MIMS
Mitoxantrone
MIMS evaluated an intensive immunosuppressive strategy in people with worsening relapsing-remitting or secondary progressive multiple sclerosis.
- Phase
- Phase III
- Population
- Worsening relapsing-remitting multiple sclerosis (RRMS) or secondary progressive multiple sclerosis (SPMS)
- Controlled period
- Jun 2, 1993 — Jul 10, 1997
What was compared
Mitoxantrone
12 mg/m² intravenously every 3 months
n=60Placebo
Matching intravenous infusion every 3 months
n=64Additional randomized arm
Exploratory mitoxantrone dose
5 mg/m² intravenously every 3 monthsn=64 (efficacy-evaluable)Primary endpoint
Multivariate composite of five clinical measures
24 months
Primary endpoint results
Multivariate composite treatment difference
Composite treatment difference (95% CI)
Composite treatment difference 0.30 (95% CI 0.17–0.44; P<0.0001).
Selected secondary outcomes
Preplanned univariate analysis favored mitoxantrone (P=0.0194).
Adjusted total treated relapses favored mitoxantrone (P=0.0002).
Who was studied
Key inclusion criteria
- Age 18–55 years
- Worsening RRMS or SPMS
- Baseline EDSS 3.0–6.0
- EDSS worsening of at least 1 point in the previous 18 months
- Left ventricular ejection fraction > 50%
- Adequate blood counts: leukocytes > 4 × 10⁹/L, neutrophils > 2 × 10⁹/L, and platelets > 100 × 10⁹/L
Key exclusion criteria
- Clinical relapse or glucocorticoid treatment within the preceding 8 weeks
- Previous mitoxantrone, interferon, glatiramer acetate, cytotoxic drugs, or total-body lymphoid irradiation
Participants at baseline
| Characteristic | Mitoxantrone 12 mg/m²N=60 | Mitoxantrone 5 mg/m²N=64 | PlaceboN=64 |
|---|---|---|---|
| Age, years — mean ± SD | 39.94 ± 6.85 | 39.92 ± 8.06 | 40.02 ± 7.88 |
| Male sex — n (%) | 32 (53%) | 25 (39%) | 33 (52%) |
| Worsening RRMS — n (%) | 28 (47%) | 37 (58%) | 29 (45%) |
| SPMS — n (%) | 32 (53%) | 27 (42%) | 35 (55%) |
| MS duration, years — mean ± SD | 9.63 ± 6.94 | 9.03 ± 6.18 | 10.27 ± 6.86 |
| EDSS — mean ± SD | 4.45 ± 1.05 | 4.64 ± 1.01 | 4.69 ± 0.97 |
| Relapses in previous 12 months — mean ± SD | 1.27 ± 1.12 | 1.42 ± 1.26 | 1.31 ± 1.14 |
SD: standard deviation; EDSS: Expanded Disability Status Scale; RRMS: relapsing-remitting multiple sclerosis; SPMS: secondary progressive multiple sclerosis.
Source: Hartung et al., Lancet 2002, Table 1
Safety signal
- The controlled trial reported no drug-related serious adverse events or clinically significant cardiac dysfunction.
- The sample and follow-up were too limited to define delayed cumulative cardiotoxicity or therapy-related leukemia risk.
Later safety context
Later regulatory context (2010): the FDA label warns about cumulative cardiotoxicity, heart failure that can occur months to years after treatment, and secondary acute myeloid leukemia. The small controlled MIMS trial could not characterize these delayed risks.
FDA, Novantrone label, 2010 ↗Why it mattered
MIMS demonstrated that an immunosuppressive treatment could affect clinical worsening in selected patients with worsening RRMS or SPMS, when options were limited. Its small, two-year controlled study could not establish the long-term safety of repeated mitoxantrone exposure.
Important limitation
The primary endpoint was an unusual multivariate composite, and the 2-year observation could not characterize the major cumulative toxicities that constrain mitoxantrone use.