Clinical Trials Register

Summary
EudraCT Number:	2012-004891-20
Sponsor's Protocol Code Number:	PNV117270
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:	2013-06-13
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

2012-004891-20

A.3

Full title of the trial

A randomised, double-blind (sponsor-unblind), placebo controlled, cross-over study to investigate the efficacy, effect on cough reflex sensitivity, safety, tolerability and pharmacokinetics of inhaled GSK2339345 in patients with chronic idiopathic cough using an aqueous droplet inhaler

A.3.1

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

A phase II clinical study to assess the effectiveness, safety, tolerability and pharmacokinetics of inhaled GSK2339345 in patients with chronic cough using an aqueous droplet inhaler.

A.4.1

Sponsor's protocol code number

PNV117270

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	GlaxoSmithKline Research and Development Ltd
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	GlaxoSmithKline Research and Development Ltd
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	GlaxoSmithKline Research & Development Ltd
B.5.2	Functional name of contact point	Clinical Trials Helpdesk
B.5.3	Address:
B.5.3.1	Street Address	Iron Bridge Road, Stockley Park West
B.5.3.2	Town/ city	Iron Bridge Road, Stockley Park West
B.5.3.3	Post code	UB11 1 BU
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	44208990 4466
B.5.5	Fax number	44208990 1234
B.5.6	E-mail	GSKClinicalSupportHD@gsk.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	GSK2339345
D.3.2	Product code	GSK2339345
D.3.4	Pharmaceutical form	Inhalation vapour, solution
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	GSK2339345
D.3.9.2	Current sponsor code	GSK2339345
D.3.9.3	Other descriptive name	GSK2339345
D.3.9.4	EV Substance Code	SUB73049
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	20
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	Inhalation vapour, 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

chronic idiopathic cough

E.1.1.1

Medical condition in easily understood language

chronic cough

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	17.0
E.1.2	Level	LLT
E.1.2	Classification code	10066656
E.1.2	Term	Chronic cough
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

EFFICACY: To evaluate the effect of a single dose of GSK2339345, administered on two occasions, four hours apart, versus placebo on objective cough counts in patients with chronic idiopathic cough.

E.2.2

Secondary objectives of the trial

TUSSIVE CHALLENGE: To evaluate the effect of single dose GSK2339345 versus placebo on cough response to tussive challenge in patients with chronic idiopathic cough.

EFFICACY: To assess the duration of effect of GSK2339345 versus placebo on objective cough counts in patients with chronic idiopathic cough.

To assess the effect of GSK2339345 versus placebo on the urge to cough in patients with chronic idiopathic cough.

To assess the effect of GSK2339345 versus placebo on the severity of cough in patients with chronic idiopathic cough.

SAFETY: To assess the safety and tolerability of GSK2339345 versus placebo in patients with chronic idiopathic cough.

PHARMACOKINETICS: To evaluate the systemic pharmacokinetics of GSK2339345 in patients with chronic idiopathic cough.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Chronic Idiopathic Cough patients according to the criteria listed below, determined by a responsible and experienced physician, based on a medical evaluation:
• Idiopathic cough defined as chronic cough resistant to treatment targeted at potential triggers.
• Chronic cough defined as cough lasting for more than 8 weeks (British Thoracic Society, 2006).
2. A patient with a clinical abnormality or laboratory parameters outside the reference range for the population being studied may be included only if the Investigator and the GSK Medical Monitor agree that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures.
3. Male/females aged ≥18 years old, at the time of signing the informed consent.
4. Non-smoker for at least 6 months with a cumulative history of ≤ 20 pack years.
• Pack years = (No. of cigarettes smoked/day/20) x (No. of years smoked)
5. Body weight ≥ 50 kg.
6. A female subject is eligible to participate if she is of:
• Non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy [for this definition, “documented” refers to the outcome of the investigator's/designee’s review of the subject's medical history for study eligibility, as obtained via a verbal interview with the subject or from the subject’s medical records]; or postmenopausal defined as 12 months of spontaneous amenorrhea [in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) > 40 MlU/ml and estradiol < 40 pg/ml (<147 pmol/L) is confirmatory]. Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the contraception methods in Section 4.3.1 if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrollment. For most forms of HRT, at least 2-4 weeks will elapse between the cessation of therapy and the blood draw; this interval depends on the type and dosage of HRT. Following confirmation of their post-menopausal status, they can resume use of HRT during the study without use of a contraceptive method.
• Child-bearing potential with negative pregnancy test as determined by serum hCG test at screening or prior to dosing AND
• Agrees to use one of the contraception methods listed in Section 4.3.1 for an appropriate period of time (as determined by the product label or investigator) prior to the start of dosing to sufficiently minimize the risk of pregnancy at that point. Female subjects must agree to use contraception until the follow up visit.
• OR has only same-sex partners, when this is her preferred and usual lifestyle.
7. Male subjects with female partners of child-bearing potential must agree to use one of the contraception methods listed in Section 4.3.1. This criterion must be followed from the time of the first dose of study medication until the follow up visit.
8. Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form
9. AST and ALT < 2xULN; alkaline phosphatase and bilirubin ≤1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).
10. Based on averaged QTc values of triplicate ECGs obtained over a brief recording period:
• QTcF < 450 msec;
• QTcF < 480 msec for patients with a Bundle Branch Block
11. A 24 hour Holter ECG at screening that demonstrates no clinically significant abnormalities or finding that could interfere with interpretation of the study results, when assessed by an appropriately trained and experienced reviewer.

