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Clinical Trial Results:
A Phase 3, Multicenter Study with a 36-Week Open-Label Period Followed by a Randomized Double-Blind Withdrawal Period from Week 36 to Week 104 to Evaluate the Long Term Efficacy and Safety of Ixekizumab (LY2439821) 80 mg Every 2 Weeks in Biologic Disease-Modifying Antirheumatic Drug–Naive Patients with Active Psoriatic Arthritis

Summary
EudraCT number	2015-002433-22
Trial protocol	SK EE CZ GB ES BG PL
Global end of trial date	30 Oct 2018

Results information
Results version number	v1(current)
This version publication date	11 Nov 2019
First version publication date	11 Nov 2019
Other versions

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

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Trial information

Top of page

Sponsor protocol code

I1F-MC-RHBF

ISRCTN number

-

US NCT number

NCT02584855

WHO universal trial number (UTN)

-

Other trial identifiers

Trial Number: 14518

Sponsor organisation name

Eli Lilly and Company

Sponsor organisation address

Lilly Corporate Center, Indianapolis, IN, United States, 46285

Public contact

Available Mon ‐ Fri 9 AM ‐ 5 PM EST, Eli Lilly and Company, 1 877‐CTLilly,

Scientific contact

Available Mon ‐ Fri 9 AM ‐ 5 PM EST, Eli Lilly and Company, 1 877‐285‐4559,

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

No

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

No

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

No

Analysis stage

Final

Date of interim/final analysis

30 Oct 2018

Is this the analysis of the primary completion data?

No

Global end of trial reached?

Yes

Global end of trial date

30 Oct 2018

Was the trial ended prematurely?

No

Main objective of the trial

The main purpose of this study is to evaluate the safety and long-term efficacy of ixekizumab compared to placebo in participants with active psoriatic arthritis.

Protection of trial subjects

This study was conducted in accordance with International Conference on Harmonization (ICH) Good Clinical Practice, and the principles of the Declaration of Helsinki, in addition to following the laws and regulations of the country or countries in which a study is conducted.

Background therapy

-

Evidence for comparator

-

Actual start date of recruitment

18 Nov 2015

Long term follow-up planned

No

Independent data monitoring committee (IDMC) involvement?

No

Number of subjects enrolled per country

Country: Number of subjects enrolled

Czech Republic: 90

Country: Number of subjects enrolled

United States: 32

Country: Number of subjects enrolled

Ukraine: 43

Country: Number of subjects enrolled

Poland: 60

Country: Number of subjects enrolled

Mexico: 16

Country: Number of subjects enrolled

South Africa: 26

Country: Number of subjects enrolled

United Kingdom: 23

Country: Number of subjects enrolled

Slovakia: 16

Country: Number of subjects enrolled

Bulgaria: 20

Country: Number of subjects enrolled

Estonia: 47

Country: Number of subjects enrolled

Russian Federation: 10

Country: Number of subjects enrolled

Spain: 11

Worldwide total number of subjects

394

EEA total number of subjects

267

Number of subjects enrolled per age group

In utero

0

Preterm newborn - gestational age < 37 wk

0

Newborns (0-27 days)

0

Infants and toddlers (28 days-23 months)

0

Children (2-11 years)

0

Adolescents (12-17 years)

0

Adults (18-64 years)

371

From 65 to 84 years

23

85 years and over

0

Subject disposition

Top of page

Recruitment details

This study had four periods: Period 1: Screening period lasting from 4 to 30 days before Week 0, Period 2: Initial open-label treatment period from Week 0 up to Week 36, Period 3: randomized double-blind withdrawal period from Week 36 to week 104 (or, early termination or relapse) and Period 4: post treatment follow-up.

Screening details

Participants were randomized during week 36 to week 64. The criteria for randomization in period 3 was having received ixekizumab (IXE) 80 mg Q2W for at least 6 months and meeting Coates criteria for minimal disease activity (MDA) for 3 consecutive months over 4 consecutive visits.The criteria was met anytime from 36 to 64 weeks.

Period 1 title

Open-Label Treatment Period

Is this the baseline period?

Yes

Allocation method

Non-randomised - controlled

Blinding used

Not blinded

Ixekizumab Open Label

Arm description

Open-Label Treatment Period (OLTP): Starting dose of 160 milligrams (mg) ixekizumab given as two subcutaneous (SC) injections at baseline (Week 0) followed by 80 mg given as one SC injection every two weeks (Q2W) from week 2 to randomization (week 36 to 64).

Arm type

Experimental

Investigational medicinal product name

Ixekizumab

Investigational medicinal product code

Other name

LY2439821

Pharmaceutical forms

Injection

Routes of administration

Subcutaneous use

Dosage and administration details

160 milligrams (mg) ixekizumab given as two subcutaneous (SC) injections at baseline (Week 0) followed by 80 mg given as one SC injection every two weeks (Q2W) from week 2 to randomization (week 36 to 64).

Number of subjects in period 1	Ixekizumab Open Label
Started	394
Received at least one dose of study drug	394
Met randomization Criteria	158 ^[1]
Non-randomized	133 ^[2]
Completed	291
Not completed	103
Consent withdrawn by subject	21
Adverse event, non-fatal	14
Death	2
No PI Available	2
Sponsor Decision	1
Lost to follow-up	1
Lack of efficacy	61
Protocol deviation	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 reason why randomized + non randomized do not sum up to the total entered participants is because 103 participants discontinued open label treatment.
[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 reason why randomized + non randomized do not sum up to the total entered participants is because 103 participants discontinued open label treatment.

Period 2 title

Double-Blind Withdrawal Period

Is this the baseline period?

No

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Are arms mutually exclusive

Yes

IXE80Q2W Non-randomized

Arm description

Participants completed open label but did not meet criteria for randomization to the double-blind Withdrawal Period. Participants continued to receive 80 mg given as one SC injection every two weeks during the double-blind withdrawal period.

Arm type

Experimental

Investigational medicinal product name

Ixekizumab

Investigational medicinal product code

Other name

LY2439821

Pharmaceutical forms

Injection

Routes of administration

Subcutaneous use

Dosage and administration details

80 mg given as one SC injection every two weeks during the double-blind withdrawal period.

Ixekizumab

Arm description

Participants completed open label and met criteria for randomization to the double-blind Withdrawal Period. Double-Blind Withdrawal Period: 80 mg ixekizumab given as one SC injection Q2W from randomization to week 104 (or, early termination or relapse).

Arm type

Experimental

Investigational medicinal product name

Ixekizumab

Investigational medicinal product code

Other name

LY2439821

Pharmaceutical forms

Injection

Routes of administration

Subcutaneous use

Dosage and administration details

80 mg ixekizumab given as one SC injection Q2W from randomization to week 104 (or, early termination or relapse).

Placebo

Arm description

Participants completed open label and met criteria for randomization to the double-blind Withdrawal Period. Double-Blind Withdrawal Period: Placebo given as one SC injection Q2W any time from randomization to week 104 (or, early termination or relapse)

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Subcutaneous use

Dosage and administration details

Placebo given as one SC injection Q2W any time from randomization to week 104 (or, early termination or relapse)

Number of subjects in period 2	IXE80Q2W Non-randomized	Ixekizumab	Placebo
Started	133	79	79
Relapsed	0 ^[3]	67 ^[4]	30 ^[5]
Completed	118	77	78
Not completed	15	2	1
Consent withdrawn by subject	-	2	-
Adverse event, non-fatal	4	-	1
Declined Transfer to a Different Site	1	-	-
Lack of efficacy	10	-	-

Notes
[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 reason why randomized + non randomized do not sum up to the total entered participants is because 103 participants discontinued open label treatment.
[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 reason why randomized + non randomized do not sum up to the total entered participants is because 103 participants discontinued open label treatment.
[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 reason why randomized + non randomized do not sum up to the total entered participants is because 103 participants discontinued open label treatment.

Period 3 title

Post Treatment follow-up Period

Is this the baseline period?

No

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

No

IXE80Q2W Post-Treatment Follow-up Period

Arm description

Participants did not receive any study treatment during post treatment follow-up period. Post-Treatment Follow-up Period was summarized by last treatment assigned to a participant prior to entering the post-treatment follow up period.

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Placebo Post-Treatment Follow-up Period

Arm description

Participants did not receive any study treatment during post treatment follow-up period. Placebo Post-Treatment Follow-up Period was summarized by last treatment assigned to a participant prior to entering the post-treatment follow up period.

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Number of subjects in period 3	IXE80Q2W Post-Treatment Follow-up Period	Placebo Post-Treatment Follow-up Period
Started	355	12
Completed	347	12
Not completed	8	0
Consent withdrawn by subject	7	-
Protocol deviation	1	-

Baseline characteristics

Top of page

Reporting group title

Open-Label Treatment Period

Reporting group description

-

Reporting group values	Open-Label Treatment Period	Total
Number of subjects	394	394
Age categorical
Units: Subjects
Age continuous
All participants who received at least one dose of study drug.
Units: years
arithmetic mean (standard deviation)	47.4 ( 11.40 )	-
Gender categorical
Units: Subjects
Female	212	212
Male	182	182
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	16	16
Not Hispanic or Latino	330	330
Unknown or Not Reported	48	48
Race (NIH/OMB)
Units: Subjects
American Indian or Alaska Native	0	0
Asian	6	6
Native Hawaiian or Other Pacific Islander	0	0
Black or African American	1	1
White	385	385
More than one race	2	2
Unknown or Not Reported	0	0
Region of Enrollment
Units: Subjects
United States	32	32
Czechia	90	90
Ukraine	43	43
Poland	60	60
Mexico	16	16
South Africa	26	26
United Kingdom	23	23
Slovakia	16	16
Bulgaria	20	20
Estonia	47	47
Russia	10	10
Spain	11	11

End points

Top of page

Reporting group title

Ixekizumab Open Label

Reporting group description

Open-Label Treatment Period (OLTP): Starting dose of 160 milligrams (mg) ixekizumab given as two subcutaneous (SC) injections at baseline (Week 0) followed by 80 mg given as one SC injection every two weeks (Q2W) from week 2 to randomization (week 36 to 64).

Reporting group title

IXE80Q2W Non-randomized

Reporting group description

Participants completed open label but did not meet criteria for randomization to the double-blind Withdrawal Period. Participants continued to receive 80 mg given as one SC injection every two weeks during the double-blind withdrawal period.

Reporting group title

Ixekizumab

Reporting group description

Participants completed open label and met criteria for randomization to the double-blind Withdrawal Period. Double-Blind Withdrawal Period: 80 mg ixekizumab given as one SC injection Q2W from randomization to week 104 (or, early termination or relapse).

Reporting group title

Placebo

Reporting group description

Participants completed open label and met criteria for randomization to the double-blind Withdrawal Period. Double-Blind Withdrawal Period: Placebo given as one SC injection Q2W any time from randomization to week 104 (or, early termination or relapse)

Reporting group title

IXE80Q2W Post-Treatment Follow-up Period

Reporting group description

Participants did not receive any study treatment during post treatment follow-up period. Post-Treatment Follow-up Period was summarized by last treatment assigned to a participant prior to entering the post-treatment follow up period.

Reporting group title

Placebo Post-Treatment Follow-up Period

Reporting group description

Participants did not receive any study treatment during post treatment follow-up period. Placebo Post-Treatment Follow-up Period was summarized by last treatment assigned to a participant prior to entering the post-treatment follow up period.

Primary: Double-Blind Withdrawal Period: Time to Relapse (No Longer Meeting Coates Criteria for Minimal Disease Activity [MDA])

Top of page

End point title

Double-Blind Withdrawal Period: Time to Relapse (No Longer Meeting Coates Criteria for Minimal Disease Activity [MDA])

End point description

Relapse is loss of MDA response. MDA is achieved if 5 of 7 outcome measures are fulfilled:TJC ≤1;SJC ≤1;psoriasis activity & severity index(PASI total score) ≤1 or body surface area(BSA) ≤3;participant pain VAS score of ≤15;participant global disease activity VAS score of ≤20;HAQ-DI score ≤0.5;and tender entheseal points ≤1.Participants met the randomization criteria if they had MDA for 3 consecutive months over 4 consecutive visits.Time-to relapse was calculated in weeks as follows:((Date of Relapse) - Date of first injection of randomized study treatment in period 3)+1) divided by 7.If the date of first dose is missing,the date of randomization will be used.Participants completing Period 3 will be censored at date of completion(the date of the last scheduled visit in the period).Participants without a date of completion or discontinuation for Period 3 will be censored at latest non-missing date out of the following dates:date of last dose & date of last attended visit in Period 3.

End point type

Primary

End point timeframe

Double Blind Randomization through Week 104 (or Early Termination or Relapse) APD:All participants who received at least one dose of study drug in randomized withdrawal Intent-to-Treat population.Censored participants were Ixekizumab=49 and Placebo=12.

End point values	Ixekizumab	Placebo
Number of subjects analysed	79 ^[1]	79
Units: Weeks
median (confidence interval 95%)	9999 (64.29 to 9999)	22.29 (16.14 to 28.29)

Notes
[1] - 9999=NA Median and upper CI not be estimated due to insufficient events in analysis duration.

Time to Relapse

Statistical analysis description

Log Rank Test adjusting for geographic region and conventional disease-modifying antirheumatic drug (cDMARD) use at the time of double blind randomization.

Comparison groups

Ixekizumab v Placebo

Number of subjects included in analysis

158

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Logrank

Confidence interval

Secondary: Double-Blind Withdrawal Period: Percentage of Participants Who Relapse in MDA

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End point title

Double-Blind Withdrawal Period: Percentage of Participants Who Relapse in MDA

End point description

Relapsed participants are defined as participants no longer meeting Coates criteria for MDA. MDA is achieved if 5 of 7 outcome measures are fulfilled: TJC ≤1; SJC ≤1; psoriasis activity and severity index (PASI total score) ≤1 or body surface area (BSA) ≤3; participant pain VAS score of ≤15; participant global disease activity VAS score of ≤20; HAQ-DI score ≤0.5; and tender entheseal points ≤1.

End point type

Secondary

End point timeframe

Double Blind Randomization through Week 104 (or Early Termination or Relapse) Analysis Population Description (APD): All participants who received at least one dose of study drug in randomized withdrawal Intent-to-Treat population.

End point values	Ixekizumab	Placebo
Number of subjects analysed	79	79
Units: percentage of participants
number (confidence interval 95%)	40.5 (29.7 to 51.3)	86.1 (78.4 to 93.7)

Percentage of Participants Who Relapse in MDA

Statistical analysis description

Logistic regression adjusting for treatment, geographic region, and cDMARD use at the time of double-blind randomization .

Comparison groups

Ixekizumab v Placebo

Number of subjects included in analysis

158

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Odds ratio (OR)

Point estimate

-45.6

Confidence interval

level

95%

sides

2-sided

lower limit

-58.8

upper limit

-32.3

Secondary: Double-Blind Withdrawal Period: Time to Loss of Response in Each Individual Component of MDA: Tender Joint Count 68 (TJC)

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End point title

Double-Blind Withdrawal Period: Time to Loss of Response in Each Individual Component of MDA: Tender Joint Count 68 (TJC)

End point description

TJC is the number of tender and painful joints determined for each participant by examination of 68 joints. TJC possible values range from 0 to 68. A lower TJC indicated less number of joints with tenderness. A higher TJC indicated more joint tenderness. Joints were assessed by pressure and joint manipulation on physical examination. Participants were asked for pain sensations on these manipulations and watched for spontaneous pain reactions. Any positive response on pressure, movement, or both was translated into a single tender-versus-nontender dichotomy. Loss of Response = Not Meeting less than or equal to 1 TJC. Time to loss of response (in weeks) = (date of loss of response - date of first injection of randomized dose of study treatment in the Randomized Double-Blind Withdrawal Period + 1)/7. Censored participants: Ixekizumab= 29 and Placebo= 16.

End point type

Secondary

End point timeframe

Double Blind Randomization through Week 104 (or Early Termination or Relapse) All participants who received at least 1 dose of study drug in the randomized withdrawal Intent-to-Treat Population who had tender joint counts <=1 at time of randomization.

End point values	Ixekizumab	Placebo
Number of subjects analysed	56 ^[2]	57
Units: weeks
median (confidence interval 95%)	64.29 (24.14 to 9999)	22.29 (12.29 to 28.71)

Notes
[2] - 9999=NA. Upper CI could not be estimated due to insufficient events in analysis duration.

No statistical analyses for this end point

Secondary: Double-Blind Withdrawal Period: Time to Loss of Response in Each Individual Component of MDA: Swollen Joint Count 66 (SJC)

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End point title

Double-Blind Withdrawal Period: Time to Loss of Response in Each Individual Component of MDA: Swollen Joint Count 66 (SJC)

End point description

SJC is the number of swollen joints determined for each participant by examination of 66 joints. SJC possible values range from 0 to 66. A lower SJC indicated less joints with swelling. A higher SJC indicated more joints with swelling. Swelling was defined as palpable fluctuating synovitis of the joint. Loss of Response = Not Meeting less than or equal to 1 SJC. Time to loss of response (in weeks) = (date of loss of response - date of first injection of randomized dose of study treatment in the Randomized Double-Blind Withdrawal Period + 1)/7. Analysis Population Description: All participants who received at least one dose of study drug in the randomized withdrawal Intent-to-Treat population who had swollen joint counts <= 1 at time of randomization. Censored participants: Ixekizumab= 61 and Placebo = 40.

End point type

Secondary

End point timeframe

Double Blind Randomization through Week 104 (or Early Termination or Relapse).

End point values	Ixekizumab	Placebo
Number of subjects analysed	72 ^[3]	73 ^[4]
Units: weeks
median (confidence interval 95%)	9999 (9999 to 9999)	28.71 (20.14 to 9999)

Notes
[3] - 9999=NA Median and CI could not be estimated due to insufficient events in analysis duration.
[4] - 9999=NA. Upper CI could not be estimated due to insufficient events in analysis duration.

No statistical analyses for this end point

Secondary: Double-Blind Withdrawal Period: Time to Loss of Response in Each Individual Component of MDA: Psoriasis Area and Severity Index (PASI)

Top of page

End point title

Double-Blind Withdrawal Period: Time to Loss of Response in Each Individual Component of MDA: Psoriasis Area and Severity Index (PASI)

End point description

The PASI is an index that combines assessments of the extent of body-surface involvement in 4 anatomical regions (head, trunk, arms, and legs) and the severity of desquamation, erythema, and plaque induration/infiltration (thickness) in each region, yielding an overall score of 0 for no psoriasis to 72 for the most severe disease. Loss of Response = Not Meeting less than or equal to 1 PASI total score. Time to loss of response (in weeks) = (date of loss of response - date of first injection of randomized dose of study treatment in the Randomized Double-Blind Withdrawal Period + 1)/7. Analysis Population Description: All participants who received at least one dose of study drug in the randomized withdrawal intent-to-treat population Who had PASI <= 1 at time of randomization. Censored participants: Ixekizumab = 64 and Placebo = 43.

End point type

Secondary

End point timeframe

Double Blind Randomization through Week 104 (or Early Termination or Relapse)

End point values	Ixekizumab	Placebo
Number of subjects analysed	73 ^[5]	77
Units: weeks
median (confidence interval 95%)	9999 (9999 to 9999)	36.00 (24.14 to 48.14)

Notes
[5] - 9999=NA. Median and CI could not be estimated due to insufficient events in analysis duration.

Time to Loss of Response (PASI)

Statistical analysis description

Log Rank Test adjusting for geographic region and cDMARD use at the time of double blind randomization.

Comparison groups

Ixekizumab v Placebo

Number of subjects included in analysis

150

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Logrank

Confidence interval

Secondary: Double-Blind Withdrawal Period: Time to Loss of Response in Each Individual Component of MDA: BSA

Top of page

End point title

Double-Blind Withdrawal Period: Time to Loss of Response in Each Individual Component of MDA: BSA

End point description

BSA is an investigator evaluated measure, where the percentage of involvement of psoriasis on each participant's BSA is assessed. BSA was measured on a continuous scale from 0% = no involvement to 100% = full involvement, where 1% corresponded to the size of the participant's handprint including the palm, fingers, and thumb. Loss of Response = Not meeting less than or equal to 3% BSA. Time to loss of response (in weeks) = (date of loss of response - date of first injection of randomized dose of study treatment in the Randomized Double-Blind Withdrawal Period + 1)/7. Analysis Population Description: All participants who received at least one dose of study drug in the randomized Withdrawal Intent-to-Treat Population who had BSA <= 3% at time of randomization. Censored participants: Ixekizumab=70 and Placebo= 59.

End point type

Secondary

End point timeframe

Double Blind Randomization through Week 104 (or Early Termination or Relapse)

End point values	Ixekizumab	Placebo
Number of subjects analysed	73 ^[6]	78 ^[7]
Units: weeks
median (confidence interval 95%)	9999 (9999 to 9999)	9999 (36.00 to 9999)

Notes
[6] - 9999=NA. Median and CI could not be estimated due to insufficient events in analysis duration.
[7] - 9999=NA. Confidence Interval could not be estimated due to insufficient events in analysis duration.

Time to Loss of Response (BSA)

Statistical analysis description

Log Rank Test adjusting for geographic region and cDMARD use at the time of double blind randomization.

Comparison groups

Ixekizumab v Placebo

Number of subjects included in analysis

151

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Logrank

Confidence interval

Secondary: Double-Blind Withdrawal Period: Time to Loss of Response in Each Individual Component of MDA: Pain Visual Analog Scale (VAS) Score

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End point title

Double-Blind Withdrawal Period: Time to Loss of Response in Each Individual Component of MDA: Pain Visual Analog Scale (VAS) Score

End point description

The pain VAS is an instrument used to measure a person's subjective quantitative evaluation of an item such as pain intensity. The VAS contains a continuous line between two endpoints whereby the respondent places a mark on the line to indicate his or her response The scale ranges from 0 (no pain) to 100 (unbearable pain). The scores were measured to the nearest millimeter from the left. Loss of Response = Not Meeting less than or equal to 15 Pain VAS. Time to loss of response (in weeks) = (date of loss of response - date of first injection of randomized dose of study treatment in the Randomized Double-Blind Withdrawal Period + 1)/7. Analysis Population Description: All participants who received at least one dose of study drug in the randomized withdrawal Intent-to-Treat Population who had Pain VAS <= 15 at time of randomization. Censored participants: Ixekizumab=42 and Placebo= 7.

End point type

Secondary

End point timeframe

Double Blind Randomization through Week 104 (or Early Termination or Relapse)

End point values	Ixekizumab	Placebo
Number of subjects analysed	72 ^[8]	68
Units: weeks
median (confidence interval 95%)	9999 (36.14 to 9999)	16.14 (12.14 to 22.71)

Notes
[8] - 9999=NA. Confidence Interval could not be estimated due to insufficient events in analysis duration.

Time to Loss of Response VAS Score

Statistical analysis description

Log Rank Test adjusting for geographic region and cDMARD use at the time of double blind randomization.

Comparison groups

Ixekizumab v Placebo

Number of subjects included in analysis

140

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Logrank

Confidence interval

Secondary: Double-Blind Withdrawal Period: Time to Loss of Response in Each Individual Component of MDA: Patients Global Assessment of Disease Activity (PatGA) Visual Analog Scale (VAS) score

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End point title

Double-Blind Withdrawal Period: Time to Loss of Response in Each Individual Component of MDA: Patients Global Assessment of Disease Activity (PatGA) Visual Analog Scale (VAS) score

End point description

Participants scored their overall assessment of their psoriatic arthritis (PsA) activity on a 0 to 100 mm horizontal VAS. The scale ranged from 0 (no disease activity) to 100 (extremely active disease activity). The scores were measured to the nearest millimeter from the left. Loss of Response = Not Meeting less than or equal to 20 PatGA. Time to loss of response (in weeks) = (date of loss of response - date of first injection of randomized dose of study treatment in the Randomized Double-Blind Withdrawal Period + 1)/7. Analysis Population Description: All participants who received at least one dose of study drug in the randomized withdrawal Intent-to-Treat population Who had PatGA VAS <= 20 at time of randomization. Censored participants: Ixekizumab= 57 and Placebo=18.

End point type

Secondary

End point timeframe

Double Blind Randomization through Week 104 (or Early Termination or Relapse)

End point values	Ixekizumab	Placebo
Number of subjects analysed	77 ^[9]	74
Units: weeks
median (confidence interval 95%)	9999 (9999 to 9999)	20.57 (16.14 to 28.14)

Notes
[9] - 9999=NA. Median and CI could not be estimated due to insufficient events in analysis duration.

Time to Loss of Response (PatGA and VAS Score)

Statistical analysis description

Log Rank Test adjusting for geographic region and cDMARD use at the time of double blind randomization.

