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Clinical Trial Results:
A Confirmatory (Phase 3) Randomized, Double-blind, Multicenter Study to Evaluate Efficacy, Safety, and Immunogenicity of M923 (a Proposed Adalimumab Biosimilar) and Humira® in Subjects with Moderate to Severe Chronic Plaque-type Psoriasis

Summary
EudraCT number	2015-001751-76
Trial protocol	SK CZ DE LV EE HU PL
Global end of trial date	04 Apr 2017

Results information
Results version number	v1(current)
This version publication date	24 Aug 2018
First version publication date	24 Aug 2018
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

911401

ISRCTN number

US NCT number

NCT02581345

WHO universal trial number (UTN)

Sponsor organisation name

Momenta Pharmaceuticals, Inc.

Sponsor organisation address

675 West Kendall Street, Cambridge, United States, 02142

Public contact

Clinical Trial Information Desk, Momenta Pharmaceuticals, Inc., clinicaltrialinformationdesk@momentapharma.com

Scientific contact

Clinical Trial Information Desk, Momenta Pharmaceuticals, Inc., clinicaltrialinformationdesk@momentapharma.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

04 Apr 2017

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

04 Apr 2017

Was the trial ended prematurely?

Main objective of the trial

The primary objective of the study was to demonstrate equivalence in measures of efficacy between M923 (test) and European Union (EU)-licensed Humira (referred to as the EU Reference Protein Product (EU RPP)) in participants with moderate to severe chronic plaque-type psoriasis.

Protection of trial subjects

This study was conducted in accordance with the protocol, the International Council for Harmonization Guideline for Good Clinical Practice E6 (ICH GCP, April 1996), Title 21 of the US Code of Federal Regulations (US CFR), the European Clinical Trial Directive (2001/20/EC and 2005/28/EC), and applicable national and local regulatory requirements. Aspects of the study concerned with the investigational medicinal product (IMP) met the requirements of EU Good Manufacturing Practice (GMP).

Background therapy

Evidence for comparator

Actual start date of recruitment

30 Sep 2015

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Slovakia: 11

Country: Number of subjects enrolled

Bulgaria: 35

Country: Number of subjects enrolled

Czech Republic: 90

Country: Number of subjects enrolled

Estonia: 58

Country: Number of subjects enrolled

Germany: 15

Country: Number of subjects enrolled

Latvia: 35

Country: Number of subjects enrolled

Poland: 180

Country: Number of subjects enrolled

Canada: 74

Country: Number of subjects enrolled

United States: 74

Worldwide total number of subjects

572

EEA total number of subjects

424

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

531

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Screening details

A total of 572 participants were enrolled and randomized equally into M923 and European Union reference protein product (EU RPP) arms. One participant in each arm did not receive any treatment. The 263 participants completing EU RPP treatment in Part 1 were randomized to 1 of 2 treatment arms in Part 2 (Transition and Continuous).

Period 1 title

Part 1: up to Week 16

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Are arms mutually exclusive

Yes

Part 1: M923

Arm description

Participants received 80 milligrams (mg) M923 (recombinant human immunoglobulin G subclass 1 [IgG1] monoclonal antibody specific for human tumor necrosis factor–alpha [TNF-α]) at Baseline (Week 0) and 40 mg every 2 weeks from Week 1 to Week 16 as a subcutaneous injection.

Arm type

Experimental

Investigational medicinal product name

M923

Investigational medicinal product code

Other name

Adalimumab

Pharmaceutical forms

Injection

Routes of administration

Subcutaneous use

Dosage and administration details

Participants received 80 milligrams (mg) M923 at Baseline (Week 0) and 40 mg every 2 weeks from Week 1 to Week 16 as a subcutaneous injection.

Part 1: EU RPP

Arm description

Participants received 80 mg European Union Reference Protein Product (EU RPP) at Baseline (Week 0) and 40 mg every 2 weeks from Week 1 to Week 16 as a subcutaneous injection.

Arm type

Active comparator

Investigational medicinal product name

EU RPP

Investigational medicinal product code

Other name

Humira, Adalimumab

Pharmaceutical forms

Injection

Routes of administration

Subcutaneous use

Dosage and administration details

Participants received 80 mg EU RPP at Baseline (Week 0) and 40 mg every 2 weeks from Week 1 to Week 16 as a subcutaneous injection.

Number of subjects in period 1	Part 1: M923	Part 1: EU RPP
Started	286	286
Completed	271	263
Not completed	15	23
Physician decision	2	4
Consent withdrawn by subject	4	7
Adverse event, non-fatal	3	8
Unspecified reason	3	3
Did not receive treatment	1	1
Lost to follow-up	2	-

Period 2 title

Part 2: Week 17 to Week 47

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Are arms mutually exclusive

Yes

Part 2: M923

Arm description

Participants who received M923 in Part 1 continued to receive 40 mg M923 every 2 weeks from Week 17 to Week 48 (last dose at Week 47) as a subcutaneous injection.

Arm type

Experimental

Investigational medicinal product name

M923

Investigational medicinal product code

Other name

Adalimumab

Pharmaceutical forms

Injection

Routes of administration

Subcutaneous use

Dosage and administration details

Participants received 40 mg M923 every 2 weeks from Week 17 to Week 48 (last dose at Week 47) as a subcutaneous injection.

Part 2: Transition EU RPP

Arm description

At Week 17, participants who received EU RPP in Part 1 transitioned from EU RPP to M923 (40 mg every 2 weeks), then to EU RPP at Week 25 (40 mg every 2 weeks), and then to M923 at Week 37 (last dose at Week 47).

Arm type

M923 and EU RPP

Investigational medicinal product name

EU RPP

Investigational medicinal product code

Other name

Humira, Adalimumab

Pharmaceutical forms

Injection

Routes of administration

Subcutaneous use

Dosage and administration details

Participants received 40 mg EU RPP every 2 weeks from Week 25 to Week 36 as a subcutaneous injection.

Investigational medicinal product name

M923

Investigational medicinal product code

Other name

Adalimumab

Pharmaceutical forms

Injection

Routes of administration

Subcutaneous use

Dosage and administration details

Participants received 40 mg M923 every 2 weeks from Week 17 to Week 24 and Week 37 to Week 48 (last dose at Week 47) as a subcutaneous injection.

Part 2: Continuous EU RPP

Arm description

Participants who received M923 in Part 1 continued to receive 40 mg M923 every 2 weeks from Week 17 to Week 48 (last dose at Week 47) as a subcutaneous injection.

Arm type

Experimental

Investigational medicinal product name

EU RPP

Investigational medicinal product code

Other name

Humira, Adalimumab

Pharmaceutical forms

Injection

Routes of administration

Subcutaneous use

Dosage and administration details

Participants received 40 mg EU RPP every 2 weeks from Week 17 to Week 48 (last dose at Week 47) as a subcutaneous injection.

Number of subjects in period 2	Part 2: M923	Part 2: Transition EU RPP	Part 2: Continuous EU RPP
Started	271	132	131
Completed	242	117	119
Not completed	29	15	12
Physician decision	3	2	1
Consent withdrawn by subject	9	7	5
Adverse event, non-fatal	5	2	2
Failure to achieve at least a PASI 50	8	3	2
Unspecified reason	2	1	1
Lost to follow-up	2	-	1

Baseline characteristics

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Reporting group title

Part 1: M923

Reporting group description

Reporting group title

Part 1: EU RPP

Reporting group description

Participants received 80 mg European Union Reference Protein Product (EU RPP) at Baseline (Week 0) and 40 mg every 2 weeks from Week 1 to Week 16 as a subcutaneous injection.

Reporting group values	Part 1: M923	Part 1: EU RPP	Total
Number of subjects	286	286	572
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	44.6 ( 12.4 )	45.5 ( 12.9 )	-
Gender categorical
Units: Subjects
Female	95	100	195
Male	191	186	377
Race (NIH/OMB)
Units: Subjects
American Indian or Alaska Native	0	1	1
Asian	2	1	3
Native Hawaiian or Other Pacific Islander	0	0	0
Black or African American	3	1	4
White	281	282	563
More than one race	0	0	0
Unknown or Not Reported	0	1	1
Number of Participants with the indicated Static Physician's Global Assessment (sPGA) Score
The sPGA is a 6-point scale ranging from 0 (clear) to 5 (very severe) used to measure the severity of disease (induration, scaling, and erythema). Analysis was conducted using the Modified Intent-to-treat (mITT) Analysis Set including all consenting subjects randomized to study treatment (Arm A or Arm B) and contributed post-baseline data for at least one efficacy endpoint.
Units: Subjects
Moderate	170	182	352
Severe	103	91	194
Very Severe	12	12	24
Missing	1	1	2
Clear	0	0	0
Almost Clear	0	0	0
Mild	0	0	0
Psoriasis Area and Severity Index (PASI) Score
The PASI measures the average redness (erythema), thickness (induration), and scaliness [each graded on a scale of 0 (no disease) to 4 (very severe)] of psoriasis lesions, weighted by the area of involvement. The total PASI score ranges from 0 to 72. The higher the total score, the more severe the disease. Analysis was conducted using the mITT Analysis Set.
Units: Units on a scale
arithmetic mean (standard deviation)	21.24 ( 9.27 )	20.16 ( 8.16 )	-

End points

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Reporting group title

Part 1: M923

Reporting group description

Reporting group title

Part 1: EU RPP

Reporting group description

Participants received 80 mg European Union Reference Protein Product (EU RPP) at Baseline (Week 0) and 40 mg every 2 weeks from Week 1 to Week 16 as a subcutaneous injection.

Reporting group title

Part 2: M923

Reporting group description

Participants who received M923 in Part 1 continued to receive 40 mg M923 every 2 weeks from Week 17 to Week 48 (last dose at Week 47) as a subcutaneous injection.

Reporting group title

Part 2: Transition EU RPP

Reporting group description

Reporting group title

Part 2: Continuous EU RPP

Reporting group description

Participants who received M923 in Part 1 continued to receive 40 mg M923 every 2 weeks from Week 17 to Week 48 (last dose at Week 47) as a subcutaneous injection.

Subject analysis set title

Part 1: M923

Subject analysis set type

Per protocol

Subject analysis set description

The Participants received 80 milligrams (mg) M923 (recombinant human immunoglobulin G subclass 1 [IgG1] monoclonal antibody specific for human tumor necrosis factor–alpha [TNF-α]) at Baseline (Week 0) and 40 mg every 2 weeks from Week 1 to Week 16 as a subcutaneous injection. The analysis was performed using Per Protocol (PP) Analysis Set defined as a subgroup of the Intent-To-Treat (ITT) Analysis Set that included all participants who did not have any deviations from the protocol deemed significant enough for exclusion from the efficacy analysis and received at least 1 dose of study drug.

Subject analysis set title

Part 1: EU RPP

Subject analysis set type

Per protocol

Subject analysis set description

Participants received 80 mg European Union Reference Protein Product (EU RPP) at Baseline (Week 0) and 40 mg every 2 weeks from Week 1 to Week 16 as a subcutaneous injection. The analysis was performed using PP Analysis Set.

Subject analysis set title

Part 2: M923

Subject analysis set type

Per protocol

Subject analysis set description

Participants who received M923 in Part 1 continued to receive 40 mg M923 every 2 weeks from Week 17 to Week 48 (last dose at Week 47) as a subcutaneous injection. The analysis was performed using PP Analysis Set.

Subject analysis set title

Part 2: Transition EU RPP

Subject analysis set type

Per protocol

Subject analysis set description

Participants who received EU RPP in Part 1 transitioned from EU RPP to M923 (40 mg every 2 weeks) at Week 17, then to EU RPP at Week 25 (40 mg every 2 weeks), and then to M923 at Week 37 (last dose at Week 47). The analysis was performed using PP Analysis Set.

Subject analysis set title

Part 2: Continuous EU RPP

Subject analysis set type

Per protocol

Subject analysis set description

Participants who received EU RPP in Part 1 continued to receive EU RPP (40 mg every 2 weeks) from Week 17 to Week 48 (last dose at Week 47). The analysis was performed using PP Analysis Set.

Subject analysis set title

Part 1: M923

Subject analysis set type

Safety analysis

Subject analysis set description

Participants received 80 mg M923 at Baseline (Week 0) and 40 mg every 2 weeks from Week 1 to Week 16 as a subcutaneous injection. The analysis was performed using Safety Analysis Set (SAS), which included all participants who received at least 1 dose of study drug.

Subject analysis set title

Part 1: EU RPP

Subject analysis set type

Safety analysis

Subject analysis set description

Subject analysis set title

Part 2: M923

Subject analysis set type

Safety analysis

Subject analysis set description

Subject analysis set title

Part 1 and Part 2: M923

Subject analysis set type

Safety analysis

Subject analysis set description

Participants received 80 mg M923 at Baseline (Week 0) and 40 mg every 2 weeks from Week 1 to Week 48 as a subcutaneous injection. The analysis was performed using SAS.

Subject analysis set title

Part 2: Transition EU RPP

Subject analysis set type

Safety analysis

Subject analysis set description

Subject analysis set title

Part 2: Continuous EU RPP

Subject analysis set type

Safety analysis

Subject analysis set description

Participants who received EU RPP in Part 1 continued to receive EU RPP (40 mg every 2 weeks) from Week 17 to Week 48 (last dose at Week 47). The analysis was performed using SAS.

Subject analysis set title

Part 1: M923

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants received 80 mg M923 at Baseline (Week 0) and 40 mg every 2 weeks from Week 1 to Week 16 as a subcutaneous injection. The analysis was performed using Pharmacokinetic (PK) Analysis Set, which included all participants who received at least 1 dose of study drug and had at least 1 measured concentration at a scheduled PK time point after start of dosing. Only participants with available data were analyzed.

Subject analysis set title

Part 1: EU RPP

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants received 80 mg EU RPP at Baseline (Week 0) and 40 mg every 2 weeks from Week 1 to Week 16 as a subcutaneous injection. The analysis was performed using PK Analysis Set.

Subject analysis set title

Part 2: M923

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

Part 2: Transition EU RPP

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants who received EU RPP in Part 1 transitioned from EU RPP to M923 (40 mg every 2 weeks) At Week 17, then to EU RPP at Week 25 (40 mg every 2 weeks), and then to M923 at Week 37 (last dose at Week 47). The analysis was performed using PK Analysis Set.

Subject analysis set title

Part 2: Continuous EU RPP

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants who received EU RPP in Part 1 continued to receive EU RPP (40 mg every 2 weeks) from Week 17 to Week 48 (last dose at Week 47). The analysis was performed using PK Analysis Set.

Primary: Percentage of Participants Who Achieved a 75% Reduction in Psoriasis Area and Severity Index (PASI) (PASI 75) Scores at Week 16

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End point title

Percentage of Participants Who Achieved a 75% Reduction in Psoriasis Area and Severity Index (PASI) (PASI 75) Scores at Week 16

End point description

The PASI combines assessments of the extent of body surface involvement in 4 anatomical regions (head, arms, trunk, and legs) and the severity of scaling, redness, and thickness in each region, yielding an overall score of 0 for no disease to 72 for the most severe disease. Each of the body areas was scored by itself, and then the 4 scores were combined into the final PASI score. Participants achieving PASI 75 are defined as having an improvement (reduction) of at least 75% in the Week 16 PASI score compared to the score at Baseline. The analysis was performed using PP Analysis Set.

End point type

Primary

End point timeframe

Baseline; Week 16

End point values	Part 1: M923	Part 1: EU RPP
Number of subjects analysed	267	271
Units: Percentage of participants
number (confidence interval 95%)	80.1 (74.9 to 84.8)	79.0 (73.6 to 83.7)

Statistical Analysis 1

Comparison groups

Part 1: M923 v Part 1: EU RPP

Number of subjects included in analysis

538

Analysis specification

Pre-specified

Analysis type

equivalence ^[1]

Method

Parameter type

Difference in proportion (M923 - EU RPP)

Point estimate

0.014

Confidence interval

level

90%

sides

2-sided

lower limit

-0.043

upper limit

0.072

Notes
[1] - Per Food and Drug Administration (FDA), the equivalence testing was made using 90% confidence interval and an equivalence margin of 18%.

Statistical Analysis 2

Comparison groups

Part 1: M923 v Part 1: EU RPP

Number of subjects included in analysis

538

Analysis specification

Pre-specified

Analysis type

equivalence ^[2]

Method

Parameter type

Difference in proportion (M923 - EU RPP)

Point estimate

0.014

Confidence interval

level

95%

sides

2-sided

lower limit

-0.054

upper limit

0.082

Notes
[2] - Per European Medicines Agency (EMA), the equivalence testing was made using 95% confidence interval and an equivalence margin of 15%.

Secondary: Percentage of Participants With a Response of Clear or Almost Clear on the Static Physician Global Assessment (sPGA) at Week 16

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End point title

Percentage of Participants With a Response of Clear or Almost Clear on the Static Physician Global Assessment (sPGA) at Week 16

End point description

The sPGA response rate was defined as the percentage of participants who had achieved a clear or almost clear response on the 6-point sPGA scale. The sPGA was the physician’s determination of the participant’s psoriasis lesions overall at a given time point. Overall lesions were categorized by descriptions for induration, erythema, and scaling. For the analysis of responses, the participant’s psoriasis was assessed at a given time point on a 6-point scale on which 0 = cleared, 1 = minimal, 2 = mild, 3 = moderate, 4 = severe, and 5 = very severe. Analysis was performed using PP Analysis Set.

End point type

Secondary

End point timeframe

Week 16

End point values	Part 1: M923	Part 1: EU RPP
Number of subjects analysed	267	271
Units: Percentage of participants
number (confidence interval 95%)	68.9 (63.0 to 74.4)	66.1 (60.1 to 71.7)

Statistical Analysis 1

Comparison groups

Part 1: M923 v Part 1: EU RPP

Number of subjects included in analysis

538

Analysis specification

Pre-specified

Analysis type

other ^[3]

Method

Parameter type

Difference in proportion (M923 - EU RPP)

Point estimate

0.031

Confidence interval

level

95%

sides

2-sided

lower limit

-0.048

upper limit

0.11

Notes
[3] - No formal hypothesis testing of equivalence was performed for the comparison between M923 and EU RPP using the secondary efficacy outcome measures. Confidence Interval for difference in proportion in original scale was calculated using stratified Newcombe method.

Secondary: Number of Participants Achieving PASI 50 Response at Week 16

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End point title

Number of Participants Achieving PASI 50 Response at Week 16

End point description

The PASI combines assessments of the extent of body surface involvement in 4 anatomical regions (head, arms, trunk, and legs) and the severity of scaling, redness, and thickness in each region, yielding an overall score of 0 for no disease to 72 for the most severe disease. Each of the body areas was scored by itself, and then the 4 scores were combined into the final PASI score. Participants achieving PASI 50 are defined as having an improvement (reduction) of at least 50% compared to Baseline. Analysis was performed using PP Analysis Set.

End point type

Secondary

End point timeframe

Baseline; Week 16

End point values	Part 1: M923	Part 1: EU RPP
Number of subjects analysed	267	271
Units: Participants	243	253

Statistical Analysis 2

Comparison groups

Part 1: M923 v Part 1: EU RPP

Number of subjects included in analysis

538

Analysis specification

Pre-specified

Analysis type

other ^[4]

Method

Parameter type

Difference in proportion (M923 - EU RPP)

Point estimate

-0.022

Confidence interval

level

95%

sides

2-sided

lower limit

-0.069

upper limit

0.024

Notes
[4] - No formal hypothesis testing of equivalence was performed for the comparison between M923 and EU RPP using the secondary efficacy outcome measures. Confidence Interval for difference in proportion in original scale calculated using stratified Newcombe method. Protocol defined margins are: [-0.15;+0.15] for 95% confidence interval.

Statistical Analysis 1

Comparison groups

Part 1: EU RPP v Part 1: M923

Number of subjects included in analysis

538

Analysis specification

Pre-specified

Analysis type

other ^[5]

Method

Parameter type

Difference in proportion (M923 - EU RPP)

Point estimate

-0.022

Confidence interval

level

90%

sides

2-sided

lower limit

-0.061

upper limit

0.016

Notes
[5] - No formal hypothesis testing of equivalence was performed for the comparison between M923 and EU RPP using the secondary efficacy outcome measures. Confidence Interval for difference in proportion in original scale calculated using stratified Newcombe method. Protocol defined margins are: [-0.18;+0.18] for 90% confidence interval.

Secondary: Number of Participants Achieving PASI 50 Response at Week 52 (Follow-Up Visit)

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End point title

Number of Participants Achieving PASI 50 Response at Week 52 (Follow-Up Visit)

End point description

The PASI combines assessments of the extent of body surface involvement in 4 anatomical regions (head, arms, trunk, and legs) and the severity of scaling, redness, and thickness in each region, yielding an overall score of 0 for no disease to 72 for the most severe disease. Each of the body areas was scored by itself, and then the 4 scores were combined into the final PASI score. Participants achieving PASI 50 are defined as having an improvement (reduction) of at least 50% compared to Baseline. Analysis was performed using PP Analysis Set. Only those participants contributing data at Week 52 were analyzed.

End point type

Secondary

End point timeframe

Baseline; Week 52

End point values	Part 2: M923	Part 2: Transition EU RPP	Part 2: Continuous EU RPP
Number of subjects analysed	258	130	129
Units: Participants	228	111	113

No statistical analyses for this end point

Secondary: Number of Participants Achieving PASI 75 Response at Week 16

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End point title

Number of Participants Achieving PASI 75 Response at Week 16

End point description

The PASI combines assessments of the extent of body surface involvement in 4 anatomical regions (head, arms, trunk, and legs) and the severity of scaling, redness, and thickness in each region, yielding an overall score of 0 for no disease to 72 for the most severe disease. Each of the body areas was scored by itself, and then the 4 scores were combined into the final PASI score. Participants achieving PASI 75 are defined as having an improvement (reduction) of at least 75% compared to Baseline. Analysis was performed using PP Analysis Set.

End point type

Secondary

End point timeframe

Baseline; Week 16

End point values	Part 1: M923	Part 1: EU RPP
Number of subjects analysed	267	271
Units: Participants	214	214

No statistical analyses for this end point

Secondary: Number of Participants Achieving PASI 75 Response at Week 52 (Follow-Up Visit)

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End point title

Number of Participants Achieving PASI 75 Response at Week 52 (Follow-Up Visit)

End point description

The PASI combines assessments of the extent of body surface involvement in 4 anatomical regions (head, arms, trunk, and legs) and the severity of scaling, redness, and thickness in each region, yielding an overall score of 0 for no disease to 72 for the most severe disease. Each of the body areas was scored by itself, and then the 4 scores were combined into the final PASI score. Participants achieving PASI 75 are defined as having an improvement (reduction) of at least 75% compared to Baseline. Analysis was performed using PP Analysis Set. Only those participants contributing data at Week 52 were analyzed.

End point type

Secondary

End point timeframe

Baseline; Week 52

End point values	Part 2: M923	Part 2: Transition EU RPP	Part 2: Continuous EU RPP
Number of subjects analysed	258	130	129
Units: Participants	202	96	101

No statistical analyses for this end point

Secondary: Number of Participants Achieving PASI 90 Response at Week 16

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End point title

Number of Participants Achieving PASI 90 Response at Week 16

End point description

The PASI combines assessments of the extent of body surface involvement in 4 anatomical regions (head, arms, trunk, and legs) and the severity of scaling, redness, and thickness in each region, yielding an overall score of 0 for no disease to 72 for the most severe disease. Each of the body areas was scored by itself, and then the 4 scores were combined into the final PASI score. Participants achieving PASI 90 are defined as having an improvement (reduction) of at least 90% compared to Baseline. Analysis was performed using PP Analysis Set.

End point type

Secondary

End point timeframe

Baseline; Week 16

End point values	Part 1: M923	Part 1: EU RPP
Number of subjects analysed	267	271
Units: Participants	165	147

Statistical Analysis 2

Comparison groups

Part 1: M923 v Part 1: EU RPP

Number of subjects included in analysis

538

Analysis specification

Pre-specified

Analysis type

other ^[6]

Method

Parameter type

Difference in proportion (M923 - EU RPP)

Point estimate

0.08

Confidence interval

level

95%

sides

2-sided

lower limit

-0.004

upper limit

0.162

Notes
[6] - No formal hypothesis testing of equivalence was performed for the comparison between M923 and EU RPP using the secondary efficacy outcome measures. Confidence Interval for difference in proportion in original scale calculated using stratified Newcombe method. Protocol defined margins are: [-0.15;+0.15] for 95% confidence interval.

Statistical Analysis 1

Comparison groups

Part 1: M923 v Part 1: EU RPP

Number of subjects included in analysis

538

Analysis specification

Pre-specified

Analysis type

other ^[7]

Method

Parameter type

Difference in proportion (M923 - EU RPP)

Point estimate

0.08

Confidence interval

level

90%

sides

2-sided

lower limit

0.01

upper limit

0.149

Notes
[7] - No formal hypothesis testing of equivalence was performed for the comparison between M923 and EU RPP using the secondary efficacy outcome measures. Confidence Interval for difference in proportion in original scale calculated using stratified Newcombe method. Protocol defined margins are: [-0.18;+0.18] for 90% confidence interval.

Secondary: Number of Participants Achieving PASI 90 Response at Week 52 (Follow-Up Visit)

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End point title

Number of Participants Achieving PASI 90 Response at Week 52 (Follow-Up Visit)

End point description

The PASI combines assessments of the extent of body surface involvement in 4 anatomical regions (head, arms, trunk, and legs) and the severity of scaling, redness, and thickness in each region, yielding an overall score of 0 for no disease to 72 for the most severe disease. Each of the body areas was scored by itself, and then the 4 scores were combined into the final PASI score. Participants achieving PASI 90 are defined as having an improvement (reduction) of at least 90% compared to Baseline. Analysis was performed using PP Analysis Set. Only those participants contributing data at Week 52 were analyzed.

End point type

Secondary

End point timeframe

Baseline; Week 52

End point values	Part 2: M923	Part 2: Transition EU RPP	Part 2: Continuous EU RPP
Number of subjects analysed	258	130	129
Units: Participants	159	71	77

No statistical analyses for this end point

Secondary: Absolute PASI Score at Baseline

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End point title

Absolute PASI Score at Baseline

End point description

The PASI combines assessments of the extent of body surface involvement in 4 anatomical regions (head, arms, trunk, and legs) and the severity of scaling, redness, and thickness in each region, yielding an overall score of 0 for no disease to 72 for the most severe disease. Each of the body areas was scored by itself, and then the 4 scores were combined into the final PASI score. Analysis was performed using PP Analysis Set including participants with evaluable data for part 1 and part 2 of the study.

End point type

Secondary

End point timeframe

Baseline

End point values	Part 1: M923	Part 1: EU RPP	Part 2: M923	Part 2: Transition EU RPP	Part 2: Continuous EU RPP
Number of subjects analysed	267	271	258	130	129
Units: Units on a scale
arithmetic mean (standard deviation)	21.34 ( 9.268 )	20.29 ( 8.266 )	21.21 ( 9.100 )	19.93 ( 8.255 )	21.00 ( 8.511 )

No statistical analyses for this end point

Secondary: Absolute PASI Score at Week 16

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End point title

Absolute PASI Score at Week 16

End point description

The PASI combines assessments of the extent of body surface involvement in 4 anatomical regions (head, arms, trunk, and legs) and the severity of scaling, redness, and thickness in each region, yielding an overall score of 0 for no disease to 72 for the most severe disease. Each of the body areas was scored by itself, and then the 4 scores were combined into the final PASI score. Analysis was performed using PP Analysis Set. Only those participants contributing data at Week 16 were analyzed.

End point type

Secondary

End point timeframe

Week 16

End point values	Part 1: M923	Part 1: EU RPP
Number of subjects analysed	261	263
Units: Units on a scale
arithmetic mean (standard deviation)	2.58 ( 4.092 )	2.50 ( 3.098 )

No statistical analyses for this end point

Secondary: Absolute PASI Score at Week 52 (Follow-Up Visit)

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End point title

Absolute PASI Score at Week 52 (Follow-Up Visit)

End point description

The PASI combines assessments of the extent of body surface involvement in 4 anatomical regions (head, arms, trunk, and legs) and the severity of scaling, redness, and thickness in each region, yielding an overall score of 0 for no disease to 72 for the most severe disease. Each of the body areas was scored by itself, and then the 4 scores were combined into the final PASI score. Analysis was performed using PP Analysis Set. Only those participants contributing data at Week 52 were analyzed.

End point type

Secondary

End point timeframe

Week 52

End point values	Part 2: M923	Part 2: Transition EU RPP	Part 2: Continuous EU RPP
Number of subjects analysed	246	120	124
Units: Units on a scale
arithmetic mean (standard deviation)	2.76 ( 4.768 )	2.85 ( 4.913 )	2.67 ( 3.919 )

No statistical analyses for this end point

Secondary: Percent Change From Baseline in PASI Score at Week 16

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End point title

Percent Change From Baseline in PASI Score at Week 16

End point description

The PASI combines assessments of the extent of body surface involvement in 4 anatomical regions (head, arms, trunk, and legs) and the severity of scaling, redness, and thickness in each region, yielding an overall score of 0 for no disease to 72 for the most severe disease. Each of the body areas was scored by itself, and then the 4 scores were combined into the final PASI score. Percent change from Baseline was calculated as: (post-Baseline value – Baseline value) / (Baseline value) * 100. Analysis was performed using PP Analysis Set. Only those participants contributing data at Week 16 were analyzed.

End point type

Secondary

End point timeframe

Baseline; Week 16

End point values	Part 1: M923	Part 1: EU RPP
Number of subjects analysed	261	263
Units: Percent change
arithmetic mean (standard deviation)	-86.21 ( 20.065 )	-86.79 ( 15.756 )

No statistical analyses for this end point

Secondary: Percent Change From Baseline in PASI Score at Week 52 (Follow-Up Visit)

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End point title

Percent Change From Baseline in PASI Score at Week 52 (Follow-Up Visit)

End point description

The PASI combines assessments of the extent of body surface involvement in 4 anatomical regions (head, arms, trunk, and legs) and the severity of scaling, redness, and thickness in each region, yielding an overall score of 0 for no disease to 72 for the most severe disease. Each of the body areas was scored by itself, and then the 4 scores were combined into the final PASI score. Percent change from Baseline was calculated as: (post-Baseline value – Baseline value) / (Baseline value) * 100. Analysis was performed using PP Analysis Set. Only those participants contributing data at Week 52 were analyzed.

End point type

Secondary

End point timeframe

Baseline; Week 52

End point values	Part 2: M923	Part 2: Transition EU RPP	Part 2: Continuous EU RPP
Number of subjects analysed	246	120	124
Units: Percent change
arithmetic mean (standard deviation)	-86.43 ( 22.570 )	-85.53 ( 21.771 )	-85.64 ( 20.968 )

No statistical analyses for this end point

Secondary: Health-Related Quality of Life During Treatment: Dermatology Life Quality Index (DLQI) Score at Baseline

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End point title

Health-Related Quality of Life During Treatment: Dermatology Life Quality Index (DLQI) Score at Baseline

End point description

The DLQI score was calculated by summing the individual scores of each question at a given time point, resulting in a maximum score of 30 and a minimum score of 0. The higher the score, the more quality of life is impaired. For the analysis of responses, the participant's results were assessed on a scoring scale on which 3 = very much or yes (applicable to question 7 only), 2 = a lot, 1 = a little, 0 = not at all or not relevant. Interpretation of DLQI scoring can be taken as 0 – 1 = no effect at all on participant's life, 2 – 5 = small effect on participant's life, 6 – 10 = moderate effect on participant's life, 11 – 20 = very large effect on participant's life, and 21 – 30 = extremely large effect on participant's life. Analysis was performed using PP Analysis Set including participants with evaluable data for part 1 and part 2 of the study.

End point type

Secondary

End point timeframe

Baseline

End point values	Part 1: M923	Part 1: EU RPP	Part 2: M923	Part 2: Transition EU RPP	Part 2: Continuous EU RPP
Number of subjects analysed	267	271	267	130	141
Units: Units on a scale
arithmetic mean (standard deviation)	12.5 ( 7.13 )	10.5 ( 6.71 )	12.5 ( 7.13 )	10.1 ( 6.57 )	10.9 ( 6.83 )

No statistical analyses for this end point

Secondary: Health-Related Quality of Life During Treatment: DLQI Score at Week 16

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End point title

Health-Related Quality of Life During Treatment: DLQI Score at Week 16

End point description

The DLQI score was calculated by summing the individual scores of each question at a given time point, resulting in a maximum score of 30 and a minimum score of 0. The higher the score, the more quality of life is impaired. For the analysis of responses, the participant's results were assessed on a scoring scale on which 3 = very much or yes (applicable to question 7 only), 2 = a lot, 1 = a little, 0 = not at all or not relevant. Interpretation of DLQI scoring can be taken as 0 – 1 = no effect at all on participant's life, 2 – 5 = small effect on participant's life, 6 – 10 = moderate effect on participant's life, 11 – 20 = very large effect on participant's life, and 21 – 30 = extremely large effect on participant's life. Analysis was performed using PP Analysis Set. Only those participants contributing data at Week 16 were analyzed.

End point type

Secondary

End point timeframe

Week 16

End point values	Part 1: M923	Part 1: EU RPP
Number of subjects analysed	258	259
Units: Units on a scale
arithmetic mean (standard deviation)	2.4 ( 4.04 )	2.1 ( 3.50 )

No statistical analyses for this end point

Secondary: Health-Related Quality of Life During Treatment: DLQI Score at Week 48 (Completion/Termination Visit)

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End point title

Health-Related Quality of Life During Treatment: DLQI Score at Week 48 (Completion/Termination Visit)

End point description

The DLQI score was calculated by summing the individual scores of each question at a given time point, resulting in a maximum score of 30 and a minimum score of 0. The higher the score, the more quality of life is impaired. For the analysis of responses, the participant's results were assessed on a scoring scale on which 3 = very much or yes (applicable to question 7 only), 2 = a lot, 1 = a little, 0 = not at all or not relevant. Interpretation of DLQI scoring can be taken as 0 – 1 = no effect at all on participant's life, 2 – 5 = small effect on participant's life, 6 – 10 = moderate effect on participant's life, 11 – 20 = very large effect on participant's life, and 21 – 30 = extremely large effect on participant's life. Analysis was performed using PP Analysis Set from Part 2 of the study. Only those participants contributing data at Week 48 were analyzed.

End point type

Secondary

End point timeframe

Week 48

End point values	Part 2: M923	Part 2: Transition EU RPP	Part 2: Continuous EU RPP
Number of subjects analysed	232	115	117
Units: Units on a scale
arithmetic mean (standard deviation)	2.1 ( 3.77 )	1.6 ( 2.83 )	2.1 ( 3.97 )

No statistical analyses for this end point

Secondary: Health-Related Quality of Life During Treatment: EuroQoL 5-Dimension Health Status Questionnaire (EQ-5D-5L) at Baseline

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End point title

Health-Related Quality of Life During Treatment: EuroQoL 5-Dimension Health Status Questionnaire (EQ-5D-5L) at Baseline

End point description

The EQ-5D-5L health score was measured on a Visual Analog Scale (VAS) anchored by 0 = "worst health you can imagine" and 100 = "best health you can imagine". Baseline was defined as the last scheduled observation prior to dosing, typically Day 1, predose. Analysis was performed using PP Analysis Set including participants with evaluable data for part 1 and part 2 of the study.

End point type

Secondary

End point timeframe

Baseline

End point values	Part 1: M923	Part 1: EU RPP	Part 2: M923	Part 2: Transition EU RPP	Part 2: Continuous EU RPP
Number of subjects analysed	267	271	258	130	129
Units: Units on a scale
arithmetic mean (standard deviation)	71.3 ( 18.70 )	72.5 ( 20.27 )	71.4 ( 18.71 )	71.2 ( 20.43 )	73.5 ( 19.84 )

No statistical analyses for this end point

Secondary: Health-Related Quality of Life During Treatment: EQ-5D-5L at Week 16

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End point title

Health-Related Quality of Life During Treatment: EQ-5D-5L at Week 16

End point description

The EQ-5D-5L health score was measured on a Visual Analog Scale (VAS) anchored by 0 = "worst health you can imagine" and 100 = "best health you can imagine". Analysis was performed using PP Analysis Set. Only those participants contributing data at Week 16 were analyzed.

End point type

Secondary

End point timeframe

Week 16

End point values	Part 1: M923	Part 1: EU RPP	Part 2: M923	Part 2: Transition EU RPP	Part 2: Continuous EU RPP
Number of subjects analysed	258	259	257	130	129
Units: Units on a scale
arithmetic mean (standard deviation)	83.7 ( 12.38 )	83.4 ( 13.92 )	83.8 ( 12.22 )	82.7 ( 14.85 )	84.1 ( 12.94 )

No statistical analyses for this end point

Secondary: Health-Related Quality of Life During Treatment: EQ-5D-5L at Week 48 (Completion/Termination Visit)

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End point title

Health-Related Quality of Life During Treatment: EQ-5D-5L at Week 48 (Completion/Termination Visit)

End point description

End point type

Secondary

End point timeframe

Week 48

End point values	Part 2: M923	Part 2: Transition EU RPP	Part 2: Continuous EU RPP
Number of subjects analysed	232	115	117
Units: Units on a scale
arithmetic mean (standard deviation)	85.3 ( 13.83 )	83.9 ( 14.92 )	84.2 ( 12.98 )

No statistical analyses for this end point

Secondary: Number of Participants With Clinically Meaningful Changes in Vital Signs

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End point title

Number of Participants With Clinically Meaningful Changes in Vital Signs

End point description

Vital signs included body temperature, respiratory rate, pulse rate, systolic and diastolic blood pressure, and weight. Clinically meaningful changes were classified as such by the Investigator and reported as adverse events. The analysis was performed using SAS.

End point type

Secondary

End point timeframe

Up to Week 52

End point values	Part 1: M923	Part 1: EU RPP	Part 2: M923	Part 2: Transition EU RPP	Part 2: Continuous EU RPP
Number of subjects analysed	285	285	271	132	131
Units: Participants	0	0	0	0	0

No statistical analyses for this end point

Secondary: Number of Participants With Clinically Meaningful Changes in Laboratory Results at Baseline

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End point title

Number of Participants With Clinically Meaningful Changes in Laboratory Results at Baseline

End point description

Laboratory results included hematology [Hemoglobin, Hematocrit, Platelet count, Mean cell volume, White blood cell count (total leucocytes), Neutrophils absolute, Neutrophils, Lymphocytes absolute, Lymphocytes, Monocytes, Eosinophils absolute, and Eosinophils], chemistry (Aspartate transaminase, Alanine transaminase, Gamma glutamyl transferase, Creatine kinase, C-reactive protein, Cholesterol, Triglycerides, Total protein, Potassium, Urea, Creatinine, Phosphate, Glucose, and Uric acid) and urinalysis [Specific Gravity] parameters. Laboratory results of a few hematology (Red Blood Cell Count and Monocytes absolute), chemistry (Alkaline Phosphatase, Total bilirubin, Sodium, Chloride, and Albumin), and urinalysis (pH) parameters were not assessed at Baseline and Week 16. Clinically meaningful changes were classified as such by the Investigator and reported as adverse events.

End point type

Secondary

End point timeframe

Baseline

End point values	Part 1: M923	Part 1: EU RPP
Number of subjects analysed	285	285
Units: Participants
Hemoglobin	0	0
Hematocrit	0	0
Platelet count	0	0
Mean cell volume	0	0
White blood cell count (total leucocytes)	1	1
Neutrophils absolute	2	1
Neutrophils	1	0
Lymphocytes absolute	1	1
Lymphocytes	1	1
Monocytes	0	0
Eosinophils absolute	0	0
Eosinophils	0	0
Aspartate transaminase	0	0
Alanine transaminase	1	1
Gamma glutamyl transferase	1	4
Creatine kinase	2	0
C-reactive protein	6	2
Cholesterol	2	4
Triglycerides	3	2
Total protein	0	1
Potassium	1	0
Urea	1	0
Creatinine	0	0
Phosphate	0	0
Glucose	1	2
Uric acid	2	0
Specific Gravity	0	0

No statistical analyses for this end point

Secondary: Number of Participants With Clinically Meaningful Changes in Laboratory Results at Week 16

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End point title

Number of Participants With Clinically Meaningful Changes in Laboratory Results at Week 16

End point description

End point type

Secondary

End point timeframe

Week 16

End point values	Part 1: M923	Part 1: EU RPP
Number of subjects analysed	285	285
Units: Participants
Hemoglobin	1	1
Hematocrit	1	1
Platelet count	0	0
Mean cell volume	0	1
White blood cell count (total leucocytes)	2	0
Neutrophils absolute	1	0
Neutrophils	0	0
Lymphocytes absolute	0	1
Lymphocytes	0	1
Monocytes	0	0
Eosinophils absolute	1	0
Eosinophils	1	0
Aspartate transaminase	2	0
Alanine transaminase	3	1
Gamma glutamyl transferase	3	2
Creatine kinase	2	0
C-reactive protein	1	0
Cholesterol	4	3
Triglycerides	5	3
Total protein	0	1
Potassium	1	0
Urea	0	0
Creatinine	0	0
Phosphate	0	0
Glucose	2	3
Uric acid	1	1
Specific Gravity	0	0

No statistical analyses for this end point

Secondary: Number of Participants With Clinically Meaningful Changes in Laboratory Results at Week 48 (Completion/Termination Visit)

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End point title

Number of Participants With Clinically Meaningful Changes in Laboratory Results at Week 48 (Completion/Termination Visit)

End point description

Laboratory results included hematology [Red Blood Cell Count, Hemoglobin, Hematocrit, Platelet count, Mean cell volume, White blood cell count (total leucocytes), Neutrophils absolute, Neutrophils, Lymphocytes absolute, Lymphocytes, Monocytes absolute, Monocytes, Eosinophils absolute, and Eosinophils], chemistry (Aspartate transaminase, Alanine transaminase, Alkaline Phosphatase, Gamma glutamyl transferase, Total bilirubin, Creatine kinase, C-reactive protein, Cholesterol, Triglycerides, Total protein, Sodium, Potassium, Chloride, Urea, Creatinine, Albumin, Phosphate, Glucose, and Uric acid) and urinalysis [pH and Specific Gravity] parameters. Clinically meaningful changes were classified as such by the Investigator and reported as adverse events.

End point type

Secondary

End point timeframe

Week 48

End point values	Part 2: M923	Part 2: Transition EU RPP	Part 2: Continuous EU RPP
Number of subjects analysed	271	132	131
Units: Participants
Red Blood Cell Count	1	0	1
Hemoglobin	1	0	1
Hematocrit	1	0	1
Platelet count	1	0	0
Mean cell volume	0	0	1
White blood cell count (total leucocytes)	2	1	1
Neutrophils absolute	3	1	2
Neutrophils	3	0	0
Lymphocytes absolute	0	0	1
Lymphocytes	1	0	0
Monocytes absolute	0	0	0
Monocytes	1	0	0
Eosinophils absolute	0	0	0
Eosinophils	2	0	0
Aspartate transaminase	2	0	1
Alanine transaminase	5	0	3
Alkaline Phosphatase	0	0	0
Gamma glutamyl transferase	3	0	3
Total bilirubin	1	0	1
Creatine kinase	0	1	1
C-reactive protein	3	0	0
Cholesterol	7	3	2
Triglycerides	11	4	2
Total protein	0	0	0
Sodium	0	0	0
Potassium	0	0	0
Chloride	0	0	0
Urea	0	0	0
Creatinine	0	0	0
Albumin	0	0	0
Phosphate	0	0	0
Glucose	5	3	0
Uric acid	1	3	3
pH	1	1	0
Specific Gravity	0	0	0

No statistical analyses for this end point

Secondary: Number of Participants With Clinically Significant Abnormalities in Electrocardiogram Parameters at Baseline

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End point title

Number of Participants With Clinically Significant Abnormalities in Electrocardiogram Parameters at Baseline

End point description

Clinically significant abnormalities were classified as such by the Investigator and reported as adverse events. The analysis was performed using SAS.

End point type

Secondary

End point timeframe

Baseline

End point values	Part 1: M923	Part 1: EU RPP
Number of subjects analysed	285	285
Units: Participants	0	0

No statistical analyses for this end point

Secondary: Number of Participants With Clinically Significant Abnormalities in Electrocardiogram Parameters at Week 16

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End point title

Number of Participants With Clinically Significant Abnormalities in Electrocardiogram Parameters at Week 16

End point description

Clinically significant abnormalities were classified as such by the Investigator and reported as adverse events. The analysis was performed using SAS.

End point type

Secondary

End point timeframe

Week 16

End point values	Part 1: M923	Part 1: EU RPP
Number of subjects analysed	285	285
Units: Participants	2	0

No statistical analyses for this end point

Secondary: Number of Participants With Clinically Significant Abnormalities in Electrocardiogram Parameters at Week 48 (Completion/Termination Visit)

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End point title

Number of Participants With Clinically Significant Abnormalities in Electrocardiogram Parameters at Week 48 (Completion/Termination Visit)

End point description

Clinically significant abnormalities were classified as such by the Investigator and reported as adverse events. The analysis was performed using SAS.

End point type

Secondary

End point timeframe

Week 48

End point values	Part 2: M923	Part 2: Transition EU RPP	Part 2: Continuous EU RPP
Number of subjects analysed	271	132	131
Units: Participants	3	0	0

No statistical analyses for this end point

Secondary: Number of participants with Treatment-emergent Adverse Events (TEAEs)

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End point title

Number of participants with Treatment-emergent Adverse Events (TEAEs)

End point description

TEAEs are adverse events that occurred during or after study drug administration. For more details on adverse events please refer the safety section. Analysis was performed using SAS.

End point type

Secondary

End point timeframe

From first administration of study drug until study completion or discontinuation i.e. up to approximately 52 weeks

End point values	Part 1: M923	Part 1: EU RPP	Part 2: M923	Part 2: Transition EU RPP	Part 2: Continuous EU RPP
Number of subjects analysed	285	285	271	132	131
Units: Participants	169	194	199	99	103

No statistical analyses for this end point

Secondary: Pharmacokinetics: Serum Concentrations by Treatment

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End point title

Pharmacokinetics: Serum Concentrations by Treatment

End point description

Serum samples were collected at Baseline (Week 0, perdose), approximately 1 week (peak) after IP administration (Weeks 8 and 16), and 2 weeks after dose administration as a trough sample collected prior to the next dose administration (Weeks 17, 21, 25, 29, 37, 41).

End point type

Secondary

End point timeframe

Baseline (Week 0), Week 8, 16, 17, 21, 25, 29, 37, and 41

End point values	Part 1: M923	Part 1: EU RPP	Part 2: M923	Part 2: Transition EU RPP	Part 2: Continuous EU RPP
Number of subjects analysed	282	281	282	149	132
Units: nanograms per milliter (ng/mL)
arithmetic mean (standard deviation)
Baseline (Week 0)/Predose; n = 279, 279, 0, 0, 0	302 ( 16.5 )	301 ( 9.69 )	0 ( 0 )	0 ( 0 )	0 ( 0 )
Week 8/Peak; n = 277, 272, 0, 0, 0	9100 ( 5450 )	7640 ( 4370 )	0 ( 0 )	0 ( 0 )	0 ( 0 )
Week 16/Peak; n = 268, 261, 0, 0, 0	8580 ( 5700 )	6990 ( 5100 )	0 ( 0 )	0 ( 0 )	0 ( 0 )
Week 17/Trough; n = 0, 0, 267, 130, 129	0 ( 0 )	0 ( 0 )	6900 ( 5270 )	5340 ( 4050 )	5840 ( 4840 )
Week 21/Trough; n = 0, 0, 257, 127, 130	0 ( 0 )	0 ( 0 )	6630 ( 4960 )	5100 ( 4040 )	6260 ( 4960 )
Week 25/Trough; 0, 0, 252, 126, 127	0 ( 0 )	0 ( 0 )	6790 ( 5210 )	4970 ( 3870 )	6320 ( 5260 )
Week 29/Trough; n = 0, 0, 248, 125, 124	0 ( 0 )	0 ( 0 )	5990 ( 4020 )	4840 ( 3480 )	5330 ( 4000 )
Week 37/Trough; n = 0, 0, 245, 121, 120	0 ( 0 )	0 ( 0 )	6120 ( 4220 )	4830 ( 3680 )	5250 ( 4190 )
Week 41/Trough; n = 0, 0, 241, 119, 117	0 ( 0 )	0 ( 0 )	5950 ( 4230 )	4740 ( 3710 )	5480 ( 4140 )

No statistical analyses for this end point

Secondary: Immunogenicity: Number of Participants With Anti-Drug Antibodies (ADA) at Baseline

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End point title

Immunogenicity: Number of Participants With Anti-Drug Antibodies (ADA) at Baseline

End point description

The M923 confirmation assay was evaluated only if the EU Humira confirmation assay was negative. Overall Result: a participant was considered to be positive if a confirmed positive result was observed at any assay (including predose; if a participant had either a negative result in the screening assay or a positive result at screening followed by a negative result in all confirmation tiers, the overall result was negative. Overall Status: a participant was considered to have developed ADA or neutralizing ADAs if a confirmed positive result was observed at any time during the treatment period inclusive of the predose results; the designation of negative required either a negative screening assay or a negative confirmation result at each sampling time. The same convention applied for the neutralizing assay results. The analysis was performed using SAS.

End point type

Secondary

End point timeframe

Baseline

End point values	Part 1: M923	Part 1: EU RPP
Number of subjects analysed	285	285
Units: Participants
EU Humera	15	11
M923	1	2
Overall Results	16	13
Neutralizing ADA	4	2

No statistical analyses for this end point

Secondary: Immunogenicity: Number of Participants With ADA at Week 16

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End point title

Immunogenicity: Number of Participants With ADA at Week 16

End point description

End point type

Secondary

End point timeframe

Week 16

End point values	Part 1: M923	Part 1: EU RPP
Number of subjects analysed	285	285
Units: Participants
EU Humera	135	144
M923	4	8
Overall Results	139	152
Neutralizing ADA	28	30

No statistical analyses for this end point

Secondary: Immunogenicity: Number of Participants With ADA at Week 25

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End point title

Immunogenicity: Number of Participants With ADA at Week 25

End point description

End point type

Secondary

End point timeframe

Week 25

End point values	Part 2: M923	Part 2: Transition EU RPP	Part 2: Continuous EU RPP
Number of subjects analysed	271	132	131
Units: Participants
EU Humera	144	80	92
M923	12	5	5
Overall result	156	85	97
Neutralizing ADA	55	25	32

No statistical analyses for this end point

Secondary: Immunogenicity: Number of Participants With ADA at Week 52 (Completion/Termination Visit)

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End point title

Immunogenicity: Number of Participants With ADA at Week 52 (Completion/Termination Visit)

End point description

End point type

Secondary

End point timeframe

Week 52

End point values	Part 2: M923	Part 2: Transition EU RPP	Part 2: Continuous EU RPP
Number of subjects analysed	271	132	131
Units: Participants
EU Humera	131	73	80
M923	10	6	7
Overall result	141	79	87
Neutralizing ADA	40	28	23

No statistical analyses for this end point

Secondary: Immunogenicity: Number of Participants With ADA and nADA by Titer at Baseline

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End point title

Immunogenicity: Number of Participants With ADA and nADA by Titer at Baseline

End point description

The M923 confirmation assay was evaluated only if the EU Humira confirmation assay was negative. Overall Result: a participant was considered to be positive if a confirmed positive result was observed at any assay (including predose); if a participant had either a negative result in the screening assay or a positive result at screening followed by a negative result in all confirmation tiers, the overall result was negative. Overall Status: a participant was considered to have developed ADA or neutralizing ADAs if a confirmed positive result was observed at any time during the treatment period inclusive of the predose results; the designation of negative required either a negative screening assay or a negative confirmation result at each sampling time. In confirmed positive samples, an assay was used to determine the relative titer of the ADA; a subsequent neutralizing antibodies assay was used to determine the presence of neutralizing antibodies. The analysis was performed using SAS.

End point type

Secondary

End point timeframe

Baseline (Week 0)

End point values	Part 1: M923	Part 1: EU RPP
Number of subjects analysed	285	285
Units: Participants
No positive result	266	271
Predose positive result	16	13

No statistical analyses for this end point

Secondary: Immunogenicity: Number of Participants With ADA and nADA by Titer at Week 16

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End point title

Immunogenicity: Number of Participants With ADA and nADA by Titer at Week 16

End point description

The M923 confirmation assay was evaluated only if the EU Humira confirmation assay was negative. Overall Result: a participant was considered to be positive if a confirmed positive result was observed at any assay (including predose); if a participant had either a negative result in the screening assay or a positive result at screening followed by a negative result in all confirmation tiers, the overall result was negative. Overall Status: a participant was considered to have developed ADA or neutralizing ADAs if a confirmed positive result was observed at any time during the treatment period inclusive of the predose results; the designation of negative required either a negative screening assay or a negative confirmation result at each sampling time. In confirmed positive samples, an assay was used to determine the relative titer of the ADA; a subsequent neutralizing antibodies assay was used to determine the presence of neutralizing antibodies. The analysis was performed using SAS.

End point type

Secondary

End point timeframe

Week 16

End point values	Part 1: M923	Part 1: EU RPP
Number of subjects analysed	285	285
Units: Participants
Titers ≤ 1:16 (postdose positive ADAs)	16	26
Titers ≤ 1:16 (postdose positive nADAs)	2	2
Titers > 1:16 to ≤ 1:128 (postdose positive ADAs)	90	73
Titers > 1:16 to ≤ 1:128 (postdose positive nADAs)	17	6
Titers >1:128 to ≤ 1:152 (postdose positive ADAs)	27	40
Titers >1:128 to ≤ 1:152 (postdose positive nADAs)	3	11
Titers >1:152 (postdose positive ADAs)	6	13
Titers >1:152 (postdose positive nADAs)	6	11

No statistical analyses for this end point

Secondary: Immunogenicity: Number of Participants With ADA and nADA by Titer at Week 25

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End point title

Immunogenicity: Number of Participants With ADA and nADA by Titer at Week 25

End point description

The M923 confirmation assay was evaluated only if the EU Humira confirmation assay was negative. Overall Result: a participant was considered to be positive if a confirmed positive result was observed at any assay (including predose); if a participant had either a negative result in the screening assay or a positive result at screening followed by a negative result in all confirmation tiers, the overall result was negative. Overall Status: a participant was considered to have developed ADA or neutralizing ADAs if a confirmed positive result was observed at any time during the treatment period inclusive of the predose results; the designation of negative required either a negative screening assay or a negative confirmation result at each sampling time. In confirmed positive samples, an assay was used to determine the relative titer of the ADA; a subsequent neutralizing antibodies assay was used to determine the presence of neutralizing antibodies. The analysis was performed using SAS.

End point type

Secondary

End point timeframe

Week 25

End point values	Part 1 and Part 2: M923	Part 2: Transition EU RPP	Part 2: Continuous EU RPP
Number of subjects analysed	285	132	131
Units: Participants
Titers ≤ 1:16 (postdose positive ADAs)	24	19	21
Titers ≤ 1:16 (postdose positive nADAs)	6	2	4
Titers > 1:16 to ≤ 1:128 (postdose positive ADAs)	86	37	42
Titers > 1:16 to ≤ 1:128 (postdose positive nADAs)	17	4	7
Titers >1:128 to ≤ 1:152 (postdose positive ADAs)	28	14	22
Titers >1:128 to ≤ 1:152 (postdose positive nADAs)	16	6	10
Titers >1:152 (postdose positive ADAs)	18	15	12
Titers >1:152 (postdose positive nADAs)	16	13	11

No statistical analyses for this end point

Secondary: Immunogenicity: Number of Participants With ADA and nADA by Titer at Week 52 (Completion/Termination Visit)

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End point title

Immunogenicity: Number of Participants With ADA and nADA by Titer at Week 52 (Completion/Termination Visit)

End point description

The M923 confirmation assay was evaluated only if the EU Humira confirmation assay was negative. Overall Result: a participant was considered to be positive if a confirmed positive result was observed at any assay (including predose); if a participant had either a negative result in the screening assay or a positive result at screening followed by a negative result in all confirmation tiers, the overall result was negative. Overall Status: a participant was considered to have developed ADA or neutralizing ADAs if a confirmed positive result was observed at any time during the treatment period inclusive of the predose results; the designation of negative required either a negative screening assay or a negative confirmation result at each sampling time. In confirmed positive samples, an assay was used to determine the relative titer of the ADA; a subsequent neutralizing antibodies assay was used to determine the presence of neutralizing antibodies. The analysis was performed using SAS.

End point type

Secondary

End point timeframe

Week 52

End point values	Part 1 and Part 2: M923	Part 2: Transition EU RPP	Part 2: Continuous EU RPP
Number of subjects analysed	285	132	131
Units: Participants
Titers ≤ 1:16 (postdose positive ADAs)	26	11	17
Titers ≤ 1:16 (postdose positive nADAs)	0	2	3
Titers > 1:16 to ≤ 1:128 (postdose positive ADAs)	62	37	38
Titers > 1:16 to ≤ 1:128 (postdose positive nADAs)	13	6	5
Titers >1:128 to ≤ 1:152 (postdose positive ADAs)	23	12	15
Titers >1:128 to ≤ 1:152 (postdose positive nADAs)	9	6	2
Titers >1:152 (postdose positive ADAs)	13	7	10
Titers >1:152 (postdose positive nADAs)	11	6	7

No statistical analyses for this end point

Secondary: Median Time to Seroconversion

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End point title

Median Time to Seroconversion

End point description

Time to seroconversion (in days) was defined as the time to the observation of the first confirmed positive ADA response. Participants with confirmed positive ADA response at baseline (Week 0 predose) were excluded. The analysis was performed using SAS. Only those participants who had a postdose seroconversion time were analyzed.

End point type

Secondary

End point timeframe

Up to Week 52

End point values	Part 1 and Part 2: M923	Part 2: Transition EU RPP	Part 2: Continuous EU RPP
Number of subjects analysed	216	120	106
Units: Days
median (full range (min-max))	113 (52 to 372)	113 (51 to 375)	112 (54 to 373)

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Up to Week 52

Adverse event reporting additional description

Adverse events were collected in members of the Safety Analysis Set (SAS), comprised of all participants who received at least 1 dose of study drug (M923 or European Union reference protein product [EU RPP]).

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

19.0

Reporting group title

Part 1: M923

Reporting group description

Reporting group title

Part 2: M923

Reporting group description

Participants who received M923 in Part 1 continued to receive 40 mg M923 every 2 weeks from Week 17 to Week 48 (last dose at Week 47) as a subcutaneous injection.

Reporting group title

Part 2: Transition EU RRP

Reporting group description

Reporting group title

Part 1: EU RPP

Reporting group description

Participants received 80 mg European Union Reference Protein Product (EU RPP) at Baseline (Week 0) and 40 mg every 2 weeks from Week 1 to Week 16 as a subcutaneous injection.

Reporting group title

Part 2: Continuous EU RRP

Reporting group description

Participants who received EU RPP in Part 1 continued to receive EU RPP (40 mg every 2 weeks) from Week 17 to Week 48 (last dose at Week 47).

Serious adverse events	Part 1: M923	Part 2: M923	Part 2: Transition EU RRP	Part 1: EU RPP	Part 2: Continuous EU RRP
Total subjects affected by serious adverse events
subjects affected / exposed	4 / 285 (1.40%)	10 / 271 (3.69%)	10 / 132 (7.58%)	7 / 285 (2.46%)	8 / 131 (6.11%)
number of deaths (all causes)	0	0	0	0	0
number of deaths resulting from adverse events	0	0	0	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Benign ovarian tumour
subjects affected / exposed	0 / 285 (0.00%)	1 / 271 (0.37%)	0 / 132 (0.00%)	0 / 285 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bladder papilloma
subjects affected / exposed	1 / 285 (0.35%)	0 / 271 (0.00%)	0 / 132 (0.00%)	0 / 285 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bladder transitional cell carcinoma
subjects affected / exposed	1 / 285 (0.35%)	0 / 271 (0.00%)	0 / 132 (0.00%)	0 / 285 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastric adenoma
subjects affected / exposed	1 / 285 (0.35%)	0 / 271 (0.00%)	0 / 132 (0.00%)	0 / 285 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Meningioma
subjects affected / exposed	0 / 285 (0.00%)	1 / 271 (0.37%)	0 / 132 (0.00%)	0 / 285 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nodular melanoma
subjects affected / exposed	0 / 285 (0.00%)	0 / 271 (0.00%)	1 / 132 (0.76%)	0 / 285 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Arteriosclerosis
subjects affected / exposed	0 / 285 (0.00%)	1 / 271 (0.37%)	0 / 132 (0.00%)	0 / 285 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypertension
subjects affected / exposed	1 / 285 (0.35%)	0 / 271 (0.00%)	0 / 132 (0.00%)	0 / 285 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Peripheral vascular disorder
subjects affected / exposed	0 / 285 (0.00%)	1 / 271 (0.37%)	0 / 132 (0.00%)	0 / 285 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Non-cardiac chest pain
subjects affected / exposed	0 / 285 (0.00%)	0 / 271 (0.00%)	0 / 132 (0.00%)	1 / 285 (0.35%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Immune system disorders
Hypersensitivity
subjects affected / exposed	0 / 285 (0.00%)	0 / 271 (0.00%)	0 / 132 (0.00%)	0 / 285 (0.00%)	1 / 131 (0.76%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Cervical dysplasia
subjects affected / exposed	0 / 285 (0.00%)	0 / 271 (0.00%)	1 / 132 (0.76%)	0 / 285 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Endometrial hyperplasia
subjects affected / exposed	0 / 285 (0.00%)	1 / 271 (0.37%)	0 / 132 (0.00%)	0 / 285 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Genital prolapse
subjects affected / exposed	0 / 285 (0.00%)	1 / 271 (0.37%)	0 / 132 (0.00%)	0 / 285 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Nasal septum deviation
subjects affected / exposed	0 / 285 (0.00%)	0 / 271 (0.00%)	0 / 132 (0.00%)	1 / 285 (0.35%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Suicide attempt
subjects affected / exposed	0 / 285 (0.00%)	1 / 271 (0.37%)	0 / 132 (0.00%)	0 / 285 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Product issues
Device loosening
subjects affected / exposed	0 / 285 (0.00%)	1 / 271 (0.37%)	0 / 132 (0.00%)	0 / 285 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Blood creatine phosphokinase increased
subjects affected / exposed	1 / 285 (0.35%)	0 / 271 (0.00%)	0 / 132 (0.00%)	0 / 285 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ejection fraction decreased
subjects affected / exposed	0 / 285 (0.00%)	0 / 271 (0.00%)	0 / 132 (0.00%)	0 / 285 (0.00%)	1 / 131 (0.76%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 2	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Brain contusion
subjects affected / exposed	0 / 285 (0.00%)	0 / 271 (0.00%)	0 / 132 (0.00%)	1 / 285 (0.35%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Facial bones fracture
subjects affected / exposed	0 / 285 (0.00%)	0 / 271 (0.00%)	1 / 132 (0.76%)	0 / 285 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hip fracture
subjects affected / exposed	0 / 285 (0.00%)	0 / 271 (0.00%)	0 / 132 (0.00%)	0 / 285 (0.00%)	1 / 131 (0.76%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Joint injury
subjects affected / exposed	1 / 285 (0.35%)	0 / 271 (0.00%)	0 / 132 (0.00%)	0 / 285 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lumbar vertebral fracture
subjects affected / exposed	0 / 285 (0.00%)	0 / 271 (0.00%)	0 / 132 (0.00%)	1 / 285 (0.35%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Meniscus injury
subjects affected / exposed	0 / 285 (0.00%)	0 / 271 (0.00%)	1 / 132 (0.76%)	0 / 285 (0.00%)	1 / 131 (0.76%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skull fractured base
subjects affected / exposed	0 / 285 (0.00%)	0 / 271 (0.00%)	0 / 132 (0.00%)	1 / 285 (0.35%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Acute myocardial infarction
subjects affected / exposed	0 / 285 (0.00%)	0 / 271 (0.00%)	0 / 132 (0.00%)	1 / 285 (0.35%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Angina pectoris
subjects affected / exposed	0 / 285 (0.00%)	1 / 271 (0.37%)	0 / 132 (0.00%)	0 / 285 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac failure
subjects affected / exposed	0 / 285 (0.00%)	1 / 271 (0.37%)	0 / 132 (0.00%)	0 / 285 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiomyopathy
subjects affected / exposed	0 / 285 (0.00%)	1 / 271 (0.37%)	0 / 132 (0.00%)	0 / 285 (0.00%)	1 / 131 (0.76%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 2	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypertensive cardiomyopathy
subjects affected / exposed	0 / 285 (0.00%)	1 / 271 (0.37%)	0 / 132 (0.00%)	0 / 285 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Left ventricular failure
subjects affected / exposed	0 / 285 (0.00%)	0 / 271 (0.00%)	0 / 132 (0.00%)	0 / 285 (0.00%)	1 / 131 (0.76%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 2	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Myocardial ischaemia
subjects affected / exposed	0 / 285 (0.00%)	0 / 271 (0.00%)	0 / 132 (0.00%)	1 / 285 (0.35%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Supraventricular tachycardia
subjects affected / exposed	0 / 285 (0.00%)	1 / 271 (0.37%)	0 / 132 (0.00%)	0 / 285 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Cerebral haemorrhage
subjects affected / exposed	0 / 285 (0.00%)	0 / 271 (0.00%)	0 / 132 (0.00%)	1 / 285 (0.35%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cervical myelopathy
subjects affected / exposed	0 / 285 (0.00%)	0 / 271 (0.00%)	1 / 132 (0.76%)	0 / 285 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Epilepsy
subjects affected / exposed	0 / 285 (0.00%)	0 / 271 (0.00%)	0 / 132 (0.00%)	1 / 285 (0.35%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Headache
subjects affected / exposed	0 / 285 (0.00%)	0 / 271 (0.00%)	1 / 132 (0.76%)	0 / 285 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Syncope
subjects affected / exposed	0 / 285 (0.00%)	1 / 271 (0.37%)	0 / 132 (0.00%)	0 / 285 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	1 / 285 (0.35%)	0 / 271 (0.00%)	0 / 132 (0.00%)	0 / 285 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Drug-induced liver injury
subjects affected / exposed	0 / 285 (0.00%)	0 / 271 (0.00%)	0 / 132 (0.00%)	0 / 285 (0.00%)	1 / 131 (0.76%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 2	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Pruritus
subjects affected / exposed	0 / 285 (0.00%)	0 / 271 (0.00%)	0 / 132 (0.00%)	1 / 285 (0.35%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	1 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pustular psoriasis
subjects affected / exposed	0 / 285 (0.00%)	0 / 271 (0.00%)	0 / 132 (0.00%)	1 / 285 (0.35%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	1 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rash
subjects affected / exposed	0 / 285 (0.00%)	0 / 271 (0.00%)	0 / 132 (0.00%)	1 / 285 (0.35%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	1 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rash generalised
subjects affected / exposed	0 / 285 (0.00%)	0 / 271 (0.00%)	1 / 132 (0.76%)	0 / 285 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	0 / 285 (0.00%)	0 / 271 (0.00%)	0 / 132 (0.00%)	1 / 285 (0.35%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ureterolithiasis
subjects affected / exposed	0 / 285 (0.00%)	0 / 271 (0.00%)	0 / 132 (0.00%)	0 / 285 (0.00%)	1 / 131 (0.76%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Intervertebral disc protrusion
subjects affected / exposed	0 / 285 (0.00%)	0 / 271 (0.00%)	1 / 132 (0.76%)	0 / 285 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Synovitis
subjects affected / exposed	0 / 285 (0.00%)	0 / 271 (0.00%)	1 / 132 (0.76%)	0 / 285 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Appendicitis
subjects affected / exposed	0 / 285 (0.00%)	1 / 271 (0.37%)	0 / 132 (0.00%)	0 / 285 (0.00%)	1 / 131 (0.76%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Peritonitis bacterial
subjects affected / exposed	0 / 285 (0.00%)	0 / 271 (0.00%)	1 / 132 (0.76%)	0 / 285 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Peritonsillar abscess
subjects affected / exposed	0 / 285 (0.00%)	0 / 271 (0.00%)	0 / 132 (0.00%)	0 / 285 (0.00%)	1 / 131 (0.76%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pyelonephritis
subjects affected / exposed	0 / 285 (0.00%)	0 / 271 (0.00%)	1 / 132 (0.76%)	0 / 285 (0.00%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Part 1: M923	Part 2: M923	Part 2: Transition EU RRP	Part 1: EU RPP	Part 2: Continuous EU RRP
Total subjects affected by non serious adverse events
subjects affected / exposed	92 / 285 (32.28%)	96 / 271 (35.42%)	47 / 132 (35.61%)	104 / 285 (36.49%)	63 / 131 (48.09%)
Nervous system disorders
Headache
subjects affected / exposed	9 / 285 (3.16%)	2 / 271 (0.74%)	7 / 132 (5.30%)	10 / 285 (3.51%)	5 / 131 (3.82%)
occurrences all number	11	7	11	13	5
General disorders and administration site conditions
Injection site reaction
subjects affected / exposed	68 / 285 (23.86%)	27 / 271 (9.96%)	15 / 132 (11.36%)	79 / 285 (27.72%)	19 / 131 (14.50%)
occurrences all number	256	116	79	261	70
Skin and subcutaneous tissue disorders
Psoriasis
subjects affected / exposed	8 / 285 (2.81%)	28 / 271 (10.33%)	14 / 132 (10.61%)	8 / 285 (2.81%)	21 / 131 (16.03%)
occurrences all number	10	32	18	8	25
Infections and infestations
Nasopharyngitis
subjects affected / exposed	19 / 285 (6.67%)	40 / 271 (14.76%)	16 / 132 (12.12%)	17 / 285 (5.96%)	20 / 131 (15.27%)
occurrences all number	20	55	20	19	25
Upper respiratory tract infection
subjects affected / exposed	9 / 285 (3.16%)	15 / 271 (5.54%)	6 / 132 (4.55%)	6 / 285 (2.11%)	11 / 131 (8.40%)
occurrences all number	9	18	7	7	13

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Were there any global substantial amendments to the protocol? Yes

27 Jul 2015

Summary of Significant Changes Adopted with Protocol Amendment 1 •Clarified that the European Union reference protein product (EU RPP) is not an approved product in the United States. •In response to Food and Drug Administration (FDA) feedback/guidance: -Primary endpoint analysis revised to occur at Week 16 instead of Week 13 -Treatment Arm C eliminated -Efficacy, safety, Pharmacokinetic (PK), and immunogenicity objectives were revised to reflect the examination of the transitions between M923 and EU RPP, rather than interchangeability -The PK sub-study was removed -The use of the terms “similar/biosimilar/or comparable” were removed or revised to adhere to FDA guidance regarding conclusory statements in the study protocol •The study drug injection parameters were revised to reflect a 2-hour observation period after Weeks 0, 1, 17, 25, and 37, and a 30 minute observation period after injections at Weeks 19, 21, 27, and 39 •The biostatistical analysis was revised to reflect the change in primary efficacy from Week 13 to Week 16, to clarify the response rate justification, and to apply the change in equivalence margin to include 18% (Confidence Interval [CI] 90%) for the US FDA and 15% (CI 95%) for the EU EMA •Timing of the following assessments was revised: Dermatology Life Quality Index (DLQI) and EuroQoL-5 dimensions Health Status Questionnaire (EQ 5D 5L); physical examination; 12 lead electrocardiogram (ECG); urinalysis, PK and immunogenicity; laboratory assessments; urine pregnancy tests; study drug injections onsite and at home; injection site evaluation, and post injection monitoring.

08 Oct 2015

Summary of Significant Change Adopted with Protocol Amendment 2 •The use of the terms “similar/biosimilar/comparable” were removed/revised in order to adhere to FDA guidance regarding conclusory statements in the study protocol or Investigator’s Brochure.

04 Aug 2016

•To clarify the study objectives: -The primary objective was changed from “to demonstrate equivalent efficacy between M923 (test) and EU RPP (reference) in participants with moderate to severe chronic plaque type psoriasis” to “to demonstrate equivalence in measures of efficacy between M923 (test) and EU RPP (reference) in participants with moderate to severe chronic plaque type psoriasis” -The secondary objective was changed from “Evaluate the safety, immunogenicity, and tolerability of M923 compared with EU RPP” to “Evaluate the continued efficacy, safety, immunogenicity, and tolerability of M923 compared with EU RPP” -The secondary objective was changed from “Evaluate exposure of EU RPP and M923” to “Evaluate concentration summaries over time” •Changes were made to Section 8.4, Outcome Measures to clarify the outcome measures and how they were to be measured •Changes to study entry criteria were made: -To clarify the maximum period where male partners should use a condom -To clarify that the subject must have had no major deviations regarding concomitant medication -To clarify the type of imaging exam acceptable for this study (i.e., “a radiograph or comparable imaging with negative finding for TB or other similar infections”) •To clarify all non-permitted treatments, topical treatments containing acetylsalicylic acid were included in the list of treatments not permitted during the course of the study •It was added that after the discontinuation visit, if the subject agreed, a Follow-up Visit was to be conducted 5 weeks after last IP dose •It was clarified that the interim analysis was to be done for the first randomized subjects and would analyze primary endpoint data, PK, and safety up through Week 25. It was also clarified that the final analysis was to be carried out in all subjects recruited (n=572). Note: The summary of change is not all-inclusive.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results: A Confirmatory (Phase 3) Randomized, Double-blind, Multicenter Study to Evaluate Efficacy, Safety, and Immunogenicity of M923 (a Proposed Adalimumab Biosimilar) and Humira® in Subjects with Moderate to Severe Chronic Plaque-type Psoriasis

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Percentage of Participants Who Achieved a 75% Reduction in Psoriasis Area and Severity Index (PASI) (PASI 75) Scores at Week 16

Primary: Percentage of Participants Who Achieved a 75% Reduction in Psoriasis Area and Severity Index (PASI) (PASI 75) Scores at Week 16

Secondary: Percentage of Participants With a Response of Clear or Almost Clear on the Static Physician Global Assessment (sPGA) at Week 16

Secondary: Percentage of Participants With a Response of Clear or Almost Clear on the Static Physician Global Assessment (sPGA) at Week 16

Secondary: Number of Participants Achieving PASI 50 Response at Week 16

Secondary: Number of Participants Achieving PASI 50 Response at Week 16

Secondary: Number of Participants Achieving PASI 50 Response at Week 52 (Follow-Up Visit)

Secondary: Number of Participants Achieving PASI 50 Response at Week 52 (Follow-Up Visit)

Secondary: Number of Participants Achieving PASI 75 Response at Week 16

Secondary: Number of Participants Achieving PASI 75 Response at Week 16

Secondary: Number of Participants Achieving PASI 75 Response at Week 52 (Follow-Up Visit)

Secondary: Number of Participants Achieving PASI 75 Response at Week 52 (Follow-Up Visit)

Secondary: Number of Participants Achieving PASI 90 Response at Week 16

Secondary: Number of Participants Achieving PASI 90 Response at Week 16

Secondary: Number of Participants Achieving PASI 90 Response at Week 52 (Follow-Up Visit)

Secondary: Number of Participants Achieving PASI 90 Response at Week 52 (Follow-Up Visit)

Secondary: Absolute PASI Score at Baseline

Secondary: Absolute PASI Score at Baseline

Secondary: Absolute PASI Score at Week 16

Secondary: Absolute PASI Score at Week 16

Secondary: Absolute PASI Score at Week 52 (Follow-Up Visit)

Secondary: Absolute PASI Score at Week 52 (Follow-Up Visit)

Secondary: Percent Change From Baseline in PASI Score at Week 16

Secondary: Percent Change From Baseline in PASI Score at Week 16

Secondary: Percent Change From Baseline in PASI Score at Week 52 (Follow-Up Visit)

Secondary: Percent Change From Baseline in PASI Score at Week 52 (Follow-Up Visit)

Secondary: Health-Related Quality of Life During Treatment: Dermatology Life Quality Index (DLQI) Score at Baseline

Secondary: Health-Related Quality of Life During Treatment: Dermatology Life Quality Index (DLQI) Score at Baseline

Secondary: Health-Related Quality of Life During Treatment: DLQI Score at Week 16

Secondary: Health-Related Quality of Life During Treatment: DLQI Score at Week 16

Secondary: Health-Related Quality of Life During Treatment: DLQI Score at Week 48 (Completion/Termination Visit)

Secondary: Health-Related Quality of Life During Treatment: DLQI Score at Week 48 (Completion/Termination Visit)

Secondary: Health-Related Quality of Life During Treatment: EuroQoL 5-Dimension Health Status Questionnaire (EQ-5D-5L) at Baseline

Secondary: Health-Related Quality of Life During Treatment: EuroQoL 5-Dimension Health Status Questionnaire (EQ-5D-5L) at Baseline

Secondary: Health-Related Quality of Life During Treatment: EQ-5D-5L at Week 16

Secondary: Health-Related Quality of Life During Treatment: EQ-5D-5L at Week 16

Secondary: Health-Related Quality of Life During Treatment: EQ-5D-5L at Week 48 (Completion/Termination Visit)

Secondary: Health-Related Quality of Life During Treatment: EQ-5D-5L at Week 48 (Completion/Termination Visit)

Secondary: Number of Participants With Clinically Meaningful Changes in Vital Signs

Secondary: Number of Participants With Clinically Meaningful Changes in Vital Signs

Secondary: Number of Participants With Clinically Meaningful Changes in Laboratory Results at Baseline

Secondary: Number of Participants With Clinically Meaningful Changes in Laboratory Results at Baseline

Secondary: Number of Participants With Clinically Meaningful Changes in Laboratory Results at Week 16

Secondary: Number of Participants With Clinically Meaningful Changes in Laboratory Results at Week 16

Secondary: Number of Participants With Clinically Meaningful Changes in Laboratory Results at Week 48 (Completion/Termination Visit)

Secondary: Number of Participants With Clinically Meaningful Changes in Laboratory Results at Week 48 (Completion/Termination Visit)

Secondary: Number of Participants With Clinically Significant Abnormalities in Electrocardiogram Parameters at Baseline

Secondary: Number of Participants With Clinically Significant Abnormalities in Electrocardiogram Parameters at Baseline

Secondary: Number of Participants With Clinically Significant Abnormalities in Electrocardiogram Parameters at Week 16

Secondary: Number of Participants With Clinically Significant Abnormalities in Electrocardiogram Parameters at Week 16

Secondary: Number of Participants With Clinically Significant Abnormalities in Electrocardiogram Parameters at Week 48 (Completion/Termination Visit)

Secondary: Number of Participants With Clinically Significant Abnormalities in Electrocardiogram Parameters at Week 48 (Completion/Termination Visit)

Secondary: Number of participants with Treatment-emergent Adverse Events (TEAEs)

Secondary: Number of participants with Treatment-emergent Adverse Events (TEAEs)

Secondary: Pharmacokinetics: Serum Concentrations by Treatment

Secondary: Pharmacokinetics: Serum Concentrations by Treatment

Secondary: Immunogenicity: Number of Participants With Anti-Drug Antibodies (ADA) at Baseline

Secondary: Immunogenicity: Number of Participants With Anti-Drug Antibodies (ADA) at Baseline

Secondary: Immunogenicity: Number of Participants With ADA at Week 16

Secondary: Immunogenicity: Number of Participants With ADA at Week 16

Secondary: Immunogenicity: Number of Participants With ADA at Week 25

Secondary: Immunogenicity: Number of Participants With ADA at Week 25

Secondary: Immunogenicity: Number of Participants With ADA at Week 52 (Completion/Termination Visit)

Secondary: Immunogenicity: Number of Participants With ADA at Week 52 (Completion/Termination Visit)

Secondary: Immunogenicity: Number of Participants With ADA and nADA by Titer at Baseline

Secondary: Immunogenicity: Number of Participants With ADA and nADA by Titer at Baseline

Secondary: Immunogenicity: Number of Participants With ADA and nADA by Titer at Week 16

Secondary: Immunogenicity: Number of Participants With ADA and nADA by Titer at Week 16

Secondary: Immunogenicity: Number of Participants With ADA and nADA by Titer at Week 25

Secondary: Immunogenicity: Number of Participants With ADA and nADA by Titer at Week 25

Clinical Trial Results:
A Confirmatory (Phase 3) Randomized, Double-blind, Multicenter Study to Evaluate Efficacy, Safety, and Immunogenicity of M923 (a Proposed Adalimumab Biosimilar) and Humira® in Subjects with Moderate to Severe Chronic Plaque-type Psoriasis