This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This is an investigator-initiated industry-sponsored phase IIA double-blind study designed to assess the safety, tolerability and CSF penetration of three dose levels of Arimoclomol. Eighty subjects from eight to ten centers will be randomized to one of four groups: placebo, Arimoclomol 25 mg t.i.d., 50 mg t.i.d. or 100 mg t.i.d. and receive study medication for 12 weeks. After four weeks of treatment, a subset of research participants (approximately half, or 40) will be admitted to the institutional GCRC for a serum and CSF pharmacokinetic study. Additional follow-up visits will occur at 8 and 12 weeks. There will be a 4-week post-treatment safety assessment. Based on both the safety and the pharmacokinetic data, an assessment will be made as to which dosages are safe and their respective drug levels in CSF. A decision will be made as to the best two dosages for the phase IIb study. Research participants in the phase IIA study will be given the option for open-label extension study. The separate open label extension protocol will be written and submitted to the site IRBs. Reliability Testing To assess rater reliability for vital capacity testing 3 to 5 subjects with ALS will be enrolled per study site. These subjects may or may not also participate in the phase IIa study. Each subject will be tested two times separated by 30 minutes to one week. Subjects participating in reliability testing must be at least 18 years of age, physically able to perform vital capacity testing and have a diagnosis of ALS. Separate informed consent will be obtained from each subject participating in reliability testing. Number of Centers This study will be conducted in the U.S. at eight to ten Northeast ALS Consortium (NEALS) ALS centers, selected because of their excellent records of recruitment, compliance with study protocols and regulations, clinical research expertise and resources. Number of Subjects Eighty subjects will be randomized to receive treatment; 20 subjects per treatment group (placebo, 75, 150 and 300 mg/day). Fifteen (15) patients will be screened for this trial at UCI; 10 patients will be recruited for this trial. All ten patients will participate in the pharmacokinetics study. Estimated Study Duration The duration of enrollment is expected to be approximately 12 weeks. For each participating subject there will be 12 weeks of intensive evaluation and 4 weeks of follow-up. The entire duration of the trial for individual subjects is anticipated to be approximately 19 weeks (enrollment, eligibility evaluation, and 16 weeks follow-up). Study Procedures Schedule of Assessments The Schedule of Assessments outlines all study procedures to be completed at each study visit (Figure 1). Visits must be completed within +/-3 days of the scheduled visit. Patients who discontinue the study prematurely must complete all procedures described under weeks 12 and 16.
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