E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients with Idiopathic Pulmonary Fibrosis (IPF) |
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E.1.1.1 | Medical condition in easily understood language |
Idiopathic Pulmonary Fibrosis |
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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 |
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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. |
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E.2.2 | Secondary objectives of the trial |
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E.2.3 | Trial contains a sub-study | No |
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 using at least two methods of birth control from the date of consent through the end of the study. If abstinence is not practiced, one of the two methods of birth control should be an oral contraceptive (e.g., oral contraceptive and a spermicide). |
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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
-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
g.Any medications containing carbocysteine (applicable only in countries where carbocysteine is used) |
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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
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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 |
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E.5.2 | Secondary end point(s) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | No |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
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 | 11 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 90 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 7 |
E.8.9.1 | In the Member State concerned days | 15 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 7 |
E.8.9.2 | In all countries concerned by the trial days | 15 |