Comparison groups

Ixekizumab v Placebo

Number of subjects included in analysis

151

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Logrank

Confidence interval

Secondary: Double-Blind Withdrawal Period: Time to Loss of Response in Each Individual Component of MDA: Health Assessment Questionnaire-Disability Index (HAQ-DI)

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End point title

Double-Blind Withdrawal Period: Time to Loss of Response in Each Individual Component of MDA: Health Assessment Questionnaire-Disability Index (HAQ-DI)

End point description

The HAQ-DI questionnaire assesses the participant's self-perception on the degree of difficulty [0 (without any difficulty), 1 (with some difficulty), 2 (with much difficulty), and 3 (unable to do)] when dressing and grooming, arising, eating, walking, hygiene, reaching, gripping, and performing other daily activities. Scores for each functional area were averaged to calculate HAQ-DI scores, which ranged from 0 (no disability) to 3 (severe disability). A decrease in HAQ-DI score indicated an improvement in the participant's condition. Loss of Response = Not Meeting less than or equal to 0.5 HAQ-DI. Time to loss of response (in weeks) = (date of loss of response - date of first injection of randomized dose of study treatment in the Randomized Double-Blind Withdrawal Period + 1)/7. Censored participants: Ixekizumab= 55 and Placebo=53.

End point type

Secondary

End point timeframe

Double Blind Randomization through Week 104 (or Early Termination or Relapse) All participants who received at least one dose of study drug in the randomized withdrawal Intent-to-Treat population Who had HAQ-DI <= 0.5 at Time of randomization.

End point values	Ixekizumab	Placebo
Number of subjects analysed	69 ^[10]	68 ^[11]
Units: weeks
median (confidence interval 95%)	9999 (9999 to 9999)	9999 (48.14 to 9999)

Notes
[10] - 9999=NA. Median and CI could not be estimated due to insufficient events in analysis duration.
[11] - 9999=NA.Median and Upper CI could not be estimated due to insufficient events in analysis duration.

Time to Loss of Response (HAQ-DI)

Statistical analysis description

Log Rank Test adjusting for geographic region and cDMARD use at the time of double blind randomization.

Comparison groups

Ixekizumab v Placebo

Number of subjects included in analysis

137

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Logrank

Confidence interval

Secondary: Double-Blind Withdrawal Period: Time to Loss of Response in Each Individual Component of MDA: Tender Entheseal Points

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End point title

Double-Blind Withdrawal Period: Time to Loss of Response in Each Individual Component of MDA: Tender Entheseal Points

End point description

Tender entheseal points was based on the assessment of the 18 entheseal points. Loss of Response = Not Meeting less than or equal to 1 Tender Entheseal Point. Time to loss of response (in weeks) = (date of loss of response - date of first injection of randomized dose of study treatment in the Randomized Double-Blind Withdrawal Period + 1)/7. Analysis Population Description: All participants who received at least one dose of study drug in the randomized withdrawal Intent-to-Treat Population who had tender Entheseal Point <= 1 at time of randomization. Censored participants: Ixekizumab= 58 and Placebo= 58.

End point type

Secondary

End point timeframe

Double Blind Randomization through Week 104 (or Early Termination or Relapse)

End point values	Ixekizumab	Placebo
Number of subjects analysed	73 ^[12]	72 ^[13]
Units: weeks
median (confidence interval 95%)	9999 (999 to 9999)	9999 (60.29 to 9999)

Notes
[12] - 9999=NA. Median and CI could not be estimated due to insufficient events in analysis duration.
[13] - 9999=NA. Median and CI could not be estimated due to insufficient events in analysis duration.

No statistical analyses for this end point

Secondary: Open-Label Treatment Period: Time to Achieve Randomization Criteria (Meeting MDA for 3 Consecutive Months over 4 Consecutive Visits)

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End point title

Open-Label Treatment Period: Time to Achieve Randomization Criteria (Meeting MDA for 3 Consecutive Months over 4 Consecutive Visits)

End point description

Time to meeting MDA for 3 Consecutive Months Over 4 Consecutive Visits. Time to first response (in weeks) = [(date of first response - date of first injection of study treatment in the Open-Label Treatment Period)+1]/7. Open-Label Treatment Period ended at the time when a participant was randomized so the end time was not the same for all participants. Participants were randomized only if they met randomization criteria which was at anytime from week 36 to week 64. Analysis Population Description: All participants who received at least one dose of study drug in initial open-label treatment period. Censored participants were 239.

End point type

Secondary

End point timeframe

Open Label Baseline through Double-Blind Randomization (Week 36 to 64)

End point values	Ixekizumab Open Label
Number of subjects analysed	394 ^[14]
Units: weeks
median (confidence interval 95%)	64.43 (56.14 to 9999)

Notes
[14] - 9999=NA. Upper CI could not be estimated due to insufficient events in analysis duration.

No statistical analyses for this end point

Secondary: Double-Blind Withdrawal Period: Time to Re-Gain MDA Following Relapse in MDA

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End point title

Double-Blind Withdrawal Period: Time to Re-Gain MDA Following Relapse in MDA

End point description

MDA is achieved if 5 of 7 outcome measures are fulfilled: TJC ≤1; SJC ≤1; psoriasis activity and severity index (PASI total score) ≤1 or BSA ≤3; participant pain VAS score of ≤15; participant global disease activity VAS score of ≤20; HAQ-DI score ≤0.5; and tender entheseal points ≤1. Time to first response (in weeks) = (date of first response - date of first injection of study treatment in the Relapse Period + 1)/7. Analysis Population Description: All participants who received at least one dose of study drug and relapsed in MDA After Double Blind Randomization Until Re-Gain MDA. Censored participants were: Ixekizumab= 3 and Placebo= 3.

End point type

Secondary

End point timeframe

Relapse in MDA After Double Blind Randomization through Week 104 (or Early Termination)

End point values	Ixekizumab	Placebo
Number of subjects analysed	30	67
Units: weeks
median (confidence interval 95%)	4.71 (4.14 to 8.29)	4.14 (4.14 to 4.29)

No statistical analyses for this end point

Secondary: Double-Blind Withdrawal Period: Change from Baseline in Physical Functioning Assessed by the Health Assessment Questionnaire-Disability Index (HAQ-DI)

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End point title

Double-Blind Withdrawal Period: Change from Baseline in Physical Functioning Assessed by the Health Assessment Questionnaire-Disability Index (HAQ-DI)

End point description

The HAQ-DI questionnaire assesses the participant's self-perception on the degree of difficulty [0 (without any difficulty), 1 (with some difficulty), 2 (with much difficulty), and 3 (unable to do)] when dressing and grooming, arising, eating, walking, hygiene, reaching, gripping, and performing other daily activities. Scores for each functional area were averaged to calculate HAQ-DI scores, which ranged from 0 (no disability) to 3 (severe disability). A decrease in HAQ-DI score indicated an improvement in the participant's condition.Least Square (LS) mean calculated using Mixed Model Repeated Measurements (MMRM) analysis with treatment group, baseline measure, geographic region, cDMARD use, treatment week, baseline measure-by-treatment week interaction term, and treatment week-by-treatment interaction term as fixed factors. Participants were randomized only if they met randomization criteria which was at anytime from week 36 to week 64.

End point type

Secondary

End point timeframe

Baseline, 40 Weeks from Double Blind Randomization (Week 36 to 64) All participants who received at least one dose of study drug had a baseline and post baseline measure in the Double-Blind Withdrawal Period.

End point values	Ixekizumab	Placebo
Number of subjects analysed	51	22
Units: score on a scale
least squares mean (standard error)	-0.79 ( 0.06 )	-0.67 ( 0.06 )

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Up To 3 Years

Adverse event reporting additional description

All participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

21.1

Reporting group title

Ixekizumab Open Label

Reporting group description

Open-Label Treatment Period: Starting dose of 160 milligrams (mg) ixekizumab given as two subcutaneous (SC) injections at baseline (week 0) followed by 80 mg given as one SC injection every two weeks (Q2W) from week 2 to randomization (week 36 to 64).

Reporting group title

Ixekizumab

Reporting group description

Participants completed open label and met criteria for randomization to the double-blind Withdrawal Period. Double-Blind Withdrawal Period: 80 mg ixekizumab given as one SC injection Q2W from randomization to week 104 (or, early termination or relapse).

Reporting group title

Placebo

Reporting group description

Participants completed open label and met criteria for randomization to the double-blind Withdrawal Period. Double-Blind Withdrawal Period: Placebo given as one SC injection Q2W any time from randomization to week 104 (or, early termination or relapse).

Reporting group title

IXE80Q2W Non-randomized Population to Withdrawal Period

Reporting group description

Participants completed open label but did not meet criteria for randomization to the double-blind Withdrawal Period. Participants continued to receive 80 mg given as one SC injection every two weeks during the double-blind withdrawal period.

Reporting group title

IXE80Q2W Relapse Period

Reporting group description

IXE80Q2W Relapse Period Double Blind Period: 80 mg ixekizumab given as one SC injection Q2W from randomization to week 104 (or, early termination or relapse). Double Blind Period: Placebo given as one SC injection Q2W any time from randomization to week 104 (or, early termination or relapse).

Reporting group title

IXE80Q2W Post-Treatment Follow-up Period

Reporting group description

Participants did not receive any study treatment during post treatment follow-up period. Post-Treatment Follow-up Period was summarized by last treatment assigned to a participant prior to entering the post-treatment follow up period.

Reporting group title

Placebo Post-Treatment Follow-up Period

Reporting group description

Participants did not receive any study treatment during post treatment follow-up period. Placebo Post-Treatment Follow-up Period was summarized by last treatment assigned to a participant prior to entering the post-treatment follow up period.

Serious adverse events	Ixekizumab Open Label	Ixekizumab	Placebo	IXE80Q2W Non-randomized Population to Withdrawal Period	IXE80Q2W Relapse Period	IXE80Q2W Post-Treatment Follow-up Period	Placebo Post-Treatment Follow-up Period
Total subjects affected by serious adverse events
subjects affected / exposed	20 / 394 (5.08%)	1 / 79 (1.27%)	2 / 79 (2.53%)	6 / 133 (4.51%)	1 / 97 (1.03%)	4 / 355 (1.13%)	0 / 12 (0.00%)
number of deaths (all causes)	2	0	0	0	0	0	0
number of deaths resulting from adverse events	1	0	0	0	0	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
uterine leiomyoma
alternative dictionary used: MedDRA 21.1
subjects affected / exposed ^[1]	1 / 212 (0.47%)	0 / 32 (0.00%)	0 / 39 (0.00%)	0 / 78 (0.00%)	0 / 53 (0.00%)	0 / 195 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
drowning
alternative dictionary used: MedDRA 21.1
subjects affected / exposed	1 / 394 (0.25%)	0 / 79 (0.00%)	0 / 79 (0.00%)	0 / 133 (0.00%)	0 / 97 (0.00%)	0 / 355 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
non-cardiac chest pain
alternative dictionary used: MedDRA 21.1
subjects affected / exposed	1 / 394 (0.25%)	0 / 79 (0.00%)	0 / 79 (0.00%)	0 / 133 (0.00%)	0 / 97 (0.00%)	0 / 355 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
endometriosis
alternative dictionary used: MedDRA 21.1
subjects affected / exposed ^[2]	0 / 212 (0.00%)	1 / 32 (3.13%)	0 / 39 (0.00%)	0 / 78 (0.00%)	0 / 53 (0.00%)	0 / 195 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ovarian cyst
alternative dictionary used: MedDRA 21.1
subjects affected / exposed ^[3]	0 / 212 (0.00%)	0 / 32 (0.00%)	0 / 39 (0.00%)	1 / 78 (1.28%)	0 / 53 (0.00%)	0 / 195 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
acute respiratory failure
alternative dictionary used: MedDRA 21.1
subjects affected / exposed	0 / 394 (0.00%)	0 / 79 (0.00%)	0 / 79 (0.00%)	0 / 133 (0.00%)	0 / 97 (0.00%)	1 / 355 (0.28%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
respiratory failure
alternative dictionary used: MedDRA 21.1
subjects affected / exposed	1 / 394 (0.25%)	0 / 79 (0.00%)	0 / 79 (0.00%)	0 / 133 (0.00%)	0 / 97 (0.00%)	0 / 355 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
troponin increased
alternative dictionary used: MedDRA 21.1
subjects affected / exposed	0 / 394 (0.00%)	0 / 79 (0.00%)	0 / 79 (0.00%)	0 / 133 (0.00%)	0 / 97 (0.00%)	1 / 355 (0.28%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
fall
alternative dictionary used: MedDRA 21.1
subjects affected / exposed	0 / 394 (0.00%)	0 / 79 (0.00%)	0 / 79 (0.00%)	1 / 133 (0.75%)	0 / 97 (0.00%)	0 / 355 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
foreign body in eye
alternative dictionary used: MedDRA 21.1
subjects affected / exposed	1 / 394 (0.25%)	0 / 79 (0.00%)	0 / 79 (0.00%)	0 / 133 (0.00%)	0 / 97 (0.00%)	0 / 355 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
humerus fracture
alternative dictionary used: MedDRA 21.1
subjects affected / exposed	0 / 394 (0.00%)	0 / 79 (0.00%)	0 / 79 (0.00%)	1 / 133 (0.75%)	0 / 97 (0.00%)	0 / 355 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
meniscus injury
alternative dictionary used: MedDRA 21.1
subjects affected / exposed	1 / 394 (0.25%)	0 / 79 (0.00%)	0 / 79 (0.00%)	1 / 133 (0.75%)	0 / 97 (0.00%)	0 / 355 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
radius fracture
alternative dictionary used: MedDRA 21.1
subjects affected / exposed	0 / 394 (0.00%)	0 / 79 (0.00%)	0 / 79 (0.00%)	1 / 133 (0.75%)	0 / 97 (0.00%)	0 / 355 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
road traffic accident
alternative dictionary used: MedDRA 21.1
subjects affected / exposed	0 / 394 (0.00%)	0 / 79 (0.00%)	0 / 79 (0.00%)	1 / 133 (0.75%)	0 / 97 (0.00%)	0 / 355 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
thermal burn
alternative dictionary used: MedDRA 21.1
subjects affected / exposed	1 / 394 (0.25%)	0 / 79 (0.00%)	0 / 79 (0.00%)	0 / 133 (0.00%)	0 / 97 (0.00%)	0 / 355 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
upper limb fracture
alternative dictionary used: MedDRA 21.1
subjects affected / exposed	0 / 394 (0.00%)	0 / 79 (0.00%)	0 / 79 (0.00%)	0 / 133 (0.00%)	1 / 97 (1.03%)	0 / 355 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
acute myocardial infarction
alternative dictionary used: MedDRA 21.1
subjects affected / exposed	1 / 394 (0.25%)	0 / 79 (0.00%)	0 / 79 (0.00%)	0 / 133 (0.00%)	0 / 97 (0.00%)	0 / 355 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
angina unstable
alternative dictionary used: MedDRA 21.1
subjects affected / exposed	1 / 394 (0.25%)	0 / 79 (0.00%)	0 / 79 (0.00%)	0 / 133 (0.00%)	0 / 97 (0.00%)	0 / 355 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
coronary artery disease
alternative dictionary used: MedDRA 21.1
subjects affected / exposed	1 / 394 (0.25%)	0 / 79 (0.00%)	0 / 79 (0.00%)	0 / 133 (0.00%)	0 / 97 (0.00%)	0 / 355 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
embolic stroke
alternative dictionary used: MedDRA 21.1
subjects affected / exposed	1 / 394 (0.25%)	0 / 79 (0.00%)	0 / 79 (0.00%)	0 / 133 (0.00%)	0 / 97 (0.00%)	0 / 355 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
transient ischaemic attack
alternative dictionary used: MedDRA 21.1
subjects affected / exposed	1 / 394 (0.25%)	0 / 79 (0.00%)	0 / 79 (0.00%)	0 / 133 (0.00%)	0 / 97 (0.00%)	0 / 355 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
vascular headache
alternative dictionary used: MedDRA 21.1
subjects affected / exposed	1 / 394 (0.25%)	0 / 79 (0.00%)	0 / 79 (0.00%)	0 / 133 (0.00%)	0 / 97 (0.00%)	0 / 355 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
crohn's disease
alternative dictionary used: MedDRA 21.1
subjects affected / exposed	1 / 394 (0.25%)	0 / 79 (0.00%)	0 / 79 (0.00%)	0 / 133 (0.00%)	0 / 97 (0.00%)	0 / 355 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
gastritis
alternative dictionary used: MedDRA 21.1
subjects affected / exposed	1 / 394 (0.25%)	0 / 79 (0.00%)	0 / 79 (0.00%)	0 / 133 (0.00%)	0 / 97 (0.00%)	0 / 355 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
gastrointestinal necrosis
alternative dictionary used: MedDRA 21.1
subjects affected / exposed	1 / 394 (0.25%)	0 / 79 (0.00%)	0 / 79 (0.00%)	0 / 133 (0.00%)	0 / 97 (0.00%)	0 / 355 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
intestinal obstruction
alternative dictionary used: MedDRA 21.1
subjects affected / exposed	1 / 394 (0.25%)	0 / 79 (0.00%)	0 / 79 (0.00%)	0 / 133 (0.00%)	0 / 97 (0.00%)	0 / 355 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
large intestine polyp
alternative dictionary used: MedDRA 21.1
subjects affected / exposed	0 / 394 (0.00%)	0 / 79 (0.00%)	1 / 79 (1.27%)	0 / 133 (0.00%)	0 / 97 (0.00%)	0 / 355 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
cholecystitis acute
alternative dictionary used: MedDRA 21.1
subjects affected / exposed	0 / 394 (0.00%)	0 / 79 (0.00%)	0 / 79 (0.00%)	0 / 133 (0.00%)	0 / 97 (0.00%)	1 / 355 (0.28%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
cholelithiasis
alternative dictionary used: MedDRA 21.1
subjects affected / exposed	2 / 394 (0.51%)	0 / 79 (0.00%)	0 / 79 (0.00%)	1 / 133 (0.75%)	0 / 97 (0.00%)	0 / 355 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
hepatic steatosis
alternative dictionary used: MedDRA 21.1
subjects affected / exposed	0 / 394 (0.00%)	0 / 79 (0.00%)	0 / 79 (0.00%)	0 / 133 (0.00%)	0 / 97 (0.00%)	1 / 355 (0.28%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
angioedema
alternative dictionary used: MedDRA 21.1
subjects affected / exposed	1 / 394 (0.25%)	0 / 79 (0.00%)	0 / 79 (0.00%)	0 / 133 (0.00%)	0 / 97 (0.00%)	0 / 355 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
foot deformity
alternative dictionary used: MedDRA 21.1
subjects affected / exposed	1 / 394 (0.25%)	0 / 79 (0.00%)	0 / 79 (0.00%)	0 / 133 (0.00%)	0 / 97 (0.00%)	0 / 355 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
osteoarthritis
alternative dictionary used: MedDRA 21.1
subjects affected / exposed	1 / 394 (0.25%)	0 / 79 (0.00%)	0 / 79 (0.00%)	0 / 133 (0.00%)	0 / 97 (0.00%)	0 / 355 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
bronchitis
alternative dictionary used: MedDRA 21.1
subjects affected / exposed	2 / 394 (0.51%)	0 / 79 (0.00%)	0 / 79 (0.00%)	1 / 133 (0.75%)	0 / 97 (0.00%)	0 / 355 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
erysipelas
alternative dictionary used: MedDRA 21.1
subjects affected / exposed	0 / 394 (0.00%)	0 / 79 (0.00%)	0 / 79 (0.00%)	0 / 133 (0.00%)	0 / 97 (0.00%)	1 / 355 (0.28%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
pneumonia
alternative dictionary used: MedDRA 21.1
subjects affected / exposed	1 / 394 (0.25%)	0 / 79 (0.00%)	0 / 79 (0.00%)	0 / 133 (0.00%)	0 / 97 (0.00%)	0 / 355 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
sinusitis
alternative dictionary used: MedDRA 21.1
subjects affected / exposed	1 / 394 (0.25%)	0 / 79 (0.00%)	0 / 79 (0.00%)	0 / 133 (0.00%)	0 / 97 (0.00%)	0 / 355 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
urinary tract infection
alternative dictionary used: MedDRA 21.1
subjects affected / exposed	0 / 394 (0.00%)	0 / 79 (0.00%)	1 / 79 (1.27%)	0 / 133 (0.00%)	0 / 97 (0.00%)	0 / 355 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

Notes
[1] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: This event is gender specific, only occurring in male or female subjects. The number of subjects exposed has been adjusted accordingly.
[2] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: This event is gender specific, only occurring in male or female subjects. The number of subjects exposed has been adjusted accordingly.
[3] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: This event is gender specific, only occurring in male or female subjects. The number of subjects exposed has been adjusted accordingly.

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

Non-serious adverse events	Ixekizumab Open Label	Ixekizumab	Placebo	IXE80Q2W Non-randomized Population to Withdrawal Period	IXE80Q2W Relapse Period	IXE80Q2W Post-Treatment Follow-up Period	Placebo Post-Treatment Follow-up Period
Total subjects affected by non serious adverse events
subjects affected / exposed	143 / 394 (36.29%)	25 / 79 (31.65%)	14 / 79 (17.72%)	37 / 133 (27.82%)	30 / 97 (30.93%)	19 / 355 (5.35%)	0 / 12 (0.00%)
Investigations
alanine aminotransferase increased
alternative dictionary used: MedDRA 21.1
subjects affected / exposed	11 / 394 (2.79%)	4 / 79 (5.06%)	1 / 79 (1.27%)	2 / 133 (1.50%)	1 / 97 (1.03%)	3 / 355 (0.85%)	0 / 12 (0.00%)
occurrences all number	14	4	2	2	2	3	0
aspartate aminotransferase increased
alternative dictionary used: MedDRA 21.1
subjects affected / exposed	6 / 394 (1.52%)	4 / 79 (5.06%)	1 / 79 (1.27%)	1 / 133 (0.75%)	1 / 97 (1.03%)	2 / 355 (0.56%)	0 / 12 (0.00%)
occurrences all number	8	4	2	1	3	2	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
uterine leiomyoma
alternative dictionary used: MedDRA 21.1
subjects affected / exposed ^[4]	0 / 212 (0.00%)	2 / 32 (6.25%)	0 / 39 (0.00%)	0 / 78 (0.00%)	0 / 53 (0.00%)	0 / 195 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	2	0	0	0	0	0
General disorders and administration site conditions
injection site reaction
alternative dictionary used: MedDRA 21.1
subjects affected / exposed	59 / 394 (14.97%)	1 / 79 (1.27%)	0 / 79 (0.00%)	2 / 133 (1.50%)	7 / 97 (7.22%)	0 / 355 (0.00%)	0 / 12 (0.00%)
occurrences all number	270	8	0	20	27	0	0
Skin and subcutaneous tissue disorders
psoriasis
alternative dictionary used: MedDRA 21.1
subjects affected / exposed	2 / 394 (0.51%)	0 / 79 (0.00%)	4 / 79 (5.06%)	2 / 133 (1.50%)	1 / 97 (1.03%)	4 / 355 (1.13%)	0 / 12 (0.00%)
occurrences all number	2	0	4	3	1	4	0
Infections and infestations
bronchitis
alternative dictionary used: MedDRA 21.1
subjects affected / exposed	18 / 394 (4.57%)	4 / 79 (5.06%)	1 / 79 (1.27%)	5 / 133 (3.76%)	4 / 97 (4.12%)	0 / 355 (0.00%)	0 / 12 (0.00%)
occurrences all number	23	4	1	5	5	0	0
nasopharyngitis
alternative dictionary used: MedDRA 21.1
subjects affected / exposed	34 / 394 (8.63%)	11 / 79 (13.92%)	4 / 79 (5.06%)	19 / 133 (14.29%)	13 / 97 (13.40%)	2 / 355 (0.56%)	0 / 12 (0.00%)
occurrences all number	37	13	4	22	17	2	0
oral herpes
alternative dictionary used: MedDRA 21.1
subjects affected / exposed	9 / 394 (2.28%)	4 / 79 (5.06%)	1 / 79 (1.27%)	2 / 133 (1.50%)	2 / 97 (2.06%)	2 / 355 (0.56%)	0 / 12 (0.00%)
occurrences all number	10	9	3	3	2	2	0
upper respiratory tract infection
alternative dictionary used: MedDRA 21.1
subjects affected / exposed	49 / 394 (12.44%)	9 / 79 (11.39%)	4 / 79 (5.06%)	12 / 133 (9.02%)	9 / 97 (9.28%)	8 / 355 (2.25%)	0 / 12 (0.00%)
occurrences all number	66	14	5	18	10	8	0

Notes
[4] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: This event is gender specific, only occurring in male or female subjects. The number of subjects exposed has been adjusted accordingly.

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Were there any global substantial amendments to the protocol? No

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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