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Dose Titration Study to Test Safety and Effects of CK-2017357 in Patients With Amyotrophic Lateral Sclerosis (ALS)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01486849
Recruitment Status : Completed
First Posted : December 7, 2011
Last Update Posted : May 3, 2019
Sponsor:
Information provided by (Responsible Party):
Cytokinetics

Study Description
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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).

Condition or disease Intervention/treatment Phase
Amyotrophic Lateral Sclerosis Drug: CK-2017357 Drug: Placebo Drug: Riluzole 50 MG Phase 2

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.

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 27 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
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 Start Date : November 2011
Actual Primary Completion Date : March 2012
Actual Study Completion Date : March 2012

Resource links provided by the National Library of Medicine

Drug Information available for: Riluzole

Arms and Interventions
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Arm Intervention/treatment
Experimental: Dose Titration of CK-2017357 (Group 1)
Dose titration of active drug as add-on therapy to riluzole
 Drug: CK-2017357
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
Other Name: tirasemtiv

Drug: Riluzole 50 MG
Placebo Comparator: Matching Placebo (Group 2)
Placebo as add-on therapy to riluzole
 Drug: Placebo
Matching placebo tablets BID for 21 days

Drug: Riluzole 50 MG


Outcome Measures
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Primary Outcome Measures :
  1. Number of participants with adverse events [ Time Frame: approximately 29 days ]

Secondary Outcome Measures :
  1. Change from baseline in score on the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) [ Time Frame: 22 days ]
    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.

  2. Change from baseline in scores on tests of maximum handgrip strength and handgrip fatigue [ Time Frame: 22 days ]
    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.

  3. Change from baseline in scores on tests of muscle strength [ Time Frame: 22 days ]
    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.

  4. Change from baseline in scores on tests of Timed Up and Go [ Time Frame: 22 days ]
    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.

  5. Change from baseline in scores on tests of Sniff Nasal Inspiratory Pressure (SNIP) [ Time Frame: 22 days ]
    SNIP will be measured using the Micro Medical Respiratory Pressure Meter (MicroRPM) at Screening, Day -7, Day 1, Day 15 and Day 22.

  6. Change from baseline in scores on tests of Slow Vital Capacity (SVC) [ Time Frame: 22 days ]
    SVC will be measured using the ndd EasyOne Spirometer System at Screening, Day -7, Day 1, Day 15 and Day 22.

  7. Change from baseline in scores on tests of Maximum Voluntary Ventilation (MVV) [ Time Frame: 21 days ]
    MVV will be measured using the EasyOne Spirometer System at Screening, Day -7, Day 1, Day 15 and Day 22.

  8. Change from baseline in Patient Global Assessment [ Time Frame: 22 days ]
    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

  9. Change from baseline in Investigator Global Assessment [ Time Frame: 22 days ]
    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.

  10. Evaluate the pharmacokinetics of CK-2017357 [ Time Frame: Day 1, Day 15, and Day 22 ]
    Plasma levels of CK-2017357 will be measured at pre-dose, and at 2 and 4 hours post AM dose

  11. Evaluate the pharmacokinetics of riluzole in patients receiving CK-2017357 [ Time Frame: Day 1, Day 15, and Day 22 ]
    Plasma levels of riluzole will be measured at pre-dose and at 2 and 4 hours post AM dose


Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01486849


Locations
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United States, California
University of California at San Francisco, Fresno Campus, Central California Neurological Institute
Fresno, California, United States, 93701
Coordinated Clinical Research
La Jolla, California, United States, 92037
University of California at Irvine, ALS and Neuromuscular Center
Orange, California, United States, 92868
United States, Connecticut
Hospital for Special Care
New Britain, Connecticut, United States, 06053
United States, Massachusetts
Massachusetts General Hospital, Neurology Clinical Trials Unit
Charlestown, Massachusetts, United States, 02129
United States, Missouri
Washington University
Saint Louis, Missouri, United States, 63110
United States, New York
Cornell Faculty, Hospital for Special Surgery
New York, New York, United States, 10021
United States, North Carolina
Duke University School of Medicine, Division of Neurology
Durham, North Carolina, United States, 27710
United States, Ohio
Ohio State University, Department of Neurology
Columbus, Ohio, United States, 43210
United States, Oregon
Providence ALS Center
Portland, Oregon, United States, 97213
United States, Texas
University of Texas Health Science Center, Department of Neurology
San Antonio, Texas, United States, 78229
Sponsors and Collaborators
Cytokinetics
Investigators
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Study Chair: Jeremy Shefner, MD, PhD State University of New York - Upstate Medical University
More Information
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Responsible Party: Cytokinetics
ClinicalTrials.gov Identifier: NCT01486849    
Other Study ID Numbers: CY 4025
First Posted: December 7, 2011    Key Record Dates
Last Update Posted: May 3, 2019
Last Verified: April 2019
Additional relevant MeSH terms:
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Motor Neuron Disease
Amyotrophic Lateral Sclerosis
Sclerosis
Pathologic Processes
Neurodegenerative Diseases
Nervous System Diseases
Neuromuscular Diseases
Spinal Cord Diseases
Central Nervous System Diseases
TDP-43 Proteinopathies
Proteostasis Deficiencies
 Metabolic Diseases
Riluzole
Anticonvulsants
Excitatory Amino Acid Antagonists
Excitatory Amino Acid Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Neuroprotective Agents
Protective Agents