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Trial registered on ANZCTR


Registration number
ACTRN12623000849695
Ethics application status
Approved
Date submitted
29/06/2023
Date registered
8/08/2023
Date last updated
25/08/2024
Date data sharing statement initially provided
8/08/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
Clinical trial of anti-Epstein-Barr virus therapies for the prevention of progression in multiple sclerosis
Scientific title
Phase III, multicentre, randomised, double-blinded, placebo-controlled, multi-arm, multi-stage (MAMS) trial of SpironolacTone and famciclOvir in the treatment of Progressive multiple sclerosis (MS) to prevent disability progression (STOP-MS)
Secondary ID [1] 310016 0
Nil known
Universal Trial Number (UTN)
U1111-1293-1787
Trial acronym
STOP-MS
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Multiple sclerosis 330521 0
Condition category
Condition code
Neurological 327374 327374 0 0
Multiple sclerosis

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Arm 1. Spironolactone 25 mg twice daily, oral tablets (overencapsulated) for 4 weeks
then, subject to safety review, increased to Spironolactone 50 mg twice daily, oral tablets (overencapsulated) thereafter.
Arm 2. Famciclovir 250 mg twice daily, oral tablets (overencapsulated) for 4 weeks then, subject to safety review, increased to Famciclovir 500 mg twice daily, oral tablets (overencapsulated) thereafter.
Stage 1 - 6 months treatment
Stage 2 - 3 years treatment
Once recruitment for Stage 1 is completed (n=150), enrolment into Stage 1 will continue into the same two treatment arms plus placebo, but there will be no requirement for salivary testing for EBV DNA.
Once stage 1 is completed and analysed the better performing treatment arm will be selected for randomisation in Stage 2 according to the criteria below. Participants from Stage 1 in the selected (successful) treatment arm and placebo arm (without unblinding) will continue automatically into Stage 2. Particpants in the unsuccessful arm will be halted.
Minimum criteria for consideration of progression to stage 2 will be a 10% reduction in mean salivary EBV DNA detection frequency or mean EBNA1 titre. The agent associated with the greatest change in these parameters will be selected for progression to stage 2. If this outcome is not achieved for either treatment then the trial will be abandoned.
Participants enrolled to the discontinued arm of Stage 1 will be invited to enrol into Stage 2 after a washout period of 4 weeks.
Compliance will be monitored by pill counts of dispensed bottles every 6 months.
Intervention code [1] 326436 0
Treatment: Drugs
Comparator / control treatment
Placebo - matched cellulose capsules, 1 capsule twice daily, oral for both Stage 1 and Stage 2
Stage 1 - 6 months treatment
Stage 2 - mean of 3 years treatment (range 2 -4 years)
Control group
Placebo

Outcomes
Primary outcome [1] 335238 0
Stage 1 - Co-primary endopoint of frequency of salivery EBV DNA detection in monthly samples and serum EBNA1 antibody titres in serum
Timepoint [1] 335238 0
Stage 1 - 6 months post-commencement of intervention
Primary outcome [2] 335312 0
Stage 2 - Time to 6 month confirmed disability progression (CDP) using a composite of expanded disability status scale (EDSS), Timed 25-Foot Walk (T25FW) and 9-Hole Pet Test (9-HPT)
Timepoint [2] 335312 0
Stage 2 - Time to event analysis, with mean follow up of 3 years post-commencement of intervention (assessed every 6 months for the duration of the study for up to 5 years post-commencement of the study)
Secondary outcome [1] 423605 0
Time to first relapse - assessed clinically as new neurological symptoms lasting more than 24 hours in the absences of fever or other signs of infection and associated with a worsening of EDSS or a worsening of a single EDSS functional scale (excepting fatigue) or new active lesions on MRI in an anatomical location relevant to the symptoms
Timepoint [1] 423605 0
Time to event analysis with mean follow up of 3 years post-commencement of intervention (assessed either when reported by the participant or at 3 monthly alternating telephone/in-person reviews)
Secondary outcome [2] 423869 0
Time to 6 month CPD - based on EDSS alone
Timepoint [2] 423869 0
Time to event analysis with mean follow up of 3 years post-commencement of intervention (assessed every 6 months up to 5 years post-commencement of intervention)
Secondary outcome [3] 423870 0
Multiple sclerosis functional composite (MSFC) Score
Timepoint [3] 423870 0
Stage 2 - assessed at 2 and 3 years post-commencement of intervention
Secondary outcome [4] 423871 0
Timed 25-Foot Walk - mobility outcome
Timepoint [4] 423871 0
Stage 2 - assessed at 2 and 3 years post-commencement of intervention
Secondary outcome [5] 423872 0
9-Hole Peg Test - upper limb/hand dexterity measure
Timepoint [5] 423872 0
Stage 2 - assessed at 2 and 3 years post-commencement of intervention
Secondary outcome [6] 423873 0
Multiple sclerosis impact scale-29 (MSIS-29)
Timepoint [6] 423873 0
Stage 2 - assessed at 2 and 3 years post-commencement of intervention
Secondary outcome [7] 423874 0
Multiple sclerosis walking scale-12 (MSWS-12)
Timepoint [7] 423874 0
Stage 2 - assessed at 2 and 3 years post-commencement of intervention
Secondary outcome [8] 423875 0
Neuropathic pain scale (NPS)
Timepoint [8] 423875 0
Stage 2 - assessed at 2 and 3 years post-commencement of intervention
Secondary outcome [9] 423876 0
Modified fatigue impact scale (MFIS)
Timepoint [9] 423876 0
Stage 2 - assessed at 2 and 3 years post-commencement of intervention
Secondary outcome [10] 423877 0
EuroQol, 5 Domains, 5 Levels (EQ-5D-5L) - quality of life, health status and economic impact measure
Timepoint [10] 423877 0
Stage 2 - assessed at 2 and 3 years post-commencement of intervention

Eligibility
Key inclusion criteria
• Age 25-70 years (inclusive)
• Diagnosed with primary or secondary progressive MS according to McDonald 2017 criteria
• EDSS of 4.0 – 8.0 (inclusive) at the time of randomisation
• Evidence of disability progression over the previous 24 months
• English speaking or non-English speaking but 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
Minimum age
25 Years
Maximum age
70 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
• A clinical relapse within 3 months of randomisation
• A significant co-morbidity that in the opinion of the principal investigator (PI) would negatively affect MS disease outcomes or preclude administration of spironolactone or famciclovir (including renal failure; estimated glomerular filtration rate < 30ml/min)
• Hypersensitivity to spironolactone or famciclovir
• Pregnant (if female)
• Currently breast feeding (if female)
• Have received treatment with steroids (intravenous and/or oral) for MS relapse/progression within 3 months before randomisation
• Have received any trial therapy within the last 6 months (other than as part of the STOP-MS Stage 1 trial)
• Unwilling or unable to use appropriate contraception for the treatment phase of the study (Up to 3 years) – if female
• Recent or current history of major depression, bipolar disorder, psychosis or suicidality
• Currently or recently taking any illicit substances (including any cannabis product)

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)
Randomisation by computer
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Permuted block randomisation
Blocks stratified by Age (3 bands), Sex (2 bands) and 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
This is a multi-arm, multi-stage trial. In Stage 1 there will be 3 arms (2 active and 1 placebo) randomly allocated 1:1:1. The most successful active arm in Stage 1 will proceed to Stage 2 where there will be just 2 arms (1 active and 1 placebo). Participants in Stage 1 will continue to be recruited and will roll into Stage 2 as soon as the outcome of Stage 1 is determined. The outcomes in Stage 1 are measures of EBV activity, whilst those for Stage 2 are clinical.
Phase
Phase 3
Type of endpoint/s
Efficacy
Statistical methods / analysis
Stage 1
We will use linear regression analysis with appropriate transformation of data and inclusion of potential confounders (e.g. age, sex, DMT, baseline EDSS) to compare mean salivary EBV DNA detection and mean EBNA1 titres between treatment arms.
Minimum criteria for consideration of progression to stage 2 will be a 10% reduction in mean salivary EBV DNA detection frequency or mean EBNA1 titre. The agent associated with the greatest change in these parameters will be selected for progression to stage 2.
Stage 2
The primary analysis will be a Cox-proportional hazards analysis of cumulative hazard of 6m CDP adjusted for potential residual imbalance at baseline for age, sex, DMT and disability level. Secondary outcome measures will be analysed with Cox (or accelerated failure time) models and mixed generalised regression models. Analyses will be conducted on an intention to treat basis. Observations will be censored upon leaving the trial for participants without an event, including for those who have withdrawn from the trial, been lost to follow-up, or who have died due to causes other than MS. Death due to MS (EDSS10) will count as 6-month CDP. Sensitivity analyses will investigate the per-protocol treatment exposure to assess the impact of non-compliance.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
30/09/2024
Actual
Date of last participant enrolment
Anticipated
30/08/2027
Actual
Date of last data collection
