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Clinical Trial Results:
A Randomised, Phase 2a, Double-Blind, Placebo-Controlled Study to Evaluate the Safety, Pharmacokinetics and Antiviral Activity of Multiple Doses of RV521 Against Respiratory Syncytial Virus infection in the Virus Challenge Model.

Summary
EudraCT number	2017-001282-24
Trial protocol	GB
Global end of trial date	31 Oct 2017

Results information
Results version number	v1(current)
This version publication date	19 Jun 2019
First version publication date	19 Jun 2019
Other versions

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

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Trial information

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Sponsor protocol code

REVC002

ISRCTN number

US NCT number

NCT03258502

WHO universal trial number (UTN)

Sponsor organisation name

ReViral Ltd

Sponsor organisation address

Stevenage Bioscience Catalyst, Gunnels Wood Road, Stevenage, Hertfordshire, United Kingdom, SG1 2FX

Public contact

Director Clinical Operations, ReViral Ltd, +44 1438 906760,

Scientific contact

Chief Operating Officer, ReViral Ltd, +44 1438 906760,

Is trial part of an agreed paediatric investigation plan (PIP)

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

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

Analysis stage

Final

Date of interim/final analysis

12 Jun 2018

Is this the analysis of the primary completion data?

Yes

Primary completion date

31 Oct 2017

Global end of trial reached?

Yes

Global end of trial date

31 Oct 2017

Was the trial ended prematurely?

Main objective of the trial

To evaluate the antiviral activity of RV521 compared to placebo in healthy adult subjects inoculated with RSV-A Memphis 37b.

Protection of trial subjects

This study will be conducted in accordance with the Ethical Principles for Medical Research Involving Human Subjects outlined in the Declaration of Helsinki 19961, the principles of ICH GCP2, current regulatory requirements as detailed in the Medicines for Human Use (Clinical Trial) Regulations (SI 2004/1031)4 and all subsequent amendments, the UK Data Protection Act 19985, any other applicable laws and guidance, and any Sponsor requirements. All ethical and legal requirements will be met before the first subject is enrolled in the study. Safety of the subjects was safeguarded through safety data review and the implementation of study stopping criteria. Safety endpoint measurements included vital signs, 12-lead ECGs, physical examinations, safety laboratory blood tests (biochemistry, haematology, coagulation and cardiac enzymes) and urinalysis. Adverse events were continuously monitored throughout the study from date of consent until the last follow up assessment.

Background therapy

Evidence for comparator

Actual start date of recruitment

19 Jul 2017

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

United Kingdom: 66

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

66 subjects were enrolled and 65 subjects have completed the study.

Screening details

Subjects were healthy males and/or females, 18 to 45 years of age, who met the eligibility criteria outlined in the Protocol.

Number of subjects started

Number of subjects completed

Period 1 title

Overall trial (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Data analyst, Carer, Assessor

Blinding implementation details

The study was conducted in a double-blind fashion, whereby subjects and clinical study site staff were blinded to the active or placebo study drug assignment. However, the subjects and clinical study site staff were aware of the dose level that was used in each cohort. As 2 dose levels are used in this study, quarantine staff were to have ensured that each subject remained in their own room without direct contact with any other subject.

Are arms mutually exclusive

Yes

Placebo

Arm description

Placebo to match RV521 (The placebo group was split equally across the 2 dose groups such that subjects received placebo at dose level 200 mg in Cohort 1 and at 350 mg in Cohort 2).

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

Placebo capsules at dose level 200 mg (Cohort 1) or 350 mg (Cohort 2), 12 hours apart (± 1 hour) for 10 consecutive doses.

200mg RV521

Arm description

200 mg of RV521 (Cohort 1)

Arm type

Experimental

Investigational medicinal product name

RV521

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

200mg Oral RV521 or placebo, 12 hours apart (± 1 hour) for 10 consecutive doses.

350mg RV521

Arm description

350mg of RV521 (Cohort 2)

Arm type

Experimental

Investigational medicinal product name

RV521

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

350mg Oral RV521 or placebo, 12 hours apart (± 1 hour) for 10 consecutive doses.

Number of subjects in period 1	Placebo	200mg RV521	350mg RV521
Started	22	22	22
Completed	21	22	22
Not completed	1	0	0
Adverse event, non-fatal	1	-	-

Baseline characteristics

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Reporting group title

Placebo

Reporting group description

Placebo to match RV521 (The placebo group was split equally across the 2 dose groups such that subjects received placebo at dose level 200 mg in Cohort 1 and at 350 mg in Cohort 2).

Reporting group title

200mg RV521

Reporting group description

200 mg of RV521 (Cohort 1)

Reporting group title

350mg RV521

Reporting group description

350mg of RV521 (Cohort 2)

Reporting group values	Placebo	200mg RV521	350mg RV521	Total
Number of subjects	22	22	22	66
Age categorical
Units: Subjects
In utero	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0
Newborns (0-27 days)	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0
Children (2-11 years)	0	0	0	0
Adolescents (12-17 years)	0	0	0	0
Adults (18-64 years)	22	22	22	66
From 65-84 years	0	0	0	0
85 years and over	0	0	0	0
Age continuous
Units: years
arithmetic mean (standard deviation)	24.6 ( 5.29 )	21.7 ( 3.09 )	24.5 ( 5.50 )	-
Gender categorical
Units: Subjects
Female	7	9	6	22
Male	15	13	16	44

End points

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Reporting group title

Placebo

Reporting group description

Placebo to match RV521 (The placebo group was split equally across the 2 dose groups such that subjects received placebo at dose level 200 mg in Cohort 1 and at 350 mg in Cohort 2).

Reporting group title

200mg RV521

Reporting group description

200 mg of RV521 (Cohort 1)

Reporting group title

350mg RV521

Reporting group description

350mg of RV521 (Cohort 2)

Primary: Primary efficacy endpoint

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End point title

Primary efficacy endpoint

End point description

The analysis of viral load AUC (first dose of IMP to Study Day 12) by nasal wash RT-qPCR, for the ITT-I Analysis Set defined as all randomised subjects who received Challenge Virus and at least one dose of IMP, and met the criterion for laboratory confirmed RSV infection, defined as the presence of viral shedding (measured in nasal wash). The ITT-I analysis set was considered the primary analysis population for efficacy endpoints.

End point type

Primary

End point timeframe

From the last RT-qPCR measurement collected prior to the first dose of IMP until the last RT-qPCR measurement collected up to Study Day 12 (Quarantine discharge).

End point values	Placebo	200mg RV521	350mg RV521
Number of subjects analysed	19	18	16
Units: log10 PFUe/mL
log mean (standard error)	501.39 ( 86.57 )	224.35 ( 37.60 )	185.26 ( 31.17 )

Descriptive Statistics

Statistical analysis description

AUC descriptive statistics (n, (arithmetic) mean, SD, median, Q1, Q3, minimum and maximum), the Satterthwaite t-test p-value, the difference in mean values (comparison of RV521 dose and placebo) and the associated 95% CI were summarised by treatment group.

Comparison groups

Placebo v 200mg RV521 v 350mg RV521

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.007 ^[1]

Method

Sensitivity Analysis

Confidence interval

Notes
[1] - RV521 resulted in statistically significant reduction in AUC of RT-qPCR RSV viral load compared with placebo; difference in mean values compared with placebo of 55.25% (p=0.007) and 63.05% (p=0.002) for the 200 mg and 350 mg RV521 doses respectively

Adverse events

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Timeframe for reporting adverse events

Collected from informed consent until final follow up visit.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

20.0

Reporting group title

Overall Summary of Adverse Events for Placebo Group

Reporting group description

Reporting group title

Overall summary of Adverse Events for RV521 200mg group

Reporting group description

Reporting group title

Overall summary of Adverse Events for RV521 350mg group

Reporting group description

Serious adverse events	Overall Summary of Adverse Events for Placebo Group	Overall summary of Adverse Events for RV521 200mg group	Overall summary of Adverse Events for RV521 350mg group
Total subjects affected by serious adverse events
subjects affected / exposed	1 / 22 (4.55%)	0 / 22 (0.00%)	0 / 22 (0.00%)
number of deaths (all causes)	0	0	0
number of deaths resulting from adverse events	0	0	0
Cardiac disorders
Sub-acute myocarditis
subjects affected / exposed	1 / 22 (4.55%)	0 / 22 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 1%

