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Clinical Trial Results:
A Safety and Efficacy Extension Study of ONO-4641 (MSC2430913A) in Patients with Relapsing-Remitting Multiple Sclerosis

Due to the EudraCT – Results system being out of service between 31 July 2015 and 12 January 2016, these results have been published in compliance with revised timelines.

Summary
EudraCT number	2010-018705-11
Trial protocol	BE ES CZ DE GR
Global end of trial date	30 Jan 2015

Results information
Results version number	v1(current)
This version publication date	28 Jul 2016
First version publication date	28 Jul 2016
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

ONO-4641POU007 (EMR200559-002)

ISRCTN number

-

US NCT number

NCT01226745

WHO universal trial number (UTN)

-

Sponsor organisation name

Merck KGaA

Sponsor organisation address

Frankfurter Strasse 250, Darmstadt, Germany, 64293

Public contact

Communication Centre Merck KGaA, Merck KGaA, +49 6151725200, service@merckgroup.com

Scientific contact

Communication Centre Merck KGaA, Merck KGaA, +49 6151725200, service@merckgroup.com

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 Jan 2015

Is this the analysis of the primary completion data?

Yes

Primary completion date

30 Jan 2015

Global end of trial reached?

Yes

Global end of trial date

30 Jan 2015

Was the trial ended prematurely?

Yes

Main objective of the trial

The objective of this active-drug Extension Study is to evaluate the continuing safety and efficacy of ONO-4641 (MSC2430913A) in subjects with relapsing-remitting multiple sclerosis (RRMS) who have completed an initial 26-week Core Study (ONO-4641POU006 [NCT01081782]).

Protection of trial subjects

Subject protection was ensured by following high medical and ethical standards in accordance with the principles laid down in the Declaration of Helsinki, and that are consistent with Good Clinical Practice and applicable regulations.

Background therapy

-

Evidence for comparator

-

Actual start date of recruitment

12 Oct 2010

Long term follow-up planned

Yes

Long term follow-up rationale

Safety, Efficacy

Long term follow-up duration

1 Months

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Spain: 15

Country: Number of subjects enrolled

Ukraine: 10

Country: Number of subjects enrolled

United States: 93

Country: Number of subjects enrolled

Belgium: 4

Country: Number of subjects enrolled

Canada: 24

Country: Number of subjects enrolled

Czech Republic: 14

Country: Number of subjects enrolled

Germany: 10

Country: Number of subjects enrolled

Greece: 2

Country: Number of subjects enrolled

Japan: 35

Country: Number of subjects enrolled

Poland: 105

Country: Number of subjects enrolled

Russian Federation: 28

Worldwide total number of subjects

340

EEA total number of subjects

150

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)

340

From 65 to 84 years

0

85 years and over

0

Subject disposition

Top of page

Recruitment details

-

Screening details

One subject received 0.15 mg of ONO-4641 instead of placebo in error in the core trial and was subsequently re-randomised during the extension trial and received 0.10 mg of ONO-4641. This subject was not reported in the participant flow for the study.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Are arms mutually exclusive

Yes

ONO-4641 0.15 milligram (mg) - 0.15 mg

Arm description

Subjects who were administered with ONO-4641 at a dose of 0.15 mg in the core study were administered with ONO-4641 at a dose of 0.15 mg once daily in the extension study for a duration of 225 weeks.

Arm type

Experimental

Investigational medicinal product name

ONO-4641

Investigational medicinal product code

Other name

MSC2430913A, Ceralifimod

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Subjects were administered with once daily dose of ONO4641 0.15mg in core as well as in extension study.

ONO-4641 0.10 mg - 0.10 mg

Arm description

Subjects who were administered with ONO-4641 at a dose of 0.10 mg in the core study were administered with ONO-4641 at a dose of 0.10 mg once daily in the extension study for a duration of 225 weeks.

Arm type

Experimental

Investigational medicinal product name

ONO-4641

Investigational medicinal product code

Other name

MSC2430913A, Ceralifimod

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Subjects were administered with once daily dose of ONO4641 0.15mg in core as well as in extension study.

ONO-4641 0.05 mg - 0.05 mg

Arm description

Subjects who were administered with ONO-4641 at a dose of 0.05 mg in the core study were administered with ONO-4641 at a dose of 0.05 mg once daily in the extension study for a duration of 225 weeks.

Arm type

Experimental

Investigational medicinal product name

ONO-4641

Investigational medicinal product code

Other name

MSC2430913A, Ceralifimod

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Subjects were administered with once daily dose of ONO4641 0.15mg in core as well as in extension study.

Placebo - ONO4641 0.15 mg

Arm description

Subjects who were administered with placebo in the core study were administered with ONO-4641 at a dose of 0.15 mg once daily in the extension study for a duration of 225 weeks.

Arm type

Experimental

Investigational medicinal product name

ONO-4641

Investigational medicinal product code

Other name

MSC2430913A, Ceralifimod

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Subjects were administered with once daily dose of 0.15 mg once daily in extension study.

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Subjects were administered with once daily dose of Placebo 0.15 mg in core study.

Placebo - ONO4641 0.10 mg

Arm description

Subjects who were administered with placebo in the core study were administered with ONO-4641 at a dose of 0.10 mg once daily in the extension study for a duration of 225 weeks.

Arm type

Experimental

Investigational medicinal product name

ONO-4641

Investigational medicinal product code

Other name

MSC2430913A, Ceralifimod

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Subjects were administered with once daily dose of ONO-4641 0.10 mg in the extension study.

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Subjects were administered with once daily dose of Placebo 0.10 mg in core study.

Placebo - ONO4641 0.05 mg

Arm description

Subjects who were administered with placebo in the core study were administered with ONO-4641 at a dose of 0.05 mg once daily in the extension study for a duration of 225 weeks.

Arm type

Experimental

Investigational medicinal product name

ONO-4641

Investigational medicinal product code

Other name

MSC2430913A, Ceralifimod

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Subjects were administered with once daily dose of ONO-4641 0.05 mg at in the extension study.

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Subjects were administered with once daily dose of Placebo 0.05 mg in core study.

Number of subjects in period 1	ONO-4641 0.15 milligram (mg) - 0.15 mg	ONO-4641 0.10 mg - 0.10 mg	ONO-4641 0.05 mg - 0.05 mg	Placebo - ONO4641 0.15 mg	Placebo - ONO4641 0.10 mg	Placebo - ONO4641 0.05 mg
Started	80	87	89	29	26	29
Completed	63	71	69	24	22	24
Not completed	17	16	20	5	4	5
Death	1	-	-	-	-	1
Unspecified	6	7	8	4	3	1
Lost to follow-up	2	6	6	1	1	2
Did not complete schedule of assessments	8	3	6	-	-	1

Baseline characteristics

Top of page

Reporting group title

ONO-4641 0.15 milligram (mg) - 0.15 mg

Reporting group description

Subjects who were administered with ONO-4641 at a dose of 0.15 mg in the core study were administered with ONO-4641 at a dose of 0.15 mg once daily in the extension study for a duration of 225 weeks.

Reporting group title

ONO-4641 0.10 mg - 0.10 mg

Reporting group description

Subjects who were administered with ONO-4641 at a dose of 0.10 mg in the core study were administered with ONO-4641 at a dose of 0.10 mg once daily in the extension study for a duration of 225 weeks.

Reporting group title

ONO-4641 0.05 mg - 0.05 mg

Reporting group description

Subjects who were administered with ONO-4641 at a dose of 0.05 mg in the core study were administered with ONO-4641 at a dose of 0.05 mg once daily in the extension study for a duration of 225 weeks.

Reporting group title

Placebo - ONO4641 0.15 mg

Reporting group description

Subjects who were administered with placebo in the core study were administered with ONO-4641 at a dose of 0.15 mg once daily in the extension study for a duration of 225 weeks.

Reporting group title

Placebo - ONO4641 0.10 mg

Reporting group description

Subjects who were administered with placebo in the core study were administered with ONO-4641 at a dose of 0.10 mg once daily in the extension study for a duration of 225 weeks.

Reporting group title

Placebo - ONO4641 0.05 mg

Reporting group description

Subjects who were administered with placebo in the core study were administered with ONO-4641 at a dose of 0.05 mg once daily in the extension study for a duration of 225 weeks.

Reporting group values	ONO-4641 0.15 milligram (mg) - 0.15 mg	ONO-4641 0.10 mg - 0.10 mg	ONO-4641 0.05 mg - 0.05 mg	Placebo - ONO4641 0.15 mg	Placebo - ONO4641 0.10 mg	Placebo - ONO4641 0.05 mg	Total
Number of subjects	80	87	89	29	26	29	340
Age categorical
Units: Subjects
Age Continuous
Units: Years
arithmetic mean (standard deviation)	36.3 ( 8.47 )	36 ( 8.64 )	38.2 ( 8.66 )	35.6 ( 9.59 )	37 ( 6.96 )	38.7 ( 9.48 )	-
Gender, Male/Female
Units: Subjects
Female	53	74	66	18	17	24	252
Male	27	13	23	11	9	5	88

End points

Top of page

Reporting group title

ONO-4641 0.15 milligram (mg) - 0.15 mg

Reporting group description

Subjects who were administered with ONO-4641 at a dose of 0.15 mg in the core study were administered with ONO-4641 at a dose of 0.15 mg once daily in the extension study for a duration of 225 weeks.

Reporting group title

ONO-4641 0.10 mg - 0.10 mg

Reporting group description

Subjects who were administered with ONO-4641 at a dose of 0.10 mg in the core study were administered with ONO-4641 at a dose of 0.10 mg once daily in the extension study for a duration of 225 weeks.

Reporting group title

ONO-4641 0.05 mg - 0.05 mg

Reporting group description

Subjects who were administered with ONO-4641 at a dose of 0.05 mg in the core study were administered with ONO-4641 at a dose of 0.05 mg once daily in the extension study for a duration of 225 weeks.

Reporting group title

Placebo - ONO4641 0.15 mg

Reporting group description

Subjects who were administered with placebo in the core study were administered with ONO-4641 at a dose of 0.15 mg once daily in the extension study for a duration of 225 weeks.

Reporting group title

Placebo - ONO4641 0.10 mg

Reporting group description

Subjects who were administered with placebo in the core study were administered with ONO-4641 at a dose of 0.10 mg once daily in the extension study for a duration of 225 weeks.

Reporting group title

Placebo - ONO4641 0.05 mg

Reporting group description

Subjects who were administered with placebo in the core study were administered with ONO-4641 at a dose of 0.05 mg once daily in the extension study for a duration of 225 weeks.

Subject analysis set title

ONO-4641 0.15 mg - 0.15 mg

Subject analysis set type

Full analysis

Subject analysis set description

Subjects who were administered with ONO-4641 at a dose of 0.15 mg in the core study were administered with ONO-4641 at a dose of 0.15 mg once daily in the extension study for a duration of 225 weeks.

Subject analysis set title

Placebo - ONO4641 0.10 mg

Subject analysis set type

Full analysis

Subject analysis set description

Subjects who were administered with placebo in the core study were administered with ONO-4641 at a dose of 0.10 mg once daily in the extension study for a duration of 225 weeks.

Primary: Number of subjects with clinically significant abnormal vital signs

Top of page

End point title

Number of subjects with clinically significant abnormal vital signs ^[1]

End point description

Vital signs included oral temperature, pulse, respiration rate and blood pressure (BP) (taken after 5 minutes in the sitting position). The abnormalities in vital signs were decided as clinically significant or not based on the clinical judgment of the investigator. Safety analysis set consisted of all the enrolled subjects.

End point type

Primary

End point timeframe

Baseline up to Week 255

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive data was presented for this endpoint.

End point values	ONO-4641 0.15 milligram (mg) - 0.15 mg	ONO-4641 0.10 mg - 0.10 mg	ONO-4641 0.05 mg - 0.05 mg	Placebo - ONO4641 0.15 mg	Placebo - ONO4641 0.10 mg	Placebo - ONO4641 0.05 mg
Number of subjects analysed	80	87	89	29	26	29
Units: subjects	0	0	0	0	0	0

No statistical analyses for this end point

Primary: Change From Baseline in Forced Expiratory Volume in one Second (FEV1) (Percent (%) predicted value)

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End point title

Change From Baseline in Forced Expiratory Volume in one Second (FEV1) (Percent (%) predicted value) ^[2]

End point description

FEV1 was defined as the maximal volume of air exhaled in the 1st second of a forced expiration from a position of full inspiration. FEV1 was obtained from spirometry, performed before study treatment administration. Early termination visit was recorded when the subject was early terminated from the study during the first 2.5 year period, while early termination 2 visit was recorded when the subject early terminated from the study during the additional 2 year period with delay shall be defined. Safety analysis set consisted of all the enrolled subjects. Here “n” signifies the number of subjects analysed for the individual time point in the outcome measure.

End point type

Primary

End point timeframe

Baseline, Week 40, 52, 76, 100, 124, 148, early termination, Week 152, 200, early termination 2, Week 255

Notes
[2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive data was presented for this endpoint.

End point values	ONO-4641 0.15 milligram (mg) - 0.15 mg	ONO-4641 0.10 mg - 0.10 mg	ONO-4641 0.05 mg - 0.05 mg	Placebo - ONO4641 0.15 mg	Placebo - ONO4641 0.10 mg	Placebo - ONO4641 0.05 mg
Number of subjects analysed	80	87	89	29	26	29
Units: Percentage of predicted value
arithmetic mean (standard deviation)
Week 40 (n=77, 83, 82, 29, 24, 24)	-0.227 ( 6.5379 )	-0.741 ( 6.2026 )	-0.062 ( 5.4947 )	-1.5 ( 5.0115 )	-1.555 ( 7.8424 )	-1.146 ( 4.7952 )
Week 52 (n=74, 84, 77, 25, 24, 21)	-0.675 ( 7.7166 )	-1.981 ( 6.8499 )	-0.484 ( 6.0952 )	-3.113 ( 5.4753 )	-2.851 ( 6.7997 )	-0.561 ( 5.504 )
Week 76 (n=72, 78, 74, 24, 24, 21)	1.148 ( 9.595 )	-2.352 ( 6.1152 )	0.65 ( 7.2084 )	-1.574 ( 6.3645 )	-2.3 ( 9.2869 )	2.657 ( 8.928 )
Week 100 (n=68, 70, 72, 24, 24, 18)	-0.746 ( 8.3955 )	-2.79 ( 8.2129 )	-1.187 ( 7.8818 )	-3.202 ( 6.7073 )	-3.748 ( 8.5817 )	-1.207 ( 7.74 )
Week 124 (n=66, 70, 68, 21, 23, 18)	-0.795 ( 9.6531 )	-2.003 ( 7.7998 )	0.197 ( 7.9068 )	-2.178 ( 9.7656 )	-1.968 ( 9.2415 )	-0.874 ( 8.2237 )
Week 148 (n=59, 67, 68, 20, 21, 18)	-1.828 ( 10.8131 )	-3.429 ( 8.4036 )	-1.234 ( 6.527 )	-0.459 ( 9.0302 )	-3.052 ( 9.497 )	-2.599 ( 10.3997 )
Early termination (n=16, 17, 13, 7, 3, 8)	-6.803 ( 6.7393 )	0.443 ( 6.084 )	-1.78 ( 11.6068 )	-2.984 ( 13.8177 )	-4.109 ( 21.4354 )	2.108 ( 8.1682 )
Week 152 (n=12, 12, 10, 4, 3, 8)	-3.786 ( 7.3297 )	4.515 ( 11.3809 )	-1.725 ( 7.4166 )	-11.929 ( 13.1156 )	-11.525 ( 12.3316 )	2.688 ( 5.5468 )
Week 200 (n=18, 18, 19, 6, 6, 3)	-0.024 ( 8.0705 )	-0.354 ( 12.8489 )	-2.144 ( 8.3421 )	-2.299 ( 8.2038 )	-4.557 ( 13.3731 )	0.944 ( 7.8955 )
Early termination 2(n=56, 63, 63, 19, 20, 16)	-1.416 ( 9.4274 )	-2.031 ( 10.6185 )	-2.859 ( 9.6661 )	-1.321 ( 8.7759 )	-1.291 ( 10.4528 )	-3.249 ( 11.5213 )
Week 255 (n=47, 48, 47, 17, 16, 13)	-0.368 ( 13.5515 )	-1.374 ( 11.092 )	-0.027 ( 13.0574 )	-0.209 ( 12.1999 )	-2.377 ( 11.6511 )	-0.963 ( 14.2975 )

No statistical analyses for this end point

Primary: Change From Baseline in Forced Vital Capacity (FVC)

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End point title

Change From Baseline in Forced Vital Capacity (FVC) ^[3]

End point description

FVC (% of predicted value) was the volume of air which was forcibly exhaled from the lungs after taking the deepest breath possible. Early termination visit was recorded when the subject was early terminated from the study during the first 2.5 year period, while early termination 2 visit was recorded when the subject early terminated from the study during the additional 2 year period with delay shall be defined. Safety analysis set consisted of all the enrolled subjects. Here “n” signifies the number of subjects analysed for the individual time point in the outcome measure.

End point type

Primary

End point timeframe

Baseline, Week 40, 52, 76, 100, 124, 148, early termination, Week 152, 200, early termination 2, Week 255

Notes
[3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive data was presented for this endpoint.

End point values	ONO-4641 0.15 milligram (mg) - 0.15 mg	ONO-4641 0.10 mg - 0.10 mg	ONO-4641 0.05 mg - 0.05 mg	Placebo - ONO4641 0.15 mg	Placebo - ONO4641 0.10 mg	Placebo - ONO4641 0.05 mg
Number of subjects analysed	80	87	89	29	26	29
Units: Percentage of predicted value
arithmetic mean (standard deviation)
Week 40 (n=77,83,82,29,24,24)	-0.123 ( 6.9868 )	-1 ( 6.406 )	0.921 ( 6.9931 )	-1.593 ( 5.052 )	1.554 ( 7.9727 )	-0.423 ( 5.5244 )
Week 52 (n=74, 84, 77, 25, 24, 21)	-0.681 ( 6.1396 )	-1.175 ( 6.1523 )	0.107 ( 7.7364 )	-2.69 ( 5.2847 )	-0.111 ( 6.2548 )	-1.442 ( 6.8125 )
Week 76 (n=72, 78, 74, 24, 24, 21)	1.397 ( 8.1634 )	-1.906 ( 6.0432 )	1.828 ( 10.0612 )	-2.487 ( 6.583 )	0.568 ( 6.453 )	-0.707 ( 11.3657 )
Week 100 (n=68, 70, 72, 24, 24, 18)	-0.308 ( 7.9759 )	-2.433 ( 6.678 )	0.118 ( 7.8025 )	-2.683 ( 4.987 )	-1.623 ( 8.3312 )	-2.927 ( 7.867 )
Week 124 (n=66, 70, 68, 21, 23, 18)	-0.794 ( 7.8392 )	-2.246 ( 6.5967 )	0.89 ( 7.8545 )	-2.582 ( 8.464 )	-0.487 ( 8.2776 )	-1.821 ( 7.7421 )
Week 148 (n=59, 67, 68, 20, 21, 18)	-0.909 ( 6.7009 )	-3.078 ( 6.6149 )	0.124 ( 7.7589 )	-2.01 ( 7.8162 )	-0.715 ( 6.7088 )	-4.803 ( 9.3143 )
Early termination(n=16, 17, 13, 7, 3, 8)	-4.225 ( 8.2667 )	-0.632 ( 5.1482 )	979.704 ( 3533.962 )	0.278 ( 9.2002 )	0.459 ( 16.2506 )	2.813 ( 6.3216 )
Week 152 (n=12, 12, 10, 4, 3, 8)	-4.256 ( 7.4403 )	-0.074 ( 6.8982 )	-2.829 ( 7.0313 )	-3.748 ( 9.0311 )	-2.726 ( 17.6042 )	-1.283 ( 9.759 )
Week 200 (n=18, 18, 19, 6, 6, 3)	-0.316 ( 5.0212 )	-3.057 ( 12.0551 )	-1.59 ( 8.9426 )	-1.109 ( 5.4668 )	-1.152 ( 14.6922 )	4.287 ( 8.1537 )
Early termination (n=56, 63, 63, 19, 20, 16)	-0.033 ( 6.5169 )	-1.952 ( 9.6157 )	-0.903 ( 10.0341 )	-1.593 ( 8.6842 )	-0.892 ( 5.6941 )	-4.731 ( 12.9422 )
Week 255 (n=47, 48, 47, 17, 16, 13)	-0.717 ( 8.1437 )	-1.686 ( 10.456 )	1.386 ( 13.997 )	-0.115 ( 13.4126 )	-1.059 ( 10.2246 )	-0.675 ( 11.1022 )

No statistical analyses for this end point

Primary: Change From Baseline in Diffusing Capacity of Lung for Carbon Monoxide (DLCO)

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End point title

Change From Baseline in Diffusing Capacity of Lung for Carbon Monoxide (DLCO) ^[4]

End point description

DLCO was one of most clinically valuable tests of lung function. The DLCO measure the ability of lungs to transfer gas from inhaled air to red blood cells in pulmonary capillaries. Early termination visit was recorded when subject was early terminated from study during the first 2.5 year period, while early termination 2 visit was recorded when subject was early terminated from the study during the additional 2 year period with delay. Values for DLCO “% of predicted” defined as mean value of 2 test results that were within 10% variability of each other. Safety analysis set consisted of all enrolled subjects. Here “n” signifies number of subjects analysed for individual time point in outcome measure. Here "99999" in ONO-4641 0.10 mg - 0.10 mg and Placebo - ONO4641 0.15 mg arm for Standard deviation signifies data not evaluable as it is assessed only for 1 subject. "99999" in Placebo - ONO4641 0.05 mg arm signifies Zero subjects were assessed for this measure. Hence, no data available.

End point type

Primary

End point timeframe

Baseline, Week 40, 52, early termination, Week 152, 200, 255

Notes
[4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive data was presented for this endpoint.

End point values	ONO-4641 0.15 milligram (mg) - 0.15 mg	ONO-4641 0.10 mg - 0.10 mg	ONO-4641 0.05 mg - 0.05 mg	Placebo - ONO4641 0.15 mg	Placebo - ONO4641 0.10 mg	Placebo - ONO4641 0.05 mg
Number of subjects analysed	80	87	89	29	26	29
Units: Percentage of predicted value
arithmetic mean (standard deviation)
Week 40 (n=22, 21, 16, 8, 9, 4)	2.4 ( 13.16 )	-1 ( 10.98 )	-2.4 ( 17.36 )	-5.3 ( 16.02 )	-2.7 ( 10.61 )	3.3 ( 6.4 )
Week 52 (n=20, 19, 19, 8, 9, 5)	-3.7 ( 8.36 )	-2.7 ( 10.74 )	0.8 ( 20.01 )	-5.3 ( 11.56 )	-4.8 ( 8.04 )	5.2 ( 6.34 )
Early termination (n=2, 1, 2, 3, 0, 0)	-6.5 ( 2.12 )	-9 ( 99999 )	-43 ( 46.67 )	-16.3 ( 12.58 )	99999 ( 99999 )	99999 ( 99999 )
Week 152 (n=3, 1, 2, 1, 0, 0)	-1 ( 1 )	11 ( 99999 )	9.5 ( 3.54 )	-14 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )
Week 200 (n=7, 5, 5, 2, 3, 2)	3 ( 43.89 )	2 ( 12.85 )	35.8 ( 34.87 )	9.5 ( 28.99 )	25 ( 12 )	5 ( 9.9 )
Week 255 (n=14, 15, 12, 4, 6, 4)	42.3 ( 40.41 )	21 ( 29.4 )	27.8 ( 37.38 )	5.8 ( 32.79 )	37.5 ( 40.78 )	16.3 ( 19.52 )

No statistical analyses for this end point

Primary: Number of subjects with clinically significant abnormal electrocardiogram (ECG) measures

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End point title

Number of subjects with clinically significant abnormal electrocardiogram (ECG) measures ^[5]

End point description

The 12-lead ECG was recorded after the subject was in supine position for 5 minutes. ECGs were acquired on digital cardiographs. Abnormal findings were analysed as clinically significant or not clinically significant as per the discretion of the study investigator. Safety analysis set consisted of all the enrolled subjects.

End point type

Primary

End point timeframe

Baseline up to Week 255

Notes
[5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive data was presented for this endpoint.

End point values	ONO-4641 0.15 milligram (mg) - 0.15 mg	ONO-4641 0.10 mg - 0.10 mg	ONO-4641 0.05 mg - 0.05 mg	Placebo - ONO4641 0.15 mg	Placebo - ONO4641 0.10 mg	Placebo - ONO4641 0.05 mg
Number of subjects analysed	80	87	89	29	26	29
Units: subjects	0	0	0	0	0	0

No statistical analyses for this end point

Primary: Number of subjects with clinically significant abnormal ophthalmologic examination

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End point title

Number of subjects with clinically significant abnormal ophthalmologic examination ^[6]

End point description

Subjects undergo comprehensive ophthalmic examination including best corrected visual acuity (Snellen),manifest refractions,pupil examination, ocular motility,nystagmus,confrontation visual fields,Ishihara color plates,Amsler grid; tonometry and biomicroscopy slit lamp examination ofconjunctiva,cornea,anterior chamber,iris andlens; and fundoscopic examination(with dilation) of vitreous,optic nerve,retinal vessels,macula, peripheralretina.Optical Coherence Tomography (OCT): Thicknesses of macularretinaand retinal nerve fiber layer atoptic nervehead in each eye assessed by OCTusing fast macular thickness mapscan andfast retinal nerve fiber layer scanfeatures. Abnormalities of ophthalmologic examination judged to beclinically significant or notas per investigatorsdiscretion. Ophthalmologic examination was performed for both right eye and left eye. Safety analysis set consisted of all enrolled subjects."n" signifies number of subjects analysed for individual time point in outcome measure.

End point type

Primary

End point timeframe

Baseline up to Week 255

Notes
[6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive data was presented for this endpoint.

End point values	ONO-4641 0.15 milligram (mg) - 0.15 mg	ONO-4641 0.10 mg - 0.10 mg	ONO-4641 0.05 mg - 0.05 mg	Placebo - ONO4641 0.15 mg	Placebo - ONO4641 0.10 mg	Placebo - ONO4641 0.05 mg
Number of subjects analysed	80	87	89	29	26	29
Units: subjects
COE: RE: Baseline (n=80, 87, 89, 29, 26,29)	1	4	3	2	0	0
COE: LE: Baseline (n=80, 87, 89, 29, 26, 29)	0	4	3	2	0	0
COE: RE: Week 40 (n=78, 81, 82, 25, 23, 24)	2	2	2	1	0	0
COE: LE: Week 40 (n=78, 81, 82, 25, 23, 24)	5	1	2	1	0	0
COE: RE: Week 52 (n=76, 83, 77, 26, 24, 21)	0	2	4	1	0	0
COE: LE: Week 52 (n=76, 83, 77, 26, 24, 21)	2	2	3	1	0	0
COE: RE: Week 76 (n=72, 79, 72, 24, 24, 21)	1	2	4	1	0	1
COE: LE: Week 76 (n=72, 79, 72, 24, 24, 21)	3	2	5	1	0	1
COE: RE: Week 100 (n=67, 72, 71, 24, 23, 18)	2	2	0	1	0	0
COE: LE: Week 100 (n=67, 72, 71, 24, 23, 18)	5	1	1	1	0	0
COE: RE: Week 124 (n=65, 69, 67, 20, 22, 18)	2	2	3	1	0	0
COE: LE: Week 124 (n=65, 69, 67, 20, 22, 18)	2	2	1	1	1	0
COE: RE: Week 148 (n=58, 66, 67, 19, 21, 18)	2	2	3	1	0	0
COE: LE: Week 148 (n=58, 66, 67, 19, 21, 18)	3	3	4	1	0	0
COE: RE: Early termination (n=15, 14, 16, 6, 2, 8)	0	0	1	0	0	0
COE: LE: Early termination (n=15, 14, 16, 6, 2, 8)	1	0	1	0	0	0
COE: RE: Week 152 (n=12, 11, 11, 3, 2, 9)	0	0	2	0	0	0
COE: LE: Week 152 (n=12, 11, 11, 3, 2, 9)	1	0	1	0	0	0
COE: RE: Week 174 (n=57, 61, 63, 17, 21, 15)	0	2	4	1	0	0
COE: LE: Week 174 (n=57, 61, 63, 17, 21, 15)	2	2	2	1	0	0
COE: RE: Week 200 (n=19, 18, 19, 5, 5, 4)	0	1	0	1	0	0
COE: LE: Week 200 (n=19, 18, 19, 5, 5, 4)	0	1	0	1	0	0
COE: RE: Week 225 (n=3, 2, 0, 0, 0, 0)	0	0	0	0	0	0
COE: LE: Week 225 (n=3, 2, 0, 0, 0, 0)	0	0	0	0	0	0
COE: RE: Early termination 2(n=50,56,62,19,21,16)	1	2	2	1	0	0
COE: LE: Early termination 2(n=50,56,62,19,21,16)	1	2	3	1	0	0
COE: RE: Week 255 (n=43, 42, 44, 16, 14, 13)	1	0	3	1	0	0
COE: LE: Week 255 (n=43, 42, 44, 16, 14, 13)	1	0	3	1	0	0
OCT: RE: Baseline (n=80, 87, 89, 29, 26, 29)	4	2	4	1	0	1
OCT: LE: Baseline (n=80, 87, 89, 29, 26, 29)	4	1	2	1	0	1
OCT: RE: Week 40 (n=76, 80, 81, 25, 23, 24)	2	1	3	0	0	1
OCT: LE: Week 40 (n=76, 80, 82, 25, 23, 24)	2	1	3	1	0	1
OCT: RE: Week 52 (n=74, 82, 74, 25, 22, 20)	1	1	2	1	0	0
OCT: LE: Week 52 (n=74, 82, 74, 25, 22, 20)	1	1	2	2	0	0
OCT: RE: Week 76 (n=69, 77, 72, 24, 24, 21)	2	0	1	0	0	0
OCT: LE: Week 76 (n=70, 77, 72, 24, 24, 21)	2	0	1	2	0	0
OCT: RE: Week 100 (n=66, 71, 70, 23, 23, 18)	3	0	1	0	0	0
OCT: LE: Week 100 (n=66, 71, 70, 23, 23, 18)	2	0	1	2	0	0
OCT: RE: Week 124 (n=64, 68, 66, 19, 21, 18)	3	0	1	0	0	0
OCT: LE: Week 124 (n=64, 68, 66, 19, 21, 18)	2	1	1	1	0	0
OCT: RE: Week 148 (n=57, 67, 67, 20, 21, 18)	2	1	2	0	0	0
OCT: LE: Week 148 (n=57, 67, 67, 20, 21, 18)	2	1	2	1	0	0
OCT: RE: Early termination (n=14, 15, 15, 8, 2, 8)	0	0	1	1	0	1
OCT: LE: Early termination (n=14, 15, 15, 8, 2, 8)	0	0	1	1	0	1
OCT: RE: Week 152 (n=12, 11, 10, 3, 2, 9)	0	0	2	0	0	1
OCT: LE: Week 152 (n=12, 11, 10, 3, 2, 9)	0	0	0	0	0	1
OCT: RE: Week 174 (n=57, 60, 63, 17, 21, 15)	2	1	3	0	0	1
OCT: LE: Week 174 (n=57, 60, 63, 17, 21, 15)	3	1	2	1	1	0
OCT: RE: Week 200 (n=18, 15, 20, 5, 5, 4)	1	0	0	0	1	0
OCT: LE: Week 200 (n=18, 15, 20, 5, 5, 4)	0	0	0	1	0	0
OCT: RE: Week 225 (n=2, 2, 0, 0, 0, 0)	0	0	0	0	0	0
OCT: LE: Week 225 (n=2, 2, 0, 0, 0, 0)	0	0	0	0	0	0
OCT:RE:Early termination 2(n=51, 55, 62,19,21,16)	4	0	2	0	0	0
OCT:LE:Early termination 2(n=51, 55, 62,19,21,16)	2	0	1	1	0	0
OCT: RE: Week 255 (n=43, 42, 41, 15, 14, 13)	2	0	2	0	0	0
OCT: LE: Week 255 (n=42, 42, 41, 15, 14, 13)	2	0	1	1	0	0

No statistical analyses for this end point

Primary: Number of subjects with clinically significant abnormalities in dermatological examination

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End point title

Number of subjects with clinically significant abnormalities in dermatological examination ^[7]

End point description

A whole body examination, paying particular attention to identify precancerous or cancerous lesions was done by a dermatologist and based on the clinical judgment of the dermatologist the abnormalities were categorized as clinically significant or clinically not significant. Early termination visit was recorded when the subject was early terminated from the study during the first 2.5 year period, while early termination 2 visit was recorded when the subject early terminated from the study during the additional 2 year period with delay shall be defined. Safety analysis set consisted of all the enrolled subjects.

End point type

Primary

End point timeframe

Baseline up to end of the treatment, assessed up to Week 255

Notes
[7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive data was presented for this endpoint.

End point values	ONO-4641 0.15 milligram (mg) - 0.15 mg	ONO-4641 0.10 mg - 0.10 mg	ONO-4641 0.05 mg - 0.05 mg	Placebo - ONO4641 0.15 mg	Placebo - ONO4641 0.10 mg	Placebo - ONO4641 0.05 mg
Number of subjects analysed	80	87	89	29	26	29
Units: subjects
Baseline	1	0	3	1	0	1
Week 40	1	2	3	1	0	0
Week 52	3	4	3	0	0	1
Week 76	4	4	3	2	1	0
Week 100	5	2	2	2	1	1
Week 124	6	7	2	2	1	1
Week 148	3	5	1	2	0	2
Early termination	0	1	0	1	0	0
Week 152	0	1	0	0	0	0
Week 174	2	1	1	0	1	1
Week 200	1	1	0	1	0	0
Early termination 2	1	0	0	1	0	1
Week 255	1	0	0	0	0	0

No statistical analyses for this end point

Primary: Number of subjects with treatment emergent adverse events (TEAEs), serious TEAEs, TEAEs leading to death and TEAEs leading to discontinuation

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End point title

Number of subjects with treatment emergent adverse events (TEAEs), serious TEAEs, TEAEs leading to death and TEAEs leading to discontinuation ^[8]

End point description

An Adverse Event (AE) was defined as any new untoward medical occurrences/worsening of pre-existing medical condition without regard to possibility of causal relationship. A Serious Adverse Event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect. TEAEs were defined as the AEs that occur between first dose of study drug administration and 35 days after the last dose of study drug administration that were absent before treatment or that worsened relative to pretreatment state. Safety analysis set consisted of all the enrolled subjects.

End point type

Primary

End point timeframe

From the first dose of study drug administration up to 35 days after the last dose of study drug administration, assessed up to 5 years

Notes
[8] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive data was presented for this endpoint.

End point values	ONO-4641 0.15 milligram (mg) - 0.15 mg	ONO-4641 0.10 mg - 0.10 mg	ONO-4641 0.05 mg - 0.05 mg	Placebo - ONO4641 0.15 mg	Placebo - ONO4641 0.10 mg	Placebo - ONO4641 0.05 mg
Number of subjects analysed	80	87	89	29	26	29
Units: subjects
TEAEs	75	85	82	27	22	29
Serious TEAEs	16	12	21	5	9	11
TEAEs leading to death	1	0	0	0	0	1
TEAEs leading to discontinuation	6	6	7	3	2	6

No statistical analyses for this end point

Secondary: Number of Gadolinium (Gd)-Enhanced Lesions

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End point title

Number of Gadolinium (Gd)-Enhanced Lesions ^[9]

End point description

Gd-enhanced lesions obtained by magnetic resonance imaging at each scheduled assessment visit over study period. Extension study baseline is defined as measurement most immediately prior to or on day of first dose day of extension study. End of treatment (EoT) lesion count is average number of lesion counts per scan, calculated by dividing the sum of all lesion counts by number of scans during extension treatment period. Early termination visit recorded when subject was early terminated from study during first 2.5 year period, while early termination 2 visit was recorded when subject early terminated from study during additional 2 year period with delay. Extension study baseline is defined as measurement most immediately prior to or on the day of first dose day of extension study.Full Analysis Set (FAS)included all subjects who provided any post baseline efficacy data. "n” signifies number of subjects analysed for individual time point in outcome measure.

End point type

Secondary

End point timeframe

Baseline, Week 40, 52, 100, 148, early termination, Week 152, 200, early termination 2, Week 255 and end of treatment (5 years)

Notes
[9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: For Efficacy analysis for this outcome measure. ONO4641 0.15mg - 0.15mg, Placebo - ONO4641 0.10 mg were presented as one of the subject was wrongly re-randomised in the extension trial hence, presented in these two reporting groups.

End point values	ONO-4641 0.10 mg - 0.10 mg	ONO-4641 0.05 mg - 0.05 mg	Placebo - ONO4641 0.15 mg	Placebo - ONO4641 0.05 mg	ONO-4641 0.15 mg - 0.15 mg	Placebo - ONO4641 0.10 mg
Number of subjects analysed	87	89	28	28	81	27
Units: Lesions
arithmetic mean (standard deviation)
Baseline	0 ( 0.18 )	0.3 ( 0.65 )	2.7 ( 3.88 )	1.6 ( 3.74 )	0.2 ( 0.57 )	3.6 ( 10.46 )
Week 40 (n=78, 84, 82, 28, 24, 25)	0.1 ( 0.62 )	0.4 ( 1.32 )	0.2 ( 0.42 )	0.2 ( 0.5 )	0.2 ( 0.67 )	0.3 ( 1 )
Week 52 (n=77, 84, 77, 25, 24, 21)	0.2 ( 1.23 )	0.4 ( 0.93 )	0.2 ( 0.65 )	0.4 ( 0.68 )	0.2 ( 0.86 )	0.1 ( 0.34 )
Week 100 (n=71, 73, 72, 22, 24, 18)	0.2 ( 0.76 )	0.4 ( 1.37 )	0.2 ( 0.53 )	0.1 ( 0.47 )	0.1 ( 0.49 )	0.1 ( 0.34 )
Week 148 (n=61, 67, 68, 18, 22, 18)	0.1 ( 0.99 )	0.6 ( 1.85 )	0 ( 0 )	0.1 ( 0.47 )	0 ( 0.22 )	0.2 ( 0.66 )
Early termination (n=16, 14, 13, 6, 3, 6)	0.1 ( 0.36 )	1.5 ( 4.68 )	0.2 ( 0.41 )	0.5 ( 0.84 )	0.8 ( 2.76 )	0 ( 0 )
Week 152 (n=11, 10, 8, 4, 3, 6)	0.6 ( 0.97 )	2.5 ( 6.3 )	0.8 ( 1.5 )	0.3 ( 0.82 )	0.2 ( 0.6 )	0 ( 0 )
Week 200 (n=20, 18, 21, 28, 27, 28)	0.5 ( 1.29 )	0.2 ( 0.89 )	0 ( 0 )	0 ( 0 )	0 ( 0 )	0.5 ( 1.22 )
Early Termination 2 (n=58, 61, 60, 17, 21, 16)	0.2 ( 0.87 )	0.2 ( 0.38 )	0.1 ( 0.33 )	0.4 ( 1.26 )	0.1 ( 0.34 )	0.2 ( 0.51 )
Week 255 (n=46, 48, 48, 16, 17, 13)	0.3 ( 1.01 )	0.4 ( 1.38 )	1.6 ( 3.9 )	0.3 ( 0.85 )	1.1 ( 5.9 )	0.2 ( 0.53 )
End of treatment (n=80, 84, 85, 28, 24, 25)	0.2 ( 0.64 )	0.4 ( 0.93 )	0.2 ( 0.39 )	0.3 ( 0.5 )	0.1 ( 0.39 )	0.2 ( 0.53 )

No statistical analyses for this end point

Secondary: Change from Baseline in Lesion Volume at the end of the treatment (EoT)

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End point title

Change from Baseline in Lesion Volume at the end of the treatment (EoT) ^[10]

End point description

Brain lesion volume was obtained by magnetic resonance imaging (MRI). Extension study baseline was defined as the measurement most immediately prior to or on the day of the first dose day of extension study. End of treatment (EOT) was defined as the last visit during the treatment period. Change from extension baseline to EOT = last treatment period value in extension study — extension baseline value. FAS included all subjects who provided any post baseline efficacy data. One randomised error subject was summarised in the sequence 0.15-0.15 as the subject received 0.15 in core study period and in the sequence Placebo-0.10 mg as the subject received 0.10 in the extension study period. FAS included all subjects who provided any post baseline efficacy data.One randomised error subject was summarized in the sequence 0.15-0.15 as the subject received 0.15 in core study period and in the sequence Placebo-0.10 mg as the subject received 0.10 in the extension study period.

End point type

Secondary

End point timeframe

Baseline, End of treatment (5 years)

Notes
[10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: For Efficacy analysis for this outcome measure. Ono4641 0.15mg - 0.15mg, Placebo - ONO4641 0.10 mg were presented as one of the subject was wrongly re-ransomised in the extension trial hence, presented in these two reporting groups.

End point values	ONO-4641 0.10 mg - 0.10 mg	ONO-4641 0.05 mg - 0.05 mg	Placebo - ONO4641 0.15 mg	Placebo - ONO4641 0.05 mg	ONO-4641 0.15 mg - 0.15 mg	Placebo - ONO4641 0.10 mg
Number of subjects analysed	87	89	28	28	81	27
Units: Cubic centimeter (cc)
arithmetic mean (standard deviation)	0.0294 ( 0.11275 )	0.0197 ( 0.19925 )	-0.4548 ( 0.96555 )	-0.1105 ( 0.36973 )	-0.0264 ( 0.15483 )	-0.4465 ( 1.22881 )

No statistical analyses for this end point

Secondary: Percent Brain Volume Change (PBVC) from Baseline at the end of treatment

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End point title

Percent Brain Volume Change (PBVC) from Baseline at the end of treatment ^[11]

End point description

Brain volume was obtained by magnetic resonance imaging (MRI). Extension study baseline is defined as the measurement most immediately prior to or on the day of the first dose day of extension study. Brain volume changes very little over time. Hence, the PBVC at the end of treatment was calculated by adding up all the PBVC values from the scans performed during the extension treatment period. FAS included all subjects who provided any post baseline efficacy data. One randomised error subject was summarised in the sequence 0.15-0.15 as the subject received 0.15 in core study period and in the sequence Placebo-0.10 mg as the subject received 0.10 in the extension study period.

End point type

Secondary

End point timeframe

Baseline and at end of treatment (Week 255)

Notes
[11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: For Efficacy analysis for this outcome measure. ONO4641 0.15mg - 0.15mg, Placebo - ONO4641 0.10 mg were presented as one of the subject was wrongly re-randomised in the extension trial hence, presented in these two reporting groups.

End point values	ONO-4641 0.10 mg - 0.10 mg	ONO-4641 0.05 mg - 0.05 mg	Placebo - ONO4641 0.15 mg	Placebo - ONO4641 0.05 mg	ONO-4641 0.15 mg - 0.15 mg	Placebo - ONO4641 0.10 mg
Number of subjects analysed	87	89	28	28	81	27
Units: Percent brain volume
arithmetic mean (standard deviation)	-0.713 ( 0.8558 )	-0.757 ( 0.7554 )	-0.756 ( 0.8239 )	-0.972 ( 0.8215 )	-0.845 ( 0.8745 )	-1.302 ( 0.9643 )

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

From the administration of study medication up to the final study visit, assessed up to 5 years

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

13.0

Reporting group title

ONO-4641 0.15 milligram (mg) - 0.15 mg

Reporting group description

Subjects who were administered with ONO-4641 at a dose of 0.15 mg in the core study were administered with ONO-4641 at a dose of 0.15 mg once daily in the extension study for a duration of 225 weeks.

Reporting group title

ONO-4641 0.10 mg - 0.10 mg

Reporting group description

Subjects who were administered with ONO-4641 at a dose of 0.10 mg in the core study were administered with ONO-4641 at a dose of 0.10 mg once daily in the extension study for a duration of 225 weeks.

Reporting group title

ONO-4641 0.05 mg - 0.05 mg

Reporting group description

Subjects who were administered with ONO-4641 at a dose of 0.05 mg in the core study were administered with ONO-4641 at a dose of 0.05 mg once daily in the extension study for a duration of 225 weeks.

Reporting group title

Placebo - ONO4641 0.15 mg

Reporting group description

Subjects who were administered with placebo in the core study were administered with ONO-4641 at a dose of 0.15 mg once daily in the extension study for a duration of 225 weeks.

Reporting group title

Placebo - ONO4641 0.10 mg

Reporting group description

Subjects who were administered with placebo in the core study were administered with ONO-4641 at a dose of 0.10 mg once daily in the extension study for a duration of 225 weeks.

Reporting group title

Placebo - ONO4641 0.05 mg

Reporting group description

Subjects who were administered with placebo in the core study were administered with ONO-4641 at a dose of 0.05 mg once daily in the extension study for a duration of 225 weeks.

Serious adverse events	ONO-4641 0.15 milligram (mg) - 0.15 mg	ONO-4641 0.10 mg - 0.10 mg	ONO-4641 0.05 mg - 0.05 mg	Placebo - ONO4641 0.15 mg	Placebo - ONO4641 0.10 mg	Placebo - ONO4641 0.05 mg
Total subjects affected by serious adverse events
subjects affected / exposed	16 / 80 (20.00%)	12 / 87 (13.79%)	21 / 89 (23.60%)	5 / 29 (17.24%)	9 / 26 (34.62%)	11 / 29 (37.93%)
number of deaths (all causes)	1	0	0	0	0	1
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma
subjects affected / exposed	0 / 80 (0.00%)	0 / 87 (0.00%)	0 / 89 (0.00%)	0 / 29 (0.00%)	0 / 26 (0.00%)	1 / 29 (3.45%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Benign breast neoplasm
subjects affected / exposed	0 / 80 (0.00%)	0 / 87 (0.00%)	0 / 89 (0.00%)	0 / 29 (0.00%)	1 / 26 (3.85%)	0 / 29 (0.00%)
occurrences causally related to treatment / all	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
Breast cancer
subjects affected / exposed	1 / 80 (1.25%)	0 / 87 (0.00%)	0 / 89 (0.00%)	0 / 29 (0.00%)	0 / 26 (0.00%)	0 / 29 (0.00%)
occurrences causally related to treatment / all	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
Breast cancer in situ
subjects affected / exposed	0 / 80 (0.00%)	0 / 87 (0.00%)	0 / 89 (0.00%)	1 / 29 (3.45%)	0 / 26 (0.00%)	0 / 29 (0.00%)
occurrences causally related to treatment / all	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
Metastatic gastric cancer
subjects affected / exposed	0 / 80 (0.00%)	0 / 87 (0.00%)	0 / 89 (0.00%)	0 / 29 (0.00%)	0 / 26 (0.00%)	1 / 29 (3.45%)
occurrences causally related to treatment / all	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 / 1
Rectal cancer
subjects affected / exposed	0 / 80 (0.00%)	1 / 87 (1.15%)	0 / 89 (0.00%)	0 / 29 (0.00%)	0 / 26 (0.00%)	0 / 29 (0.00%)
occurrences causally related to treatment / all	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
Uterine cancer
subjects affected / exposed	0 / 80 (0.00%)	0 / 87 (0.00%)	1 / 89 (1.12%)	0 / 29 (0.00%)	0 / 26 (0.00%)	0 / 29 (0.00%)
occurrences causally related to treatment / all	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
Vascular disorders
Venous insufficiency
subjects affected / exposed	0 / 80 (0.00%)	0 / 87 (0.00%)	1 / 89 (1.12%)	0 / 29 (0.00%)	0 / 26 (0.00%)	0 / 29 (0.00%)
occurrences causally related to treatment / all	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
Surgical and medical procedures
Female sterilisation
subjects affected / exposed	2 / 80 (2.50%)	0 / 87 (0.00%)	0 / 89 (0.00%)	0 / 29 (0.00%)	0 / 26 (0.00%)	0 / 29 (0.00%)
occurrences causally related to treatment / all	0 / 2	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
Pregnancy, puerperium and perinatal conditions
Pregnancy
subjects affected / exposed	0 / 80 (0.00%)	1 / 87 (1.15%)	0 / 89 (0.00%)	0 / 29 (0.00%)	0 / 26 (0.00%)	0 / 29 (0.00%)
occurrences causally related to treatment / all	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
General disorders and administration site conditions
Chest pain
subjects affected / exposed	0 / 80 (0.00%)	0 / 87 (0.00%)	1 / 89 (1.12%)	0 / 29 (0.00%)	0 / 26 (0.00%)	0 / 29 (0.00%)
occurrences causally related to treatment / all	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
Oedema peripheral
subjects affected / exposed	1 / 80 (1.25%)	0 / 87 (0.00%)	0 / 89 (0.00%)	0 / 29 (0.00%)	0 / 26 (0.00%)	0 / 29 (0.00%)
occurrences causally related to treatment / all	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
Pyrexia
subjects affected / exposed	1 / 80 (1.25%)	0 / 87 (0.00%)	0 / 89 (0.00%)	0 / 29 (0.00%)	0 / 26 (0.00%)	0 / 29 (0.00%)
occurrences causally related to treatment / all	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
Reproductive system and breast disorders
Pelvic prolapse
subjects affected / exposed	1 / 80 (1.25%)	0 / 87 (0.00%)	0 / 89 (0.00%)	0 / 29 (0.00%)	0 / 26 (0.00%)	0 / 29 (0.00%)
occurrences causally related to treatment / all	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
Uterine polyp
subjects affected / exposed	1 / 80 (1.25%)	0 / 87 (0.00%)	0 / 89 (0.00%)	0 / 29 (0.00%)	0 / 26 (0.00%)	0 / 29 (0.00%)
occurrences causally related to treatment / all	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
Respiratory, thoracic and mediastinal disorders
Asthma
subjects affected / exposed	1 / 80 (1.25%)	0 / 87 (0.00%)	0 / 89 (0.00%)	0 / 29 (0.00%)	0 / 26 (0.00%)	0 / 29 (0.00%)
occurrences causally related to treatment / all	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
Psychiatric disorders
Autism spectrum disorder
subjects affected / exposed	0 / 80 (0.00%)	1 / 87 (1.15%)	0 / 89 (0.00%)	0 / 29 (0.00%)	0 / 26 (0.00%)	0 / 29 (0.00%)
occurrences causally related to treatment / all	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
Mania
subjects affected / exposed	0 / 80 (0.00%)	0 / 87 (0.00%)	0 / 89 (0.00%)	0 / 29 (0.00%)	0 / 26 (0.00%)	1 / 29 (3.45%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Suicide attempt
subjects affected / exposed	0 / 80 (0.00%)	0 / 87 (0.00%)	1 / 89 (1.12%)	0 / 29 (0.00%)	0 / 26 (0.00%)	0 / 29 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Alanine aminotransferase increased
subjects affected / exposed	0 / 80 (0.00%)	0 / 87 (0.00%)	0 / 89 (0.00%)	1 / 29 (3.45%)	0 / 26 (0.00%)	1 / 29 (3.45%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood human chorionic gonadotropin increased
subjects affected / exposed	1 / 80 (1.25%)	0 / 87 (0.00%)	0 / 89 (0.00%)	0 / 29 (0.00%)	0 / 26 (0.00%)	0 / 29 (0.00%)
occurrences causally related to treatment / all	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
Gamma-glutamyltransferase increased
subjects affected / exposed	0 / 80 (0.00%)	0 / 87 (0.00%)	0 / 89 (0.00%)	1 / 29 (3.45%)	0 / 26 (0.00%)	0 / 29 (0.00%)
occurrences causally related to treatment / all	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
Neutrophil count decreased
subjects affected / exposed	0 / 80 (0.00%)	0 / 87 (0.00%)	0 / 89 (0.00%)	0 / 29 (0.00%)	0 / 26 (0.00%)	1 / 29 (3.45%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Chemical poisoning
subjects affected / exposed	0 / 80 (0.00%)	0 / 87 (0.00%)	0 / 89 (0.00%)	0 / 29 (0.00%)	1 / 26 (3.85%)	0 / 29 (0.00%)
occurrences causally related to treatment / all	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
Fall
subjects affected / exposed	1 / 80 (1.25%)	0 / 87 (0.00%)	0 / 89 (0.00%)	0 / 29 (0.00%)	0 / 26 (0.00%)	0 / 29 (0.00%)
occurrences causally related to treatment / all	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
Nervous system disorders
Multiple sclerosis relapse
subjects affected / exposed	4 / 80 (5.00%)	8 / 87 (9.20%)	11 / 89 (12.36%)	1 / 29 (3.45%)	6 / 26 (23.08%)	6 / 29 (20.69%)
occurrences causally related to treatment / all	0 / 4	0 / 8	0 / 11	0 / 1	0 / 6	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cerebral infarction
subjects affected / exposed	0 / 80 (0.00%)	0 / 87 (0.00%)	1 / 89 (1.12%)	0 / 29 (0.00%)	0 / 26 (0.00%)	0 / 29 (0.00%)
occurrences causally related to treatment / all	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
Paraparesis
subjects affected / exposed	0 / 80 (0.00%)	0 / 87 (0.00%)	0 / 89 (0.00%)	0 / 29 (0.00%)	1 / 26 (3.85%)	0 / 29 (0.00%)
occurrences causally related to treatment / all	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
Syncope
subjects affected / exposed	0 / 80 (0.00%)	0 / 87 (0.00%)	0 / 89 (0.00%)	0 / 29 (0.00%)	0 / 26 (0.00%)	1 / 29 (3.45%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 80 (0.00%)	1 / 87 (1.15%)	0 / 89 (0.00%)	0 / 29 (0.00%)	0 / 26 (0.00%)	0 / 29 (0.00%)
occurrences causally related to treatment / all	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
Ear and labyrinth disorders
External ear inflammation
subjects affected / exposed	1 / 80 (1.25%)	0 / 87 (0.00%)	0 / 89 (0.00%)	0 / 29 (0.00%)	0 / 26 (0.00%)	0 / 29 (0.00%)
occurrences causally related to treatment / all	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
Eye disorders
Retinal detachment
subjects affected / exposed	0 / 80 (0.00%)	0 / 87 (0.00%)	1 / 89 (1.12%)	0 / 29 (0.00%)	0 / 26 (0.00%)	0 / 29 (0.00%)
occurrences causally related to treatment / all	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
Retinal tear
subjects affected / exposed	0 / 80 (0.00%)	0 / 87 (0.00%)	1 / 89 (1.12%)	0 / 29 (0.00%)	0 / 26 (0.00%)	0 / 29 (0.00%)
occurrences causally related to treatment / all	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
Gastrointestinal disorders
Colonic polyp
subjects affected / exposed	0 / 80 (0.00%)	0 / 87 (0.00%)	1 / 89 (1.12%)	0 / 29 (0.00%)	0 / 26 (0.00%)	0 / 29 (0.00%)
occurrences causally related to treatment / all	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
Gastritis haemorrhagic
subjects affected / exposed	0 / 80 (0.00%)	0 / 87 (0.00%)	1 / 89 (1.12%)	0 / 29 (0.00%)	0 / 26 (0.00%)	0 / 29 (0.00%)
occurrences causally related to treatment / all	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
Peritonitis
subjects affected / exposed	0 / 80 (0.00%)	0 / 87 (0.00%)	1 / 89 (1.12%)	0 / 29 (0.00%)	0 / 26 (0.00%)	0 / 29 (0.00%)
occurrences causally related to treatment / all	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
Renal and urinary disorders
Nephrolithiasis
subjects affected / exposed	1 / 80 (1.25%)	0 / 87 (0.00%)	0 / 89 (0.00%)	0 / 29 (0.00%)	0 / 26 (0.00%)	0 / 29 (0.00%)
occurrences causally related to treatment / all	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
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	0 / 80 (0.00%)	0 / 87 (0.00%)	0 / 89 (0.00%)	0 / 29 (0.00%)	1 / 26 (3.85%)	0 / 29 (0.00%)
occurrences causally related to treatment / all	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
Connective tissue disorder
subjects affected / exposed	0 / 80 (0.00%)	1 / 87 (1.15%)	0 / 89 (0.00%)	0 / 29 (0.00%)	0 / 26 (0.00%)	0 / 29 (0.00%)
occurrences causally related to treatment / all	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
Intervertebral disc protrusion
subjects affected / exposed	0 / 80 (0.00%)	0 / 87 (0.00%)	0 / 89 (0.00%)	1 / 29 (3.45%)	0 / 26 (0.00%)	0 / 29 (0.00%)
occurrences causally related to treatment / all	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
Infections and infestations
Appendicitis perforated
subjects affected / exposed	0 / 80 (0.00%)	0 / 87 (0.00%)	1 / 89 (1.12%)	0 / 29 (0.00%)	0 / 26 (0.00%)	0 / 29 (0.00%)
occurrences causally related to treatment / all	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
Clostridium difficile colitis
subjects affected / exposed	0 / 80 (0.00%)	0 / 87 (0.00%)	1 / 89 (1.12%)	0 / 29 (0.00%)	0 / 26 (0.00%)	0 / 29 (0.00%)
occurrences causally related to treatment / all	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
Encephalitic infection
subjects affected / exposed	0 / 80 (0.00%)	0 / 87 (0.00%)	1 / 89 (1.12%)	0 / 29 (0.00%)	0 / 26 (0.00%)	0 / 29 (0.00%)
occurrences causally related to treatment / all	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
Herpes zoster
subjects affected / exposed	0 / 80 (0.00%)	0 / 87 (0.00%)	0 / 89 (0.00%)	1 / 29 (3.45%)	0 / 26 (0.00%)	0 / 29 (0.00%)
occurrences causally related to treatment / all	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
Lymphangitis
subjects affected / exposed	0 / 80 (0.00%)	0 / 87 (0.00%)	0 / 89 (0.00%)	0 / 29 (0.00%)	1 / 26 (3.85%)	0 / 29 (0.00%)
occurrences causally related to treatment / all	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
Meningitis aseptic
subjects affected / exposed	1 / 80 (1.25%)	0 / 87 (0.00%)	0 / 89 (0.00%)	0 / 29 (0.00%)	0 / 26 (0.00%)	0 / 29 (0.00%)
occurrences causally related to treatment / all	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

