abcd Clinical Study Synopsis for Public Disclosure This clinical study synopsis is provided in line with Boehringer Ingelheim s Policy on Transparency and Publication of Clinical Study Data. The synopsis which is part of the clinical study report had been prepared in accordance with best practice and applicable legal and regulatory requirements at the time of study completion. The synopsis may include approved and non approved uses, doses, formulations, treatment regimens and/or age groups; it has not necessarily been submitted to regulatory authorities. A synopsis is not intended to provide a comprehensive analysis of all data currently available regarding a particular drug. More current information regarding a drug is available in the approved labeling information which may vary from country to country.. Additional information on this study and the drug concerned may be provided upon request based on Boehringer Ingelheim s Policy on Transparency and Publication of Clinical Study Data. The synopsis is supplied for informational purposes only in the interests of scientific disclosure. It must not be used for any commercial purposes and must not be distributed, published, modified, reused, posted in any way, or used for any other purpose without the express written permission of Boehringer Ingelheim.
Boehringer Ingelheim Page 2 of 14 XX Oct 2017 2.0 SYNOPSIS Trial Period: (Date of first enrollment) 02 Oct 2013 (Date of program termination) 03 Sep 2015 (Date of last completed) 08 Nov 2017 Phase of Development: Phase III Title of Trial: Safety and efficacy of in patients with moderately to severely active rheumatoid arthritis: an open-label extension trial Coordinating Investigator: Dr., United Kingdom Trial Center: This was a multinational, multi-center trial conducted in 13 countries. Publication (Reference): None Objectives: Due to program termination and subsequent trial discontinuation, a limited evaluation was conducted and an Abbreviated Clinical Trial Report (CTR) is provided. Data were evaluated and will be presented in order to accomplish the objectives as completely as feasible. Primary objectives: To evaluate the long-term safety of in adult patients with moderate to severe active rheumatoid arthritis (RA) who have successfully completed treatment in Trial 1301.1. Secondary objective: To assess the long-term efficacy of in patients with moderately to severely active RA. These analyses were to be displayed by the groups that patients were randomized to in Trial 1301.1, as well as overall.
Boehringer Ingelheim Page 3 of 14 XX Oct 2017 Methodology: To assess the continued safety and efficacy of repeated courses with, patients from the initial randomized trial (1301.1) who were eligible for further treatment courses, were to receive two 1000 mg drug infusions of (on Day 1 and Day 15). This included patients who were initially randomized to receive Rituxan /MabThera in Trial 1301.1; who were to be transitioned to treatment with in this open-label extension trial. Number of Patients (Planned and Analyzed): All patients from Trial 1301.1, who were eligible for further treatment courses, were planned to be entered in the trial (approx. 300 patients). A total of 97 patients from Trial 1301.1 were screened for inclusion into this open-label extension trial. Six patients were screen failure. Of the 91 patients who were assigned treatment, 90 patients received treatment. One patient did not return for the treatment/further visits and was lost to follow-up. A total of 38 patients completed the trial. Of the 54 discontinuations, a majority of the patients (38 patients) did not complete the trial as the trial was terminated by the Sponsor; the other common reasons for discontinuation included withdrawal of consent (6 patients) and lost to follow-up (4 patients). Diagnosis and Main Criteria for Inclusion: Adult patients (18 to 80 years of age) with moderately to severely active RA who had previously participated in, and completed, Trial 1301.1. Test Product, Dose and Mode of Administration, Batch Number: concentrate for solution for infusion (10 mg/ml) was administered in two 1000-mg infusions, separated by 2 weeks, via intravenous (IV) infusion. Batch numbers used in the trial were 207622, 307241, E2710F01, E3701F01-1, and E3710F02. Reference Therapies, Dose, and Mode of Administration, Batch Number:. Duration of Treatment: Each patient was treated with on Days 1 and 15, with a possible further 2 infusions at Weeks 24 and 26 for eligible responders. The trial was to consist of a 48-week open-label period. Criteria for Evaluation:
Boehringer Ingelheim Page 4 of 14 XX Oct 2017 Further development of has been stopped and the program was therefore prematurely discontinued on 03 Sep 2015. The decision was made by the Sponsor based on a strategic review of the company s product portfolio and was not due to any safety concern. Due to program termination and subsequent trial discontinuation, an Abbreviated CTR is provided. Evaluation was limited as follows: Descriptive statistics of the primary and secondary endpoints are included No subgroup analyses, except for safety analysis, has been performed No sensitivity analyses have been produced No population pharmacokinetic (PK) analysis was performed. Plasma drug concentrations were listed and summarized for each planned time point. No PK parameters were derived. Safety The primary endpoint was defined as the number (proportion) of patients with drug related adverse events (AEs) during the treatment phase Other safety endpoints Infusion reaction AEs Rate of infections/serious infections (seriousness of infection defined as requirement of IV antibiotics for treatment and/or meeting seriousness criteria to be qualified as an serious AE) Additional safety criteria include physical examination, vital signs (blood pressure, pulse rate, respiratory rate, and body temperature), 12-lead electrocardiogram, laboratory tests, concomitant medication, and tolerability; relevant findings in these safety assessments were reported as AEs. Efficacy Efficacy was evaluated as secondary and other endpoints, but only descriptive statistics were provided: Secondary efficacy endpoints The change from Baseline in Trial 1301.1 in disease activity score 28 (DAS28) (erythrocyte sedimentation rate [ESR]) at Week 48 of Trial 1301.4 The proportion of patients meeting the American College of Rheumatology 20% (ACR20) response criteria (based on improvement since Baseline in Trial 1301.1) at Week 48 of Trial 1301.4
Boehringer Ingelheim Page 5 of 14 XX Oct 2017 The proportion of patients who meet the ACR/European League Against Rheumatism (EULAR) definition of remission (based on improvement since Baseline in Trial 1301.1) at Week 48 of Trial 1301.4 The proportion of patients who meet the EULAR response (good response, moderate response, or no response; based on DAS28 improvement since Baseline in Trial 1301.1) at Week 48 of Trial 1301.4 Further efficacy endpoints The change from Baseline in Trial 1301.1 in DAS28 (ESR) at Week 24 of Trial 1301.4 The change from Baseline in Trial 1301.1 in DAS28 (CRP) at Week 24 of Trial 1301.4 The change from Baseline in Trial 1301.1 in DAS28 (CRP) at Week 48 of Trial 1301.4 The change from Baseline in Trial 1301.4 in DAS28 (ESR) at Week 24 of Trial 1301.4 The change from Baseline in Trial 1301.4 in DAS28 (ESR) at Week 48 of Trial 1301.4 The proportion of patients meeting ACR20 response criteria (based on improvement since Baseline in Trial 1301.1) at Week 24 of Trial 1301.4 The proportion of patients meeting ACR20 response criteria (based on improvement since Baseline in Trial 1301.4) at Week 24 of Trial 1301.4 The proportion of patients meeting ACR20 response criteria (based on improvement since Baseline in Trial 1301.4) at Week 48 of Trial 1301.4 ACR50 and ACR70 responders (based on improvement since Baseline in Trial 1301.1) at Week 24 of Trial 1301.4 ACR50 and ACR70 responders (based on improvement since Baseline in Trial 1301.1) at Week 48 of Trial 1301.4 Individual parameters of the ACR improvement criteria (based on improvement since Baseline