Anticipated
30/06/2029
Actual
Sample size
Target
350
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,TAS,WA,VIC
Recruitment hospital [1] 25019 0
Gold Coast University Hospital - Southport
Recruitment hospital [2] 25020 0
Royal Brisbane & Womens Hospital - Herston
Recruitment hospital [3] 25021 0
Princess Alexandra Hospital - Woolloongabba
Recruitment hospital [4] 25022 0
Mater Hospital Brisbane - South Brisbane
Recruitment hospital [5] 25023 0
Sunshine Coast University Hospital - Birtinya
Recruitment hospital [6] 25024 0
Royal Hobart Hospital - Hobart
Recruitment hospital [7] 25025 0
Brain and Mind Centre - University of Sydney - Camperdown
Recruitment hospital [8] 25026 0
Concord Private Hospital - Concord
Recruitment hospital [9] 25027 0
St Vincent's Hospital (Darlinghurst) - Darlinghurst
Recruitment hospital [10] 25028 0
Royal North Shore Hospital - St Leonards
Recruitment hospital [11] 25029 0
Westmead Hospital - Westmead
Recruitment hospital [12] 25030 0
Liverpool Hospital - Liverpool
Recruitment hospital [13] 25031 0
John Hunter Hospital - New Lambton
Recruitment hospital [14] 25033 0
Royal Melbourne Hospital - City campus - Parkville
Recruitment hospital [15] 25034 0
Monash Medical Centre - Clayton campus - Clayton
Recruitment hospital [16] 25035 0
The Alfred - Melbourne
Recruitment hospital [17] 25036 0
Box Hill Hospital - Box Hill
Recruitment hospital [18] 25037 0
Flinders Medical Centre - Bedford Park
Recruitment hospital [19] 25038 0
Perron Institute for Neurological and Translational Science - Nedlands
Recruitment postcode(s) [1] 40678 0
4215 - Southport
Recruitment postcode(s) [2] 40679 0
4029 - Herston
Recruitment postcode(s) [3] 40680 0
4102 - Woolloongabba
Recruitment postcode(s) [4] 40681 0
4101 - South Brisbane
Recruitment postcode(s) [5] 40682 0
4575 - Birtinya
Recruitment postcode(s) [6] 40683 0
7000 - Hobart
Recruitment postcode(s) [7] 40684 0
2050 - Camperdown
Recruitment postcode(s) [8] 40685 0
2137 - Concord
Recruitment postcode(s) [9] 40686 0
2010 - Darlinghurst
Recruitment postcode(s) [10] 40687 0
2065 - St Leonards
Recruitment postcode(s) [11] 40688 0
2145 - Westmead
Recruitment postcode(s) [12] 40689 0
2170 - Liverpool
Recruitment postcode(s) [13] 40690 0
2305 - New Lambton
Recruitment postcode(s) [14] 40692 0
3050 - Parkville
Recruitment postcode(s) [15] 40693 0
3168 - Clayton
Recruitment postcode(s) [16] 40694 0
3004 - Melbourne
Recruitment postcode(s) [17] 40695 0
3128 - Box Hill
Recruitment postcode(s) [18] 40696 0
5042 - Bedford Park
Recruitment postcode(s) [19] 40697 0
6009 - Nedlands

Funding & Sponsors
Funding source category [1] 314193 0
Government body
Name [1] 314193 0
Department of Health and Aged Care, Medical Research Future Fund
Country [1] 314193 0
Australia
Primary sponsor type
University
Name
Griffith University
Address
Griffith University
170 Kessels Road
Nathan Qld 4111
Country
Australia
Secondary sponsor category [1] 316112 0
None
Name [1] 316112 0
.
Address [1] 316112 0
.
Country [1] 316112 0
Other collaborator category [1] 282727 0
Charities/Societies/Foundations
Name [1] 282727 0
Multiple Sclereosis Australia
Address [1] 282727 0
Head Office Level 19
Northpoint, 100 Miller Street
North Sydney NSW 2060
Country [1] 282727 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 313320 0
Gold Coast Hopsital and Health Service Human Research Ethics Committee
Ethics committee address [1] 313320 0
GCH-HREC
Level 2, E Block
Gold Coast University Hospital
1 Hospital Boulevard
Southport QLD 4215
Ethics committee country [1] 313320 0
Australia
Date submitted for ethics approval [1] 313320 0
31/08/2023
Approval date [1] 313320 0
13/03/2024
Ethics approval number [1] 313320 0
HREC/2023/QGC/101052