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

Non-serious adverse events	ONO-4641 0.15 milligram (mg) - 0.15 mg	ONO-4641 0.10 mg - 0.10 mg	ONO-4641 0.05 mg - 0.05 mg	Placebo - ONO4641 0.15 mg	Placebo - ONO4641 0.10 mg	Placebo - ONO4641 0.05 mg
Total subjects affected by non serious adverse events
subjects affected / exposed	67 / 80 (83.75%)	80 / 87 (91.95%)	72 / 89 (80.90%)	21 / 29 (72.41%)	21 / 26 (80.77%)	27 / 29 (93.10%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Melanocytic naevus
subjects affected / exposed	2 / 80 (2.50%)	3 / 87 (3.45%)	5 / 89 (5.62%)	1 / 29 (3.45%)	2 / 26 (7.69%)	2 / 29 (6.90%)
occurrences all number	2	3	5	1	2	2
Vascular disorders
Hypertension
subjects affected / exposed	6 / 80 (7.50%)	2 / 87 (2.30%)	3 / 89 (3.37%)	1 / 29 (3.45%)	4 / 26 (15.38%)	5 / 29 (17.24%)
occurrences all number	6	2	3	1	4	5
General disorders and administration site conditions
Fatigue
subjects affected / exposed	6 / 80 (7.50%)	10 / 87 (11.49%)	9 / 89 (10.11%)	1 / 29 (3.45%)	3 / 26 (11.54%)	3 / 29 (10.34%)
occurrences all number	6	10	9	1	3	3
Pyrexia
subjects affected / exposed	3 / 80 (3.75%)	4 / 87 (4.60%)	6 / 89 (6.74%)	0 / 29 (0.00%)	2 / 26 (7.69%)	0 / 29 (0.00%)
occurrences all number	3	4	6	0	2	0
Immune system disorders
Seasonal allergy
subjects affected / exposed	3 / 80 (3.75%)	5 / 87 (5.75%)	6 / 89 (6.74%)	0 / 29 (0.00%)	0 / 26 (0.00%)	0 / 29 (0.00%)
occurrences all number	3	5	6	0	0	0
Reproductive system and breast disorders
Anxiety
subjects affected / exposed	7 / 80 (8.75%)	2 / 87 (2.30%)	2 / 89 (2.25%)	1 / 29 (3.45%)	0 / 26 (0.00%)	2 / 29 (6.90%)
occurrences all number	7	2	2	1	0	2
Dysmenorrhoea
subjects affected / exposed	1 / 80 (1.25%)	0 / 87 (0.00%)	1 / 89 (1.12%)	2 / 29 (6.90%)	0 / 26 (0.00%)	0 / 29 (0.00%)
occurrences all number	1	0	1	2	0	0
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	4 / 80 (5.00%)	6 / 87 (6.90%)	8 / 89 (8.99%)	2 / 29 (6.90%)	2 / 26 (7.69%)	3 / 29 (10.34%)
occurrences all number	4	6	8	2	2	3
Oropharyngeal pain
subjects affected / exposed	7 / 80 (8.75%)	3 / 87 (3.45%)	2 / 89 (2.25%)	1 / 29 (3.45%)	1 / 26 (3.85%)	2 / 29 (6.90%)
occurrences all number	7	3	2	1	1	2
Sinus congestion
subjects affected / exposed	3 / 80 (3.75%)	1 / 87 (1.15%)	5 / 89 (5.62%)	0 / 29 (0.00%)	1 / 26 (3.85%)	1 / 29 (3.45%)
occurrences all number	3	1	5	0	1	1
Dyspnoea
subjects affected / exposed	1 / 80 (1.25%)	5 / 87 (5.75%)	2 / 89 (2.25%)	0 / 29 (0.00%)	0 / 26 (0.00%)	0 / 29 (0.00%)
occurrences all number	1	5	2	0	0	0
Psychiatric disorders
Insomnia
subjects affected / exposed	4 / 80 (5.00%)	10 / 87 (11.49%)	6 / 89 (6.74%)	2 / 29 (6.90%)	1 / 26 (3.85%)	2 / 29 (6.90%)
occurrences all number	4	10	6	2	1	2
Depression
subjects affected / exposed	4 / 80 (5.00%)	7 / 87 (8.05%)	5 / 89 (5.62%)	1 / 29 (3.45%)	0 / 26 (0.00%)	4 / 29 (13.79%)
occurrences all number	4	7	5	1	0	4
Investigations
Alanine aminotransferase increased
subjects affected / exposed	8 / 80 (10.00%)	8 / 87 (9.20%)	12 / 89 (13.48%)	6 / 29 (20.69%)	3 / 26 (11.54%)	6 / 29 (20.69%)
occurrences all number	8	8	12	6	3	6
Gamma-glutamyltransferase increased
subjects affected / exposed	7 / 80 (8.75%)	9 / 87 (10.34%)	9 / 89 (10.11%)	4 / 29 (13.79%)	3 / 26 (11.54%)	5 / 29 (17.24%)
occurrences all number	7	9	9	4	3	5
Aspartate aminotransferase increased
subjects affected / exposed	3 / 80 (3.75%)	4 / 87 (4.60%)	4 / 89 (4.49%)	3 / 29 (10.34%)	0 / 26 (0.00%)	4 / 29 (13.79%)
occurrences all number	3	4	4	3	0	4
Activated partial thromboplastin time
subjects affected / exposed	2 / 80 (2.50%)	3 / 87 (3.45%)	2 / 89 (2.25%)	0 / 29 (0.00%)	2 / 26 (7.69%)	1 / 29 (3.45%)
occurrences all number	2	3	2	0	2	1
Blood cholesterol increased
subjects affected / exposed	2 / 80 (2.50%)	2 / 87 (2.30%)	3 / 89 (3.37%)	0 / 29 (0.00%)	2 / 26 (7.69%)	1 / 29 (3.45%)
occurrences all number	2	2	3	0	2	1
Blood creatine phosphokinase increased
subjects affected / exposed	3 / 80 (3.75%)	1 / 87 (1.15%)	4 / 89 (4.49%)	0 / 29 (0.00%)	2 / 26 (7.69%)	0 / 29 (0.00%)
occurrences all number	3	1	4	0	2	0
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	3 / 80 (3.75%)	8 / 87 (9.20%)	3 / 89 (3.37%)	1 / 29 (3.45%)	2 / 26 (7.69%)	5 / 29 (17.24%)
occurrences all number	3	8	3	1	2	5
Fall
subjects affected / exposed	4 / 80 (5.00%)	3 / 87 (3.45%)	3 / 89 (3.37%)	1 / 29 (3.45%)	2 / 26 (7.69%)	3 / 29 (10.34%)
occurrences all number	4	3	3	1	2	3
Procedural pain
subjects affected / exposed	4 / 80 (5.00%)	4 / 87 (4.60%)	1 / 89 (1.12%)	1 / 29 (3.45%)	1 / 26 (3.85%)	0 / 29 (0.00%)
occurrences all number	4	4	1	1	1	0
Muscle strain
subjects affected / exposed	4 / 80 (5.00%)	4 / 87 (4.60%)	1 / 89 (1.12%)	0 / 29 (0.00%)	0 / 26 (0.00%)	1 / 29 (3.45%)
occurrences all number	4	4	1	0	0	1
Excoriation
subjects affected / exposed	0 / 80 (0.00%)	4 / 87 (4.60%)	1 / 89 (1.12%)	0 / 29 (0.00%)	2 / 26 (7.69%)	2 / 29 (6.90%)
occurrences all number	0	4	1	0	2	2
Joint sprain
subjects affected / exposed	2 / 80 (2.50%)	2 / 87 (2.30%)	1 / 89 (1.12%)	0 / 29 (0.00%)	1 / 26 (3.85%)	2 / 29 (6.90%)
occurrences all number	2	2	1	0	1	2
Foreign body in eye
subjects affected / exposed	0 / 80 (0.00%)	0 / 87 (0.00%)	0 / 89 (0.00%)	0 / 29 (0.00%)	2 / 26 (7.69%)	0 / 29 (0.00%)
occurrences all number	0	0	0	0	2	0
Cardiac disorders
Palpitations
subjects affected / exposed	1 / 80 (1.25%)	5 / 87 (5.75%)	2 / 89 (2.25%)	1 / 29 (3.45%)	0 / 26 (0.00%)	0 / 29 (0.00%)
occurrences all number	1	5	2	1	0	0
Nervous system disorders
Headache
subjects affected / exposed	13 / 80 (16.25%)	13 / 87 (14.94%)	13 / 89 (14.61%)	7 / 29 (24.14%)	5 / 26 (19.23%)	2 / 29 (6.90%)
occurrences all number	13	13	13	7	5	2
Multiple sclerosis relapse
subjects affected / exposed	4 / 80 (5.00%)	9 / 87 (10.34%)	12 / 89 (13.48%)	1 / 29 (3.45%)	7 / 26 (26.92%)	7 / 29 (24.14%)
occurrences all number	4	9	12	1	7	7
Dizziness
subjects affected / exposed	4 / 80 (5.00%)	8 / 87 (9.20%)	3 / 89 (3.37%)	2 / 29 (6.90%)	1 / 26 (3.85%)	1 / 29 (3.45%)
occurrences all number	4	8	3	2	1	1
Hypoaesthesia
subjects affected / exposed	5 / 80 (6.25%)	3 / 87 (3.45%)	5 / 89 (5.62%)	2 / 29 (6.90%)	0 / 26 (0.00%)	2 / 29 (6.90%)
occurrences all number	5	3	5	2	0	2
Migraine
subjects affected / exposed	5 / 80 (6.25%)	4 / 87 (4.60%)	3 / 89 (3.37%)	0 / 29 (0.00%)	2 / 26 (7.69%)	0 / 29 (0.00%)
occurrences all number	5	4	3	0	2	0
Muscle spasticity
subjects affected / exposed	1 / 80 (1.25%)	5 / 87 (5.75%)	2 / 89 (2.25%)	0 / 29 (0.00%)	1 / 26 (3.85%)	1 / 29 (3.45%)
occurrences all number	1	5	2	0	1	1
Paraesthesia
subjects affected / exposed	4 / 80 (5.00%)	2 / 87 (2.30%)	1 / 89 (1.12%)	0 / 29 (0.00%)	0 / 26 (0.00%)	1 / 29 (3.45%)
occurrences all number	4	2	1	0	0	1
Sciatica
subjects affected / exposed	0 / 80 (0.00%)	2 / 87 (2.30%)	3 / 89 (3.37%)	1 / 29 (3.45%)	0 / 26 (0.00%)	2 / 29 (6.90%)
occurrences all number	0	2	3	1	0	2
Tremor
subjects affected / exposed	1 / 80 (1.25%)	2 / 87 (2.30%)	1 / 89 (1.12%)	0 / 29 (0.00%)	0 / 26 (0.00%)	2 / 29 (6.90%)
occurrences all number	1	2	1	0	0	2
Memory impairment
subjects affected / exposed	1 / 80 (1.25%)	1 / 87 (1.15%)	0 / 89 (0.00%)	0 / 29 (0.00%)	0 / 26 (0.00%)	2 / 29 (6.90%)
occurrences all number	1	1	0	0	0	2
Blood and lymphatic system disorders
Lymphopenia
subjects affected / exposed	1 / 80 (1.25%)	3 / 87 (3.45%)	0 / 89 (0.00%)	0 / 29 (0.00%)	2 / 26 (7.69%)	0 / 29 (0.00%)
