Clinical Trials Register

Summary
EudraCT Number:	2010-024283-18
Sponsor's Protocol Code Number:	AF219-006
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:	2011-02-21
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

2010-024283-18

A.3

Full title of the trial

A Study to Assess the Efficacy of AF-219, a P2X3 Receptor Antagonist, in Subjects with Chronic Cough

A.3.1

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

A study of investigational drug AF-219 and its affect on treating subjects with chronic cough

A.3.2

Name or abbreviated title of the trial where available

EPICC

A.4.1

Sponsor's protocol code number

AF219-006

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	Afferent Pharmaceuticals, Inc.
B.1.3.4	Country	United States
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	Afferent Pharmaceuticals Inc
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Afferent Pharmaceuticals Inc
B.5.2	Functional name of contact point	Study Coordinator
B.5.3	Address:
B.5.3.1	Street Address	2755 Campus Drive, Suite 100
B.5.3.2	Town/ city	San Mateo
B.5.3.3	Post code	CA 94403
B.5.3.4	Country	United States
B.5.4	Telephone number	+1650286 9308
B.5.5	Fax number	+1650403 0805
B.5.6	E-mail	bruce.mccarthy@afferentpharmaceuticals.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	AF-219
D.3.2	Product code	AF-219
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.2	Current sponsor code	AF-219
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	300
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	Tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Subjects with Chronic 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	17.1
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

To evaluate the effectiveness of AF-219 in reducing daytime objective cough frequency

E.2.2

Secondary objectives of the trial

To evaluate the effectiveness of AF-219 in:
• reducing night time objective cough frequency,
• reducing subjective scores of cough severity,
• showing global rating of change scale,
• improving cough-specific quality of life.
To evaluate the safety of AF-219 in a subject population with chronic cough (CC).
To evaluate the relationship between AF219 plasma trough concentration and cough relief.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Subjects are eligible for inclusion if they meet the following inclusion criteria:
1. Men and women ≥18 and ≤80 years of age
2. Written informed consent from the subject
3. History of cough for more than 8 weeks
4. Normal chest radiograph
5. Idiopathic or treatment resistant cough (idiopathic defined as a cough for which no objective evidence of an underlying trigger can be determined after investigation) or a cough that is unresponsive to 8 weeks of targeted treatment for identified underlying triggers including reflux disease, asthma and post-nasal drip (treatment-resistant).*
6. Women must be post-menopausal, with no menses for 12 months without an alternative medical cause, or if of child-bearing potential must have a negative pregnancy test and agree to use one of the following acceptable birth control methods from screening visit to follow-up contact:
• True complete abstinence when this is in line with the preferred and usual lifestyle of the subject (periodic abstinence such as calendar, ovulation, symptothermal or post-ovulation methods are not acceptable methods of contraception),
or
• Surgical sterilization of either the female subject in study (e.g., bilateral tubal ligation) or of her male partner (vasectomy with documented azoospermia) if he is the sole partner of that subject,
or
• Established hormonal contraception (implantable, patch, oral or intramuscular [IM]) administered for at least one month prior to study medication administration
• An intrauterine device (IUD) or intrauterine system (IUS) with failure rate of less than 1% per year inserted by qualified physician at least one month prior to study medication administration,
or
• Double barrier method: condom and occlusive cap (diaphragm) with spermicidal foam/gel/film/cream/suppository,

* Investigations will include bronchial provocation testing (to exclude asthma), ear, nose, and throat (ENT) examination (to exclude post-nasal drip syndrome) and either 24 hour impedance/pH testing or an 8 week trial of twice daily proton pump inhibitor/H2 receptor blocker (to exclude reflux disease). All these tests are performed routinely according to North West Lung Centre management protocol in the clinic and only subjects who have already been investigated will be invited to participate in the study

