Zephyrus II: Efficacy and Safety Study of Pamrevlumab in Participants With Idiopathic Pulmonary Fibrosis (IPF)

Zephyrus II: A Phase 3, Randomized, Double-Blind, Placebo-Controlled Efficacy and Safety Study of Pamrevlumab in Subjects With Idiopathic Pulmonary Fibrosis (IPF)

Status

Terminated

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT04419558

Enrollment

372

Registered

2020-06-05

Start date

2020-09-30

Completion date

2023-09-04

Last updated

2024-08-12

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Idiopathic Pulmonary Fibrosis

Keywords

Idiopathic Pulmonary Fibrosis, IPF, Idiopathic Interstitial Pneumonia, Interstitial Lung Disease, Lung Fibrosis

Brief summary

This is a Phase 3 trial to evaluate the efficacy and safety of 30 milligrams (mg)/kilogram (kg) intravenous (IV) infusions of pamrevlumab administered every 3 weeks as compared to placebo in participants with Idiopathic Pulmonary Fibrosis (IPF). There is a 48-week randomized treatment phase followed by an optional, open-label extension phase.

Detailed description

The intent of this study is to evaluate the efficacy and safety of pamrevlumab as monotherapy in participants with IPF. Participants who are not being treated with approved IPF therapies (that is, nintedanib or pirfenidone) may be eligible for screening. Examples of reasons participants may not be treated with approved IPF therapies include but are not limited to: * Intolerant or not responsive to approved IPF therapies * Ineligible to receive these therapies * Participant voluntarily declines to receive approved IPF therapies after being fully informed of the potential benefits/risks NOTE: No participant should discontinue an approved IPF therapy for the purpose of enrolling in this study. During the 48-week treatment phase of the study, co-administration of an approved IPF therapy (such as, pirfenidone or nintedanib) is acceptable if clinically indicated in the Investigator's opinion, after assessment of potential risks/benefits of such combination with blinded study treatment. Participants who complete the 48-week study will be eligible for an optional, open-label extension phase with continued access to pamrevlumab, regardless of their randomized assignment.

Interventions

DRUGPamrevlumab

Sterile solution for injection

DRUGPlacebo

Sterile solution for injection

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Masking description

During the Open-label extension phase, all participants will receive pamrevlumab in an open-label manner. No unblinding of participant's treatment assignment in the treatment phase (main study) will occur for purposes of open-label extension participation.

Eligibility

Sex/Gender

ALL

Age

40 Years to 85 Years

Healthy volunteers

Inclusion criteria

Key Inclusion Criteria: 1. Diagnosis of IPF as defined by American Thoracic Society/European Respiratory Society/Japanese Respiratory Society/Latin American Thoracic Association (ATS/ERS/JRS/ALAT) guidelines within the past 7 years prior to study participation. 2. High-resolution computed tomography (HRCT) scan at Screening, with ≥10% to \<50% parenchymal fibrosis (reticulation) and \<25% honeycombing. 3. FVCpp value \>45% and \<95% at Screening and Day 1 (prior to randomization). 4. Diffusing capacity of the lungs for carbon monoxide (DLCO) percent predicted ≥25% and ≤90%. 5. Not currently receiving treatment for IPF with an approved therapy for IPF (such as, pirfenidone or nintedanib) for any reason, including prior intolerance or lack of response to an approved IPF therapy, or choice to forego treatment with an approved IPF therapy after a full discussion with the Investigator regarding risks/benefits of such therapy. Key

Exclusion criteria

1. Previous exposure to pamrevlumab. 2. Evidence of significant obstructive lung disease, as evidenced by spirometry or HRCT. 3. Female participants who are pregnant or nursing. 4. Smoking within 3 months of Screening and/or unwilling to avoid smoking throughout the study. 5. Interstitial lung disease other than IPF. 6. Sustained improvement in the severity of IPF during the 12 months prior to screening. 7. Other types of respiratory diseases that, in the opinion of the Investigator, would impact the primary protocol endpoint or otherwise preclude participation in the study, including diseases of the airways, lung parenchyma, pleural space, mediastinum, diaphragm, or chest wall. 8. Certain medical conditions, that, in the opinion of the Investigator, would impact the primary protocol endpoint or otherwise preclude participation in the study (such as, myocardial infarction/stroke, severe chronic heart failure, pulmonary hypertension, or cancers). 9. Acute IPF exacerbation during Screening or Randomization including hospitalization due to acute IPF exacerbation within 4 weeks prior to or during screening. 10. Use of any investigational drugs or unapproved therapies, or participation in any clinical trial with an investigational new drug within 30 days prior to screening. Or use of approved IPF therapies (such as, pirfenidone or nintedanib) within 1 week prior to screening. 11. History of allergic or anaphylactic reaction to human, humanized, chimeric or murine monoclonal antibodies, or to any component of the excipient.

Design outcomes

Primary

Measure	Time frame	Description
DB Period: Change From Baseline in FVC at Week 48	Baseline, Week 48	FVC is a standard pulmonary function test used to quantify respiratory muscle weakness. FVC was the volume of air that can forcibly be blown out after full inspiration in the upright position, measured in liters. Least square (LS) mean and standard error (SE) were analyzed using mixed model repeated measures (MMRM).

Secondary

Measure	Time frame	Description
DB Period: Change From Baseline in Quantitative Lung Fibrosis (QLF) Volume at Week 48	Baseline, Week 48	The QLF volume is calculated as QLF=total lung capacity volume (TLC) \* % of quantitative lung fibrosis for fibrosis of the whole lung. LS mean and SE were analyzed using MMRM.
DB Period: Time to First Occurrence of Any Component of the Clinical Composite Endpoint, Whichever Occurred First	Up to Week 48	The components of the clinical composite endpoints included acute idiopathic pulmonary fibrosis (IPF) exacerbation, respiratory hospitalization, or death. 'Median Time to Event' is an estimated value, which was calculated based on Kaplan-Meier method. For an endpoint in which less than half of the participants have encountered the events, the 'Median Time to Event' might be longer than the reported timeframe of 48 weeks.
DB Period: Time to Disease Progression	Up to Week 48	Time to disease progression was defined as time from randomization to either the first occurrence of an absolute FVC percent predicted (FVCpp) decline of ≥10% from baseline or death, whichever occurred first. 'Median Time to Event' is an estimated value, which was calculated based on Kaplan-Meier method. For an endpoint in which less than half of the participants have encountered the events, the 'Median Time to Event' might be longer than the reported timeframe of 48 weeks.
DB Period: Time to All-Cause Mortality	Up to Week 48	'Median Time to Event' is an estimated value, which was calculated based on Kaplan-Meier method. For an endpoint in which less than half of the participants have encountered the events, the 'Median Time to Event' might be longer than the reported timeframe of 48 weeks.
DB Period: Time to First Respiratory Hospitalization	Up to Week 48	'Median Time to Event' is an estimated value, which was calculated based on Kaplan-Meier method. For an endpoint in which less than half of the participants have encountered the events, the 'Median Time to Event' might be longer than the reported timeframe of 48 weeks.
DB Period: Time to First Acute IPF Exacerbation	Up to Week 48	'Median Time to Event' is an estimated value, which was calculated based on Kaplan-Meier method. For an endpoint in which less than half of the participants have encountered the events, the 'Median Time to Event' might be longer than the reported timeframe of 48 weeks.

Countries

Argentina, Brazil, China, Colombia, Czechia, Denmark, Dominican Republic, France, Georgia, Germany, Hungary, Ireland, Italy, Lebanon, Mexico, Netherlands, Peru, Poland, Serbia, South Korea, Spain, Switzerland, Ukraine, United Kingdom, United States

Participant flow

Pre-assignment details

The study included a Double-blind (DB) Period and an Open-label Extension (OLE) Period.

Participants by arm

Arm	Count
Pamrevlumab Participants received pamrevlumab 30 mg/kg, administered by IV infusion, every 3 weeks, for a total of up to 17 infusions over 48 weeks in the DB period. Participants who completed the treatment in DB period and entered in the OLE period, continued to receive pamrevlumab 30 mg/kg administered by IV infusion, every 3 weeks for up to 48 weeks.	184
Placebo Participants received pamrevlumab-matching placebo, administered by IV infusion every 3 weeks for a total of up to 17 infusions over 48 weeks in the DB period. Participants who completed the treatment in DB period and entered in the OLE period, received pamrevlumab 30 mg/kg administered by IV infusion, every 3 weeks for up to 48 weeks.	188
Total	372

