Clinical Trial Results:
A Randomized, Controlled, Double-Blind, Parallel-Group, Phase 3 Study to Compare the Pharmacokinetics, Efficacy and Safety between CT-P10, Rituxan and MabThera in Patients with Rheumatoid Arthritis
Summary
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EudraCT number |
2013-004555-21 |
Trial protocol |
AT LV PT DE SK HU GR |
Global end of trial date |
25 Jan 2017
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Results information
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Results version number |
v1(current) |
This version publication date |
04 Jan 2018
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First version publication date |
04 Jan 2018
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Other versions |
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 |
CT-P10 3.2
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02149121 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Celltrion, Inc.
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Sponsor organisation address |
23 Academy-ro (13-6, Songdo-dong), Yeonsu-gu, Incheon, Korea, Republic of, 22014
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Public contact |
Clinical Operations Management Department, CELLTRION, Inc., +82 32 850 6724, SuEun.Song@celltrion.com
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Scientific contact |
Clinical Planning Department, CELLTRION, Inc., +82 32 850 6532, SungYoung.Lee@celltrion.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 |
25 Jan 2017
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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 |
25 Jan 2017
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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 |
The primary objective of Part 1 of the study is:
• To evaluate and compare pharmacokinetics in terms of area under the serum concentration-time curve from zero to time of last quantifiable concentration (AUC0-last), AUC from zero to infinity (AUC0-∞) and maximum serum concentration (Cmax) (after the second infusion) of CT-P10 to Rituxan, CT-P10 to MabThera and Rituxan to MabThera during the first course of treatment (over the first 24 weeks).
The primary objective of Part 2 of the study is:
• To demonstrate that CT-P10 is similar to Rituxan and MabThera in terms of efficacy as determined by clinical response according to change from baseline in disease activity measured by Disease Activity Score using 28 joint counts (DAS28) (C-reactive protein [CRP]) at Week 24.
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Protection of trial subjects |
Hypersensitivity had been assessed by vital sign monitoring on each dosing day and recorded on each dosing day at the following time points:
• Before administration (within 15 minutes prior to the beginning of the study drug infusion)
• Within 15 minutes after the end of the study drug infusion
• 1 hour (±15 minutes) after the end of the study drug infusion
In addition, hypersensitivity should be monitored by routine continuous clinical monitoring including 12-lead ECG monitoring 1 hour (±15 minutes) after the end of the study drug infusion.
Emergency equipment, such as adrenaline, antihistamines, corticosteroids, and respiratory support including inhalational therapy, oxygen, and artificial ventilator must be available.
For patients who experience or develop life threatening infusion related anaphylactic reactions, study treatment must be stopped immediately and the patient withdrawn from the study.
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Background therapy |
Methotrexate will be administered at a dosage of between 7.5 and 25 mg orally or parenterally every week (dose and route must be maintained from beginning to study end). Folic acid will be administered at a dosage of at least 5 mg/week for as long as MTX treatment is continued. | ||
Evidence for comparator |
CT P10 is being developed as a biosimilar candidate of Rituxan and MabThera, a compound with established efficacy in its registered indications and CT-P10 is intended to offer a more affordable treatment than Rituxan and MabThera, if similar efficacy and safety can be demonstrated during the conduct of these key clinical studies. | ||
Actual start date of recruitment |
06 Aug 2014
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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: 52
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Country: Number of subjects enrolled |
Portugal: 5
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Country: Number of subjects enrolled |
Romania: 7
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Country: Number of subjects enrolled |
Austria: 4
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Country: Number of subjects enrolled |
Germany: 22
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Country: Number of subjects enrolled |
Greece: 2
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Country: Number of subjects enrolled |
Hungary: 5
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Country: Number of subjects enrolled |
Latvia: 6
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Country: Number of subjects enrolled |
Bosnia and Herzegovina: 34
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Country: Number of subjects enrolled |
Israel: 17
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Country: Number of subjects enrolled |
Russian Federation: 21
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Country: Number of subjects enrolled |
Ukraine: 38
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Country: Number of subjects enrolled |
Chile: 13
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Country: Number of subjects enrolled |
Colombia: 18
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Country: Number of subjects enrolled |
Mexico: 41
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Country: Number of subjects enrolled |
Peru: 63
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Country: Number of subjects enrolled |
Korea, Republic of: 24
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Worldwide total number of subjects |
372
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EEA total number of subjects |
103
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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) |
326
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From 65 to 84 years |
46
