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Clinical Trial Results:
A Randomized, Double-Blind, Parallel-Group, Placebo- and Active-Controlled, Multicenter Phase III Study of the Efficacy and Safety of Olokizumab in Subjects with Moderately to Severely Active Rheumatoid Arthritis Inadequately Controlled by Methotrexate Therapy

Summary
EudraCT number	2015-005307-83
Trial protocol	LV CZ DE LT HU PL BG RO
Global end of trial date	05 Nov 2019

Results information
Results version number	v1(current)
This version publication date	15 Nov 2020
First version publication date	15 Nov 2020
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

CL04041023

ISRCTN number

US NCT number

NCT02760407

WHO universal trial number (UTN)

Other trial identifiers

IND No: 104933

Sponsor organisation name

R-Pharm International

Sponsor organisation address

19 1, Berzarina Street, Moscow, Russian Federation, 123154

Public contact

Medical Department, R-Pharm International, +7 495 956 7937,

Scientific contact

Medical Department, R-Pharm International, +7 495 956 7937,

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

05 Nov 2019

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

05 Nov 2019

Was the trial ended prematurely?

Main objective of the trial

To demonstrate superiority of Olokizumab (OKZ) 64 milligrams (mg) administered subcutaneously (SC) once every 2 weeks (q2w) or once every 4 weeks (q4w) plus methotrexate (MTX) relative to placebo plus MTX and non-inferiority of OKZ 64 mg q2w or q4w administered SC plus MTX relative to Adalimumab plus MTX with respect to the American College of Rheumatology 20% response criteria (ACR20) at Week 12 in subjects with moderately to severely active rheumatoid arthritis (RA) inadequately controlled by MTX therapy.

Protection of trial subjects

The study was conducted in accordance with the protocol, the ethical principles derived from international guidelines including the Declaration of Helsinki and Council for International Organizations of Medical Sciences International Ethical Guidelines, applicable International Council for Harmonisation, Good Clinical Practice Guidelines, and applicable laws and regulations.

Background therapy

Stable MTX dose was continued during the study. Folic acid ≥5 mg per week or equivalent was required during the study.

Evidence for comparator

Actual start date of recruitment

06 Jun 2016

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Poland: 308

Country: Number of subjects enrolled

Romania: 1

Country: Number of subjects enrolled

United Kingdom: 11

Country: Number of subjects enrolled

Bulgaria: 65

Country: Number of subjects enrolled

Czech Republic: 189

Country: Number of subjects enrolled

Estonia: 13

Country: Number of subjects enrolled

Germany: 40

Country: Number of subjects enrolled

Hungary: 51

Country: Number of subjects enrolled

Latvia: 4

Country: Number of subjects enrolled

Lithuania: 74

Country: Number of subjects enrolled

Argentina: 153

Country: Number of subjects enrolled

Brazil: 112

Country: Number of subjects enrolled

Colombia: 59

Country: Number of subjects enrolled

Korea, Republic of: 11

Country: Number of subjects enrolled

Mexico: 215

Country: Number of subjects enrolled

Russian Federation: 77

Country: Number of subjects enrolled

Taiwan: 8

Country: Number of subjects enrolled

United States: 257

Worldwide total number of subjects

1648

EEA total number of subjects

756

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)

1327

From 65 to 84 years

320

85 years and over

Subject disposition

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Recruitment details

This was a randomized, double-blind, parallel-group, placebo- and active-controlled, multicenter Phase III study conducted at 209 study centers in 18 countries between 06 June 2016 and 05 November 2019. A total of 3359 subjects were screened, of which 1711 subjects were screen failures and 1648 subjects were randomized in the study.

Screening details

Subjects with moderately to severely active, adult onset, RA with an inadequate response to MTX therapy for at least 12 weeks prior to Screening were assessed for eligibility. Eligible subjects were randomized in a 2:2:2:1 ratio to receive 64 mg OKZ q4w, 64 mg OKZ q2w, adalimumab 40 mg q2w, or placebo in a 24-week double-blind treatment period.

Period 1 title

Overall Trial (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Assessor

Blinding implementation details

Since the study treatments were distinguishable, they were prepared by the unblinded pharmacist (or their unblinded designee) and administered by a trained, unblinded study team member who was not involved in the management of study subjects.

Are arms mutually exclusive

Yes

OKZ 64 mg q4w

Arm description

Subjects received a SC injection of OKZ 64 mg q4w alternating with SC injections of placebo q4w to maintain blinding and stable dose of MTX. The last dose of study treatment was at Week 22 of the Treatment Period from Week 0 to Week 24. After completion of the double-blind Treatment Period at Week 24, subjects were offered the opportunity to enter the optional open-label extension (OLE) study. Subjects who did not consent to participate in the OLE study attended the End of Treatment (EoT) Visit at Week 24. After the EoT Visit, these subjects were scheduled for 3 Safety Follow-Up Visits up to Week 44.

Arm type

Experimental

Investigational medicinal product name

Olokizumab

Investigational medicinal product code

Other name

OKZ, CDP6038, L04041

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Subjects received 64 mg q4w OKZ by SC injection in either abdomen or thigh, prepared in blinded syringes of 0.4 milliliter (mL).

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Subjects received placebo (sodium chloride 0.9%) q4w by SC injection in either abdomen or thigh, prepared in blinded syringes of 0.4 mL.

OKZ 64 mg q2w

Arm description

Subjects received a SC injection of OKZ 64 mg q2w and stable dose of MTX. The last dose of study treatment was at Week 22 of the Treatment Period from Week 0 to Week 24. After completion of the double-blind Treatment Period at Week 24, subjects were offered the opportunity to enter the optional OLE study. Subjects who did not consent to participate in the OLE study attended the EoT Visit at Week 24. After the EoT Visit, these subjects were scheduled for 3 Safety Follow-Up Visits up to Week 44.

Arm type

Experimental

Investigational medicinal product name

Olokizumab

Investigational medicinal product code

Other name

OKZ, CDP6038, L04041

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Subjects received 64 mg q2w OKZ by SC injection in either abdomen or thigh, prepared in blinded syringes of 0.4 mL.

Adalimumab 40 mg q2w

Arm description

Subjects received a SC injection of adalimumab 40 mg q2w and stable dose of MTX. The last dose of study treatment was at Week 22 of the Treatment Period from Week 0 to Week 24. After completion of the double-blind Treatment Period at Week 24, subjects were offered the opportunity to enter the optional OLE study. Subjects who did not consent to participate in the OLE study attended the EoT Visit at Week 24. After the EoT Visit, these subjects were scheduled for 3 Safety Follow-Up Visits up to Week 44.

