Clinical Trials Register

Summary
EudraCT Number:	2015-000464-34
Sponsor's Protocol Code Number:	AF219-015
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:	2015-03-26
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

2015-000464-34

A.3

Full title of the trial

A Study to Assess the Effect of AF-219 on Cough Reflex Sensitivity in Both Healthy and Chronic Cough Subjects

A.3.1

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

A study to determine the ability of AF-219 to affect the cough reflex in healthy volunteers and in people affected by long-term coughing

A.4.1

Sponsor's protocol code number

AF219-015

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	Peter Butera, Clinical Operations
B.5.3	Address:
B.5.3.1	Street Address	2929 Campus Drive, Suite 230
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	1650638 9491
B.5.5	Fax number	1650286 1833
B.5.6	E-mail	peter.butera@afferentpharma.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.3.2	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.3.11 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

Chronic Cough

E.1.1.1

Medical condition in easily understood language

Long-term cough

E.1.1.2

Therapeutic area

Diseases [C] - Respiratory Tract Diseases [C08]

MedDRA Classification

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 assess the effect of single doses of 300 mg and 50 mg AF-219 on cough reflex sensitivity to capsaicin in both healthy and chronic cough subjects

E.2.2

Secondary objectives of the trial

-To assess the effect of single doses of 300 mg and 50 mg AF 219 on cough reflex sensitivity to ATP in both healthy and chronic cough subjects
-To determine the effect of single doses of 300 mg and 50 mg AF 219 on the urge to cough evoked by capsaicin and ATP in both healthy and chronic cough subjects
-To determine the effect of single doses of 300 mg and 50 mg AF 219 on daytime cough frequency in subjects with chronic cough
-To determine the effect of single doses of 300 mg and 50 mg AF 219 on cough severity VAS and urge-to-cough VAS in subjects with chronic cough
-To assess the safety and tolerability of AF-219

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Both healthy and chronic cough subjects who meet all of the following criteria will be included in the study:
1. Be informed of the nature of the study and have provided written informed voluntary consent;
2. Be able to speak, read, and understand English;
3. Be males or females, of any race, between 18 and 80 years of age, inclusive;
4. Have a body mass index (BMI) ≥ 18 and < 35.0 kg/m2;
5. FEV1 ≥ 80% at Screening (healthy volunteers only);
6. Have an Emax ≥ 4 following the capsaicin challenge at Screening;
7. Be in good general health with no clinically relevant abnormalities based on the medical history, physical examination, clinical laboratory evaluations (hematology, clinical chemistry, and urinalysis), and 12 lead electrocardiogram;
8. Women of child bearing potential (i.e., women who are not surgically sterile, not having had hysterectomy, bilateral tubal occlusion or bilateral oophorectomy, or are not post-menopausal) must have a negative pregnancy test at Screening and prior to randomization. Definition of postmenopausal status is having been naturally (spontaneously) amenorrhoeic for more than 12 months with an appropriate clinical profile, e.g., age appropriate, history of vasomotor symptoms. Women of child-bearing potential must be using 2 forms of acceptable birth control method from Screening until 3 months after the last dose of study drug. Women of child-bearing potential must use 2 methods of acceptable birth control from Screening until 3 months after the last dose of study drug. (acceptable birth control methods are given in section 5.3);
9. Male subjects with partners of child-bearing potential (as defined in Inclusion No. 8) must use 2 methods of acceptable birth control, 1 of which must be a barrier method. Contraception must start from Screening and continue until 3 months after last dose of study drug. Donation of sperm is not permitted from Screening until 3months after the last dose of study drug (acceptable birth control methods are given in section 5.3);
10. Subjects with chronic cough must:
a. Have Treatment Refractory Cough for at least one year: a cough that is unresponsive to at least 8 weeks of targeted treatment for identified underlying triggers including reflux disease, asthma and post-nasal drip (treatment is defined as any of the following):
i. first-generation antihistamine for post-nasal drip;
ii. oral steroid course for asthma;
iii. twice daily proton pump inhibitor for an adequate period of time (typically 8 weeks) for reflux disease; or
b. Have a cough for which no objective evidence of an underlying trigger can be determined after investigation.
11. Be able to communicate effectively with the Investigator and other study center personnel and agree to comply with the study procedures and restrictions.

