Minocycline in MS: Confirmation of Benefit

Description

Background: Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) characterized by the presence of multifocal lesions with inflammation, demyelination and axonal injury. Most people with MS present with a first clinical demyelinating event. This trial will determine the effects of minocycline treatment after a first clinical demyelinating event.

The investigators recently showed that minocycline, a second-generation tetracycline antibiotic with immune modulating properties, delays conversion from a first clinical demyelinating event to MS within 6 months. While benefit remained significant at 12 months, the investigators were unable to confirm benefit at 24 months. Another trial is needed to confirm the benefit at 6 and 12 months and to determine if the benefit lasts to 24 months. Since this earlier trial the diagnostic criteria for MS have changed and most people with first clinical demyelinating events, previously called a clinically isolated syndrome (CIS), who meet the trial inclusion criteria can now be diagnosed with MS. The outcome of this trial remains clinically important however because it represents the time until new disease activity occurs. It is new activity (brain inflammation or brain damage) which the investigators are trying to prevent with treatment. In Alberta, other proven therapies for CIS, even when MS can now be diagnosed at onset, are not reimbursed by Alberta Blue Cross. Therefore, most people still do not have access to treatment, other than minocycline. Minocycline is therefore a reasonable treatment at this stage of the disease. While the investigators have been lobbying for these reimbursement criteria to be changed there will still be delays in access to other therapies. This will make minocycline valuable, at least as a bridge therapy, while waiting for the option of starting other therapies. Therefore, confirming its' efficacy remains clinically important.

Objective: This proposal will allow the investigators to confirm that minocycline treatment reduces the risk in individuals with a first clinical demyelinating event (CIS or CIS/MS) to have further inflammatory disease activity that is equivalent to the endpoint indicating they converted to MS (by 2005 McDonald MS Criteria).

Patient Population: Participants must meet the same inclusion and exclusion criteria that were used in the investigators previous phase III minocycline trial. These criteria are identical to those of the investigators earlier CIS trial and very similar to other CIS trials. In addition, to assure the cohort remains consistent with participants in previous CIS trials, the investigators will monitor the characteristics of the participating population to assure they reflect the majority of previous CIS trials. The investigators expect the time since onset of CIS may need to be reduced during the trial to ensure the investigators limit the number of participants with longer time from onset to match the investigators earlier trial. This will be monitored closely.

Recruitment: Patients referred to the Calgary MS Clinic with new onset of suspected MS are generally seen within 4 weeks of referral. An MRI scan of their brain will have been completed prior to referral or will be arranged on an urgent basis. This will be the screening/baseline MRI. Patients are routinely assessed for conditions that mimic MS as standard practice in the MS Clinic. If a diagnosis of CIS or CIS/MS is made they are educated about their diagnosis, informed of the risk of MS and of further CNS inflammation (clinical, or subclinical if detected by MRI), and they are offered treatments that may reduce these risks. Clinical and MRI follow-up are arranged and they are advised to contact a clinic nurse if they have new or worsening neurologic symptoms. Current approved therapies for MS are not reimbursed through the Alberta Blue Cross special authorization program until a diagnosis of MS is confirmed and a second inflammatory event has occurred. Therefore, few patients initiate the currently approved MS therapies which cost $13,154 to $34,780 per year. Even a co-pay of 20% is very expensive. However, most patients can afford minocycline 100 mg twice daily (less than $500 per year) and therefore many now choose to start it. Most others choose no treatment. Patients diagnosed with CIS or CIS/MS will be invited to be screened for eligibility to participate in this open-label trial. All consenting patients who meet the study criteria will be enrolled.

Over 48 months, 148 patients will be enrolled. Up to 200 patients may be screened because some screened patients will not meet the MRI criteria for inclusion and some may choose to take another treatment.

Treatment: Study participants will be included in this study if they decide to start treatment with minocycline. Participants who enroll and take at least one dose of minocycline will be evaluated in the intention to treat population. Participants will be asked to continue minocycline and trial participation for up to 24 months but will be discontinued earlier if they reach the study endpoint (MS according to the 2005 McDonald criteria). Continuation of minocycline after this period will be decided by the participant and their neurologist as this period will not be part of the clinical trial.

Participants will be included in a per-protocol analysis group if they take 80% of the prescribed minocycline and have all on study clinical and imaging evaluations prior to reaching the study endpoint. Adherence will be determined based on drug dispensed and pill counts. Participants will be asked to bring in their empty and partially used pill bottles for a pill count. Other MS disease modifying therapies, chronic systemic steroids, and investigational therapies are prohibited. Use of contraception during treatment with minocycline will be required for sexually active participants. Use of other concurrent medications will not be influenced by study participation.

Study Procedures: Clinic visits will occur at screening, baseline, and months 1, 3, 6, 12, 18 and 24, and telephone visits will occur at months 9, 15 and 21. The screening and baseline visit may be on the same day. MRI scans will be done at baseline (or within the previous 2 weeks), and at months 3, 6, 12 and 24 (+/- 14 days). The timing of clinical assessments and MRI scans in the minocycline group will mirror the investigators previous trial which reflected previous CIS trials. Participants will continue in the study until month 24 or until they reach the primary endpoint. They will be considered early drop-outs if they discontinue participation before reaching the primary endpoint. Standard clinical follow-up of CIS and CIS/MS patients generally mirrors this pattern of follow-up.

Clinic visits are routine at months 6, 12 and 24. Study visits at months 1, 3 and 18 are required only for the trial. Telephone visits are only for the trial. Brain MRI is routine at months 6, 12 and 24 and clinic patients who have enhancing lesions on their baseline MRI typically also have a scan at 3 months because they are at very high risk of early new disease activity. Study participants without enhancing lesions on their baseline MRI will therefore have an MRI at 3 months only because they are study participants. These are the only MRI scans being done outside of standard clinical practice.

Masking: Clinical assessments and MRI interpretations will be completed by masked assessors. A masked clinician will complete the neurologic exam and EDSS. While this is a single arm study several trials are ongoing at the investigators centre and the assessor will be masked as to which trial the patient is participating in. The radiologist interpreting the MRI will be masked because they will not know that this is a study MRI.

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