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Pharmacodynamic Study of CK-2017357 in Patients With Generalized Myasthenia Gravis

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ClinicalTrials.gov Identifier: NCT01268280
Recruitment Status : Terminated (Closed after complete treatment of 32 patients after 21 months' recruitment.)
First Posted : December 30, 2010
Last Update Posted : September 24, 2019
Sponsor:
Collaborator:
National Institute of Neurological Disorders and Stroke (NINDS)
Information provided by (Responsible Party):
Cytokinetics

Brief Summary:
The primary objective of this early-stage clinical study is to demonstrate an effect of single doses of CK-2017357 on measures of skeletal muscle function and fatigability in patients with generalized myasthenia gravis (MG).

Condition or disease Intervention/treatment Phase
Myasthenia Gravis Drug: Placebo Drug: 250 mg CK-2017357 Drug: 500 mg CK-2017357 Phase 2

Detailed Description:
This study is a Phase II, double-blind, randomized, three-way crossover, placebo-controlled, PD study of CK-2017357 in patients with generalized MG on standard therapy. 36 to 78 patients will be randomized at approximately 15 study centers to one of six different treatment sequences. Each treatment sequence consists of three dosing periods in which patients receive single oral doses of placebo, 250 mg, and 500 mg of CK-2017357. All six treatment sequences will enroll 6 patients. A wash out period of at least 7 days (to a maximum of 10 days) will be employed between the individual doses for each patient. This study is designed to assess the effects of CK-2017357 on the standardized Quantitative Myasthenia Gravis (QMG) score, Manual Muscle Test, Myasthenia Gravis Composite Assessment (MGCA) and Forced Vital Capacity. The pharmacokinetic (PK) and pharmacodynamic (PD) relationship of CK-2017357 after two single doses will be assessed versus placebo.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 32 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Phase II, Double-Blind, Randomized, Three-Way Crossover, Placebo-Controlled, Pharmacodynamic Study of CK-2017357 in Patients With Generalized Myasthenia Gravis on Standard Therapy
Study Start Date : December 2010
Actual Primary Completion Date : October 2012
Actual Study Completion Date : October 2012

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Treatment Sequence 1
Dosing Period 1 Placebo; Dosing Period 2 CK-2017357 250 mg; Dosing Period 3 CK-2017357 500 mg
Drug: Placebo
Matching placebo in capsules administered as a single oral dose.

Drug: 250 mg CK-2017357
250 mg CK-2017357 in capsules administered as a single oral dose.
Other Name: tirasemtiv

Drug: 500 mg CK-2017357
500 mg CK-2017357 in capsules administered as a single oral dose.
Other Name: tirasemitiv

Experimental: Treatment Sequence 2
Dosing Period 1 Placebo; Dosing Period 2 CK-2017357 500 mg; Dosing Period 3 CK-2017357 250 mg
Drug: Placebo
Matching placebo in capsules administered as a single oral dose.

Drug: 250 mg CK-2017357
250 mg CK-2017357 in capsules administered as a single oral dose.
Other Name: tirasemtiv

Drug: 500 mg CK-2017357
500 mg CK-2017357 in capsules administered as a single oral dose.
Other Name: tirasemitiv

Experimental: Treatment Sequence 3
Dosing Period 1 CK-2017357 250 mg; Dosing Period 2 Placebo; Dosing Period 3 CK-2017357 500 mg
Drug: Placebo
Matching placebo in capsules administered as a single oral dose.

Drug: 250 mg CK-2017357
250 mg CK-2017357 in capsules administered as a single oral dose.
Other Name: tirasemtiv

Drug: 500 mg CK-2017357
500 mg CK-2017357 in capsules administered as a single oral dose.
Other Name: tirasemitiv

Experimental: Treatment Sequence 4
Dosing Period 1 CK-2017357 250 mg; Dosing Period 2 CK-2017357 500 mg; Dosing Period 3 Placebo
Drug: Placebo
Matching placebo in capsules administered as a single oral dose.

Drug: 250 mg CK-2017357
250 mg CK-2017357 in capsules administered as a single oral dose.
Other Name: tirasemtiv

Drug: 500 mg CK-2017357
500 mg CK-2017357 in capsules administered as a single oral dose.
Other Name: tirasemitiv

Experimental: Treatment Sequence 5
Dosing Period 1 CK-2017357 500 mg; Dosing Period 2 Placebo; Dosing Period 3 CK-2017357 250 mg
Drug: Placebo
Matching placebo in capsules administered as a single oral dose.

Drug: 250 mg CK-2017357
250 mg CK-2017357 in capsules administered as a single oral dose.
Other Name: tirasemtiv

Drug: 500 mg CK-2017357
500 mg CK-2017357 in capsules administered as a single oral dose.
Other Name: tirasemitiv

Experimental: Treatment Sequence 6
Dosing Period 1 CK-2017357 500 mg; Dosing Period 2 CK-2017357 250 mg; Dosing Period 3 Placebo
Drug: Placebo
Matching placebo in capsules administered as a single oral dose.

Drug: 250 mg CK-2017357
250 mg CK-2017357 in capsules administered as a single oral dose.
Other Name: tirasemtiv

Drug: 500 mg CK-2017357
500 mg CK-2017357 in capsules administered as a single oral dose.
Other Name: tirasemitiv




Primary Outcome Measures :
  1. Quantitative Myasthenia Gravis score (QMG) [ Time Frame: 1 day ]
    A quantitative motor assessment of muscular weakness on a scale of 0 to 3 with 0 representing "none" and 3 representing "severe". Muscular assessments included in the overall score are effects on double vision, ptosis, facial muscles, swallowing, speech, outstretched arms and legs, forced vital capacity, hand grip strength, and ability to lift head.

  2. Pulmonary Function Test (VC in liters) [ Time Frame: 1 day ]
    Forced Vital Capacity

  3. Manual Muscle Test (MMT) [ Time Frame: 1 day ]
    Sum of strength or function values assessed by physician on the neck, shoulder, hip and ankle


Secondary Outcome Measures :
  1. Characterize dose and plasma concentrations of CK-2017357 and QMG [ Time Frame: 2 days ]
  2. Characterize dose and plasma concentrations of CK-2017357 and Forced Vital Capacity (FVC) [ Time Frame: 2 days ]
  3. Characterize dose and plasma concentrations of CK-2017357 and Manual Muscle Test (MMT) [ Time Frame: 2 days ]
  4. Number of patients with adverse events [ Time Frame: 4 weeks ]
  5. Modified MG Symptom Score [ Time Frame: 2 days ]
    Patients will be asked questions regarding five myasthenia gravis systems including trouble using eyes, trouble eating, difficulty speaking, trouble walking and trouble performing personal grooming needs. Each of the areas is scored 0 (none at all) to 3 (very much) and the overall score combining the score of all five areas on a scale of 0 to 15 with 0 being normal and 15 being severe weakness

  6. Patient Global Assessment [ Time Frame: 2 days ]
    Patients answer a single question as to whether they feel the same, better or worse as compared to how they felt pre-dose

  7. Investigator Global Assessment [ Time Frame: 2 days ]
    Investigator answer a single as question as to whether they think the patient appears the same, better or worse as compared to the patient's status at pre-dose



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion criteria:

  • Ability to comprehend and willing to sign an Informed Consent Form (ICF)
  • Ability to understand written and oral English language
  • Males and females between 18 and 80 years of age, inclusive
  • Patient's signs and symptoms not better explained by another disease process
  • Established diagnosis of MG defined as clinical evidence of muscle weakness and positive AChR-binding antibody titer (>0.02 nmol/L)
  • Myasthenia Gravis Foundation of America (MGFA) clinical classification II or III
  • Stable MG disease for 4 weeks prior to randomization
  • Ability to refrain from IVIg treatments during the course of the study
  • Ability to refrain from cholinesterase-inhibitors (e.g. pyridostigmine) for 12 hours before each dose
  • Ability to perform all elements of the QMG
  • Grade of 2 or 3 in two or more of the following muscle groups as measured by QMG: right or left arm flexion, head lift, and right or left leg raise at 45° Note: Patients may re-screen if they fail due to inadequate weakness from taking pyridostigmine within 12 hours of screening
  • Body mass index (BMI) of 18.0 to 36.0 kg/m2, inclusive
  • Pre-study clinical laboratory findings (including troponin I [TnI] and creatine phosphokinase [CPK]) within the normal range, or if outside of the normal range, deemed not clinically significant by the Investigator
  • For female patients only: Agreement to use a double barrier during sexual intercourse (1 hormonal, plus 1 barrier method, or 2 simultaneous barrier methods) birth control (birth control pills, male condom, female condom, intrauterine device, Norplant, tubal ligation, or other sterilization procedures)
  • For male patients only: Agreement either to use a condom during sexual intercourse with female partners who are of reproductive potential and to have female partners use an additional effective means of contraception (e.g., diaphragm plus spermicide, or oral contraceptives) for the duration of the study and 10 weeks after the end of the study or to abstain from sexual intercourse for the duration of the study and 10 weeks after the end of the study

