Clinical trial NCT00666887: Minocycline in Clinically Isolated Syndromes (CIS)
Official title: A Phase III Double-blind, Randomized, Placebo-controlled Trial of Minocycline in Clinically Isolated Syndromes (CIS) and Early Single Relapse Multiple Sclerosis (MS)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Clinically Isolated Syndromes
Early Single Relapse of Multiple Sclerosis
Keywords: Multiple Sclerosis
Clinically Isolated Syndrome
Minocycline
Placebo
Lead sponsor: University of Calgary
Sponsor class: OTHER
Collaborators: name: Multiple Sclerosis Society of Canada
First posted: 2008-04-25
Enrollment: 142
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: The aim of the trial is to demonstrate that 100 mg of oral minocycline twice daily reduces the conversion of CIS to McDonald Criteria MS (McDMS) by an absolute 25% as compared to placebo, over a 6 month follow-up period (primary outcome).

A key secondary outcome is to confirm that this early treatment benefit is maintained at two years.

Detailed description: * Minocycline 100 mg bid orally compared to identical placebo
* Clinically Isolated Syndrome (CIS): Patients with a first clinical demyelinating event suggestive of multiple sclerosis (At baseline participants may meet 2010 McDonald diagnostic criteria for MS, but not 2005 criteria)
* Men and women, aged 18-60y, first event within the previous 180 days; brain magnetic resonance imaging (MRI) with at least two brain T2 lesions which are at least 3 mm in diameter, and at least one of which is ovoid or periventricular or infratentorial.
* Up to 24 months of study drug (Up to 12 months of study drug for patients recruited after December 31, 2012)
* Patients will be discontinued from the study when they convert to McDMS based on the 2005 McDonald definition.
* 12 Canadian MS Clinics
* A total of 154 patients will be randomized. Because 30% of screened patients with CIS who are clinically eligible are not expected to meet the MRI criteria for inclusion, up to 280 patients will be screened.

Eligibility criteria: Inclusion Criteria:

* Age between 18 and 60 years.
* First focal clinical episode suggestive of demyelinating disease within the previous 180 days (measured from onset of the first symptom to treatment start), based on the appearance of a neurological abnormality, present for at least 24 hours.
* Objective clinical evidence must be present or documented. Patients will be included irrespective of whether the first clinical demyelinating episode was monosymptomatic (i.e. clinical evidence of a single lesion) or polysymptomatic (i.e. clinical evidence of more than one lesion).
* At least two lesions on the T2-weighted brain MRI\* scan at least one of which is ovoid or periventricular or infratentorial. MRI eligibility will be determined centrally by the UBC MS/MRI Research Group.\*One lesion on spinal MRI may substitute for one brain lesion as per the 2005 McDonald Criteria.
* Sexually active women of child-bearing potential must agree to use adequate contraception.
* Written informed consent

Exclusion Criteria:

* Any disease other than MS that could better explain the patient's signs and symptoms.
* Any previous clinical event reasonably attributable to acute demyelination, regardless of whether medical attention was obtained.
* Complete transverse myelitis or bilateral optic neuritis. A waiver can be obtained for bilateral optic neuritis but must be obtained prior to randomization. Waivers must be approved by 3 neurologists including a member of the Clinical Eligibility / Endpoint Committee, a member of the DSMC, and by an experienced MS neurophthalmologist.

Primary outcomes:
measure: To demonstrate that 100 mg of oral minocycline twice daily reduces the conversion of CIS to McDonald Criteria MS (McDMS) by an absolute 25% as compared to placebo, over a 6 month follow-up period.
timeFrame: 6 Months
Secondary outcomes:
measure: To confirm that this early treatment benefit is maintained at two years.
timeFrame: 2 years
measure: Change in T2 lesion volume
timeFrame: 6 months and 24 months
measure: Cumulative number of enhancing T1 lesions
timeFrame: 6 months and 24 months
measure: cumulative combined unique lesions (new enhancing T1-weighted lesions plus new and enlarging T2 lesions, without lesion double counting)
timeFrame: 6 months and 24 months
Other outcomes:
Locations:
city: Calgary
country: Canada
facility: University of Calgary, Calgary Health Region
state: Alberta
city: Edmonton
country: Canada
facility: University of Alberta
state: Alberta
city: Burnaby
country: Canada
facility: Fraser Health Multiple Sclerosis Clinic
state: British Columbia
city: Vancouver
country: Canada
facility: UBC Hospital
state: British Columbia
city: Winnipeg
country: Canada
facility: MS Research Unit, Health Sciences Centre
state: Manitoba
city: Halifax
country: Canada
facility: Dalhousie MS Research Unit
state: Nova Scotia
city: London
country: Canada
facility: MS Clinic, London Health Sciences Centre
state: Ontario
city: Ottawa
country: Canada
facility: The Ottawa Hospital, Multiple Sclerosis Research Clinic
state: Ontario
city: Toronto
country: Canada
facility: Sunnybrook Health Sciences Centre
state: Ontario
city: Greenfield Park
country: Canada
facility: Clinique Neuro Rive-Sud
state: Quebec
city: Montreal
country: Canada
facility: CHUM Notre-Dame
state: Quebec
city: Quebec City
country: Canada
facility: CHAUQ Enfant-Jesus
state: Quebec
Study officials:
affiliation: University of Calgary
name: Luanne Metz, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Camara-Lemarroy C, Metz L, Kuhle J, Leppert D, Willemse E, Li DK, Traboulsee A, Greenfield J, Cerchiaro G, Silva C, Yong VW. Minocycline treatment in clinically isolated syndrome and serum NfL, GFAP, and metalloproteinase levels. Mult Scler. 2022 Nov;28(13):2081-2089. doi: 10.1177/13524585221109761. Epub 2022 Jul 18.
citation: Metz LM, Li DKB, Traboulsee AL, Duquette P, Eliasziw M, Cerchiaro G, Greenfield J, Riddehough A, Yeung M, Kremenchutzky M, Vorobeychik G, Freedman MS, Bhan V, Blevins G, Marriott JJ, Grand'Maison F, Lee L, Thibault M, Hill MD, Yong VW; Minocycline in MS Study Team. Trial of Minocycline in a Clinically Isolated Syndrome of Multiple Sclerosis. N Engl J Med. 2017 Jun 1;376(22):2122-2133. doi: 10.1056/NEJMoa1608889.
citation: Kang H, Metz LM, Traboulsee AL, Eliasziw M, Zhao GJ, Cheng Y, Zhao Y, Li DK; Minocycline in CIS Study Group. Application and a proposed modification of the 2010 McDonald criteria for the diagnosis of multiple sclerosis in a Canadian cohort of patients with clinically isolated syndromes. Mult Scler. 2014 Apr;20(4):458-63. doi: 10.1177/1352458513501230. Epub 2013 Aug 22.