E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Idiopathic pulmonary fibrosis |
|
E.1.1.1 | Medical condition in easily understood language |
lung fibrosis of unknown 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 | 14.1 |
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 | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective of this study is:
• To determine the effect of GS-6624 on progression free survival
(PFS) as determined by either a categorical decline in forced
vital capacity (FVC) or all-cause mortality |
|
E.2.2 | Secondary objectives of the trial |
• Effects of GS-6624 on all-cause mortality
• Predictive effects of baseline serum lysyl oxidase like 2
(sLOXL2) levels
• Effects of GS-6624 on change in lung function
• Effects of GS-6624 on adjudicated acute exacerbations
• Effects of GS-6624 on adjudicated respiratory hospitalizations
• Effects of GS-6624 on 6-minute walk distance (6MWD)
• Effects of GS-6624 on quality of life
• The safety and tolerability of GS-6624
Exploratory objectives include evaluation of:
• Effect of GS-6624 on degree of fibrosis on high resolution
computed tomography (HRCT) scans
• Effect of GS-6624 on sLOXL2 levels compared to placebo
• Prognostic effect of baseline sLOXL2 on primary and
secondary objectives (among placebo treated subjects only)
• Predictive effect of baseline sLOXL2 on the secondary
objectives and subsequent sLOXL2 levels |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Male or female subjects from 45 to 85 years of age
2. Diagnosis of definite IPF according to American Thoracic Society/European Respiratory Society (ATS/ERS) Consensus Statement, using HRCT or surgical lung biopsy (SLB) (both to be confirmed by a central service); the diagnosis must be made within 3 years prior to screening
3. 6MWD ≥ 50 meters (164 feet): use of ≤ 6 L/min supplemental O2 is required for all subjects
4. Able to maintain oxygen saturation of ≥ 89% while breathing room air at rest
5. Able to perform complete breath hold for diffusing lung capacity for carbon monoxide (DLCO) measurement
6. Negative serum pregnancy test at screening and negative urine pregnancy test at randomization for female subjects of childbearing potential
7. Willingness of female subjects of childbearing potential to undergo urine pregnancy tests every 28 days
8. Females of childbearing potential must agree to use highly effective methods of contraception from the screening visit throughout the study period and for 30 days following the last dose of IMP. Please refer to Section 8.11.2 for protocol recommended methods of contraception; females of childbearing potential must have negative serum β-hCG at screening.
9. Non-vasectomized male subjects must agree to use a highly effective method of contraception if sexually active and refrain from sperm donation from Day 1 throughout the study period
until 90 days following the last dose of investigational medicinal product (IMP)
10. Lactating females must agree to discontinue nursing before enrolling in the study and for the duration of the study while receiving IMP
11. Competency to understand the information given in the Institutional Review Board (IRB) or Independent Ethics Committee (IEC) approved Informed Consent Form (ICF); subjects must sign the ICF prior to the initiation of any study procedures/assessments, unless it is performed as standard of
care for this disease |
|
E.4 | Principal exclusion criteria |
Subjects meeting any of the exclusion criteria will not be permitted to participate.
Related to other medical conditions or diagnoses:
1. Pregnant or breastfeeding
2. Clinically significant respiratory diseases other than IPF, including asbestosis, other pneumoconiosis or hypersensitivity pneumonitis
3. Obstructive lung disease determined by Pulmonary Function Test (PFTs) or HRCT as follows:
• Evidence of reactive airway disease by absolute increase in forced expiratory volume in 1 second (FEV1) of > 12% following bronchodilator challenge
OR
• FEV1/FVC ratio < age adjusted lower limit of normal (LLN) OR
• Residual volume (RV) > 120% by plethysmography or significant emphysema on HRCT defined as more emphysema than fibrosis interpreted by a central radiology service
4. Hemoglobin corrected, not volume corrected, DLCO <25% of predicted normal
5. Surgical lung biopsy (SLB) showing, pneumoconiosis, hypersensitivity pneumonitis nonspecific pneumonia or other idiopathic interstitial lung disease
6. Any collagen vascular disease
7. History of aortic aneurysm ≥ 3.5cm in diameter
8. History of cerebrovascular accident (stroke) within the preceding 26 weeks
9. Clinically significant heart disease defined as a myocardial infarction documented by an ST elevation (STEMI) on electrocardiogram (ECG) within 6 months prior to screening, percutaneous coronary intervention or coronary artery bypass surgery within 6 months prior to screening, unstable angina
pectoris, congestive heart failure (NYHA class III/IV or known left ventricular ejection fraction < 25%), right heart failure, significant right ventricular hypertrophy, or uncontrolled arrhythmia
10. Require pharmaceutical treatment for pulmonary hypertension
11. Hospitalization for acute respiratory illness < 26 weeks prior to screening
12. Aspiration pneumonia < 26 weeks prior to screening
13. Active or recent (< 4 weeks prior to enrollment) respiratory bacterial, viral, fungal, or other infection (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement)
