Clinical Trial Results:
A Randomized, Double-Blind, Parallel-Group Study Assessing the Efficacy And Safety of Sarilumab Monotherapy Versus Adalimumab Monotherapy in Patients With Rheumatoid Arthritis
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Summary
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EudraCT number |
2014-002541-22 |
Trial protocol |
DE CZ HU ES GB |
Global end of trial date |
29 Dec 2020
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Results information
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Results version number |
v1(current) |
This version publication date |
11 Jan 2022
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First version publication date |
11 Jan 2022
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
EFC14092
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02332590 | ||
WHO universal trial number (UTN) |
U1111-1160-6154 | ||
Other trial identifiers |
Study name: SARIL-RA-MONARCH | ||
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Sponsors
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Sponsor organisation name |
Sanofi aventis recherche & développement
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Sponsor organisation address |
1 avenue Pierre Brossolette, Chilly-Mazarin, France, 91380
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Public contact |
Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com
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Scientific contact |
Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
28 Jan 2021
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
29 Dec 2020
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
To demonstrate that sarilumab monotherapy is superior to adalimumab monotherapy with respect to signs and symptoms as assessed by disease activity score 28 (DAS28)-erythrocyte sedimentation rate (ESR) in subjects with active rheumatoid arthritis (RA) who are either intolerant of or considered inappropriate candidates for continued treatment with methotrexate (MTX), or after at least 12 weeks of continuous treatment with MTX, are determined to be inadequate responders.
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Protection of trial subjects |
Subjects were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time in language and terms appropriate for the subject and considering the local culture. During the course of the trial, subjects were provided with individual subject cards indicating the nature of the trial the subject is participating, contact details and any information needed in the event of a medical emergency. Collected personal data and human biological samples were processed in compliance with the Sanofi-Aventis Group Personal Data Protection Charter ensuring that the Group abides by the laws governing personal data protection in force in all countries in which it operates.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
28 Jan 2015
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Poland: 75
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Country: Number of subjects enrolled |
Romania: 4
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Country: Number of subjects enrolled |
Spain: 21
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Country: Number of subjects enrolled |
Czechia: 25
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Country: Number of subjects enrolled |
Germany: 3
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Country: Number of subjects enrolled |
Hungary: 22
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Country: Number of subjects enrolled |
Chile: 53
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Country: Number of subjects enrolled |
Israel: 16
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Country: Number of subjects enrolled |
Korea, Republic of: 9
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Country: Number of subjects enrolled |
Peru: 18
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Country: Number of subjects enrolled |
Russian Federation: 44
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Country: Number of subjects enrolled |
South Africa: 4
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Country: Number of subjects enrolled |
Ukraine: 39
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Country: Number of subjects enrolled |
United States: 36
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Worldwide total number of subjects |
369
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EEA total number of subjects |
150
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
303
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From 65 to 84 years |
66
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85 years and over |
0
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Recruitment
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Recruitment details |
The study was conducted at 86 centres in 15 countries. A total of 540 subjects were involved in the study from 28 January 2015 to 29-December-2020, of whom 369 subjects were randomised and 171 were screen failures. Screen failures were mainly due to exclusion criteria met and inclusion criteria not met. | ||||||||||||||||||||||||||||||
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Pre-assignment
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Screening details |
Subjects were randomised in 1:1 ratio (Adalimumab 40 milligrams [mg] every 2 weeks [q2w]: Sarilumab 200 mg q2w) and treated for 24 weeks in double-blind (DB) period of the study. Out of 321 subjects who completed DB period, 320 subjects entered the open label extension (OLE) period of the study. | ||||||||||||||||||||||||||||||
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Period 1
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Period 1 title |
DB Period (Up to 24-weeks)
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | ||||||||||||||||||||||||||||||
Roles blinded |
Investigator, Carer, Subject, Assessor | ||||||||||||||||||||||||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Adalimumab 40 mg/Sarilumab 200 mg | ||||||||||||||||||||||||||||||
Arm description |
Adalimumab 40 mg subcutaneous (SC) injection in combination with placebo for sarilumab q2w for 24 weeks during the DB period. The dosing frequency of adalimumab was adjusted to 40 mg every week (qw) dosing in case of subjects with inadequate response (less than [<] 20% improvement from baseline in tender joint count [TJC] and swollen joint count [SJC] for 2 consecutive visits) at or after Week 16 until Week 23. Subjects who completed 24 weeks in the DB period had the option to continue OLE period and received sarilumab 200 mg q2w until commercial availability of sarilumab in their country or up to a maximum of an additional 276 weeks (i.e. up to Week 300). | ||||||||||||||||||||||||||||||
Arm type |
Active comparator | ||||||||||||||||||||||||||||||
Investigational medicinal product name |
Adalimumab
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Investigational medicinal product code |
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Other name |
Humira
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Pharmaceutical forms |
Solution for injection in pre-filled syringe
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
One SC injection of adalimumab 40 mg in combination with matching placebo was administered q2w for 24 weeks.
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Arm title
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Sarilumab 200 mg/Sarilumab 200 mg | ||||||||||||||||||||||||||||||
Arm description |
Sarilumab 200 mg SC injection in combination with placebo for adalimumab q2w for 24 weeks during the DB period. The dosing frequency of placebo for adalimumab was adjusted to 40 mg qw dosing in case of subjects with inadequate response (<20% improvement from baseline in TJC and SJC for 2 consecutive visits) at or after Week 16 until Week 23. Subjects who completed 24 weeks in the DB period had the option to continue in OLE period and received sarilumab 200 mg q2w until commercial availability of sarilumab in their country or up to a maximum of an additional 276 weeks (i.e. up to Week 300). | ||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||
Investigational medicinal product name |
Sarilumab
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Investigational medicinal product code |
SAR153191
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Other name |
REGN88
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Pharmaceutical forms |
Solution for injection in pre-filled syringe
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
One SC injection of sarilumab 200 mg in combination with matching placebo was administered q2w for 24 weeks.
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Period 2
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Period 2 title |
OLE Period (Week 24 up to Week 300)
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Is this the baseline period? |
No | ||||||||||||||||||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||||||||||||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Adalimumab 40 mg/Sarilumab 200 mg | ||||||||||||||||||||||||||||||
Arm description |
Adalimumab 40 mg subcutaneous (SC) injection in combination with placebo for sarilumab q2w for 24 weeks during the DB period. The dosing frequency of adalimumab was adjusted to 40 mg every week (qw) dosing in case of subjects with inadequate response (less than [<] 20% improvement from baseline in tender joint count [TJC] and swollen joint count [SJC] for 2 consecutive visits) at or after Week 16 until Week 23. Subjects who completed 24 weeks in the DB period had the option to continue OLE period and received sarilumab 200 mg q2w until commercial availability of sarilumab in their country or up to a maximum of an additional 276 weeks (i.e. up to Week 300). | ||||||||||||||||||||||||||||||
Arm type |
Active comparator | ||||||||||||||||||||||||||||||
Investigational medicinal product name |
Adalimumab
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Investigational medicinal product code |
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Other name |
Humira
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Pharmaceutical forms |
Solution for injection in pre-filled syringe
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Subjects who completed 24 weeks in the DB period and continued in OLE period: received sarilumab 200 mg q2w until commercial availability of sarilumab in their country or up to a maximum of an additional 276 weeks.
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Arm title
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Sarilumab 200 mg/Sarilumab 200 mg | ||||||||||||||||||||||||||||||
Arm description |
Sarilumab 200 mg SC injection in combination with placebo for adalimumab q2w for 24 weeks during the DB period. The dosing frequency of placebo for adalimumab was adjusted to 40 mg qw dosing in case of subjects with inadequate response (<20% improvement from baseline in TJC and SJC for 2 consecutive visits) at or after Week 16 until Week 23. Subjects who completed 24 weeks in the DB period had the option to continue in OLE period and received sarilumab 200 mg q2w until commercial availability of sarilumab in their country or up to a maximum of an additional 276 weeks (i.e. up to Week 300). | ||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||
Investigational medicinal product name |
Sarilumab
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Investigational medicinal product code |
SAR153191
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Other name |
REGN88
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Pharmaceutical forms |
Solution for injection in pre-filled syringe
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Subjects who completed 24 weeks in the DB period and continued OLE period; received sarilumab 200 mg q2w until commercial availability of sarilumab in their country or up to a maximum of an additional 276 weeks (i.e. up to Week 300).
