|E.1 Medical condition or disease under investigation
|Medical condition(s) being investigated
| Idiopathic Pulmonary Fibrosis (IPF)
|Medical condition in easily understood language
|Deadly lung disease with unknown cause in which the lung tissue that is needed to get oxygen into the blood becomes thick and stiff, which leads to difficulties with breathing
|Body processes [G] - Circulatory and Respiratory Physiological Phenomena [G09]
|E.1.2 Medical condition or disease under investigation
|Idiopathic pulmonary fibrosis
|System Organ Class
|10038738 - Respiratory, thoracic and mediastinal disorders
|Condition being studied is a rare disease
|E.2 Objective of the trial
|Main objective of the trial
|Determine the effect size of PRM-151 relative to placebo in change from Baseline to Week 28 in mean FVC% predicted, pooling subjects on a stable dose of pirfenidone or nintedanib with subjects not on other treatment for IPF.
|Secondary objectives of the trial
|•Determine the effect size of PRM-151 relative to placebo in change from Baseline to Week 28 in:
-normal lung parenchyma as quantified on HRCT imaging analysis, pooling subjects on a stable dose of pirfenidone or nintedanib with subjects not on other treatment for IPF.
-mean FVC% predicted, separately in subjects on a stable dose of pirfenidone or nintedanib and separately in subjects not on other treatments for IPF.
-normal lung parenchyma as quantified on HRCT imaging analysis, separately in subjects on a stable dose of pirfenidone or nintedanib and in subjects not on other treatments for IPF.
•Assess the tolerability and safety of PRM-151 in subjects with IPF through Week 28
•Assess the ability of PRM-151 to reduce disease-related events associated with mortality.
•Determine the effect size of PRM-151 relative to placebo on:
-pulmonary function in addition to mean change in FVC% predicted.
-6 minute walk distance.
|Trial contains a sub-study
|Principal inclusion criteria
|1.Subject is aged 40-80 years.
2.Subject has IPF satisfying the ATS/ERS/JRS/ALAT diagnostic criteria (Raghu, Collard et al. 2011).
In the absence of a surgical lung biopsy, HRCT must be “consistent with UIP” defined as meeting either criteria A, B, and C, or criteria A and C, or criteria B and C below:
A.Definite honeycomb lung destruction with basal and peripheral predominance.
B.Presence of reticular abnormality AND traction bronchiectasis consistent with fibrosis, with basal and peripheral predominance.
C.Atypical features are absent, specifically nodules and consolidation. Ground glass opacity, if present, is less extensive than reticular opacity pattern.
3.If on pirfenidone or nintedanib, subject must have been on a stable dose of pirfenidone or nintedanib for at least 3 months without increase in FVC% predicted on two consecutive PFTs, including screening PFTs. Subjects may not be on both pirfenidone and nintedanib.
4.If not currently receiving pirfenidone or nintedanib, subject must have been off pirfenidone or nintedanib for ≥ 4 weeks before baseline.
5.Subject has a FVC ≥ 50% and ≤ 90% of predicted.
6.Subject has a DLCO ≥ 25% and ≤ 90% of predicted.
7.Minimum distance on 6MWT of 150 meters.
8.Subject has a forced expiratory volume in 1 second (FEV1)/FVC ratio > 0.70.
9.Women of child bearing potential (WCBP), defined as a sexually mature woman not surgically sterilized or not post-menopausal for at least 24 consecutive months if ≤ 55 years or 12 months if > 55 years, must have a negative serum pregnancy test within four weeks prior to the first dose of study drug and must agree to use adequate methods of birth control throughout the study. Adequate methods of contraception include use of oral contraceptives or Depo-Provera, with an additional barrier method (diaphragm with spermicidal gel or condoms with spermicide), double-barrier methods (diaphragm with spermicidal gel and condoms with spermicide), partner vasectomy, and total abstinence.
10.Subject has a life expectancy of at least 9 months
11.Subject, according to the investigator’s best judgment, can comply with the requirements of the protocol.
12. Subject and the treating physician considered all medicinal treatment options and / or possibly a lung transplantation prior to considering participation in the study.
13.Subject has provided written informed consent to participate in the study.
|Principal exclusion criteria
|1.Subject has emphysema ≥ 50% on HRCT or the extent of emphysema is greater than the extent of fibrosis according to reported results from the most recent HRCT.
2.Subject has a history of cigarette smoking within the previous 3 months.
3.Subject has received investigational therapy for IPF within 4 weeks before baseline.
4.Subject is receiving systemic corticosteroids equivalent to prednisone > 10 mg/day or equivalent within 2 weeks of baseline.
5.Subject received azathioprine, cyclophosphamide, or cyclosporine A within 4 weeks of baseline.
6.Subject has a history of a malignancy within the previous 5 years, with the exception of basal cell skin neoplasms. In addition, a malignant diagnosis or condition first occurring prior to 5 years must be considered cured, inactive, and not under current treatment.
7.Subject has any concurrent condition other than IPF that, in the Investigator’s opinion, is unstable and/or would impact the likelihood of survival for the study duration or the subject’s ability to complete the study as designed, or may influence any of the safety or efficacy assessments included in the study.
8.Subject has baseline resting oxygen saturation of < 89% on room air or supplemental oxygen.
9.Subjects that are unable to refrain from use of the following:
a)Short acting bronchodilators on the day of and within 12 hours of pulmonary function, DLCO, and 6 minute walk assessments.
b)Long acting bronchodilators on the day of and within 24 hours of these assessments.
