Clinical Trials Register

Summary
EudraCT Number:	2014-005615-17
Sponsor's Protocol Code Number:	RPL554-008-2014
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2015-03-02
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

UK - MHRA

A.2

EudraCT number

2014-005615-17

A.3

Full title of the trial

A Phase II, randomised, double blind, placebo controlled, seven way crossover study to assess the effect of single doses of RPL554 compared to salbutamol and placebo administered by nebuliser on lung function of patients with chronic asthma

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

A study to assess the effect of single doses of RPL554 compared to salbutamol and placebo administered by nebuliser in patients with chronic asthma

A.3.2

Name or abbreviated title of the trial where available

Single doses of RPL554 in adult patients with chronic asthma

A.4.1

Sponsor's protocol code number

RPL554-008-2014

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Verona Pharma plc
B.1.3.4	Country	United Kingdom
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Verona Pharma plc
B.4.2	Country	United Kingdom
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Verona Pharma plc
B.5.2	Functional name of contact point	Senior Scientist, Development
B.5.3	Address:
B.5.3.1	Street Address	3 More London Riverside
B.5.3.2	Town/ city	London
B.5.3.3	Post code	SE1 2RE
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	020 3283 4201
B.5.6	E-mail	kathy.abbott-banner@veronapharma.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	RPL554
D.3.2	Product code	RPL554
D.3.4	Pharmaceutical form	Nebuliser suspension
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Inhalation use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	RPL554
D.3.9.1	CAS number	298680-25-8
D.3.9.2	Current sponsor code	RPL554
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	0.5
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	RPL554
D.3.9.1	CAS number	298680-25-8
D.3.9.2	Current sponsor code	RPL554
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	1.5
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	RPL554
D.3.9.1	CAS number	298680-25-8
D.3.9.2	Current sponsor code	RPL554
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	6
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Comparator
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Salbutamol 5mg/2.5ml Nebuliser Solution (Arrow) & Salbutamol 2.5mg/2.5ml Nebuliser Solution (Arrow)
D.2.1.1.2	Name of the Marketing Authorisation holder	Breath Limited
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Salbutamol 5mg/2.5ml & 2.5mg/2.5ml Nebuliser Solution (Arrow)
D.3.4	Pharmaceutical form	Nebulisation solution
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Inhalation use
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Nebuliser solution
D.8.4	Route of administration of the placebo	Inhalation use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Patients with chronic asthma

E.1.1.1

Medical condition in easily understood language

Patients with Asthma - illness with breathing difficulties

E.1.1.2

Therapeutic area

Diseases [C] - Respiratory Tract Diseases [C08]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	17.1
E.1.2	Level	LLT
E.1.2	Classification code	10049106
E.1.2	Term	Asthma chronic
E.1.2	System Organ Class	100000004855

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To investigate the bronchodilator effect of single doses of RPL554 administered by nebuliser on peak and average* FEV1 over 12 hours compared with placebo and salbutamol.

*The average effect will be calculated as the area under the curve divided by the length of the time interval of interest, and the peak effect as the minimum value for diastolic blood pressure or maximum value for other variables

E.2.2

Secondary objectives of the trial

• To investigate the bronchodilator effect of single doses of RPL554 administered by nebuliser on peak and average* FEV1 over 4, 6 and 8 hours compared with placebo and salbutamol
• To investigate the pharmacodynamic effect of single doses of RPL554 administered by nebuliser on peak and average* blood pressure, pulse rate and ECG heart rate over 4 hours compared with placebo and salbutamol
• To analyse plasma concentrations and assess the pharmacokinetics of RPL 554
• To assess the tolerability and safety of single doses of RPL554 administered by nebuliser compared with placebo and salbutamol
*The average effect will be calculated as the area under the curve divided by the length of the time interval of interest, and the peak effect as the minimum value for diastolic blood pressure or maximum value for other variables

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Provision of written informed consent prior to any study specific procedures
2. Males or females aged 18 to 65 years (inclusive)
3. a) Males must be willing, able and agree to meet the following from the first dose up to 30 days after the last dose of study drug:
- Not donate sperm
- Either: be sexually abstinent in accordance with a patient’s usual and preferred lifestyle (but agree to abide by the contraception requirements below should their circumstances change)
Or: use a condom with all sexual partners. If the partner is of childbearing potential the condom must be used with spermicide and a second reliable form of contraception must also be used (e.g. diaphragm/cap with spermicide, established hormonal contraception, intra-uterine device)
b) Females must be either post-menopausal (defined as amenorrheic for 12 months and follicle stimulating hormone plasma concentration within the post-menopausal range as defined by the laboratory) or surgically sterile (hysterectomy, tubal ligation, hysteroscopic sterilisation)
4. Body mass index (BMI) between 18 and 30 kg/m2 (inclusive)
5. Non-smoker or ex-smoker who has stopped smoking for >6 months before screening and have a smoking history of not more than 10 pack years
6. Diagnosed asthma for at least 6 months. Asthma is defined according to the global initiative for asthma (GINA), 2012
7. Pre-bronchodilator FEV1 ≥60% and ≤90% of predicted normal value and ≥1.5 L at screening
8. Increase in FEV1 of ≥15% within 30 minutes after a 2.5mg dose of nebulised salbutamol
9. Able to correctly use the study nebuliser
10. Able to complete the clinical study
11. Systolic blood pressure 90 to 145 mmHg, diastolic blood pressure 50 to 90 mmHg and heart rate 45 to 80 beats per minute (bpm) after resting for 5 minutes in a supine position (average from two measurements)
12. Patients must be capable of withdrawing from long acting β2 agonists (LABAs) and long acting muscarinic antagonists (LAMAs) for 72 hours and short acting muscarinic antagonists (SAMAs) for 8 hours before the reversibility test at screening and expected to be able to withhold during study
13. Patients must be capable of withdrawing from short acting β2 agonists (SABAs) for 8 hours before the reversibility test at screening and 8 hours before all study drug administrations

