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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
27
Total daily oral dose of 250 mg (125 mg BID) of CK-2017357 for 7 days followed by total daily oral dose of 375 mg (125 mg AM and 250 mg PM) for 7 days followed by total daily oral dose of 500 mg (250 mg BID) of CK-2017357 for 7 days
Matching placebo tablets BID for 21 days
University of California at San Francisco, Fresno Campus, Central California Neurological Institute
Fresno, California, United States
Coordinated Clinical Research
La Jolla, California, United States
University of California at Irvine, ALS and Neuromuscular Center
Number of participants with adverse events
Time frame: approximately 29 days
Change from baseline in score on the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R)
An instrument for evaluating the functional status of patients with ALS. Minimum score is 0 and maximum score is 40. The higher the score the more function is retained. This will be administered at Screening, Day -7, Day 1, Day 15 and Day 22.
Time frame: 22 days
Change from baseline in scores on tests of maximum handgrip strength and handgrip fatigue
Measured using the DynEx Electronic Hand Dynamometer. Patients asked to squeeze the device with the maximum possible force to establish the maximum voluntary contraction. Handgrip fatigue is then measured. Patient is asked to squeeze the device until they can no longer stay above 60% of target or 120 seconds. This will be measured at Screening, Day -7, Day 1, Day 15 and Day 22.
Time frame: 22 days
Change from baseline in scores on tests of muscle strength
Muscle strength is measured using Hand Held Dynamometry. A series of assessments are done on different muscle groups. This will be measured at Day -7, Day 1, and Day 22.
Time frame: 22 days
Change from baseline in scores on tests of Timed Up and Go
TUG is measured by timing how long it takes for a subject to stand up from a chair, walk 10 feet, turn around, walk back to the chair and sit down. This will be measured at Day -7, Day 1, and Day 22.
Time frame: 22 days
Change from baseline in scores on tests of Sniff Nasal Inspiratory Pressure (SNIP)
SNIP will be measured using the Micro Medical Respiratory Pressure Meter (MicroRPM) at Screening, Day -7, Day 1, Day 15 and Day 22.
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Orange, California, United States
Hospital for Special Care
New Britain, Connecticut, United States
Massachusetts General Hospital, Neurology Clinical Trials Unit
Charlestown, Massachusetts, United States
Washington University
St Louis, Missouri, United States
Cornell Faculty, Hospital for Special Surgery
New York, New York, United States
Duke University School of Medicine, Division of Neurology
Durham, North Carolina, United States
Ohio State University, Department of Neurology
Columbus, Ohio, United States
Providence ALS Center
Portland, Oregon, United States
...and 1 more locations
Time frame: 22 days
Change from baseline in scores on tests of Slow Vital Capacity (SVC)
SVC will be measured using the ndd EasyOne Spirometer System at Screening, Day -7, Day 1, Day 15 and Day 22.
Time frame: 22 days
Change from baseline in scores on tests of Maximum Voluntary Ventilation (MVV)
MVV will be measured using the EasyOne Spirometer System at Screening, Day -7, Day 1, Day 15 and Day 22.
Time frame: 21 days
Change from baseline in Patient Global Assessment
Patients will be asked to assess whether they feel the same, better or worse as compared to how they felt at pre-dose on Day 1
Time frame: 22 days
Change from baseline in Investigator Global Assessment
Investigator will assess whether the patient appears the same, better or worse as compared to the patient's status at pre-dose on Day 1.
Time frame: 22 days
Evaluate the pharmacokinetics of CK-2017357
Plasma levels of CK-2017357 will be measured at pre-dose, and at 2 and 4 hours post AM dose
Time frame: Day 1, Day 15, and Day 22
Evaluate the pharmacokinetics of riluzole in patients receiving CK-2017357
Plasma levels of riluzole will be measured at pre-dose and at 2 and 4 hours post AM dose
Time frame: Day 1, Day 15, and Day 22