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Efficacy, Safety and Immunogenicity of BI 695501 Versus Humira® in Patients With Moderate to Severe Chronic Plaque Psoriasis

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ClinicalTrials.gov Identifier: NCT02850965
Recruitment Status : Completed
First Posted : August 1, 2016
Results First Posted : February 8, 2019
Last Update Posted : February 8, 2019
Sponsor:
Information provided by (Responsible Party):
Boehringer Ingelheim

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double (Participant, Investigator);   Primary Purpose: Treatment
Condition Psoriasis
Interventions Drug: BI 695501
Drug: Humira
Enrollment 318
Recruitment Details This was a Phase III, multinational, randomized, double-blind, parallel-arm, multiple-dose, active-comparator trial of BI 695501 and US-licensed Humira with a 24-week treatment period and 10 weeks of safety follow up, in patients with moderate to severe chronic plaque psoriasis.
Pre-assignment Details All patients were screened for eligibility to participate in the trial. Patients attended specialist sites to ensure that all patients met all inclusion/exclusion criteria. Patients were not to be entered to trial treatment if any one of the specific entry criteria were not met.
Arm/Group Title BI 695501 US-licensed Humira
Hide Arm/Group Description Patients were administered with BI 695501 via subcutaneous (SC) injection 80 milligram (mg) on Day 1 and 40 milligram (mg) on every other week from Week 1 to Week 23. Patients were administered US-licensed Humira via subcutaneous (SC) injection 80 mg on Day 1 and 40 milligram on every other week from Week 1 to Week 23.
Period Title: Overall Study
Started [1] 159 159
Treated 159 158
Completed 141 134
Not Completed 18 25
Reason Not Completed
Other than listed             3             4
Protocol Violation             0             2
Lost to Follow-up             5             3
Lack of Efficacy             4             8
Adverse Event             3             2
Withdrawal by Subject             3             4
Physician Decision             0             1
Randomized but not treated             0             1
[1]
Randomized
Arm/Group Title BI 695501 US-licensed Humira Total
Hide Arm/Group Description Patients were administered with BI 695501 via subcutaneous (SC) injection 80 milligram (mg) on Day 1 and 40 milligram (mg) on every other week from Week 1 to Week 23. Patients were administered US-licensed Humira via subcutaneous (SC) injection 80 mg on Day 1 and 40 milligram on every other week from Week 1 to Week 23. Total of all reporting groups
Overall Number of Baseline Participants 159 158 317
Hide Baseline Analysis Population Description
Safety Analysis Set (SAF): The SAF contained all patients who provided signed informed consent, who were randomized, and who received at least one dose of trial medication.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 159 participants 158 participants 317 participants
42.1  (12.79) 44.7  (13.92) 43.4  (13.41)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 159 participants 158 participants 317 participants
Female
58
  36.5%
56
  35.4%
114
  36.0%
Male
101
  63.5%
102
  64.6%
203
  64.0%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 159 participants 158 participants 317 participants
Hispanic or Latino
12
   7.5%
10
   6.3%
22
   6.9%
Not Hispanic or Latino
147
  92.5%
146
  92.4%
293
  92.4%
Unknown or Not Reported
0
   0.0%
2
   1.3%
2
   0.6%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 159 participants 158 participants 317 participants
American Indian or Alaska Native
0
   0.0%
0
   0.0%
0
   0.0%
Asian
0
   0.0%
0
   0.0%
0
   0.0%
Native Hawaiian or Other Pacific Islander
0
   0.0%
1
   0.6%
1
   0.3%
Black or African American
1
   0.6%
1
   0.6%
2
   0.6%
White
157
  98.7%
156
  98.7%
313
  98.7%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
Unknown or Not Reported
1
   0.6%
0
   0.0%
1
   0.3%
1.Primary Outcome
Title The Percentage of Patients With at Least 75% Reduction in Psoriasis Area and Severity Index (PASI 75) Response at Week 16
Hide Description

The PASI tool provides numeric scoring for a patient’s overall psoriasis disease state, ranging from 0 to 72. Head (h), trunk (t), upper extremities (u) and lower extremities (l) areas were assessed; correspond to 10, 30, 20, and 40% of the total body area, respectively. The signs of severity, erythema (E), induration (I) and desquamation (D) of lesions were assessed using a numeric scale of 0 to 4 where 0 was a complete lack of cutaneous involvement and 4 was the severest possible involvement. The area of psoriatic involvement of these areas (Ah, At, Au, and Al) was given a numerical value: 0 = no involvement, 1 = <10%, 2 = 10 to <30%, 3 = 30 to <50%, 4 = 50 to <70%, 5 = 70 to <90%, and 6 = 90 to 100% involvement.

PASI = 0.1(Eh+Ih+Dh)Ah + 0.3(Et+It+Dt)At + 0.2(Eu+Iu+Du)Au + 0.4(El+Il+Dl)Al.

Percentage = least squares means per treatment groups back transformed using inverse logit function.

Time Frame Week 16
Hide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Set (FAS): The FAS contained all randomized patients who received at least one dose of trial medication, and had all efficacy measures relevant for the PASI 75, measured at baseline and at least once post-baseline (prior to or on Week 16).
Arm/Group Title BI 695501 US-licensed Humira
Hide Arm/Group Description:
Patients were administered with BI 695501 via subcutaneous (SC) injection 80 milligram (mg) on Day 1 and 40 milligram (mg) on every other week from Week 1 to Week 23.
Patients were administered US-licensed Humira via subcutaneous (SC) injection 80 mg on Day 1 and 40 milligram on every other week from Week 1 to Week 23.
Overall Number of Participants Analyzed 158 157
Measure Type: Number
Unit of Measure: Percentage (%)
68.2 70.4
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection BI 695501, US-licensed Humira
Comments The week 16 confidence interval for the estimated difference in percentage are produced using the cumulative distribution function method of Reeve.
Type of Statistical Test Equivalence
Comments Protocol defined margins are: [-18.0%, +18.0%] for Week 16, 95% confidence interval. Between-imputation variance is zero. Confidence interval is based on one imputed set.
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in PASI 75 Response Rate
Estimated Value -2.2
Confidence Interval (2-Sided) 95%
-14.4 to 8.7
Estimation Comments Difference in PASI 75 Response Rate = (BI 695501 – US-licensed Humira, %).
Other Statistical Analysis The statistical model: Logit (response to treatment at Week 16)=Treatment+Baseline PASI+Prior exposure to a biologic agent+random error. Model included fixed, categorical effects of treatment (BI 695501 vs US-licensed Humira) and prior exposure to a biologic agent (yes/no), continuous effect of baseline PASI. The random error was assumed to be binomially distributed.
2.Secondary Outcome
Title The Percentage of Patients With a PASI 75 Response at Week 24
Hide Description

The PASI tool provides numeric scoring for a patient’s overall psoriasis disease state, ranging from 0 to 72. Head (h), trunk (t), upper extremities (u) and lower extremities (l) areas were assessed; correspond to 10, 30, 20, and 40% of the total body area, respectively. The signs of severity, erythema (E), induration (I) and desquamation (D) of lesions were assessed using a numeric scale of 0 to 4 where 0 was a complete lack of cutaneous involvement and 4 was the severest possible involvement. The area of psoriatic involvement of these areas (Ah, At, Au, and Al) was given a numerical value: 0 = no involvement, 1 = <10%, 2 = 10 to <30%, 3 = 30 to <50%, 4 = 50 to <70%, 5 = 70 to <90%, and 6 = 90 to 100% involvement.

PASI = 0.1(Eh+Ih+Dh)Ah + 0.3(Et+It+Dt)At + 0.2(Eu+Iu+Du)Au + 0.4(El+Il+Dl)Al.

Percentage = least squares means per treatment groups back transformed using inverse logit function.

Time Frame Week 24
Hide Outcome Measure Data
Hide Analysis Population Description
FAS
Arm/Group Title BI 695501 US-licensed Humira
Hide Arm/Group Description:
Patients were administered with BI 695501 via subcutaneous (SC) injection 80 milligram (mg) on Day 1 and 40 milligram (mg) on every other week from Week 1 to Week 23.
Patients were administered US-licensed Humira via subcutaneous (SC) injection 80 mg on Day 1 and 40 milligram on every other week from Week 1 to Week 23.
Overall Number of Participants Analyzed 158 157
Measure Type: Number
Unit of Measure: Percentage (%)
75.3 72.4
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection BI 695501, US-licensed Humira
Comments The week 24 confidence interval for the estimated difference in percentage are produced using the cumulative distribution function method of Reeve.
Type of Statistical Test Other
Comments Missing PASI 75 at Week 24 data were imputed using a combination of non-responder imputation (NRI) and last observed carried forward (LOCF).
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in PASI 75 Response Rate
Estimated Value 2.9
Confidence Interval (2-Sided) 95%
-8.5 to 12.6
Estimation Comments Difference in PASI 75 Response Rate = (BI 695501 – US-licensed Humira, %).
Other Statistical Analysis The statistical model: Logit (response to treatment at Week 24)=Treatment+Baseline PASI+Prior exposure to a biologic agent+random error. Model included fixed, categorical effects of treatment (BI 695501 vs US-licensed Humira) and prior exposure to a biologic agent (yes/no), continuous effect of baseline PASI. The random error was assumed to be binomially distributed.
3.Secondary Outcome
Title The Mean Percentage Improvement in PASI at Week 16
Hide Description

The PASI tool provides numeric scoring for a patient’s overall psoriasis disease state, ranging from 0 to 72. Head (h), trunk (t), upper extremities (u) and lower extremities (l) areas were assessed; correspond to 10, 30, 20, and 40% of the total body area, respectively. The signs of severity, erythema (E), induration (I) and desquamation (D) of lesions were assessed using a numeric scale of 0 to 4 where 0 was a complete lack of cutaneous involvement and 4 was the severest possible involvement. The area of psoriatic involvement of these areas (Ah, At, Au, and Al) was given a numerical value: 0 = no involvement, 1 =<10%, 2 =10 to <30%, 3 =30 to <50%, 4 =50 to <70%, 5 =70 to <90%, and 6 =90 to 100% involvement.

PASI = 0.1(Eh+Ih+Dh)Ah + 0.3(Et+It+Dt)At + 0.2(Eu+Iu+Du)Au + 0.4(El+Il+Dl)Al.

Results based on PASI mean percentage improvement from Baseline after 16 weeks of treatment = overall mean + treatment group + Baseline PASI + prior exposure to a biological agent + random error.

Time Frame Week 16
Hide Outcome Measure Data
Hide Analysis Population Description
FAS
Arm/Group Title BI 695501 US-licensed Humira
Hide Arm/Group Description:
Patients were administered with BI 695501 via subcutaneous (SC) injection 80 milligram (mg) on Day 1 and 40 milligram (mg) on every other week from Week 1 to Week 23.
Patients were administered US-licensed Humira via subcutaneous (SC) injection 80 mg on Day 1 and 40 milligram on every other week from Week 1 to Week 23.
Overall Number of Participants Analyzed 149 149
Least Squares Mean (95% Confidence Interval)
Unit of Measure: Percentage (%)
83.7
(80.2 to 87.2)
82.1
(78.6 to 85.6)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection BI 695501, US-licensed Humira
Comments Analysis of covariance (ANCOVA) was performed based on the following model: PASI percentage improvement from baseline at Week 16= Treatment + Baseline PASI +Prior exposure to a biologic agent + random error.
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method ANCOVA
Comments Analysis of covariance (ANCOVA)
Method of Estimation Estimation Parameter Difference of Least Squares Means
Estimated Value 1.7
Confidence Interval (2-Sided) 95%
-2.7 to 6.0
Estimation Comments Difference of Least Squares Means (LSM)= LSM of (BI 695501 – Humira)
4.Secondary Outcome
Title The Percentage of Patients With a Static Physician’s Global Assessment (sPGA) ≤1 (Clear or Almost Clear) at Week 16
Hide Description

The Static Physician’s Global Assessment (sPGA) is a 5-point score ranging from 0 to 4, based on the physician’s assessment of the average thickness, erythema, and scaling of all psoriatic lesions.

The assessment was considered “static”, which referred to the patient’s disease state at the time of the assessment, without comparison to any of the patient’s previous disease states (dynamic), whether at Baseline or at a previous visit. A lower score indicated less body coverage, with 0 being clear, 1 being almost clear, and 4 being.

Percentage = least squares means per treatment groups back transformed using inverse logit function.

