To 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 and subjects not on other treatment for IPF.
ID
Source
Brief title
Condition
- Lower respiratory tract disorders (excl obstruction and infection)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary endpoint is the mean change in FVC % predicted from Baseline to
Week 28.
Secondary outcome
* Structural Imaging:
* 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 mild 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
b. Pulmonary embolism
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.
Background summary
A double blinded, randomised, placebo controlled Phase 2 Trial to Evaluate the
Efficacy of PRM-151 in Subjects with Idiopathic Pulmonary Fibrosis (IPF). The
objective is to 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 and subjects not on other treatment
for IPF.
Study objective
To 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 and subjects not on other treatment for IPF.
Study design
This study is a Phase 2, randomized, double-blind, placebo controlled, pilot
study designed to evaluate the efficacy and safety of PRM 151 administered
through Week 24 to subjects with IPF. Subjects meeting the eligibility criteria
for the study will be randomized with a 2:1 ratio to PRM-151 at a dose of 10
mg/kg every 4 weeks or placebo. The randomization will be stratified according
to other treatments for IPF (patients receiving pirfenidone or nintedanib and
patients with no other treatment for IPF, with a minimum of 25% of patients on
no other treatment). Efficacy will be evaluated through pulmonary function
tests (PFTs) including spirometry, Diffusion Capacity (DLco) and Total Lung
Capacity by Nitrogen washout method, quantitative imaging analysis of high
resolution CT (HRCT), 6 minute walk test (6MWT), and patient reported outcomes
(PROs).
Subjects will be evaluated for study eligibility during Screening within 4
weeks before enrollment and Baseline assessments. Subjects who are determined
to be eligible, based on Screening assessments, will be enrolled in the study
and randomly allocated to treatment with PRM 151 or placebo. Subjects will
receive study drug treatment for at least 24 weeks.
Approximately 117 subjects will be randomly assigned on a 2:1 basis to
treatment with PRM 151 or placebo, as follows:
* PRM 151 10 mg/kg IV infusion over 60 minutes days 1, 3, and 5, then one
infusion every 4 weeks
* Placebo IV infusion over 60 minutes on days 1, 3, and 5, then one infusion
every 4 weeks
After completing 24 weeks of treatment, subjects may continue with PRM-151
dosing in the open label extension in the absence of disease progression or
toxicity warranting discontinuation of therapy.
All subjects will receive PRM-151 10 mg/kg IV Days 1, 3, 5 then every 4 weeks
in the extension. Dosing on days 1, 3 and 5 will be repeated every 28 weeks
during the extension. PROs, PFTs, spirometry and 6MWT will be done every 4
weeks for the first 24 weeks and then every 12 weeks. DLco, FRC &TLC by
nitrogen washout method will be done every 12 weeks. HRCT will be done at 1.5
years (Week 76) and 2.5 years (Week 128) on the same day as DLco and FRC & TLC
by nitrogen washout. Subjects are allowed to begin treatment with, or restart
treatment with, pirfenidone or nintedanib after the week 28 end of study
assessments have been performed.
Intervention
After the subject decided to participate in the trial, the patient will be
randomized to either PRM-151 or placebo, both administered by intravenous
infusion for 9 treatments in a period of 24 weeks.
With (almost) every visit all subjects need to complete 2 questionnaires. Next
to that physical examination, 6 Minutes walk test, pulmonary function test and
blood tests need to be done. next to that, at baseline and at 28 weeks a HRCT
is planned.
Study burden and risks
See protocol section 1.5. Risk/Benefit Assessment:
PRM 151, a recombinant form of an endogenous human protein, has been
well tolerated in preclinical toxicology studies and Phase 1 and 2 clinical
studies, and has shown an early trend towards efficacy in subjects with IPF.
Based on encouraging Phase 1 data in subjects with IPF, PRM 151 has the
potential to be a safe, disease modifying treatment for a broad spectrum of
fibrotic diseases, including IPF.
PRM 151 represents the recombinant version of an endogenous human serum
protein, and as such was predicted to have a very favorable safety index. This
prediction has been confirmed in multiple preclinical and clinical studies to
date. Two Phase 1 studies of PRM 151 administered IV to normal volunteers and
IPF subjects have been completed, with no SAEs reported and no other safety
signals seen. The single ascending dose study (PRM151A-11EU) tested dose levels
as high as 20 mg/kg. The multiple ascending dose study (PRM151F-12GL)
demonstrated that PRM 151 administered by 30 minute IV infusion on Days 1, 3,
5, 8 and 15 at up to 10 mg/kg was safe and well tolerated in subjects with IPF,
with no SAEs noted in 57 days; similar types and number of TEAEs were reported
in both PRM 151 and placebo treated subjects. Safety data from 27 patients
with MF, including 24 weeks of safety data in 20 subjects and an additional 12
weeks of safety data in 10, confirms the excellent safety profile of PRM-151 to
date. Most adverse events have been Grade 1 or 2 and unrelated to PRM-151, and
5 possibly related SAEs, including one death, have been reported in a group of
older patients (median age 67 years) with a serious, life threatening disease.
Risks associated with PRM 151 are inherent in its being the recombinant
form of a naturally occurring human protein, and consist of potential
development of anti-drug antibodies and infusion reactions. PRM 151 has an
endogenous counterpart, and, therefore, anti-drug antibodies could develop that
could potentially affect the efficacy of PRM 151 treatments in addition to
having the potential to cross-react with endogenous hPTX-2. Anti-drug
antibodies were detected in 3 subjects in the MF trial, with no apparent impact
on pharmacokinetics, safety, or efficacy. Two subjects had mild infusion
reactions which were easily managed and prevented in the one subject that was
rechallenged; anti-drug antibody was detected in one of them.
PRM 151 is not a general immunosuppressant, and treatment with PRM 151
is not expected to increase rates of infection or adversely affect wound
healing.
As with any protein therapeutic, the potential for reactions exists and
safety procedures will be implemented including careful monitoring of subjects
during infusions and of infusion sites. Appropriate personnel, medication, and
other requirements for the treatment of potential infusion reactions will be
required by the protocol.
PRM 151 is an investigational agent. Subjects are not anticipated to
derive direct benefit from participation in studies; the potential benefits of
PRM 151 as a therapy for IPF remain to be proven in clinical efficacy studies.
Hartwell Ave 101
Lexington MA 02421
US
Hartwell Ave 101
Lexington MA 02421
US
Listed location countries
Age
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 prior to screening 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, with or without supplemental oxygen
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 (only if total abstinence is the preferred method and usual lifestyle of the subject).
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. If the subject is on a lung transplant list, the Investigator anticipates the subject will be able to complete the study prior to transplant.
13. Subject has provided written informed consent to participate in the study.
Exclusion criteria
1. Subject has emphysema * 50% on HRCT or the extent of emphysema is greater than the extent of fibrosis according to the reported results of 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. Subjects received Immuno-suppressants (e.g. methotrexate, azathioprine, cyclophosphamide, cyclosporine, everolimus or other immunosuppressants including those used after organ transplant) are prohibited within 4 weeks of baseline and during the study.
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 with 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%.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2014-004782-24-NL |
| ClinicalTrials.gov | NCT02550873 |
| CCMO | NL51502.078.14 |