Clinical Trials Register

Summary
EudraCT Number:	2012-000564-14
Sponsor's Protocol Code Number:	PIPF-023
National Competent Authority:	Sweden - MPA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2013-05-24
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

Sweden - MPA

A.2

EudraCT number

2012-000564-14

A.3

Full title of the trial

A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Study of the Safety and Tolerability of N–Acetylcysteine in Patients with Idiopathic Pulmonary Fibrosis with Background Treatment of Pirfenidone

A.3.1

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

A.3.2

Name or abbreviated title of the trial where available

PANORAMA

A.4.1

Sponsor's protocol code number

PIPF-023

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	InterMune International AG.
B.1.3.4	Country	Switzerland
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	InterMune International AG.
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	Theorem Clinical Research GmbH
B.5.2	Functional name of contact point	Project Management
B.5.3	Address:
B.5.3.1	Street Address	Königsteiner Str. 10
B.5.3.2	Town/ city	Bad Soden
B.5.3.3	Post code	65812
B.5.3.4	Country	Germany
B.5.4	Telephone number	+49619652280
B.5.5	Fax number	+4961965228403

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	Fluimucil® 600 mg effervescent tablets
D.2.1.1.2	Name of the Marketing Authorisation holder	ZAMBON ITALIA s.r.l.
D.2.1.2	Country which granted the Marketing Authorisation	Italy
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.3.4	Pharmaceutical form	Effervescent 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	ACETYLCYSTEINE
D.3.9.3	Other descriptive name	N-Acetylcysteine, (NAC)
D.3.9.4	EV Substance Code	SUB05229MIG
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	600
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	Effervescent 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

Patients with Idiopathic Pulmonary Fibrosis (IPF)

E.1.1.1

Medical condition in easily understood language

Idiopathic Pulmonary Fibrosis

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	17.0
E.1.2	Level	PT
E.1.2	Classification code	10021240
E.1.2	Term	Idiopathic pulmonary fibrosis
E.1.2	System Organ Class	10038738 - Respiratory, thoracic and mediastinal disorders

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 assess the safety and tolerability of treatment with NAC (1800 mg/d) in patients with mild to moderate IPF on the background of pirfenidone therapy.

E.2.2

Secondary objectives of the trial

None

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Clinical symptoms consistent with IPF of ≥3 months duration (relative to Day 1)
2. Diagnosis of IPF ≥3 months before Day 1 (and no more than 4 years ago). Diagnosis date is defined as the first instance in which a patient was informed of having IPF or there is documented evidence of UIP diagnosed by HRCT
3. Age ≥40 and 80 years inclusive, on Day 1
4. Diagnosis of UIP or IPF by HRCT and surgical lung biopsy (SLB). Previous HRCT scans, typically and if available, one at the point of time of diagnosis and one more recent, made during the last year before study inclusion) will be used and assessed by a central Reading Committee.
5. Extent of fibrotic changes (honeycombing, reticular changes) greater than the extent of emphysema on the HRCT scan
6. No features supporting an alternative diagnosis on SLB, transbronchial biopsy (TBB), or bronchoalveolar lavage (BAL), if available. (SLB, TBB and BAL are not required for entry into the study.)
7. Percent predicted FVC ≥50% and ≤90% at Screening, confirmed by central review
8. Percent predicted DLCO ≥30% and ≤90% corrected by hemoglobin, at Screening, confirmed by central review.
9. Forced expiratory volume in 1 second (FEV1)/FVC ratio ≥0.75 confirmed by central review

Must be on a dose of pirfenidone not less than 1602 mg/day for at least 8 weeks prior to randomization at Day 1.

10. Able to understand and sign a written informed consent form
11. Able to understand the importance of adherence to study treatment and the study protocol and willing to follow all study requirements, including the concomitant medication restrictions, throughout the study
12. Women of childbearing capacity are required to have a negative serum pregnancy test before treatment and must agree to maintain highly effective contraception by practicing abstinence or by one highly effective method for birth control as long as the method is associated with a protection from pregnancy with a pearl index of <1.
The following methods for birth control (with typical use) offer a protection from pregnancy with a pearl index of <1 and can be accepted as highly effective.
- Oral (except low-dose gestagen( lynestrenol and norestisteron)), injectable or implanted hormonal contraceptives
- Intrauterine device
- Intrauterine system (e.g. progestin-releasing coil)
- Vasectomized male with appropriate post vasectomy documentation of the absence of sperm in the ejaculate

E.4

Principal exclusion criteria

1. Significant clinical worsening of IPF between Screen. and Day 1, in the opinion of the Inv.
2. Unlikely to comply with the requirements of this study, in the opinion of the Inv.
3. Patient-reported cigarette smoking within 3 months of Screen. or unwilling to avoid use of tobacco products throughout the study
4. Hist. 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
5. Known cause of interstitial lung disease, including but not limited to radiation, drug toxicity, sarcoidosis, hypersensitivity pneumonitis, cryptogenic organizing pneumonia
6. Human immunodeficiency virus (HIV), viral hepatitis B or C
7. Clinical diagnosis of any connective tissue disease, including but not limited to scleroderma, polymyositis/dermatomyositis, systemic lupus erythematosus, and rheumatoid arthritis
8. Clinical evidence of active infection, including but not limited to bronchitis, pneumonia, sinusitis, urinary tract infection, or cellulitis (as a diffuse inflammation of connective tissue and or skin)
9. In list for lung transplantation: expected to receive a lung transplant within 6 months from Day 1
10. Any hist. of malignancy likely to result in significant disability or likely to require significant medical or surgical intervention within the next 6 months (relative to Day 1). This does not include minor surgical procedures for localized cancer (e.g., basal cell carcinoma, squamous skin carcinoma)
11. Any condition other than IPF that, in the opinion of the Inv., is likely to result in the death of the patient within the next 12 months
12. Hist. of severe hepatic impairment or end-stage liver disease
13. Hist. of end-stage renal disease requiring dialysis
14. Hist. of unstable or deteriorating cardiac or pulmonary disease (other than IPF) within the previous 6 months (relative to Day 1), including but not limited to the following:
a. Unstable angina pectoris or myocardial infarction
b. Congestive heart failure requiring hospitalization
c. Uncontrolled clinically significant arrhythmias
15. Any condition that, in the opinion of the Inv., might be significantly exacerbated by the known side effects associated with the administration of NAC taken as a single medication
16. Known or suspected presence of a peptic ulcer
17. Pregnancy or lactation
18. Hist. of alcohol or substance abuse in the past 2 years
19. Family or personal hist. of long QT syndrome
20. Any contraindications according to the current NAC-product SPC
21. Any of the following liver chemistry criteria above specified limits:
a. Total bilirubin above the upper limit of normal (ULN)
b. Aspartate or alanine aminotransferase (AST/SGOT or ALT/SGPT) >2 x ULN
c. Alkaline phosphatase >2.5 x ULN
22. Creatinine clearance (CrCl) <30 mL/min, calculated using the Cockcroft-Gault formula
23. ECG with a heart-rate–corrected QT interval using Bazett’s formula (QTcB) >500 ms at Screening
24. Suspected intolerance, allergy, or hypersensitivity to NAC or any of its components
25. Known intolerance, allergy, or hypersensitivity to NAC or any of its components
26. Use of any of the following therapies within 28 days before randomization:
a. Any investigational therapy, defined as any drug that has not MA for any indication in the country of the participating site
b. Corticosteroids when used for the treatment of IPF (except for durations of up to 21 days for acute IPF exacerbation). No restrictions apply to corticosteroids used for reasons other than IPF therapy (e.g., allergic reactions, sepsis); however, the specific reason for use must be recorded
c. Any cytotoxic, immunosuppressive, cytokine-modulating, or receptor-antagonist agent, including but not limited to azathioprine, bosentan, ambrisentan, cyclophosphamide, cyclosporine, prostaglandin analogues such as iloprost, TNF-α inhibitors such as infliximab and etanercept, tyrosine kinase inhibitors such as imatinib, leukotriene receptor antagonists such as montelukast, methotrexate, mycophenolate mofetil, tacrolimus, interferon gamma-1b (IFN-y 1b)
d. The following medications (or class) may be used during the study only if given for a non-IPF indication:
- Antithrombotic agents: heparin group
- Lipid-modifying agents: 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors
- Angiotension-coverting enzyme (ACE) inhibitors and ACE receptor blockers
- Prior treatment of NAC for the indication IPF within the last 3 months. Periodic treatment up to 28 days with NAC for approved indications within the last 6 months is allowed
- Anti-gout preparations: colchicine
e. Strong inhibitors or inducers of CYP1A2 such as fluvoxamine, tobacco, rifampicin
f. Phosphodiesterase type 5 (PDE-5) inhibitors such as sildenafil, tadalafil, vardenafil (intermittent use for non-IPF indication [e.g., for erectile dysfunction] is permitted

E.5 End points

E.5.1

Primary end point(s)

• Tolerability assessment and safety: Review of AEs/SAEs, dose reductions and discontinuations, changes in clinical laboratory findings, and deaths
• Worsening of the disease: Spirometry, 6MWT procedure and DLCO
• IPF exacerbations

E.5.1.1

Timepoint(s) of evaluation of this end point

• Telephone interviews: W2, W8, W16, W20
• Review of AEs/SAEs, concomitant meds, supplemental O2 use: Screening and washout, D1, W2, W4, W8, W12, W16, W20, W24, Follow-up
• Changes in clinical laboratory findings: Screening and washout, D1, W4, W12, W24, follow-up
• Spirometry and 6MWT procedure and Borg scale, UCSD SOBQ, DLCO: screening (DLCO only), D1, W12, W24

E.5.2

Secondary end point(s)

not applicable

E.5.2.1

Timepoint(s) of evaluation of this end point

not applicable

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

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

tolerability

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

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

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

120

F.4.2.2

In the whole clinical trial

120

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
G.4 Investigator Network to be involved in the Trial: 1

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2013-06-25

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-06-19

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2015-02-24

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