Clinical Trials Register

Summary
EudraCT Number:	2014-002022-12
Sponsor's Protocol Code Number:	EPOS-CT-001
National Competent Authority:	Denmark - DHMA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2014-11-04
Trial 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

Denmark - DHMA

A.2

EudraCT number

2014-002022-12

A.3

Full title of the trial

A European multi-centre, randomised, double-blind trial of pirfenidone in bronchiolitis-obliterans-syndrome grade 1-3 in lung transplant recipients.

A.3.1

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

European Trial of Pirfenidone in BOS (EPOS).

A.3.2

Name or abbreviated title of the trial where available

EPOS Trial

A.4.1

Sponsor's protocol code number

EPOS-CT-001

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	Clinical Trials Unit, Rigshospitalet
B.1.3.4	Country	Denmark
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	F. Hoffmann La Roche Ltd
B.4.2	Country	Switzerland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Rigshopitalet
B.5.2	Functional name of contact point	Dr. Michael Perch
B.5.3	Address:
B.5.3.1	Street Address	Blegdamsvej 9
B.5.3.2	Town/ city	Copenhagen
B.5.3.3	Post code	2100
B.5.3.4	Country	Denmark
B.5.4	Telephone number	004535459702
B.5.5	Fax number	004535452931
B.5.6	E-mail	Michael.Perch@regionh.dk

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	Yes
D.2.1.1.1	Trade name	Esbriet
D.2.1.1.2	Name of the Marketing Authorisation holder	F. Hoffmann La Roche Ltd
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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	Pirfenidone
D.3.4	Pharmaceutical form	Capsule, hard
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	PIRFENIDONE
D.3.9.1	CAS number	53179-13-8
D.3.9.2	Current sponsor code	PIR
D.3.9.3	Other descriptive name	5-Methyl-1-Phenyl-2-1-(H)-Pyridone
D.3.9.4	EV Substance Code	SUB09907MIG
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	267
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	Capsule, hard
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

Bronchiolitis Obliterans Syndrome (BOS) in patients following lung transplantation. This syndrome occurs due to rejection of the transplanted organ (s).

E.1.1.1

Medical condition in easily understood language

A lung disease in which the small airway branches (bronchioles) are compressed and narrowed by scar tissue (fibrosis) and/or inflammation. This leads to partial or complete blockage of the airways.

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	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10049202
E.1.2	Term	Bronchiolitis obliterans
E.1.2	System Organ Class	100000004855

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

To evaluate the effect of Pirfenidone on the change in FEV1 over 6 months in lung transplant recipients with bronchiolitis obliterans syndrome, who are treated with Azithromycin.

E.2.2

Secondary objectives of the trial

• Categorical percentage change in FEV1 [Categorical percentage change in FEV1 ≥ 10 % (increase or decrease) relative to FEV1 (ml) at baseline]
• Change of FVC in liters
• Change in TLC in liters
• FEV1/FVC ratio change
• Number of patients with treatment failure
• Change in BOS grade
• Change in percent predicted DLco.
• Change in functional level as assessed by the 6MWT
• Hospital admission for any reason
• Death or re-transplantation rates
• Change in EQ5D scale

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Patients >18 years of age
2. Azithromycin therapy for at least 4 weeks prior to study start, with an Azithromycin dose of minimum 250mg /day at least 3 times per week
3. Double lung transplantation is required;
4. Patients must be at least 6 months after transplantation and must have documented post-transplant, base-line value of FEV1 (mean of the 2 highest values measured at least 3 weeks apart according to ISHLT criteria)
5. Patients must have BOS grade 1 - 3.
6. Patients must have documented progressive disease as demonstrated by:
• At least 3 FEV1 measurements in the last 6 months each at least 3 weeks apart
• a total decline of at least 200mL in FEV1 in the last six months
• a mean decline of at least 50 mL in the last two measurements

E.4

Principal exclusion criteria

1. Patients with redo lung transplantation or combined transplantation (including heart and lung transplantation) Or Single lung recipients
2. Patients with any severe comorbidity complicating BOS which might determine the prognosis and functional level of the patient (e.g. invasive aspergillosis, active malignant disease within last 12 months (i.e. disease free since at least 12 months))
3. FEV1 decline related to other non BOS causes (eg pneumothorax, bronchial stenosis, effusion, etc.)
4. Screening ECG shows QTc > 500 ms
5. Patients who on Thorax CT at entry demonstrate new significant findings which are not compatible with BOS like interstitial fibrosis, consolidation, appearances suggesting restrictive Allograft Syndrome (RAS) and acute pulmonary infection as cause of decline in lung function
6. Documented acute perivascular rejection higher than grade A1 or findings compatible with antibody mediated rejection at the last trans-bronchial biopsy performed.
7. Pregnancy or lactation.
8. Renal insufficiency (Creatinine clearance <30 ml/min calculated by the CKD-Epi formula).
9. Any of the following liver test criteria above the specified limit:
• Total bilirubin above the upper limit of the normal range (ULN), except in patients with predominantly unconjugated hyperbilirubinemia (e.g., Gilbert’s syndrome)
• Aspartate or alanine aminotransferase (AST or ALT) >3 × ULN
• Subjects with severe liver impairment (Child Pugh C)
10. Known allergy or hypersensitivity to Pirfenidone
11. Ongoing use or expected use of any of the following therapies:
• trong inhibitors of CYP1A2 (fluvoxamine or enoxacin)
• Moderate inhibitors of CYP1A2 (mexiletine, thiabendazole, oral contraceptives or phenylpropanolamine [Note: ciprofloxacin will be allowed only at doses ≤500 mg BID])
• Moderate inducers (montelukast, phenytoin)
• Cimetidine
• Previous treatment with Pirfenidone after transplantation
12. Patients who have resumed smoking after transplantation
13. Initiation of a new bronchodilator therapy or treatment with Montelukast within 4 weeks prior to randomization

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint of the study is the change in FEV1 (ml) from baseline to 6 months.

E.5.1.1

Timepoint(s) of evaluation of this end point

This endpoint will be evaluated at the end of the study (the 6 month visit for each patient).

E.5.2

Secondary end point(s)

E.5.2.1

Timepoint(s) of evaluation of this end point

All secondary endpoints will be evaluated at the end of the study (the 6 month visit for each patient).

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

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

Yes

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

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

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

Yes

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

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)

Treatment will be given as per routine care. Subjects who have completed the EPOS trial will also be offered open label Pirfenidone for up to 1 year if they wish to receive this 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

2014-12-15

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-12-10

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2021-01-31

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