A Phase 2 interventional study of VAY736 and Placebo in Idiopathic Pulmonary Fibrosis, sponsored by Novartis Pharmaceuticals. Terminated at 16 sites in 6 countries. Open to participants aged 40 Years to 80 Years. Per ClinicalTrials.gov, last updated 2024-06-18.
Sponsored by Novartis Pharmaceuticals · Phase 2, Interventional, and Treatment
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).
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.
Exclusion Criteria:
Participants received 300 mg VAY736 administered subcutaneously every 4 weeks for 48 weeks on top of current standard-of-care therapy
Drug: VAY736 · Drug: Standard of Care (SoC)
Participants received placebo administered subcutaneously every 4 weeks for 48 weeks on top of current standard-of-care therapy
Drug: Placebo · Drug: Standard of Care (SoC)
300 mg VAY736 administered subcutaneously every 4 weeks for 48 weeks
Also known as: Ianalumab
Placebo administered subcutaneously every 4 weeks for 48 weeks
Background standard-of-care treatment for IPF: nintedanib, pirfenidone, or no background therapy
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.
Time frame: From baseline up to 48 weeks post first dose of study treatment
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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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
Time frame: At pre-dose on Day 1, 29, 57, 85, 113, 141, 169, 197, 225, 253, 281, 309 and 337
The study was conducted across 16 centers in 6 countries.
| Milestone | VAY736 | Placebo |
|---|---|---|
| Started | 14 | 16 |
| Treated | 13 | 16 |
| Completed | 6 | 12 |
| Not completed | 8 | 4 |
| Withdrew: Adverse event | 0 | 1 |
| Withdrew: Study terminated by sponsor | 2 | 2 |
| Withdrew: Subject/guardian decision | 4 | 0 |
| Withdrew: Discontinued early with reason "other" selected | 1 | 1 |
| Withdrew: Withdrawal by subject | 1 | 0 |
| Milestone | VAY736 | Placebo |
|---|---|---|
| Started | 7 | 13 |
| Completed | 7 | 13 |
| Not completed | 0 | 0 |
| Milestone | VAY736 | Placebo |
|---|---|---|
| Started | 7 | 0 |
| Completed | 5 | 0 |
| Not completed | 2 | 0 |
| Withdrew: Lost to follow-up | 1 | 0 |
| Withdrew: Subject/guardian decision | 1 | 0 |
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.
| Liter (L) | VAY736 | Placebo |
|---|---|---|
| Change From Baseline to End of Treatment Epoch (48 Weeks of Treatment) in Forced Vital Capacity (FVC). | 0.039 ± 0.1116 | -0.023 ± 0.0773 |
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.
| Percentage of participants | VAY736 | Placebo |
|---|---|---|
| Percentage of Participants With All-cause Mortality Events | 8.3 (2.39 to 26.92) | 0 (NA to NA) |
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.
| Percentage of participants | VAY736 | Placebo |
|---|---|---|
| Percentage of Participants With Survival Idiopathic Pulmonary Fibrosis (IPF) -Related Mortality Events | 0 (NA to NA) | 0 (NA to NA) |
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.
| Percentage of participants | VAY736 | Placebo |
|---|---|---|
| PFS1 | 61.0 (38.22 to 84.20) | 31.9 (18.04 to 52.51) |
| PFS2 | 57.1 (33.44 to 82.86) | 31.9 (18.04 to 52.51) |
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.
| Percentage of participants | VAY736 | Placebo |
|---|---|---|
| FVC | 57.1 (33.44 to 82.86) | 31.9 (18.04 to 52.51) |
| DLCO | 73.8 (46.56 to 94.24) | 56.1 (38.65 to 75.10) |
| 6MWD | 38.3 (19.96 to 64.88) | 75.0 (58.52 to 88.74) |
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.
| Percentage of participants | VAY736 | Placebo |
|---|---|---|
| Composite Endpoint 1 | 81.0 (63.86 to 93.29) | 66.3 (50.84 to 81.18) |
| Composite Endpoint 2 | 79.2 (61.07 to 92.70) | 66.3 (50.84 to 81.18) |
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.
| mililiter/minute/millimeter Mercury | VAY736 | Placebo |
|---|---|---|
| Change From Baseline to End of Treatment Epoch (48 Weeks of Treatment) in Diffusing Capacity of the Lungs | -1.954 ± 1.0816 | -1.033 ± 0.7244 |
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.
| Meter (m) | VAY736 | Placebo |
|---|---|---|
| Change From Baseline to the End of Treatment Epoch (48 Weeks of Treatment) in 6-minute Walk Distance (6MWD) | 19.743 ± 53.5268 | -12.479 ± 28.9400 |
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.
