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Trial registered on ANZCTR


Registration number
ACTRN12618000279224
Ethics application status
Approved
Date submitted
21/12/2017
Date registered
22/02/2018
Date last updated
22/02/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
A trial to compare alternating Brenzys® and Enbrel® versus only Enbrel® in maintaining efficacy of medication in participants with rheumatoid arthritis.
Scientific title
An Assessor-blind, randomised, parallel non-inferiority trial to compare multiple switching of Brenzys® (etanercept biosimilar) and Enbrel® (etanercept reference product) versus non-switching Enbrel® in maintaining efficacy of Enbrel® in participants with rheumatoid arthritis
Secondary ID [1] 293664 0
ER-RA2017-001
Universal Trial Number (UTN)
U1111-1206-9206
Trial acronym
MSD IIS
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Rheumatoid Arthritis 305955 0
Condition category
Condition code
Inflammatory and Immune System 305152 305152 0 0
Rheumatoid arthritis

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The study is a single blind, non-inferiority 2 parallel arm randomised controlled trial in participants with stable low disease activity rheumatoid arthritis currently on Enbrel®. Eight-eight participants (n=88, inclusive of 10% drop-out rate) will be recruited and randomised in a 1:1 allocation to (i) remaining on Enbrel® for 12 months and (ii) multiple switching according to a switching sequence for 12 months. Participants will be stratified 1:1 by co-treatment with methotrexate. Switching will be determined by randomized block allocation between retention of Enbrel and switch arms. Those on multi-switch allocation will switch open label every 2 months for a total of 5 switches over a 12 month period, with study assessments being completed by assessors blinded to treatment allocation.

Subjects will be using equipotent 50mg doses of Enbrel and Brenzys. These preparations will be self administered subcutaneously on a weekly basis and text message reminders will be sent to improve adherence. Since preparations are both etanercept, no washout period will be undertaken.



Intervention code [1] 299925 0
Treatment: Drugs
Comparator / control treatment
The control group will receive Enbrel® over the course of the study. The intervention group will switch between the etanercept biosimilar Brenzys® and the etanercept reference product Enbrel®.

Control group
Active

Outcomes
Primary outcome [1] 304304 0
The primary outcome is a measure of disease activity DAS28 which is used in trials of Rheumatoid Arthritis. DAS28 is a composite measure of 28 tender joint count, 28 swollen joint count, CRP and patient-reported VAS general health (DAS28-CRP = 0.56*SQRT(TJC28) + 0.28SQRT(SJC28) + 0.36*ln(CRP+1) + 0.014*GH + 0.96). It is a continuous measure (range 0 to 9.4 with values < 3.2 indicating low/minimal disease activity, and >=3.2 to <= 5.1 indicating moderate disease activity. A change of 1.2 is considered to be clinically significant. The non-inferiority margin in this study is 0.4 (see sample size / power).
Timepoint [1] 304304 0
12 months after Screening.
Secondary outcome [1] 341530 0
Treatment Failure defined as the rheumatologist stopping and/or changing biologic or biosimilar due to loss of efficacy or unacceptable toxicity. To account for variations along the way, loss of efficacy would be determined by both a) group loss of control as assessed by mean DAS28-ESR (Disease Activity Score-28 for Rheumatoid Arthritis with Erythrocyte Sedimentation Rate) by 0.6 and b) individual increase in DAS28-ESR score by 0.6 on three separate occasions during the follow-up period to account for the variability that we can see from time to time in these scores.
Timepoint [1] 341530 0
Measured at Screening and at 12 months from Screening.
Secondary outcome [2] 343066 0
Patient reported outcomes of physical function on the arthritis specific HAQ (Health Assessment Questionnaire).
Timepoint [2] 343066 0
Measured at Screening and at 2, 4, 6, 8,10 and 12 months from Screening.
Secondary outcome [3] 343067 0
Clinical adverse events and reactions noted through study assessments including physical exam, vital signs and laboratory assessments including full blood examination (FBE), liver function tests (LFT), urea and electrolytes (U & E).

All patients will have had a stable dose of etanercept (50mg weekly via SC injection) for at least one month prior to study commencement. Adverse events/reactions that may be experienced during the trial include cutaneous reactions and reactions and infections at injection site. These reactions will be measured by standard clinical assessments including physical exam of the injection site.
Timepoint [3] 343067 0
Measured at Screening and at 2, 4, 6, 8,10 and 12 months from Screening.
Secondary outcome [4] 343069 0
Use of rescue medication through review of concomitant medications taken during the study.
Timepoint [4] 343069 0
Measured at Screening and at 2, 4, 6, 8,10 and 12 months from Screening.
Secondary outcome [5] 343345 0
Patient reported outcomes of physical function on the generic quality of life on the SF-36 (Medical Outcome Short Form Survey).
Timepoint [5] 343345 0
Measured at Screening and at 10 and 12 months from Screening.
Secondary outcome [6] 343461 0
Changes in disease activity on DAS28 (Disease Activity Score-28 for Rheumatoid Arthritis), ESR (Erythrocyte Sedimentation Rate), hsCRP (High Sensitivity C-Reactive Protein) and PGA (Physician Global Assessment of disease activity and Participants Global Assessment of disease activity).
Timepoint [6] 343461 0
Measured at Screening and at 2, 4, 6, 8,10 and 12 months from Screening.
Secondary outcome [7] 343462 0
Change in pain levels on Visual Analogue Scale (VAS) and Tender Joint 28 Count.
Timepoint [7] 343462 0
Measured at Screening and at 2, 4, 6, 8,10 and 12 months from Screening.
Secondary outcome [8] 343463 0
Anti-drug antibody levels quantitatively measured using the Promonitor® ADA ELISA kit for Etanercept.
Timepoint [8] 343463 0
Measured at Screening and at 2, 4, 6, 8,10 and 12 months from Screening.
Secondary outcome [9] 343464 0
Falling drug trough levels across the randomised arms using the Promonitor ELISA kit for Etanercept.
Timepoint [9] 343464 0
Measured at Screening and at 2, 4, 6, 8,10 and 12 months from Screening.

Eligibility
Key inclusion criteria
Participants must meet the following criteria to be considered eligible to enrol into the study:
1) Participant must be over the age of 18 years, capable of providing informed consent and agree to attend the research centre for the required study assessments.
2) Participants must have a diagnosis of Rheumatoid Arthritis (RA), which has been stable for at least 6-months as determined by the Investigator.
3) Participants must have been treated successfully with Enbrel® for at least 6-months and meet the Medicare continuation criteria.
4) DAS28-CRP of 3.2 calculated prior to study enrolment.
5) History of a negative chest x-ray, negative Hepatitis B, C, HIV serology and Quantiferon Gold Assay prior to commencement of biologics.
6) Any conventional DMARDs at entry doses must be stable for a minimum of three months prior to study entry and remain stable throughout the study unless mandated by safety considerations.
7) At study entry the dose of Prednisone must be 10 mg/day or less, be stable for a minimum of one month prior to study entry and remain stable throughout the study unless mandated by safety considerations.
8) At study entry NSAID doses must be stable for a minimum of two weeks and remain stable throughout the study unless mandated by safety reasons.
9) Females of childbearing potential (FCBP) must have a negative pregnancy test at study entry. While taking the study product FCBP who engage in activity in which conception is possible must use one of the approved contraceptive options described below:
• Hormonal contraception (oral, injection, implant, transdermal patch, vaginal ring);
• Intrauterine device (IUD);
• Tubal Ligation; or
• Partner’s Vasectomy;
10) Male participants who have not had a vasectomy who engage in activity in which conception is possible must use barrier contraception i.e. male condom while taking the product under study.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Participants will be excluded from participating in the study if they meet any of the following exclusion criteria:
1) Change, interruption or cessation in treatment with Enbrel® during the last 6 months due to treatment related adverse events, including recent hospitalizations.
2) Women who are pregnant or breast feeding or plan to become pregnant during the course of the study.
3) Treatment with any other investigational drug or biological drug within the previous six months.
4) Not willing to return for required follow-up visits or clear demonstration of likely poor compliance.
5) Poor compliance with current biologic or with monitoring of disease activity and toxicity.
6) Any medical condition including current infections that in the judgement of the investigator would prohibit the patient from participating in the study e.g. major co-morbidities, such as severe malignancies, severe diabetic mellitus, severe infections, uncontrollable hypertension, severe cardiovascular disease (NYHA class 3 or 4) and/or severe respiratory diseases.
7) Psychiatric or mental disorders, alcohol abuse or other substance abuse.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation is not concealed.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Eight-eight participants (n=88, inclusive of 10% drop-out rate) will be recruited and randomised in a 1:1 allocation to (i) remaining on Enbrel® for 12 months, and (ii) multiple switching according to a switching sequence for 12 months. Participants will be stratified 1:1 by co-treatment with methotrexate.

