Clinical Trials Register

Summary
EudraCT Number:	2017-000149-30
Sponsor's Protocol Code Number:	Edge92882
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	GB - no longer in EU/EEA
Date on which this record was first entered in the EudraCT database:	2017-09-05
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

UK - MHRA

A.2

EudraCT number

2017-000149-30

A.3

Full title of the trial

A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Study of Safety, Tolerability and Efficacy of Pirfenidone in Patients with Rheumatoid Arthritis Interstitial Lung Disease

A.3.1

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

A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Study of Safety, Tolerability and Efficacy of Pirfenidone in Patients with Rheumatoid Arthritis Interstitial Lung Disease

A.3.2

Name or abbreviated title of the trial where available

TRAIL1

A.4.1

Sponsor's protocol code number

Edge92882

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT02808871

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	University Hospitals of Leicester NHS Trust
B.1.3.4	Country	United Kingdom
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	Genentech 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	University Hospitals of Leicester NHS Trust
B.5.2	Functional name of contact point	Felix Woodhead
B.5.3	Address:
B.5.3.1	Street Address	Glenfield Hospital
B.5.3.2	Town/ city	Groby Road
B.5.3.3	Post code	LE3 9QP
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	0116 258 3507
B.5.6	E-mail	felix.woodhead@uhl-tr.nhs.uk

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	Roche Registration Limited
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
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	Esbriet
D.3.4	Pharmaceutical form	Capsule
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.3.9.4	EV Substance Code	AS1
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
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

Rheumatoid arthritis associated interstitial lung disease (RA-ILD)

E.1.1.1

Medical condition in easily understood language

ILD is inflammation and scarring of the lung tissue. In the case of RA-ILD, the scarring is caused when the over-active immune system attacks the lungs causing scarring to build up over time.

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

1.To assess the efficacy and safety of pirfenidone 2403 mg/day as compared to placebo in patients with rheumatoid arthritis-associated interstitial lung disease (RA-ILD).

E.2.2

Secondary objectives of the trial

1. To explore the role of peripheral blood biomarkers in predicting disease progression and survival in patients with RA-associated interstitial lung disease.

2. To explore a spectrum of validated questionnaires to assess disease specific patient reported outcomes including overall health, and perspectives on symptoms, performance and quality of life.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Age 18 through 85 years, inclusive, at Screening
2. Probable or definite diagnosis of RA according to revised 2010 ACR/EULAR criteria, without evidence or suspicion of an alternative diagnosis that may contribute to their interstitial lung disease.
3. Diagnosis of ILD
a. supported by clinically indicated HRCT, and when available surgical lung biopsy (SLB), prior to Screening, and
b. presence of fibrotic abnormality affecting more than 10% of the lung parenchyma, with or without traction bronchiectasis or honeycombing, on Screening and confirmed by adjudicated HRCT prior to Baseline
4. Clinical symptoms consistent with ILD (i.e., cough, dyspnea)
5. No features supporting an alternative diagnosis on transbronchial biopsy, or SLB, if performed prior to Screening
6. Attainment of the following centralized spirometry criteria (based on local spirometry on standardized equipment and centralized quality controlled):
a. percent predicted FVC ≥ 40% at Screening
b. change in pre-bronchodilator FVC (measured in liters) between Screening (Visit 1) and Baseline (Visit 2) must be a <10% relative difference, calculated as:
100% * [absolute value (Screening FVC – Baseline FVC) / Screening FVC]
c. percent predicted DLCO ≥30% or TLCO at Screening
d. Screening (Visit 1) Pre-bronchodilator (BD) and Post-BD spirometry meets ATS quality criteria as determined by a central reviewer.
d. Screening (Visit 1) Pre-bronchodilator (BD) and Post-BD spirometry meets ATS quality criteria as determined by a central reviewer.
e. Baseline (Visit 2) Pre-BD spirometry meets ATS quality criteria as determined by either a site Investigator or the central reviewer.