Summary
Brief summary
Multiple sclerosis (MS) is a potentially devastating disease of the central nervous system and progressive MS, which occurs in up to two-thirds is the most severe form. Current therapies for MS have limited effect in the progressive stage. Recent studies have confirmed that the primary cause of MS is latent infection with Epstein-Barr virus (EBV). We have conducted a systematic review of existing drugs with potential anti-EBV effects. Through an internationally peer reviewed process we have selected two promising agents with known acceptable safety profiles and proven efficacy against EBV. In order to maximise efficiency to find the best such treatment we have partnered with experts in the UK in designing a state of the art trial to test these agents in progressive MS. We propose to run an innovative adaptive phase III clinical trial to evaluate the effectiveness of promising anti-EBV therapies for progressive MS by repurposing old drugs (Spironolactone and Famciclovir) for a new indication. In stage 1 we will compare the effect of the two agents against dummy-treatment (placebo) in their ability to reduce antibodies to EBV and the amount of EBV shed in saliva in relatively small numbers (total 150) over 6 months. The agent that produces the largest reduction in these measures will then progress to state 2, where the clinical effectiveness of this treatment will be compared to placebo over a period of 3 years in a larger group (total 300). This study will facilitate the participation of Australians with progressive MS in a novel trial of anti-EBV therapies. If the outcomes of this study are positive then the impacts would be immense. It has been noted that the lack of treatment for progressive forms of MS is the single greatest unmet need for people with MS. The advent of an effective therapy to prevent further progression or even improvement would be a huge step forward. There would be similar implications for the wider MS community.
Trial website
Trial related presentations / publications
Public notes
The Epstein-Barr virus that causes glandular fever has recently been identified as the likely primary cause of multiple sclerosis. Progressive forms of multiple sclerosis can have significant impact on quality of life and are currently hard to treat. We have selected two potential anti-EBV therapies (spironolactone and famciclovir) to test in an innovative multi-stage, multi-arm trial in order to identify the best treatment for progressive MS. Treatments will be compared to dummy-treatment.

Contacts
Principal investigator
Name 127726 0
Prof Simon Broadley
Address 127726 0
School of Medicine and Dentistry
Gold Coast Campus
Griffith University QLD 4222
Country 127726 0
Australia
Phone 127726 0
+61 7 5678 0174
Fax 127726 0
+61 7 5678 0303
Email 127726 0
[email protected]
Contact person for public queries
Name 127727 0
Fiona McKay
Address 127727 0
Multiple Sclerosis Australia, Suite 3.01, 18 Flour Mill Way, Summer Hill NSW 2130
Country 127727 0
Australia
Phone 127727 0
+61 2 8413 7922
Fax 127727 0
Email 127727 0
[email protected]
Contact person for scientific queries
Name 127728 0
Fiona McKay
Address 127728 0
Multiple Sclerosis Australia, Suite 3.01, 18 Flour Mill Way, Summer Hill NSW 2130
Country 127728 0
Australia
Phone 127728 0
+61 2 8413 7922
Fax 127728 0
Email 127728 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
Baseline demographic data
Primary outcome measure data for Stage 1 and 2
When will data be available (start and end dates)?
When all primary analyses have been completed (approx. 1/1/2029) until 15 years after the completion of the trial (approx. 31/12/2043)
Available to whom?
Any suitably qualified researchers subject to submission of a brief proposal and HREC approval
Available for what types of analyses?
To be determined on a case-by-case basis in conjunction with HREC review
How or where can data be obtained?
From the Coordinating Principal Investigator
[email protected]


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
24119Study protocol    v2.0 Amendment 1 386167-(Uploaded-21-08-2024-16-08-13)-STOP-MS Trial Protocol v2.0 Amend 1 - 2024-06-10 Approved signed.pdf



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