blind data review meeting. Here, 'n' signifies subjects evaluable at the specified timepoints.


End point type 
Secondary


End point timeframe 
Baseline (predose on Day 1), 60 hours and 156 hours after first dose on Day 1




Statistical analysis title 
Placebo versus RV521 2.5 mg/kg  
Statistical analysis description 
Analysis was performed using mixed effects analysis of covariance model on change from baseline in viral load, including a random effect for subject and fixed effects for treatment group, baseline human rhinovirus/enterovirus status (present or absent), visit, vist by treatment group interaction, and baseline viral load as a covariate.


Comparison groups 
Cohort 4 and 5 combined: Placebo v Cohort 4 and 5 combined: RV521 2.5 mg/kg


Number of subjects included in analysis 
18


Analysis specification 
Prespecified


Analysis type 
other ^{[115]}  
Method 

Parameter type 
Mean difference (net)  
Point estimate 
15.22


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
40.15  
upper limit 
9.7  
Notes [115]  156 hours 

Statistical analysis title 
Placebo versus RV521 2.5 mg/kg  
Statistical analysis description 
Analysis was performed using mixed effects analysis of covariance model on change from baseline in viral load, including a random effect for subject and fixed effects for treatment group, baseline human rhinovirus/enterovirus status
(present or absent), visit, vist by treatment group interaction, and baseline viral load as a covariate.


Comparison groups 
Cohort 4 and 5 combined: Placebo v Cohort 4 and 5 combined: RV521 2.5 mg/kg


Number of subjects included in analysis 
18


Analysis specification 
Prespecified


Analysis type 
other ^{[116]}  
Method 

Parameter type 
Mean difference (net)  
Point estimate 
8.02


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
31.78  
upper limit 
15.74  
Notes [116]  60 hours 


End point title 
Part B: Percent Change From Baseline in Logarithm to Base10 (Log10) Total RSV Viral Load by CellBased Infectivity Assay (CBIA)  
End point description 
Percent change from baseline in log10 total RSV viral load was analysed using a mixed effects ANCOVA model. The model was fitted to the subjects treated at the final doses selected for Cohort 5 as preplanned in statistical analysis plan. mITT population included all subjects who received at least 1 dose of IMP (RV521 or placebo) and had a pretreatment positive RSV nasopharyngeal swab confirmed by the central laboratory and agreed by the project team during blind data review meeting. Here, 'n' signifies subjects evaluable at the specified timepoints.


End point type 
Secondary


End point timeframe 
Baseline (predose on Day 1), 60 hours and 156 hours after first dose on Day 1




Statistical analysis title 
Placebo versus RV521 2.5 mg/kg  
Statistical analysis description 
Analysis was performed using mixed effects analysis of covariance model on change from baseline in viral load, including a random effect for subject and fixed effects for treatment group, baseline human rhinovirus/enterovirus status (present or absent), visit, vist by treatment group interaction, and baseline viral load as a covariate.


Comparison groups 
Cohort 4 and 5 combined: Placebo v Cohort 4 and 5 combined: RV521 2.5 mg/kg


Number of subjects included in analysis 
18


Analysis specification 
Prespecified


Analysis type 
other ^{[117]}  
Method 

Parameter type 
Mean difference (net)  
Point estimate 
31.19


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
143.96  
upper limit 
81.57  
Notes [117]  156 hours 

Statistical analysis title 
Placebo versus RV521 2.5 mg/kg  
Statistical analysis description 
Analysis was performed using mixed effects analysis of covariance model on change from baseline in viral load, including a random effect for subject and fixed effects for treatment group, baseline human rhinovirus/enterovirus status (present or absent), visit, vist by treatment group interaction, and baseline viral load as a covariate.


Comparison groups 
Cohort 4 and 5 combined: Placebo v Cohort 4 and 5 combined: RV521 2.5 mg/kg


Number of subjects included in analysis 
18


Analysis specification 
Prespecified


Analysis type 
other ^{[118]}  
Method 

Parameter type 
Mean difference (net)  
Point estimate 
14.82


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
91.68  
upper limit 
121.33  
Notes [118]  60 hours 


End point title 
Part B: Time to Resolution of RSVRelated Signs and Symptoms  
End point description 
Time to resolution was calculated for RSVrelated signs and symptoms that were present at study start and was defined as the time of randomisation to the time that RSVrelated signs and symptoms were absent. mITT population included all subjects who received at least 1 dose of IMP (RV521 or placebo) and had a pretreatment positive RSV nasopharyngeal swab confirmed by the central laboratory and agreed by the project team during blind data review meeting. Here, 'Number of Subjects Analysed' signifies number of subjects evaluable for this endpoint.


End point type 
Secondary


End point timeframe 
Up to 13 days




No statistical analyses for this end point 


End point title 
Part B: Time to Improvement in RSVRelated Signs and Symptoms  
End point description 
Time to improvement was calculated for RSVrelated signs and symptoms that were classified as moderate or severe during the course of the study and was defined as the time from randomisation to the time that RSVrelated signs and symptoms were mild or absent. mITT population included all subjects who received at least 1 dose of IMP (RV521 or placebo) and had a pretreatment positive RSV nasopharyngeal swab confirmed by the central laboratory and agreed by the project team during blind data review meeting. Here, 'Number of Subjects Analysed' signifies number of subjects evaluable for this endpoint.


End point type 
Secondary


End point timeframe 
Up to 13 days




No statistical analyses for this end point 


End point title 
Part B: RSV Clinical Scoring System Scores  
End point description 
RSV clinical score was a composite score for infants with RSV infection >= 1 month of age based on 4 items (respiratory rate, wheezing, retraction of respiratory muscles and general condition). Score for each item ranged from 0 to 3 where 0=none/normal and 3=severe. Total score was calculated as sum of individual items and ranged from 0 to 12, where higher score indicated severe disease. RSV symptoms were graded as mild: score <=5, moderate: score > 5 but < 9 and severe: score >=9. mITT population was analysed. Here, 'Number of Subjects Analysed' signifies subjects evaluable for this endpoint and 'n' signifies subjects evaluable at the specified timepoints. 99999 signifies data could not be calculated due to insufficient subjects.


End point type 
Secondary


End point timeframe 
Baseline (predose 1 on Day 1), predose 3, predose 5, predose 7, predose 9, anytime between 40 to 48 hours postdose 10 on Day 5