14. History of cancer, precancerous state (eg, familial polyposis, BRCA1, BRCA2), other than non-melanomatous skin cancer, within 5 years prior to screening, or active work-up for suspected lung cancer
15. History of human immunodeficiency virus (HIV), hepatitis C, or hepatitis B
16. Co-morbid condition or illness limiting life expectancy to < 2 years at time of screening
17. Major surgery, as defined by the investigator, < 30 days prior to screening or scheduled elective surgery during the expected duration of the study
18. History or evidence of a clinically significant disorder, condition, or disease that, in the opinion of the investigator and the Gilead medical monitor, would pose a risk to subject safety or interfere with the study evaluations, procedures, or completion
19. Current excessive (as determined by the investigator) consumption of alcohol or use of illegal drugs Related to physiologic or organ specific abnormalities:
20. Use of supplemental O2 > 6L/min during activity
21. Inadequate organ function reflected by any of the following:
• Platelets < 100 x 109/L
• Hemoglobin < 11.0 g/dL
• Absolute Neutrophil Count (ANC) < 1.5 x 109/L
• PT/INR and PTT > 1.5 x upper limit of normal (ULN)
• AST/ALT > 3 x ULN
• Total bilirubin > 1.5 x ULN
• Serum creatinine > 2.0 mg/dL
Related to treatment for IPF or investigational drugs:
22. Treatment with immunosuppressive, cytotoxic, or antifibrotic drugs including pirfenidone, colchicine, cyclosporine A, TNF-α antagonists, tyrosine kinase inhibitor, interferon-gamma,
cyclophosphamide, or azathioprine < 28 days prior to randomization are not permitted
• N-acetylcysteine is permitted provided the subject has been on stable dose for > 12 weeks prior to screening
• Once a subject meets the FVC criteria for PFS, the subject may at the investigators discretion be prescribed any drug that is approved for treatment of IPF in the subject’s country of
residence, including pirfenidone
23. Chronic use (> 28 days) of moderate or high dose oral corticosteroids (equivalent of > 10 mg of prednisone per day); short courses of higher corticosteroid doses within 1-6 months prior to randomization are permitted but limited to ≤ 28 days
24. Participation in an investigational drug or device trial < 30 days prior to screening or within 5 times the half-life of the investigational agent in the other clinical study, if known
25. Treatment with GS-6624 in another clinical study
26. Listed as active on a lung transplant waiting list |
|
E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint is:
• PFS among intent-to-treat (ITT) subjects. PFS is defined as time between randomization and all-cause mortality or a categorical decrease in FVC % predicted (≥ 10% relative decrease in FVC and a ≥ 5% absolute decrease in FVC). |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Following randomization (Day 0), abbreviated study visits will occur at Weeks 2, 6, 14, 18,
26, 30, 38, 42, 50, 54, 62, 66, 74, 78, 82, 94, 106, 118, 130, 142, 154, 166, and 178. The
interval for abbreviated study visits will be increased to every 12 weeks if a subject meets the
FVC component of the PFS endpoint and chooses to remain in the study to receive blinded
study drug.
Following randomization (Day 0), Full Study visits will occur at Weeks 10, 22, 34, 46, 58,
and 70. Full study visits will be discontinued when a subject meets a PFS event. |
|
E.5.2 | Secondary end point(s) |
Key secondary endpoints are:
• All cause mortality among ITT subjects
• PFS among subjects with “high” sLOXL2 at baseline
• All-cause mortality among subjects with “high” sLOXL2 at baseline
Other secondary endpoints are:
• Adjudicated acute exacerbations
• Adjudicated respiratory hospitalizations
• Change in FVC % predicted
• Change in DLCO % predicted
• Absolute change in 6MWD
• Change in SGRQ score
• Change in TDI score
• Change in CPI score
The exploratory endpoints are:
• Change in HRCT findings since baseline
• Change in sLOXL2 levels
• Determine whether baseline sLOXL2 levels are prognostic for disease progression (evaluated in placebo arm)
• Evaluate the predictive effects of baseline sLOXL2 levels on various clinical endpoints outlined as secondary objectives |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Following randomization (Day 0), abbreviated study visits will occur at Weeks 2, 6, 14, 18,
26, 30, 38, 42, 50, 54, 62, 66, 74, 78, 82, 94, 106, 118, 130, 142, 154, 166, and 178. The
interval for abbreviated study visits will be increased to every 12 weeks if a subject meets the
FVC component of the PFS endpoint and chooses to remain in the study to receive blinded
study drug.
Following randomization (Day 0), Full Study visits will occur at Weeks 10, 22, 34, 46, 58,
and 70. Full study visits will be discontinued when a subject meets a PFS event. |
|
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 | Yes |
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 | No |
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 | Information not present in EudraCT |
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 | Information not present in EudraCT |
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 | 8 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 60 |
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 | No |
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 |
Israel |
Korea, Republic of |
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
|
Last patient, last visit. |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 3 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |