The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers
Trial registered on ANZCTR


Registration number
ACTRN12619000257167
Ethics application status
Approved
Date submitted
15/02/2019
Date registered
20/02/2019
Date last updated
24/10/2019
Date data sharing statement initially provided
20/02/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Long term monitoring of multiple sclerosis patients on cladribine treatment
Scientific title
Cladribine: a multicenter, LOng-term efficacy and Biomarker Australian Study in patients with relapsing-remitting multiple sclerosis.
Secondary ID [1] 297343 0
Merck study ID MS700568_0090
Universal Trial Number (UTN)
U1111-1228-2165
Trial acronym
CLOBAS
Linked study record
N/A

Health condition
Health condition(s) or problem(s) studied:
Multiple Sclerosis 311459 0
Condition category
Condition code
Neurological 310099 310099 0 0
Multiple sclerosis

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The standard dose of cladribine is 3.5mg/kg body weight over 2 years, administered as 1 treatment course of 1.75mg/kg per year. Each treatment course normally consists of 2 treatment weeks, one at the beginning of the first month followed by another one 4 weeks later. Each treatment week consists of 4-5 days in which a subject receives 10 or 20 mg as a single daily dose, depending on body weight as per PBS approved dosing.

After 24 months, if there is evidence of disease activity (either clinical relapse or MRI activity) the patient will be offered either a third course of treatment (1.75mg/kg body weight, taken as 2 treatment weeks, 4 weeks apart), a switch in treatment, or no change.

Further to this, at time points baseline, 3, 7, 12, 18, 24, 36, 48, 60, 72 months and the disease activity time point (clinical deterioration - either relapse or MRI activity) bloods will be taken to assess blood based biomarkers such as Neurofilament light chain levels and lymphocyte proportions. These will be assessed at the end of the study to determine 1) if there are biomarkers for treatment efficacy and 2) if there are biomarkers that indicate the need for a third course.
Intervention code [1] 313591 0
Early detection / Screening
Intervention code [2] 313592 0
Treatment: Drugs
Comparator / control treatment
After two courses of treatment, if there is evidence of disease activity, patients will be offered a third course of cladribine or a change in treatment. The patients who switched treatment will be compared to patients who chose a third dose of cladribine to determine which patient group achieves a higher rate of NEDA 3 (No Evidence of Disease Activity).
Control group
Active

Outcomes
Primary outcome [1] 318995 0
The primary outcome is the treatment response status of patients taking cladribine tablets over 6-years according to NEDA3 (No Evidence of Disease Activity) criteria.
Timepoint [1] 318995 0
at 72 months (6 years) post-baseline.
Secondary outcome [1] 366682 0
Treatment response status of patients taking cladribine tablets over 6-years according to NEDA4 (No Evidence of Disease Activity) criteria (which includes brain volume loss).
Timepoint [1] 366682 0
72 months post-baseline
Secondary outcome [2] 366683 0
Composite secondary outcome: Biomarker analysis using whole blood flow cytometry assays to assess changes in the proportion of lymphocytes (T-cells, B-cells and natural killer (NK) cells) and the proportion of B memory cells.
Timepoint [2] 366683 0
3, 7, 12, 18, 24, 36, 48, 60, and 72 months post=baseline
Secondary outcome [3] 367092 0
Biomarker analysis using digital ELISA assays to assess changes in the concentration of serum neurofilament light chain.
Timepoint [3] 367092 0
7, 12, 18, 24, 36, and 72 months post-baseline
Secondary outcome [4] 367093 0
Exploratory outcome: Biomarker analysis using whole blood DNA methylation assays to assess genome-wide changes in DNA methylation profile
Timepoint [4] 367093 0
7, 24 and 72 months post-baseline

Eligibility
Key inclusion criteria
To be eligible for inclusion into this study, the subjects must fulfill all of the following criteria:

• Subjects must be eligible for and already intending to commence cladribine tablets in accordance with the Australian PI.
• Subjects must have the ability to understand the purpose and risks of the study, as outlined in the Patient Informed Consent Form (PICF) and provide signed and informed consent and authorization to use protected health information (PHI) in accordance with nation and local privacy regulations.
• Subjects must meet the McDonald criteria (2017) for the diagnosis of RRMS.
• Male or female subjects aged 18-70 years old
• Be able to provide details for or consent to providing access to a stored minimum dataset (ie demographics, date of diagnosis, relapse information, baseline EDSS)
• Be able and willing to comply with all study procedures, including MRI scanning as per protocol.
• Must agree to use contraception from baseline until 6 months after the last dose of cladribine tablets, unless their partners are infertile or surgically sterile.
• Subjects must be aware of all precautions listed in the PI for Mavenclad® and any subsequent DMD treatment received within this clinical study must be adhered to
Minimum age
18 Years
Maximum age
70 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
To be eligible for inclusion in this study the subjects must not meet any of the following criteria:

• Subjects must not have a concurrent diagnosis of a neurological, psychiatric or other disease which, in the opinion of the investigator, could impair capacity to provide informed consent, interfere with study assessments or impair the participant’s ability to comply with the study protocol.
• Any contra-indication to MRI scanning including:
• Cardiac pacemaker
• Cardiac defibrillator
• Metal fragments in the eye
• Any other non-MRI compatible medical device / implant or medical condition
• Severe claustrophobia
• Subjects who have any contraindication listed on the Australian PI or who have any of the listed precautions listed on the Australian PI.
• Patients who have highly active MS (defined as one relapse in the previous year and at least 1 T1Gd+ lesion or 9 or more T2 lesions, while on therapy with other DMTs. Two or more relapses in the previous year, whether on DMT treatment or not), who also have an EDSS of less than or equal to 5.0) and have not had prior exposure to drugs such as fingolimod, natalizumab, alemtuzumab, mitoxantrone and ocrelizumab.
• The Subject is considered by the Investigator, for any reason, to be an unsuitable candidate for the trial.

