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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

Tracking Information
First Submitted Date  ICMJE December 28, 2010
First Posted Date  ICMJE December 30, 2010
Last Update Posted Date September 24, 2019
Study Start Date  ICMJE December 2010
Actual Primary Completion Date October 2012   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 4, 2019)
  • 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.
  • Pulmonary Function Test (VC in liters) [ Time Frame: 1 day ]
    Forced Vital Capacity
  • Manual Muscle Test (MMT) [ Time Frame: 1 day ]
    Sum of strength or function values assessed by physician on the neck, shoulder, hip and ankle
Original Primary Outcome Measures  ICMJE
 (submitted: December 29, 2010)
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 ]
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)
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: September 4, 2019)
  • Characterize dose and plasma concentrations of CK-2017357 and QMG [ Time Frame: 2 days ]
  • Characterize dose and plasma concentrations of CK-2017357 and Forced Vital Capacity (FVC) [ Time Frame: 2 days ]
  • Characterize dose and plasma concentrations of CK-2017357 and Manual Muscle Test (MMT) [ Time Frame: 2 days ]
  • Number of patients with adverse events [ Time Frame: 4 weeks ]
  • 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
  • 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
  • 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
Original Secondary Outcome Measures  ICMJE
 (submitted: December 29, 2010)
  • 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 ]
  • To evaluate the safety and tolerability of CK-2017357 administered as single oral doses to patients with MG [ Time Frame: 4 weeks ]
  • 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 ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Pharmacodynamic Study of CK-2017357 in Patients With Generalized Myasthenia Gravis
Official Title  ICMJE 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
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).
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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Myasthenia Gravis
Intervention  ICMJE
  • 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
Study Arms  ICMJE
  • Experimental: Treatment Sequence 1
    Dosing Period 1 Placebo; Dosing Period 2 CK-2017357 250 mg; Dosing Period 3 CK-2017357 500 mg
    Interventions:
    • Drug: Placebo
    • Drug: 250 mg CK-2017357
    • Drug: 500 mg CK-2017357
  • Experimental: Treatment Sequence 2
    Dosing Period 1 Placebo; Dosing Period 2 CK-2017357 500 mg; Dosing Period 3 CK-2017357 250 mg
    Interventions:
    • Drug: Placebo
    • Drug: 250 mg CK-2017357
    • Drug: 500 mg CK-2017357
  • Experimental: Treatment Sequence 3
    Dosing Period 1 CK-2017357 250 mg; Dosing Period 2 Placebo; Dosing Period 3 CK-2017357 500 mg
    Interventions:
    • Drug: Placebo
    • Drug: 250 mg CK-2017357
    • Drug: 500 mg CK-2017357
  • Experimental: Treatment Sequence 4
    Dosing Period 1 CK-2017357 250 mg; Dosing Period 2 CK-2017357 500 mg; Dosing Period 3 Placebo
    Interventions:
    • Drug: Placebo
    • Drug: 250 mg CK-2017357
    • Drug: 500 mg CK-2017357
  • Experimental: Treatment Sequence 5
    Dosing Period 1 CK-2017357 500 mg; Dosing Period 2 Placebo; Dosing Period 3 CK-2017357 250 mg
    Interventions:
    • Drug: Placebo
    • Drug: 250 mg CK-2017357
    • Drug: 500 mg CK-2017357
  • Experimental: Treatment Sequence 6
    Dosing Period 1 CK-2017357 500 mg; Dosing Period 2 CK-2017357 250 mg; Dosing Period 3 Placebo
    Interventions:
    • Drug: Placebo
    • Drug: 250 mg CK-2017357
    • Drug: 500 mg CK-2017357
Publications * 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

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: October 30, 2012)
32
Original Estimated Enrollment  ICMJE
 (submitted: December 29, 2010)
36
Actual Study Completion Date  ICMJE October 2012
Actual Primary Completion Date October 2012   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 80 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01268280
Other Study ID Numbers  ICMJE CY 4023
1RC3NS070670-01 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Cytokinetics
Study Sponsor  ICMJE Cytokinetics
Collaborators  ICMJE National Institute of Neurological Disorders and Stroke (NINDS)
Investigators  ICMJE
Study Director: Andrew Wolff, MD, FACC Cytokinetics, Inc.
PRS Account Cytokinetics
Verification Date September 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP