Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12609000747224
Ethics application status
Approved
Date submitted
14/05/2009
Date registered
28/08/2009
Date last updated
17/03/2010
Type of registration
Retrospectively registered

Titles & IDs
Public title
Extension Phase of the Multi-National Open-Label Study to Evaluate the Safety, Tolerability and Efficacy of Tocilizumab in Patients with Active Rheumatoid Arthritis on Background Non-biologic Disease-Modifying Anti-Rheumatic Drugs (DMARDs) who have an Inadequate Response to Current Non-biologic DMARD and/or Anti Tumor necrosis factor (Anti-TNF) Therapy
Scientific title
Extension Phase of the Multi-National Open-Label Study to Evaluate the Safety, Tolerability and Efficacy of Tocilizumab in Patients with Active Rheumatoid Arthritis on Background Non-biologic Disease-Modifying Anti-Rheumatic Drugs (DMARDs) who have an Inadequate Response to Current Non-biologic DMARD and/or Anti Tumor necrosis factor (Anti-TNF) Therapy
Secondary ID [1] 870 0
MA22460
Universal Trial Number (UTN)
Trial acronym
ACT-SURE long term extension study (LTE)
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Patients with severe to moderate rheumatoid arthritis 4785 0
Condition category
Condition code
Inflammatory and Immune System 237125 237125 0 0
Rheumatoid arthritis

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
For the MA22460 extension study:
Tocilizumab (TCZ) 8 mg/kg Intravenous (IV), 60-minute infusion period, every 4 weeks until Pharmaceutical Benefit Scheme (PBS) reimbursement in Australia.
The last visit at week 24 of the MA21573 core study is considered the Screening and Day 1 visit of the extension study if study drug is administered at this visit. In case the study drug administration cannot occur at the Week 24 visit, it can be delayed by a maximum of 2 weeks. Day 1 is defined as the day of first study drug administration under MA22460.
Intervention code [1] 4558 0
Treatment: Drugs
Comparator / control treatment
Nil comparator
Control group
Uncontrolled

Outcomes
Primary outcome [1] 237952 0
Incidence of Adverse Events (AEs) and Serious Adverse Events (SAEs) of TCZ monotherapy or combined treatment with TCZ and one or more of the background non-biologic DMARD approved for Rheumatoid Arthritis (RA) in patients with moderate to severe active RA.
The incidence of adverse events will be primarily evaluated at each study visit by the investigator via patient questioning and laboratory tests and assessments with medical equipment where applicable.
Timepoint [1] 237952 0
This extension study will be analyzed jointly with the 24-week MA21573 core study.
A statistical analysis plan (SAP) will be evaluated throughout the study (no defined timelines) and finalised before closure of the study database.
Secondary outcome [1] 242047 0
Number and percentage of patients with AE and SAE related discontinuation of TCZ at every visit.
Timepoint [1] 242047 0
AE and SAEs are evaluated by the investigator at each study visit by asking patient questions.
Secondary outcome [2] 242048 0
Number and percentage of patients with all-cause discontinuation of TCZ at every visit.
Timepoint [2] 242048 0
AE and SAEs are evaluated by the investigator at each study visit by asking patient questions.
Secondary outcome [3] 242402 0
Incidence of AEs, SAEs and discontinuations in current and prior users of TNF antagonists at every visit
Timepoint [3] 242402 0
AE and SAEs are evaluated by the investigator at each study visit by asking patient questions.
Secondary outcome [4] 242403 0
Number of percentage of patients with Alanine aminotransferase (ALT) or Aspartate aminotransferase (AST) elevations >1.5 upper limit of normal (ULN), >3ULN and >5ULN every 12 weeks
Timepoint [4] 242403 0
Laboratory test results are evaluated by the investigator at each investigator assessment study visit every 12 weeks
Secondary outcome [5] 242404 0
Incidence of serious infections
Timepoint [5] 242404 0
AE and SAEs are evaluated by the investigator at each 12 weekly study visit
Secondary outcome [6] 242405 0
Number and percentage of pateints with elevations in lipids and meeting the Adult Treatment Panel (ATP) III guidelines every 12 weeks
Timepoint [6] 242405 0
Laboratory test results are evaluated by the investigator at each investigator assessment study visit every 12 weeks
Secondary outcome [7] 242406 0
Incidence of AEs of special interest: lipid elevations, major adverse cardiac events, strokes, infections, reduced neutrophil counts and raised transaminases
Timepoint [7] 242406 0
AE and SAEs, and laboratory test results are evaluated by the investigator at each study visit every 12 weeks
Secondary outcome [8] 242407 0
Change from baseline to highest values for ALT, AST, and total cholesterol and to lowest value for absolute neutrophil count (ANC)
Timepoint [8] 242407 0
AE and SAEs, and laboratory test results are evaluated by the investigator at each study visit every 12 weeks
Secondary outcome [9] 242408 0
Number and percentage of patients achieving low disease activity every 12 weeks and time to low disease activity
Timepoint [9] 242408 0
Evaluated by the investigator every 12 weeks at each study visit where the investigator completes full assessments
Secondary outcome [10] 242409 0
Number and percentage of patients achieving remission every 12 weeks and time to DAS28 remission
Timepoint [10] 242409 0
Evaluated by the investigator every 12 weeks at each study visit where the investigator completes full assessments
Secondary outcome [11] 242410 0
Mean change from baseline in DAS28 over time
Timepoint [11] 242410 0
Evaluated by the investigator every 12 weeks at each study visit where the investigator completes full assessments
Secondary outcome [12] 242411 0
Mean change from baseline in individual paramaters of American College of Rheumatology (ACR) core data set over time
Timepoint [12] 242411 0
Evaluated by the investigator every 12 weeks at each study visit where the investigator completes full assessments
Secondary outcome [13] 242412 0
ACR20,50,70,90 response over time and time to response
Timepoint [13] 242412 0
Evaluated by the investigator every 12 weeks at each study visit where the investigator completes full assessments
Secondary outcome [14] 242426 0
Number and percentage of patients achieving a clinically meaningful improvement in DAS28 every 12 weeks and time to clinically meaningful improvements in DAS28
Timepoint [14] 242426 0
Evaluated by the investigator every 12 weeks at each study visit where the investigator completes full assessments
Secondary outcome [15] 242427 0
Improvement in physical functioning as measured using the Health Assessment Questionnaire (HAQ) every 12 weeks
Timepoint [15] 242427 0
Patient completes questionnaire every 12 weeks during the study
Secondary outcome [16] 242428 0
Proportion of patients achieving clinically meaningful HAQ response, defined as n improvement of at least 0.22 units from baseline of core study in the HAQ disability index every 12 weeks
Timepoint [16] 242428 0
Patient completes questionnaire every 12 weeks during the study
Secondary outcome [17] 242429 0
Improvement in Medical Outcomes Study Short Form Health Survey (SF-36) score every 12 weeks
Timepoint [17] 242429 0
Patient completes questionnaire every 12 weeks during the study
Secondary outcome [18] 242430 0
Changes in patients' fatigue assessed using the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score every 12 weeks
Timepoint [18] 242430 0
Patient completes questionnaire every 12 weeks during the study

