Trial Outcomes & Findings for Long-term Assessment of Safety and Efficacy of BI 695501 in Patients With Rheumatoid Arthritis (NCT NCT02640612)

Last Updated: 2018-12-05

Results Overview

The analysis of AEs was based on the concept of treatment-emergent AEs (TEAEs). Thus, all AEs with an onset after the first dose of trial drug up to a period of ten weeks after the last dose of trial drug were assigned to the current treatment for evaluation. Investigator assessed drug related AEs were AEs with a relationship to drug ticked "yes" according to the Investigator.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

430 participants

Primary outcome timeframe

From the first drug administration until 10 weeks after the last drug administration, up to 58 weeks.

Results posted on

2018-12-05

Participant Flow

This study was an open-label extension trial. Adult patients with moderate to severely active rheumatoid arthritis (RA) who completed Trial NCT02137226 (1297.2), wished to participate in this extension trial and per Investigator's assessment could benefit from continuing to receive BI 695501 were included in this trial.

All patients were screened for eligibility to participate in the trial. The screening visit of this trial was the Week 48 visit in Trial 1297.2.

Participant milestones

Participant milestones
Measure	BI 695501 to BI 695501 Patients initially randomized to BI 695501 in Period 1 and re-randomized to BI 695501 in Period 2 of the 1297.2 trial. Each patient received 40 milligram (mg)/0.8 millilitre (mL) BI 695501 in period 1 and 40 mg/0.8 mL BI 695501 in period 2. The respective treatment was administered by subcutaneous (SC) injection every 2 weeks from Day 1 to Week 48.	Humira® to Humira® Patients initially randomized to Humira® in Period 1 and re-randomized to Humira® in Period 2 of the 1297.2 trial. Each patient received 40 mg/0.8 mL Humira® in period 1 and 40 mg/0.8 mL Humira® in period 2. The respective treatment was administered by SC injection every 2 weeks from Day 1 to Week 48.	Humira® to BI 695501 Patients initially randomized to Humira® in Period 1 and re- randomized to BI 695501 in Period 2 of the 1297.2 trial. Each patient received 40 mg/0.8 mL Humira® in period 1 and 40 mg/0.8 mL BI 695501 in period 2. The respective treatment was administered by SC injection every 2 weeks from Day 1 to Week 48.
Overall Study STARTED	225	103	102
Overall Study COMPLETED	203	89	96
Overall Study NOT COMPLETED	22	14	6

Reasons for withdrawal

Reasons for withdrawal
Measure	BI 695501 to BI 695501 Patients initially randomized to BI 695501 in Period 1 and re-randomized to BI 695501 in Period 2 of the 1297.2 trial. Each patient received 40 milligram (mg)/0.8 millilitre (mL) BI 695501 in period 1 and 40 mg/0.8 mL BI 695501 in period 2. The respective treatment was administered by subcutaneous (SC) injection every 2 weeks from Day 1 to Week 48.	Humira® to Humira® Patients initially randomized to Humira® in Period 1 and re-randomized to Humira® in Period 2 of the 1297.2 trial. Each patient received 40 mg/0.8 mL Humira® in period 1 and 40 mg/0.8 mL Humira® in period 2. The respective treatment was administered by SC injection every 2 weeks from Day 1 to Week 48.	Humira® to BI 695501 Patients initially randomized to Humira® in Period 1 and re- randomized to BI 695501 in Period 2 of the 1297.2 trial. Each patient received 40 mg/0.8 mL Humira® in period 1 and 40 mg/0.8 mL BI 695501 in period 2. The respective treatment was administered by SC injection every 2 weeks from Day 1 to Week 48.
Overall Study Adverse Event	6	7	2
Overall Study Death	1	0	0
Overall Study Withdrawal by Subject	10	3	3
Overall Study Lost to Follow-up	4	1	1
Overall Study Protocol Violation	0	2	0
Overall Study Lack of Efficacy	1	1	0

Baseline Characteristics

SAF

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	BI 695501 to BI 695501 n=225 Participants Patients initially randomized to BI 695501 in Period 1 and re-randomized to BI 695501 in Period 2 of the 1297.2 trial. Each patient received 40 milligram (mg)/0.8 millilitre (mL) BI 695501 in period 1 and 40 mg/0.8 mL BI 695501 in period 2. The respective treatment was administered by subcutaneous (SC) injection every 2 weeks from Day 1 to Week 48.	Humira® to Humira® n=103 Participants Patients initially randomized to Humira® in Period 1 and re-randomized to Humira® in Period 2 of the 1297.2 trial. Each patient received 40 mg/0.8 mL Humira® in period 1 and 40 mg/0.8 mL Humira® in period 2. The respective treatment was administered by SC injection every 2 weeks from Day 1 to Week 48.	Humira® to BI 695501 n=102 Participants Patients initially randomized to Humira® in Period 1 and re- randomized to BI 695501 in Period 2 of the 1297.2 trial. Each patient received 40 mg/0.8 mL Humira® in period 1 and 40 mg/0.8 mL BI 695501 in period 2. The respective treatment was administered by SC injection every 2 weeks from Day 1 to Week 48.	Total n=430 Participants Total of all reporting groups
Age, Continuous	53.8 Years STANDARD_DEVIATION 11.87 • n=93 Participants • SAF	51.7 Years STANDARD_DEVIATION 11.21 • n=4 Participants • SAF	54.6 Years STANDARD_DEVIATION 9.90 • n=27 Participants • SAF	53.5 Years STANDARD_DEVIATION 11.30 • n=483 Participants • SAF
Sex: Female, Male Female	188 Participants n=93 Participants • SAF	88 Participants n=4 Participants • SAF	84 Participants n=27 Participants • SAF	360 Participants n=483 Participants • SAF
Sex: Female, Male Male	37 Participants n=93 Participants • SAF	15 Participants n=4 Participants • SAF	18 Participants n=27 Participants • SAF	70 Participants n=483 Participants • SAF
Ethnicity (NIH/OMB) Hispanic or Latino	23 Participants n=93 Participants • SAF	8 Participants n=4 Participants • SAF	10 Participants n=27 Participants • SAF	41 Participants n=483 Participants • SAF
Ethnicity (NIH/OMB) Not Hispanic or Latino	199 Participants n=93 Participants • SAF	94 Participants n=4 Participants • SAF	92 Participants n=27 Participants • SAF	385 Participants n=483 Participants • SAF
Ethnicity (NIH/OMB) Unknown or Not Reported	3 Participants n=93 Participants • SAF	1 Participants n=4 Participants • SAF	0 Participants n=27 Participants • SAF	4 Participants n=483 Participants • SAF
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=93 Participants • SAF	0 Participants n=4 Participants • SAF	0 Participants n=27 Participants • SAF	0 Participants n=483 Participants • SAF
Race (NIH/OMB) Asian	7 Participants n=93 Participants • SAF	2 Participants n=4 Participants • SAF	0 Participants n=27 Participants • SAF	9 Participants n=483 Participants • SAF
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=93 Participants • SAF	0 Participants n=4 Participants • SAF	0 Participants n=27 Participants • SAF	0 Participants n=483 Participants • SAF
Race (NIH/OMB) Black or African American	3 Participants n=93 Participants • SAF	0 Participants n=4 Participants • SAF	2 Participants n=27 Participants • SAF	5 Participants n=483 Participants • SAF
Race (NIH/OMB) White	215 Participants n=93 Participants • SAF	100 Participants n=4 Participants • SAF	100 Participants n=27 Participants • SAF	415 Participants n=483 Participants • SAF
Race (NIH/OMB) More than one race	0 Participants n=93 Participants • SAF	0 Participants n=4 Participants • SAF	0 Participants n=27 Participants • SAF	0 Participants n=483 Participants • SAF
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=93 Participants • SAF	1 Participants n=4 Participants • SAF	0 Participants n=27 Participants • SAF	1 Participants n=483 Participants • SAF

PRIMARY outcome

Timeframe: From the first drug administration until 10 weeks after the last drug administration, up to 58 weeks.

Population: Safety Analysis Set (SAF): All patients who received at least 1 dose during trial 1297.3. In the event of doubt as to whether a patient was treated or not, they were assumed to have been treated for the purposes of analysis, and thus included in the SAF. Patients were classified according to randomized/re-randomized treatments of Trial 1297.2.

Outcome measures

Outcome measures
Measure	BI 695501 to BI 695501 n=225 Participants Patients initially randomized to BI 695501 in Period 1 and re-randomized to BI 695501 in Period 2 of the 1297.2 trial. Each patient received 40 milligram (mg)/0.8 millilitre (mL) BI 695501 in period 1 and 40 mg/0.8 mL BI 695501 in period 2. The respective treatment was administered by subcutaneous (SC) injection every 2 weeks from Day 1 to Week 48.	Humira® to Humira® n=103 Participants Patients initially randomized to Humira® in Period 1 and re-randomized to Humira® in Period 2 of the 1297.2 trial. Each patient received 40 mg/0.8 mL Humira® in period 1 and 40 mg/0.8 mL Humira® in period 2. The respective treatment was administered by SC injection every 2 weeks from Day 1 to Week 48.	Humira® to BI 695501 n=102 Participants Patients initially randomized to Humira® in Period 1 and re- randomized to BI 695501 in Period 2 of the 1297.2 trial. Each patient received 40 mg/0.8 mL Humira® in period 1 and 40 mg/0.8 mL BI 695501 in period 2. The respective treatment was administered by SC injection every 2 weeks from Day 1 to Week 48.
Percentage of Patients With Drug-related Adverse Events (AEs) During the Treatment Phase	21.3 Percentage of patients (%)	20.4 Percentage of patients (%)	17.6 Percentage of patients (%)

SECONDARY outcome

Timeframe: Baseline and Week 48.

Population: FullAnalysisSet(FAS) includes patients from the all subjects assigned set who received at least 1 dose of trial drug in Trial 1297.3 and had at least 1 DAS28(ESR and C-reactive protein) or american college of rheumatology 20% response criteria (ACR20) measured during trial. Classified according to randomized/rerandomized treatments of trial 1297.2.

The DAS28 (ESR) score was derived using the following formulae: DAS28 (ESR) = 0.56\*√(TJC28) + 0.28\*√(SJC28) + 0.014\*(GH) + 0.7\*ln(ESR) Where: • TJC28 = 28 joint count for tenderness • SJC28 = 28 joint count for swelling • GH = General Health component of the DAS (patient's global assessment of disease activity) • Ln (ESR) = natural logarithm of ESR. Last observation carried forward (LOCF) is the method used for handling missing components post baseline. Baseline for this trial was taken from the baseline of 1297.2. Improvement in DAS28 was also categorized using the European League Against Rheumatism (EULAR) response criteria. The DAS28 provides a number on a scale from 0 to 10 where higher values mean a higher disease activity. A DAS28 above 5.1 means high disease activity whereas a DAS28 below 3.2 indicates low disease activity. Remission is achieved by a DAS28 lower than 2.6.

Outcome measures

Outcome measures
Measure	BI 695501 to BI 695501 n=225 Participants Patients initially randomized to BI 695501 in Period 1 and re-randomized to BI 695501 in Period 2 of the 1297.2 trial. Each patient received 40 milligram (mg)/0.8 millilitre (mL) BI 695501 in period 1 and 40 mg/0.8 mL BI 695501 in period 2. The respective treatment was administered by subcutaneous (SC) injection every 2 weeks from Day 1 to Week 48.	Humira® to Humira® n=103 Participants Patients initially randomized to Humira® in Period 1 and re-randomized to Humira® in Period 2 of the 1297.2 trial. Each patient received 40 mg/0.8 mL Humira® in period 1 and 40 mg/0.8 mL Humira® in period 2. The respective treatment was administered by SC injection every 2 weeks from Day 1 to Week 48.	Humira® to BI 695501 n=101 Participants Patients initially randomized to Humira® in Period 1 and re- randomized to BI 695501 in Period 2 of the 1297.2 trial. Each patient received 40 mg/0.8 mL Humira® in period 1 and 40 mg/0.8 mL BI 695501 in period 2. The respective treatment was administered by SC injection every 2 weeks from Day 1 to Week 48.
Change From Baseline in Disease Activity Score in 28 Joints (DAS 28) by Erythrocyte Sedimentation Rate (ESR) at Week 48	-3.01 Unit on scale Standard Deviation 1.385	-2.91 Unit on scale Standard Deviation 1.323	-2.98 Unit on scale Standard Deviation 1.218

SECONDARY outcome

Timeframe: Week 48.

Population: FAS, All patients who discontinue treatment, are lost-to-follow-up or have any severe violation related to any therapy that may significantly impact efficacy assessment prior to the secondary endpoint assessment will be considered as a non-responder (NRI).

The proportion of patients meeting the ACR20 response criteria was assessed. A patient had an ACR20 response if all of the following occurred: A ≥ 20 % improvement in the swollen joint count (66 joints), A ≥ 20 % improvement in the tender joint count (68 joints), A ≥ 20 % improvement in at least three of the following assessments: Patient's assessment of pain, Patient's global assessment of disease activity (equivalent to the General Health component of the Disease Activity Score (\[DAS\]), Physician's global assessment of disease activity, Patient's assessment of physical function, as measured by the Health Assessment Questionnaire - Disability Index (HAQ-DI) Acute phase reactant (C-reactive protein \[CRP\]).