Arm type

Active comparator

Investigational medicinal product name

Adalimumab

Investigational medicinal product code

Other name

Humira®

Pharmaceutical forms

Solution for injection in pre-filled syringe

Routes of administration

Subcutaneous use

Dosage and administration details

Subjects received 40 mg q2w adalimumab by SC injection in either abdomen or thigh, prepared in blinded syringes of either 0.4 or 0.8 mL.

Placebo

Arm description

Subjects received a SC injection of Placebo q2w and stable dose of MTX. The last dose of study treatment was at Week 22 of the Treatment Period from Week 0 to Week 24. After completion of the double-blind Treatment Period at Week 24, subjects were offered the opportunity to enter the optional OLE study. Subjects who did not consent to participate in the OLE study attended the EoT Visit at Week 24. After the EoT Visit, these subjects were scheduled for 3 Safety Follow-Up Visits up to Week 44.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Subjects received placebo (sodium chloride 0.9%) q2w by SC injection in either abdomen or thigh, prepared in blinded syringes of 0.4 mL.

Number of subjects in period 1	OKZ 64 mg q4w	OKZ 64 mg q2w	Adalimumab 40 mg q2w	Placebo
Started	479	464	462	243
Received Treatment	478	462	462	243
Completed Treatment Period	437 ^[1]	421	413	208
Continued into Safety Follow Up Period	37 ^[2]	28 ^[3]	35 ^[4]	17 ^[5]
Enrolled in OLE	422 ^[6]	410 ^[7]	397 ^[8]	199 ^[9]
Completed	443	421	412	207
Not completed	36	43	50	36
Consent withdrawn by subject	25	31	37	25
Other	8	2	8	4
Death	2	3	1	1
Lost to follow-up	1	7	4	6

Notes
[1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: The subjects in each milestone is for information only and does not impact the number of subjects that completed the study.
[2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: The subjects in each milestone is for information only and does not impact the number of subjects that completed the study.
[3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: The subjects in each milestone is for information only and does not impact the number of subjects that completed the study.
[4] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: The subjects in each milestone is for information only and does not impact the number of subjects that completed the study.
[5] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: The subjects in each milestone is for information only and does not impact the number of subjects that completed the study.
[6] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: The subjects in each milestone is for information only and does not impact the number of subjects that completed the study.
[7] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: The subjects in each milestone is for information only and does not impact the number of subjects that completed the study.
[8] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: The subjects in each milestone is for information only and does not impact the number of subjects that completed the study.
[9] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: The subjects in each milestone is for information only and does not impact the number of subjects that completed the study.

Baseline characteristics

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Reporting group title

OKZ 64 mg q4w

Reporting group description

Reporting group title

OKZ 64 mg q2w

Reporting group description

Reporting group title

Adalimumab 40 mg q2w

Reporting group description

Reporting group title

Placebo

Reporting group description

Reporting group values	OKZ 64 mg q4w	OKZ 64 mg q2w	Adalimumab 40 mg q2w	Placebo	Total
Number of subjects	479	464	462	243	1648
Age categorical
Units: Subjects
Adults (18-64 years)	389	379	367	192	1327
From 65-84 years	90	85	95	50	320
85 years and over	0	0	0	1	1
Age continuous
Units: years
arithmetic mean (standard deviation)	53.7 ± 12.09	53.3 ± 11.92	54.3 ± 12.32	54.7 ± 11.85	-
Gender categorical
Units: Subjects
Female	378	352	363	190	1283
Male	101	112	99	53	365
Race
Units: Subjects
Asian	6	10	4	5	25
Black or African American	15	20	23	11	69
White	406	382	385	203	1376
Other / Mixed	52	52	50	24	178

End points

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Reporting group title

OKZ 64 mg q4w

Reporting group description

Reporting group title

OKZ 64 mg q2w

Reporting group description

Reporting group title

Adalimumab 40 mg q2w

Reporting group description

Reporting group title

Placebo

Reporting group description

Primary: Percentage of Subjects Meeting the ACR20 at Week 12 (OKZ Comparison with Placebo)

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End point title

Percentage of Subjects Meeting the ACR20 at Week 12 (OKZ Comparison with Placebo) ^[1]

End point description

To meet ACR20 response criteria at Week 12, a subject must have had at least 20% improvement from baseline in the following ACR Core Set values: • Tender joint count (TJC) (68 joint count) • Swollen joint count (SJC) (66 joint count) An improvement of at least 20% from baseline in at least 3 of the following 5 components: 1) Subject Global Assessment of Disease Activity (Visual Analog Scale [VAS]); 2) Subject Assessment of Pain (VAS); 3) Health Assessment Questionnaire - Disability Index (HAQ-DI); 4) Physician Global Assessment (VAS); 5) Level of acute phase reactant (C-reactive protein [CRP]). A responder was a subject meeting the ACR20 criteria and remaining on randomized treatment and in the study at Week 12. Analysis was performed on the intent-to-treat (ITT) population, which included all randomized subjects.

End point type

Primary

End point timeframe

From Baseline to Week 12

Notes
[1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Reporting group "Adalimumab 40 mg q2w" was not analyzed for this endpoint.

End point values	OKZ 64 mg q4w	OKZ 64 mg q2w	Placebo
Number of subjects analysed	479	464	243
Units: Percentage of subjects
number (not applicable)	71.4	70.3	44.4

Comparison of OKZ 64 mg q4w Vs Placebo

Comparison groups

OKZ 64 mg q4w v Placebo

Number of subjects included in analysis

722

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[2]

Method

Chi-squared

Parameter type

Risk difference (RD)

Point estimate

0.27

Confidence interval

level

97.5%

sides

2-sided

lower limit

0.183

upper limit

0.352

Notes
[2] - P-values are 1-sided α=0.025 significance level from 2x2 chi-square test.

Comparison of OKZ 64 mg q2w Vs Placebo

Comparison groups

OKZ 64 mg q2w v Placebo

Number of subjects included in analysis

707

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[3]

Method

Chi-squared

Parameter type

Risk difference (RD)

Point estimate

0.258

Confidence interval

level

97.5%

sides

2-sided

lower limit

0.171

upper limit

0.341

Notes
[3] - P-values are 1-sided α=0.025 significance level from 2x2 chi-square test.

Secondary: Percentage of Subjects Meeting the ACR20 at Week 12 (OKZ Comparison with Adalimumab)

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End point title

Percentage of Subjects Meeting the ACR20 at Week 12 (OKZ Comparison with Adalimumab)

End point description

To meet ACR20 response criteria at Week 12, a subject must have had at least 20% improvement from baseline in the following ACR Core Set values: • TJC (68 joint count) • SJC (66 joint count) An improvement of at least 20% from baseline in at least 3 of the following 5 components: 1) Subject Global Assessment of Disease Activity (VAS); 2) Subject Assessment of Pain (VAS); 3) HAQ-DI; 4) Physician Global Assessment (VAS); 5) Level of acute phase reactant (CRP). A responder was a subject meeting the ACR20 criteria and remaining on randomized treatment and in the study at Week 12. Analysis was performed on the ITT population, which included all randomized subjects.

End point type

Secondary

End point timeframe

From Baseline to Week 12

End point values	OKZ 64 mg q4w	OKZ 64 mg q2w	Adalimumab 40 mg q2w	Placebo
Number of subjects analysed	479	464	462	243
Units: Percentage of subjects
number (not applicable)	71.4	70.3	66.9	44.4

Comparison of Adalimumab 40 mg q2w Vs Placebo

Comparison groups

Adalimumab 40 mg q2w v Placebo

Number of subjects included in analysis

705

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[4]

Method

Chi-squared

Parameter type

Risk difference (RD)

Point estimate

0.224

Confidence interval

level

95%

sides

2-sided

lower limit

0.148

upper limit

0.298

Notes
[4] - P-values are 1-sided α=0.025 significance level from 2x2 chi-square test.

Comparison of OKZ 64 mg q4w Vs Adalimumab 40mg q2w

Comparison groups

Adalimumab 40 mg q2w v OKZ 64 mg q4w

Number of subjects included in analysis

941

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[5]

Method

Parameter type

Risk difference (RD)

Point estimate

0.045

Confidence interval

level

97.5%

sides

2-sided

lower limit

-0.022

upper limit

0.112

Notes
[5] - Non-inferiority for each OKZ dosing regimen versus adalimumab is achieved if the lower limit of the 97.5% confidence interval is greater than the protocol defined non-inferiority margin of -12%.

Comparison of OKZ 64 mg q2w Vs Adalimumab 40mg q2w

Comparison groups

OKZ 64 mg q2w v Adalimumab 40 mg q2w

Number of subjects included in analysis

926

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[6]

Method

Parameter type

Risk difference (RD)

Point estimate

0.034

Confidence interval

level

97.5%

sides

2-sided

lower limit

-0.035

upper limit

0.102

Notes
[6] - Non-inferiority for each OKZ dosing regimen versus adalimumab is achieved if the lower limit of the 97.5% confidence interval is greater than the protocol defined non-inferiority margin of -12%.

Secondary: Percentage of Subjects Achieving Low Disease Activity, Defined as Disease Activity Score 28-Joint Count CRP (DAS 28 [CRP]) <3.2 at Week 12

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End point title

Percentage of Subjects Achieving Low Disease Activity, Defined as Disease Activity Score 28-Joint Count CRP (DAS 28 [CRP]) <3.2 at Week 12

End point description

The DAS28 (CRP) was calculated using the SJC (28 joints), TJC (28 joints), CRP level (mg/mL), and the Subject Global Assessment of Disease Activity (VAS) (in millimeters) according to the formula: DAS28 (CRP) = 0.56 × √(TJC) + 0.28 × √(SJC) + 0.36 × ln (CRP + 1) + 0.014 × Subject Global Assessment of Disease Activity (VAS) + 0.96. The 28 joints evaluated for the SJC and TJC were: shoulders, elbows, wrists, hands and knees. Subjects who remained on randomized treatment and who were in the study at Week 12 and had a DAS28 (CRP) <3.2 were classed as having low disease activity. Analysis was performed on the ITT population which included all randomized subjects.

End point type

Secondary

End point timeframe

Week 12

End point values	OKZ 64 mg q4w	OKZ 64 mg q2w	Adalimumab 40 mg q2w	Placebo
Number of subjects analysed	479	464	462	243
Units: Percentage of subjects
number (not applicable)	45.7	45.3	38.3	12.8

Comparison of OKZ 64 mg q4w Vs Placebo

Comparison groups

OKZ 64 mg q4w v Placebo

Number of subjects included in analysis

722

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[7]

Method

Chi-squared

Parameter type

Risk difference (RD)

Point estimate

0.33

Confidence interval

level

97.5%

sides

2-sided

lower limit

0.255

upper limit

0.395

Notes
[7] - P-values are 1-sided α=0.025 significance level from 2x2 chi-square test.

Comparison of OKZ 64 mg q2w Vs Placebo

Comparison groups

OKZ 64 mg q2w v Placebo

Number of subjects included in analysis

707

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[8]

Method

Chi-squared

Parameter type

Risk difference (RD)

Point estimate

0.325

Confidence interval

level

97.5%

sides

2-sided

lower limit

0.25

upper limit

0.391

Notes
[8] - P-values are 1-sided α=0.025 significance level from 2x2 chi-square test.

Comparison of Adalimumab 40 mg q2w Vs Placebo

Comparison groups

Adalimumab 40 mg q2w v Placebo

Number of subjects included in analysis

705

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[9]

Method

Chi-squared

Parameter type

Risk difference (RD)

Point estimate

0.256

Confidence interval

level

95%

sides

2-sided

lower limit

0.191

upper limit

0.313

Notes
[9] - P-values are 1-sided α=0.025 significance level from 2x2 chi-square test.

Comparison of OKZ 64 mg q4w Vs Adalimumab 40mg q2w

Comparison groups

OKZ 64 mg q4w v Adalimumab 40 mg q2w

Number of subjects included in analysis

941

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[10]

Method

Parameter type

Risk difference (RD)

Point estimate

0.074

Confidence interval

level

97.5%

sides

2-sided

lower limit

0.002

upper limit

0.145

Notes
[10] - Non-inferiority for each OKZ dosing regimen versus adalimumab is achieved if the lower limit of the 97.5% confidence interval is greater than the protocol defined non-inferiority margin of -7.5%.

Comparison of OKZ 64 mg q2w Vs Adalimumab 40mg q2w

Comparison groups

OKZ 64 mg q2w v Adalimumab 40 mg q2w

Number of subjects included in analysis

926

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[11]

Method

Parameter type

Risk difference (RD)

Point estimate

0.069

Confidence interval

level

97.5%

sides

2-sided

lower limit

-0.003

upper limit

0.141

Notes
[11] - Non-inferiority for each OKZ dosing regimen versus adalimumab is achieved if the lower limit of the 97.5% confidence interval is greater than the protocol defined non-inferiority margin of -7.5%.

Secondary: Mean Change from Baseline to Week 12 in HAQ-DI

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End point title

Mean Change from Baseline to Week 12 in HAQ-DI

End point description

The HAQ-DI is a patient reported questionnaire that provided an assessment of the impact of the disease and its treatment on physical function. The HAQ-DI assessed the degree of difficulty experienced in 8 domains of daily living activities using 20 questions. For each question, the level of difficulty was scored from 0 to 3 where 0 = without any difficulty, 1 = with some difficulty, 2 = much difficulty, and 3 = unable to do. Each category was scored by taking the maximum score of each question. The HAQ-DI was calculated by dividing the sum of the category scores by the number of categories with at least 1 question answered. A decrease from baseline indicated an improvement in physical ability. Analysis of covariance (ANCOVA) with treatment as fixed effect and baseline value as covariate was used to determine Least Square Mean (LSM) change from baseline for the ITT population, which included all randomized subjects.

End point type

Secondary

End point timeframe

From Baseline to Week 12

End point values	OKZ 64 mg q4w	OKZ 64 mg q2w	Adalimumab 40 mg q2w	Placebo
Number of subjects analysed	423	404	394	197
Units: Units on HAQ-DI scale
least squares mean (standard error)	-0.61 ± 0.026	-0.64 ± 0.027	-0.61 ± 0.027	-0.42 ± 0.038

Comparison of OKZ 64 mg q4w Vs Placebo

Comparison groups

OKZ 64 mg q4w v Placebo

Number of subjects included in analysis

620

Analysis specification

Pre-specified

Analysis type

superiority ^[12]

P-value

< 0.0001 ^[13]

Method

ANCOVA

Parameter type

LSM difference

Point estimate

-0.19

Confidence interval

level

97.5%

sides

2-sided

lower limit

-0.29

upper limit

-0.09

Variability estimate

Standard error of the mean

Dispersion value

0.046

Notes
[12] - ANCOVA model included treatment as fixed effect and baseline value as a covariate. LSMs and P-value were obtained using Rubins's rule.
[13] - P-values represent a 1-sided combined test for treatment effect from the ANCOVA model.

Comparison of OKZ 64 mg q2w Vs Placebo

Comparison groups

OKZ 64 mg q2w v Placebo

Number of subjects included in analysis

601

Analysis specification

Pre-specified

Analysis type

superiority ^[14]

P-value

< 0.0001 ^[15]

Method

ANCOVA

Parameter type

LSM difference

Point estimate

-0.22

Confidence interval

level

97.5%

sides

2-sided

lower limit

-0.33

upper limit

-0.12

Variability estimate

Standard error of the mean

Dispersion value

0.046

Notes
[14] - ANCOVA model included treatment as fixed effect and baseline value as a covariate. LSMs and P-value were obtained using Rubins's rule.
[15] - P-values represent a 1-sided combined test for treatment effect from the ANCOVA model.

Comparison of Adalimumab 40 mg q2w Vs Placebo

Comparison groups

Adalimumab 40 mg q2w v Placebo

Number of subjects included in analysis

591

Analysis specification

Pre-specified

Analysis type

superiority ^[16]

Method

Parameter type

LSM difference

Point estimate

-0.19

Confidence interval

level

95%

sides

2-sided

lower limit

-0.28

upper limit

-0.1

Variability estimate

Standard error of the mean

Dispersion value

0.046

Notes
[16] - ANCOVA model included treatment as fixed effect and baseline value as a covariate. LSMs were obtained using Rubins's rule.

Comparison of OKZ 64 mg q4w Vs Adalimumab 40mg q2w

Comparison groups

OKZ 64 mg q4w v Adalimumab 40 mg q2w

Number of subjects included in analysis

817

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[17]

Method

Parameter type

LSM difference

Point estimate

Confidence interval

level

97.5%

sides

2-sided

lower limit

-0.08

upper limit

0.08

Variability estimate

Standard error of the mean

Dispersion value

0.037

Notes
[17] - ANCOVA model included treatment as fixed effect and baseline value as a covariate. LSMs were obtained using Rubins's rule.

Comparison of OKZ 64 mg q2w Vs Adalimumab 40mg q2w

Comparison groups

OKZ 64 mg q2w v Adalimumab 40 mg q2w

Number of subjects included in analysis

798

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[18]

Method

Parameter type

LSM difference

Point estimate

-0.03

Confidence interval

level

97.5%

sides

2-sided

lower limit

-0.12

upper limit

0.05

Variability estimate

Standard error of the mean

Dispersion value

0.038

Notes
[18] - ANCOVA model included treatment as fixed effect and baseline value as a covariate. LSMs were obtained using Rubins's rule.

Secondary: Percentage of Subjects Achieving American College of Rheumatology 50% Response Criteria (ACR50) at Week 24

Top of page

End point title

Percentage of Subjects Achieving American College of Rheumatology 50% Response Criteria (ACR50) at Week 24

End point description

To meet ACR50 response criteria at Week 24, a subject must have had at least 50% improvement from baseline in the following ACR Core Set values: • TJC (68 joint count) • SJC (66 joint count) An improvement of at least 50% in at least 3 of the following 5 components: 1) Subject Global Assessment of Disease Activity (VAS); 2) Subject Assessment of Pain (VAS); 3) HAQ-DI; 4) Physician Global Assessment (VAS); 5) Level of acute phase reactant (CRP). Subjects must have been remaining on randomized treatment and in the study at Week 24. Analysis was performed on the ITT population, which included all randomized subjects.

End point type

Secondary

End point timeframe

From Baseline to Week 24

End point values	OKZ 64 mg q4w	OKZ 64 mg q2w	Adalimumab 40 mg q2w	Placebo
Number of subjects analysed	479	464	462	243
Units: Percentage of subjects
number (not applicable)	50.1	50.4	46.3	22.6

Comparison of OKZ 64 mg q4w Vs Placebo

Comparison groups

OKZ 64 mg q4w v Placebo

Number of subjects included in analysis

722

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[19]

Method

Chi-squared

Parameter type

Risk difference (RD)

Point estimate

0.275

Confidence interval

level

97.5%

sides

2-sided

lower limit

0.192

upper limit

0.349

Notes
[19] - P-values are 1-sided α=0.025 significance level from 2x2 chi-square test.

Comparison of OKZ 64 mg q2w Vs Placebo

Comparison groups

OKZ 64 mg q2w v Placebo

Number of subjects included in analysis

707

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[20]

Method

Chi-squared

Parameter type

Risk difference (RD)

Point estimate

0.278

Confidence interval

level

97.5%

sides

2-sided

lower limit

0.195

upper limit

0.353

Notes
[20] - P-values are 1-sided α=0.025 significance level from 2x2 chi-square test.

Comparison of Adalimumab 40 mg q2w Vs Placebo

Comparison groups

Adalimumab 40 mg q2w v Placebo

Number of subjects included in analysis

705

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Risk difference (RD)

Point estimate

0.237

Confidence interval

level

95%

sides

2-sided

lower limit

0.165

upper limit

0.303

Comparison of OKZ 64 mg q4w Vs Adalimumab 40mg q2w

Comparison groups

OKZ 64 mg q4w v Adalimumab 40 mg q2w

Number of subjects included in analysis

941

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[21]

Method

Parameter type

Risk difference (RD)

Point estimate

0.038

Confidence interval

level

97.5%

sides

2-sided

lower limit

-0.035

upper limit

0.11

Notes
[21] - Confidence Interval is calculated using Newcombe hybrid score method.

Comparison of OKZ 64 mg q2w Vs Adalimumab 40mg q2w

Comparison groups

OKZ 64 mg q2w v Adalimumab 40 mg q2w

Number of subjects included in analysis

926

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[22]

Method

Parameter type

Risk difference (RD)

Point estimate

0.041

Confidence interval

level

97.5%

sides

2-sided

lower limit

-0.032

upper limit

0.114

Notes
[22] - Confidence Interval is calculated using Newcombe hybrid score method.

Secondary: Percentage of Subjects Achieving Remission, Defined as Clinical Disease Activity Index (CDAI) ≤2.8 (Remission) at Week 24

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End point title

Percentage of Subjects Achieving Remission, Defined as Clinical Disease Activity Index (CDAI) ≤2.8 (Remission) at Week 24

End point description

The CDAI was calculated using the SJC (28 joints), TJC (28 joints), the Subject Global Assessment of Disease Activity (VAS) (in centimeters), and the Physician Global Assessment (VAS) (in centimeters) according to the formula: CDAI = SJC + TJC + Subject Global Assessment of Disease Activity (VAS) + Physician Global Assessment (VAS). Subjects remaining on randomized treatment and in the study at Week 24 and with a CDAI of ≤2.8 were classed as in remission. Analysis was performed on the ITT population, which included all randomized subjects.

End point type

Secondary

End point timeframe

At Week 24

End point values	OKZ 64 mg q4w	OKZ 64 mg q2w	Adalimumab 40 mg q2w	Placebo
Number of subjects analysed	479	464	462	243
Units: Percentage of subjects
number (not applicable)	12.1	11.2	13.0	4.1

Comparison of OKZ 64 mg q4w Vs Placebo

Comparison groups

OKZ 64 mg q4w v Placebo

Number of subjects included in analysis

722

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0003 ^[23]

Method

Chi-squared

Parameter type

Risk difference (RD)

Point estimate

0.08

Confidence interval

level

97.5%

sides

2-sided

lower limit

0.031

upper limit

0.123

Notes
[23] - P-values are 1-sided α=0.025 significance level from 2x2 chi-square test.

Comparison of OKZ 64 mg q2w Vs Placebo

Comparison groups

OKZ 64 mg q2w v Placebo

Number of subjects included in analysis

707

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0008 ^[24]

Method

Chi-squared

Parameter type

Risk difference (RD)

Point estimate

0.071

Confidence interval

level

97.5%

sides

2-sided

lower limit

0.022

upper limit

0.113

Notes
[24] - P-values are 1-sided α=0.025 significance level from 2x2 chi-square test.

Comparison of Adalimumab 40 mg q2w Vs Placebo

Comparison groups

Adalimumab 40 mg q2w v Placebo

Number of subjects included in analysis

705

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Risk difference (RD)

Point estimate

0.089

Confidence interval

level

95%

sides

2-sided

lower limit

0.046

upper limit

0.127

Comparison of OKZ 64 mg q4w Vs Adalimumab 40mg q2w

Comparison groups

OKZ 64 mg q4w v Adalimumab 40 mg q2w

Number of subjects included in analysis

941

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[25]

Method

Parameter type

Risk difference (RD)

Point estimate

-0.009

Confidence interval

level

97.5%

sides

2-sided

lower limit

-0.058

upper limit

0.04

Notes
[25] - Confidence Interval is calculated using Newcombe hybrid score method.

Comparison of OKZ 64 mg q2w Vs Adalimumab 40mg q2w

Comparison groups

OKZ 64 mg q2w v Adalimumab 40 mg q2w

Number of subjects included in analysis

926

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[26]

Method

Parameter type

Risk difference (RD)

Point estimate

-0.018

Confidence interval

level

97.5%

sides

2-sided

lower limit

-0.066

upper limit

0.031

Notes
[26] - Confidence Interval is calculated using Newcombe hybrid score method.

Adverse events

Top of page

Timeframe for reporting adverse events

Treatment emergent adverse events (TEAEs) were recorded after the first dose of the study treatment until the last visit of the subject in the study (up to 44 weeks in total) regardless of relationship to study treatment.

Adverse event reporting additional description

The safety population included all subjects who received at least 1 dose of study treatment. Data for TEAEs were reported below. A TEAE was defined as an adverse event that first occurred or worsened in severity after the first dose of the study treatment.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

22.1

Reporting group title

OKZ 64 mg q4w

Reporting group description

Subjects received a SC injection of OKZ 64 mg q4w alternating with SC injections of placebo q4w to maintain blinding and stable dose of MTX. The last dose of study treatment was at Week 22 of the Treatment Period from Week 0 to Week 24. After completion of the double-blind Treatment Period at Week 24, subjects were offered the opportunity to enter the optional OLE study. Subjects who did not consent to participate in the OLE study attended the EoT Visit at Week 24. After the EoT Visit, these subjects were scheduled for 3 Safety Follow-Up Visits up to Week 44.

Reporting group title

OKZ 64 mg q2w

Reporting group description

Reporting group title

Adalimumab 40 mg q2w

Reporting group description

Reporting group title

Placebo

Reporting group description

Serious adverse events	OKZ 64 mg q4w	OKZ 64 mg q2w	Adalimumab 40 mg q2w	Placebo
Total subjects affected by serious adverse events
subjects affected / exposed	20 / 477 (4.19%)	22 / 463 (4.75%)	26 / 462 (5.63%)	12 / 243 (4.94%)
number of deaths (all causes)	2	3	1	1
number of deaths resulting from adverse events	2	3	1	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Papillary thyroid cancer
subjects affected / exposed	1 / 477 (0.21%)	1 / 463 (0.22%)	0 / 462 (0.00%)	1 / 243 (0.41%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Prostate cancer
subjects affected / exposed	1 / 477 (0.21%)	0 / 463 (0.00%)	1 / 462 (0.22%)	0 / 243 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Adenocarcinoma of colon
subjects affected / exposed	0 / 477 (0.00%)	0 / 463 (0.00%)	0 / 462 (0.00%)	1 / 243 (0.41%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bladder transitional cell carcinoma stage IV
subjects affected / exposed	0 / 477 (0.00%)	1 / 463 (0.22%)	0 / 462 (0.00%)	0 / 243 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bronchial carcinoma
subjects affected / exposed	0 / 477 (0.00%)	0 / 463 (0.00%)	1 / 462 (0.22%)	0 / 243 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Leiomyoma
subjects affected / exposed	0 / 477 (0.00%)	1 / 463 (0.22%)	0 / 462 (0.00%)	0 / 243 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lung adenocarcinoma stage III
subjects affected / exposed	0 / 477 (0.00%)	0 / 463 (0.00%)	0 / 462 (0.00%)	1 / 243 (0.41%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Deep vein thrombosis
subjects affected / exposed	1 / 477 (0.21%)	1 / 463 (0.22%)	1 / 462 (0.22%)	0 / 243 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypertension
subjects affected / exposed	1 / 477 (0.21%)	0 / 463 (0.00%)	0 / 462 (0.00%)	0 / 243 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Thrombophlebitis
subjects affected / exposed	0 / 477 (0.00%)	1 / 463 (0.22%)	0 / 462 (0.00%)	0 / 243 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Surgical and medical procedures
Surgery
subjects affected / exposed	1 / 477 (0.21%)	0 / 463 (0.00%)	0 / 462 (0.00%)	0 / 243 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Injection site inflammation
subjects affected / exposed	0 / 477 (0.00%)	1 / 463 (0.22%)	0 / 462 (0.00%)	0 / 243 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Non-cardiac chest pain
subjects affected / exposed	0 / 477 (0.00%)	1 / 463 (0.22%)	0 / 462 (0.00%)	0 / 243 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Polyp
subjects affected / exposed	1 / 477 (0.21%)	0 / 463 (0.00%)	0 / 462 (0.00%)	0 / 243 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	0 / 477 (0.00%)	0 / 463 (0.00%)	1 / 462 (0.22%)	0 / 243 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Sudden death
subjects affected / exposed	0 / 477 (0.00%)	0 / 463 (0.00%)	0 / 462 (0.00%)	1 / 243 (0.41%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Reproductive system and breast disorders
Uterine prolapse
subjects affected / exposed	1 / 477 (0.21%)	0 / 463 (0.00%)	0 / 462 (0.00%)	0 / 243 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Interstitial lung disease
subjects affected / exposed	0 / 477 (0.00%)	0 / 463 (0.00%)	2 / 462 (0.43%)	0 / 243 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	0 / 477 (0.00%)	1 / 463 (0.22%)	0 / 462 (0.00%)	0 / 243 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Rheumatoid lung
subjects affected / exposed	0 / 477 (0.00%)	0 / 463 (0.00%)	1 / 462 (0.22%)	0 / 243 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Confusional state
subjects affected / exposed	0 / 477 (0.00%)	0 / 463 (0.00%)	1 / 462 (0.22%)	0 / 243 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Alanine aminotransferase increased
subjects affected / exposed	2 / 477 (0.42%)	1 / 463 (0.22%)	1 / 462 (0.22%)	0 / 243 (0.00%)
occurrences causally related to treatment / all	2 / 2	2 / 2	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Transaminases increased
subjects affected / exposed	0 / 477 (0.00%)	2 / 463 (0.43%)	0 / 462 (0.00%)	1 / 243 (0.41%)
occurrences causally related to treatment / all	0 / 0	2 / 2	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatic enzyme increased
subjects affected / exposed	0 / 477 (0.00%)	0 / 463 (0.00%)	0 / 462 (0.00%)	1 / 243 (0.41%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Femur fracture
subjects affected / exposed	0 / 477 (0.00%)	1 / 463 (0.22%)	0 / 462 (0.00%)	0 / 243 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Tibia fracture
subjects affected / exposed	0 / 477 (0.00%)	0 / 463 (0.00%)	0 / 462 (0.00%)	1 / 243 (0.41%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Pericarditis
subjects affected / exposed	0 / 477 (0.00%)	0 / 463 (0.00%)	1 / 462 (0.22%)	0 / 243 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	0 / 477 (0.00%)	0 / 463 (0.00%)	1 / 462 (0.22%)	0 / 243 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Myocardial infarction
subjects affected / exposed	1 / 477 (0.21%)	0 / 463 (0.00%)	0 / 462 (0.00%)	0 / 243 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Myocardial ischaemia
subjects affected / exposed	1 / 477 (0.21%)	0 / 463 (0.00%)	0 / 462 (0.00%)	0 / 243 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
Nervous system disorders
Cerebral haemorrhage
subjects affected / exposed	0 / 477 (0.00%)	1 / 463 (0.22%)	0 / 462 (0.00%)	0 / 243 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cerebral infarction
subjects affected / exposed	0 / 477 (0.00%)	0 / 463 (0.00%)	1 / 462 (0.22%)	0 / 243 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cerebrovascular accident
subjects affected / exposed	0 / 477 (0.00%)	1 / 463 (0.22%)	0 / 462 (0.00%)	0 / 243 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Ischaemic stroke
subjects affected / exposed	0 / 477 (0.00%)	0 / 463 (0.00%)	1 / 462 (0.22%)	0 / 243 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Sciatica
subjects affected / exposed	0 / 477 (0.00%)	1 / 463 (0.22%)	0 / 462 (0.00%)	0 / 243 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 477 (0.00%)	0 / 463 (0.00%)	1 / 462 (0.22%)	0 / 243 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Microcytic anaemia
subjects affected / exposed	0 / 477 (0.00%)	0 / 463 (0.00%)	1 / 462 (0.22%)	0 / 243 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pancytopenia
subjects affected / exposed	1 / 477 (0.21%)	0 / 463 (0.00%)	0 / 462 (0.00%)	0 / 243 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Eye disorders
Cataract
subjects affected / exposed	1 / 477 (0.21%)	0 / 463 (0.00%)	0 / 462 (0.00%)	0 / 243 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Colitis
subjects affected / exposed	0 / 477 (0.00%)	0 / 463 (0.00%)	1 / 462 (0.22%)	0 / 243 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diverticulum intestinal
subjects affected / exposed	0 / 477 (0.00%)	1 / 463 (0.22%)	0 / 462 (0.00%)	0 / 243 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Food poisoning
subjects affected / exposed	0 / 477 (0.00%)	0 / 463 (0.00%)	1 / 462 (0.22%)	0 / 243 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal inflammation
subjects affected / exposed	0 / 477 (0.00%)	0 / 463 (0.00%)	1 / 462 (0.22%)	0 / 243 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumoperitoneum
subjects affected / exposed	0 / 477 (0.00%)	1 / 463 (0.22%)	0 / 462 (0.00%)	0 / 243 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Hepatotoxicity
subjects affected / exposed	1 / 477 (0.21%)	0 / 463 (0.00%)	0 / 462 (0.00%)	1 / 243 (0.41%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cholecystitis
subjects affected / exposed	0 / 477 (0.00%)	1 / 463 (0.22%)	0 / 462 (0.00%)	0 / 243 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cholelithiasis
subjects affected / exposed	0 / 477 (0.00%)	1 / 463 (0.22%)	0 / 462 (0.00%)	0 / 243 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatic steatosis
subjects affected / exposed	1 / 477 (0.21%)	0 / 463 (0.00%)	0 / 462 (0.00%)	0 / 243 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Intervertebral disc disorder
subjects affected / exposed	0 / 477 (0.00%)	1 / 463 (0.22%)	0 / 462 (0.00%)	0 / 243 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Joint effusion
subjects affected / exposed	0 / 477 (0.00%)	0 / 463 (0.00%)	1 / 462 (0.22%)	0 / 243 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Osteoarthritis
subjects affected / exposed	0 / 477 (0.00%)	0 / 463 (0.00%)	1 / 462 (0.22%)	0 / 243 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Pneumonia
subjects affected / exposed	1 / 477 (0.21%)	1 / 463 (0.22%)	6 / 462 (1.30%)	0 / 243 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	2 / 6	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	1 / 477 (0.21%)	1 / 463 (0.22%)	2 / 462 (0.43%)	0 / 243 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 1	0 / 1	0 / 0
Urosepsis
subjects affected / exposed	0 / 477 (0.00%)	0 / 463 (0.00%)	2 / 462 (0.43%)	2 / 243 (0.82%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 2	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	2 / 477 (0.42%)	0 / 463 (0.00%)	0 / 462 (0.00%)	0 / 243 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Erysipelas
subjects affected / exposed	1 / 477 (0.21%)	1 / 463 (0.22%)	0 / 462 (0.00%)	0 / 243 (0.00%)
occurrences causally related to treatment / all	1 / 1	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Intervertebral discitis
subjects affected / exposed	0 / 477 (0.00%)	1 / 463 (0.22%)	1 / 462 (0.22%)	0 / 243 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	0 / 477 (0.00%)	0 / 463 (0.00%)	2 / 462 (0.43%)	0 / 243 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal abscess
subjects affected / exposed	0 / 477 (0.00%)	1 / 463 (0.22%)	0 / 462 (0.00%)	0 / 243 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Abscess limb
subjects affected / exposed	0 / 477 (0.00%)	0 / 463 (0.00%)	0 / 462 (0.00%)	1 / 243 (0.41%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Appendicitis
subjects affected / exposed	0 / 477 (0.00%)	0 / 463 (0.00%)	1 / 462 (0.22%)	0 / 243 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	0 / 477 (0.00%)	0 / 463 (0.00%)	1 / 462 (0.22%)	0 / 243 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	0 / 477 (0.00%)	0 / 463 (0.00%)	1 / 462 (0.22%)	0 / 243 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Herpes zoster
subjects affected / exposed	0 / 477 (0.00%)	0 / 463 (0.00%)	1 / 462 (0.22%)	0 / 243 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Keratouveitis
subjects affected / exposed	0 / 477 (0.00%)	0 / 463 (0.00%)	0 / 462 (0.00%)	1 / 243 (0.41%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Latent tuberculosis
subjects affected / exposed	0 / 477 (0.00%)	0 / 463 (0.00%)	1 / 462 (0.22%)	0 / 243 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lyme disease
subjects affected / exposed	0 / 477 (0.00%)	0 / 463 (0.00%)	1 / 462 (0.22%)	0 / 243 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pharyngitis streptococcal
subjects affected / exposed	1 / 477 (0.21%)	0 / 463 (0.00%)	0 / 462 (0.00%)	0 / 243 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Postoperative wound infection
subjects affected / exposed	0 / 477 (0.00%)	0 / 463 (0.00%)	1 / 462 (0.22%)	0 / 243 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary tuberculosis
subjects affected / exposed	1 / 477 (0.21%)	0 / 463 (0.00%)	0 / 462 (0.00%)	0 / 243 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory tract infection
subjects affected / exposed	0 / 477 (0.00%)	0 / 463 (0.00%)	1 / 462 (0.22%)	0 / 243 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Septic shock
subjects affected / exposed	0 / 477 (0.00%)	1 / 463 (0.22%)	0 / 462 (0.00%)	0 / 243 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
Metabolism and nutrition disorders
Hypoglycaemia
subjects affected / exposed	0 / 477 (0.00%)	0 / 463 (0.00%)	1 / 462 (0.22%)	0 / 243 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 4%

Non-serious adverse events	OKZ 64 mg q4w	OKZ 64 mg q2w	Adalimumab 40 mg q2w	Placebo
Total subjects affected by non serious adverse events
subjects affected / exposed	177 / 477 (37.11%)	183 / 463 (39.52%)	129 / 462 (27.92%)	71 / 243 (29.22%)
Investigations
Alanine aminotransferase increased
subjects affected / exposed	53 / 477 (11.11%)	41 / 463 (8.86%)	9 / 462 (1.95%)	4 / 243 (1.65%)
occurrences all number	88	70	20	7
Aspartate aminotransferase increased
subjects affected / exposed	24 / 477 (5.03%)	23 / 463 (4.97%)	8 / 462 (1.73%)	2 / 243 (0.82%)
occurrences all number	38	27	15	2
Vascular disorders
Hypertension
subjects affected / exposed	27 / 477 (5.66%)	25 / 463 (5.40%)	13 / 462 (2.81%)	8 / 243 (3.29%)
occurrences all number	31	26	13	8
Nervous system disorders
Headache
subjects affected / exposed	11 / 477 (2.31%)	10 / 463 (2.16%)	14 / 462 (3.03%)	12 / 243 (4.94%)
occurrences all number	12	11	17	12
General disorders and administration site conditions
Injection site erythema
subjects affected / exposed	8 / 477 (1.68%)	8 / 463 (1.73%)	20 / 462 (4.33%)	2 / 243 (0.82%)
occurrences all number	8	12	51	2
Infections and infestations
Nasopharyngitis
subjects affected / exposed	26 / 477 (5.45%)	29 / 463 (6.26%)	29 / 462 (6.28%)	18 / 243 (7.41%)
occurrences all number	34	35	32	23
Upper respiratory tract infection
subjects affected / exposed	29 / 477 (6.08%)	28 / 463 (6.05%)	26 / 462 (5.63%)	16 / 243 (6.58%)
occurrences all number	33	31	30	17
Urinary tract infection
subjects affected / exposed	14 / 477 (2.94%)	7 / 463 (1.51%)	19 / 462 (4.11%)	9 / 243 (3.70%)
occurrences all number	14	9	20	10
Bronchitis
subjects affected / exposed	10 / 477 (2.10%)	12 / 463 (2.59%)	11 / 462 (2.38%)	11 / 243 (4.53%)
occurrences all number	10	12	13	11
Metabolism and nutrition disorders
Hypercholesterolaemia
subjects affected / exposed	20 / 477 (4.19%)	29 / 463 (6.26%)	6 / 462 (1.30%)	3 / 243 (1.23%)
occurrences all number	20	29	6	3
Dyslipidaemia
subjects affected / exposed	15 / 477 (3.14%)	25 / 463 (5.40%)	4 / 462 (0.87%)	4 / 243 (1.65%)
occurrences all number	15	28	4	4
Hyperlipidaemia
subjects affected / exposed	10 / 477 (2.10%)	22 / 463 (4.75%)	5 / 462 (1.08%)	2 / 243 (0.82%)
occurrences all number	10	24	6	2

More information

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Were there any global substantial amendments to the protocol? Yes

29 Sep 2016

The significant changes to the protocol included: • The primary efficacy assessment and all secondary efficacy endpoints which previously planned to be assessed at Week 14 were moved from Week 14 to Week 12. • A new secondary efficacy endpoint, the percentage of subjects achieving low disease activity, defined as DAS28 (CRP) <3.2 was added. • One of the secondary efficacy endpoints was changed from the percentage of subjects with Simplified Disease Activity Index ≤3.3 evaluated at Week 24 to the percentage of subjects with CDAI ≤2.8 evaluated at Week 24. • The percentage of subjects with CDAI ≤2.8 at all other applicable time points and change from baseline to Weeks 12 and 24 in the Short Form 36 Mental Component Summary total score were added as other efficacy endpoints. • Folic acid was added as a required concomitant medication to counteract the potential side effects of MTX. • The prior use of all biologic disease-modifying anti-rheumatic drugs (including anakinra and abatacept) was made exclusionary. • Subjects with positive interferon-gamma release assay result at screening, or a history of untreated latent tuberculosis infection (LTBI) were allowed to enroll in the study if active tuberculosis was ruled out by a certified tuberculosis specialist or pulmonologist who was experienced in diagnosing and treating tuberculosis and in case of presence prophylactic treatment of LTBI. • Additional guidance for monitoring and reporting events of potential hepatotoxicity was added and potential hepatotoxicity events that fulfilled certain criteria were to be recorded as serious. • Guidance for the management of LTBI was added.

23 Nov 2016

The study protocol was amended to indicate that both the 0.4 mL and 0.8 mL prefilled syringes were to be used in the study. There were no changes to the conduct of the study as a result of this amendment.

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 Randomized, Double-Blind, Parallel-Group, Placebo- and Active-Controlled, Multicenter Phase III Study of the Efficacy and Safety of Olokizumab in Subjects with Moderately to Severely Active Rheumatoid Arthritis Inadequately Controlled by Methotrexate Therapy

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Percentage of Subjects Meeting the ACR20 at Week 12 (OKZ Comparison with Placebo)

Primary: Percentage of Subjects Meeting the ACR20 at Week 12 (OKZ Comparison with Placebo)

Secondary: Percentage of Subjects Meeting the ACR20 at Week 12 (OKZ Comparison with Adalimumab)

Secondary: Percentage of Subjects Meeting the ACR20 at Week 12 (OKZ Comparison with Adalimumab)

Secondary: Percentage of Subjects Achieving Low Disease Activity, Defined as Disease Activity Score 28-Joint Count CRP (DAS 28 [CRP]) <3.2 at Week 12

Secondary: Percentage of Subjects Achieving Low Disease Activity, Defined as Disease Activity Score 28-Joint Count CRP (DAS 28 [CRP]) <3.2 at Week 12

Secondary: Mean Change from Baseline to Week 12 in HAQ-DI

Secondary: Mean Change from Baseline to Week 12 in HAQ-DI

Secondary: Percentage of Subjects Achieving American College of Rheumatology 50% Response Criteria (ACR50) at Week 24

Secondary: Percentage of Subjects Achieving American College of Rheumatology 50% Response Criteria (ACR50) at Week 24

Secondary: Percentage of Subjects Achieving Remission, Defined as Clinical Disease Activity Index (CDAI) ≤2.8 (Remission) at Week 24

Secondary: Percentage of Subjects Achieving Remission, Defined as Clinical Disease Activity Index (CDAI) ≤2.8 (Remission) at Week 24

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical trials

Clinical Trial Results: A Randomized, Double-Blind, Parallel-Group, Placebo- and Active-Controlled, Multicenter Phase III Study of the Efficacy and Safety of Olokizumab in Subjects with Moderately to Severely Active Rheumatoid Arthritis Inadequately Controlled by Methotrexate Therapy

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Percentage of Subjects Meeting the ACR20 at Week 12 (OKZ Comparison with Placebo)

Primary: Percentage of Subjects Meeting the ACR20 at Week 12 (OKZ Comparison with Placebo)

Secondary: Percentage of Subjects Meeting the ACR20 at Week 12 (OKZ Comparison with Adalimumab)

Secondary: Percentage of Subjects Meeting the ACR20 at Week 12 (OKZ Comparison with Adalimumab)

Secondary: Percentage of Subjects Achieving Low Disease Activity, Defined as Disease Activity Score 28-Joint Count CRP (DAS 28 [CRP]) <3.2 at Week 12

Secondary: Percentage of Subjects Achieving Low Disease Activity, Defined as Disease Activity Score 28-Joint Count CRP (DAS 28 [CRP]) <3.2 at Week 12

Secondary: Mean Change from Baseline to Week 12 in HAQ-DI

Secondary: Mean Change from Baseline to Week 12 in HAQ-DI

Secondary: Percentage of Subjects Achieving American College of Rheumatology 50% Response Criteria (ACR50) at Week 24

Secondary: Percentage of Subjects Achieving American College of Rheumatology 50% Response Criteria (ACR50) at Week 24

Secondary: Percentage of Subjects Achieving Remission, Defined as Clinical Disease Activity Index (CDAI) ≤2.8 (Remission) at Week 24

Secondary: Percentage of Subjects Achieving Remission, Defined as Clinical Disease Activity Index (CDAI) ≤2.8 (Remission) at Week 24

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Randomized, Double-Blind, Parallel-Group, Placebo- and Active-Controlled, Multicenter Phase III Study of the Efficacy and Safety of Olokizumab in Subjects with Moderately to Severely Active Rheumatoid Arthritis Inadequately Controlled by Methotrexate Therapy