Eligibility
Key inclusion criteria
1. Completed the 24-week MA21573 core study, had at least a moderate response (European League Against Rheumatism [EULAR] definition criteria) and no AEs, SAEs or conditions that lead to unacceptable risk of continued treatment. Patients should be scheduled to receive the first tocilizumab (TCZ) infusion in MA22460 between 4 and 16 weeks after the last iv infusion in the core study.
2. Willing to give written informed consent for participation in the extension study
3. Able and willing to comply with the requirements of the extension study protocol
Minimum age
18 Years
Maximum age
Not stated
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Disease
1. Functional class IV as defined by the ACR Classification of Functional Status in RA (largely or wholly incapacitated with patient bedridden or confined to wheel chair, permitting little or no self-care)
If female and of child-bearing potential, the patient must have a negative urine pregnancy test at day 1
Laboratory analyses (at transition from core study)
2. Serum creatinine > 142 micromol/L (1.6 mg/dL) in female patients and > 168 micromol/L (1.9 mg/dL) in male patients and no active renal disease
3. ALT or AST > 3 ULN (If initial yield ALT or AST =3 ULN, a second sample may be taken and tested)
4. Platelet count < 100 x 109/L (100,000/mm3)
5. Hemoglobin < 85 g/L (8.5 g/dL; 5.3 mmol/L)
6. WBC < 1.0 x 109/L (1000/mm3), ANC < 1 x 109/L (1000/mm3)
7. Absolute lymphocyte count < 0.5 x 109/L (500/mm3)
8. Known positive hepatitis B surface antigen or hepatitis C antibody
9. Total bilirubin > ULN (If initial sample yields bilirubin > ULN, a second sample may be taken and tested)
10. Triglycerides > 10 mmol/L (> 900 mg/dL) at inclusion in extension study

