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

Myasthenia Gravis Clinical Trial

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01268280
• Other study ID #: CY 4023
• Secondary ID: 1RC3NS070670-01
• Status: Terminated
• Phase: Phase 2
• Start date: December 2010
• Est. completion date: October 2012

Study information

• Verified date: September 2019
• Source: Cytokinetics
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 32
• Est. completion date: October 2012
• Est. primary completion date: October 2012
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

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

Related Conditions & MeSH terms

• Muscle Weakness
• Myasthenia Gravis

Intervention

Drug:
• Placebo
Matching placebo in capsules administered as a single oral dose.
• 250 mg CK-2017357
250 mg CK-2017357 in capsules administered as a single oral dose.
• 500 mg CK-2017357
500 mg CK-2017357 in capsules administered as a single oral dose.

Locations

Country	Name	City	State
United States	Johns Hopkins	Baltimore	Maryland
United States	University of North Carolina	Chapel Hill	North Carolina
United States	University of Virginia Health System	Charlottesville	Virginia
United States	Duke University	Durham	North Carolina
United States	UCSF - Fresno	Fresno	California
United States	Baylor College of Medicine	Houston	Texas
United States	The University of Kansas Medical Center	Kansas City	Kansas
United States	Hospital for Special Care	New Britain	Connecticut
United States	Neurocare Center for Research	Newton	Massachusetts
United States	University of California - Irvine	Orange	California
United States	Drexel University College of Medicine	Philadelphia	Pennsylvania
United States	West Penn Allegheny Health System	Pittsburgh	Pennsylvania
United States	University of Texas Health Science Center	San Antonio	Texas
United States	California Pacific Medical Center	San Francisco	California
United States	Stanford University	Stanford	California

Sponsors (2)

Lead Sponsor	Collaborator
Cytokinetics	National Institute of Neurological Disorders and Stroke (NINDS)

Country where clinical trial is conducted

United States, 

References & Publications (1)

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

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	Pulmonary Function Test (VC in liters)	Forced Vital Capacity	1 day
Primary	Manual Muscle Test (MMT)	Sum of strength or function values assessed by physician on the neck, shoulder, hip and ankle	1 day
Secondary	Characterize dose and plasma concentrations of CK-2017357 and QMG		2 days
Secondary	Characterize dose and plasma concentrations of CK-2017357 and Forced Vital Capacity (FVC)		2 days
Secondary	Characterize dose and plasma concentrations of CK-2017357 and Manual Muscle Test (MMT)		2 days
Secondary	Number of patients with adverse events		4 weeks
Secondary	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
Secondary	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
Secondary	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