E.4

Principal exclusion criteria

Criteria Based Upon Medical Histories
1. Subjects who have evidence of current asthma, as confirmed by the Investigator or designee.
2. Subjects with any clinically significant respiratory condition or lung pathology that could cause cough (apart from chronic idiopathic cough).
3. Known lung cancer or other active malignancy, or history of.
4. Subjects with current or a chronic history of cardiovascular disease (including uncontrolled hypertension, ischaemic heart disease, angina, myocardial infarct, congestive heart failure, stroke).
5. Subjects with current central nervous system / peripheral nervous system conditions e.g. epilepsy and myasthenia gravis.
6. Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
7. Any subject with a respiratory tract infection within 4 weeks of screening.
8. Radiological imaging prior to the study, including chest X-rays, that have shown any evidence of clinically significant lung disease, as judged by the Investigator or designee.
9. History of regular alcohol consumption within 6 months of the study defined as:
• An average weekly intake of >21 units for males or >14 units for females. One unit is equivalent to 8 g of alcohol: a half-pint (~240 ml) of beer, 1 glass (125 ml) of wine or 1 (25 ml) measure of spirits.
10. Any subject who has a history of an allergic reaction to a local anaesthetic. History of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that, in the opinion of the investigator or GSK Medical Monitor, contraindicates their participation.
11. Any subject who has a known hypersensitivity to capsaicin or citric acid.

Criteria Based Upon Diagnostic Assessments
12. A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening.
13. Any subject who, upon oropharyngeal examination, is deemed by the Investigator to be unsuitable for oropharyngeal sensation assessments. This includes any injuries to the mucosa of the mouth or pharynx that could potentially increase systemic absorption e.g. oropharyngeal candidiasis.
14. FEV1 less than 80% of the predicted normal value prior to first dosing of the study.
15. Any subject who does not reach C5 following an oral inhalation of capsaicin at a dose level of 250 μM at screening.
16. Urinary cotinine levels indicative of smoking or history or regular use of tobacco- or nicotine-containing products within 6 months prior to screening.
17. A positive pre-study drug/alcohol screen.

Other Criteria
18. Subjects who are unable to use the inhaler satisfactorily.
19. Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56 day period.
20. Lactating females.
21. The subject has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer).
22. Exposure to more than four new chemical entities within 12 months prior to the first dosing day.

E.5 End points

E.5.1

Primary end point(s)

EFFICACY: Total cough counts (8 hours of recording) at Visits 1, 2 and 3 (4 hours of post-dose recording for each of the two doses administered).

E.5.1.1

Timepoint(s) of evaluation of this end point

Continuous cough monitoring 8 hours (4 hours post-dose for each of the two doses administered) post-first dose at visits 1, 2 & 3.

E.5.2

Secondary end point(s)

TUSSIVE CHALLENGE: Number of coughs following each dose of capsaicin, following a single dose of GSK2339345 or placebo.

Number of coughs following each dose of citric acid, following a single dose of GSK2339345 or placebo.

EFFICACY:Cough counts following GSK2339345 or placebo at Visits 1, 2 and 3 over shorter epochs (e.g. 1 hour or 15 minute intervals).

Urge to cough VAS 1 hour post-last dose at Visits 1, 2 and 3.

Cough severity VAS 1 hour post-last dose at Visits 1, 2 and 3.

SAFETY: Safety parameters: AEs, vital signs, ECGs, body temperature, laboratory assessments (including haematology, clinical chemistry and cardiac troponin), FEV1; and oropharyngeal sensate changes (four point scale).

PHARMACOKINETICS: Plasma concentrations of GSK2339345 and derived pharmacokinetic parameters including Cmax, tmax, AUC(0-1) and AUC(0-4) as appropriate and predicted AUC(0-24) following two repeated doses where data allow, at Visits 1, 2 and 3.

E.5.2.1

Timepoint(s) of evaluation of this end point

TUSSIVE CHALLENGE: Continuous cough monitoring for 1 hour post-dose on visits 4, 5, 6 & 7.
EFFICACY:Cough counts following GSK2339345 or placebo at Visits 1, 2 and 3 for 8 hours post dose (total and also divided into shorter epochs (e.g. 1 hour or 15 minute intervals). Urge to cough VAS 1 hour post-last dose at Visits 1, 2 and 3. Cough severity VAS 1 hour post-last dose at Visits 1, 2 and 3 (as above).
SAFETY:Up to a minimum of 1 hour post-dose during visits 1, 2, 3, 4, 5, 6 & 7. Period of monitoring and assessments may continue for longer in the event of any safety concerns. Follow-up of each subject will occur 7-14days following the last dose.
PHARMACOKINETICS(PK):Blood samples for PK analysis will be collected at intervals from pre-dose until 2 hours post each dose during visits 1-3.

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

Yes

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

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

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

LSLV

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 years

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

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

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.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)

Subjects will not receive any additional treatment from GSK after completion of the study because the indication being studied is not life threatening or seriously debilitating and/or other treatment options are available.
The investigator is responsible for ensuring that consideration has been given to the post-study care of the patient’s medical condition, whether or not GSK is providing specific post-study treatment.

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

2013-07-24

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-09-06

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2014-10-02

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