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 | 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 | 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 and and all cause mortality, in all subjects enrolled or in a subset of subjects who are classified as Lysyl Oxidase-like-2 (LOXL2) High based on a pre-specified level in serum at baseline. |
|
E.2.2 | Secondary objectives of the trial |
• Effects of GS-6624 on all-cause mortality
• Predictive effects of baseline serum LOXL2 levels on treatment response as measured by primary and secondary endpoints
• 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 and abjudicated deaths
• Effects of GS-6624 on 6-minute walk distance (6MWD)
• Effects of GS-6624 on quality of life
• The safety and tolerability of simtuzumab
Exploratory objectives include evaluation of:
Effect of simtuzumab on degree of fibrosis on high resolution
computed tomography (HRCT) scans
• Effect of simtuzumab on sLOXL2 levels compared to placebo
• Prognostic effects of baseline levels of sLOXL2 on disease prognosis
as determined in placebo arm. |
|
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. A confident diagnosis of IPF consistent with American Thoracic Society/European Respiratory Society (ATS/ERS) Consensus Statement. HRCT or surgical lung biopsy (SLB) will be interpreted by a central service. The term "surgical lung biopsy" encompasses biopsies obtained at open thoracotomy and thorascoscopy, as well as, cryobiopsies obtained through bronchoscopy. The he diagnosis must have been made within 3 years prior to screening, or if diagnosis was made > 3 years prior to screening, there must be evidence of clinical worsening within 12 months prior to screening, as judged by the investigator.
3. 6MWD ≥ 50 meters (164 feet): use of ≤ 6 L/min supplemental O2 is permitted for all subjects
4. Able to maintain oxygen saturation of ≥ 89% while breathing room air at rest at sea level. If the study site is located at more than 1000 meters above sea level, the subject must be able to maintain oxygen saturation of ≥ 89% while on 2 litres of supplemental oxygen at rest (eligible subjects are permitted to use supplemental oxygen during sleep and on exertion based on the clinical judgement of the investigator, to a maximm of 6 litres/minute).
5. Able to perform complete breath hold for diffusing lung capacity so that a carbon monoxide (DLCO) measurement can be safely undertaken
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 at each visit starting at randomization.
8. Females of childbearing potential must agree to use highly effective methods of contraception from the screening visit throughout the study period and for 90 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 with a partner who is of child bearing potential. Subjects must refrain from sperm donation from randomization 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 |
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 an increase in forced expiratory volume in 1 second (FEV1) following bronchodilator challenge
that exceeds both 200 mL AND exceeds a 12% increase from the prebronchodilator value
OR
• FEV1/FVC ratio < age adjusted lower limit of normal (LLN)
OR
• Residual volume (RV) > 120% by plethysmography (see Section 6.5 for alternative methods)
OR
• Significant emphysema on HRCT defined as more emphysema than fibrosis interpreted by a central radiology service
4. FVC > 90%
5. Hemoglobin corrected, not volume corrected, DLCO <25% of predicted normal
6. Surgical lung biopsy diagnostic for pneumoconiosis, hypersensitivity pneumonitis nonspecific interstitial pneumonia or other idiopathic
interstitial lung disease
7. Any clinically diagnosed collagen vascular disease
8. History of aortic aneurysm ≥ 3.5cm in diameter
9. History of cerebrovascular accident (stroke) within the preceding 26 weeks
10. 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
11. Require pharmaceutical treatment for pulmonary hypertension
12. Hospitalization for acute respiratory illness < 26 weeks prior to screening, unless reviewed with the Medical Monitor
13. Aspiration pneumonia < 26 weeks prior to screening
14. Active or recent (< 4 weeks prior to Screening and/or during the screening period) respiratory bacterial, viral, fungal, or other infection
(defined as exhibiting ongoing signs/symptoms related to the infection and without improvement)
15. Active work-up for suspected lung cancer or history of cancer or precancerous state (eg, familial polyposis, BRCA1, BRCA2, carcinoma insitu)
within 5 years prior to screening except for the following:
• Definitive prophylactic surgery for precancerous state
• Excision of non melanomatous skin cancer treated with clear margins
• Prostate carcinoma treated with surgery or radiation with normal PSA for 24 months, not requiring either chemotherapy or hormone therapy
16. History of human immunodeficiency virus (HIV), or active hepatitis C or hepatitis B infection (subjects with hepatitis C who have had
successful curative therapy will be eligible)
17. Co-morbid condition or illness limiting life expectancy to < 2 years
at time of screening
18. Major surgery, as defined by the investigator, < 30 days prior to screening or scheduled major elective surgery during the expected
duration of the study
19. 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
20. Current excessive consumption of alcohol or use of illegal drugs as determined by the investigator
Related to physiologic or organ specific abnormalities:
21. Use of supplemental O2 > 6L/min during activity
22. 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) (Except for
subjects on anticoagulants)
•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:
23. Treatment with immunosuppressive, cytotoxic, or antifibrotic drugs including colchicine, cyclosporine A, TNF α antagonists, imatinib
(Gleevec©), interferon-gamma, cyclophosphamide, or azathioprine < 28 days prior to randomization are not permitted
•N-acetylcysteine is permitted provided the subject has been on a stable dose for > 4 weeks prior to screening
•Concomitant use of pirfenidone or nintedanib must be in accordance with the approved prescribing instructions in the country where the site
is located.
24. Oral doses of corticosteroids exceeding the equivalent of 10 mg prednisone per day within the 60 days prior to Screening and/or during
the screening period
25. 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
26. Treatment with simtuzumab in another clinical study
27. Subjects actively listed for lung transplant are excluded. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
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 and a ≥ 5% absolute decrease) from baseline.
PFS in a subset of ITT subjects who are classified as LOXL2 High based on a pre-specified threshold level of LOXL2 in serum at baseline |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary endpoint will be evaluated at every visit from randomisation onwards. |
|
E.5.2 | Secondary end point(s) |
Secondary endpoints are:
• All cause mortality as measured by overall survival among ITT subjects
• All-cause mortality among subjects who are sLOXL2 high at baseline
Exploratory 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 HRCT findings since baseline
• Change in sLOXL2 levels
• Determine whether baseline sLOXL2 levels are prognostic for disease progression in the placebo arm of the study
• Evaluate the predictive effects of baseline sLOXL2 levels on various clinical endpoints as outlined in secondary objectives |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
The primary endpoint will be evaluated at every visit from randomisation onwards.
PK through serum simtuzumab levels will be measured approximately every 12 weeks. |
|
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 | 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 | 18 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 82 |
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 | 6 |
E.8.9.1 | In the Member State concerned days | 20 |
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 | 20 |