Clinical Trial Results:
A multicenter, open-label, long-term extension study of WA22762 and NA25220 to evaluate safety and efficacy of subcutaneous tocilizumab in patients with moderate to severe rheumatoid arthritis
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Summary
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EudraCT number |
2012-002632-87 |
Trial protocol |
ES |
Global end of trial date |
19 May 2015
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Results information
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Results version number |
v1(current) |
This version publication date |
03 Aug 2016
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First version publication date |
03 Aug 2016
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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 |
ML28488
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01772316 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
F. Hoffmann-La Roche AG
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Sponsor organisation address |
Grenzacherstrasse 124, Basel, Switzerland, CH-4070
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Public contact |
F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com
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Scientific contact |
F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.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 |
19 May 2015
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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 |
19 May 2015
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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 evaluate the long-term safety of subcutaneous (SC) tocilizumab therapy with regard to adverse events (AEs) and clinical laboratory assessments, including immunogenicity in subjects who have completed the 2010-018375-22 or 2010-019912-18 core studies and who may continue to benefit from tocilizumab treatment administered subcutaneously.
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Protection of trial subjects |
All study subjects were required to read and sign an Informed Consent Form.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
17 Dec 2012
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Long term follow-up planned |
Yes
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Long term follow-up rationale |
Safety | ||
Long term follow-up duration |
2 Months | ||
Independent data monitoring committee (IDMC) involvement? |
No
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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 |
Spain: 47
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Worldwide total number of subjects |
47
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EEA total number of subjects |
47
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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) |
30
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From 65 to 84 years |
17
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85 years and over |
0
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Recruitment
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Recruitment details |
- | ||||||||||||||
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Pre-assignment
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Screening details |
A total of 47 subjects were enrolled in the trial and received treatment. All subjects enrolled were included in the safety analysis. Of the 47 subjects , 13 subjects were not included in the statistical analysis for outcome measures because they did not meet eligibility criteria. | ||||||||||||||
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Period 1
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Period 1 title |
Overall Period
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Is this the baseline period? |
Yes | ||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||
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Arms
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Arm title
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Tocilizumab Subcutaneous (SC) | ||||||||||||||
Arm description |
Subjects received Tocilizumab 162 milligram (mg) given as 0.9 milliliter (mL) of a 180 milligram per milliliter (mg/mL) solution administered once a week (for subjects entering from 2012-002632-87) or once every two weeks (for subjects entering from 2010-019912-18) by SC injection and as a single fixed dose irrespective of body weight. | ||||||||||||||
Arm type |
Experimental | ||||||||||||||
Investigational medicinal product name |
Tocilizumab
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Investigational medicinal product code |
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Other name |
Roactemra
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Subjects received tocilizumab 162 mg SC weekly or every two weeks, 96 weeks
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Baseline characteristics reporting groups
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Reporting group title |
Overall Period
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Reporting group description |
- | |||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Tocilizumab Subcutaneous (SC)
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Reporting group description |
Subjects received Tocilizumab 162 milligram (mg) given as 0.9 milliliter (mL) of a 180 milligram per milliliter (mg/mL) solution administered once a week (for subjects entering from 2012-002632-87) or once every two weeks (for subjects entering from 2010-019912-18) by SC injection and as a single fixed dose irrespective of body weight. | ||
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End point title |
Percentage of Subjects With an Adverse Event (AE) [1] | ||||||||
End point description |
An AE was defined as any untoward medical occurrence in a clinical investigation subject that was administered study drug, regardless of causal attribution. Safety analysis set included all subjects who received at least one dose of study medication.
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End point type |
Primary
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End point timeframe |
Randomisation of first subject to clinical cutoff date (19MAY2015) (approximately 29 months)
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: The descriptive data was planned to be reported for the endpoint. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Percentage of Subjects Withdrawn From the Study Due to Lack of Therapeutic Response [2] | ||||||||
End point description |
Per-protocol population included all subjects who had at least one dose of study medication and at least one safety evaluation after dose administration.
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End point type |
Primary
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End point timeframe |
Randomisation of first subject to clinical cutoff date (19MAY2015) (approximately 29 months)
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| Notes [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: The descriptive data was planned to be reported for the endpoint. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Change From Baseline in Disease Activity Score 28 - Erythrocyte Sedimentation Rate (DAS28-ESR) at Week 48 [3] | ||||||||||||
End point description |
The DAS28 is a combined index for measuring disease activity in rheumatoid arthritis. The index included SJC, TJC, acute phase response (ESR or high sensitivity C-reactive protein [hsCRP]) and general health status. For this study, ESR was used to calculate DAS28 score. The index was calculated using the following formula: DAS28 = (0.56 × √[TJC28]) + (0.28 × √[SJC28]) + (0.7 × ln[ESR]) + (0.014 × GH). The DAS28 scale ranges from 0 to 10, where higher scores represent higher disease activity. Change in DAS28ESR=DAS28-ESR at Week 48 - DAS28-ESR at Baseline. Per-protocol population included all subjects who had at least one dose of study medication and at least one safety evaluation after dose administration. Here, n signifies the number of subjects evaluable at specified time points.
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End point type |
Primary
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End point timeframe |
Baseline, Week 48
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| Notes [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: The descriptive data was planned to be reported for the endpoint. |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Change From Baseline in DAS28-ESR at Week 96 [4] | ||||||||
End point description |
The DAS28 is a combined index for measuring disease activity in rheumatoid arthritis. The index included SJC, TJC, acute phase response (ESR or high sensitivity C-reactive protein [hsCRP]) and general health status. For this study, ESR was used to calculate DAS28 score. The index was calculated using the following formula: DAS28 = (0.56 × √[TJC28]) + (0.28 × √[SJC28]) + (0.7 × ln[ESR]) + (0.014 × GH). The DAS28 scale ranges from 0 to 10, where higher scores represent higher disease activity. Change in DAS28-ESR = DAS28-ESR at Week 96 - DAS28-ESR at Baseline. Per-protocol population included all subjects who had at least one dose of study medication and at least one safety evaluation after dose administration.
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End point type |
Primary
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End point timeframe |
Baseline, Week 96
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| Notes [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: The descriptive data was planned to be reported for the endpoint. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Change From Baseline in Simplified Disease Activity Index (SDAI) at Week 48 [5] | ||||||||||||
End point description |
The SDAI was the numerical sum of five outcome parameter: SJC and TJC, Patient Global Assessment of Disease Activity (PGA) and Investigator Global Assessment of Disease Activity (IGA), and level of hsCRP. The index was calculated using the following formula SDAI = TJC28 + SJC28 + PGA + IGA + CRP. Change in SDAI = SDAI at Week 48 - SDAI at Baseline. SDAI total score = 0-86. SDAI <=3.3 indicates clinical remission, >3.4 to 11 = low disease activity, >11 to 26 = moderate disease activity, and >26 = high (or severe) disease activity. Per-protocol population included all subjects who had at least one dose of study medication and at least one safety evaluation after dose administration. Here, n signifies the number of subjects evaluable at specified time points.
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End point type |
Primary
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End point timeframe |
Baseline, Week 48
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| Notes [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: The descriptive data was planned to be reported for the endpoint. |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Change From Baseline in SDAI at Week 96 [6] | ||||||||
End point description |
The SDAI was the numerical sum of five outcome parameter: SJC and TJC, PGA and IGA, and level of hsCRP. The index was calculated using the following formula SDAI = TJC28 + SJC28 + PGA + IGA + CRP. Change in SDAI = SDAI at Week 96 - SDAI at Baseline. SDAI total score = 0-86. SDAI <=3.3 indicates clinical remission, >3.4 to 11 = low disease activity, >11 to 26 = moderate disease activity, and >26 = high (or severe) disease activity. Per-protocol population included all subjects who had at least one dose of study medication and at least one safety evaluation after dose administration.
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End point type |
Primary
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End point timeframe |
Baseline, Week 96
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| Notes [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: The descriptive data was planned to be reported for the endpoint. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Change From Baseline in Total Tender Joint Count (TJC) at Week 48 [7] | ||||||||||||
End point description |
An assessment of 66 joints for swelling and 68 joints for tenderness was made. Joints were assessed and classified as tender/not tender and swollen/not swollen by pressure and joint manipulation on physical examination. A smaller number indicated improvement. Per-protocol population included all subjects who had at least one dose of study medication and at least one safety evaluation after dose administration. Here, 'n' represents the number of subjects with a measure at specified time point.
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End point type |
Primary
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End point timeframe |
Baseline, Week 48
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| Notes [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: The descriptive data was planned to be reported for the endpoint. |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Change From Baseline in Total TJC at Week 96 [8] | ||||||||
End point description |
An assessment of 66 joints for swelling and 68 joints for tenderness was made. Joints were assessed and classified as tender/not tender and swollen/not swollen by pressure and joint manipulation on physical examination. A smaller number indicated improvement. Per-protocol population included all subjects who had at least one dose of study medication and at least one safety evaluation after dose administration.
