A PHASE II, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, STUDY TO ASSESS THE EFFICACY AND SAFETY OF LEBRIKIZUMAB IN PATIENTS WITH IDIOPATHIC PULMONARY
A phase II study of Lebrikizumab
version:
date:
Chugai Pharmaceutical Co., Ltd.
clinical-trials@chugai-pharm.co.jp
Chugai Pharmaceutical Co., Ltd.
clinical-trials@chugai-pharm.co.jp
480
Interventional
RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY
2
*Have a diagnosis of IPF based on the ATS/ERS/JRS/ALAT consensus statement on IPF (Raghu et al. 2011) within the previous 5 years from time of screening and confirmed at baseline.
*Have a central review assessment of an HRCT performed during the screening period or within 12 months prior to the start of screening.
*Eligibility will be determined on the basis of surgical lung biopsy.
*A Multidisciplinary Discussion of Diagnosis (MDD) based on 2011 ATS/ERS/JRS/ALAT guidelines will be utilized to finalize the diagnosis in the event the initial central review
*outcome results for HRCT and SLB are disparate (inconsistent with UIP/definite UIP)
*History of a severe allergic reaction or anaphylactic reaction to a biologic agent or known hypersensitivity to any component of the lebrikizumab injection
*Evidence of other known causes of interstitial lung disease (ILD) (e.g., domestic and occupational environmental exposures, connective-tissue disease (CTD), and drug toxicity)
*Evidence of clinically significant lung disease other than IPF (e.g., asthma or chronic obstructive pulmonary disease [COPD])
*Past use of any anti-IL-13 or anti-IL-4/IL-13 therapy, including lebrikizumab
*Female patients of reproductive potential who are not willing to use a highly effective method of contraception (e.g., contraceptive pill or transdermal patch, spermicide and barrier [i.e., condoms], intrauterine device, implants for contraception, injections for contraception [with prolonged release], hormonal vaginal device, sterilization, surgical tubal ligation) for the duration of the study and for at least 18 weeks after the last dose of study treatment)
*Pregnant or lactating
*Body weight <40 kg
40age old over
No limit
Both
IDIOPATHIC PULMONARY FIBROSIS
investigational material(s)
Generic name etc : RO5490255
INN of investigational material : Lebrikizumab
Therapeutic category code : 229 Other agents affecting respiratory organs
Dosage and Administration for Investigational material : 250mg SC injection every 4 weeks
control material(s)
Generic name etc : Placebo
INN of investigational material :
Therapeutic category code : --- Other
Dosage and Administration for Investigational material : SC injection every 4 weeks
To evaluate lebrikizumab compared with
placebo as monotherapy or as combination therapy with pirfenidone background compared with placebo in patients with IPF, as measured by the absolute change from baseline to Week 52 in percent predicted FVC.
The statistical analysis will be based on a linear mixed effects model with absolute change as the dependent variable.
Independent variables will be baseline % predicted FVC, treatment arm, post-baseline visit, treatment arm-by-visit interaction, and the stratification variables with the same categories used for the stratified randomization.
From the model, least squares means for the absolute change from baseline as well as placebo corrected absolute changes with 95% confidence intervals for each treatment arm at each post baseline visit will be estimated.
Missing data will be handled by the model under the missing-at-random assumption
without need for imputation for early discontinuation.
*PFS, defined as the time from study treatment randomization to the first occurrence of any of the following events:
- Death from any cause
- Non-elective hospitalization for any cause
- A decrease from baseline of >=10% in FVC (L)
*Annualized rate of change in FVC (L)
*Time from randomization to first decrease from baseline of >=10% in FVC (L)
*Time from randomization to first decrease from baseline of >=15% in DLCO
(mL CO/min-1/mmHg-1) at Week 52
*Change from baseline to Week 52 in the ATAQ-IPF
*Time from randomization to non-elective hospitalization from any cause
*Change from baseline to Week 52 in the 6MWT
*Time from randomization to first event of acute IPF exacerbation
*Change from baseline to Week 52 in the SGRQ
All continuous endpoints will be analyzed using the same methodology as the primary endpoint (see previous section).
For time to event endpoints, a Cox Proportional Hazards (CPH) model will be performed to compare the treatment groups, with stratification variables included in the model as covariates. Time will be measured relative to the date of study treatment randomization (Day 1). Patient's not experiencing an event during the treatment period will have their data censored at the time when they were last known to be event free (EOT visit) or at the time of early treatment discontinuation, whichever occurs earlier. In fitting the CPH model, Efron's approach to the treatment of tied event times will be used (Therneau and Grambsch 2000). Under this model, the exponent of the regression coefficient corresponding to the treatment group covariate represents the estimated hazard ratio (lebrikizumab vs. placebo). Inference will focus on estimating this hazard ratio and a corresponding 95% CI based on the PH regression model. Risk rates at Week 52 by treatment group will be estimated using Kaplan-Meyer curves for PFS, and p-values comparing the two curves based on the score test statistic will be reported.
Summary statistics of the PRO endpoints and the changes from baseline will be calculated at each assessment time-point for each treatment group. The mean,
standard error, and median of the absolute scores and the mean changes from baseline (and 95% CIs) between treatment groups will be reported for the endpoint. For scores involving change from baseline, patients without baseline values will be excluded from the analyses. Line charts depicting the means and mean changes of subscales over time will be also provided. Scoring for the questionnaire will be based on relevant user manuals.
Frequencies and percentages of missing data for the PRO endpoints will be compared between the two treatment arms. Differences in the proportion of dropouts (defined as patients withdrawing from treatment for reasons other than documented disease progression or death) between the two treatment arms will be tested using the chi-square test. The PRO endpoints assessed at multiple timepoints will be analyzed using mixed-model repeated measures. Each model will have an intercept term, a linear time trend term (in weeks), a term for treatment group, and a term for treatment-by-time interaction. A baseline score and appropriate covariates will also be added.
For all endpoints, treatment effects will be summarized using point estimates and corresponding two-sided 95% CIs will be provided.