Outcome measures

Outcome measures
Measure	BI 695501 to BI 695501 n=225 Participants Patients initially randomized to BI 695501 in Period 1 and re-randomized to BI 695501 in Period 2 of the 1297.2 trial. Each patient received 40 milligram (mg)/0.8 millilitre (mL) BI 695501 in period 1 and 40 mg/0.8 mL BI 695501 in period 2. The respective treatment was administered by subcutaneous (SC) injection every 2 weeks from Day 1 to Week 48.	Humira® to Humira® n=103 Participants Patients initially randomized to Humira® in Period 1 and re-randomized to Humira® in Period 2 of the 1297.2 trial. Each patient received 40 mg/0.8 mL Humira® in period 1 and 40 mg/0.8 mL Humira® in period 2. The respective treatment was administered by SC injection every 2 weeks from Day 1 to Week 48.	Humira® to BI 695501 n=101 Participants Patients initially randomized to Humira® in Period 1 and re- randomized to BI 695501 in Period 2 of the 1297.2 trial. Each patient received 40 mg/0.8 mL Humira® in period 1 and 40 mg/0.8 mL BI 695501 in period 2. The respective treatment was administered by SC injection every 2 weeks from Day 1 to Week 48.
Percentage of Patients Meeting American College of Rheumatology (ACR) 20% Response Criteria at Week 48	76.9 Percentage of patients (%)	76.7 Percentage of patients (%)	73.3 Percentage of patients (%)

SECONDARY outcome

Timeframe: Week 48.

Population: FAS

The ACR/EULAR remission criteria were based on a Boolean definition. At any time point, the patient must have satisfied all of the following: * Tender joint count (TJC) ≤ 1 * Swollen joint count (SJC) ≤ 1 * C-reactive protein (CRP) ≤ 1 mg/dL * Patient global assessment of disease activity ≤ 10 (on a 0 to 100 scale) For TJC and SJC, use of a 28-joint count may have missed actively involved joints, particularly in the feet and ankles. It was preferable to include the feet and ankles when evaluating remission.

Outcome measures

Outcome measures
Measure	BI 695501 to BI 695501 n=225 Participants Patients initially randomized to BI 695501 in Period 1 and re-randomized to BI 695501 in Period 2 of the 1297.2 trial. Each patient received 40 milligram (mg)/0.8 millilitre (mL) BI 695501 in period 1 and 40 mg/0.8 mL BI 695501 in period 2. The respective treatment was administered by subcutaneous (SC) injection every 2 weeks from Day 1 to Week 48.	Humira® to Humira® n=103 Participants Patients initially randomized to Humira® in Period 1 and re-randomized to Humira® in Period 2 of the 1297.2 trial. Each patient received 40 mg/0.8 mL Humira® in period 1 and 40 mg/0.8 mL Humira® in period 2. The respective treatment was administered by SC injection every 2 weeks from Day 1 to Week 48.	Humira® to BI 695501 n=101 Participants Patients initially randomized to Humira® in Period 1 and re- randomized to BI 695501 in Period 2 of the 1297.2 trial. Each patient received 40 mg/0.8 mL Humira® in period 1 and 40 mg/0.8 mL BI 695501 in period 2. The respective treatment was administered by SC injection every 2 weeks from Day 1 to Week 48.
Percentage of Patients Who Meet the American College of Rheumatology (ACR) / European League Against Rheumatism (EULAR) Definition of Remission at Week 48	8.4 Percentage of patients (%)	9.7 Percentage of patients (%)	6.9 Percentage of patients (%)

SECONDARY outcome

Timeframe: Week 48.

Population: FAS

Percentage of patients with European League Against Rheumatism (EULAR) response (good response, moderate response, or no response) were calculated at Week 48 for assessment of this outcome measure. No response: If improvement in DAS28 (ESR) at w48 \<=0.6, or if DAS28(ESR) at w48 \>5.1 and improvement is in range \>0.6 to \<1.2. Moderate response: If DAS28(ESR) at w48 \<=5.1 and improvement is in range \>0.6 to \<1.2, or, DAS28(ESR) at w48 \>3.2 and improvement is in range \>=1.2. Good response: If DAS28(ESR) at w48 \<=3.2 and improvement \>=1.2.

