Clinical Trials Register

Summary
EudraCT Number:	2019-000375-16
Sponsor's Protocol Code Number:	BUS-P2-01
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2019-03-13
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

2019-000375-16

A.3

Full title of the trial

A Randomized, Double-blind, Placebo-Controlled, Crossover, Dose Escalation Study of BLU-5937 in Subjects with Unexplained or Refractory Chronic Cough

A.3.1

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

A Study Of The Efficacy, Safety, And Tolerability of BLU-5937 for the Treatment of Chronic Cough with no Apparent Cause

A.3.2

Name or abbreviated title of the trial where available

RELIEF

A.4.1

Sponsor's protocol code number

BUS-P2-01

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	Bellus Health Inc.
B.1.3.4	Country	Canada
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	Bellus Health Inc.
B.4.2	Country	Canada
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Bellus Health Inc.
B.5.2	Functional name of contact point	Senior VP Drug Development
B.5.3	Address:
B.5.3.1	Street Address	275 Boulevard Armand-Frappier
B.5.3.2	Town/ city	Laval, QC
B.5.3.3	Post code	H7V 4A7
B.5.3.4	Country	Canada
B.5.4	Telephone number	+14506804400
B.5.6	E-mail	dgarceau@bellushealth.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	BLU-5937
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.3.8	INN - Proposed INN	Methyl (S)-2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylate
D.3.9.2	Current sponsor code	BLU-5937
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	25
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	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	BLU-5937
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.3.8	INN - Proposed INN	Methyl (S)-2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylate
D.3.9.2	Current sponsor code	BLU-5937
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	200
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
D.8 Placebo: 2
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

Unexplained or Refractory Chronic Cough

E.1.1.1

Medical condition in easily understood language

Chronic cough with no apparent cause

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	21.1
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

The primary objective of this study is to assess the efficacy and safety of BLU-5937 for the treatment unexplained, refractory chronic cough.

E.2.2

Secondary objectives of the trial

The secondary objective is to establish the optimal therapeutic doses for the Phase 2b/3 studies.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Have provided written consent and are willing and able to comply with all aspects of the protocol
2. Women and Men between 18 and 80 years of age inclusive
3. Chest radiograph or CT thorax within the last 12 months not demonstrating any abnormality considered to be significantly contributing to the chronic cough in the opinion of the Principal Investigator and Medical Monitor
4. Have unexplained or refractory chronic 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 or unexplained cough; or a cough for which no objective evidence of an underlying trigger can be determined after investigation (see Appendix 1)
5. Cough Count of ≥ 10 per hour (Cough Count at Screening)
6. A score of ≥ 40mm on the Cough Severity VAS at Screening
7. Women of child-bearing potential must have a negative serum pregnancy test at Screening.
8. Women of child-bearing potential must use a highly effective contraception method from Screening through to the Follow-Up Visit. Acceptable birth control methods include:
a. Intrauterine device (IUD) or intrauterine system (IUS);
b. Tubal ligation; or male sterilization.
c. When in line with the preferred life style of the subject, true and complete abstinence (not periodic abstinence) is acceptable.
For the purposes of this study, a female of childbearing potential is defined as any female who has experienced menarche and is pre-menopausal; a postmenopausal state is defined as no menses for 12 months without an alternative medical cause in a previously menstruating female.
Note: In this study, oral, injected or implanted contraceptives are not considered an acceptable birth control method due to the fact that BLU-5937 showed potential induction of CYP3A4 in vitro and no DDI studies have been conducted with these contraceptives yet.
9. Male subjects and their partners of child-bearing potential must use 2 methods of acceptable birth control (one method as listed in Inclusion Criteria 8), 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

E.4

Principal 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. Diagnosis of COPD, bronchiectasis, idiopathic pulmonary fibrosis based on clinician assessment
4. 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 the Baseline/Visit 2 (Day 0)
5. FEV1/FVC < 60%
6. History of upper respiratory tract infection or recent significant change in pulmonary status within 4 weeks of the Baseline/Visit 2 (Day 0)
7. History of opioid use within 1 week of the Baseline/Visit 2 (Day 0)
8. Requiring concomitant therapy with prohibited medications (see Section 4.4)
9. Medical history of hypogeusia/dysgeusia or known presence of a dysfunction in his/her ability to taste
10. History of concurrent malignancy or recurrence of malignancy within 2 years prior to Screening (not including subjects with <3 excised basal cell carcinomas)
11. History of a diagnosis of drug or alcohol dependency or abuse within the last 3 years
12. Any condition possibly affecting drug absorption (e.g., gastrectomy, gastroplasty, any type of bariatric surgery, vagotomy, or bowel resection)
13. Screening systolic blood pressure (SBP) >160 mm Hg or a diastolic blood pressure (DBP) >100 mm Hg
14. Clinically significant abnormal electrocardiogram (ECG) at Screening, including any of the following: a. QTcF interval > 450 milliseconds
b. Atrial fibrillation or atrial flutter
c. Heart rate <40 beats per minute >110 bpm
d. Second degree or third degree (complete) AV block
e. Left bundle branch block (including hemiblock)
f. Wolf-Parkinson-White Syndrome
g. Personal or family history of congenital long QT syndrome or family history of sudden death
15. Clinically significant abnormal laboratory tests at Screening, including: a. Alkaline phosphatase (ALP), alanine aminotransferase (ALT, SGPT), aspartate aminotransferase (AST, SGOT), >150% of the upper limit of normal (ULN), gamma-glutamyl transferase (GGT) >200% of the upper limit of normal (ULN) or Total bilirubin above the upper limit of normal (ULN)
b. Creatinine >200% of the upper limit of normal (ULN)
c. Haemoglobin < 10 gm/dL, WBC count <2500 mm3, neutrophil count <1500 mm3, platelet count <100 × 103/mm3
d. Positive tests for drugs of abuse (certain drugs of abuse are acceptable for non-cough indications see section 4.4)
16. Significant coagulopathy as defined by a known hereditary deficiency of coagulation factors or platelet function or an unexplained elevation of the prothrombin time (PT) or international normalized ratio (INR) of ≥1.5
17. Unexplained creatine kinase concentration >3 × ULN
18. Breastfeeding
19. 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
20. Blood donation within 56 days or plasma donation within 7 days prior to dosing
21. 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 (cough recorder) at end of each dose level.

E.5.1.1

Timepoint(s) of evaluation of this end point

At end of each dose level

E.5.2

Secondary end point(s)

• Change from baseline in 24-hour cough frequency (cough recorder) at end of each dose level and follow up
• Change from baseline in awake cough frequency (cough recorder) at follow up
• Change from baseline in cough severity as measured with VAS at end of each dose level and follow up
• Change from baseline in Leicester cough questionnaire total score at end of each treatment period
• Global Rating of Change scale at end of each dose level and follow up

E.5.2.1

Timepoint(s) of evaluation of this end point

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

Yes

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

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

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

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)

At the end of the study, treatment of subjects with refractory chronic
cough will be left to the discretion of their treating physicians based on
standard of care guidelines applicable in the UK.

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

2019-04-23

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-06-14

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2020-04-20

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