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
Other
Other design features
Patients who are already commencing cladribine tablets for their MS, will be eligible for the study. From 24-72 months, patients who experience clinical relapse will be offered an optional third course of cladribine tablets or a change in disease modifying treatment (DMT). At the end of the study, those who choose the optional third course will be compared to those who opted to switch to a different DMT.
Phase
Phase 3 / Phase 4
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
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)
NSW,QLD,TAS,WA,VIC
Recruitment hospital [1] 13111 0
John Hunter Hospital - New Lambton
Recruitment hospital [2] 13112 0
Box Hill Hospital - Box Hill
Recruitment hospital [3] 13113 0
Royal Melbourne Hospital - Royal Park campus - Parkville
Recruitment hospital [4] 13114 0
Royal Hobart Hospital - Hobart
Recruitment hospital [5] 13115 0
The Alfred - Prahran
Recruitment hospital [6] 13116 0
Liverpool Hospital - Liverpool
Recruitment hospital [7] 13117 0
Royal Brisbane & Womens Hospital - Herston
Recruitment hospital [8] 13118 0
The Western Australian Neuroscience Research Institute - Nedlands
Recruitment hospital [9] 13119 0
Brain and Mind Centre - University of Sydney - Camperdown
Recruitment postcode(s) [1] 25625 0
2305 - New Lambton
Recruitment postcode(s) [2] 25626 0
3128 - Box Hill
Recruitment postcode(s) [3] 25627 0
3052 - Parkville
Recruitment postcode(s) [4] 25628 0
7000 - Hobart
Recruitment postcode(s) [5] 25629 0
3004 - Prahran
Recruitment postcode(s) [6] 25630 0
2170 - Liverpool
Recruitment postcode(s) [7] 25631 0
4029 - Herston
Recruitment postcode(s) [8] 25632 0
6009 - Nedlands
Recruitment postcode(s) [9] 25633 0
2050 - Camperdown

Funding & Sponsors
Funding source category [1] 301907 0
Commercial sector/Industry
Name [1] 301907 0
Merck Serono Australia
Address [1] 301907 0
Unit 3-4, 25 Frenchs Forest Road East, Frenchs Forest, NSW, Australia, 2086
Country [1] 301907 0
Australia
Primary sponsor type
Hospital
Name
John Hunter Hospital of Hunter New England Local Health District
Address
Lookout Road, New Lambton Heights, NSW, Australia 2305
Country
Australia
Secondary sponsor category [1] 301764 0
None
Name [1] 301764 0
Address [1] 301764 0
Country [1] 301764 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 302595 0
Hunter New England Human Research Ethics Committee
Ethics committee address [1] 302595 0
Hunter New England Research Ethics and Governance office
Locked Bag No 1
HRMC, NSW
2310
Ethics committee country [1] 302595 0
Australia
Date submitted for ethics approval [1] 302595 0
02/10/2018
Approval date [1] 302595 0
08/11/2018
Ethics approval number [1] 302595 0
18/10/17/3.04

Summary
Brief summary
Multiple sclerosis (MS) is the most common non-traumatic neurological disorder that affects young adults. Cladribine tablets (Mavenclad®) is a new oral therapy for MS. The current dosing for cladribine tablets is 2 courses given one year apart. This has been shown to be effective in reducing relapses in 75% of patients for up to 4 years (based on annualised relapse rate). However, re-initiation of treatment after year 4 has not been studied.
This will be a multicenter, 6-year, phase IV, low interventional trial. Subjects meeting the eligibility criteria will receive an initial treatment course in year 1 and a continuing treatment course in year 2. After 3 years, patients will have the option for re-initiation of treatment, if clinically indicated or the option to switch to another disease modifying therapy (DMT). This study is testing the hypothesis that patients who receive an additional course of cladribine tablets will experience less disease activity than those who chose to change DMT.

During the study we will evaluate blood-based molecules called biomarkers, brain scans and brain function tests. At the end of the study, we will use the results of these tests to determine if there are ways to decide if re-initiation of treatment after the initial 2-year course is appropriate. This may be one test or a combination of several tests. In addition, we determine if these biomarkers can be used at onset of disease to determine if patients will respond to cladribine therapy before they start.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 90762 0
Prof Jeannette Lechner-Scott
Address 90762 0
Department of Neurology
John Hunter Hospital
Locked Bag 1
Hunter Region Mail Centre, NSW
2310
Country 90762 0
Australia
Phone 90762 0
+61249213540
Fax 90762 0
Email 90762 0
jeannette.lechner-scott@hnehealth.nsw.gov.au
Contact person for public queries
Name 90763 0
Prof Jeannette Lechner-Scott
Address 90763 0
Department of Neurology
John Hunter Hospital
Locked Bag 1
Hunter Region Mail Centre, NSW
2310
Country 90763 0
Australia
Phone 90763 0
+61249213540
Fax 90763 0
Email 90763 0
jeannette.lechner-scott@hnehealth.nsw.gov.au
Contact person for scientific queries
Name 90764 0
Dr Vicki Maltby
Address 90764 0
Department of Neurology
John Hunter Hospital
Locked Bag 1
Hunter Region Mail Centre, NSW
2310
Country 90764 0
Australia
Phone 90764 0
+61240420286
Fax 90764 0
Email 90764 0
vicki.e.maltby@newcastle.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
IPD will be loaded to MSBase and will only be made available upon request to the study investigators at the conclusion of the study
What supporting documents are/will be available?
No other documents available
Summary results
No Results