| Meter% (m%) | VAY736 | Placebo |
|---|---|---|
| Change From Baseline to the End of Treatment Epoch (48 Weeks of Treatment) in Distance Saturation Product | 9.746 ± 52.2985 | -19.420 ± 28.3755 |
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.
| Percentage (%) | VAY736 | Placebo |
|---|---|---|
| Change From Baseline to the End of Treatment Epoch (48 Weeks of Treatment) in Resting Oxygen Saturation Level (on Room Air) | -0.117 ± 1.0179 | -1.887 ± 0.9415 |
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.
| Participants | VAY736 | Placebo |
|---|---|---|
| Day 1 | 1 | 3 |
| Day 29 | 1 | 2 |
| Day 85 | 1 | 1 |
| Day 169 | 0 | 2 |
| Day 253 | 2 | 1 |
| Day 337 | 0 | 0 |
The lowest serum concentration of VAY736 observed during a dosing interval at steady state (Ctrough) was determined
| nanogram (ng) / mililiter (mL) | VAY736 |
|---|---|
| Day 1 | 0.00 ± 0.000 |
| Day 29 | 676.79 ± 499.931 |
| Day 57 | 779.89 ± 645.363 |
| Day 85 | 786.63 ± 501.225 |
| Day 113 | 771.88 ± 623.268 |
| Day 141 | 1316.05 ± 877.240 |
| Day 169 | 1019.00 ± 587.097 |
| Day 197 | 985.50 ± 495.652 |
| Day 225 | 1271.10 ± 863.055 |
| Day 253 | 998.57 ± 947.343 |
| Day 281 | 705.00 ± 997.021 |
| Day 309 | 827.40 ± 678.836 |
| Day 337 | 688.50 ± 1172.124 |
Collected over From baseline up to end of study, assessed up to approximately 2.4 years. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| VAY736 | 1/13 (7.7%) | 5/13 (38.5%) | 13/13 (100%) |
| Placebo | 0/16 (0%) | 9/16 (56.3%) | 15/16 (93.8%) |
| Total | 1/29 (3.4%) | 14/29 (48.3%) | 28/29 (96.6%) |
| Event | VAY736 | Placebo | Total |
|---|---|---|---|
| PneumoniaInfections and infestations | 0/13 | 3/16 | 3/29 |
| Myocardial infarctionCardiac disorders | 1/13 | 1/16 | 2/29 |
| PancreatitisGastrointestinal disorders | 1/13 | 0/16 | 1/29 |
| Basal cell carcinomaNeoplasms benign, malignant and unspecified (incl cysts and polyps) | 1/13 | 0/16 | 1/29 |
| HypoxiaRespiratory, thoracic and mediastinal disorders | 1/13 | 0/16 | 1/29 |
| Idiopathic pulmonary fibrosisRespiratory, thoracic and mediastinal disorders | 1/13 | 1/16 | 2/29 |
| VasculitisVascular disorders | 1/13 | 0/16 | 1/29 |
| Aortic valve incompetenceCardiac disorders | 0/13 | 1/16 | 1/29 |
| VertigoEar and labyrinth disorders | 0/13 | 1/16 | 1/29 |
| Retinal vein occlusionEye disorders | 0/13 | 1/16 | 1/29 |
| Event | VAY736 | Placebo | Total |
|---|---|---|---|
| Weight decreasedInvestigations | 1/13 | 4/16 | 5/29 |
| DiarrhoeaGastrointestinal disorders | 3/13 | 1/16 | 4/29 |
| Injection site pruritusGeneral disorders | 3/13 | 2/16 | 5/29 |
| CoughRespiratory, thoracic and mediastinal disorders | 3/13 | 1/16 | 4/29 |
| Idiopathic pulmonary fibrosisRespiratory, thoracic and mediastinal disorders | 1/13 | 3/16 | 4/29 |
| DyspepsiaGastrointestinal disorders | 2/13 | 0/16 | 2/29 |
| FatigueGeneral disorders | 2/13 | 1/16 | 3/29 |
| Injection site erythemaGeneral disorders | 2/13 | 1/16 | 3/29 |
| BronchitisInfections and infestations | 2/13 | 2/16 | 4/29 |
| Respiratory tract infectionInfections and infestations | 2/13 | 1/16 | 3/29 |
Baseline characteristics are provided for all participants who received at least one dose of any study drug
| Age, Continuous(Years) | VAY736 | Placebo | Total |
|---|---|---|---|
| Mean | 69.7 ± 9.30 | 68.3 ± 8.15 | 68.9 ± 8.55 |
| Sex: Female, Male(Participants) | VAY736 | Placebo | Total |
|---|---|---|---|
| Female | 1 | 1 | 2 |
| Male | 12 | 15 | 27 |
| Race/Ethnicity, Customized(Participants) | VAY736 | Placebo | Total |
|---|---|---|---|
| White | 13 | 16 | 29 |
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Plan to share: Yes — Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com
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