Clinical Trials Register

Summary
EudraCT Number:	2015-005064-42
Sponsor's Protocol Code Number:	AF219-012
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:	2015-12-02
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

2015-005064-42

A.3

Full title of the trial

A 12-Week Study to Assess the Efficacy and Safety of AF-219 in Subjects with Treatment Refractory Chronic Cough

A.3.1

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

A 12 week study to assess the efficacy and safety of AF-219 in patients with long term cough

A.4.1

Sponsor's protocol code number

AF219-012

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	11650638 9491
B.5.5	Fax number	11650286 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 evaluate the effectiveness of 3 doses of AF-219, as compared to placebo, after 12 weeks of treatment in reducing awake objective cough frequency

E.2.2

Secondary objectives of the trial

•To evaluate the effectiveness of three different doses of AF-219 as compared to placebo after 4 and 8 weeks of treatment in reducing awake objective cough frequency
•To evaluate the effectiveness of three different doses of AF-219 as compared to placebo after 4, 8, and 12 weeks of treatment in reducing 24-hour objective cough frequency and in reducing sleep objective cough frequency
•To evaluate the effectiveness of AF-219 in:
o reducing the cough severity measured by a Visual Analog Scale (VAS)
o reducing subjective scores from the cough severity diary (CSD) and daily cough score (DCS)
o improving cough-specific quality of life
•To evaluate the persistence of the anti-tussive effect once treatment is discontinued compared with placebo
•To evaluate the safety of AF-219 in a patient population with treatment refractory chronic cough
•To evaluate the tolerability of the taste effect as measured

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Subjects who meet all of the following criteria will be included in the study:
1. Women and Men between 18 and 80 years of age inclusive
2. Have a diagnosis of refractory chronic cough or unexplained cough for at least one year (see ACCP/BTS guidelines in Appendix 1)
3. Have a score of ≥ 40mm on the Cough Severity VAS at Screening
4. Women of child-bearing potential must use 2 forms of acceptable birth control method from Screening through the Follow-Up Visit. Acceptable birth control methods include established use of oral, injected, or implanted hormonal methods of contraception; intrauterine device (IUD) or intrauterine system (IUS); tubal ligation; or male sterilization. Double-barrier method (diaphragm for female subject and condom for male partner with spermicidal) satisfies the requirement for 2 forms of acceptable birth control. When in line with the preferred life style of the subject, true and complete abstinence (not periodic abstinence) is acceptable.
5. Male subjects and their partners of child-bearing potential must use 2 methods of acceptable birth control, 1 of which must be a barrier method, and make no donation of sperm from Screening until 3 months after the last dose of study drug.
6. Have provided written informed consent.
7. Are willing and able to comply with all aspects of the protocol.

E.4

Principal exclusion criteria

Subjects are NOT eligible for this study if they meet any of the following criteria:
1. Current smoker
2. Individuals who have given up smoking within the past 6 months
3. Initiation of treatment with an ACE-inhibitor within 4 weeks prior to the Baseline Visit (Day 0) or during the study
4. FEV1/FVC < 60%
5. History of upper or lower respiratory tract infection or recent significant change in pulmonary status within 4 weeks of the Baseline Visit (Day 0)
6. History of cystic fibrosis or bronchiectasis
7. History of opioid use within 1 week of the Baseline Visit (Day 0)
8. Requiring concomitant therapy with prohibited medications (see Section 6.6)
9. Body mass index (BMI) <18 kg/m2 or ≥ 40 kg/m2
10. History or symptoms of renal disease or renal obstructive disease
11. History of triple phosphate kidney/bladder stones (nephro/uro-lithiasis)
12. History of conditions or disorders that predispose to nephrolithiasis such as inflammatory bowel disease (i.e., crohn’s disease and active ulcerative colitis) or short bowel syndrome
13. 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
14. History of concurrent malignancy or recurrence of malignancy within 2 years prior to Screening (not including subjects with <3 excised basal cell carcinomas)
15. History of a diagnosis of drug or alcohol dependency or abuse within approximately the last 3 years
16. Any condition possibly affecting drug absorption (e.g., gastrectomy, gastroplasty, any type of bariatric surgery, or vagotomy)
17. Screening systolic blood pressure (SBP) >160 mm Hg or a diastolic blood pressure (DBP) >90 mm Hg
18. Clinically significant abnormal electrocardiogram (ECG) at Screening, including any of the following:
a. QTc interval >450 milliseconds in males and >470 milliseconds in females
b. Atrial fibrillation or atrial flutter
c. Heart rate <40 beats per minute >110 bpm
19. Personal or family history of congenital long QT syndrome or family history of sudden death
20. 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 tests for drugs of abuse
21. History of cutaneous adverse drug reaction to sulfonamides or signs and symptoms suggestive of anaphylaxis to sulfonamides
22. Pregnant or Breastfeeding
23. Treatment with an investigational drug (except AF-219) or investigational 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
24. Blood donation within 56 days or plasma donation within 7 days prior to dosing
25. 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 or Sponsor, would make the subject inappropriate for entry into this trial.

E.5 End points

E.5.1

Primary end point(s)

Change from Baseline in Awake Cough Frequency after AF-219 therapy at each dose studied after 12 weeks (Day 84) of treatment

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)

Key Secondary
•Change from Baseline in 24-hr objective cough frequency after 12 weeks (Day 84) of treatment
•Change from Baseline in Awake objective cough frequency after 4 weeks (Day 28) of treatment
•Change from Baseline in Awake objective cough frequency after 8 weeks (Day 56) of treatment
•Change from Baseline in 24-hr objective cough frequency after 4 weeks (Day 28) of treatment
•Change from Baseline in 24-hr objective cough frequency after 8 weeks (Day 56) of treatment
•Change from baseline in awake objective cough frequency at the Follow-Up visit (Day 98)
•Cough Severity Visual Analog Scale (VAS)

Other Secondary
•Awake cough frequency responder endpoints: ≥30% reduction, ≥50% reduction, and ≥70% reduction
•24-hr cough frequency responder endpoints: ≥30% reduction, ≥50% reduction, and ≥70% reduction
•Change from Baseline in sleep objective cough frequency after 4,8 and 12 weeks (Day 28, 56 and 84) of treatment
•Daily Cough Severity Diary (CSD)
•Daily Cough Score
•Leicester Cough Questionnaire/Leicester Cough Questionnaire (LCQ)
•(LCQ): individual Domain and Total scores
•Patient's Global Impression of Change (PGIC)
•Clinician's Global Impression of Change (CGIC)
•Acceptability Questionnaire
•Response to taste assessments over time (based on taste questionnaire)

E.5.2.1

Timepoint(s) of evaluation of this end point

Secondary 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

Yes

E.6.7

Pharmacodynamic

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

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

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

United States

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 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.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

200

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

2016-01-15

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-02-26

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2016-11-04

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