E.4

Principal exclusion criteria

Subjects will be excluded if any of the following apply:
1. Current smoker;
2. Individuals who have given up smoking within the past 6 months, or those with >20 pack-year smoking history (chronic cough subjects), or >10 pack-year smoking history (healthy subjects);
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 2 months prior to Screening;
4. History of upper respiratory tract infection or recent significant change in pulmonary status within 4 weeks prior to Screening or prior to randomization;
5. History of opioid use within 1 week prior to Screening or prior to randomization;
6. History of pregabalin, gabapentin or thalidomide use within 2 weeks of the Screening Visit;
7. Requiring concomitant therapy with prohibited medications;
8. History or symptoms of renal disease or renal obstructive disease;
9. History of kidney/bladder stones (nephro/uro-lithiasis) within 5 years of Screening;
10. History of conditions or disorders that predispose to nephrolithiasis such Type 1 renal tubular acidosis, cystinuria, gout, hyperparathyroidism, inflammatory bowel disease (i.e., ulcerative colitis and Crohn‟s disease), short bowel syndrome, or bariatric surgery;
11. History of concurrent malignancy or recurrence of malignancy within 2 years prior to Screening (with the exception of < 3 excised basal cell carcinomas);
12. History of a diagnosis of drug or alcohol dependency or abuse within the last 3 years;
13. In the opinion of the Principal Investigator, an uncontrolled or unstable clinically significant neurological, psychiatric, respiratory, cardiovascular, peripheral vascular, gastrointestinal, hepatic, pancreatic, endocrinological, hematological, or immunological disorder or an active infection (discussion with the Afferent Medical Monitor is needed if clarifications are required);
14. Any condition possibly affecting drug absorption (e.g., gastrectomy, gastroplasty, any type of bariatric surgery, vagotomy, or bowel resection);
15. Estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 (using the Chronic Kidney Disease Epidemiology Collaboration (CKD EPI) formula [http://mdrd.com/]) at Screening;
16. Screening systolic blood pressure (SBP) >160 mm Hg or a diastolic blood pressure (DBP) >90 mm Hg;
17. Screening Heart rate <40 beats per minute >110 bpm
18. Clinically significant abnormal electrocardiogram (ECG) at Screening, including any of the following:
a. QT (QTcF) interval >450 milliseconds in males, >470 milliseconds in females
b. Atrial fibrillation or atrial flutter
c. Second degree or third degree (complete) AV block
d. Left bundle branch block (including hemiblock)
e. Wolf-Parkinson-White Syndrome
19. Personal or family history of congenital long QT syndrome or family history of sudden death;
20. Cardiac pacemaker;
21. Significantly abnormal laboratory tests at Screening, including:
a. alkaline phosphatase (AP), alanine aminotransferase (ALT, SGPT), aspartate aminotransferase (AST, SGOT), or bilirubin >150% of the upper limit of normal (ULN)
b. hemoglobin < 10 gm/dL, WBC count <2500 mm3, neutrophil count <1500 mm3, platelet count <100 × 103/mm3
c. Positive urine tests for drugs of abuse
d. Positive tests at Screening for HIV, viral hepatitis defined by positive immunoglobulin M (IgM) anti-hepatitis A virus (HAV), hepatitis B virus (HepB) sAg, or anti-hepatitis C virus (HCV)
22. History of cutaneous adverse drug reaction to sulfonamides or signs and symptoms suggestive of anaphylaxis to sulphonamides;
23. Breastfeeding;
24. Treatment with an investigational drug or biologic within 30 days preceding the first dose of study drug or plans to take another investigational drug or biologic within 30 days of study completion (Follow-Up);
25. Blood donation within 56 days prior to dosing;
26. Plasma donation within 7 days prior to dosing;
27. In the judgement of the Principal Investigator, 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 would make the subject inappropriate for entry into this trial (discussion with the Afferent Medical Monitor is needed if clarifications are required).

E.5 End points

E.5.1

Primary end point(s)

Emax response to capsaicin inhalation
ED50 for capsaicin challenge

E.5.1.1

Timepoint(s) of evaluation of this end point

Primary endpoints are evaluated during entire treatment period

E.5.2

Secondary end point(s)

Emax response to ATP inhalation
ED50 for ATP challenge
C2 and C5 for capsaicin challenge
C2 and C5 for ATP challenge
Reported urge to cough (UTC) during the cough challenges for both capsaicin and ATP
Daytime cough frequency in subjects with chronic cough
Daytime UTC and cough severity VAS in subjects with chronic cough

E.5.2.1

Timepoint(s) of evaluation of this end point

Primary endpoints are evaluated during entire treatment period

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

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.8.5

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

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

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

Yes

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)

None

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

2015-04-29

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-04-01

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2016-05-19

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