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End point type |
Primary
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End point timeframe |
Baseline, Week 96
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| Notes [8] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: The descriptive data was planned to be reported for the endpoint. |
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| Notes [9] - Number of subjects analysed signifies those subjects who were evaluable for this endpoint. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Change From Baseline in Swollen Joint Count (SJC) at Week 48 [10] | ||||||||||||
End point description |
An assessment of 66 joints for swelling and 68 joints for tenderness was made. Joints were assessed and classified as tender/not tender and swollen/not swollen by pressure and joint manipulation on physical examination. A negative number indicated improvement. Per-protocol population included all subjects who had at least one dose of study medication and at least one safety evaluation after dose administration.
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End point type |
Primary
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End point timeframe |
Baseline, Week 48
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| Notes [10] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: The descriptive data was planned to be reported for the endpoint. |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Change From Baseline in SJC at Week 96 [11] | ||||||||
End point description |
An assessment of 66 joints for swelling and 68 joints for tenderness was made. Joints were assessed and classified as tender/not tender and swollen/not swollen by pressure and joint manipulation on physical examination. Change in SJC = SJC at Week 96 - SJC at Baseline. A negative number indicated improvement.Per-protocol population included all subjects who had at least one dose of study medication and at least one safety evaluation after dose administration.
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End point type |
Primary
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End point timeframe |
Randomisation of first subject to clinical cutoff date (19MAY2015) (approximately 29 months)
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| Notes [11] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: The descriptive data was planned to be reported for the endpoint. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Percentage of Subjects With Remission (DAS28 Less Than [<]2.6 or SDAI Less Than or equal to [<=] 3.3) at Weeks 48 and 96 | ||||||||||||||||
End point description |
Per-protocol population included all subjects who had at least one dose of study medication and at least one safety evaluation after dose administration.
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End point type |
Secondary
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End point timeframe |
Week 48, Week 96
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
Percentage of Subjects With Disease-Modifying Antirheumatic Drugs (DMARDs)/Corticosteroid Dose Reductions and/or Discontinuation | ||||||||
End point description |
Per-protocol population included all subjects who had at least one dose of study medication and at least one safety evaluation after dose administration.
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End point type |
Secondary
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End point timeframe |
Randomisation of first subject to clinical cutoff date (19MAY2015) (approximately 29 months)
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| No statistical analyses for this end point | |||||||||
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End point title |
Patient Global Visual Analog Score (VAS) at Specified Time Points | ||||||||||||||
End point description |
This assessment represents the patient’s overall assessment of their current disease activity on a 100 millimeter (mm) horizontal VAS. The extreme left end of the line should be described as “no disease activity” (symptom free and no arthritis symptoms) and the extreme right end as “maximum disease activity” (maximum arthritis disease activity). Scores ranged from 0 to 100 with a higher score indicating more disease activity. A negative change score indicated less disease activity. Per-protocol population included all subjects who had at least one dose of study medication and at least one safety evaluation after dose administration. Here, 'n' represents the number of subjects with a measure at specified time point.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 48, Week 96
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| No statistical analyses for this end point | |||||||||||||||
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End point title |
Patient Pain VAS Score at Specified Time Points | ||||||||||||||
End point description |
This assessment represents the patient’s assessment of his/her current level of pain on a 100 mm horizontal VAS. The extreme left end of the line should be described as “no pain” and the extreme right end as “unbearable pain”. Scores ranged from 0 to 100 with a higher score indicating more pain. A negative change score indicated less pain. Per-protocol population included all subjects who had at least one dose of study medication and at least one safety evaluation after dose administration. Here, 'n' represents the number of subjects with a measure at specified time point.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 48, Week 96
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| No statistical analyses for this end point | |||||||||||||||
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End point title |
Health Assessment Questionnaire-Disability Index (HAQ-DI) Score at Specified Time Points | ||||||||||||||
End point description |
The HAQ-DI is a questionnaire specific for rheumatoid arthritis and consists of 20 questions referring to 8 domains: Dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities. A negative change score indicates improvement. Per-protocol population included all subjects who had at least one dose of study medication and at least one safety evaluation after dose administration. Here, 'n' represents the number of subjects with a measure at specified time point.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 48, Week 96
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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 |
Randomisation of first subject to clinical cutoff date (19MAY2015) (approximately 29 months)
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Adverse event reporting additional description |
An AE was defined as any untoward medical occurrence in a clinical investigation subject that was administered study drug, regardless of causal attribution.
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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 |
14
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Reporting groups
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Reporting group title |
Tocilizumab
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Reporting group description |
Subjects received Tocilizumab 162 mg given as 0.9 mL of a 180 mg/mL solution administered once a week (for subjects entering from 2012-002632-87) or once every two weeks (for subjects entering from 2010-019912-18) by SC injection and as a single fixed dose irrespective of body weight. All subjects receiving study drug were included in the safety analysis set. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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? No | |||
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 | |||