E.4

Principal exclusion criteria

Subjects must NOT meet any of the following exclusion criteria:
1. Current smoker
2. Individuals who have given up smoking within the past 6 months, or those with >20 pack-year smoking history
3. Treatment with an ACE-inhibitor as the potential cause of a subject’s cough, or requiring treatment with an ACE-inhibitor during the study or within 4 weeks prior to Day 0.
4. FEV1/FVC <60%
5. History of upper respiratory tract infection within 4 weeks of the Baseline Visit
6. History of opioid use within 1 week of the Baseline Visit
7. History of pregabalin use within 4 weeks of the Baseline Visit
8. Body mass index (BMI) <18 or >35
9. History of urinary tract infection within 6 months prior to Screening
10. History or symptoms of renal disease, including nephro/urolithiasis, pyelonephritis, or renal obstructive disease
11. History of conditions or disorders which predispose to nephrolithiasis such as frequent and recurrent urinary tract infections, Type 1 renal tubular acidosis, cystinuria, gout, hyperparathyroidism, inflammatory bowel disease, short bowel syndrome, bariatric surgery
12. History of stroke or transient ischemic attack within 2 years prior to Screening or residual deficits that would preclude completion of study activities
13. History of life-threatening neoplasms within 5 years prior to study entry, other than carcinoma in situ of the cervix or squamous or basal cell carcinoma of the skin
14. History of drug or alcohol dependency or abuse within approximately the last 5 years
15. Clinically significant depression or a history of suicide behavior or suicidal ideation unless the Investigator and Medical Monitor conclude, based upon an assessment by a qualified mental health professional, that the subject may safely participate in the study
16. In the opinion of the Investigator and Medical Monitor, an uncontrolled or unstable, clinically significant neurological, psychiatric, respiratory, cardiovascular, peripheral vascular, gastrointestinal, hepatic, pancreatic, endocrinological, hematological, or immunological disorder or an active infection
17. Any condition possibly affecting drug absorption (e.g., gastrectomy, vagotomy or bowel resection)
18. Estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 (using the Modification of Diet in Renal Disease [MDRD] formula [http://mdrd.com/])
19. Screening systolic blood pressure greater than 160 mm Hg or a diastolic blood pressure greater than 90 mm Hg
20. Clinically significant abnormal electrocardiogram (ECG) at Screening, including
a. Prolongation of QT/QTc (corrected QT) interval (>450 milliseconds in males, >460 milliseconds in females)
b. atrial fibrillation, atrial flutter,
c. notable bradycardia (heart rate <45 bpm) or tachycardia (HR >100 bpm)
d. complete (left or right) branch block,
e. Wolf-Parkinson-White Syndrome,
f. cardiac pacemaker
21. Significantly abnormal laboratory tests, including:
a. Screening alkaline phosphatase (AP), alanine aminotransferase (SGPT, ALT), aspartate aminotransferase (SGOT, AST), or bilirubin greater than 150% of the upper limit of normal (ULN)
b. Screening haemoglobin <10 g/dL,white blood cell (WBC) <2500 mm3, neutrophil count <1500 mm3, platelet count <100 × 103/mm3
c. Screening haemoglobin A1C ≥7.0
d. Screening microscopic haematuria, defined as ≥5 red blood count (RBC) per high-power field (hpf) on microscopic urinalysis
22. Post-void residual >200 mL at Screening
23. Clinically significant abnormalities on renal/bladder ultrasound at Screening
24. Requires concomitant therapy during or prior to Day 0 with prohibited medications
25. History of a cutaneous adverse drug reaction to sulphonamides
26. Pregnant or nursing females; females of childbearing potential who are unwilling or unable to use an acceptable method of contraception for the duration of the study
27. Treatment with an investigational drug or biologic within 60 days preceding the first dose of study medication or plans to take another investigational drug or biologic within 30 days of study completion
28. Blood donation of approximately 1 pint (500 mL) or more within 56 days prior to dosing
29. Flu vaccination within 30 days of Day 0
30. Subjects who are known to be Human Immunodeficiency Virus (HIV)-positive
31. Subjects who are known to have viral hepatitis (A, B, or C) as demonstrated by positive serology (positive IgM anti-HAV, HepB sAg or anti-HCV)
32. Other severe, acute, or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with trial participation or investigational product administration or may interfere with the interpretation of trial results and, in the judgment of the Investigator, would make the subject inappropriate for entry into this trial

E.5 End points

E.5.1

Primary end point(s)

To determine whether 2 weeks of
treatment with AF-219 is superior to placebo as measured by change from Baseline in daytime objective cough frequency.

E.5.1.1

Timepoint(s) of evaluation of this end point

At close of study

E.5.2

Secondary end point(s)

To determine whether AF-219 is superior
to placebo as measured by change from Baseline in:
i. night time objective cough frequency
ii. cough VAS day/night
iii. urge to cough
iv. global rating of change
v. cough quality of life

E.5.2.1

Timepoint(s) of evaluation of this end point

At close of study

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

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.8.4.1

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

Last subject, last visit

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

Number of subjects for this age range:

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.4.2

For a multinational trial

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)

Normal care for the condition

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

2011-04-18

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2011-05-20

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2013-02-21

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