occurrences all number	1	3	0	0	2	0
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	5 / 80 (6.25%)	5 / 87 (5.75%)	5 / 89 (5.62%)	0 / 29 (0.00%)	1 / 26 (3.85%)	1 / 29 (3.45%)
occurrences all number	5	5	5	0	1	1
Eye disorders
Conjunctivitis
subjects affected / exposed	2 / 80 (2.50%)	1 / 87 (1.15%)	6 / 89 (6.74%)	0 / 29 (0.00%)	1 / 26 (3.85%)	0 / 29 (0.00%)
occurrences all number	2	1	6	0	1	0
Retinal disorder
subjects affected / exposed	1 / 80 (1.25%)	2 / 87 (2.30%)	2 / 89 (2.25%)	2 / 29 (6.90%)	0 / 26 (0.00%)	0 / 29 (0.00%)
occurrences all number	1	2	2	2	0	0
Blepharospasm
subjects affected / exposed	2 / 80 (2.50%)	0 / 87 (0.00%)	0 / 89 (0.00%)	0 / 29 (0.00%)	0 / 26 (0.00%)	2 / 29 (6.90%)
occurrences all number	2	0	0	0	0	2
Conjunctival hyperaemia
subjects affected / exposed	0 / 80 (0.00%)	0 / 87 (0.00%)	0 / 89 (0.00%)	0 / 29 (0.00%)	2 / 26 (7.69%)	0 / 29 (0.00%)
occurrences all number	0	0	0	0	2	0
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	8 / 80 (10.00%)	10 / 87 (11.49%)	4 / 89 (4.49%)	1 / 29 (3.45%)	2 / 26 (7.69%)	1 / 29 (3.45%)
occurrences all number	8	10	4	1	2	1
Nausea
subjects affected / exposed	8 / 80 (10.00%)	7 / 87 (8.05%)	4 / 89 (4.49%)	0 / 29 (0.00%)	0 / 26 (0.00%)	3 / 29 (10.34%)
occurrences all number	8	7	4	0	0	3
Abdominal pain upper
subjects affected / exposed	3 / 80 (3.75%)	5 / 87 (5.75%)	4 / 89 (4.49%)	0 / 29 (0.00%)	0 / 26 (0.00%)	1 / 29 (3.45%)
occurrences all number	3	5	4	0	0	1
Abdominal pain
subjects affected / exposed	4 / 80 (5.00%)	2 / 87 (2.30%)	4 / 89 (4.49%)	0 / 29 (0.00%)	0 / 26 (0.00%)	1 / 29 (3.45%)
occurrences all number	4	2	4	0	0	1
Vomiting
subjects affected / exposed	4 / 80 (5.00%)	4 / 87 (4.60%)	1 / 89 (1.12%)	0 / 29 (0.00%)	0 / 26 (0.00%)	1 / 29 (3.45%)
occurrences all number	4	4	1	0	0	1
Dyspepsia
subjects affected / exposed	4 / 80 (5.00%)	2 / 87 (2.30%)	2 / 89 (2.25%)	1 / 29 (3.45%)	0 / 26 (0.00%)	0 / 29 (0.00%)
occurrences all number	4	2	2	1	0	0
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 80 (0.00%)	1 / 87 (1.15%)	5 / 89 (5.62%)	0 / 29 (0.00%)	1 / 26 (3.85%)	0 / 29 (0.00%)
occurrences all number	0	1	5	0	1	0
Abdominal discomfort
subjects affected / exposed	0 / 80 (0.00%)	0 / 87 (0.00%)	1 / 89 (1.12%)	0 / 29 (0.00%)	0 / 26 (0.00%)	2 / 29 (6.90%)
occurrences all number	0	0	1	0	0	2
Skin and subcutaneous tissue disorders
Acne
subjects affected / exposed	5 / 80 (6.25%)	5 / 87 (5.75%)	5 / 89 (5.62%)	0 / 29 (0.00%)	0 / 26 (0.00%)	0 / 29 (0.00%)
occurrences all number	5	5	5	0	0	0
Eczema
subjects affected / exposed	7 / 80 (8.75%)	4 / 87 (4.60%)	1 / 89 (1.12%)	0 / 29 (0.00%)	0 / 26 (0.00%)	2 / 29 (6.90%)
occurrences all number	7	4	1	0	0	2
Increased tendency to bruise
subjects affected / exposed	2 / 80 (2.50%)	7 / 87 (8.05%)	0 / 89 (0.00%)	1 / 29 (3.45%)	0 / 26 (0.00%)	0 / 29 (0.00%)
occurrences all number	2	7	0	1	0	0
Ecchymosis
subjects affected / exposed	3 / 80 (3.75%)	2 / 87 (2.30%)	1 / 89 (1.12%)	0 / 29 (0.00%)	1 / 26 (3.85%)	2 / 29 (6.90%)
occurrences all number	3	2	1	0	1	2
Rash
subjects affected / exposed	1 / 80 (1.25%)	5 / 87 (5.75%)	1 / 89 (1.12%)	0 / 29 (0.00%)	0 / 26 (0.00%)	1 / 29 (3.45%)
occurrences all number	1	5	1	0	0	1
Dermatitis
subjects affected / exposed	2 / 80 (2.50%)	0 / 87 (0.00%)	1 / 89 (1.12%)	0 / 29 (0.00%)	1 / 26 (3.85%)	2 / 29 (6.90%)
occurrences all number	2	0	1	0	1	2
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	11 / 80 (13.75%)	8 / 87 (9.20%)	12 / 89 (13.48%)	1 / 29 (3.45%)	5 / 26 (19.23%)	2 / 29 (6.90%)
occurrences all number	11	8	12	1	5	2
Arthralgia
subjects affected / exposed	7 / 80 (8.75%)	8 / 87 (9.20%)	6 / 89 (6.74%)	1 / 29 (3.45%)	3 / 26 (11.54%)	5 / 29 (17.24%)
occurrences all number	7	8	6	1	3	5
Pain in extremity
subjects affected / exposed	11 / 80 (13.75%)	4 / 87 (4.60%)	8 / 89 (8.99%)	3 / 29 (10.34%)	0 / 26 (0.00%)	2 / 29 (6.90%)
occurrences all number	1	4	8	3	0	2
Muscle spasms
subjects affected / exposed	4 / 80 (5.00%)	4 / 87 (4.60%)	5 / 89 (5.62%)	0 / 29 (0.00%)	1 / 26 (3.85%)	0 / 29 (0.00%)
occurrences all number	4	4	5	0	1	0
Musculoskeletal pain
subjects affected / exposed	2 / 80 (2.50%)	3 / 87 (3.45%)	5 / 89 (5.62%)	0 / 29 (0.00%)	0 / 26 (0.00%)	2 / 29 (6.90%)
occurrences all number	2	3	5	0	0	2
Neck pain
subjects affected / exposed	2 / 80 (2.50%)	2 / 87 (2.30%)	3 / 89 (3.37%)	1 / 29 (3.45%)	1 / 26 (3.85%)	3 / 29 (10.34%)
occurrences all number	2	2	3	1	1	3
Muscular weakness
subjects affected / exposed	3 / 80 (3.75%)	2 / 87 (2.30%)	6 / 89 (6.74%)	0 / 29 (0.00%)	0 / 26 (0.00%)	0 / 29 (0.00%)
occurrences all number	3	2	6	0	0	0
Intervertebral disc protrusion
subjects affected / exposed	0 / 80 (0.00%)	0 / 87 (0.00%)	1 / 89 (1.12%)	2 / 29 (6.90%)	1 / 26 (3.85%)	0 / 29 (0.00%)
occurrences all number	0	0	1	2	1	0
Infections and infestations
Nasopharyngitis
subjects affected / exposed	18 / 80 (22.50%)	21 / 87 (24.14%)	22 / 89 (24.72%)	3 / 29 (10.34%)	8 / 26 (30.77%)	7 / 29 (24.14%)
occurrences all number	18	21	22	3	8	7
Upper respiratory tract infection
subjects affected / exposed	14 / 80 (17.50%)	21 / 87 (24.14%)	15 / 89 (16.85%)	4 / 29 (13.79%)	5 / 26 (19.23%)	6 / 29 (20.69%)
occurrences all number	14	21	15	4	5	6
Urinary tract infection
subjects affected / exposed	7 / 80 (8.75%)	16 / 87 (18.39%)	13 / 89 (14.61%)	2 / 29 (6.90%)	4 / 26 (15.38%)	6 / 29 (20.69%)
occurrences all number	7	16	13	2	4	6
Bronchitis
subjects affected / exposed	12 / 80 (15.00%)	8 / 87 (9.20%)	8 / 89 (8.99%)	2 / 29 (6.90%)	0 / 26 (0.00%)	0 / 29 (0.00%)
occurrences all number	12	8	8	2	0	0
Oral herpes
subjects affected / exposed	2 / 80 (2.50%)	9 / 87 (10.34%)	7 / 89 (7.87%)	0 / 29 (0.00%)	5 / 26 (19.23%)	0 / 29 (0.00%)
occurrences all number	2	9	7	0	5	0
Pharyngitis
subjects affected / exposed	3 / 80 (3.75%)	9 / 87 (10.34%)	6 / 89 (6.74%)	2 / 29 (6.90%)	0 / 26 (0.00%)	3 / 29 (10.34%)
occurrences all number	3	9	6	2	0	3
Sinusitis
subjects affected / exposed	8 / 80 (10.00%)	6 / 87 (6.90%)	7 / 89 (7.87%)	0 / 29 (0.00%)	2 / 26 (7.69%)	0 / 29 (0.00%)
occurrences all number	8	6	7	0	2	0
Influenza
subjects affected / exposed	3 / 80 (3.75%)	6 / 87 (6.90%)	5 / 89 (5.62%)	1 / 29 (3.45%)	1 / 26 (3.85%)	3 / 29 (10.34%)
occurrences all number	3	6	5	1	1	3
Gastroenteritis viral
subjects affected / exposed	4 / 80 (5.00%)	2 / 87 (2.30%)	6 / 89 (6.74%)	0 / 29 (0.00%)	1 / 26 (3.85%)	0 / 29 (0.00%)
occurrences all number	4	2	6	0	1	0
Gastroenteritis
subjects affected / exposed	3 / 80 (3.75%)	3 / 87 (3.45%)	1 / 89 (1.12%)	1 / 29 (3.45%)	0 / 26 (0.00%)	2 / 29 (6.90%)
occurrences all number	3	3	1	1	0	2
Cystitis
subjects affected / exposed	3 / 80 (3.75%)	1 / 87 (1.15%)	2 / 89 (2.25%)	0 / 29 (0.00%)	2 / 26 (7.69%)	1 / 29 (3.45%)
occurrences all number	3	1	2	0	2	1
Herpes zoster
subjects affected / exposed	0 / 80 (0.00%)	0 / 87 (0.00%)	2 / 89 (2.25%)	1 / 29 (3.45%)	0 / 26 (0.00%)	2 / 29 (6.90%)
occurrences all number	0	0	2	1	0	2
Onychomycosis
subjects affected / exposed	1 / 80 (1.25%)	0 / 87 (0.00%)	0 / 89 (0.00%)	0 / 29 (0.00%)	0 / 26 (0.00%)	2 / 29 (6.90%)
occurrences all number	1	0	0	0	0	2
Metabolism and nutrition disorders
Hypercholesterolaemia
subjects affected / exposed	1 / 80 (1.25%)	1 / 87 (1.15%)	5 / 89 (5.62%)	0 / 29 (0.00%)	1 / 26 (3.85%)	1 / 29 (3.45%)
occurrences all number	1	1	5	0	1	1

More information

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Were there any global substantial amendments to the protocol? Yes

23 Aug 2010

The following changes were made in this amended protocol: - The number of sites was increased. - Added the US as an additional country to enroll patients. - Adjusted enrollment figures. - Study Investigators must be blinded to magnetic resonance imaging (MRI) results after a schedule visit. - Further clarification was made for the Unscheduled Visit for Patients with delayed Entry into the Extension Study. - Blinding of WBC, Neutrophil, and Lymphocyte Count. - Laboratory values were also done for the investigator.

30 Nov 2010

The following changes were made in this amended protocol - Increased the extension study period from 26 weeks to 122 weeks. - Added an additional 96 weeks to the study. - Adjusted the dose-blinded extension from 6 months to 2.5 years. - Clarification was made when subjects should return for an Early Termination visit.

02 Apr 2012

The following changes were made in the amended protocol: - Change in the interim analysis; there was an interim database lock at the time point of Interim Analysis. The clinical team directly involved in the conduct of the study was remain blinded to the interim analysis results. Details of the maintenance of the blind was documented in a separate document. The final database lock was occurred at the end of the trial. - Changes in Population Pharmacokinetic (PK)/Pharmacodynamic (PD) analysis.

05 Feb 2013

The following changes were made in the amended protocol: - Study duration was changed from 122 weeks to 225 weeks (4.5 years). - Update on number of subjects enrolled; 343 patients were enrolled in the extension trial. - Withdrawal criteria for the subject was updated. - Management of Infections, Lymphopenia, and Arrhythmias, Bradycardia, and Precaution for Patients with Impaired Renal Function section was updated for the lymchocyte count criteria. - PK sampling was elaborately defined.

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.

Company decided to not pursue phase 3 development of ceralifimod (ONO-4641). The decision was not related to any safety and efficacy findings.

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