E.4

Principal exclusion criteria

1. Asthma exacerbation (defined as requiring medical intervention) in the 3 months before screening
2. Any prior life threatening episode of asthma (intensive care admission)
3. Any clinically significant disease or disorder (e.g. cardiovascular, pulmonary other than asthma, chronic obstructive pulmonary disease [COPD], gastrointestinal, liver, renal, neurological, musculoskeletal, endocrine, metabolic, malignant, psychiatric, major physical impairment) which, in the opinion of the Investigator, may either put the patient at risk because of participation in the study, or influence the result of the study, or the patient´s ability to participate in the study
4. Any clinically relevant abnormal findings in physical examination, clinical chemistry, haematology, urinalysis, vital signs, ECG or lung function at screening, which, in the opinion of the Investigator, may put the patient at risk because of his/her participation in the study
5. QTcF interval >450 ms or QT interval >500 ms or other abnormality in ECG making interpretation more difficult, as judged by the Investigator
6. History of ischemic heart disease or heart failure. History of recurrent or current clinically significant arrhythmia or ECG abnormality as judged by the investigator
7. Treatment with systemic glucocorticosteroids within 30 days before screening
8. A definite or suspected personal history of intolerance or hypersensitivity to drugs and/or their excipients, judged to be clinically relevant by the Investigator
9. Donation of blood within 1 month or donation of plasma within 14 days before screening
10. History of, or current alcohol or drug abuse, as judged by the Investigator
11. A suspected/manifested infection according to the World Health Organisation (WHO) risk classification 2, 3 or 4
12. Positive results on screening tests for hepatitis B and/or C and/or human immunodeficiency virus (HIV)
13. Previous randomisation to treatment in the present study
14. Participation in another investigational medicinal product study within 3 months or five half-lives (whichever is longer) before screening
15. Planned in-patient surgery, dental procedure or hospitalisation during the study
16. Patients who, in the opinion of the Investigator, should not participate in the study
17. Involvement in the planning and/or conduct of the study (applies to both Sponsor staff and/or staff at the study centre, or their relatives in both cases)

E.5 End points

E.5.1

Primary end point(s)

Peak and average FEV1 following start of nebulisation

E.5.1.1

Timepoint(s) of evaluation of this end point

12 hours

E.5.2

Secondary end point(s)

• Average FEV1 following start of nebulisation and onset of action
• Peak and average blood pressure and pulse rate and ECG heart rate following start of nebulisation (pharmacodynamics)
• RPL554 pharmacokinetics (area under the curve [AUC], maximum concentration of RPL554 in blood [Cmax], time to maximum concentration [tmax,] half life of RPL554 [t1/2], mean residence time [MRT])
• Safety and tolerability:
o Continuous monitoring of AEs
o Laboratory safety tests [haematology, biochemistry and urinalysis] pre-dose and post dose with further post-dose measurements of glucose and potassium only
o 12-lead ECG, supine vital signs

E.5.2.1

Timepoint(s) of evaluation of this end point

• Average FEV1 over 4, 6 and 8 hours following start of nebulisation and onset of action
• Peak and average blood pressure and pulse rate and ECG heart rate over 4 hours following start of nebulisation (pharmacodynamics)
• RPL554 pharmacokinetics (area under the curve [AUC], maximum concentration of RPL554 in blood [Cmax], time to maximum concentration [tmax,] half life of RPL554 [t1/2], mean residence time [MRT]) from a 12 hour profile
• Safety and tolerability:
o Continuous monitoring of AEs
o Laboratory safety tests [haematology, biochemistry and urinalysis] pre-dose and 12 hours post-dose with further post-dose measurements of glucose and potassium only over 2 hours
o 12-lead ECG, supine vital signs over 12 hours

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

E.8.1.6

Cross over

Yes

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

Salbutamol

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

Medication will not be provided by the sponsor to study subjects at the end trial. The investigator will ensure that subjects continue to receive the best available treatment once thay have completed the study, referring them back to their GP.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2015-04-14

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-04-22

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2015-11-17

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