ANZCTR - Registration

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Trial registered on ANZCTR

Registration number

ACTRN12621001502820

Ethics application status

Approved

Date submitted

27/09/2021

Date registered

4/11/2021

Date last updated

13/04/2024

Date data sharing statement initially provided

4/11/2021

Type of registration

Prospectively registered

Titles & IDs

Public title

Reducing the frequency of Autoimmune adverse events in the treatment of Multiple sclerosis with alemtuzumab using B-celL dEpletion (RAMBLE): a phase II, randomised, placebo-controlled clinical trial.

Scientific title

Reducing the frequency of Autoimmune adverse events in the treatment of Multiple sclerosis with alemtuzumab using B-celL dEpletion (RAMBLE): a phase II, randomised, placebo-controlled clinical trial.

Secondary ID [1]

nil

Universal Trial Number (UTN)

N/A

Trial acronym

RAMBLE

Linked study record

N/A

Health condition

Health condition(s) or problem(s) studied:

Multiple Sclerosis

Condition category

Condition code

Neurological

Multiple sclerosis

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

The investigational product is rituximab, which is a monoclonal antibody against CD20 that cause lysis of B-lymphocytes. The antibody is a humanised mouse antibody and is administered intravenously via an infusion over 30 minutes. The dosage to be used is 100 mg/m2 of estimated body surface area (BSA). BSA will be estimated based on height and weight according to the Du Bois formula.

Arm 1: Intervention
Arm 2: Placebo

Intervention code [1]

Treatment: Drugs

Comparator / control treatment

Placebo will be 0.9% sodium chloride, which as a colourless solution is indistinguishable from diluted rituximab

Control group

Placebo

Outcomes

Primary outcome [1]

Frequency of autoimmune adverse events (time to event)

Assessed via Monitoring visits , MRI scans, blood tests, liver function tests and urine tests

Timepoint [1]

Time point: at 3 years post trial commencement (31/12/2024)

Monitoring Visits (every 6 months) intercurrent illness, relapse history and concomitant medications, EDSS change, MSIS-29 change

MRI every 12 months - Looking for Number of new T2 MRI brain lesions, Number of new Gd-enhancing lesions

FBC/lymphocyte subsets – lymphocyte subsets will be performed at weeks -1, 4, 9, 13, 26, 35, 50, 57, 61, 65, 78, 83 and 104. - B cell subpopulation counts at theses times

Secondary outcome [1]

To assess the safety and efficacy (MS disease activity related) of this therapeutic approach.
To assess the profile of the immune repertoire of T and B-cells that re-emerge with this therapeutic approach. Assessed via Monitoring visits , MRI scans, blood tests, liver function tests and urine tests

Timepoint [1]

Eligibility

Key inclusion criteria

- Diagnosed with relapsing remitting MS (RRMS) by a neurologist
- Diagnosis of MS meeting 2017 McDonald criteria
- Diagnosed with MS within the previous 10 years
-Expanded disability status scale (EDSS)15 score < 5.0
-English speaking or non-English speaking who can ensure external interpreter assistance (e.g. relative or friend) to attend all visits for the duration of the clinical trial.
-Available to attend clinic visits
-Willing to sign up for and comply with Bloodwatch monitoring program

Minimum age

18 Years

Maximum age

55 Years

Sex

Both males and females

Can healthy volunteers participate?

Key exclusion criteria

-Known or suspected prior autoimmune disease (other than MS)
-Any other serious co-morbidity that in the view of the investigator would preclude participation in the study
- Pregnant (if female)
- Currently lactating (if female)
-Unwilling or unable to use appropriate contraception for the treatment phase of the study (2 years) – male or female
-Recent or current history of major depression, bipolar disorder, psychosis or suicidality
-Currently or recently taking any illicit substances (including any cannabis product)
-Allergy to valaciclovir
-Allergy to Bactrim, Trimethoprim or Sulphur based antibiotics

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)

At the screening visit, participants will be assigned a unique participant Screening Number. At the baseline/enrolment visit, after eligibility is confirmed and the full consent form has been signed, a Participant Identification Number (PIDN) will be assigned. PIDNs will be randomly assigned to intervention or placebo groups according to the randomisation code provided to the pharmacy. Randomisation codes will only be visible to site pharmacists who will make up the active treatment and placebo.

Methods used to generate the sequence in which subjects will be randomised (sequence generation)

Participants will be randomised at enrolment to treatment with rituximab or placebo at a 2:1 ratio. Randomisation will be performed using the ranomisation module of the REDCap database based on a random number sequence produced in Excel®, Microsoft (Seattle, CA, USA) stratified by site, sex and age. This randomization sheet will be generated by Assoc/Prof Jing Sun. There will a cap of 20 participants for any single site.

Masking / blinding

Blinded (masking used)

Who is / are masked / blinded?

The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes

Intervention assignment

Parallel

Other design features

Phase

Phase 2 / Phase 3

Type of endpoint/s

Safety/efficacy

Statistical methods / analysis

The two groups will be compared using a Cox Proportional Hazards time to event analysis (with onset of autoimmune adverse event as the event of interest). An intention to treat method incorporating any potential confounders identified as having a significant impact on this outcome to confirm any findings are not due to random or stratified bias in baseline parameters will be used. Other adverse events will be compared using frequencies and chi-squared statistics where relevant. Efficacy in terms of MS outcomes will be analysed using time to event analysis (Cox Proportional Hazards method) for annualized relapse rate and sustained disability progression (6 months). Other secondary outcomes (e.g. change in EDSS, new T2 and Gd-enhancing MR imaging lesions) will be assessed using appropriate non-parametric statistics. Any effect of laboratory measures (lymphocyte subsets, vitamin D levels) and baseline characteristics will be explored using appropriate single and multivariable statistics. All statistical analyses will be conducted using STATA® v16 software .

Recruitment

Recruitment status

Recruiting

Date of first participant enrolment

Anticipated

1/01/2022

Actual

3/05/2022

Date of last participant enrolment

Anticipated

31/12/2024

Actual

Date of last data collection

Anticipated

31/12/2026

Actual

Sample size

Target

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

QLD

Recruitment hospital [1]

Gold Coast University Hospital - Southport

Recruitment hospital [2]

Princess Alexandra Hospital - Woolloongabba

Recruitment hospital [3]

Sunshine Coast University Hospital - Birtinya

Recruitment hospital [4]

Townsville University Hospital - Douglas

Recruitment hospital [5]

Mater Private Hospital - South Brisbane

Recruitment hospital [6]

Royal Brisbane & Womens Hospital - Herston

Recruitment postcode(s) [1]

4215 - Southport

Recruitment postcode(s) [2]

4102 - Woolloongabba

Recruitment postcode(s) [3]

4575 - Birtinya

Recruitment postcode(s) [4]

4814 - Douglas

Recruitment postcode(s) [5]

4101 - South Brisbane

Recruitment postcode(s) [6]

4029 - Herston

Funding & Sponsors

Funding source category [1]

Charities/Societies/Foundations

Name [1]

Brazil Family Foundation

Address [1]

77 Anchorfield Rd
Condamine Plains QLD 4352
Australia

Country [1]

Australia

Primary sponsor type

University

Name

Griffith University

Address

1 Parklands Dr
Gold Cost Campus
Griffith University QLD 4111
Australia

Country

Australia

Secondary sponsor category [1]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Griffth University Human Research Ethics Committee

Ethics committee address [1]

170 Kessels Rd
Nathan Campus
Griffith University
 QLD 4111

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

27/09/2021

Approval date [1]

31/01/2022

Ethics approval number [1]

HREC/2021/QGC/75077

Summary

Brief summary

To reduce the occurrence of autoimmune adverse events from the treatment of multiple sclerosis (MS) with alemtuzumab through the subsequent targeted use of rituximab. The hypothesis to be tested is that rituximab therapy following alemtuzumab treatment for MS will reduce the frequency of autoimmune adverse events.

If this strategy proves to be safe and is effective in preventing or significantly reducing the frequency of autoimmune adverse events in the treatment of MS with alemtuzumab, then this approach could be adopted immediately in a large number of pwMS with an immediate reduction in co-morbidity.

Trial website

N/A

Trial related presentations / publications

N/A

Public notes

N/A

Contacts

Principal investigator

Name

Prof Simon Broadley

Address

School of Medicine and Dentistry
Gold Coast Campus
Griffith University QLD 4222

Country

Australia

Phone

+61 07 5678 0174

Fax

simon.broadley@griffith.edu.au

Contact person for public queries

Name

Simon Broadley

Address

School of Medicine and Dentistry
Gold Coast Campus
Griffith University QLD 4222

Country

Australia

Phone

+61 07 5678 0174

Fax

simon.broadley@griffith.edu.au

Contact person for scientific queries

Name

Simon Broadley

Address

School of Medicine and Dentistry
Gold Coast Campus
Griffith University QLD 4222

Country

Australia

Phone

+61 07 5678 0174

Fax

simon.broadley@griffith.edu.au

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

Yes

What data in particular will be shared?

Individual participant data can be made available on request to the principal investigator and subject to approval by the Griffith University Human Research Ethics Committee.

When will data be available (start and end dates)?

After completion of the study (31/12/2026) and for a period of 15 years thereafter.

Available to whom?

Appropriately qualified researchers as judged by the principal investigator and Griffith University Human Research Ethics Committee

Available for what types of analyses?

Appropriate secondary analyses

How or where can data be obtained?

By direct approach to the principal investigator

Simon Broadley
Professor of Neurology
School of Medicine
Gold Coast Campus
Griffith University QLD 4222
AUSTRALIA
Tel: +61 7 5678 0174
Fax: +61 7 5678 0303
simon.broadley@griffith.edu.au

What supporting documents are/will be available?

Doc. No.	Type	Citation	Link	Email	Other Details	Attachment
13377	Study protocol					382809-(Uploaded-21-02-2024-17-42-33)-Study-related document.pdf

Results publications and other study-related documents

Documents added manually

No documents have been uploaded by study researchers.

Documents added automatically

No additional documents have been identified.

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