in Trial 1301.1): swollen joint count, tender joint count, patient s and physician s global assessments of disease activity, patient s assessment of pain, Health Assessment Questionnaire - Disability Index and acute phase reactant (CRP) at Week 24 of Trial 1301.4 Individual parameters of the ACR improvement criteria (based on improvement since Baseline in Trial 1301.1): swollen joint count, tender joint count, patient s and physician s global assessments of disease activity, patient s assessment of pain, Health Assessment Questionnaire - Disability Index and acute phase reactant (CRP) at Week 48 of Trial 1301.4
Boehringer Ingelheim Page 6 of 14 XX Oct 2017 The proportion of patients who meet the ACR/EULAR definition of remission (based on improvement since Baseline in Trial 1301.1) at Week 24 of Trial 1301.4 The proportion of patients who meet the EULAR response (good response, moderate response, or no response) (based on DAS28 improvement since Baseline in Trial 1301.1) at Week 24 of Trial 1301.4 The change from Baseline in Trial 1301.1 in 36-item Short Form Health Survey (SF-36) at Week 24 of Trial 1301.4 The change from Baseline in Trial 1301.1 in SF-36 at Week 48 of Trial 1301.4 The change from Baseline in Trial 1301.4 in SF-36 at Week 24 of Trial 1301.4 The change from Baseline in Trial 1301.4 in SF-36 at Week 48 of Trial 1301.4 Other endpoints/parameters of interest Immunogenicity (proportion of patients with anti-drug antibodies [ADAs] and neutralizing antibodies [nabs] at Weeks 24 and 48 Pharmacodynamic analysis of CD19+ B-cells, CD3+, CD4+, and CD8+ T-cells, total RF, RF immunoglobulin (Ig) isotypes, Igs (total Ig, IgG, IgA and IgM) A population PK analysis with sparse blood sampling throughout the treatment period and at follow-up to assess the PK of in the underlying population was planned but was not carried out. Statistical Methods: Descriptive statistics for efficacy, safety and other endpoints were provided for all participating patients in this trial. A comparison of patients who continued to receive and patients who were initially randomized to receive Rituxan/MabThera in Trial 1301.1 was performed using descriptive statistical methods. No interim analysis was planned for this trial.
Boehringer Ingelheim Page 7 of 14 XX Oct 2017 Summary Conclusions: Patient Demography: Patient demography (Safety Randomized Analysis Set) was as follows: Characteristic (unit) (N = 30) Rituxan (N = 29) MabThera (N = 29) Total (N = 88) Age (years) n (missing) 30 (0) 29 (0) 29 (0) 88 (0) Mean 54.6 56.3 56.8 55.9 SD 11.23 11.02 8.95 10.38 Gender [n (%)] Male 9 (30.0%) 5 (17.2%) 7 (24.1%) 21 (23.9%) Female 21 (70.0%) 24 (82.8%) 22 (75.9%) 67 (76.1%) % = percentage of patients calculated relative to the total number of patients in the analysis set, percentage of patients with childbearing potential calculated relative to the total number of females in the analysis set; N=total number of patients, n=number of patients with an observation: SD=standard deviation. Disposition: A total of 97 patients from Trial 1301.1 were screened for inclusion into this open-label extension trial. Six patients were screen failures and 91 patients were assigned treatment out of which 90 patients received treatment. A total of 38 patients completed the trial. Of the 54 discontinuations, a majority of the patients (38 patients) did not complete the trial as the trial was terminated by the Sponsor; the other common reasons for discontinuation included withdrawal of consent (6 patients) and lost to follow-up (4 patients). Demographics and Baseline Characteristics: This section is not applicable for an Abbreviated CTR. Pharmacokinetic Results: This section is not applicable for an Abbreviated CTR. Efficacy Results: The least square mean change from Baseline in Trial 1301.1 in DAS28 (ESR) at Week 48 was -2.0 for the patients in the formerly (hereafter referred to as ) and formerly Rituxan (hereafter referred to as Rituxan) treatment groups and -1.6 in the formerly MabThera (hereafter referred to as MabThera) treatment group.
Boehringer Ingelheim Page 8 of 14 XX Oct 2017 One patient each in the 3 treatment groups met the ACR20 response criteria. The number of patients with non-responder imputation was 11 (40.7%), 16 (69.6%), and 19 (76.0%) in the BI 695500, Rituxan, and MabThera treatment groups, respectively. Treatment discontinuation was the main reason for non-responder imputation. One patient in the Rituxan and 2 patients in the MabThera treatment groups received therapy with impact on efficacy. The ACR20 responder rate (improvement since Baseline in 1301.1) at Week 48 was higher in (38.5%) treatment group as compared to Rituxan (13.0%) and MabThera (16.0%) treatment groups. None of the patients met the ACR/EULAR definition of remission (based on improvement since Baseline in 1301.1) at Week 48. None of the patients showed good EULAR response (improvement since Baseline in 1301.1). The DAS28 remission at Week 48 was not reported for any of the patients. Due to the early termination of this trial, and subsequent small sample size, no conclusions regarding efficacy can be made. Safety Results: A total of 55.7% of patients (56.7% in the treatment group, 48.3% in the Rituxan treatment group, and 62.1% in the MabThera treatment group) experienced at least 1 TEAE during the trial. The overall incidence of TEAEs that were reported as related to trial medication higher in the (16.7%) treatment group as compared to the Rituxan (6.9%) and MabThera (3.4%) treatment groups. Severe TEAEs were reported for 1 patient each in the (3.3%) and Rituxan (3.4%) treatment groups and 2 patients in the MabThera (6.9%) treatment group. None of the patients died during the trial. Two (6.9%) patients each in the Rituxan and MabThera treatment groups reported a total of 10 SAEs; one of which (in the MabThera treatment group) was considered as related to trial medication (cellulitis). None of the patients in the treatment group had a SAE. One patient (Patient 55270002) in the treatment group experienced a TEAE that led to permanent discontinuation of trial medication; none were reported in the Rituxan or MabThera treatment groups.
Boehringer Ingelheim Page 9 of 14 XX Oct 2017 No adverse events of special interest were reported. However, infusion site reactions were reported in 3 patients and infections (of which 1 AE was serious) were reported in 27 patients. The overall incidence of AEs is summarized below: Description Rituxan MabThera Total (N=30) (N=29) (N=29) (N=88) n (%) n (%) n (%) n (%) Number of patients with At least 1 TEAE 17 (56.7%) 14 (48.3%) 18 (62.1%) 49 (55.7%) At least 1 TEAE related to 5 (16.7%) 2 (6.9%) 1 (3.4%) 8 (9.1%) the trial medication At least 1 serious TEAE 0 (0.0%) 2 (6.9%) 2 (6.9%) 4 (4.5%) At least 1 non-serious 7 (23.3%) 8 (27.6) 9 (31.0%) 24 (27.3%) TEAE a At least 1 serious TEAE 0 (0.0%) 0 (0.0%) 1 (3.4%) 1 (1.1%) related to the trial medication A TEAE leading to trial 1 (3.3%) 0 (0.0%) 0 (0.0%) 1 (1.1%) medication discontinuation A TEAE leading to death 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) At least 1 AESI 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) At least 1 infusion site 2 (6.7%) 1 (3.4%) 0 (0.0%) 3 (3.4%) reaction At least 1 infection 8 (26.7%) 8 (27.6%) 11 (37.9%) 27 (30.7%) At least 1 serious infection 0 (0.0%) 0 (0.0%) 1 (3.4%) 1 (1.1%) Number of deaths b 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) AESI=adverse events of special interest; TEAE=treatment-emergent adverse event a Subjects with at least one or more non-serious AE >5% incidence in a preferred term. b Deaths of any causes reported in the database (post treatment). Immunogenicity Results: Overall, a total of 19 patients (21.6%) tested positive for the presence of ADAs during the trial.
Boehringer Ingelheim Page 10 of 14 XX Oct 2017 A higher proportion of patients in the Rituxan (37.9%) treatment group were ADA positive as compared with the patients in the MabThera (17.2%) and (10.0%) treatment groups. All these patients had positive ADA results at both Week 24 and Week 48. Conclusion: PK/PD/Efficacy: Due to the early termination of this trial, no formal comparisons of PK/PD/Efficacy can be made between the treatment groups. Immunogenicity: There were no notable differences between the treatment groups in terms the immunogenicity profile. Safety: was generally well tolerated in trial participants. There were no notable differences between the treatment groups in terms of safety and tolerability.
Boehringer Ingelheim Page 11 of 14 XX Oct 2017 Primary Endpoints The primary endpoint of this trial was safety; efficacy was to be evaluated as secondary and other endpoints. Secondary Endpoints Efficacy Statistical methodology DAS28 Endpoint: Change from Baseline in trial 1301.1 in DAS28 (ESR) score at Week 48 of trial 1301.4 DAS28 (ESR) score was to be derived at every planned efficacy assessment visit and the change from Baseline in DAS28 (ESR) (baseline-post baseline) was to be calculated for every planned post-baseline efficacy assessment visit. The mean for change from baseline at Week 48 in DAS28 (ESR) score with two-sided 90% and 95% confidence interval (CI)s was to be presented for each treatment group and overall. These CIs were to be obtained using the SAS procedure PROCMIXED, and were to be interpreted in an exploratory fashion only. Table 1 Secondary Endpoint: Efficacy: Change from Baseline in Trial 1301.1 in DAS28 (ESR) at Week 48 (MMRM) - FAS n (LS) Mean 90% CI 95% CI (N = 30) 19-2.0 (-2.70, -1.33) (-2.84, -1.18) Rituxan (N = 26) 19-2.0 (-2.66, -1.38) (-2.80, -1.24) MabThera (N = 28) 17-1.6 (-2.42, -0.88) (-2.58, -0.72) Total (N = 84) 55-1.9 (-2.29, -1.51) (-2.38, -1.43) CI=Confidence interval; DAS28= Disease Activity Score 28; FAS=Full analysis set; LS mean= Least- Squares means; N=total number of patients; n = number of subjects with DAS28 (ESR) results; MMRM=Mixed model for repeated measures; covariance matrix used for MMRM: UN. DAS28(ESR) change from Baseline in trial 1301.1 at each on treatment visit of trial 1301.4 = overall mean + treatment + DAS28 Baseline score in trial 1301.1 + visit + visit by treatment interaction + baseline-by-visit interaction + random error ACR20 Endpoint: The proportion of subjects meeting the ACR20 response criteria (based on improvement since Baseline in trial 1301.1) at Week 48 of Trial 1301.4. ACR20 response was to be calculated at every planned efficacy assessment visit. The number of ACR20 responders at Week 48 and the ACR20 responder rate were to be displayed. The two-sided Wilson score 90% and 95% CIs of responder rates were to be
Boehringer Ingelheim Page 12 of 14 XX Oct 2017 calculated for each treatment group and overall. These CIs were to be interpreted in an exploratory fashion only. Table 2 Secondary Endpoint: Efficacy: ACR20 Summary of Missing Data Imputation (NRI+LOCF) - FAS Description Rituxan MabThera Total (N=30) (N=26) (N=28) (N=84) n (%) n (%) n (%) n (%) Number of subjects with 27 (90.0%) 23 (88.5%) 25 (89.3%) 75 (89.3%) ACR20 results a Number of subjects meeting 1 (3.7%) 1 (4.3%) 1 (4.0%) 3 (4.0%) the ACR20 response criteria Number of subjects with NRI 11 (40.7%) 16 (69.6%) 19 (76.0%) 46 (61.3%) Reason for NRI Discontinue Treatment 11 (100.0%) 16 (100.0%) 18 (94.7%) 45 (97.8%) Lost to follow-up 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) Receive therapy with 0 (0.0%) 1 (6.3%) 2 (10.5%) 3 (6.5%) impact on efficacy %= percentage of subjects with ACR20 results calculated relative to the total number of subjects in the analysis set. percentage of subjects meeting the ACR20 response criteria and percentage of subject with NRI calculated relative to the total number of subjects with ACR20 results. percentage of subjects by NRI reason is calculated relative to the number of subject with NRI. FAS=Full Analysis Set; N=total number of patients; n=number of patients with an observation; NRI=non responder imputation. a Missing data have been imputed according to non-responder Imputation (NRI)+ Last Observation Carried Forward (LOCF). ACR/EULAR Remission: The proportion of subjects who meet the ACR/EULAR definition of remission (based on improvement since Baseline in trial 1301.1) at Week 48 of trial 1301.4. The ACR/EULAR Remission was to be evaluated at Week 24 and Week 48. The number of subjects meeting the ACR/EULAR definition of remission at Week 48 and the proportion of subjects were to be displayed.