7. Stable dose (at least three months at the time of Screening) of corticosteroids or any cytotoxic, immunosuppressive or cytokine-modulating, or receptor- antagonist agent prescribed for rheumatoid arthritis, including but not limited to azathioprine, cyclophosphamide, cyclosporine, etanercept, iloprost, infliximab, leukotriene antagonists, methotrexate, mycophenolate mofetil, tacrolimus, montelukast, tetrathiomolybdate, TNF-α inhibitors, rituximab, abatacept, tofacitintib, tociluzimab.
8. Able to understand and sign a written informed consent form
9. For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use two adequate methods of contraception, including at least one method with a failure rate of <1% per year, during the 52 weeks of treatment.
a. A woman is considered to be of childbearing potential if she is postmenarcheal, has not reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus).
b. Examples of contraceptive methods with a failure rate of <1% per year include bilateral tubal ligation, male sterilization, established and proper use of hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices.
c. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception.
10. For men who are not surgically sterile: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm, as defined below:
a. With female partners of childbearing potential, men must remain abstinent or use a condom plus an additional contraceptive method that together result in a failure rate of < 1% per year during the treatment period and for at least 118 days after the last dose of pirfenidone.
b. Men must refrain from donating sperm during this same period.

E.4

Principal exclusion criteria

1.Not a suitable candidate for enrollment or unlikely to comply with the requirements of this study, in the opinion of the investigator
2. Cigarette smoking or vaping within 3 months of Screening or unwilling to avoid tobacco products throughout the study (this excludes vaping. Vaping is not an exclusion to the study).
3. History of clinically significant environmental exposure known to cause pulmonary fibrosis (PF), including but not limited to drugs (such as amiodarone), asbestos, beryllium, radiation, and domestic birds
4. Concurrent presence of other interstitial lung disease, including but not limited to radiation, drug toxicity, sarcoidosis, hypersensitivity pneumonitis, bronchiolitis obliterans organizing pneumonia, human immunodeficiency virus (HIV), viral hepatitis (positive Hep A antibody in the absence of elevated liver enzymes is not an exclusion), and cancer
5. Concurrent presence of other pleuropulmonary manifestations of RA, including but not limited to rheumatoid nodular disease of the lung, pleuritis/pleural thickening, and obliterative bronchiolitis
6. Post-bronchodilator FEV1/FVC < 0.7 at Screening
7. Presence of pleural effusion occupying more than 20% of the hemithorax on Screening HRCT
8. Clinical diagnosis of a second connective tissue disease or overlap syndrome (including but not limited to scleroderma, Sjogren’s, polymyositis/dermatomyositis, systemic lupus erythematosus)
9. Coexistent clinically significant COPD/emphysema or asthma in the opinion of the site principle investigator
10. Clinical evidence of active infection, including but not limited to bronchitis, pneumonia, sinusitis, urinary tract infection, or cellulitis
11. Any history of malignancy diagnosed within 5 years of screening, other than basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or low grade cervical carcinoma in situ.
12. History of severe hepatic impairment or end-stage liver disease
13. History of end-stage renal disease requiring dialysis
14. History of unstable or deteriorating cardiac or disease, or unstable cardiac arrhythmia or arrhythmia requiring modification of drug therapy, myocardial infarction within the previous year, heart failure requiring hospitalisation
15. Any condition that, in the opinion of the investigator, might be significantly exacerbated by the known side effects associated with the administration of pirfenidone
16. Investigational therapy, defined as any drug that has not been approved for marketing for any indication in the country of the participating site, at the time of Screening
17. History of alcohol or substance abuse in the past 2 years, at the time of Screening
18. Family or personal history of long QT syndrome
19. Any of the following liver function test criteria above specified limits:
a. Total bilirubin above the upper limit of normal (ULN), excluding patients with Gilbert’s syndrome; aspartate or alanine aminotransferase (AST/SGOT or ALT/SGPT) >3 × ULN; alkaline phosphatase >2.5 × ULN
b. Creatinine clearance (CrCl <30) mL/min, calculated using the Cockcroft-Gault formula
c. Electrocardiogram (ECG) with a QTcB interval >500 msec at Screening
20. Prior use of pirfenidone or known hypersensitivity to any of the components of study treatment
21. Use of any of the following therapies within 28 days before Screening:
a. Investigational therapy, defined as any drug that has not been approved for marketing for any indication in the country of the participating site
b. Fluboxamine
c. Sildenafil (daily use). Note: intermittent use for erectile dysfunction is allowed
d. Potent CYP1A2 inducers
21. Any use of an approved anti-fibrotic medication within 28 days of screening.

