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Clinical Trial Results:
A Randomized, Double-Blind, Parallel-Group, Placebo-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	2014-004719-36
Trial protocol	BG
Global end of trial date	29 Apr 2019

Results information
Results version number	v1(current)
This version publication date	07 May 2020
First version publication date	07 May 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

CL04041022

ISRCTN number

US NCT number

NCT02760368

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

29 Apr 2019

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

29 Apr 2019

Was the trial ended prematurely?

Main objective of the trial

The primary objective was to evaluate the efficacy of Olokizumab (OKZ) 64 milligrams (mg) administered subcutaneously (SC) once every 2 weeks (q2w) or once every 4 weeks (q4w) relative to placebo in subjects with moderately to severely active rheumatoid arthritis (RA) inadequately controlled by methotrexate (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

All subjects continued to receive their prior background therapy (MTX) during the study. In accordance with the inclusion criteria, subjects must have been treated with MTX at a dose of 15 to 25 mg/week (or ≥10 mg/week if there was documented intolerance to higher doses) for at least 12 weeks prior to Screening with a stable dose and an unchanged mode of administration (oral, SC, or intramuscular [IM]) for at least 6 weeks prior to Screening. The dose of background MTX was to remain unchanged throughout the study but could be adjusted once during the study and only for safety reasons according to the Investigator’s discretion. Concomitant treatment with folic acid ≥5 mg per week or equivalent was required for all subjects starting by Visit 2 (Week 0). Folic acid or equivalent was not to be taken on the same day as MTX.

Evidence for comparator

Actual start date of recruitment

19 May 2016

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Belarus: 20

Country: Number of subjects enrolled

Bulgaria: 27

Country: Number of subjects enrolled

Russian Federation: 381

Worldwide total number of subjects

428

EEA total number of subjects

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)

378

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

This was a randomized, double-blind, parallel-group, placebo-controlled, multicenter study running between 19 May 2016 and 29 April 2019. Four hundred and twenty eight subjects in 3 countries (Belarus, Russian Federation and Bulgaria) were eligible to enter the study and receive treatment.

Screening details

Subjects with moderately to severely active, adult onset, RA disease with an inadequate response to treatment with oral, SC, or IM MTX for at least 12 weeks prior to Screening were assessed for eligibility. Eligible subjects were randomized in a 1:1:1 ratio to receive 64 mg OKZ q2w, 64 mg OKZ q4w, or placebo for 24 weeks.

Period 1 title

Overall Period

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Carer, Assessor

Blinding implementation details

The placebo differed in appearance from OKZ, and was prepared by independent unblinded pharmacist or designee and provided to the blinded site staff in blinded syringes.

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. All subjects continued to receive MTX during the study. After completion of the double-blind Treatment Period at Week 22, subjects could enter an 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

OKZ

Other name

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 q4w (alternating with OKZ 64 mg q4w, in order to maintain the blinding). Placebo (sodium chloride 0.9%) was administered 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. All subjects continued to receive MTX during the study. All subjects continued to receive MTX during the study. After completion of the double-blind Treatment Period with at Week 22, subjects could enter an 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

OKZ

Other name

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.

Placebo

Arm description

Subjects received a SC injection of placebo q2w. All subjects continued to receive MTX during the study. After completion of the double-blind Treatment Period with at Week 22, subjects could enter an 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	Placebo
Started	142	143	143
Completed Treatment	131 ^[1]	129 ^[2]	134
Continued into Safety Follow Up	7 ^[3]	13 ^[4]	8 ^[5]
Enrolled in OLE Study	127 ^[6]	122 ^[7]	126 ^[8]
Completed	134	130	132
Not completed	8	13	11
Consent withdrawn by subject	8	12	9
Withdrawal by Sponsor	-	-	1
Death	-	1	-
Screen failure	-	-	1

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.

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

Placebo

Reporting group description

Reporting group values	OKZ 64 mg q4w	OKZ 64 mg q2w	Placebo	Total
Number of subjects	142	143	143	428
Age categorical
Units: Subjects
Adults (18-64 years)	129	125	124	378
From 65-84 years	13	18	19	50
85 years and over	0	0	0	0
Age continuous
Units: years
arithmetic mean (standard deviation)	49.1 ± 12.07	52.0 ± 11.77	52.7 ± 11.29	-
Gender categorical
Units: Subjects
Female	118	116	120	354
Male	24	27	23	74
Race
Units: Subjects
Asian	0	0	1	1
Black or African American	0	0	0	0
White	142	143	142	427
Other / Mixed	0	0	0	0

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

Placebo

Reporting group description

Primary: Percentage of Subjects Meeting the American College of Rheumatology 20% Response Criteria (ACR20) at Week 12

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End point title

Percentage of Subjects Meeting the American College of Rheumatology 20% Response Criteria (ACR20) at Week 12

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

End point values	OKZ 64 mg q4w	OKZ 64 mg q2w	Placebo
Number of subjects analysed	142	143	143
Units: Percentage of subjects
number (not applicable)	70.4	63.6	25.9

Comparison of OKZ 64 mg q4w vs Placebo

Comparison groups

OKZ 64 mg q4w v Placebo

Number of subjects included in analysis

285

Analysis specification

Pre-specified

Analysis type

superiority ^[1]

P-value

< 0.0001 ^[2]

Method

Chi-squared

Parameter type

Risk difference (RD)

Point estimate

0.445

Confidence interval

level

97.5%

sides

2-sided

lower limit

0.318

upper limit

0.552

Notes
[1] - Confidence Interval was calculated using Newcombe hybrid score method.
[2] - P-value was 1-sided p-value 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

286

Analysis specification

Pre-specified

Analysis type

superiority ^[3]

P-value

< 0.0001 ^[4]

Method

Chi-squared

Parameter type

Risk difference (RD)

Point estimate

0.378

Confidence interval

level

97.5%

sides

2-sided

lower limit

0.248

upper limit

0.489

Notes
[3] - Confidence Interval was calculated using Newcombe hybrid score method.
[4] - P-value was 1-sided p-value from 2x2 chi-square test.

Secondary: Percentage of Subjects with 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 with 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	Placebo
Number of subjects analysed	142	143	143
Units: Percentage of Subjects
number (not applicable)	38.7	33.6	3.5

Comparison of OKZ 64 mg q4w Vs Placebo

Comparison groups

OKZ 64 mg q4w v Placebo

Number of subjects included in analysis

285

Analysis specification

Pre-specified

Analysis type

superiority ^[5]

P-value

< 0.0001 ^[6]

Method

Chi-squared

Parameter type

Risk difference (RD)

Point estimate

0.352

Confidence interval

level

97.5%

sides

2-sided

lower limit

0.251

upper limit

0.449

Notes
[5] - Confidence Interval was calculated using Newcombe hybrid score method.
[6] - P-value was 1-sided p-value 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

286

Analysis specification

Pre-specified

Analysis type

superiority ^[7]

P-value

< 0.0001 ^[8]

Method

Chi-squared

Parameter type

Risk difference (RD)

Point estimate

0.301

Confidence interval

level

97.5%

sides

2-sided

lower limit

0.203

upper limit

0.396

Notes
[7] - Confidence Interval was calculated using Newcombe hybrid score method.
[8] - P-value was 1-sided p-value from 2x2 chi-square test.

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	Placebo
Number of subjects analysed	142	141	140
Units: Units on HAQ-DI scale
least squares mean (standard error)	-0.56 ± 0.042	-0.54 ± 0.041	-0.20 ± 0.042

Comparison of OKZ 64 mg q4w Vs Placebo

Comparison groups

OKZ 64 mg q4w v Placebo

Number of subjects included in analysis

282

Analysis specification

Pre-specified

Analysis type

superiority ^[9]

P-value

< 0.0001 ^[10]

Method

ANCOVA

Parameter type

LSM difference

Point estimate

-0.36

Confidence interval

level

97.5%

sides

2-sided

lower limit

-0.49

upper limit

-0.23

Variability estimate

Standard error of the mean

Dispersion value

0.059

Notes
[9] - ANCOVA model included treatment as fixed effect and Baseline value as a covariate. LSMs and P-value were obtained using Rubins's rule.
[10] - P-value represents a 1-sided combined test for treatment effect from the ANCOVA model.

Comparison of OKZ 64 mg q2w Vs Placebo

Comparison groups

Placebo v OKZ 64 mg q2w

Number of subjects included in analysis

281

Analysis specification

Pre-specified

Analysis type

superiority ^[11]

P-value

< 0.0001 ^[12]

Method

ANCOVA

Parameter type

LSM difference

Point estimate

-0.34

Confidence interval

level

97.5%

sides

2-sided

lower limit

-0.47

upper limit

-0.21

Variability estimate

Standard error of the mean

Dispersion value

0.059

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

Secondary: Percentage of Subjects Achieving an ACR50 response at Week 24

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End point title

Percentage of Subjects Achieving an ACR50 response 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	Placebo
Number of subjects analysed	142	143	143
Units: Percentage of Subjects
number (not applicable)	48.6	42.7	7.7

Comparison of OKZ 64 mg q4w Vs Placebo

Comparison groups

OKZ 64 mg q4w v Placebo

Number of subjects included in analysis

285

Analysis specification

Pre-specified

Analysis type

superiority ^[13]

P-value

< 0.0001 ^[14]

Method

Chi-squared

Parameter type

Risk difference (RD)

Point estimate

0.409

Confidence interval

level

97.5%

sides

2-sided

lower limit

0.296

upper limit

0.509

Notes
[13] - Confidence Interval was calculated using Newcombe hybrid score method.
[14] - P-value was 1 sided p-value 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

286

Analysis specification

Pre-specified

Analysis type

superiority ^[15]

P-value

< 0.0001 ^[16]

Method

Chi-squared

Parameter type

Risk difference (RD)

Point estimate

0.35

Confidence interval

level

97.5%

sides

2-sided

lower limit

0.239

upper limit

0.45

Notes
[15] - Confidence Interval was calculated using Newcombe hybrid score method.
[16] - P-value was 1 sided p-value from 2x2 chi-square test.

Secondary: Percentage of Subjects with Clinical Disease Activity Index (CDAI) ≤2.8 (remission) at Week 24

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End point title

Percentage of Subjects with 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 mm) 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	Placebo
Number of subjects analysed	142	143	143
Units: Percentage of Subjects
number (not applicable)	7.7	8.4	0.0

Comparison of OKZ 64 mg q4w Vs Placebo

Comparison groups

OKZ 64 mg q4w v Placebo

Number of subjects included in analysis

285

Analysis specification

Pre-specified

Analysis type

superiority ^[17]

P-value

= 0.0003 ^[18]

Method

Chi-squared

Parameter type

Risk difference (RD)

Point estimate

0.077

Confidence interval

level

97.5%

sides

2-sided

lower limit

0.027

upper limit

0.143

Notes
[17] - Confidence Interval was calculated using Newcombe hybrid score method.
[18] - P-value was 1-sided p-value 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

286

Analysis specification

Pre-specified

Analysis type

superiority ^[19]

P-value

= 0.0002 ^[20]

Method

Chi-squared

Parameter type

Risk difference (RD)

Point estimate

0.084

Confidence interval

level

97.5%

sides

2-sided

lower limit

0.032

upper limit

0.151

Notes
[19] - Confidence Interval was calculated using Newcombe hybrid score method.
[20] - P-value was 1-sided p-value from 2x2 chi-square test.

Adverse events

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Timeframe for reporting adverse events

Treatment emergent adverse events were recorded after the first dose of the study treatment until 22 weeks after the last dose of study treatment (a total of 44 weeks).

Adverse event reporting additional description

The safety population included all subjects who received at least 1 dose of study treatment.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

21.1

Reporting group title

OKZ 64 mg q4w

Reporting group description

Subjects received a SC injection of OKZ 64 mg q4w, alternating with SC injection of placebo q4w to maintain blinding. All subjects continued to receive MTX during the study.After completion of the double-blind Treatment Period with at Week 22, subjects could enter an 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

Subjects received a SC injection of OKZ 64 mg q2w. All subjects continued to receive MTX during the study. After completion of the double-blind Treatment Period with at Week 22, subjects could enter an 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

Placebo

Reporting group description

Serious adverse events	OKZ 64 mg q4w	OKZ 64 mg q2w	Placebo
Total subjects affected by serious adverse events
subjects affected / exposed	8 / 142 (5.63%)	8 / 143 (5.59%)	4 / 142 (2.82%)
number of deaths (all causes)	0	1	0
number of deaths resulting from adverse events	0	1	0
Investigations
Alanine aminotransferase increased
subjects affected / exposed	4 / 142 (2.82%)	2 / 143 (1.40%)	1 / 142 (0.70%)
occurrences causally related to treatment / all	5 / 5	2 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Aspartate aminotransferase increased
subjects affected / exposed	3 / 142 (2.11%)	0 / 143 (0.00%)	0 / 142 (0.00%)
occurrences causally related to treatment / all	3 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cervix carcinoma stage II
subjects affected / exposed	1 / 142 (0.70%)	0 / 143 (0.00%)	0 / 142 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vascular disorders
Diabetic vascular disorder
subjects affected / exposed	1 / 142 (0.70%)	0 / 143 (0.00%)	0 / 142 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nervous system disorders
Vertebrobasilar insufficiency
subjects affected / exposed	1 / 142 (0.70%)	0 / 143 (0.00%)	0 / 142 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Obstructive pancreatitis
subjects affected / exposed	1 / 142 (0.70%)	0 / 143 (0.00%)	0 / 142 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Drug-induced liver injury
subjects affected / exposed	1 / 142 (0.70%)	0 / 143 (0.00%)	0 / 142 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Renal cyst
subjects affected / exposed	0 / 142 (0.00%)	1 / 143 (0.70%)	0 / 142 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Rheumatoid arthritis
subjects affected / exposed	0 / 142 (0.00%)	2 / 143 (1.40%)	1 / 142 (0.70%)
occurrences causally related to treatment / all	0 / 0	0 / 2	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Fistula
subjects affected / exposed	1 / 142 (0.70%)	0 / 143 (0.00%)	0 / 142 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infections and infestations
Subcutaneous abscess
subjects affected / exposed	0 / 142 (0.00%)	2 / 143 (1.40%)	0 / 142 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	0 / 142 (0.00%)	0 / 143 (0.00%)	1 / 142 (0.70%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 142 (0.00%)	0 / 143 (0.00%)	1 / 142 (0.70%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pulmonary tuberculosis
subjects affected / exposed	0 / 142 (0.00%)	1 / 143 (0.70%)	0 / 142 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Staphylococcal sepsis
subjects affected / exposed	0 / 142 (0.00%)	1 / 143 (0.70%)	0 / 142 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Toxic shock syndrome
subjects affected / exposed	0 / 142 (0.00%)	1 / 143 (0.70%)	0 / 142 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0

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

Non-serious adverse events	OKZ 64 mg q4w	OKZ 64 mg q2w	Placebo
Total subjects affected by non serious adverse events
subjects affected / exposed	53 / 142 (37.32%)	51 / 143 (35.66%)	35 / 142 (24.65%)
Investigations
Alanine aminotransferase increased
subjects affected / exposed	30 / 142 (21.13%)	25 / 143 (17.48%)	11 / 142 (7.75%)
occurrences all number	24	32	14
Aspartate aminotransferase increased
subjects affected / exposed	19 / 142 (13.38%)	16 / 143 (11.19%)	10 / 142 (7.04%)
occurrences all number	27	22	12
White blood cell count decreased
subjects affected / exposed	6 / 142 (4.23%)	7 / 143 (4.90%)	4 / 142 (2.82%)
occurrences all number	13	9	5
Neutrophil count decreased
subjects affected / exposed	7 / 142 (4.93%)	6 / 143 (4.20%)	3 / 142 (2.11%)
occurrences all number	10	6	4
Blood cholesterol increased
subjects affected / exposed	4 / 142 (2.82%)	6 / 143 (4.20%)	3 / 142 (2.11%)
occurrences all number	4	7	3
Gamma-glutamyltransferase increased
subjects affected / exposed	6 / 142 (4.23%)	3 / 143 (2.10%)	4 / 142 (2.82%)
occurrences all number	9	5	5
Blood and lymphatic system disorders
Leukopenia
subjects affected / exposed	7 / 142 (4.93%)	8 / 143 (5.59%)	4 / 142 (2.82%)
occurrences all number	10	10	4
Neutropenia
subjects affected / exposed	9 / 142 (6.34%)	5 / 143 (3.50%)	2 / 142 (1.41%)
occurrences all number	11	6	2
Anaemia
subjects affected / exposed	3 / 142 (2.11%)	4 / 143 (2.80%)	6 / 142 (4.23%)
occurrences all number	3	4	9
Infections and infestations
Nasopharyngitis
subjects affected / exposed	3 / 142 (2.11%)	4 / 143 (2.80%)	6 / 142 (4.23%)
occurrences all number	3	4	8
Upper respiratory tract infection
subjects affected / exposed	6 / 142 (4.23%)	2 / 143 (1.40%)	4 / 142 (2.82%)
occurrences all number	9	2	4

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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 2 of the secondary efficacy endpoints (DAS28 [CRP] and HAQ-DI) were moved from Week 14 to Week 12. • 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 additional efficacy endpoints. • The definition of moderate response in the other efficacy endpoint assessing the proportion of subjects with moderate to good response based on DAS28 (CRP) was revised to DAS28 (CRP) ≤5.1 with an improvement from baseline in DAS28 (CRP) >0.6 and ≤1.2, or DAS28 (CRP) >3.2 with an improvement from baseline in DAS28 (CRP) >1.2. • The requirement that subjects must be anti-citrullinated protein antibody positive or rheumatoid factor positive at Screening was removed as an inclusion criterion. • The prior use of all biologic disease-modifying anti-rheumatic drugs was made exclusionary. • Subjects with a history of no response to the rescue medications used in this study were excluded. • Subjects with positive interferon-gamma release assay result, history of latent tuberculosis infection (LTBI) or who developed LTBI during the study were allowed to begin or continue study treatment if active tuberculosis was ruled out and the subject has started and agreed to complete the recommend course of LTBI therapy. • Additional guidance for monitoring and reporting hepatotoxicity events was added and potential hepatotoxicity events that fulfilled certain criteria were to be recorded as serious.

Were there any global interruptions to the trial? Yes

Date	Interruption	Restart date
10 Jun 2016	After 1 subject was randomized in Bulgaria, the sponsor temporarily suspended the trial as data indicated that the Investigational Product was out of specification. The 1 subject was removed from the trial. Subject enrolment was reinitiated in all sites beginning on 10 Jan 2017.	10 Jan 2017

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-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 American College of Rheumatology 20% Response Criteria (ACR20) at Week 12

Primary: Percentage of Subjects Meeting the American College of Rheumatology 20% Response Criteria (ACR20) at Week 12

Secondary: Percentage of Subjects with Disease Activity Score 28-Joint Count CRP (DAS 28 [CRP]) <3.2 at Week 12

Secondary: Percentage of Subjects with 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 an ACR50 response at Week 24

Secondary: Percentage of Subjects Achieving an ACR50 response at Week 24

Secondary: Percentage of Subjects with Clinical Disease Activity Index (CDAI) ≤2.8 (remission) at Week 24

Secondary: Percentage of Subjects with Clinical Disease Activity Index (CDAI) ≤2.8 (remission) at Week 24

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

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Clinical trials

Clinical Trial Results: A Randomized, Double-Blind, Parallel-Group, Placebo-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 American College of Rheumatology 20% Response Criteria (ACR20) at Week 12

Primary: Percentage of Subjects Meeting the American College of Rheumatology 20% Response Criteria (ACR20) at Week 12

Secondary: Percentage of Subjects with Disease Activity Score 28-Joint Count CRP (DAS 28 [CRP]) <3.2 at Week 12

Secondary: Percentage of Subjects with 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 an ACR50 response at Week 24

Secondary: Percentage of Subjects Achieving an ACR50 response at Week 24

Secondary: Percentage of Subjects with Clinical Disease Activity Index (CDAI) ≤2.8 (remission) at Week 24

Secondary: Percentage of Subjects with 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-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