Non-serious adverse events	Overall Summary of Adverse Events for Placebo Group	Overall summary of Adverse Events for RV521 200mg group	Overall summary of Adverse Events for RV521 350mg group
Total subjects affected by non serious adverse events
subjects affected / exposed	13 / 22 (59.09%)	12 / 22 (54.55%)	20 / 22 (90.91%)
Cardiac disorders
Myocarditis
subjects affected / exposed	1 / 22 (4.55%)	0 / 22 (0.00%)	0 / 22 (0.00%)
occurrences all number	1	0	0
Blood and lymphatic system disorders
Lymphadenopathy
subjects affected / exposed	1 / 22 (4.55%)	1 / 22 (4.55%)	0 / 22 (0.00%)
occurrences all number	1	1	0
General disorders and administration site conditions
Catheter site erythema
subjects affected / exposed	0 / 22 (0.00%)	0 / 22 (0.00%)	1 / 22 (4.55%)
occurrences all number	0	0	1
Catheter site paraesthesia
subjects affected / exposed	1 / 22 (4.55%)	1 / 22 (4.55%)	0 / 22 (0.00%)
occurrences all number	1	1	0
Pyrexia
subjects affected / exposed	1 / 22 (4.55%)	0 / 22 (0.00%)	0 / 22 (0.00%)
occurrences all number	1	0	0
Vessel puncture site bruise
subjects affected / exposed	0 / 22 (0.00%)	1 / 22 (4.55%)	0 / 22 (0.00%)
occurrences all number	0	1	0
Eye disorders
Eye pain
subjects affected / exposed	1 / 22 (4.55%)	0 / 22 (0.00%)	1 / 22 (4.55%)
occurrences all number	1	0	1
Ocular hyperaemia
subjects affected / exposed	1 / 22 (4.55%)	0 / 22 (0.00%)	0 / 22 (0.00%)
occurrences all number	1	0	0
Gastrointestinal disorders
Abdominal discomfort
subjects affected / exposed	0 / 22 (0.00%)	0 / 22 (0.00%)	1 / 22 (4.55%)
occurrences all number	0	0	1
Abdominal distension
subjects affected / exposed	0 / 22 (0.00%)	0 / 22 (0.00%)	1 / 22 (4.55%)
occurrences all number	0	0	1
Abdominal pain
subjects affected / exposed	0 / 22 (0.00%)	3 / 22 (13.64%)	4 / 22 (18.18%)
occurrences all number	0	3	5
Abdominal pain lower
subjects affected / exposed	0 / 22 (0.00%)	0 / 22 (0.00%)	1 / 22 (4.55%)
occurrences all number	0	0	1
Diarrhoea
subjects affected / exposed	1 / 22 (4.55%)	4 / 22 (18.18%)	9 / 22 (40.91%)
occurrences all number	1	4	11
Food poisoning
subjects affected / exposed	1 / 22 (4.55%)	1 / 22 (4.55%)	0 / 22 (0.00%)
occurrences all number	1	1	0
Lip dry
subjects affected / exposed	0 / 22 (0.00%)	0 / 22 (0.00%)	1 / 22 (4.55%)
occurrences all number	0	0	1
Nausea
subjects affected / exposed	2 / 22 (9.09%)	2 / 22 (9.09%)	12 / 22 (54.55%)
occurrences all number	2	2	12
Vomiting
subjects affected / exposed	0 / 22 (0.00%)	1 / 22 (4.55%)	2 / 22 (9.09%)
occurrences all number	0	1	2

More information

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Were there any global substantial amendments to the protocol? No

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

A substantial amendment related to the change of the Principle Investigator took place after the End of Trial (LSLV) on the 28th November 2017.

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Clinical trials

Clinical Trial Results:
A Randomised, Phase 2a, Double-Blind, Placebo-Controlled Study to Evaluate the Safety, Pharmacokinetics and Antiviral Activity of Multiple Doses of RV521 Against Respiratory Syncytial Virus infection in the Virus Challenge Model.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Primary efficacy endpoint

Primary: Primary efficacy endpoint

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

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Clinical trials

Clinical Trial Results: A Randomised, Phase 2a, Double-Blind, Placebo-Controlled Study to Evaluate the Safety, Pharmacokinetics and Antiviral Activity of Multiple Doses of RV521 Against Respiratory Syncytial Virus infection in the Virus Challenge Model.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Primary efficacy endpoint

Primary: Primary efficacy endpoint

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Randomised, Phase 2a, Double-Blind, Placebo-Controlled Study to Evaluate the Safety, Pharmacokinetics and Antiviral Activity of Multiple Doses of RV521 Against Respiratory Syncytial Virus infection in the Virus Challenge Model.