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85 years and over |
0
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Recruitment
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Recruitment details |
First patient randomly assigned to treatment: 06 August 2014 A toal of 98 study centers were initiated in Europe, Asia Pacific, and Latin America. | ||||||||||||||||||||||||||||||||||||||||||||
Pre-assignment
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Screening details |
Key Inclusion Criteria 1.Patient is male or female between 18 and 75 years old, inclusive 2.Patient has a diagnosis of RA according to the revised 1987 ACR classification criteria for at least 6 months prior to randomization 3.Patient has experienced an inadequate or intolerance response to previous treatment with the antitumor necrosis factor | ||||||||||||||||||||||||||||||||||||||||||||
Pre-assignment period milestones
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Number of subjects started |
495 [1] | ||||||||||||||||||||||||||||||||||||||||||||
Intermediate milestone: Number of subjects |
Subject screened: 495
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Intermediate milestone: Number of subjects |
Enrolled: 372
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Number of subjects completed |
372 | ||||||||||||||||||||||||||||||||||||||||||||
Pre-assignment subject non-completion reasons
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Reason: Number of subjects |
Screening Failure: 111 | ||||||||||||||||||||||||||||||||||||||||||||
Reason: Number of subjects |
GCP non-compliant site: 12 | ||||||||||||||||||||||||||||||||||||||||||||
Notes [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same. Justification: The 'Number of subjects reported to have started the pre-assignment period' means subjects who consented to participate in this trial through the Screening procedure. If these subjects meet Inclusion and Exclusion criteria defined by the protocol, they can be randomized which will have study drug administration. Subject who received at least 1 dose of study drug (CT-P10, Rituxan or MabThera) is considered as 'Enrolled' in the trial. |
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Period 1
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Period 1 title |
Main Study Period-1st treatment course
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | ||||||||||||||||||||||||||||||||||||||||||||
Roles blinded |
Subject, Investigator, Monitor, Data analyst, Carer, Assessor | ||||||||||||||||||||||||||||||||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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CT-P10 | ||||||||||||||||||||||||||||||||||||||||||||
Arm description |
CT-P10 (1000mg) coadministered with MTX between 7.5 and 25 mg/week (oral or parenteral dose) and folic acid (≥ 5mg/week) | ||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
CT-P10
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Concentrate for solution for injection
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Routes of administration |
Intravenous use
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Dosage and administration details |
CT-P10 (1000mg), MTX (between 7.5 to 25 mg/week, oral or parenteral dose), folic acid (≥ 5mg/week)
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Arm title
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Rituxan | ||||||||||||||||||||||||||||||||||||||||||||
Arm description |
US-licensed reference product. Rituxan (1000mg) coadministered with MTX between 7.5 to 25 mg/week (oral or parenteral dose) and folic acid (≥ 5mg/week) | ||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Active comparator | ||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Rituxan
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Concentrate for solution for injection
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Routes of administration |
Intravenous use
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Dosage and administration details |
Rituxan (1000mg), MTX (between 7.5 to 25 mg/week, oral or parenteral dose), folic acid (≥ 5mg/week)
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Arm title
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MabThera | ||||||||||||||||||||||||||||||||||||||||||||
Arm description |
EU-approved reference product. MabThera (1000mg) coadministered with MTX between 7.5 to 25 mg/week (oral or parenteral dose) and folic acid (≥ 5mg/week) | ||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Active comparator | ||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
MabThera
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Concentrate for solution for injection
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Routes of administration |
Intravenous use
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Dosage and administration details |
MabThera (1000mg), MTX (between 7.5 to 25 mg/week, oral or parenteral dose), folic acid (≥ 5mg/week)
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Period 2
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Period 2 title |
Main Study Period-2nd treatment course
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Is this the baseline period? |
No | ||||||||||||||||||||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | ||||||||||||||||||||||||||||||||||||||||||||
Roles blinded |
Subject, Investigator, Monitor, Data analyst, Carer, Assessor | ||||||||||||||||||||||||||||||||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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CT-P10 | ||||||||||||||||||||||||||||||||||||||||||||
Arm description |
CT-P10 (1000mg) coadministered with MTX between 7.5 to 25 mg/week (oral or parenteral dose) and folic acid (≥ 5mg/week) | ||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
CT-P10
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Concentrate for solution for injection
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Routes of administration |
Intravenous use
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Dosage and administration details |
CT-P10 (1000mg), MTX (between 7.5 to 25 mg/week, oral or parenteral dose), folic acid (≥ 5mg/week)
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Arm title
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Rituxan | ||||||||||||||||||||||||||||||||||||||||||||
Arm description |
US-licensed reference product. Rituxan (1000mg) coadministered with MTX between 7.5 to 25 mg/week (oral or parenteral dose) and folic acid (≥ 5mg/week) | ||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Active comparator | ||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Rituxan
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Concentrate for solution for injection
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Routes of administration |
Intravenous use
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Dosage and administration details |
Rituxan (1000mg), MTX (between 7.5 to 25 mg/week, oral or parenteral dose), folic acid (≥ 5mg/week)
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Arm title
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MabThera | ||||||||||||||||||||||||||||||||||||||||||||
Arm description |
EU-approved reference product. MabThera (1000mg) coadministered with MTX between 7.5 to 25 mg/week (oral or parenteral dose) and folic acid (≥ 5mg/week) | ||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Active comparator | ||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
MabThera
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Concentrate for solution for injection
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Routes of administration |
Intravenous use
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Dosage and administration details |
MabThera (1000mg), MTX (between 7.5 to 25 mg/week, oral or parenteral dose), folic acid (≥ 5mg/week)
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Notes [2] - 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: Seven subjects did not initiated the 2nd course after completion of the 1st course. Among them, 4 subjects did not meet safety criteria for the 2nd course initiation (each 2 subjects from the CT-P10 and Rituxan groups), and were monitored up to Week 48. The other 3 subjects were discontinued after Week 24 and entered as "discontinued after course 2, not treated" in Period 2 Section (1 subject in CT-P10: withdrew consent; 2 subjects in Rituxan: 1 lack of efficacy and 1 disease progression). |
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Period 3
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Period 3 title |
Extension Study Period
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Is this the baseline period? |
No | ||||||||||||||||||||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | ||||||||||||||||||||||||||||||||||||||||||||
Roles blinded |
Subject, Investigator, Monitor, Data analyst, Carer, Assessor | ||||||||||||||||||||||||||||||||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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CT-P10 maintenance | ||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Patients who were assigned to receive CT-P10 for their first infusion in the study were considered to be CT-P10 maintenance and continued to receive CT-P10 for the treatment course in the Extension Study Period. CT-P10 (1000mg) coadministered with MTX between 7.5 to 25mg/week (oral or parenteral dose) and folic acid (≥ 5mg.week) | ||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
CT-P10
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Concentrate for solution for injection
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Routes of administration |
Intravenous use
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Dosage and administration details |
CT-P10 (1000mg), MTX (between 7.5 to 25 mg/week, oral or parenteral dose), folic acid (≥ 5mg/week)
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Arm title
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Rituxan maintenance | ||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Patients who were assigned to receive Rituxan for their first infusion in the study were assigned again at Extension Week 0 to Rituxan maintenance group, who continued to receive Rituxan for the treatment course of the Extension Study PEriod. Rituxan (1000mg) coadministered with MTX between 7.5 to 25mg/week (oral or parenteral dose) and folic acid (≥ 5mg.week) | ||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Active comparator | ||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Rituxan
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Concentrate for solution for injection
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Routes of administration |
Intravenous use
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Dosage and administration details |
Rituxan (1000mg), MTX (between 7.5 to 25 mg/week, oral or parenteral dose), folic acid (≥ 5mg/week)
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Arm title
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Switched from Rituxan | ||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Patients who were assigned to receive Rituxan for their first infusion in the study were assigned again to Switched from Rituxan group and received CT-P10 for the treatment course of the Extension study period. CT-P10 (1000mg) coadministered with MTX between 7.5 to 25mg/week (oral or parenteral dose) and folic acid (≥ 5mg.week). | ||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Active comparator | ||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
CT-P10
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Concentrate for solution for injection
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Routes of administration |
Intravenous use
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Dosage and administration details |
CT-P10 (1000mg), MTX (between 7.5 to 25 mg/week, oral or parenteral dose), folic acid (≥ 5mg/week)
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Arm title
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Switched from MabThera | ||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Patients who were assigned to receive MabThera for their first infusion in the study were considered to be Switched from MabThera group and received CT-P10 for the treatment course of the Extension study period. CT-P10 (1000mg) coadministered with MTX between 7.5 to 25mg/week (oral or parenteral dose) and folic acid (≥ 5mg.week) | ||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Active comparator | ||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
CT-P10
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Concentrate for solution for injection
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Routes of administration |
Intravenous use
