dose titration study to test safety and effects of ck-2017357 in patients with amyotrophic lateral sclerosis (als)

Conditions: Amyotrophic Lateral Sclerosis

Summary: a phase ii, double-blind, randomized, placebo-controlled ascending dose titration study to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamic effects of multiple ascending doses of ck-2017357 to an individual patient maximum tolerated dose (mtd), using a within-patient twice daily (bid) dose-titration regimen in als patients on 50 mg riluzole once daily (qd).

patients will be randomized to one of two dosing groups, active ck-2017357 or placebo, in a 3:1 ratio. prior to study drug dosing, patients will be required to decrease their riluzole dose to 50 mg qd for 7 days; after this 7 day period patients will either receive placebo or start the titration on active ck-2017357 while continuing to take riluzole at 50 mg qd. potential patients will be screened to assess their eligibility to enter the study within 21 days prior to day -7, when they will begin taking riluzole at the decreased dose of 50 mg qd. patients will be randomized in a 3:1 ratio to ck-2017357 (group 1) or placebo (group 2). on day 1, patients will begin taking a total daily dose of 250 mg (125 mg bid) of ck-2017357 or matching placebo tablets bid for 7 days. then they will take a total daily dose of 375 mg (125 mg morning \[am\] and 250 mg evening \[pm\]) of ck-2017357 or matching placebo tablets bid for 7 days, and finally, they will take a total daily dose of 500 mg (250 mg bid) of ck-2017357 or matching placebo tablets bid for 7 days. a final dose of 250 mg of ck-2017357 or placebo will be taken in the morning on day 22 at the study site. dose-escalation of ck-2017357 or placebo may be stopped, or the dose reduced to a lower level, based on tolerability. all patients who return to a lower dose will stay on that dose for the remainder of the study. patients will remain on the decreased dose of riluzole until the follow-up visit approximately 7 days after day 22.

Eligibility criteria:
inclusion criteria: 1. able to comprehend and willing to sign an informed consent form (icf) 2. males or females 18 years of age or older 3. a diagnosis of familial or sporadic als (defined as meeting the possible, laboratory-supported probable, probable, or definite criteria for a diagnosis of als according to the world federation of neurology el escorial criteria) 4. maximum voluntary grip strength in at least one hand between 10 \& 40 pounds (females) and 10 \& 60 pounds (males) 5. able to swallow tablets with water 6. currently taking and tolerating a stable dose of 50 mg bid riluzole 7. willing and able to reduce daily dose of riluzole to 50mg qd for 5 weeks 8. not currently taking or willing and able to remain off theophylline-containing medications during study participation 9. patient has a caregiver who is capable of observing and reporting patient status 10. upright slow vital capacity (svc) \>50% of predicted for age, height, and sex 11. able to perform pulmonary function tests exclusion criteria: 1. life expectancy \<3 months 2. receipt of investigational study drug within 30 days or 5 half-lives of the prior agent, whichever is greater, prior to dosing 3. any prior treatment with ck-2017357 4. any use of non-invasive positive pressure ventilation (nippv), such as continuous positive airway pressure (cpap) or bilevel positive airway pressure (bipap) other protocol-defined inclusion/exclusion criteria may apply.