Study About Efficacy and Safety to Treat Multi-System-Atrophy
Condition: Multi-System-Atrophy; Minocycline
MeSH terms: Multiple System Atrophy; Shy-Drager Syndrome; Atrophy
Study type: Interventional
Phase: Phase 3

Summary: 
      Study Hypothesis:

      - Does a treatment with Minocycline of 2 x daily 2 x 50 mg effect the progression of clinical
      symptoms and diagnosis in patients with MSA?

      Background and Rationale:

        -  The Parkinson-Syndrome which is characterised by the clinical triad akinesis, rigor and
           passive tremor, is caused by Parkinson's disease (PD) in about 70 % of the cases (Oertel
           et al., 2003). However, beside the Parkinson's disease there are several, to some extent
           rare, so-called atypical Parkinson's syndromes. The two most frequent of these atypical
           Parkinson-Syndromes are the

        -  Multi-System-Atrophy (MSA) and the Progressive Supranuclear Palsy (PSP). Due to the
           often much varying courses and since they are not well known, these diseases are
           frequently diagnosed late or not diagnosed at all. Nevertheless, an early diagnosis is
           substantial for further treatment, since the prognosis and therapy of atypical Parkinson
           Syndromes differ essentially from those of PD. Whereas the neuronal death of cells in PD
           is restricted essentially to the Substantia nigra, a dominant destruction of neurons in
           brain stem, Cerebellum and Striatum additionally happens in cases of MSA and PSP.

        -  Up to now no adequate treatment strategies are at disposal. Initially the giving of
           L-Dopa can lead to an improvement for < 10% of the patients only.

        -  Minocycline is an antibiotic belonging to the group of the Tetracyclines.

        -  Recently, it could be demonstrated that Minocycline has a neuroprotective impact besides
           the anti-inflammatory impact.
    

Detailed description: 
      Study Hypothesis:

        -  Does a treatment with Minocycline of 2 x daily 2 x 50 mg effect the progression of
           clinical symptoms and diagnosis in patients with MSA?

        -  Minocycline is an antibiotic belonging to the group of the Tetracyclines. It is applied
           in treating bacterial infections and skin disorders (acne), but there are studies that
           prove a good effect on the inflammatory changes with rheumatoid arthritis (O´Dell, 1999;
           O´Dell et al., 2001; Pillemar et. al., 1997). In a four-years-lasting
           double-blind-placebo-controlled study it could be demonstrated that Minocycline
           represents an effective therapy for the seropositive rheumatoid arthritis. Moreover,
           during the long term therapy only a low side effect rate was observed (O´Dell et al.,
           1999; Langevitz et al., 2000; Alarcon, 2000).

        -  Recently, it could be demonstrated that Minocycline has a neuroprotective impact besides
           the anti-inflammatory impact. In the focal and global animal stroke model there was a
           clearly reduced stroke volume during the treatment of Minocycline in comparison to an
           untreated group (Yrjanheikki, 1998; Yrjanheikki, 1999). These data were replicated by
           various groups, from our group as well (unpublished data). Furthermore, the
           neuroprotective impact of Minocycline was examined with a number of animal experiences
           (Chen et al., 2000; Zhu et al., 2002; Kriz et al. 2002, Sanchez et al., 2001; Van Den
           Bosch et al., 2002; Popovic et al., 2002): amyotrophic lateral sclerosis, M. Huntington,
           trauma, multiple sclerosis.In these trials it could be demonstrated that Minocycline
           slows down the neuronal cell death.

        -  Recently, in cooperation with American colleagues we were able to demonstrate that
           Minocycline possesses a high neuroprotective potency in the MPTP-Mouse model, (an
           animal-model of Parkinson's disease, in which a degeneration of neuronal cells in the
           basal ganglia occurs (Lin et al., 2001; Du et al., 2001). Dependent on the applied
           dosage (30-120 mg/kg), a neuroprotection of up to 77% could be observed. In our results
           we could prove, that NO as well as Caspase-1 play an important role in the pathogenesis
           of cell death. Both, the expression of iNOS and the activation of Caspase-1 could be
           blocked in the presence of Minocycline in the animal-model and in further cell culture
           trials. In addition, there was a decrease of inflammatory microglia activation in the
           examined brain sections in the presence of Minocycline. Similar results could be
           presented from the study group Przedborski (Wu et al., 2002).

        -  In various studies it could be demonstrated that the regulation of iNOS as well as the
           activation of Microglia at the MSA play an important role. This activation of Microglia
           in persons can be proved by Positron-emission-tomography (PET) with the
           Benzodiazepine-Ligands PK11195. PK11195
           (1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3isoquinoline- carboxamide) is a highly
           specific Ligand for peripheral Benzodiazepine-binding sites (PBBS) (Leong et al., 1996).
           As in a normal brain only a few binding sites for PK11195 can be verified, a significant
           increase of the PBBS-Expression by activated microglia after neuronal cell death can be
           verified (Gerhard et al., 2001).

        -  The results of our examinations and the results out of literature suggest that
           Minocycline could also have an effect on neuro-degenerative diseases and particularly
           have an effect with MSA. In the USA a study already examining the impact of orally given
           Minocycline to patients with Chorea Huntington or amyotrophic lateral sclerosis is
           taking place. The National Institutes of Health (NIH) in the USA will perform a
           multicentre, double-blind study about the effect of Minocycline on Parkinson's Disease
           (NIH website, www.nih.gov).

        -  In this study, the effectiveness of Minocycline on the progression of clinical symptoms
           of MSA shall be examined.
    

Intervention name(s): Minocyline
Intervention type(s): Drug
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double
Primary purpose: Treatment
Keywords: Multi-System-Atrophy; Minocycline