Clinical trial NCT01486849: Dose Titration Study to Test Safety and Effects of CK-2017357 in Patients With Amyotrophic Lateral Sclerosis (ALS)
Official title: A Phase II, Multicenter, Double-Blind, Randomized, Placebo-Controlled Dose Titration Study to Evaluate the Safety, Tolerability and Pharmacodynamic Effects of CK-2017357 in Patients With Amyotrophic Lateral Sclerosis (ALS)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Amyotrophic Lateral Sclerosis
Lead sponsor: Cytokinetics
Sponsor class: INDUSTRY
First posted: 2011-12-07
Enrollment: 27
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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).

Detailed description: 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.

Primary outcomes:
measure: Number of participants with adverse events
timeFrame: approximately 29 days
Secondary outcomes:
measure: Change from baseline in score on the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R)
timeFrame: 22 days
measure: Change from baseline in scores on tests of maximum handgrip strength and handgrip fatigue
timeFrame: 22 days
measure: Change from baseline in scores on tests of muscle strength
timeFrame: 22 days
measure: Change from baseline in scores on tests of Timed Up and Go
timeFrame: 22 days
measure: Change from baseline in scores on tests of Sniff Nasal Inspiratory Pressure (SNIP)
timeFrame: 22 days
measure: Change from baseline in scores on tests of Slow Vital Capacity (SVC)
timeFrame: 22 days
measure: Change from baseline in scores on tests of Maximum Voluntary Ventilation (MVV)
timeFrame: 21 days
measure: Change from baseline in Patient Global Assessment
timeFrame: 22 days
measure: Change from baseline in Investigator Global Assessment
timeFrame: 22 days
measure: Evaluate the pharmacokinetics of CK-2017357
timeFrame: Day 1, Day 15, and Day 22
measure: Evaluate the pharmacokinetics of riluzole in patients receiving CK-2017357
timeFrame: Day 1, Day 15, and Day 22
Other outcomes:
Locations:
city: Fresno
country: United States
facility: University of California at San Francisco, Fresno Campus, Central California Neurological Institute
state: California
city: La Jolla
country: United States
facility: Coordinated Clinical Research
state: California
city: Orange
country: United States
facility: University of California at Irvine, ALS and Neuromuscular Center
state: California
city: New Britain
country: United States
facility: Hospital for Special Care
state: Connecticut
city: Charlestown
country: United States
facility: Massachusetts General Hospital, Neurology Clinical Trials Unit
state: Massachusetts
city: Saint Louis
country: United States
facility: Washington University
state: Missouri
city: New York
country: United States
facility: Cornell Faculty, Hospital for Special Surgery
state: New York
city: Durham
country: United States
facility: Duke University School of Medicine, Division of Neurology
state: North Carolina
city: Columbus
country: United States
facility: Ohio State University, Department of Neurology
state: Ohio
city: Portland
country: United States
facility: Providence ALS Center
state: Oregon
city: San Antonio
country: United States
facility: University of Texas Health Science Center, Department of Neurology
state: Texas
Study officials:
affiliation: State University of New York - Upstate Medical University
name: Jeremy Shefner, MD, PhD
role: STUDY_CHAIR
References: