Study WA42294 is a Phase III open-label extension (OLE) study to assess the long-term safety, efficacy, and pharmacokinetics of PRM-151 in patients with IPF with or without concurrent treatment with pirfenidone or nintedanib. Patients with IPF who…
ID
Source
Brief title
Condition
- Pulmonary vascular disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
This study will evaluate the long-term safety, efficacy and pharmacokinetics of
open label PRM 151 in patients with idiopathic pulmonary fibrosis (IPF).
Specific objectives and corresponding endpoints for the study are outlined
below.
The safety objective for this study is to confirm the long term safety and
tolerability of 10 mg/kg of PRM 151 administered every 4 weeks (Q4W) via
intravenous (IV) infusion plus standard of care (SOC) treatment, on the basis
of the following endpoints:
• Incidence and severity of all adverse events (AEs), with severity determined
according to the 5 point severity scale (National Cancer Institute Common
Terminology Criteria for Adverse Events, Version 5.0 [NCI CTCAE, v.5.0])
• Incidence and severity of infusion related reactions (IRRs) and other AEs of
special interest
• Proportion of patients permanently discontinuing study treatment due to AEs
• Change from baseline of targeted clinical laboratory test results
The efficacy objectives are to assess the long term efficacy of 10 mg/kg PRM
151 plus SOC (excluding lung transplantation) administered Q4W via IV infusion
on the basis of the following endpoints:
• Annual rate of decline in forced vital capacity (FVC [mL])
• Annual rate of change in 6 minute walk distance (6MWD)
• Annual rate of decline in FVC% predicted
• Progression free survival, defined as time to first occurrence of *10%
absolute decline in % predicted FVC, *15% relative decline in 6MWD, or death
• Change from baseline in University of California, San Diego Shortness of
Breath Questionnaire (UCSD SOBQ)
• Change from baseline in St. George Respiratory Questionnaire (SGRQ) Total
Score
• Change from baseline in carbon monoxide diffusing capacity (DLCO)
• Survival, as measured by all cause mortality
Secondary outcome
Exploratory analyses may also be performed for additional measures and
subgroups of interest including concurrent use of IPF treatment and geographic
region. Details of all such analyses will be provided in the Statistical
Analysis Plan (SAP).
Pharmacokinetic Objectives
The pharmacokinetic (PK) objective for this study is to characterize
pharmacokinetics of PRM 151 in patients with IPF (from Cohort A only), on the
basis of the following endpoint:
• Serum concentrations of PRM 151 at specified timepoints
The exploratory PK objectives are to evaluate the potential relationship
between drug exposure and the efficacy and safety of PRM 151 on the basis of
the following endpoints:
• Relationship between PK for PRM 151 and efficacy endpoints
• Relationship between PK for PRM 151 and safety endpoints
The immunogenicity objective for this study is to evaluate the immune response
to PRM 151 in patients with IPF (from Cohort A only) on the basis of the
following:
• Prevalence of ADAs at baseline and incidence of ADAs during the study
The exploratory immunogenicity objective for this study is to evaluate
potential effects of ADAs on the basis of the following:
• Relationship between ADA status and efficacy, safety, or PK endpoints
The exploratory biomarker objective for this study (from Cohort A only) is to
identify and/or evaluate biomarkers that can provide evidence of PRM 151
activity and the duration of that activity (i.e., pharmacodynamic biomarkers),
are associated with acquired resistance to PRM 151, are associated with
susceptibility to developing AEs or can lead to improved AE monitoring or
investigation (i.e., safety biomarkers), or can increase the knowledge and
understanding of disease biology and drug safety, on the basis of the following
endpoint:
• Relationship between biomarkers in blood and efficacy, safety, PK,
immunogenicity, or other biomarker endpoints.
The exploratory health status utility objective for this study is to evaluate
health status utility scores of patients treated with PRM 151 plus SOC on the
basis of the following endpoint:
• Annual rate of change in EuroQol 5 Dimension, 5 Level Questionnaire (EQ 5D
5L) index based, and visual analog scale (VAS) scores
added by protocol v.3:
Two objectives based on PRO assessments were moved from efficacy section to
exploratory section because of the unblinded nature of the administration of
PRM 151 in this extension study. Two additional exploratory objectives were
added to highlight the noteworthiness of these objectives (Section 2.3).
Serious adverse events has been added to list of the criteria based on which
safety analyses for this study will be performed (Section 6.3).
* Language has been updated to include efficacy analysis, additional healthcare
utilization for respiratory events analysis, and exploratory analysis to
reflect suggestions from regulatory agencies and to improve clarity of the text
(Sections 6.4 and 6.41).
added by protocol v3:
Annual rate of change in DLCO and IPF-related mortality and respiratory-related
mortality are added as an efficacy objective to better align with the rest of
the protocol. This was missed in the previous version of the protocol.
Additional changes have been done in the efficacy objectives for improved
clarity (Section 2.2).
Background summary
Idiopathic pulmonary fibrosis is a specific form of a chronic-fibrosing
interstitial pneumonia limited to the lung. It is a progressive inflammatory
lung disease that leads to significant morbidity and mortality. Pentraxin-2
(PTX-2) is a highly conserved endogenous serum protein and a soluble pattern
recognition receptor (PRR) of the innate immune system that regulates monocyte
activation and differentiation. PRM-151 is a recombinant human pentraxin-2
(rhPTX-2) protein. Of importance, patients with IPF (in comparison to healthy
subjects) have both increased fibrocyte numbers in circulation and decreased
levels of circulating PTX-2.
Supplementing endogenous PTX-2 levels through intravenous administration of
PRM-151 should theoretically increase the regulatory capacity of PTX-2 in
circulation and at the site of disease, thereby promoting healing and reducing
fibrosis.
Robust nonclinical and clinical data exist to support the investigation of
PRM-151 in the treatment of fibrotic diseases. Efficacy and safety of PRM-151
is also being investigated in patients with myelofibrosis in a Phase II study.
(see Protocol, section 1. background)
Study objective
Study WA42294 is a Phase III open-label extension (OLE) study to assess the
long-term safety, efficacy, and pharmacokinetics of PRM-151 in patients with
IPF with or without concurrent treatment with pirfenidone or nintedanib.
Patients with IPF who have already completed the Phase II 28-week
placebo-controlled period (PRM-151-202) and taken part in the OLE (Cohort A);
or completed the Phase III Study WA42293 will be eligible to
enroll in this study (Cohort B). Additionally, patients who have discontinued
treatment or completed the Phase III Study WA42293, and do not wish to receive
open-label PRM-151 in this study will be followed-up for survival (Cohort C).
No safety or efficacy assessments will be required for these patients. This
open-label design will allow an examination of the impact of longer treatment
duration on safety, durability of response in lung function, exercise
tolerance, and patient reported outcomes as well as pharmacokinetics of
PRM-151. (See Protocol, section 1.3.)
Study design
This OLE study is being conducted to confirm the long term safety, efficacy,
and pharmacokinetics of PRM 151 in the treatment of eligible patients with IPF
who have taken part in Study PRM 151 202 and received the open label study drug
(Cohort A) or completed the Phase III Study WA42293 (Cohort B) with PRM 151.
Additionally, patients who have discontinued treatment from or have completed
Study WA42293 and do not want to receive open label PRM 151 in this study, will
be invited to enroll in survival follow up Cohort C. Patients in Cohort C will
not receive any treatment and will not undergo any safety or efficacy
assessments during the study. Patients who discontinue treatment from Cohorts
A and B will automatically transition to Cohort C for long term follow up,
unless they withdraw consent from the study.
Approximately 600-700 patients are expected to enroll in the study. Patients
will initially receive loading doses of either PRM 151 10 mg/kg IV infusion
and/or placebo over 50*70 minutes on Days 1, 3, and 5, then one infusion of PRM
151 Q4W until the end of the study. Patients previously on the placebo arm of
Study WA42293 will receive PRM 151 in all three loading doses, whereas patients
previously on the active treatment arm of Study WA42293 will receive PRM 151
for the first dose, followed by placebo doses at the 2nd and 3rd loading dose
visit. The 2nd and 3rd loading doses will be blinded for Cohort B, to ensure
that the blind in Study WA42293 is maintained for patients, site staff, and the
Sponsor.
Intervention
Patients will receive IV infusions of 10 mg/kg PRM 151 over approximately 50*70
minutes, with dose based on the patient*s weight recorded at each visit (for
loading or reloading doses, weight taken at the clinic visit for the first dose
can be applied to the 2nd and 3rd doses).
The non-investigational medicinal products (NIMP) for this study are
pirfenidone and nintedanib. The NIMPs are considered background therapy for
those patients already receiving either product when entering the study, and
rescue therapy for any patient who commences treatment with either product
during the study.
added/updated by protocol v3;
* Urinalysis collection has been updated from every 24 weeks to every 12 weeks
to align with the collection of urine for optional biomarker sampling (Appendix
1).
* It has been clarified that study completion visit is not required for
patients in Cohort C (Appendix 2).
Study burden and risks
PRM 151, a recombinant form of an endogenous human protein, was generally well
tolerated in nonclinical toxicity studies and in Phase I and II clinical
studies. Clinically and statistically significant positive effects with PRM 151
were observed in the Phase II IPF Study PRM 151 202, both for change in FVC (%
predicted) and 6MWD through 28 weeks of treatment. Based on encouraging Phase
I and II data in patients with IPF, PRM 151 has the potential to be a well
tolerated, disease modifying treatment for a broad spectrum of fibrotic
diseases, including IPF.
In the two Phase I studies of PRM-151 administered intravenously to normal
volunteers and patients with IPF, no serious adverse events were reported and
no other safety signals were 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 serious adverse events noted in 57
days.
As with any protein therapeutic, the potential for reactions exists and safety
procedures will be implemented, including careful monitoring of patients 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 and the potential benefits
of PRM 151 as a therapy for IPF remain to be proven in clinical efficacy
studies. (see Protocol, section 1.3.1)
Grenzacherstrasse 124
Basel 4070
CH
Grenzacherstrasse 124
Basel 4070
CH
Listed location countries
Age
Inclusion criteria
Patients must meet the following criteria for study entry:
* Signed Informed Consent Form
* In the opinion of the Principle Investigator, participation in the study is
in the best
interest of the patient
* Ability to comply with the requirements of the study protocol, according to
the
investigator*s best judgment
* Taken part in a previous study of PRM-151, as follows:
o Participated in Study PRM-151-202 (completed the 28-week
placebo-controlled period and entered the OLE), and tolerated the study
drug in the opinion of the investigator (Cohort A) OR
o Completed study treatment in Study WA42293 (Cohort B) OR
o Participated in Study WA42293 but have discontinued from
study treatment (Cohort C; patients who completed treatment in
Study WA42293, but no longer wish to take PRM-151 may also join
Cohort C)
* For women of childbearing potential: agreement to remain abstinent (refrain
from
heterosexual intercourse) or use contraception, as defined below:
Women must remain abstinent or use contraceptive methods with a failure rate of
*1% per year during the treatment period and for 8 weeks after the final dose of
PRM-151.
A woman is considered to be of childbearing potential if she is postmenarchal,
has
not reached a postmenopausal state (*12 continuous months of amenorrhea with
no identified cause other than menopause), and is not permanently infertile due
to
surgery (i.e., removal of ovaries, fallopian tubes, and/or uterus) or another
cause as
determined by the investigator (e.g., Müllerian agenesis). The definition of
childbearing potential may be adapted for alignment with local guidelines or
regulations.
Examples of contraceptive methods with a failure rate of *1% per year include
bilateral tubal ligation, male sterilization, hormonal contraceptives that
inhibit
ovulation, hormone-releasing intrauterine devices, and copper intrauterine
devices.
Hormonal contraceptive methods must be supplemented by a barrier method.
The reliability of sexual abstinence should be evaluated in relation to the
duration of
the clinical trial and the preferred and usual lifestyle of the patient.
Periodic
abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods)
and
withdrawal are not adequate methods of contraception. If required per local
guidelines or regulations, locally recognized adequate methods of contraception
and
information about the reliability of abstinence will be described in the local
Informed
Consent Form.
* For men: agreement to remain abstinent (refrain from heterosexual
intercourse) or
use a condom, and agreement to refrain from donating sperm, as defined below:
With a female partner of childbearing potential or pregnant female partner, men
must remain abstinent or use a condom during the treatment period and for 8
weeks
after the final dose of PRM-151 to avoid exposing the embryo. Men must refrain
from donating sperm during this same period.
The reliability of sexual abstinence should be evaluated in relation to the
duration of
the clinical trial and the preferred and usual lifestyle of the patient.
Periodic
abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods)
and
withdrawal are not adequate methods of preventing drug exposure. If required per
local guidelines or regulations, information about the reliability of
abstinence will be
described in the local Informed Consent Form.
Exclusion criteria
Patients who meet any of the following criteria will be excluded from study
entry:
* Received any experimental treatment other than PRM-151 within 4 weeks or
five half-lives of the experimental drug, whichever is longer, prior to the
first dose in
the OLE study
* Receiving strong inhibitor or inducer of CYP1A2 in patients taking pirfenidone
* Receiving potent inhibitor or inducer of P-gp in patients taking nintedanib
* Acute respiratory or systemic bacterial, viral, or fungal infection at the
first visit of the
OLE, or within 2 weeks of the first visit for patients joining Cohort A (from
Study PRM-151-202)
* History of smoking (including cigarette, cannabis, cigar, pipe, and vaping)
within
3 months prior to the first visit in the OLE
* History of alcohol or substance use disorder within 2 years prior to the
first visit of
the OLE or known or suspected active alcohol or substance-use disorder.
* History of severe allergic reaction or anaphylactic reaction to PRM-151
* Clinically significant abnormality on ECG during eligibility assessment
that, in the opinion of the investigator, may pose an additional risk in
administering study drug to the patient.
* Prolonged corrected QT interval > 450 ms (for men) or > 470 ms (for
women) based on the Fridericia correction formula.
* Clinically significant laboratory test abnormalities (hematology, serum
chemistry, and urinalysis) that, in the opinion of the investigator, may
pose an additional risk in administering study drug to the patient.
* Any of the following laboratory abnormalities known at the time of the first
visit
- ALT and/or AST *2.5*upper limit of normal (ULN)
- Total bilirubin *2*ULN
* Pregnant or breastfeeding, or intending to become pregnant during the study
(for Cohort A or B patients)
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 | EUCTR2020-001429-30-NL |
| ClinicalTrials.gov | NCT04594707 |
| CCMO | NL75035.078.21 |