Exclusion criteria:

  • History of chronic degenerative, psychiatric, or neurologic disorder other than MG that can produce weakness or fatigue
  • Other major chronic or debilitating illnesses within six months prior to study entry
  • Hepatic insufficiency (defined as ALT or AST > 3x ULN, or total bilirubin > 3 mg/dL)
  • Renal insufficiency (defined as serum creatinine > 2.5 mg/dL or receiving dialysis)
  • Other myasthenic syndromes (e.g. Lambert Eaton syndrome; inherited myasthenic syndrome)
  • Female patients who are premenopausal and are: (a) pregnant on the basis of a serum pregnancy test, (b) breast-feeding, or (c) not using an effective method of double barrier (1 hormonal plus 1 barrier method or 2 simultaneous barrier methods) birth control (birth control pills, male condom, female condom, intrauterine device, Norplant, tubal ligation, or other sterilization procedures)
  • Receipt of IVIg or plasmapheresis treatment within 6 weeks prior to the first dose of study drug
  • Changes to immunosuppressive treatments (i.e., prednisone) within 6 weeks prior to the first dose of study drug
  • Rituxan treatment within 3 months prior to study entry
  • Participation in any other investigational study drug or device trial in which receipt of an investigational study drug or device occurred within 30 days prior to dosing
  • Any prior treatment with CK-2017357
  • Recent history of alcoholism or drug abuse, or significant behavioral or psychiatric problems, or other conditions which in the Investigator's opinion may impair ability to adequately comply with the requirements of the study

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): NCT01268280


Locations
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United States, California
UCSF - Fresno
Fresno, California, United States, 93721
University of California - Irvine
Orange, California, United States, 92868
California Pacific Medical Center
San Francisco, California, United States, 94115
Stanford University
Stanford, California, United States, 94305
United States, Connecticut
Hospital for Special Care
New Britain, Connecticut, United States, 06053
United States, Kansas
The University of Kansas Medical Center
Kansas City, Kansas, United States, 26506
United States, Maryland
Johns Hopkins
Baltimore, Maryland, United States, 21205
United States, Massachusetts
Neurocare Center for Research
Newton, Massachusetts, United States, 02459
United States, North Carolina
University of North Carolina
Chapel Hill, North Carolina, United States, 27599
Duke University
Durham, North Carolina, United States, 27710
United States, Pennsylvania
Drexel University College of Medicine
Philadelphia, Pennsylvania, United States, 19107
West Penn Allegheny Health System
Pittsburgh, Pennsylvania, United States, 15212
United States, Texas
Baylor College of Medicine
Houston, Texas, United States, 77030
University of Texas Health Science Center
San Antonio, Texas, United States, 78229
United States, Virginia
University of Virginia Health System
Charlottesville, Virginia, United States, 22908
Sponsors and Collaborators
Cytokinetics
National Institute of Neurological Disorders and Stroke (NINDS)
Investigators
Layout table for investigator information
Study Director: Andrew Wolff, MD, FACC Cytokinetics, Inc.

Publications of Results:
Sanders DB, Rosenfeld J, Dimachkie M, Meng L, Malik FI. A Study to Evaluate Efficacy, Safety and Tolerability of Single Doses of Tirasemtiv in Patients with Myasthenia Gravis. 65th Annual Meeting of the American Academy of Neurology, San Diego, CA, March 2013

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Responsible Party: Cytokinetics
ClinicalTrials.gov Identifier: NCT01268280     History of Changes
Other Study ID Numbers: CY 4023
1RC3NS070670-01 ( U.S. NIH Grant/Contract )
First Posted: December 30, 2010    Key Record Dates
Last Update Posted: September 24, 2019
Last Verified: September 2019
Additional relevant MeSH terms:
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Muscle Weakness
Myasthenia Gravis
Muscular Diseases
Musculoskeletal Diseases
Neuromuscular Manifestations
Neurologic Manifestations
Nervous System Diseases
Pathologic Processes
Signs and Symptoms
Autoimmune Diseases of the Nervous System
Neuromuscular Junction Diseases
Neuromuscular Diseases
Autoimmune Diseases
Immune System Diseases