Boehringer Ingelheim Page 13 of 14 XX Oct 2017 Table 3 Secondary Endpoint: Efficacy: ACR20 (Improvement Since Baseline in 1301.1) at Week 48 (NRI +LOCF) - FAS n Number of ACR20 responders ACR20 responder rate (%) 90% CI 95% CI (N = 30) 26 10 38.5 (0.25; 0.55) (0.22; 0.57) Rituxan (N = 26) 23 3 13.0 (0.05; 0.29) (0.05; 0.32) MabThera (N = 28) 25 4 16.0 (0.07; 0.31) (0.06; 0.35) Total (N = 84) 74 17 23.0 (0.16; 0.32) (0.15; 0.34) ACR20=American College of Rheumatology 20%; CI=Confidence interval; FAS=Full Analysis Set; LOCF=Last Observation Carried Forward; N=total number of patients; n=number of subjects with ACR20 results; NRI=non-responder imputation. The percentage of subjects meeting the ACR20 criteria (based on improvement since baseline in trial 1301.1) at Week 48 of Trial 1301.4 was 10.0 (, 7.7 (Rituxan), and 7.1 (MabThera). EULAR Response: The proportion of subjects who meet the EULAR response (good response, moderate response or no response) (based on DAS28 improvement since Baseline in trial 1301.1) at Week 48 of Trial 1301.4. The EULAR response (with categories good response, moderate response or no response) was to be derived at Week 24 and Week 48. In addition, DAS28 remission, defined as a DAS28 score of < 2.6, was to be derived at Week 24 and Week 48. The number of subjects meeting EULAR response at Week 48 and the EULAR response rate were to be displayed. Table 4 Secondary Endpoint: Efficacy: ACR/EULAR Remission (Improvement Since Baseline in 1301.1) at Week 48 - FAS Description Category Treatment Group Meet the ACR/EULAR definition of remission (based on improvement since Baseline in Trial 1301.1) at Week 48 Rituxan Treatment Group MabThera Treatment Group Total (N=30) (N=26) (N=28) (N=84) n (%) n (%) n (%) n (%) Yes 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) No 21 (70.0%) 16 (61.5%) 16 (57.1%) 53 (63.1%) %=percentage of patients calculated relative to the total number of patients in the analysis set; ACR= American College of Rheumatology; EULAR= European League Against Rheumatism; FAS=Full Analysis Set; N=total number of patients, n=number of patients with an observation.
Boehringer Ingelheim Page 14 of 14 XX Oct 2017 Table 5 Secondary Endpoint: Efficacy: DAS28 (ESR) EULAR Response (Improvement Since Baseline in 1301.1) and DAS28 (ESR) Remission at Week 48 - FAS Description Category Treatment Group Rituxan Treatment Group MabThera Treatment Group Total (N=30) (N=26) (N=28) (N=84) n (%) n (%) n (%) n (%) EULAR Response Good Response 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) Moderate Response 1 (3.3%) 2 (7.7%) 0 (0.0%) 3 (3.6%) No Response 4 (13.3%) 4 (15.4%) 4 (14.3%) 12 (14.3%) Missing 13 (43.3%) 4 (15.4%) 4 (14.3%) 21 (25.0%) DAS28 Remission Yes 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) No 5 (16.7%) 6 (23.1%) 4 (14.3%) 15 (17.9%) Missing 13 (43.3%) 4 (15.4%) 4 (14.3%) 21 (25.0%) %=percentage of patients calculated relative to the total number of patients in the analysis set; DAS28=Disease Activity Score 28; ESR= erythrocyte sedimentation rate; EULAR= European League Against Rheumatism; FAS=Full Analysis Set; N=total number of patients, n=number of patients with an observation.