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| Notes [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period. Justification: 155 subjects entered OLE period and 1 did not enroll. |
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Baseline characteristics reporting groups
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Reporting group title |
Adalimumab 40 mg/Sarilumab 200 mg
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Reporting group description |
Adalimumab 40 mg subcutaneous (SC) injection in combination with placebo for sarilumab q2w for 24 weeks during the DB period. The dosing frequency of adalimumab was adjusted to 40 mg every week (qw) dosing in case of subjects with inadequate response (less than [<] 20% improvement from baseline in tender joint count [TJC] and swollen joint count [SJC] for 2 consecutive visits) at or after Week 16 until Week 23. Subjects who completed 24 weeks in the DB period had the option to continue OLE period and received sarilumab 200 mg q2w until commercial availability of sarilumab in their country or up to a maximum of an additional 276 weeks (i.e. up to Week 300). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Sarilumab 200 mg/Sarilumab 200 mg
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Reporting group description |
Sarilumab 200 mg SC injection in combination with placebo for adalimumab q2w for 24 weeks during the DB period. The dosing frequency of placebo for adalimumab was adjusted to 40 mg qw dosing in case of subjects with inadequate response (<20% improvement from baseline in TJC and SJC for 2 consecutive visits) at or after Week 16 until Week 23. Subjects who completed 24 weeks in the DB period had the option to continue in OLE period and received sarilumab 200 mg q2w until commercial availability of sarilumab in their country or up to a maximum of an additional 276 weeks (i.e. up to Week 300). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Adalimumab 40 mg/Sarilumab 200 mg
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Reporting group description |
Adalimumab 40 mg subcutaneous (SC) injection in combination with placebo for sarilumab q2w for 24 weeks during the DB period. The dosing frequency of adalimumab was adjusted to 40 mg every week (qw) dosing in case of subjects with inadequate response (less than [<] 20% improvement from baseline in tender joint count [TJC] and swollen joint count [SJC] for 2 consecutive visits) at or after Week 16 until Week 23. Subjects who completed 24 weeks in the DB period had the option to continue OLE period and received sarilumab 200 mg q2w until commercial availability of sarilumab in their country or up to a maximum of an additional 276 weeks (i.e. up to Week 300). | ||
Reporting group title |
Sarilumab 200 mg/Sarilumab 200 mg
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Reporting group description |
Sarilumab 200 mg SC injection in combination with placebo for adalimumab q2w for 24 weeks during the DB period. The dosing frequency of placebo for adalimumab was adjusted to 40 mg qw dosing in case of subjects with inadequate response (<20% improvement from baseline in TJC and SJC for 2 consecutive visits) at or after Week 16 until Week 23. Subjects who completed 24 weeks in the DB period had the option to continue in OLE period and received sarilumab 200 mg q2w until commercial availability of sarilumab in their country or up to a maximum of an additional 276 weeks (i.e. up to Week 300). | ||
Reporting group title |
Adalimumab 40 mg/Sarilumab 200 mg
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Reporting group description |
Adalimumab 40 mg subcutaneous (SC) injection in combination with placebo for sarilumab q2w for 24 weeks during the DB period. The dosing frequency of adalimumab was adjusted to 40 mg every week (qw) dosing in case of subjects with inadequate response (less than [<] 20% improvement from baseline in tender joint count [TJC] and swollen joint count [SJC] for 2 consecutive visits) at or after Week 16 until Week 23. Subjects who completed 24 weeks in the DB period had the option to continue OLE period and received sarilumab 200 mg q2w until commercial availability of sarilumab in their country or up to a maximum of an additional 276 weeks (i.e. up to Week 300). | ||
Reporting group title |
Sarilumab 200 mg/Sarilumab 200 mg
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Reporting group description |
Sarilumab 200 mg SC injection in combination with placebo for adalimumab q2w for 24 weeks during the DB period. The dosing frequency of placebo for adalimumab was adjusted to 40 mg qw dosing in case of subjects with inadequate response (<20% improvement from baseline in TJC and SJC for 2 consecutive visits) at or after Week 16 until Week 23. Subjects who completed 24 weeks in the DB period had the option to continue in OLE period and received sarilumab 200 mg q2w until commercial availability of sarilumab in their country or up to a maximum of an additional 276 weeks (i.e. up to Week 300). | ||
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End point title |
DB Period: Change From Baseline in Disease Activity Score for 28 Joints - Erythrocyte Sedimentation Rate (DAS28-ESR) Score at Week 24 | ||||||||||||
End point description |
DAS28-ESR is a composite score that includes 4 variables: TJC (based on 28 joints); SJC (based on 28 joints); GH assessment by the subject assessed from the ACR and RA core set questionnaire (subject global assessment) in 100 mm VAS; marker of inflammation assessed by ESR in mm/hr. The DAS28-ESR score provides a number indicating the current disease activity of the RA. DAS28-ESR total score ranges from 2-10. A DAS28-ESR score above 5.1 means high disease activity, DAS28-ESR score below 3.2 indicates low disease activity and DAS28-ESR score below 2.6 means disease remission. Least square (LS) mean and standard error (SE) at Week 24 were obtained using Mixed-effect model with repeated measures (MMRM) approach. Intent-to-treat (ITT) population included all subjects. Here, number of subjects analysed = subjects with DAS28-ESR assessment at both baseline and Week 24.
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End point type |
Primary
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End point timeframe |
Baseline, Week 24
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Statistical analysis title |
Adalimumab 40 mg/Sarilumab 200 mg, Sarilumab 200mg | ||||||||||||
Statistical analysis description |
Analysis was performed using MMRM approach with treatment, region, visits, and treatment-by-visit interaction as fixed effects and baseline DAS28-ESR score as a continuous covariate. Hierarchical testing procedure was used to control overall alpha error rate at 0.05 level and handle multiple endpoint analyses. Testing was then performed sequentially in order endpoints are reported. Hierarchical testing sequence continued only when previous endpoint was statistically significant at 0.05 level.
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Comparison groups |
Adalimumab 40 mg/Sarilumab 200 mg v Sarilumab 200 mg/Sarilumab 200 mg
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Number of subjects included in analysis |
328
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
< 0.0001 [1] | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Parameter type |
LS Mean Difference | ||||||||||||
Point estimate |
-1.077
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-1.361 | ||||||||||||
upper limit |
-0.793 | ||||||||||||
| Notes [1] - Threshold for significance at 0.05 level. |
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End point title |
DB Period: Percentage of Subjects Achieving Clinical Remission Score (DAS28-ESR <2.6) at Week 24 | ||||||||||||
End point description |
DAS28-ESR is a composite score that includes 4 variables: TJC (based on 28 joints); SJC (based on 28 joints); GH assessment by the subject assessed from the ACR RA core set questionnaire (subject global assessment) in 100 mm VAS; marker of inflammation assessed by ESR in mm/hr. The DAS28-ESR score provides a number indicating the current disease activity of the RA. DAS28-ESR total score ranges from 2-10. A DAS28-ESR score above 5.1 means high disease activity, DAS28-ESR score below 3.2 indicates low disease activity and DAS28-ESR score below 2.6 means disease remission. Subjects who discontinued treatment prior to Week 24 were analysed as non-responders. ITT population.
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End point type |
Secondary
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End point timeframe |
Week 24
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Statistical analysis title |
Adalimumab 40 mg/Sarilumab 200 mg, Sarilumab 200mg | ||||||||||||
Statistical analysis description |
Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant). Analysis was performed using Cochran-Mantel-Haenszel method stratified by region.
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Comparison groups |
Sarilumab 200 mg/Sarilumab 200 mg v Adalimumab 40 mg/Sarilumab 200 mg
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Number of subjects included in analysis |
369
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
< 0.0001 [2] | ||||||||||||
Method |
Cochran-Mantel-Haenszel | ||||||||||||
Parameter type |
Odds ratio (OR) | ||||||||||||
Point estimate |
4.879
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
2.536 | ||||||||||||
upper limit |
9.389 | ||||||||||||
| Notes [2] - Threshold for significance at 0.05 level. |
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End point title |
DB Period: Percentage of Subjects Achieving ACR50 Criteria at Week 24 | ||||||||||||
End point description |
ACR responses are assessed with a composite rating scale of the ACR that includes 7 variables: TJC (68 joints); SJC (66 joints); levels of an acute phase reactant (C-reactive protein [CRP] level); subject’s assessment of pain (measured on 0 [no pain]-100 mm [worst pain] VAS); subject’s global assessment of disease activity (measured on 0 [no arthritis activity]-100 mm [maximal arthritis activity] VAS); physician’s global assessment of disease activity (measured on 0 [no arthritis activity]-100 mm [maximal arthritis activity] VAS); subject’s assessment of physical function (measured by Health Assessment Questionnaire - Disability Index [HAQ-DI], with scoring range of 0 [better physical function] - 3 [worst physical function]). ACR50 is defined as achieving at least 50% improvement in both TJC and SJC, and at least 50% improvement in at least 3 of the 5 other assessments of the ACR. Subjects were analysed as non-responders from the time they discontinued treatment. ITT Population.
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End point type |
Secondary
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End point timeframe |
Week 24
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Statistical analysis title |
Adalimumab 40 mg/Sarilumab 200 mg, Sarilumab 200mg | ||||||||||||
Statistical analysis description |
Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant). Analysis was performed using Cochran-Mantel-Haenszel method stratified by region.
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Comparison groups |
Adalimumab 40 mg/Sarilumab 200 mg v Sarilumab 200 mg/Sarilumab 200 mg
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Number of subjects included in analysis |
369
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.0017 [3] | ||||||||||||
Method |
Cochran-Mantel-Haenszel | ||||||||||||
Parameter type |
Odds ratio (OR) | ||||||||||||
Point estimate |
1.976
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
1.289 | ||||||||||||
upper limit |
3.028 | ||||||||||||
| Notes [3] - Threshold for significance at 0.05 level. |
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End point title |
DB Period: Percentage of Subjects Achieving ACR70 Criteria at Week 24 | ||||||||||||
End point description |
ACR responses are assessed with a composite rating scale of the ACR that includes 7 variables: TJC (68 joints); SJC (66 joints); levels of an acute phase reactant (CRP level); subject’s assessment of pain (measured on 0 [no pain]-100 mm [worst pain] VAS); subject’s global assessment of disease activity (measured on 0 [no arthritis activity]-100 mm [maximal arthritis activity] VAS); physician’s global assessment of disease activity (measured on 0 [no arthritis activity]-100 mm [maximal arthritis activity] VAS); subject’s assessment of physical function (measured by HAQ-DI, with scoring range of 0 [better physical function] - 3 [worst physical function]). ACR70 was defined as achieving at least 70% improvement in both TJC and SJC, and at least 70% improvement in at least 3 of the 5 other assessments. Subjects were analysed as non-responders from the time they discontinued treatment. ITT Population.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Week 24
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Adalimumab 40 mg/Sarilumab 200 mg, Sarilumab 200mg | ||||||||||||
Statistical analysis description |
Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant). Analysis was performed using Cochran-Mantel- Haenszel method stratified by region.
|
||||||||||||
Comparison groups |
Adalimumab 40 mg/Sarilumab 200 mg v Sarilumab 200 mg/Sarilumab 200 mg
|
||||||||||||
Number of subjects included in analysis |
369
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.0036 [4] | ||||||||||||
Method |
Cochran-Mantel-Haenszel | ||||||||||||
Parameter type |
Odds ratio (OR) | ||||||||||||
Point estimate |
2.286
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
1.3 | ||||||||||||
upper limit |
4.02 | ||||||||||||
| Notes [4] - Threshold for significance at 0.05 level. |
|||||||||||||
|
|||||||||||||
End point title |
DB Period: Percentage of Subjects Achieving ACR20 Criteria at Week 24 | ||||||||||||
End point description |
ACR responses are assessed with a composite rating scale of the ACR that includes 7 variables: TJC (68 joints); SJC (66 joints); levels of an acute phase reactant (CRP level); subject’s assessment of pain (measured on 0 [no pain]-100 mm [worst pain] VAS); subject’s global assessment of disease activity (measured on 0 [no arthritis activity]-100 mm [maximal arthritis activity] VAS); physician’s global assessment of disease activity (measured on 0 [no arthritis activity]-100 mm [maximal arthritis activity] VAS); subject’s assessment of physical function (measured by HAQ-DI, with scoring range of 0 [better physical function] - 3 [worst physical function]). ACR20 was defined as achieving at least 20% improvement in both TJC and SJC, and at least 20% improvement in at least 3 of the 5 other assessments. Subjects were analysed as non-responders from the time they discontinued treatment. ITT population.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Week 24
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Adalimumab 40 mg/Sarilumab 200 mg, Sarilumab 200mg | ||||||||||||
Statistical analysis description |
Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant). Analysis was performed using Cochran-Mantel-Haenszel method stratified by region.
|
||||||||||||
Comparison groups |
Adalimumab 40 mg/Sarilumab 200 mg v Sarilumab 200 mg/Sarilumab 200 mg
|
||||||||||||
Number of subjects included in analysis |
369
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.0074 [5] | ||||||||||||
Method |
Cochran-Mantel-Haenszel | ||||||||||||
Parameter type |
Odds ratio (OR) | ||||||||||||
Point estimate |
1.8
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
1.168 | ||||||||||||
upper limit |
2.773 | ||||||||||||
| Notes [5] - Threshold for significance 0.05 level. |
|||||||||||||
|
|||||||||||||
End point title |
DB Period: Change From Baseline in HAQ-DI at Week 24 | ||||||||||||
End point description |
Physical function was assessed by HAQ-DI. It consisted of at least 2 or 3 questions per category, subject reported assessment of ability to perform tasks in 8 categories of daily living activities: dress/groom; arise; eat; walk; reach; grip; hygiene; and common activities over past week rated on a 4-point scale where 0 = no difficulty; 1 = some difficulty; 2 = much difficulty; 3 = unable to do. Overall score was computed as the sum of category scores and divided by the number of categories answered, ranging from 0 to 3, where 0 = no disability and 3 = unable to do, high-dependency disability. LS mean and SE at Week 24 were obtained using MMRM approach. ITT population. Here, number of subjects analysed = subjects with HAQ-DI assessment at both baseline and Week 24.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline, Week 24
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Adalimumab 40 mg/Sarilumab 200 mg, Sarilumab 200mg | ||||||||||||
Statistical analysis description |
Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant). Analysis was performed using MMRM approach with treatment, region, visits, and treatment-by-visit interaction as fixed effects and baseline HAQ-DI score as a continuous covariate.
|
||||||||||||
Comparison groups |
Adalimumab 40 mg/Sarilumab 200 mg v Sarilumab 200 mg/Sarilumab 200 mg
|
||||||||||||
Number of subjects included in analysis |
323
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.0037 [6] | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Parameter type |
LS Mean Difference | ||||||||||||
Point estimate |
-0.182
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-0.305 | ||||||||||||
upper limit |
-0.059 | ||||||||||||
| Notes [6] - Threshold for significance at 0.05 level. |
|||||||||||||
|
|||||||||||||
End point title |
DB Period: Change From Baseline in Short-Form-36 (SF-36) - Physical Component Summary (PCS) Score at Week 24 | ||||||||||||
End point description |
SF-36 is a generic 36-item questionnaire of 8 sub-scales, measures health-related quality of life (HRQL) in last 4 weeks covering 2 summary measures: PCS and mental component summary (MCS). PCS with 4 sub-scales: physical function, role limitations due to physical problems, pain, general health perception; and MCS with 4 subscales: vitality, social function, role limitations due to emotional problems, and mental health. Subjects self-report on items in a sub-scale that have between 2-6 choices per item using Likert-type responses (e.g. none of the time, some of the time, etc.). Summations of item scores of same sub-scale give the sub-scale scores, which are transformed into a range from 0-100; 0= worst HRQL, 100=best HRQL. Both PCS and MCS range from 0-100 with higher scores indicating better physical and mental health. LS mean and SE at Week 24 by MMRM approach. ITT population. Here, number of subjects analysed = subjects with SF-36 PCS score assessment at baseline and week 24.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline, Week 24
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Adalimumab 40 mg/Sarilumab 200 mg, Sarilumab 200mg | ||||||||||||
Statistical analysis description |
Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant). Analysis was performed using MMRM approach with treatment, region, visits, and treatment-by-visit interaction as fixed effects and baseline SF-36 PCS score as a continuous covariate.
|
||||||||||||
Comparison groups |
Sarilumab 200 mg/Sarilumab 200 mg v Adalimumab 40 mg/Sarilumab 200 mg
|
||||||||||||
Number of subjects included in analysis |
316
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.0006 [7] | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Parameter type |
LS Mean Difference | ||||||||||||
Point estimate |
2.65
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
1.147 | ||||||||||||
upper limit |
4.153 | ||||||||||||
| Notes [7] - Threshold for significance at 0.05 level. |
|||||||||||||
|
|||||||||||||
End point title |
DB Period: Change From Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Score at Week 24 | ||||||||||||
End point description |
The FACIT-F is a 13-item questionnaire assessing fatigue where subjects scored each item on a 5-point scale (0-4): 0=not at all, 1=a little bit, 2=somewhat, 3=quite a bit, 4=very much. A total score ranges from 0 to 52, where higher score corresponds to a lower level of fatigue. A positive change from baseline score indicates an improvement. LS mean and SE at Week 24 by MMRM approach. ITT population. Here, number of subjects analysed = subjects with FACIT-F score assessment both at baseline and Week 24.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline, Week 24
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Adalimumab 40 mg/Sarilumab 200 mg, Sarilumab 200mg | ||||||||||||
Statistical analysis description |
Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant). Analysis was performed using MMRM approach with treatment, region, visits, and treatment-by-visit interaction as fixed effects and baseline FACIT-F score as a continuous covariate.
|
||||||||||||
Comparison groups |
Adalimumab 40 mg/Sarilumab 200 mg v Sarilumab 200 mg/Sarilumab 200 mg
|
||||||||||||
Number of subjects included in analysis |
323
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.0689 [8] | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Parameter type |
LS Mean Difference | ||||||||||||
Point estimate |
1.768
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-0.137 | ||||||||||||
upper limit |
3.674 | ||||||||||||
| Notes [8] - Threshold for significance at 0.05 level. |
|||||||||||||
|
|||||||||||||
End point title |
DB Period: Change From Baseline in SF-36 - Mental Health Component Summary Score at Week 24 | ||||||||||||
End point description |
SF-36 is a generic 36-item questionnaire consisting of 8 sub-scales, measures HRQL in the last 4 weeks covering 2 summary measures: PCS and MCS. PCS with 4 subscales: physical function, role limitations due to physical problems, pain, and general health perception; and MCS with 4 subscales: vitality, social function, role limitations due to emotional problems, and mental health. Subjects self-report on items in a subscale that have between 2-6 choices per item using Likert-type responses (e.g. none of the time, some of the time, etc.). Summations of item scores of the same subscale give the sub-scale scores, which are transformed into a range from 0 to 100; 0= worst HRQL, 100=best HRQL. Both PCS and MCS range from 0-100 with higher scores indicating better physical and mental health. LS mean and SE at Week 24 by MMRM approach. ITT population. Here, number of subjects analysed = subjects with SF-36 - mental health component summary score assessment both at baseline and Week 24.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline, Week 24
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
DB Period: Change From Baseline in Disease Activity Score for 28 Joints Based on C-Reactive Protein (DAS28-CRP Score) at Week 24 | ||||||||||||
End point description |
DAS28-CRP is a composite score that includes 4 variables: TJC (based on 28 joints); SJC (based on 28 joints); GH assessment by the subject assessed from the ACR RA core set questionnaire (subject global assessment) in 100 mm VAS; Marker of inflammation assessed by high sensitivity C-reactive protein (hs-CRP) in mg/L. The DAS28-CRP score provides a number indicating the current disease activity of the RA. DAS28-CRP total score ranges from 2-10. A DAS28-CRP score above 5.1 means high disease activity, whereas a DAS28-CRP score below 3.2 indicates low disease activity and a DAS28-CRP score below 2.6 means disease remission. LS mean and SE at Week 24 were obtained using MMRM approach. ITT population. Here, number of subjects analysed = subjects with DAS28-CRP score assessment at both baseline and Week 24.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline, Week 24
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
DB Period: Percentage of Subjects Achieving Clinical Remission Score (DAS28-CRP <2.6) at Week 24 | ||||||||||||
End point description |
DAS28-CRP is a composite score that includes 4 variables: TJC (based on 28 joints); SJC (based on 28 joints); GH assessment by the subject assessed from the ACR RA core set questionnaire (subject global assessment) in 100 mm VAS; Marker of inflammation assessed by hs-CRP in mg/L. The DAS28-CRP score provides a number indicating the current disease activity of the RA. DAS28-CRP total score ranges from 2-10. A DAS28-CRP score above 5.1 means high disease activity, whereas a DAS28-CRP score below 3.2 indicates low disease activity and a DAS28-CRP score below 2.6 means disease remission. Subjects were analysed as non-responders from the time they discontinued treatment. ITT population.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Week 24
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
DB Period: Percentage of Subjects Achieving Low Disease Activity (DAS28-ESR < 3.2) at Week 24 | ||||||||||||
End point description |
DAS28-ESR is a composite score that includes 4 variables: TJC (based on 28 joints); SJC (based on 28 joints); GH assessment by the subject assessed from the ACR RA core set questionnaire (subject global assessment) in 100 mm VAS; Marker of inflammation assessed by ESR in mm/hr. The DAS28-ESR score provides a number indicating the current disease activity of the RA. DAS28-ESR total score ranges from 2-10. A DAS28-ESR score above 5.1 means high disease activity, DAS28-ESR score below 3.2 indicates low disease activity and DAS28-ESR score below 2.6 means disease remission. Subjects were analysed as non-responders from the time they discontinued treatment. ITT population.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Week 24
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
DB Period: Percentage of Subjects Achieving Clinical Disease Activity Index (CDAI) Remission (CDAI <=2.8) at Week 24 | ||||||||||||
End point description |
CDAI is a composite index constructed to measure clinical remission in RA that does not include a laboratory test, and is a numerical summation of 4 components: SJC (28 joints), TJC (28 joints), subject’s global assessment of disease activity (in cm), and physician’s global assessment of disease activity (in cm). Total score ranges from 0 to 76 with a lower score indicating less disease activity. Subjects were analysed as non-responders from the time they discontinued treatment. ITT population.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Week 24
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
DB Period: Change From Baseline in CDAI at Week 24 | ||||||||||||
End point description |
CDAI is a composite index constructed to measure clinical remission in RA that does not include a laboratory test, and is a numerical summation of 4 components: SJC (28 joints), TJC (28 joints), subject’s global assessment of disease activity (in cm), and physician’s global assessment of disease activity (VAS in cm). Total score ranges from 0 to 76 with a lower score indicating less disease activity. A negative change in CDAI score indicates an improvement in disease activity and a positive change in score indicates a worsening of disease activity. LS means and SE at Week 24 were obtained using MMRM approach. ITT population. Here, number of subjects analysed = subjects with CDAI assessment both at baseline and Week 24.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline, Week 24
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||||||||
End point title |
DB Period: Change From Baseline in European Quality of Life-5 Dimension 3 Level (EQ-5D-3L) Scores at Week 24 | ||||||||||||||||||
End point description |
EQ-5D-3L is a standardised, generic measure of health outcome. EQ-5D was designed for self-completion by subjects. EQ-5D was specifically included to address concerns regarding health economic impact of RA. EQ-5D-3L comprises of 5 questions on mobility, self-care, pain/discomfort, usual activities, and psychological status with 3 possible answers for each item (1=no problem, 2=moderate problems, 3=severe problems). 5-dimensional 3-level systems are converted into a single index utility score between 0 to 1, where higher score indicates a better health state. EQ-5D-3L-VAS records the subject’s self-rated health on a vertical VAS that allows the subjects to indicate their health state ranging from 0 (worst imaginable) to 100 (best imaginable). LS mean and SE at Week 24 were obtained using MMRM approach. ITT population. Here, "number of subjects analysed" = subjects with EQ-5D-3L score assessment both at baseline and Week 24, and "n" = subjects with available data for specified category.
|
||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||
End point timeframe |
Baseline, Week 24
|
||||||||||||||||||
|
|||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||
|
|||||||||||||
End point title |
DB Period: Change From Baseline in Rheumatoid Arthritis Impact of Disease (RAID) at Week 24 | ||||||||||||
End point description |
RAID is a composite measure of the impact of RA on subjects that takes into account 7 domains: pain, functional disability, fatigue, physical and emotional well-being, quality of sleep, and coping. The RAID is calculated based on 7 numerical rating scales (NRS) questions. Each NRS is assessed as a number between 0 and 10 that corresponds to the 7 domains. The values for each of these domains are weighed by subject assessment of relative importance and combined in a single score with a total score range of 0 (not affected, very good) to 10 (most affected). LS mean and SE at Week 24 were obtained using MMRM approach. ITT population. Here, number of subjects analysed = subjects with RAID assessment both at baseline and Week 24.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline, Week 24
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
DB Period: Change From Baseline in Work Productivity Survey - Rheumatoid Arthritis (WPS-RA) at Week 24: Work Days Missed Due to Arthritis | ||||||||||||
End point description |
The WPS-RA is a validated questionnaire that evaluates productivity limitations within work and within home associated with RA over the previous month. The questionnaire is interviewer-administered and based on subject self-report. It contains 9 questions addressing employment status (1 item), productivity at work (3 items), and within and outside the home (5 items). Number of work days missed in the last month by the subject was reported. LS mean and SE at Week 24 were obtained using MMRM approach. ITT population. Here, number of subjects analysed = subjects with WPS-RA values available: Individual items assessment both at baseline and Week 24.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline, Week 24
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
DB Period: Change From Baseline in WPS-RA at Week 24: Days With Work Productivity Reduced by >= 50% Due to Arthritis | ||||||||||||
End point description |
The WPS-RA is a validated questionnaire that evaluates productivity limitations within work and within home associated with RA over the previous month. The questionnaire is interviewer-administered and based on subject self-report. It contains 9 questions addressing employment status (1 item), productivity at work (3 items), and within and outside the home (5 items). Number of work days with reduced productivity by >= 50% in the last month by the subjects was reported. LS mean and SE at Week 24 were obtained using MMRM approach. ITT population. Here, number of subjects analysed = subjects with WPS-RA values available: Individual items assessment both at baseline and Week 24.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline, Week 24
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
DB Period: Change From Baseline in WPS-RA at Week 24: Arthritis Interference With Work Productivity | ||||||||||||
End point description |
The WPS-RA is a validated questionnaire that evaluates productivity limitations within work and within home associated with RA over the previous month. The questionnaire is interviewer-administered and based on subject self-report. It contains 9 questions addressing employment status (1 item), productivity at work (3 items), and within and outside the home (5 items). Interference in the last month with work productivity was measured on a scale that ranges from 0 (no interference) to 10 (complete interference). LS mean and SE at Week 24 were obtained using MMRM approach. ITT Population. Here, number of subjects analysed = subjects with WPS-RA values available: Individual items assessment both at baseline and Week 24.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline, Week 24
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
DB Period: Change From Baseline in WPS-RA at Week 24: House Work Days Missed Due to Arthritis | ||||||||||||
End point description |
The WPS-RA is a validated questionnaire that evaluates productivity limitations within work and within home associated with RA over the previous month. The questionnaire is interviewer-administered and based on subject self-report. It contains 9 questions addressing employment status (1 item), productivity at work (3 items), and within and outside the home (5 items). Number of days with no household work in the last month by the subjects was reported. LS mean and SE at Week 24 were obtained using MMRM approach. ITT population. Here, number of subjects analysed = subjects with WPS-RA values available: Individual items assessment both at baseline and Week 24.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline, Week 24
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
DB Period: Change From Baseline in WPS-RA at Week 24: Days With Household Work Productivity Reduced by >= 50% Due to Arthritis | ||||||||||||
End point description |
The WPS-RA is a validated questionnaire that evaluates productivity limitations within work and within home associated with RA over the previous month. The questionnaire is interviewer-administered and based on subject self-report. It contains 9 questions addressing employment status (1 item), productivity at work (3 items), and within and outside the home (5 items). Number of days with reduced household work productivity by >= 50% in the last month by the subjects was reported. LS mean and SE at Week 24 were obtained using MMRM approach. ITT population. Here, number of subjects analysed = subjects with WPS-RA values available: Individual items assessment both at baseline and Week 24.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline, Week 24
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
DB Period: Change From Baseline in WPS-RA at Week 24: Days With Family/Social/Leisure Activities Missed Due to Arthritis | ||||||||||||
End point description |
The WPS-RA is a validated questionnaire that evaluates productivity limitations within work and within home associated with RA over the previous month. The questionnaire is interviewer-administered and based on subject self-report. It contains 9 questions addressing employment status (1 item), productivity at work (3 items), and within and outside the home (5 items). Number of days missed of family/social/leisure activities in the last month by the subjects was reported. LS mean and SE at Week 24 were obtained using MMRM approach. ITT population. Here, number of subjects analysed = subjects with WPS-RA values available: Individual items assessment both at baseline and Week 24.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline, Week 24
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
DB Period: Change From Baseline in WPS-RA at Week 24: Days With Outside Help Hired Due to Arthritis | ||||||||||||
End point description |
The WPS-RA is a validated questionnaire that evaluates productivity limitations within work and within home associated with RA over the previous month. The questionnaire is interviewer-administered and based on subject self-report. It contains 9 questions addressing employment status (1 item), productivity at work (3 items), and within and outside the home (5 items). Number of days with outside help hired in the last month by the subject was reported. LS mean and SE at Week 24 were obtained using MMRM approach. ITT population. Here, number of subjects analysed = subjects with WPS-RA values available: Individual items assessment both at baseline and Week 24.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline, Week 24
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
DB Period: Change From Baseline in WPS-RA at Week 24: RA Interference With Household Work Productivity | ||||||||||||
End point description |
The WPS-RA is a validated questionnaire that evaluates productivity limitations within work and within home associated with RA over the previous month. The questionnaire is interviewer-administered and based on subject self-report. It contains 9 questions addressing employment status (1 item), productivity at work (3 items), and within and outside the home (5 items). The RA interference in the last month with household work productivity was measured on a scale that ranges from 0 (no interference) to 10 (complete interference). LS mean and SE at Week 24 were obtained using MMRM approach. ITT population. Here, number of subjects analysed = subjects with WPS-RA values available: Individual items assessment both at baseline and Week 24.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline, Week 24
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
DB Period: Change From Baseline in Morning Stiffness VAS at Week 24 | ||||||||||||
End point description |
RA is associated with stiffness of joints, especially in the morning after prolonged stationery state. The degree of stiffness can be an indicator of disease severity. The severity of morning stiffness was assessed on a VAS scale from 0 mm (no problem) to 100 mm (major problem). LS mean and SE at Week 24 were obtained using MMRM approach. ITT population. Here, number of subjects analysed = subjects with morning stiffness VAS assessment both at baseline and Week 24.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline, Week 24
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||||||||
End point title |
DB Period: Change From Baseline in Individual ACR Component - TJC and SJC at Week 24 | ||||||||||||||||||
End point description |
ACR components were: TJC, SJC, physician global VAS, subject global VAS, pain VAS, HAQ-DI & acute phase reactant (hs-CRP and ESR levels). 68 joints were assessed for tenderness (TJC scoring 0-68) and 66 joints for swelling (SJC scoring 0-66). The 66 SJC evaluated the following joints: temporomandibular, sternoclavicular, acromioclavicular, shoulder, elbow, wrist, metacarpophalangeal, interphalangeal of thumb, distal interphalangeal, proximal interphalangeal, knee, ankle mortise, ankle tarsus, metatarsophalangeal, interphalangeal of great toe, and proximal/distal interphalangeal of the toes. The TJC examined hip joints, in addition to the joints assessed for SJC. Increase in number of tender joints/swollen joints indicated severity. LS mean and SE at Week 24 were obtained using MMRM approach. ITT population. Here, number of subjects analysed = subjects with TJC and SJC assessment both at baseline and Week 24.
|
||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||
End point timeframe |
Baseline, Week 24
|
||||||||||||||||||
|
|||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||
|
||||||||||||||||||||||
End point title |
DB Period: Change From Baseline in Individual ACR Component - Physician Global VAS, Subject Global VAS and Pain VAS at Week 24 | |||||||||||||||||||||
End point description |
ACR components were: TJC, SJC, physician global VAS, subject global VAS, pain VAS, HAQ-DI & acute phase reactant (hs-CRP and ESR levels). Physician global VAS & subject global VAS was done on 100 mm horizontal anchored VAS, ranging from 0 “no arthritis activity” to 100 “maximal arthritis activity” and Pain VAS on 100 mm VAS, ranging from 0 “no pain” to 100 “worst pain”. LS mean and SE at Week 24 were obtained using MMRM approach. ITT population. Here, number of subjects analysed = subjects with individual ACR components assessment both at baseline and Week 24, and "n" = subjects with available data for specified category for each arm, respectively.
|
|||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||
End point timeframe |
Baseline, Week 24
|
|||||||||||||||||||||
|
||||||||||||||||||||||
| No statistical analyses for this end point | ||||||||||||||||||||||
|
|||||||||||||
End point title |
DB Period: Change From Baseline in Individual ACR Component - CRP Level at Week 24 | ||||||||||||
End point description |
ACR components were: TJC, SJC, physician global VAS, subject global VAS, pain VAS, HAQ-DI and acute phase reactant (hs-CRP and ESR levels). An elevated CRP level is considered a non-specific "marker" for RA. A decrease indicates improvement. LS mean and SE at Week 24 were obtained using MMRM approach. ITT population. Here, number of subjects analysed = subjects with CRP assessment both at baseline and Week 24.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline, Week 24
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
DB Period: Change From Baseline in Individual ACR Component- ESR Level at Week 24 | ||||||||||||
End point description |
ACR components were: TJC, SJC, physician global VAS, subject global VAS, pain VAS, HAQ-DI & acute phase reactant (hs-CRP and ESR levels). The ESR is a blood test that can reveal inflammatory activity. Inflammation can cause the cells to clump together. The farther the red blood cells have descended, the greater the inflammatory response. LS mean and SE at Week 24 were obtained using MMRM approach. ITT population. Here, number of subjects analysed = subjects with ESR assessment both at baseline and Week 24.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline, Week 24
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
||||||||||||||||
End point title |
DB Period: Number of Subjects With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | |||||||||||||||
End point description |
Adverse event (AE) was defined as any untoward medical occurrence in subject who received investigational medicinal product (IMP) and did not necessarily had to have causal relationship with treatment. All reported AEs were TEAEs developed/worsened during 'on treatment period' (time from first dose of study drug up to day before first dose of open-label treatment for subjects who completed 24-week randomised//DB treatment). SAEs were AEs resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalisation; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly or a medically important event. DB period safety population which consisted of all randomised subjects who received at least one dose of study medication analysed according to the treatment they have actually received.
|
|||||||||||||||
End point type |
Secondary
|
|||||||||||||||
End point timeframe |
From Week 0 to Week 24
|
|||||||||||||||
|
||||||||||||||||
| No statistical analyses for this end point | ||||||||||||||||
|
||||||||||||||||
End point title |
OLE Period: Number of Subjects With Treatment-emergent Adverse Events and Serious Adverse Events | |||||||||||||||
End point description |
AE was defined as any untoward medical occurrence in subject who received IMP and did not necessarily had to have causal relationship with treatment. All reported AEs were TEAEs developed/worsened during 'on treatment period' (from end of week 24 [Baseline of OLE Period] up to last dose in OLE period + 6 weeks [follow-up], regardless of unplanned intermittent discontinuations). SAEs were AEs resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalisation; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly or a medically important event. OLE period safety population which included all randomised subjects who continued OLE period and received at least one dose of the study medication during OLE period, analysed according to the treatment they have actually received.
|
|||||||||||||||
End point type |
Secondary
|
|||||||||||||||
End point timeframe |
From end of Week 24 (Baseline of OLE Period) up to last dose in OLE + 6 weeks of follow up (i.e. up to Week 306)
|
|||||||||||||||
|
||||||||||||||||
| No statistical analyses for this end point | ||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
DB Period: Number of Subjects With Potentially Clinically Significant Abnormalities (PCSA) - Hematological Parameters | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Criteria for PCSA included:
• Hemoglobin (Hb): less than or equal to (<=) 115 grammes per litre (g/L)(Male), <= 95 g/L (Female); greater than or equal to (>=) 185 g/L (18.5 g/dL) (Male), >= 165 g/L (16.5 g/dL) (Female); Decrease From Baseline (DFB) = 20 g/L (2g/dL).
• Hematocrit: <= 0.37 volume/volume (v/v) (Male); <= 0.32 v/v (Female); >= 0.55 v/v (Male); >= 0.5 v/v(Female).
• Red Blood Cells (RBCs): >=6 Tera/ litre (L).
• Platelets: < 50 Giga/L (G/L), 50 - 100 G/L, >= 700 G/L.
• White blood cells (WBC): < 3.0 G/L (Non-Black); < 2.0 G/L (Black), >= 16.0 G/L.
• Neutrophils: < 1.0 G/L, < 1.5 G/L (Non-Black); < 1.0 G/L (Black).
• Lymphocytes: < 0.5 G/L, >= 0.5 G/L - lower limit of normal (LLN), > 4.0 G/L.
• Monocytes: > 0.7 G/L.
• Basophils: > 0.1 G/L.
• Eosinophils: > 0.5 G/L or > upper limit of normal (ULN) (if ULN >= 0.5 G/L).
DB safety population. Here, 'n' = subjects with available data for each specified category.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
From Week 0 to Week 24
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
OLE Period: Number of Subjects With Potentially Clinically Significant Abnormalities - Hematological Parameters | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Criteria for PCSA included:
• Hb: <=115 g/L (Male), <= 95 g/L (Female); >=185 g/L (18.5 g/dL) (Male), >= 165 g/L (16.5 g/dL)(Female);DFB >= 20 g/L (2g/dL).
• Hematocrit: <= 0.37 v/v (Male); <= 0.32 v/v (Female); >= 0.55 v/v (Male); >= 0.5 v/v (Female).
• RBCs: >=6 Tera/ L.
• Platelets: < 50 G/L, 50 - 100 G/L, >= 700 G/L.
• WBC: < 3.0 G/L (Non-Black); < 2.0 G/L (Black), >= 16.0 G/L.
• Neutrophils: < 1.0 G/L, < 1.5 G/L (Non-Black); < 1.0 G/L (Black).
• Lymphocytes: < 0.5 G/L, >= 0.5 G/L - LLN, > 4.0 G/L.
• Monocytes: > 0.7 G/L.
• Basophils: > 0.1 G/L.
• Eosinophils: > 0.5 G/L or > ULN (if ULN >= 0.5 G/L).
OLE period safety population. Here, number of subjects analysed = subjects evaluable for this endpoint.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
From end of Week 24 (Baseline of OLE Period) up to Week 300
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
DB Period: Number of Subjects With Potentially Clinically Significant Abnormalities - Liver Function Tests | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Criteria for PCSA:
• Alanine Aminotransferase (ALT): >1 ULN and <=1.5 ULN; >1.5 ULN and <=3 ULN; >3 ULN and <=5 ULN; >5 ULN and <=10 ULN; >10 ULN and <=20 ULN; >20 ULN.
• Aspartate aminotransferase (AST): >1 ULN and <=1.5 ULN; >1.5 ULN and <=3 ULN; >3 ULN and <=5 ULN; >5 ULN and <=10 ULN; >10 ULN and <=20 ULN; >20 ULN.
• Alkaline phosphatase: >1.5 ULN.
• Total bilirubin (TBILI): >1.5 ULN; >2 ULN.
• Conjugated bilirubin (CBILI): >1.5 ULN.
• Unconjugated bilirubin: >1.5 ULN, >2 ULN.
• ALT >3 ULN and TBILI >2 ULN.
• CBILI >35% TBILI and TBILI >1.5 ULN.
• Albumin: <=25 g/L.
DB Period safety population. Here, number of subjects analysed = subjects evaluable for this endpoint.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
From Week 0 to Week 24
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
OLE Period: Number of Subjects With Potentially Clinically Significant Abnormalities - Liver Function Tests | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Criteria for PCSA:
• ALT: >1 ULN and <=1.5 ULN; >1.5 ULN and <=3 ULN; >3 ULN and <=5 ULN; >5 ULN and <=10 ULN; >10 ULN and <=20 ULN; >20 ULN.
• AST: >1 ULN and <=1.5 ULN; >1.5 ULN and <=3 ULN; >3 ULN and <=5 ULN; >5 ULN and <=10 ULN; >10 ULN and <=20 ULN; >20 ULN.
• Alkaline phosphatase: >1.5 ULN.
• TBILI: >1.5 ULN; >2 ULN.
• CBILI: >1.5 ULN.
• Unconjugated bilirubin: >1.5 ULN, >2 ULN.
• ALT >3 ULN and TBILI >2 ULN.
• CBILI >35% TBILI and TBILI >1.5 ULN.
• Albumin: <=25 g/L.
OLE period safety population. Here, number of subjects analysed = subjects evaluable for this endpoint.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
From end of Week 24 (Baseline of OLE Period) up to Week 300
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||
End point title |
DB Period: Number of Subjects With Potentially Clinically Significant Abnormalities - Metabolic Parameters | ||||||||||||||||||||||||||||||||||||
End point description |
Criteria for potentially clinically significant abnormalities:
• Glucose: <=3.9 millimole/litre (mmol/L) and <LLN; >=11.1 mmol/L (unfasted [UF]) or >=7 mmol/L (fasted [FA]).
• Hemoglobin A1c (HbA1c): >8%.
• Total cholesterol: >=6.2 mmol/L; >=7.74 mmol/L.
• LDL cholesterol: >=4.1 mmol/L; >=4.9 mmol/L.
• Triglycerides: >=4.6 mmol/L; >=5.6 mmol/L.
DB period safety population. Here "n" = subjects with available data for each specified category.
|
||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||
End point timeframe |
From Week 0 to Week 24
|
||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||
End point title |
OLE Period: Number of Subjects With Potentially Clinically Significant Abnormalities - Metabolic Parameters | ||||||||||||||||||||||||||||||||||||
End point description |
Criteria for potentially clinically significant abnormalities:
• Glucose: <=3.9 mmol/L and <LLN; >=11.1 mmol/L (UF) or >=7 mmol/L (FA).
• HbA1c: >8%.
• Total cholesterol: >=6.2 mmol/L; >=7.74 mmol/L.
• LDL cholesterol: >=4.1 mmol/L; >=4.9 mmol/L.
• Triglycerides: >=4.6 mmol/L; >=5.6 mmol/L.
OLE period safety population. Here, "n" = subjects with available data for each specified category.
|
||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||
End point timeframe |
From end of Week 24 (Baseline of OLE Period) up to Week 300
|
||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||
End point title |
DB Period: Number of Subjects With Different Post-baseline Categories of High-density Lipoprotein (HDL) | ||||||||||||||||||
End point description |
Number of subjects with different post-baseline status of HDL: < 40 mg/dL, 40 - < 60 mg/dL, >= 60 mg/dL, is reported here. DB period safety population. Here, number of subjects analysed = subjects evaluable for this endpoint.
|
||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||
End point timeframe |
From Week 0 to Week 24
|
||||||||||||||||||
|
|||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||
|
|||||||||||||||||||
End point title |
OLE Period: Number of Subjects With Different Post-baseline Categories of High-density Lipoprotein | ||||||||||||||||||
End point description |
Number of subjects with different post-baseline status of HDL: < 40 mg/dL, 40 - < 60 mg/dL, >=60 mg/dL, is reported here. OLE period safety population. Here, number of subjects analysed = subjects evaluable for this endpoint.
|
||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||
End point timeframe |
From end of Week 24 (Baseline of OLE Period) up to Week 300
|
||||||||||||||||||
|
|||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||
End point title |
DB Period: Number of Subjects With Potentially Clinically Significant Abnormalities - Renal Function | |||||||||||||||||||||||||||||||||||||||
End point description |
Criteria for potentially clinically significant abnormalities:
• Creatinine: >=150 micromol/L (adults); >=30% change from baseline, >=100% change from baseline.
• Creatinine clearance: <15 mL/min; >=15 to <30 mL/min; >=30 to <60 mL/min; >=60 to <90 mL/min.
• Blood urea nitrogen: >=17 mmol/L.
• Uric acid: <120 micromol/L; >408 micromol/L.
DB period safety population. Here, number of subjects analysed = subjects evaluable for this endpoint.
|
|||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||||||||||||||||
End point timeframe |
From Week 0 to Week 24
|
|||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | ||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||
End point title |
OLE Period: Number of Subjects With Potentially Clinically Significant Abnormalities - Renal Function | |||||||||||||||||||||||||||||||||||||||
End point description |
Criteria for potentially clinically significant abnormalities:
• Creatinine: >=150 micromol/L (adults); >=30% change from baseline, >=100% change from baseline.
• Creatinine clearance: <15 mL/min; >=15 to <30 mL/min; >=30 to <60 mL/min; >=60 to <90 mL/min.
• Blood urea nitrogen: >=17 mmol/L.
• Uric acid: <120 micromol/L; >408 micromol/L.
OLE period safety population. Here, number of subjects analysed = subjects evaluable for this endpoint.
|
|||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||||||||||||||||
End point timeframe |
From end of Week 24 (Baseline of OLE Period) up to Week 300
|
|||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | ||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||
End point title |
DB Period: Number of Subjects With Potentially Clinically Significant Abnormalities - Urinalysis | |||||||||||||||
End point description |
Criteria with potentially clinically significant urine abnormalities: pH: <= 4.6; pH: >= 8.0. DB period safety population. Here, number of subjects analysed = subjects evaluable for this endpoint.
|
|||||||||||||||
End point type |
Secondary
|
|||||||||||||||
End point timeframe |
From Week 0 to Week 24
|
|||||||||||||||
|
||||||||||||||||
| No statistical analyses for this end point | ||||||||||||||||
|
||||||||||||||||
End point title |
OLE Period: Number of Subjects With Potentially Clinically Significant Abnormalities - Urinalysis | |||||||||||||||
End point description |
Criteria with potentially clinically significant urine abnormalities: pH: <= 4.6; pH: >= 8.0. OLE period safety population. Here, number of subjects analysed = subjects evaluable for this endpoint.
|
|||||||||||||||
End point type |
Secondary
|
|||||||||||||||
End point timeframe |
From end of Week 24 (Baseline of OLE Period) up to Week 300
|
|||||||||||||||
|
||||||||||||||||
| No statistical analyses for this end point | ||||||||||||||||
|
||||||||||||||||||||||||||||
End point title |
DB Period: Number of Subjects With Potentially Clinically Significant Abnormalities - Electrolytes | |||||||||||||||||||||||||||
End point description |
Criteria for potentially clinically significant abnormalities:
• Sodium: <=129 mmol/L; >=160 mmol/L.
• Potassium: <3 mmol/L; >=5.5 mmol/L.
• Chloride: <80 mmol/L; >115 mmol/L.
DB period safety population. Here, number of subjects analysed = subjects evaluable for this endpoint.
|
|||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||||
End point timeframe |
From Week 0 to Week 24
|
|||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||
| No statistical analyses for this end point | ||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||
End point title |
OLE Period: Number of Subjects With Potentially Clinically Significant Abnormalities - Electrolytes | |||||||||||||||||||||||||||
End point description |
Criteria for potentially clinically significant abnormalities:
• Sodium: <=129 mmol/L; >=160 mmol/L.
• Potassium: <3 mmol/L; >=5.5 mmol/L.
• Chloride: <80 mmol/L; >115 mmol/L.
OLE period safety population. Here, number of subjects analysed = subjects evaluable for this endpoint.
|
|||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||||
End point timeframe |
From end of Week 24 (Baseline of OLE Period) up to Week 300
|
|||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||
| No statistical analyses for this end point | ||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
DB Period: Number of Subjects With Potentially Clinically Significant Electrocardiogram (ECG) Abnormalities | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Criteria for potentially clinically significant ECG abnormalities:
• Heart rate (HR): <50 beats per minute (bpm); <50 bpm and DFB >=20 bpm; <40 bpm; <40 bpm and DFB >=20
bpm; <30 bpm; <30 bpm and DFB >=20 bpm; >90 bpm; >=90 bpm and increase from baseline (IFB) >=20 bpm;
>100 bpm; >=100 bpm and IFB >=20 bpm; >120 bpm; >=120 bpm and IFB >=20 bpm.
• PR Interval: >200 millisecond (ms); >200 ms and IFB >=25%; >220 ms; >220 ms and IFB >=25%; >240 ms; >240
ms and IFB >=25%.
• QRS Interval: >110 ms; >110 ms and IFB >=25%; >120 ms; >120 ms and IFB >=25%.
• QT Interval: >500 ms.
• QTc Bazett (QTc B): >450 ms; >480 ms; >500 ms; IFB >30 and <=60 ms; IFB >60 ms.
• QTc Fridericia (QTc F): >450 ms; >480 ms; >500 ms; IFB >30 and <=60 ms; IFB >60 ms.
DB period safety population. Here, number of subjects analysed = subjects evaluable for this endpoint and "n" = subjects with available data for each specified category.
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End point type |
Secondary
|
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End point timeframe |
From Week 0 to Week 24
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End point title |
OLE Period: Number of Subjects With Potentially Clinically Significant Electrocardiogram Abnormalities | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Criteria for potentially clinically significant ECG abnormalities:
• HR: <50 bpm; <50 bpm and DFB >=20 bpm; <40 bpm; <40 bpm and DFB >=20 bpm; <30 bpm; <30 bpm and DFB >=20 bpm; >90 bpm; >=90 bpm and IFB >=20 bpm; >100 bpm; >=100 bpm and IFB >=20 bpm; >120 bpm; >=120 bpm and IFB >=20 bpm.
• PR Interval: >200 ms; >200 ms and IFB >=25%; >220 ms; >220 ms and IFB >=25%; >240 ms; >240 ms and IFB >=25%.
• QRS Interval: >110 ms; >110 ms and IFB >=25%; >120 ms; >120 ms and IFB >=25%.
• QT Interval: >500 ms.
• QTc B: >450 ms; >480 ms; >500 ms; IFB >30 and <=60 ms; IFB >60 ms.