10.Subject has a known post bronchodilator (short acting beta agonist [SABA] – albuterol or salbutamol) increase in FEV1 of >10% and in FVC of >7.5%.
|E.5 End points
|Primary end point(s)
|The primary endpoint is the mean change in FVC % predicted from Baseline to Week 28.
|Timepoint(s) of evaluation of this end point
|Secondary end point(s)
•Mean change from Baseline to Week 28 in total lung volume and volume of parenchymal features on HRCT (in ml and % of total lung volume) representative of interstitial lung abnormalities (ILA) including ground glass density, reticular changes, and honeycombing, using quantitative imaging software.
•Mean change from Baseline to Week 28 in volume of parenchymal features on HRCT (in ml and % of total lung volume) representative of normal lung (non-ILA), including normal and low attenuation areas, using quantitative imaging software.
•Correlation between mean change from Baseline to Week 28 in FVC % predicted and mean change from Baseline to Week 28 in total lung volume and volume of parenchymal features on HRCT (in ml and % of total lung volume) representative of interstitial lung abnormalities (ILA), including ground glass density, reticular changes, and honeycombing by quantitative imaging software.
Safety: Tolerability/safety will be assessed over the 28 week study period by the following parameters:
•Incidence of AEs.
•Incidence of serious adverse events (SAEs).
•Incidence of respiratory AEs and SAEs.
•Proportion of subjects discontinuing study drug due to AEs.
•Change from Baseline in hematology and serum chemistries.
•All cause mortality.
•Mortality due to respiratory deterioration.
Disease related events associated with mortality: The number of “respiratory decline” events over the 28 week study period as defined below:
•Unscheduled visits to a healthcare professional for respiratory status deterioration.
•Urgent care visit for respiratory status deterioration.
•Hospitalization due to a worsening or exacerbation of respiratory symptoms.
All “respiratory decline” events will be further characterized according to the definitions of IPF related acute exacerbation, as proposed by an expert committee sponsored by the IPF Clinical Research Network and the National Heart Lung and Blood Institute (NHLBI) (Collard, Moore et al. 2007) and applied by (Collard, Yow et al. 2013)
•Acute onset of symptoms (< 30 days in duration)
•New radiographic abnormalities (bilateral ground glass or consolidation on HRCT with no pneumothorax or pleural effusion)
•The absence of an identified infectious etiology by routine clinical practice
•Exclusion of alternative causes by routine clinical practice, including:
a.Left heart failure
c.Identifiable cause of acute lung injury
Pulmonary Function Tests
•Proportion (%) of subjects with a decline in FVC% predicted of ≥ 5% and ≥ 10% from Baseline to Week 28.
•Proportion (%) of subjects with a decline in FVC in ml of ≥ 100 ml and ≥ 200 ml from Baseline to Week 28.
•Proportion of subjects with an increase in FVC % predicted of ≥ 5% and ≥ 10% from Baseline to Week 28.
•Proportion of subjects with an increase in FVC in ml of ≥100 ml and ≥ 200 ml from Baseline to Week 28.
•Proportion of subjects with stable disease by FVC %, defined as a change in FVC % predicted of <5% from Baseline to Week 28.
•Proportion of subjects with stable disease by FVC in ml, defined as a change in FVC of < 100ml from Baseline to Week 28.
•Mean change from Baseline to Week 28 in % predicted diffusion capacity of carbon monoxide (DLCO).
•Change in 6-minute walk distance, in meters, from Baseline to Week 28.
•Examine the change from Baseline at Weeks 4, 8, 12, 16, 20, and 24 for the FVC % predicted, FVC in ml, and 6MWT distance
•Transitions from Baseline to Week 28 between all categories of lung features (normal, ground glass density, reticular changes, honeycombing, and mild, moderate, and severe low attenuation areas) by quantitative imaging software.
•Correlation of transitions between categories of lung features by quantitative imaging and changes in FVC% predicted.
•Correlation of transitions between categories of lung features by quantitative imaging and changes in DLCO.
•Impact of inspiratory effort on results of HRCT quantitative imaging.
Patient Reported Outcomes
•Change in Patient Reported Outcomes as measured by King’s Brief Interstitial Lung Disease Questionnaire (K-BILD) and Leicester Cough Questionnaire (LCQ) from Baseline to Week 28.
•Changes in serum and cellular biomarkers and response according to baseline genetic characteristics: including but not limited to TLR3, L412F polymorphism, and MUC5B promoter polymorphism.
|Timepoint(s) of evaluation of this end point
|With every visit after randomisation and at week 28
|E.6 and E.7 Scope of the trial
|Scope of the trial
|Trial type and phase
|Human pharmacology (Phase I)
|First administration to humans
|Other trial type description
|Therapeutic exploratory (Phase II)
|Therapeutic confirmatory (Phase III)
|Therapeutic use (Phase IV)
|E.8 Design of the trial
| Comparator of controlled trial
|Other medicinal product(s)
|Number of treatment arms in the trial
The trial involves single site in the Member State concerned
| The trial involves multiple sites in the Member State concerned
|Number of sites anticipated in Member State concerned
|The trial involves multiple Member States
|Number of sites anticipated in the EEA
|E.8.6 Trial involving sites outside the EEA
|Trial being conducted both within and outside the EEA
|Trial being conducted completely outside of the EEA
|If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
|Trial has a data monitoring committee
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|E.8.9 Initial estimate of the duration of the trial
|In the Member State concerned years
|In the Member State concerned months
|In the Member State concerned days
|In all countries concerned by the trial years
|In all countries concerned by the trial months