Minocycline in Clinically Isolated Syndromes (CIS) (MinoCIS)

A Phase III Double-blind, Randomized, Placebo-controlled Trial of Minocycline in Clinically Isolated Syndromes (CIS) and Early Single Relapse Multiple Sclerosis (MS)

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.

Study Overview

• Status: Completed
• Conditions: Clinically Isolated Syndromes; Early Single Relapse of Multiple Sclerosis
• Intervention / Treatment: Drug: Minocycline; Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 142
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 4N1
      • University of Calgary, Calgary Health Region
    • Edmonton, Alberta, Canada, T6G 2G3
      • University of Alberta
  • British Columbia
    • Burnaby, British Columbia, Canada, V5G 2X6
      • Fraser Health Multiple Sclerosis Clinic
    • Vancouver, British Columbia, Canada, V6T 2B5
      • UBC Hospital
  • Manitoba
    • Winnipeg, Manitoba, Canada, R3A 1R9
      • MS Research Unit, Health Sciences Centre
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3H 1V7
      • Dalhousie MS Research Unit
  • Ontario
    • London, Ontario, Canada, N6A 5A5
      • MS Clinic, London Health Sciences Centre
    • Ottawa, Ontario, Canada, K1H 8L6
      • The Ottawa Hospital, Multiple Sclerosis Research Clinic
    • Toronto, Ontario, Canada, M4N 3M5
      • Sunnybrook Health Sciences Centre
  • Quebec
    • Greenfield Park, Quebec, Canada, J4V2J2
      • Clinique Neuro Rive-Sud
    • Montreal, Quebec, Canada, H2L 4M1
      • CHUM Notre-Dame
    • Quebec City, Quebec, Canada, G1J 1Z4
      • CHAUQ Enfant-Jesus

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Minocycline; Minocycline 100 mg oral for up to 24 months	Drug: Minocycline; 100 mg twice daily to be taken for up to 2 years; Other Names: Minocycline Hydrochloride; MINOCIN
Placebo Comparator: Placebo; Lactose Monohydrate NF (Spray-dried) 235 mg/cap Magnesium Stearate NF 1 mg/cap Croscarmellose Sodium NF 4 mg/cap Stearic Acid 10 mg/cap Placebo CAP Lt orange OP-Purple OP (APO 100)	Drug: Placebo; placebo twice daily for 2 years

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
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.	6 Months

Secondary Outcome Measures

Outcome Measure	Time Frame
To confirm that this early treatment benefit is maintained at two years.	2 years
Change in T2 lesion volume	6 months and 24 months
Cumulative number of enhancing T1 lesions	6 months and 24 months
cumulative combined unique lesions (new enhancing T1-weighted lesions plus new and enlarging T2 lesions, without lesion double counting)	6 months and 24 months

Collaborators and Investigators

• Sponsor: Dr. Luanne Metz
• Collaborators: Multiple Sclerosis Society of Canada
• Investigators: Principal Investigator: Luanne Metz, MD, University Of Calgary

Publications and helpful links

General Publications

• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start: January 1, 2009
• Primary Completion (Actual): December 1, 2014
• Study Completion (Actual): July 1, 2015

Study Registration Dates

• First Submitted: April 23, 2008
• First Submitted That Met QC Criteria: April 24, 2008
• First Posted (Estimate): April 25, 2008

Study Record Updates

• Last Update Posted (Actual): February 27, 2017
• Last Update Submitted That Met QC Criteria: February 23, 2017
• Last Verified: February 1, 2017

More Information

Terms related to this study

• Keywords: Multiple Sclerosis; Placebo; Clinically Isolated Syndrome; Minocycline
• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Immune System Diseases; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Demyelinating Diseases; Autoimmune Diseases; Disease Attributes; Disease; Multiple Sclerosis; Sclerosis; Syndrome; Recurrence; Anti-Infective Agents; Anti-Bacterial Agents; Minocycline
• Other Study ID Numbers: Grant ID # 21569; Health Canada Control #120007 (Other Identifier: Health Canada)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Consent to share IPD was not obtained from subjects so data cannot be shared except amongst investigators.