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Dosage and administration details |
CT-P10 (1000mg), MTX (between 7.5 to 25 mg/week, oral or parenteral dose), folic acid (≥ 5mg/week)
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Notes [3] - 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: According to the protocol, only the eligible subjects can be participated in the Extension Study Period. When the subjects had completed the Main Study Period, and met the predefined safety criteria based on the results assess within 8 weeks from Week 0 of the Extension Study period, subjects could continue on to the Extension Study Period with an additional treatment course. Due to the ineligibility of evaluation result, some of subjects were not enrolled in the Extension study period. |
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Baseline characteristics reporting groups
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
CT-P10
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
CT-P10 (1000mg) coadministered with MTX between 7.5 and 25 mg/week (oral or parenteral dose) and folic acid (≥ 5mg/week) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Rituxan
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
US-licensed reference product. Rituxan (1000mg) coadministered with MTX between 7.5 to 25 mg/week (oral or parenteral dose) and folic acid (≥ 5mg/week) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
MabThera
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
EU-approved reference product. MabThera (1000mg) coadministered with MTX between 7.5 to 25 mg/week (oral or parenteral dose) and folic acid (≥ 5mg/week) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||
End points reporting groups
|
|||
Reporting group title |
CT-P10
|
||
Reporting group description |
CT-P10 (1000mg) coadministered with MTX between 7.5 and 25 mg/week (oral or parenteral dose) and folic acid (≥ 5mg/week) | ||
Reporting group title |
Rituxan
|
||
Reporting group description |
US-licensed reference product. Rituxan (1000mg) coadministered with MTX between 7.5 to 25 mg/week (oral or parenteral dose) and folic acid (≥ 5mg/week) | ||
Reporting group title |
MabThera
|
||
Reporting group description |
EU-approved reference product. MabThera (1000mg) coadministered with MTX between 7.5 to 25 mg/week (oral or parenteral dose) and folic acid (≥ 5mg/week) | ||
Reporting group title |
CT-P10
|
||
Reporting group description |
CT-P10 (1000mg) coadministered with MTX between 7.5 to 25 mg/week (oral or parenteral dose) and folic acid (≥ 5mg/week) | ||
Reporting group title |
Rituxan
|
||
Reporting group description |
US-licensed reference product. Rituxan (1000mg) coadministered with MTX between 7.5 to 25 mg/week (oral or parenteral dose) and folic acid (≥ 5mg/week) | ||
Reporting group title |
MabThera
|
||
Reporting group description |
EU-approved reference product. MabThera (1000mg) coadministered with MTX between 7.5 to 25 mg/week (oral or parenteral dose) and folic acid (≥ 5mg/week) | ||
Reporting group title |
CT-P10 maintenance
|
||
Reporting group description |
Patients who were assigned to receive CT-P10 for their first infusion in the study were considered to be CT-P10 maintenance and continued to receive CT-P10 for the treatment course in the Extension Study Period. CT-P10 (1000mg) coadministered with MTX between 7.5 to 25mg/week (oral or parenteral dose) and folic acid (≥ 5mg.week) | ||
Reporting group title |
Rituxan maintenance
|
||
Reporting group description |
Patients who were assigned to receive Rituxan for their first infusion in the study were assigned again at Extension Week 0 to Rituxan maintenance group, who continued to receive Rituxan for the treatment course of the Extension Study PEriod. Rituxan (1000mg) coadministered with MTX between 7.5 to 25mg/week (oral or parenteral dose) and folic acid (≥ 5mg.week) | ||
Reporting group title |
Switched from Rituxan
|
||
Reporting group description |
Patients who were assigned to receive Rituxan for their first infusion in the study were assigned again to Switched from Rituxan group and received CT-P10 for the treatment course of the Extension study period. CT-P10 (1000mg) coadministered with MTX between 7.5 to 25mg/week (oral or parenteral dose) and folic acid (≥ 5mg.week). | ||
Reporting group title |
Switched from MabThera
|
||
Reporting group description |
Patients who were assigned to receive MabThera for their first infusion in the study were considered to be Switched from MabThera group and received CT-P10 for the treatment course of the Extension study period. CT-P10 (1000mg) coadministered with MTX between 7.5 to 25mg/week (oral or parenteral dose) and folic acid (≥ 5mg.week) | ||
Subject analysis set title |
All-randomized population
|
||
Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
The all-randomized population consisted of all patients enrolled and randomly assigned to receive a dose of study drug, regardless of whether or not any study drug dosing was completed.
|
||
Subject analysis set title |
Pharmacokinetic Population
|
||
Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
The PK population of the Main Study Period consisted of all patients who received 2 full doses (Week 0 and Week 2) of the study drug and provided at least 1 post-treatment PK concentration result during the first course of treatment in the Main Study Period.
Note. The PK population was the primary population for the summary of PK data.
|
||
Subject analysis set title |
Efficacy Population
|
||
Subject analysis set type |
Per protocol | ||
Subject analysis set description |
The efficacy population for the Main Study Period consisted of all patients who received at least 1 full dose (1000 mg) of study drug and provided at least 1 post-treatment efficacy result during the first course of treatment in the Main Study Period
|
||
Subject analysis set title |
Pharmacodynamic Population
|
||
Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
The PD population for the Main Study Period consisted of all patients who received at least 1 full dose (1000 mg) of study drug and provided at least 1 post-treatment PD result during the first course of treatment in the Main Study Period.
|
||
Subject analysis set title |
Safety Population
|
||
Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
The safety population consisted of all patients who received at least 1 (full or partial) dose of study drug during any dosing period.
|
||
Subject analysis set title |
All-randomized - Extension Study Period subset
|
||
Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
The “all-randomized population – Extension Study Period subset” consisted of all patients in the all-randomized population who received at least 1 (full or partial) dose of study drug in the Extension Study Period.
|
||
Subject analysis set title |
Efficacy - Extension Study Period subset
|
||
Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
The “efficacy – Extension Study Period subset” consisted of all patients in the efficacy population who received at least 1 full dose (1000 mg) of study drug and provided at least 1 post-treatment efficacy result during the Extension Study Period.
|
||
Subject analysis set title |
Pharmacodynamic - Extension Study Period subset
|
||
Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
The “pharmacodynamic – Extension Study Period subset” consisted of all patients in the PD population who received at least 1 full dose (1000 mg) of study drug and provided at least 1 post-treatment PD result during the Extension Study Period.
|
||
Subject analysis set title |
Safety - Extension Study Period subset
|
||
Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
The “safety – Extension Study Period subset” consisted of all patients in the safety population who received at least 1 (full or partial) dose of study drug during the Extension Study Period.
|
||
Subject analysis set title |
CT-P10: 1st treatment course in the Main Study Period
|
||
Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
This subject analysis set received an infusion of study drug (CT-P10) at Week 0 and Week 2 of the 1st treatment course in the Main Study Period.
|
||
Subject analysis set title |
Reference products: 1st treatment course in Main Study Period
|
||
Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
This subject analysis set received an infusion of reference products (Rituxan and MabThera) at Week 0 and Week 2 of the 1st treatment course in the Main Study Period.
|
||
Subject analysis set title |
Rituxan: 1st treatment course in Main Study Period
|
||
Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
This subject analysis set received an infusion of reference product (Rituxan) at Week 0 and Week 2 of the 1st treatment course in the Main Study Period.
|
||
Subject analysis set title |
MabThera: 1st treatment course in Main Study Period
|
||
Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
This subject analysis set received an infusion of reference product (MabThera) at Week 0 and Week 2 of the 1st treatment course in the Main Study Period.
|
|
|||||||||||||||||
End point title |
AUC0-last | ||||||||||||||||
End point description |
AUC0-last: Area under the concentration-time curve from time 0 to the last measurable concentration.
Note: Measure Type is geometric least squares mean.
|
||||||||||||||||
End point type |
Primary
|
||||||||||||||||
End point timeframe |
over the first 24 weeks
|
||||||||||||||||
|
|||||||||||||||||
Notes [1] - Pharmacokinetics population [2] - Pharmacokinetics population [3] - Pharmacokinetics population |
|||||||||||||||||
Statistical analysis title |
Co-primary Pharmacokinetics Endpoints - AUC0-last | ||||||||||||||||
Statistical analysis description |
Analysis Method: Analysis of covariance (ANCOVA).
Response value:log transformed values of AUC0-last, Fixed effect: treatment group, Covariates: gender, region, race, prior anti-TNF-α blocker status and RF or anti-CCP status.
Point estimates (geometric means and ratio of geometric means) and 90% confidence intervals for differences on the log scale were exponentiated to obtain estimates for ratios of geometric least square means on the original scale.
|
||||||||||||||||
Comparison groups |
CT-P10: 1st treatment course in the Main Study Period v Rituxan: 1st treatment course in Main Study Period
|
||||||||||||||||
Number of subjects included in analysis |
122
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
equivalence [4] | ||||||||||||||||
Method |
|||||||||||||||||
Parameter type |
Ratio of geometric least square means | ||||||||||||||||
Point estimate |
97.07
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
90% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
88.08 | ||||||||||||||||
upper limit |
106.99 | ||||||||||||||||
Notes [4] - Equivalence margin: 80%-125% |
|||||||||||||||||
Statistical analysis title |
Co-primary Pharmacokinetics Endpoints - AUC0-last | ||||||||||||||||
Statistical analysis description |
Analysis Method: Analysis of covariance (ANCOVA).
Response value:log transformed values of AUC0-last, Fixed effect: treatment group, Covariates: gender, region, race, prior anti-TNF-α blocker status and RF or anti-CCP status.
Point estimates (geometric means and ratio of geometric means) and 90% confidence intervals for differences on the log scale were exponentiated to obtain estimates for ratios of geometric least square means on the original scale.
|
||||||||||||||||
Comparison groups |
CT-P10: 1st treatment course in the Main Study Period v MabThera: 1st treatment course in Main Study Period
|
||||||||||||||||
Number of subjects included in analysis |
121
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
equivalence [5] | ||||||||||||||||
Method |
|||||||||||||||||
Parameter type |
Ratio of geometric least square means | ||||||||||||||||
Point estimate |
94.18
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
90% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
85.4 | ||||||||||||||||
upper limit |
103.86 | ||||||||||||||||
Notes [5] - Equivalence margin: 80%-125% |
|||||||||||||||||
Statistical analysis title |
Co-primary Pharmacokinetics Endpoints - AUC0-last | ||||||||||||||||
Statistical analysis description |
Analysis Method: Analysis of covariance (ANCOVA).
Response value:log transformed values of AUC0-last, Fixed effect: treatment group, Covariates: gender, region, race, prior anti-TNF-α blocker status and RF or anti-CCP status.
Point estimates (geometric means and ratio of geometric means) and 90% confidence intervals for differences on the log scale were exponentiated to obtain estimates for ratios of geometric least square means on the original scale.
|
||||||||||||||||
Comparison groups |
Rituxan: 1st treatment course in Main Study Period v MabThera: 1st treatment course in Main Study Period
|
||||||||||||||||
Number of subjects included in analysis |
119
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
equivalence [6] | ||||||||||||||||
Method |
|||||||||||||||||
Parameter type |
Ratio of geometric least square means | ||||||||||||||||
Point estimate |
103.07
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
90% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
93.32 | ||||||||||||||||
upper limit |
113.85 | ||||||||||||||||
Notes [6] - Equivalence margin: 80%-125% |
|
|||||||||||||||||
End point title |
AUC0-inf | ||||||||||||||||
End point description |
AUC0-inf: Area under the concentration-time curve from time 0 extrapolated to infinity
Note: Measure Type is geometric least squares mean.
|
||||||||||||||||
End point type |
Primary
|
||||||||||||||||
End point timeframe |
over the first 24 weeks
|
||||||||||||||||
|
|||||||||||||||||
Notes [7] - Pharmacokinetics population [8] - Pharmacokinetics population [9] - Pharmacokinetics population |
|||||||||||||||||
Statistical analysis title |
Co-primary Pharmacokinetics Endpoints - AUC0-inf | ||||||||||||||||
Statistical analysis description |
Analysis Method: Analysis of covariance (ANCOVA).
Response value:log transformed values of AUC0-inf, Fixed effect: treatment group, Covariates: gender, region, race, prior anti-TNF-α blocker status and RF or anti-CCP status.
Point estimates (geometric means and ratio of geometric means) and 90% confidence intervals for differences on the log scale were exponentiated to obtain estimates for ratios of geometric least square means on the original scale.
|
||||||||||||||||
Comparison groups |
CT-P10: 1st treatment course in the Main Study Period v Rituxan: 1st treatment course in Main Study Period
|
||||||||||||||||
Number of subjects included in analysis |
119
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
equivalence [10] | ||||||||||||||||
Method |
|||||||||||||||||
Parameter type |
Ratio of geometric least square means | ||||||||||||||||
Point estimate |
95.81
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
90% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
87.39 | ||||||||||||||||
upper limit |
105.04 | ||||||||||||||||
Notes [10] - Equivalence margin: 80%-125% |
|||||||||||||||||
Statistical analysis title |
Co-primary Pharmacokinetics Endpoints - AUC0-inf | ||||||||||||||||
Statistical analysis description |
Analysis Method: Analysis of covariance (ANCOVA).
Response value:log transformed values of AUC0-inf, Fixed effect: treatment group, Covariates: gender, region, race, prior anti-TNF-α blocker status and RF or anti-CCP status.
Point estimates (geometric means and ratio of geometric means) and 90% confidence intervals for differences on the log scale were exponentiated to obtain estimates for ratios of geometric least square means on the original scale.
|
||||||||||||||||
Comparison groups |
CT-P10: 1st treatment course in the Main Study Period v MabThera: 1st treatment course in Main Study Period
|
||||||||||||||||
Number of subjects included in analysis |
115
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
equivalence [11] | ||||||||||||||||
Method |
|||||||||||||||||
Parameter type |
Ratio of geometric least square means | ||||||||||||||||
Point estimate |
89.89
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
90% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
81.85 | ||||||||||||||||
upper limit |
98.72 | ||||||||||||||||
Notes [11] - Equivalence margin: 80%-125% |
|||||||||||||||||
Statistical analysis title |
Co-primary Pharmacokinetics Endpoints - AUC0-inf | ||||||||||||||||
Statistical analysis description |
Analysis Method: Analysis of covariance (ANCOVA).
Response value:log transformed values of AUC0-inf, Fixed effect: treatment group, Covariates: gender, region, race, prior anti-TNF-α blocker status and RF or anti-CCP status.