Withdrawals & dropouts

Period	Reason	FG000	FG001
DB Period (48 Weeks)	Adverse Event	6	6
DB Period (48 Weeks)	Death	14	11
DB Period (48 Weeks)	Disease Progression	1	0
DB Period (48 Weeks)	Investigator Decision	0	1
DB Period (48 Weeks)	Lost to Follow-up	1	3
DB Period (48 Weeks)	Lung Transplant	1	0
DB Period (48 Weeks)	Participant Decision	4	3
DB Period (48 Weeks)	Study terminated by sponsor	99	101
DB Period (48 Weeks)	Withdrawal by Subject	11	7
OLE Period (48 Weeks)	Adverse Event	3	1
OLE Period (48 Weeks)	Death	4	6
OLE Period (48 Weeks)	Study terminated by sponsor	34	37
OLE Period (48 Weeks)	Withdrawal by Subject	0	1

Baseline characteristics

Characteristic	Pamrevlumab	Placebo	Total
Age, Continuous	70.2 years STANDARD_DEVIATION 7.8	70.1 years STANDARD_DEVIATION 8.2	70.1 years STANDARD_DEVIATION 8
Ethnicity (NIH/OMB) Hispanic or Latino	52 Participants	45 Participants	97 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	125 Participants	141 Participants	266 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	7 Participants	2 Participants	9 Participants
Forced Vital Capacity (FVC)	2.4811 liters STANDARD_DEVIATION 0.6477	2.5097 liters STANDARD_DEVIATION 0.6573	2.4955 liters STANDARD_DEVIATION 0.6518
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	2 Participants	2 Participants
Race (NIH/OMB) Asian	42 Participants	55 Participants	97 Participants
Race (NIH/OMB) Black or African American	2 Participants	1 Participants	3 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	29 Participants	16 Participants	45 Participants
Race (NIH/OMB) White	111 Participants	114 Participants	225 Participants
Sex: Female, Male Female	45 Participants	44 Participants	89 Participants
Sex: Female, Male Male	139 Participants	144 Participants	283 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk
deaths Total, all-cause mortality	16 / 184	15 / 188	12 / 86
other Total, other adverse events	83 / 183	74 / 188	21 / 86
serious Total, serious adverse events	38 / 183	37 / 188	20 / 86

Outcome results

Primary

DB Period: Change From Baseline in FVC at Week 48

FVC is a standard pulmonary function test used to quantify respiratory muscle weakness. FVC was the volume of air that can forcibly be blown out after full inspiration in the upright position, measured in liters. Least square (LS) mean and standard error (SE) were analyzed using mixed model repeated measures (MMRM).

Time frame: Baseline, Week 48

Population: The ITT population included all randomized participants. Here, 'Overall number of participants analyzed' = participants evaluable for this outcome measure.

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Pamrevlumab	DB Period: Change From Baseline in FVC at Week 48	-0.30 liters	Standard Error 0.057
Placebo	DB Period: Change From Baseline in FVC at Week 48	-0.33 liters	Standard Error 0.059

p-value: 0.657995% CI: [-0.12, 0.19]Mixed Models Analysis

Secondary

DB Period: Change From Baseline in Quantitative Lung Fibrosis (QLF) Volume at Week 48

The QLF volume is calculated as QLF=total lung capacity volume (TLC) \* % of quantitative lung fibrosis for fibrosis of the whole lung. LS mean and SE were analyzed using MMRM.

Time frame: Baseline, Week 48

Population: The ITT population included all randomized participants. Here, 'Overall number of participants analyzed' = participants evaluable for this outcome measure.

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Pamrevlumab	DB Period: Change From Baseline in Quantitative Lung Fibrosis (QLF) Volume at Week 48	255.14 milliliters	Standard Error 72.028
Placebo	DB Period: Change From Baseline in Quantitative Lung Fibrosis (QLF) Volume at Week 48	269.15 milliliters	Standard Error 60.898

Secondary

DB Period: Time to All-Cause Mortality

'Median Time to Event' is an estimated value, which was calculated based on Kaplan-Meier method. For an endpoint in which less than half of the participants have encountered the events, the 'Median Time to Event' might be longer than the reported timeframe of 48 weeks.

Time frame: Up to Week 48