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

This study has been terminated.
(Closed after complete treatment of 32 patients after 21 months' recruitment.)
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Cytokinetics
ClinicalTrials.gov Identifier:
NCT01268280
First received: December 28, 2010
Last updated: September 16, 2013
Last verified: October 2012
  Purpose

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 Intervention Phase
Myasthenia Gravis
Drug: Placebo
Drug: 250 mg CK-2017357
Drug: 500 mg CK-2017357
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacodynamics Study
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Caregiver, 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

Resource links provided by NLM:


Further study details as provided by Cytokinetics:

Primary Outcome Measures:
  • To demonstrate an effect of single doses of CK-2017357 on measures of skeletal muscle function and fatigability in patients with generalized MG. [ Time Frame: 1 day ] [ Designated as safety issue: No ]

    In this hypothesis-generating Phase II study, multiple assessments of skeletal muscle function and fatigability will be made without specifying a single primary endpoint, including:

    • Quantitative MG score (QMG)
    • Pulmonary Function Test (VC in liters)
    • Manual Muscle Test (MMT)


Secondary Outcome Measures:
  • To evaluate and characterize the relationship, if any, between the doses and plasma concentrations of CK-2017357 and its pharmacodynamic effects (PK/PD relationship) [ Time Frame: 2 days ] [ Designated as safety issue: No ]
  • To evaluate the safety and tolerability of CK-2017357 administered as single oral doses to patients with MG [ Time Frame: 4 weeks ] [ Designated as safety issue: Yes ]
  • To evaluate the effect of CK-2017357 on investigator and patient determined global functional assessment and the Modified MG Symptom Score [ Time Frame: 2 days ] [ Designated as safety issue: No ]

Enrollment: 32
Study Start Date: December 2010
Study Completion Date: October 2012
Primary Completion Date: October 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Three-way crossover
2 oral dose levels of CK-2017357 and 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.

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 measures of muscle strength, muscle fatigue and pulmonary function utilizing the standardized Quantitative MG (QMG) score and Manual Muscle Test (MMT). The pharmacokinetic (PK) and pharmacodynamic (PD) relationship of CK-2017357 after two single doses will be assessed versus placebo, and the CK-2017357 concentration versus time data obtained in this study may be used to develop a population PK model to estimate intra- and inter-patient variability of PK parameters in patients with MG.

  Eligibility

Ages Eligible for Study:   18 Years to 80 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Patients who meet the following criteria may be included in the study:

  1. Ability to comprehend and willing to sign an Informed Consent Form (ICF)
  2. Ability to understand written and oral English language
  3. Males and females between 18 and 80 years of age, inclusive
  4. Patient's signs and symptoms not better explained by another disease process
  5. Established diagnosis of MG defined as clinical evidence of muscle weakness and positive AChR-binding antibody titer (>0.02 nmol/L)
  6. Myasthenia Gravis Foundation of America (MGFA) clinical classification II or III
  7. Stable MG disease for 4 weeks prior to randomization
  8. Ability to refrain from IVIg treatments during the course of the study
  9. Ability to refrain from cholinesterase-inhibitors (e.g. pyridostigmine) for 12 hours before each dose
  10. Ability to perform all elements of the QMG
  11. 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
  12. Body mass index (BMI) of 18.0 to 36.0 kg/m2, inclusive
  13. 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
  14. 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)
  15. 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 b. to abstain from sexual intercourse for the duration of the study and 10 weeks after the end of the study

The following criteria exclude potential patients from the study:

  1. History of chronic degenerative, psychiatric, or neurologic disorder other than MG that can produce weakness or fatigue
  2. Other major chronic or debilitating illnesses within six months prior to study entry
  3. Hepatic insufficiency (defined as ALT or AST > 3x ULN, or total bilirubin > 3 mg/dL)
  4. Renal insufficiency (defined as serum creatinine > 2.5 mg/dL or receiving dialysis)
  5. Other myasthenic syndromes (e.g. Lambert Eaton syndrome; inherited myasthenic syndrome)
  6. 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)
  7. Receipt of IVIg or plasmapheresis treatment within 6 weeks prior to the first dose of study drug
  8. Changes to immunosuppressive treatments (i.e., prednisone) within 6 weeks prior to the first dose of study drug
  9. Rituxan treatment within 3 months prior to study entry
  10. 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
  11. Any prior treatment with CK-2017357
  12. 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
  Contacts and Locations
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, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01268280

Locations
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
Pittsburg, Pennsylvania, United States, 15212
United States, Texas
Baylor College of Medicine
Houston, Texas, United States, 77030
United States, Virginia
University of Virginia Health System
Charlottesville, Virginia, United States, 22908
Sponsors and Collaborators
Cytokinetics
Investigators
Study Director: Andrew Wolff, MD, FACC Cytokinetics, Inc.
  More Information

No publications provided

Responsible Party: Cytokinetics
ClinicalTrials.gov Identifier: NCT01268280     History of Changes
Other Study ID Numbers: CY 4023, 1RC3NS070670-01
Study First Received: December 28, 2010
Last Updated: September 16, 2013
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Myasthenia Gravis
Autoimmune Diseases
Autoimmune Diseases of the Nervous System
Immune System Diseases
Nervous System Diseases
Neuromuscular Diseases
Neuromuscular Junction Diseases

ClinicalTrials.gov processed this record on October 21, 2014