Point estimates (geometric means and ratio of geometric means) and 90% confidence intervals for differences on the log scale were exponentiated to obtain estimates for ratios of geometric least square means on the original scale.
|
||||||||||||||||
Comparison groups |
Rituxan: 1st treatment course in Main Study Period v MabThera: 1st treatment course in Main Study Period
|
||||||||||||||||
Number of subjects included in analysis |
116
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
equivalence [12] | ||||||||||||||||
Method |
|||||||||||||||||
Parameter type |
Ratio of geometric least square means | ||||||||||||||||
Point estimate |
106.58
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
90% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
97.03 | ||||||||||||||||
upper limit |
117.08 | ||||||||||||||||
Notes [12] - Equivalence margin: 80%-125% |
|
|||||||||||||||||
End point title |
Cmax | ||||||||||||||||
End point description |
Cmax: Observed maximum concentration after the second infusion
Note: Measure Type is geometric least squares mean.
|
||||||||||||||||
End point type |
Primary
|
||||||||||||||||
End point timeframe |
over the first 24 weeks
|
||||||||||||||||
|
|||||||||||||||||
Notes [13] - Pharmacokinetics population [14] - Pharmacokinetics population [15] - Pharmacokinetics population |
|||||||||||||||||
Statistical analysis title |
Co-primary Pharmacokinetics Endpoints - Cmax | ||||||||||||||||
Statistical analysis description |
Analysis Method: Analysis of covariance (ANCOVA).
Response value:log transformed values of Cmax, Fixed effect: treatment group, Covariates: gender, region, race, prior anti-TNF-α blocker status and RF or anti-CCP status.
Point estimates (geometric means and ratio of geometric means) and 90% confidence intervals for differences on the log scale were exponentiated to obtain estimates for ratios of geometric least square means on the original scale.
|
||||||||||||||||
Comparison groups |
CT-P10: 1st treatment course in the Main Study Period v Rituxan: 1st treatment course in Main Study Period
|
||||||||||||||||
Number of subjects included in analysis |
121
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
equivalence [16] | ||||||||||||||||
Method |
|||||||||||||||||
Parameter type |
Ratio of geometric least square means | ||||||||||||||||
Point estimate |
94.92
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
90% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
89.61 | ||||||||||||||||
upper limit |
100.55 | ||||||||||||||||
Notes [16] - Equivalence margin: 80%-125% |
|||||||||||||||||
Statistical analysis title |
Co-primary Pharmacokinetics Endpoints - Cmax | ||||||||||||||||
Statistical analysis description |
Analysis Method: Analysis of covariance (ANCOVA).
Response value:log transformed values of Cmax, Fixed effect: treatment group, Covariates: gender, region, race, prior anti-TNF-α blocker status and RF or anti-CCP status.
Point estimates (geometric means and ratio of geometric means) and 90% confidence intervals for differences on the log scale were exponentiated to obtain estimates for ratios of geometric least square means on the original scale.
|
||||||||||||||||
Comparison groups |
CT-P10: 1st treatment course in the Main Study Period v MabThera: 1st treatment course in Main Study Period
|
||||||||||||||||
Number of subjects included in analysis |
121
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
equivalence [17] | ||||||||||||||||
Method |
|||||||||||||||||
Parameter type |
Ratio of geometric least square means | ||||||||||||||||
Point estimate |
89
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
90% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
84.01 | ||||||||||||||||
upper limit |
94.28 | ||||||||||||||||
Notes [17] - Equivalence margin: 80%-125% |
|||||||||||||||||
Statistical analysis title |
Co-primary Pharmacokinetics Endpoints - Cmax | ||||||||||||||||
Statistical analysis description |
Analysis Method: Analysis of covariance (ANCOVA).
Response value:log transformed values of Cmax, Fixed effect: treatment group, Covariates: gender, region, race, prior anti-TNF-α blocker status and RF or anti-CCP status.
Point estimates (geometric means and ratio of geometric means) and 90% confidence intervals for differences on the log scale were exponentiated to obtain estimates for ratios of geometric least square means on the original scale.
|
||||||||||||||||
Comparison groups |
Rituxan: 1st treatment course in Main Study Period v MabThera: 1st treatment course in Main Study Period
|
||||||||||||||||
Number of subjects included in analysis |
118
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
equivalence [18] | ||||||||||||||||
Method |
|||||||||||||||||
Parameter type |
Ratio of geometric least square means | ||||||||||||||||
Point estimate |
106.66
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
90% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
100.56 | ||||||||||||||||
upper limit |
113.13 | ||||||||||||||||
Notes [18] - Equivalence margin: 80%-125% |
|
|||||||||||||
End point title |
Change from baseline of DAS28 (CRP) | ||||||||||||
End point description |
Note: Measure Type is adjusted least squares mean.
|
||||||||||||
End point type |
Primary
|
||||||||||||
End point timeframe |
Week 24
|
||||||||||||
|
|||||||||||||
Notes [19] - Efficacy population [20] - The combined Rituxan and MabThera treatment groups. Efficacy population |
|||||||||||||
Statistical analysis title |
Co-primary Efficacy Endpoint - CFB of DAS28 (CRP) | ||||||||||||
Statistical analysis description |
Analysis Method: Analysis of covariance (ANCOVA).
