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

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

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).

Study Overview

• Status: Terminated
• Conditions: Myasthenia Gravis
• Intervention / Treatment: Drug: Placebo; Drug: 250 mg CK-2017357; Drug: 500 mg CK-2017357

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: Interventional
• Enrollment (Actual): 32
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Fresno, California, United States, 93721
      • UCSF - Fresno
    • Orange, California, United States, 92868
      • University of California - Irvine
    • San Francisco, California, United States, 94115
      • California Pacific Medical Center
    • Stanford, California, United States, 94305
      • Stanford University
  • Connecticut
    • New Britain, Connecticut, United States, 06053
      • Hospital for Special Care
  • Kansas
    • Kansas City, Kansas, United States, 26506
      • The University of Kansas Medical Center
  • Maryland
    • Baltimore, Maryland, United States, 21205
      • Johns Hopkins
  • Massachusetts
    • Newton, Massachusetts, United States, 02459
      • Neurocare Center for Research
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • University of North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • Drexel University College of Medicine
    • Pittsburgh, Pennsylvania, United States, 15212
      • West Penn Allegheny Health System
  • Texas
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine
    • San Antonio, Texas, United States, 78229
      • University of Texas Health Science Center
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • University Of Virginia Health System

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

6

Arms and Interventions

Participant Group / 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 Names: tirasemtiv; Drug: 500 mg CK-2017357; 500 mg CK-2017357 in capsules administered as a single oral dose.; Other Names: 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 Names: tirasemtiv; Drug: 500 mg CK-2017357; 500 mg CK-2017357 in capsules administered as a single oral dose.; Other Names: 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 Names: tirasemtiv; Drug: 500 mg CK-2017357; 500 mg CK-2017357 in capsules administered as a single oral dose.; Other Names: 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 Names: tirasemtiv; Drug: 500 mg CK-2017357; 500 mg CK-2017357 in capsules administered as a single oral dose.; Other Names: 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 Names: tirasemtiv; Drug: 500 mg CK-2017357; 500 mg CK-2017357 in capsules administered as a single oral dose.; Other Names: 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 Names: tirasemtiv; Drug: 500 mg CK-2017357; 500 mg CK-2017357 in capsules administered as a single oral dose.; Other Names: tirasemitiv

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Quantitative Myasthenia Gravis score (QMG)	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.	1 day
Pulmonary Function Test (VC in liters)	Forced Vital Capacity	1 day
Manual Muscle Test (MMT)	Sum of strength or function values assessed by physician on the neck, shoulder, hip and ankle	1 day

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of patients with adverse events		4 weeks
Characterize dose and plasma concentrations of CK-2017357 and QMG		2 days
Characterize dose and plasma concentrations of CK-2017357 and Forced Vital Capacity (FVC)		2 days
Characterize dose and plasma concentrations of CK-2017357 and Manual Muscle Test (MMT)		2 days
Modified MG Symptom Score	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	2 days
Patient Global Assessment	Patients answer a single question as to whether they feel the same, better or worse as compared to how they felt pre-dose	2 days
Investigator Global Assessment	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	2 days

Collaborators and Investigators

• Sponsor: Cytokinetics
• Collaborators: National Institute of Neurological Disorders and Stroke (NINDS)
• Investigators: Study Director: Andrew Wolff, MD, FACC, Cytokinetics, Inc.

Publications and helpful links

General Publications

• Sanders DB, Rosenfeld J, Dimachkie MM, Meng L, Malik FI; Tirasemtiv in Myasthenia Gravis Study Group. A Double-Blinded, Randomized, Placebo-Controlled Trial to Evaluate Efficacy, Safety, and Tolerability of Single Doses of Tirasemtiv in Patients with Acetylcholine Receptor-Binding Antibody-Positive Myasthenia Gravis. Neurotherapeutics. 2015 Apr;12(2):455-60. doi: 10.1007/s13311-015-0345-y.

Study record dates

Study Major Dates

• Study Start: December 1, 2010
• Primary Completion (Actual): October 1, 2012
• Study Completion (Actual): October 1, 2012

Study Registration Dates

• First Submitted: December 28, 2010
• First Submitted That Met QC Criteria: December 29, 2010
• First Posted (Estimate): December 30, 2010

Study Record Updates

• Last Update Posted (Actual): September 24, 2019
• Last Update Submitted That Met QC Criteria: September 18, 2019
• Last Verified: September 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Immune System Diseases; Neoplasms; Autoimmune Diseases of the Nervous System; Autoimmune Diseases; Neoplasms by Site; Neurologic Manifestations; Musculoskeletal Diseases; Muscular Diseases; Neuromuscular Diseases; Neurodegenerative Diseases; Neuromuscular Manifestations; Nervous System Neoplasms; Paraneoplastic Syndromes, Nervous System; Paraneoplastic Syndromes; Neuromuscular Junction Diseases; Muscle Weakness; Myasthenia Gravis
• Other Study ID Numbers: CY 4023; 1RC3NS070670-01 (U.S. NIH Grant/Contract)