• QTc F: >450 ms; >480 ms; >500 ms; IFB >30 and <=60 ms; IFB >60 ms.
OLE period safety population. Here, number of subjects analysed = subjects evaluable for this endpoint and n = subjects with available data for each specified category.
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End point type |
Secondary
|
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End point timeframe |
From end of Week 24 (Baseline of OLE Period) up to Week 300
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End point title |
DB Period: Number of Subjects With Potentially Clinically Significant Vital Signs Abnormalities | |||||||||||||||||||||||||||||||||||||||
End point description |
Criteria for potentially clinically significant vital sign abnormalities:
Systolic blood pressure (SBP) supine: <=95 mmHg and DFB>=20 mmHg; >=160 mmHg and IFB >=20 mmHg.
Diastolic blood pressure (DBP) supine: <=45 mmHg and DFB >=10 mmHg; >=110 mmHg and IFB >=10 mmHg.
SBP (Orthostatic): <=-20 mmHg. DBP (Orthostatic): <=-10 mmHg. HR supine: <=50 bpm and DFB >=20 bpm; >=120 bpm and IFB >=20 bpm. Weight: >=5% DFB; >=5% IFB.
DB period safety population. Here, "n" = subjects evaluable for this endpoint.
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End point type |
Secondary
|
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End point timeframe |
From Week 0 to Week 24
|
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| No statistical analyses for this end point | ||||||||||||||||||||||||||||||||||||||||
|
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End point title |
OLE Period: Number of Subjects With Potentially Clinically Significant Vital Signs Abnormalities | |||||||||||||||||||||||||||||||||||||||
End point description |
Criteria for potentially clinically significant vital sign abnormalities:
SBP supine: <=95 mmHg and DFB >=20 mmHg; >=160 mmHg and IFB >=20 mmHg. DBP supine: <=45 mmHg and
DFB >=10 mmHg; >=110 mmHg and IFB >=10 mmHg. SBP (Orthostatic): <=-20 mmHg. DBP (Orthostatic): <=-10
mmHg. HR supine: <=50 bpm and DFB >=20 bpm; >=120 bpm and IFB >=20 bpm. Weight: >=5% DFB; >=5% IFB.
OLE period safety population. Here, "n" = subjects with available data for each specified category.
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End point type |
Secondary
|
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End point timeframe |
From end of Week 24 (Baseline of OLE Period) up to Week 300
|
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| No statistical analyses for this end point | ||||||||||||||||||||||||||||||||||||||||
|
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End point title |
DB Period: Number of Subjects With Treatment-emergent and Treatment-boosted Anti-drug Antibody (ADA) Responses [9] | ||||||||||
End point description |
Anti-drug antibody response was categorised as: Treatment emergent and Treatment-boosted. Treatment emergent ADAs was defined as a subject with no positive assay response at baseline but with a positive assay response during the TEAE period. Treatment boosted ADAs: was defined as subjects with a positive ADA assay response at baseline and with at least a 4-fold increase in titer compared to baseline during the TEAE period. TEAE period: time from first dose of the study drug up to the day before first dose of open-label treatment for subjects who completed 24-week randomised/DB treatment. Analysis was performed on ADA population which consisted of all subjects who had signed informed consent and had been allocated to a randomised treatment; received at least 1 dose or part of a dose of IMP with at least 1 post-dose evaluable ADA sample. Data for this endpoint was not planned to be collected and analysed for Adalimumab 40 mg/Sarilumab 200 mg arm.
|
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End point type |
Secondary
|
||||||||||
End point timeframe |
From Week 0 to Week 24
|
||||||||||
| 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: Endpoint is reporting data for applicable arms in the study. |
|||||||||||
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| No statistical analyses for this end point | |||||||||||
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End point title |
Number of Subjects With Treatment-emergent and Treatment-boosted Anti-drug Antibody Response During Entire Treatment-emergent Adverse Event Period | |||||||||||||||
End point description |
Anti-drug antibody response was categorised as: Treatment emergent ADAs was defined as a subject with no positive assay response at baseline but with a positive assay response during the entire TEAE period. Treatment boosted ADAs was defined as a subjects with a positive ADA assay response at baseline and with at least a 4-fold increase in titer compared to baseline during the entire TEAE period. Entire TEAE period: last OLE dose - first DB dose date + 6 weeks (follow-up), regardless of unplanned intermittent discontinuations. Analysis was performed on immunogenicity population which consisted of all subjects who received at least 1 dose or part of a dose with at least 1 post-dose evaluable ADA sample.
|
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End point type |
Secondary
|
|||||||||||||||
End point timeframe |
From Week 0 up to last dose in OLE + 6 weeks of follow up (i.e. up to Week 306)
|
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|
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| No statistical analyses for this end point | ||||||||||||||||
|
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End point title |
DB Period: Pharmacokinetics: Serum Trough (Pre-Dose) Concentrations of Functional Sarilumab [10] | ||||||||||||||||||||||
End point description |
Data for this endpoint was not planned to be collected and analysed for "Adalimumab 40 mg/Sarilumab 200 mg” arm. Analysis was performed on Pharmacokinetic (PK) population which consisted of all randomised Sarilumab subjects who received at least 1 dose of IMP with at least one post-dose, non-missing concentration of functional Sarilumab in serum concentration value. Here, "n" = subjects with available data for each specified category.
|
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End point type |
Secondary
|
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End point timeframe |
Pre-dose at Week 0 (Baseline), 2, 4, 12, 16, 20, and 24
|
||||||||||||||||||||||
| 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: Endpoint is reporting data for applicable arms in the study. |
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| No statistical analyses for this end point | |||||||||||||||||||||||
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End point title |
OLE Period: Pharmacokinetics: Serum Trough (Pre-Dose) Concentrations of Functional Sarilumab | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Analysis was performed on PK population (OLE period) which consisted of all subjects from the randomised population who received at least 1 dose of IMP with at least one post-dose, non-missing serum sarilumab concentration. Here, "n" = subjects with available data for each specified category and '99999' is used as space filler which denotes that no subject was available for the assessment at the specified timepoint.
|
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End point type |
Secondary
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Pre-dose at Week 24 (Baseline of OLE period), 36, 48, 60, 84, 108, 132, 156, 180, 204, 228, 252, 276, 300 and 306
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| No statistical analyses for this end point | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Adverse events information
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Timeframe for reporting adverse events |
All Adverse Events (AEs) were collected from up to Week 24 in DB period and from end of Week 24 (Baseline of OLE Period) up to Week 306 in OLE Period regardless of seriousness or relationship to study drug.
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Adverse event reporting additional description |
Reported AEs are TEAEs developed/worsened during ‘on treatment period’(DB:time from first dose up to day before first dose of open-label treatment; OLE:from end of Week 24 [Baseline of OLE Period] up to the last dose in OLE + 6 weeks [follow-up]). Safety population. For OLE, data was reported for pooled population (all subjects received Sarilumab).
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
23.1
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Reporting groups
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Reporting group title |
DB Period - Adalimumab 40 mg
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Reporting group description |
Adalimumab 40 mg SC injection in combination with placebo for sarilumab q2w for 24 weeks during DB period. The dosing frequency of adalimumab was adjusted to 40 mg qw dosing in case of subjects with inadequate response (<20% improvement from baseline in TJC and SJC for 2 consecutive visits) at or after Week 16 until Week 23. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
DB Period - Sarilumab 200mg
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Reporting group description |
Sarilumab 200 mg SC injection in combination with placebo for adalimumab q2w for 24 weeks during DB period. The dosing frequency of placebo for adalimumab was adjusted to 40 mg qw dosing in case of subjects with inadequate response (<20% improvement from baseline in TJC and SJC for 2 consecutive visits) at or after Week 16 until Week 23. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
OLE Period - Sarilumab 200mg
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Reporting group description |
All subjects who completed 24 weeks DB period had the option to continue in OLE period and received sarilumab 200 mg q2w until commercial availability of sarilumab in their country or up to maximum of additional 276 weeks (i.e. up to Week 300). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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17 Jun 2015 |
Following changes were made:
i) added the assessment of potential opportunistic infections and study treatment continuation.
ii) correct errors or inconsistencies in the protocol schedule of events and footnotes.
iii) correct inconsistencies in criteria for dose escalation.
iv) detail the requirement for an independent joint assessor. |
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20 Nov 2015 |
Following changes were made: modified the study duration in order to provide long-term open-label treatment with sarilumab 200 mg q2w beyond Week 48, until anticipated commercial availability of sarilumab or until 2020, and collect long-term data for sarilumab in the monotherapy setting. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
