Study of Pharmacodynamics, Pharmacokinetics, Safety and Tolerability of VAY736 in Patients With Idiopathic Pulmonary Fibrosis

Study Overview
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Brief Summary
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The purpose of this study was to investigate the safety, tolerability and efficacy of VAY736 as potential therapy for the treatment of idiopathic pulmonary fibrosis (IPF).

Detailed Description
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This was an exploratory (non-confirmatory) randomized, patient-, investigator-, sponsor- blinded, placebo controlled study of VAY736 in IPF patients. This study investigated the safety and efficacy of 300 mg VAY736 administered subcutaneously (s.c.) every 4 weeks for 48 weeks. Participants were randomized in a 1:1 ratio on top of local standard of care (SOC), to receive VAY736 or placebo. Randomized subjects entered the treatment epoch (for up to 48 weeks), followed by two follow-up epochs: the PK/safety follow-up epoch and the PD/safety follow-up epoch. The PK/safety follow-up epoch lasted for 20 weeks. When the PK/safety follow-up epoch was completed, participants in the placebo arm were discharged from the study; but participants in the active arm (those who had received VAY736) continued into the PD/safety follow-up epoch. Participants in the PD/safety follow-up epoch were followed until B-cell recovery (in the peripheral blood), defined as: B cells >=50/μL or B cells >= 80% of baseline (whichever occurred first). If a participant had not recovered his/her B-cells after a period of 2 years from the last dose of VAY736, then this participant was discharged from the study.

Official Title
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A Subject-, Investigator-, and Sponsor-blinded, Randomized, Placebo-controlled, Multicenter Study to Investigate Efficacy, Safety, and Tolerability of VAY736 in Patients With Idiopathic Pulmonary Fibrosis

Conditions
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Idiopathic Pulmonary Fibrosis

Intervention / Treatment
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* Drug: VAY736
* Drug: Placebo
* Drug: Standard of Care (SoC)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: A diagnosis of definite or probable IPF within 5 years of the screening visit Forced Vital Capacity (FVC) 40-90% predicted (inclusive) Diffusing Capacity of the Lungs (DLCO), corrected for hemoglobin, 25-79% predicted (inclusive) Forced Expiratory Volume in first second (FEV1)/FVC >70% Unlikely to die from cause other than IPF within the next 3 years, in the opinion of the investigator Unlikely to undergo lung transplantation during this trial Exclusion Criteria: Emphysema > fibrosis on screening high-resolution computed tomography (must be confirmed by central reader) History of major organ, hematopoietic stem cell or bone marrow transplant Clinically diagnosed acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) or other significant clinical worsening within 3 months of randomization New York Heart Association (NYHA) class III/IV Congestive Heart Failure (CHF), Ejection Fraction (EF) <25% Current smoker Prior use of any B-cell depleting therapy (e.g., rituximab, ofatumumab, or other anti-CD20 mAb, anti-CD40, anti-CD19,anti-CD22 mAb, anti-CD52 mAb, or anti-BAFF mAb)

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: VAY736<br>Participants received 300 mg VAY736 administered subcutaneously every 4 weeks for 48 weeks on top of current standard-of-care therapy | Drug: VAY736<br>* 300 mg VAY736 administered subcutaneously every 4 weeks for 48 weeks<br>* Other names: Ianalumab;Drug: Standard of Care (SoC)<br>* Background standard-of-care treatment for IPF: nintedanib, pirfenidone, or no background therapy<br>|
| Placebo Comparator: Placebo<br>Participants received placebo administered subcutaneously every 4 weeks for 48 weeks on top of current standard-of-care therapy | Drug: Placebo<br>* Placebo administered subcutaneously every 4 weeks for 48 weeks<br>Drug: Standard of Care (SoC)<br>* Background standard-of-care treatment for IPF: nintedanib, pirfenidone, or no background therapy<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to End of Treatment Epoch (48 Weeks of Treatment) in Forced Vital Capacity (FVC). | FVC was defined as the maximum amount of air that an individual was able to forcibly exhale from his / her lungs after taking the deepest breath they could. Change from baseline to end of treatment epoch (48 weeks of treatment) in Forced Vital Capacity (FVC) was analyzed using a Mixed Effects Model for Repeated Measures (MMRM) and considering all assessments collected during the treatment epoch. The model included treatment and visit as fixed effects, standard of care treatment (Nintedanib, Pirfenidone, or no treatment) as factor and baseline value as a covariate, treatment-by-visit and baseline-by-visit as interaction terms. A positive change from baseline indicates improvement. Baseline was defined as the last available assessment pre-dose before or on randomization date. | From baseline up to 48 weeks post first dose of study treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With All-cause Mortality Events | All-cause mortality events were defined as deaths due to any cause. Kaplan-Meier estimates of the percentage of participants with the event of interest along with 80% two-sided confidence intervals using Greenwood's formula are provided. | Up to 48 weeks post first dose of study treatment | 
| Percentage of Participants With Survival Idiopathic Pulmonary Fibrosis (IPF) -Related Mortality Events | IPF-related mortality events were defined as deaths due to IPF related cause. Kaplan-Meier estimates of the percentage of participants with the event of interest along with 80% two-sided confidence intervals using Greenwood's formula are provided. | Up to 48 weeks post first dose of study treatment | 
| Percentage of Participants With Progression-free Survival (PFS) Events | PFS events were divided into: 1) PFS1 events including progression (relative reduction in FVC ≥ 10%) or death due to all causes, and 2) PFS2 events including progression (relative reduction in FVC ≥ 10%) or death due to IPF-related causes. Kaplan-Meier estimates of the percentage of participants with the event of interest (PFS1 events or PFS2 events) along with 80% two-sided confidence intervals using Greenwood's formula are provided. | Up to 48 weeks post first dose of study treatment | 
| Percentage of Participants With Disease Progression Events | The following disease progression events were considered: a) relative reduction in FVC ≥ 10%; b) relative reduction in Diffusing Capacity of the Lungs (DLCO) ≥ 15%; c) absolute reduction in Six Minute Walk Distance (6MWD) ≥ 50 m. Kaplan-Meier estimates of the percentage of participants with the event of interest along with 80% two-sided confidence intervals using Greenwood's formula are provided. | Up to 48 weeks post first dose of study treatment | 
| Percentage of Participants With Composite Events | Composite events were defined as: 1) death (all-cause mortality), or relative reduction in FVC ≥ 10%, or relative reduction in DLCO ≥ 15%, or relative reduction in 6MWD ≥ 50 m (composite endpoint 1); and 2) Death (IPF-related mortality), or relative reduction in FVC ≥ 10%, or relative reduction in DLCO ≥ 15%, or relative reduction in 6MWD ≥ 50 m (composite endpoint 2). Kaplan-Meier estimates of the percentage of participants with the event of interest along with 80% two-sided confidence intervals using Greenwood's formula are provided. | Up to 48 weeks post first dose of study treatment | 
| Change From Baseline to End of Treatment Epoch (48 Weeks of Treatment) in Diffusing Capacity of the Lungs | DLCO is a measurement to assess the lungs' ability to transfer gas from inspired air to the bloodstream. DLCO was determined according to ATS guidelines. Change from baseline to end of treatment epoch (48 weeks of treatment) in diffusing capacity of the lung for carbon monoxide (DLCO) was analyzed using a Mixed Effects Model for Repeated Measures (MMRM) and considering all assessments collected during the treatment epoch. The model included treatment and visit as fixed effects, standard of care treatment (Nintedanib, Pirfenidone, or no treatment) as factor and baseline value as a covariate, treatment-by-visit and baseline-by-visit as interaction terms. A positive change from baseline indicates improvement. Baseline was defined as the last available assessment pre-dose before or on randomization date. | From baseline up to 48 weeks post first dose of study treatment | 
| Change From Baseline to the End of Treatment Epoch (48 Weeks of Treatment) in 6-minute Walk Distance (6MWD) | A standardized 6-minute walk test (6MWT) was performed in accordance with the guidelines of the American Thoracic Society 2002. The distance walked in six minutes (6MWD) was recorded. Change from baseline to end of treatment epoch (48 weeks of treatment) in 6MWD was analyzed using a Mixed Effects Model for Repeated Measures (MMRM) and considering all assessments collected during the treatment epoch. The model included treatment and visit as fixed effects, standard of care treatment (Nintedanib, Pirfenidone, or no treatment) as factor and baseline value as a covariate, treatment-by-visit and baseline-by-visit as interaction terms. A positive change from baseline indicates improvement. Baseline was defined as the last available assessment pre-dose before or on randomization date. | From baseline up to 48 weeks post first dose of study treatment | 
| Change From Baseline to the End of Treatment Epoch (48 Weeks of Treatment) in Distance Saturation Product | Distance saturation product is the product of distance walked and lowest oxygen saturation during the 6-min walk test. Change from baseline to end of treatment epoch (48 weeks of treatment) in distance saturation product was analyzed using a Mixed Effects Model for Repeated Measures (MMRM) and considering all assessments collected during the treatment epoch. The model included treatment and visit as fixed effects, standard of care treatment (Nintedanib, Pirfenidone, or no treatment) as factor and baseline value as a covariate, treatment-by-visit and baseline-by-visit as interaction terms. A positive change from baseline indicates improvement. Baseline was defined as the last available assessment pre-dose before or on randomization date. | From baseline up to 48 weeks post first dose of study treatment | 
| Change From Baseline to the End of Treatment Epoch (48 Weeks of Treatment) in Resting Oxygen Saturation Level (on Room Air) | Change from baseline to end of treatment epoch (48 weeks of treatment) in resting oxygen saturation (on room air) was analyzed using a Mixed Effects Model for Repeated Measures (MMRM) and considering all assessments collected during the treatment epoch. The model included treatment and visit as fixed effects, standard of care treatment (Nintedanib, Pirfenidone, or no treatment) as factor and baseline value as a covariate, treatment-by-visit and baseline-by-visit as interaction terms. A positive change from baseline indicates improvement. Baseline was defined as the last available assessment pre-dose before or on randomization date. | From baseline up to 48 weeks post first dose of study treatment | 
| Number of Participants With Positive Serum Anti-VAY736 Antibodies | Number of participants with positive serum anti-VAY736 antibodies. A bridging ELISA method that is designed to detect the presence of anti-VAY736 antibodies in human serum was used. | Day 1, 29, 85, 169, 253 and 337 | 
| Ctrough of VAY736 From the Serum Concentration-time Data | The lowest serum concentration of VAY736 observed during a dosing interval at steady state (Ctrough) was determined | At pre-dose on Day 1, 29, 57, 85, 113, 141, 169, 197, 225, 253, 281, 309 and 337 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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VAY736, idiopathic pulmonary fibrosis