General medical
11. Treatment with any investigational agent since the last administration of study drug in the MA21573 study
12. Previous treatment with any cell depleting therapies, including investigational agents (e.g. CAMPATH, anti-CD4, anti-CD5, anti-CD3, anti-CD19 and anti-CD20) since the last administration of study drug in the MA21573 study
13. Treatment with iv gamma globulin, plasmapheresis or Prosorba (trademark) column since the last administration of study drug in the MA21573 study
14. Treatment with an anti-TNF or anti-IL1 agent, or a T-cell co-stimulation modulator or any biologic or participation in any research study since the last administration of study drug in the MA21573 study
15. Parenteral, intramuscular or intra-articular corticosteroids within 6 weeks since the last administration of study drug in the MA21573 study
16. Immunization with a live/attenuated vaccine since the last administration of study drug in the MA21573 study
17. Any previous treatment with alkylating agents such as cyclophosphamide or chlorambucil, or with total lymphoid irradiation since the last administration of study drug in the MA21573 study
18. Females of child-bearing potential who are not using a reliable means of contraception, e.g. physical barrier (patient and partner), contraceptive pill or patch, spermicide and barrier, or intrauterine device (IUD)
19. Evidence of serious uncontrolled concomitant cardiovascular, nervous system, pulmonary (including obstructive pulmonary disease), renal, hepatic, endocrine (including uncontrolled diabetes mellitus) or GI disease
20. Uncontrolled disease states, such as asthma, psoriasis or inflammatory bowel disease where flares are commonly treated with oral or parenteral corticosteroids
21. Current liver disease as determined by the investigator. Patients with prior history of ALT elevation are not excluded
22. Known active current or history of recurrent bacterial, viral, fungal, mycobacterial or other infections (including but not limited to tuberculosis and atypical mycobacterial disease, hepatitis B and C, and herpes zoster, but excluding fungal infections of nail beds), or any major episode of infection requiring hospitalization or treatment with IV antibiotics or oral antibiotics
23. History of or currently active primary or secondary immunodeficiency
24. Evidence of active malignant disease, malignancies diagnosed within the previous 5 years (including hematological malignancies and solid tumors, except non-melanoma skin cancer that has been excised and cured), or breast cancer diagnosed within the previous 5 years
25. Human immunodeficiency virus (HIV) positive patients
26. History of alcohol, drug or chemical abuse within the 24-week MA21573 core study
27. Neuropathies or other painful conditions that might interfere with pain evaluation
28. Patients with lack of peripheral venous access

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 3
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
4/03/2009
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
56
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
Recruitment postcode(s) [1] 1703 0
3220
Recruitment postcode(s) [2] 1704 0
3168
Recruitment postcode(s) [3] 1705 0
2450
Recruitment postcode(s) [4] 1706 0
2217
Recruitment postcode(s) [5] 1707 0
3065
Recruitment postcode(s) [6] 1708 0
2601
Recruitment postcode(s) [7] 1709 0
4870
Recruitment outside Australia
Country [1] 1761 0
Canada
State/province [1] 1761 0
Country [2] 1762 0
Czech Republic
State/province [2] 1762 0
Country [3] 1763 0
France
State/province [3] 1763 0
Country [4] 1764 0
Greece
State/province [4] 1764 0
Country [5] 1765 0
Hungary
State/province [5] 1765 0
Country [6] 1766 0
Ireland
State/province [6] 1766 0
Country [7] 1767 0
Italy
State/province [7] 1767 0
Country [8] 1768 0
Netherlands
State/province [8] 1768 0
Country [9] 1769 0
Poland
State/province [9] 1769 0
Country [10] 1770 0
Romania
State/province [10] 1770 0
Country [11] 1771 0
Saudi Arabia
State/province [11] 1771 0
Country [12] 1772 0
Switzerland
State/province [12] 1772 0
Country [13] 1773 0
Spain
State/province [13] 1773 0
Country [14] 1774 0
Turkey
State/province [14] 1774 0
Country [15] 1775 0
United Kingdom
State/province [15] 1775 0

Funding & Sponsors
Funding source category [1] 4959 0
Commercial sector/Industry
Name [1] 4959 0
Roche Products Pty Limited
Country [1] 4959 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Roche Products Pty Limited
Address
4 - 10 Inman Road, Dee Why, NSW, 2099
Country
Australia
Secondary sponsor category [1] 4484 0
None
Name [1] 4484 0
Address [1] 4484 0
Country [1] 4484 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 7059 0
Repatriation General Hospital Research and Ethics Committee
Ethics committee address [1] 7059 0
Ethics committee country [1] 7059 0
Australia
Date submitted for ethics approval [1] 7059 0
Approval date [1] 7059 0
03/03/2009
Ethics approval number [1] 7059 0

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 29607 0
Address 29607 0
Country 29607 0
Phone 29607 0
Fax 29607 0
Email 29607 0
Contact person for public queries
Name 12854 0
Fiona Milgrom
Address 12854 0
Roche Products Pty Ltd
4 - 10 Inman Road,
Dee Why, NSW 2099
Country 12854 0
Australia
Phone 12854 0
+61 2 9454 9558
Fax 12854 0
+61 2 9982 5269
Email 12854 0
[email protected]
Contact person for scientific queries
Name 3782 0
Fiona Milgrom
Address 3782 0
Roche Products Pty Ltd
4 - 10 Inman Road,
Dee Why, NSW 2099
Country 3782 0
Australia
Phone 3782 0
+61 2 9454 9558
Fax 3782 0
+61 2 9982 5269
Email 3782 0
[email protected]

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