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

NCT ID: NCT01268280

Last Updated: 2019-09-24

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE2
• Total Enrollment: 32 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2010-12-31
• Study Completion Date: 2012-10-31

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.

Conditions

Myasthenia Gravis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Treatment Sequence 1

Dosing Period 1 Placebo; Dosing Period 2 CK-2017357 250 mg; Dosing Period 3 CK-2017357 500 mg

Group Type: EXPERIMENTAL

Placebo

Intervention Type: DRUG

Matching placebo in capsules administered as a single oral dose.

250 mg CK-2017357

Intervention Type: DRUG

250 mg CK-2017357 in capsules administered as a single oral dose.

500 mg CK-2017357

Intervention Type: DRUG

500 mg CK-2017357 in capsules administered as a single oral dose.

Treatment Sequence 2

Dosing Period 1 Placebo; Dosing Period 2 CK-2017357 500 mg; Dosing Period 3 CK-2017357 250 mg

Group Type: EXPERIMENTAL

Placebo

Intervention Type: DRUG

Matching placebo in capsules administered as a single oral dose.

250 mg CK-2017357

Intervention Type: DRUG

250 mg CK-2017357 in capsules administered as a single oral dose.

500 mg CK-2017357

Intervention Type: DRUG

500 mg CK-2017357 in capsules administered as a single oral dose.

Treatment Sequence 3

Dosing Period 1 CK-2017357 250 mg; Dosing Period 2 Placebo; Dosing Period 3 CK-2017357 500 mg

Group Type: EXPERIMENTAL

Placebo

Intervention Type: DRUG

Matching placebo in capsules administered as a single oral dose.

250 mg CK-2017357

Intervention Type: DRUG

250 mg CK-2017357 in capsules administered as a single oral dose.

500 mg CK-2017357

Intervention Type: DRUG

500 mg CK-2017357 in capsules administered as a single oral dose.

Treatment Sequence 4

Dosing Period 1 CK-2017357 250 mg; Dosing Period 2 CK-2017357 500 mg; Dosing Period 3 Placebo

Group Type: EXPERIMENTAL

Placebo

Intervention Type: DRUG

Matching placebo in capsules administered as a single oral dose.

250 mg CK-2017357

Intervention Type: DRUG

250 mg CK-2017357 in capsules administered as a single oral dose.

500 mg CK-2017357

Intervention Type: DRUG

500 mg CK-2017357 in capsules administered as a single oral dose.

Treatment Sequence 5

Dosing Period 1 CK-2017357 500 mg; Dosing Period 2 Placebo; Dosing Period 3 CK-2017357 250 mg

Group Type: EXPERIMENTAL

Placebo

Intervention Type: DRUG

Matching placebo in capsules administered as a single oral dose.

250 mg CK-2017357

Intervention Type: DRUG

250 mg CK-2017357 in capsules administered as a single oral dose.

500 mg CK-2017357

Intervention Type: DRUG

500 mg CK-2017357 in capsules administered as a single oral dose.

Treatment Sequence 6

Dosing Period 1 CK-2017357 500 mg; Dosing Period 2 CK-2017357 250 mg; Dosing Period 3 Placebo

Group Type: EXPERIMENTAL

Placebo

Intervention Type: DRUG

Matching placebo in capsules administered as a single oral dose.

250 mg CK-2017357

Intervention Type: DRUG

250 mg CK-2017357 in capsules administered as a single oral dose.

500 mg CK-2017357

Intervention Type: DRUG

500 mg CK-2017357 in capsules administered as a single oral dose.

Interventions

Placebo

Matching placebo in capsules administered as a single oral dose.

Intervention Type: DRUG

250 mg CK-2017357

250 mg CK-2017357 in capsules administered as a single oral dose.

Intervention Type: DRUG

500 mg CK-2017357

500 mg CK-2017357 in capsules administered as a single oral dose.

Intervention Type: DRUG

Other Intervention Names

tirasemtiv; tirasemitiv

Eligibility 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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Institute of Neurological Disorders and Stroke (NINDS)

NIH

Sponsor Role: collaborator

Cytokinetics

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Andrew Wolff, MD, FACC

Role: STUDY_DIRECTOR

Cytokinetics, Inc.

Locations

UCSF - Fresno

Fresno, California, United States

University of California - Irvine

Orange, California, United States

California Pacific Medical Center

San Francisco, California, United States

Stanford University

Stanford, California, United States

Hospital for Special Care

New Britain, Connecticut, United States

The University of Kansas Medical Center

Kansas City, Kansas, United States

Johns Hopkins

Baltimore, Maryland, United States

Neurocare Center for Research

Newton, Massachusetts, United States

University of North Carolina

Chapel Hill, North Carolina, United States

Duke University

Durham, North Carolina, United States

Drexel University College of Medicine

Philadelphia, Pennsylvania, United States

West Penn Allegheny Health System

Pittsburgh, Pennsylvania, United States

Baylor College of Medicine

Houston, Texas, United States

University of Texas Health Science Center

San Antonio, Texas, United States

University of Virginia Health System

Charlottesville, Virginia, United States

Countries

United States

References

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

Reference Type: RESULT

Other Identifiers

1RC3NS070670-01

Identifier Type: NIH

Identifier Source: secondary_id

View Link

CY 4023

Identifier Type: -

Identifier Source: org_study_id