E.5 End points

E.5.1

Primary end point(s)

Incidence of the composite endpoint of decline from baseline in percent predicted FVC of 10% or greater or death during the 52-week treatment period.

E.5.1.1

Timepoint(s) of evaluation of this end point

52 weeks

E.5.2

Secondary end point(s)

1. Incidence of the composite endpoint of decline from baseline in percent predicted FVC of 10% or greater during the 52-week treatment period
2. Frequency of progressive disease as defined by OMERACT: Relative decline from baseline in percent predicted FVC of ≥10%, or relative change from baseline in percent predicted FVC ≥ 5% and < 10%, and ≥15% relative DLCO (Khanna, Mittoo et al. 2015)
3. Change from baseline to week 52 in absolute value of FVC
4. Change from baseline to week 52 of percent predicted FVC
5. Slope of percent predicted FVC over 52-week treatment period
6. Slope of absolute FVC over 52-week treatment period
7. Time to decline of 10% or greater in percent predicted FVC at death or over 52-week treatment period
8. Proportion of participants with all-cause mortality
9. Proportion of participants with all-cause hospitalization
10. Proportion of participants with hospitalization for respiratory cause
11. Number of respiratory exacerbations requiring hospitalizations
12. Proportion of participants with and number of treatment-emergent AEs
13. Proportion of participants with and number of treatment-emergent serious adverse events (SAEs)
14. Proportion of participants with and number of treatment-emergent/treatment-related AEs
15. Proportion of participants with and number of treatment-emergent/treatment-related SAEs
16. Proportion of participants with and number of AEs leading to early discontinuation of study treatment
17. Proportion of participants with and number of treatment-emergent death or transplant
18. Proportion of participants with and number of treatment-emergent RA-ILD-related mortality
19. Change from Baseline to Week 52 in dyspnea, as measured by the Dyspnea 12 questionnaire

Exploratory:
1. Change from Baseline to Week 52 in Disease Activity Score (DAS) and RAPID3 score (RA disease activity score)
2. Change from Baseline to Week 52 in Routine Assessment of Patient Index Data 3 (RAPID3) score (RA disease activity score)
3. Change from Baseline to Week 52 in Erythrocyte Sedimentation Rate (ESR)
4. Change from Baseline to Week 52 in C-Reactive Protein (CRP)
5. Candidate biomarker expression in the peripheral blood of patients with RA-ILD over the 52 weeks of treatment and the study follow-up period
6. Changes from Baseline to 52 weeks in HRCT parameters evaluated by quantitative functional imaging
7. Changes from Baseline to Week 13, 26, 39 and 52 in the St. George’s Respiratory Questionnaire (SGRQ)
8. Changes from Baseline to Week 13, 26 and 39 in Dyspnea 12 questionnaire
9. Changes from Baseline to Week 13, 26, 39 and 52 in Leicester Cough Questionnaire (LCQ)
10. Changes from Baseline to Week 13, 26, 39 and 52 in the Patient global assessment
11. Changes from Baseline to Week 13, 26, 39 and 52 in the Health assessment questionnaire

E.5.2.1

Timepoint(s) of evaluation of this end point

52 weeks

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

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

Yes

E.6.13.1

Other scope of the trial description

Biomarkers (role of blood biomarkers in predicting disease progression and survival)

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.8.3

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

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

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

Australia

Canada

United Kingdom

United States

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

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