None listed
Conditions
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.
Interventions
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
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.
Sponsors
Griffith University
Study design
Allocation
Randomised controlled trial
Intervention model
Parallel
Primary purpose
Treatment
Masking
Blinded (masking used) (Subject, Caregiver, Outcomes Assessor)
Eligibility
Sex/Gender
All
Age
25 Years to 70 Years
Healthy volunteers
No
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
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)
Outcome results
None listed