Outcome measures

Outcome measures
Measure	BI 695501 to BI 695501 n=225 Participants Patients initially randomized to BI 695501 in Period 1 and re-randomized to BI 695501 in Period 2 of the 1297.2 trial. Each patient received 40 milligram (mg)/0.8 millilitre (mL) BI 695501 in period 1 and 40 mg/0.8 mL BI 695501 in period 2. The respective treatment was administered by subcutaneous (SC) injection every 2 weeks from Day 1 to Week 48.	Humira® to Humira® n=103 Participants Patients initially randomized to Humira® in Period 1 and re-randomized to Humira® in Period 2 of the 1297.2 trial. Each patient received 40 mg/0.8 mL Humira® in period 1 and 40 mg/0.8 mL Humira® in period 2. The respective treatment was administered by SC injection every 2 weeks from Day 1 to Week 48.	Humira® to BI 695501 n=101 Participants Patients initially randomized to Humira® in Period 1 and re- randomized to BI 695501 in Period 2 of the 1297.2 trial. Each patient received 40 mg/0.8 mL Humira® in period 1 and 40 mg/0.8 mL BI 695501 in period 2. The respective treatment was administered by SC injection every 2 weeks from Day 1 to Week 48.
Percentage of Patients With European League Against Rheumatism (EULAR) Response (Good Response, Moderate Response, or no Response) at Week 48 Good Response	37.8 Percentage of patients (%)	37.9 Percentage of patients (%)	41.6 Percentage of patients (%)
Percentage of Patients With European League Against Rheumatism (EULAR) Response (Good Response, Moderate Response, or no Response) at Week 48 Moderate Response	49.8 Percentage of patients (%)	54.4 Percentage of patients (%)	51.5 Percentage of patients (%)
Percentage of Patients With European League Against Rheumatism (EULAR) Response (Good Response, Moderate Response, or no Response) at Week 48 No Response	9.3 Percentage of patients (%)	5.8 Percentage of patients (%)	3.0 Percentage of patients (%)

Adverse Events

BI 695501 to BI 695501

Serious events: 14 serious events

Other events: 9 other events

Deaths: 1 deaths

Humira® to Humira®

Serious events: 8 serious events

Other events: 6 other events

Deaths: 0 deaths

Humira® to BI 695501

Serious events: 4 serious events

Other events: 2 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	BI 695501 to BI 695501 n=225 participants at risk Patients initially randomized to BI 695501 in Period 1 and re-randomized to BI 695501 in Period 2 of the 1297.2 trial. Each patient received 40 milligram (mg)/0.8 millilitre (mL) BI 695501 in period 1 and 40 mg/0.8 mL BI 695501 in period 2. The respective treatment was administered by subcutaneous (SC) injection every 2 weeks from Day 1 to Week 48.	Humira® to Humira® n=103 participants at risk Patients initially randomized to Humira® in Period 1 and re-randomized to Humira® in Period 2 of the 1297.2 trial. Each patient received 40 mg/0.8 mL Humira® in period 1 and 40 mg/0.8 mL Humira® in period 2. The respective treatment was administered by SC injection every 2 weeks from Day 1 to Week 48.	Humira® to BI 695501 n=102 participants at risk Patients initially randomized to Humira® in Period 1 and re- randomized to BI 695501 in Period 2 of the 1297.2 trial. Each patient received 40 mg/0.8 mL Humira® in period 1 and 40 mg/0.8 mL BI 695501 in period 2. The respective treatment was administered by SC injection every 2 weeks from Day 1 to Week 48.
Infections and infestations Upper respiratory tract infection	4.0% 9/225 • From the first drug administration until 10 weeks after the last drug administration, up to 58 weeks. An Adverse Event (AE) was defined as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which did not necessarily have to have a causal relationship with this treatment. SAF was used for AE assessment.	5.8% 6/103 • From the first drug administration until 10 weeks after the last drug administration, up to 58 weeks. An Adverse Event (AE) was defined as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which did not necessarily have to have a causal relationship with this treatment. SAF was used for AE assessment.	2.0% 2/102 • From the first drug administration until 10 weeks after the last drug administration, up to 58 weeks. An Adverse Event (AE) was defined as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which did not necessarily have to have a causal relationship with this treatment. SAF was used for AE assessment.

Additional Information

Boehringer Ingelheim, Call Center

Boehringer Ingelheim

Phone: 1-800-243-0127

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Boehringer Ingelheim (BI) acknowledges that investigators have the right to publish the study results. Investigators shall provide BI with a copy of any publication or presentation for review prior to any submission. Such review will be done with regard to proprietary information, information related to patentable inventions, medical, scientific, and statistical accuracy within 60 days. BI may request a delay of the publication in order to protect BI's intellectual property rights.
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Restriction type: OTHER