Response value: change from baseline of DAS28 (CRP), Fixed effect: treatment group, Covariates: gender, region, race, prior anti-TNF-α blocker status, and RF or anti-CCP status.
Adjusted least squares means and standard error, estimate of treatment difference [CT-P10 - (Reference products)] and 2-sided 95% confidence interval calculated from the ANCOVA model.
|
||||||||||||
Comparison groups |
CT-P10: 1st treatment course in the Main Study Period v Reference products: 1st treatment course in Main Study Period
|
||||||||||||
Number of subjects included in analysis |
334
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
equivalence [21] | ||||||||||||
Method |
|||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
-0.04
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-0.29 | ||||||||||||
upper limit |
0.21 | ||||||||||||
Notes [21] - Equivalence margin: +/- 0.60 |
|
|||||||||||||
End point title |
B-cell counts | ||||||||||||
End point description |
Note: Measure Type is geometric least squares mean.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
up to 24 weeks
|
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Notes [22] - Pharmacodynamic population [23] - The combined Rituxan and MabThera treatment groups. Pharmacodynamic Population |
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Statistical analysis title |
Secondary Pharmacodynamics endpoint-B-cell kinetic | ||||||||||||
Statistical analysis description |
Analysis Method: Analysis of covariance (ANCOVA).
Response value:log transformed values of B-cell kinetics, Fixed effect: treatment group, Covariates:baseline result, gender, region, race, prior anti-TNF-α blocker status and RF or anti-CCP status.
Estimate of Geometric Least Square Mean and ratio of Geometric Least Square Means (CT-P10 / reference products) were obtained from back transforming the least square means from the ANCOVA model.
|
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Comparison groups |
CT-P10: 1st treatment course in the Main Study Period v Reference products: 1st treatment course in Main Study Period
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Number of subjects included in analysis |
296
|
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Analysis specification |
Pre-specified
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Analysis type |
other | ||||||||||||
Method |
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Parameter type |
Ratio of geometric least square means | ||||||||||||
Point estimate |
102.62
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
92.86 | ||||||||||||
upper limit |
113.39 |
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Adverse events information
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Timeframe for reporting adverse events |
Up to 48 weeks (Main Study Period)
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
18.1
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Reporting groups
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Reporting group title |
CT-P10
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Reporting group description |
The safety population consisted of all patients who received at least 1 (full or partial) dose of study drug during any dosing period. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Rituxan
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
MabThera
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 3% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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18 Nov 2013 |
Summary of significant changes included the following:
• Downgraded ACR20 as a secondary endpoint.
• Clarified follow-up of B-cell, IgM and IgG monitoring.
• Clarified the schedule of infusions in the second treatment course.
• Other administrative changes. |
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02 Jun 2014 |
Summary of significant change included the following:
• Changed equivalence margin of DAS28 from 0.75 to 0.6 to reflect recommendation from the Committee for Medicinal Products for Human Use and other regulatory agencies.
• Updated sections regarding statistical analysis according to the update of DAS28 margin.
• Added AUC0-day14 as one of secondary PK endpoints to reflect recommendation from the Food and Drug Administration.
• Added mean change in DAS28 at Week 12 as one of secondary efficacy endpoints to reflect recommendation from the European Medicines Agency.
• Combined Rituxan and MabThera groups for the Part 2 analyses.
• Added a section for diagnosis of anaphylactic reactions based on the Sampson criteria (Sampson et al., 2006).
• Clarified EOS visit.
• Other administrative changes. |
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05 Aug 2015 |
Summary of significant changes included the following:
• Revised to have additional course of treatment with single transition to evaluate additional safety and efficacy.
• Other administrative changes. |
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11 Mar 2016 |
Summary of significant changes includes the followings:
• Updated covariates of ANCOVA for PK and efficacy primary endpoints and the comparison of the concentration of B-cell counts to include clinically relevant variables at baseline.
• Updated Section to prepare additional clinical study report(s) by regulatory or academic purpose and to remove a report to be developed for data from each patient up to Week 48.
• Other administrative changes. |
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29 Mar 2016 |
Summary of significant changes included the following:
• Updated covariates of ANCOVA for PK and efficacy primary endpoints and the comparison of the concentration of B-cell counts to include clinically relevant variables at baseline.
• Updated Section to prepare additional clinical study report(s) by regulatory or academic purpose and to remove a report to be developed for data from each patient up to Week 48.
• Added immunogenicity sampling time points at Extension Weeks 8 and 16 for further evaluation of immunogenicity in the Extension Study Period.
• Other administrative changes. |
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Interruptions (globally) |
|||
Were there any global interruptions to the trial? No | |||
Limitations and caveats |
|||
Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
None reported |