Block randomisation will be used to allocate participants to one of the two study arms, the Control arm and the Treatment arm. There will be 3 random blocks generated by an independent statistician of 2, 4 and 6 participants. The blocks of 2 would contain 2 participants, one in each group in random order. The blocks of 4 participants would have 2 from each group in random order and the blocks of 6 participants would have 3 from each group in random order until 88 participants are reached.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?


The people assessing the outcomes
Intervention assignment
Parallel
Other design features
Phase
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 9634 0
Emeritus Research - Camberwell
Recruitment postcode(s) [1] 18390 0
3124 - Camberwell

Funding & Sponsors
Funding source category [1] 298284 0
Commercial sector/Industry
Name [1] 298284 0
MSD Australia
Address [1] 298284 0
Building A
26 Talavera Road
Macquarie Park NSW 2113
Country [1] 298284 0
Australia
Primary sponsor type
Hospital
Name
Emeritus Research
Address
Level 2
1180 Toorak Road
Camberwell VIC 3124
Country
Australia
Secondary sponsor category [1] 297400 0
None
Name [1] 297400 0
Address [1] 297400 0
Country [1] 297400 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 299284 0
Bellberry Ltd
Ethics committee address [1] 299284 0
129 Glen Osmond Road
Eastwood SA 5063
Ethics committee country [1] 299284 0
Australia
Date submitted for ethics approval [1] 299284 0
11/12/2017
Approval date [1] 299284 0
15/12/2017
Ethics approval number [1] 299284 0
2017-07-524

Summary
Brief summary
The overall goal of the study is to evaluate whether Enbrel® and its biosimilar Brenzys® are interchangeable in the treatment of patients with rheumatoid arthritis. That is, different sequences of Enbrel® and Brenzys® use are not associated with increased immunogenicity as evident by treatment related loss of clinical efficacy and development of treatment related clinical toxicity.

The specific aim of the study is to test whether multiple switching between the etanercept biosimilar Brenzys® and the etanercept reference product Enbrel® (the intervention group) is non-inferior with regard to disease control and clinical immunogenicity compared to no switching, that is, continuing on Enbrel® (the control group), in participants with stable rheumatoid arthritis on Enbrel® who are in clinical remission or a low disease activity state by the DAS28-CRP.
Trial website
Trial related presentations / publications
Public notes
Attachments [1] 2303 2303 0 0

Contacts
Principal investigator
Name 79906 0
Prof Stephen Hall
Address 79906 0
Emeritus Research
Level 2
1180 Toorak Road
Camberwell VIC 3124
Country 79906 0
Australia
Phone 79906 0
+61 3 9509 6166
Fax 79906 0
Email 79906 0
stephenhall@emeritusresearch.com
Contact person for public queries
Name 79907 0
Ms Michelle Nash
Address 79907 0
Emeritus Research
Level 2
1180 Toorak Road
Camberwell VIC 3124
Country 79907 0
Australia
Phone 79907 0
+61 3 9509 6166
Fax 79907 0
Email 79907 0
michellenash@emeritusresearch.com
Contact person for scientific queries
Name 79908 0
Prof Stephen Hall
Address 79908 0
Emeritus Research
Level 2
1180 Toorak Road
Camberwell VIC 3124
Country 79908 0
Australia
Phone 79908 0
+61 3 9509 6166
Fax 79908 0
Email 79908 0
stephenhall@emeritusresearch.com

No data has been provided for results reporting
Summary results
Not applicable