Time Frame Week 16
Hide Outcome Measure Data
Hide Analysis Population Description
FAS
Arm/Group Title BI 695501 US-licensed Humira
Hide Arm/Group Description:
Patients were administered with BI 695501 via subcutaneous (SC) injection 80 milligram (mg) on Day 1 and 40 milligram (mg) on every other week from Week 1 to Week 23.
Patients were administered US-licensed Humira via subcutaneous (SC) injection 80 mg on Day 1 and 40 milligram on every other week from Week 1 to Week 23.
Overall Number of Participants Analyzed 158 157
Measure Type: Number
Unit of Measure: Percentage (%)
59.6 52.1
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection BI 695501, US-licensed Humira
Comments The week 16 confidence interval for the estimated difference in percentage are produced using the cumulative distribution function method of Reeve.
Type of Statistical Test Other
Comments Missing sPGA at Week 16 data were imputed using a combination of non-responder imputation (NRI) and last observed carried forward (LOCF).
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in sPGA <= 1 Response Rate
Estimated Value 7.5
Confidence Interval (2-Sided) 95%
-4.8 to 19.1
Estimation Comments Difference in sPGA <= 1 Response Rate = (BI 695501 – US-licensed Humira, %)
Other Statistical Analysis The statistical model: Logit (response to treatment at Week 16)=Treatment+Baseline PASI+Prior exposure to a biologic agent+random error. Model included fixed, categorical effects of treatment (BI 695501 vs US-licensed Humira) and prior exposure to a biologic agent (yes/no), continuous effect of baseline PASI.
5.Secondary Outcome
Title The Percentage of Patients Achieving a Dermatology Life Quality Index (DLQI) of 0 or 1 at Week 16
Hide Description

The DLQI is a subject-administered, 10-question, that covers 6 domains including symptoms and feelings, daily activities, leisure, work and school, personal relationships, and treatment. It has a 1-week recall period. Every item score ranges from 0 (not relevant/not at all) to 3 (very much). Question 7 is a “yes/no” question where “yes” is scored as 3.

The DLQI total score was calculated by summing the scores of each question resulting in a range of 0 to 30 where 0-1 = no effect on subject’s life, 2-5 = small effect, 6-10 = moderate effect, 11-20 = very large effect, and 21-30 = extremely large effect on the subject’s life.

The higher the score, the more the quality of life is impaired. If the answer to 1 question in a domain was missing, that domain was treated as missing. If 2 or more questions were left unanswered (missing), DLQI total score was treated as missing. Percentage = least squares means per treatment groups back transformed using inverse logit function.

Time Frame Week 16
Hide Outcome Measure Data
Hide Analysis Population Description
FAS
Arm/Group Title BI 695501 US-licensed Humira
Hide Arm/Group Description:
Patients were administered with BI 695501 via subcutaneous (SC) injection 80 milligram (mg) on Day 1 and 40 milligram (mg) on every other week from Week 1 to Week 23.
Patients were administered US-licensed Humira via subcutaneous (SC) injection 80 mg on Day 1 and 40 milligram on every other week from Week 1 to Week 23.
Overall Number of Participants Analyzed 158 157
Measure Type: Number
Unit of Measure: Percentage (%)
67.2 66.8
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection BI 695501, US-licensed Humira
Comments The week 16 confidence interval for the estimated difference in percentage are produced using the cumulative distribution function method of Reeve.
Type of Statistical Test Other
Comments Missing DLQI at Week 16 data were imputed using a combination of non-responder imputation (NRI) and last observed carried forward (LOCF).
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in DLQI Response Rate
Estimated Value 0.4
Confidence Interval (2-Sided) 95%
-11.7 to 11.3
Estimation Comments Difference in DLQI (0, 1) Response Rate = (BI 695501 – US-licensed Humira, %)
Other Statistical Analysis The statistical model: Logit (response to treatment at Week 16)=Treatment+Baseline PASI+Prior exposure to a biologic agent+random error. Model included fixed, categorical effects of treatment (BI 695501 vs US-licensed Humira) and prior exposure to a biologic agent (yes/no), continuous effect of baseline PASI.
6.Secondary Outcome
Title The Percentage of Patients With Drug-related Adverse Events (AEs)
Hide Description The secondary safety endpoint was defined as the percentage of patients with drug-related adverse events (AEs).
Time Frame From first drug administration until 10 weeks after last drug administration, up to 34 weeks.
Hide Outcome Measure Data
Hide Analysis Population Description
Safety Analysis Set (SAF): The SAF contained all patients who provided signed informed consent, who were randomized, and who received at least one dose of trial medication.
Arm/Group Title BI 695501 US-licensed Humira
Hide Arm/Group Description:
Patients were administered with BI 695501 via subcutaneous (SC) injection 80 milligram (mg) on Day 1 and 40 milligram (mg) on every other week from Week 1 to Week 23.
Patients were administered US-licensed Humira via subcutaneous (SC) injection 80 mg on Day 1 and 40 milligram on every other week from Week 1 to Week 23.
Overall Number of Participants Analyzed 159 158
Measure Type: Number
Unit of Measure: Percentage of patients (%)
13.2 20.3
Time Frame From first drug administration until 10 weeks after last drug administration, up to 33 weeks.
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title BI 695501 US-licensed Humira
Hide Arm/Group Description Patients were administered with BI 695501 via subcutaneous (SC) injection 80 milligram (mg) on Day 1 and 40 milligram (mg) on every other week from Week 1 to Week 23. Patients were administered US-licensed Humira via subcutaneous (SC) injection 80 mg on Day 1 and 40 milligram on every other week from Week 1 to Week 23.
All-Cause Mortality
BI 695501 US-licensed Humira
Affected / at Risk (%) Affected / at Risk (%)
Total   0/159 (0.00%)   0/158 (0.00%) 
Show Serious Adverse Events Hide Serious Adverse Events
BI 695501 US-licensed Humira
Affected / at Risk (%) Affected / at Risk (%)
Total   5/159 (3.14%)   7/158 (4.43%) 
Cardiac disorders     
Congestive cardiomyopathy  1  1/159 (0.63%)  0/158 (0.00%) 
Pericarditis  1  0/159 (0.00%)  1/158 (0.63%) 
Gastrointestinal disorders     
Pancreatitis chronic  1  0/159 (0.00%)  1/158 (0.63%) 
Hepatobiliary disorders     
Hepatitis toxic  1  0/159 (0.00%)  1/158 (0.63%) 
Infections and infestations     
Abdominal abscess  1  1/159 (0.63%)  0/158 (0.00%) 
Furuncle  1  0/159 (0.00%)  1/158 (0.63%) 
Kidney infection  1  0/159 (0.00%)  1/158 (0.63%) 
Oral herpes  1  1/159 (0.63%)  0/158 (0.00%) 
Orchitis  1  0/159 (0.00%)  1/158 (0.63%) 
Upper respiratory tract infection  1  1/159 (0.63%)  0/158 (0.00%) 
Musculoskeletal and connective tissue disorders     
Exostosis  1  0/159 (0.00%)  1/158 (0.63%) 
Foot deformity  1  0/159 (0.00%)  1/158 (0.63%) 
Nervous system disorders     
Transient ischaemic attack  1  0/159 (0.00%)  1/158 (0.63%) 
Renal and urinary disorders     
Renal colic  1  0/159 (0.00%)  1/158 (0.63%) 
Skin and subcutaneous tissue disorders     
Psoriasis  1  1/159 (0.63%)  0/158 (0.00%) 
1
Term from vocabulary, MedDRA 20.1
Indicates events were collected by systematic assessment
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
BI 695501 US-licensed Humira
Affected / at Risk (%) Affected / at Risk (%)
Total   17/159 (10.69%)   24/158 (15.19%) 
General disorders     
Injection site erythema  1  5/159 (3.14%)  10/158 (6.33%) 
Injection site pain  1  3/159 (1.89%)  10/158 (6.33%) 
Infections and infestations     
Nasopharyngitis  1  12/159 (7.55%)  7/158 (4.43%) 
1
Term from vocabulary, MedDRA 20.1
Indicates events were collected by systematic assessment
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
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.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Boehringer Ingelheim, Call Centre
Organization: Boehringer Ingelheim
Phone: 1-800-243-0127
EMail: clintriage.rdg@boehringer-ingelheim.com
Layout table for additonal information
Responsible Party: Boehringer Ingelheim
ClinicalTrials.gov Identifier: NCT02850965     History of Changes
Other Study ID Numbers: 1297.12
2016-000613-79 ( EudraCT Number )
First Submitted: July 28, 2016
First Posted: August 1, 2016
Results First Submitted: January 16, 2019
Results First Posted: February 8, 2019
Last Update Posted: February 8, 2019