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

Primary Purpose

Myasthenia Gravis

Status
Terminated
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Placebo
250 mg CK-2017357
500 mg CK-2017357
Sponsored by
Cytokinetics
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Myasthenia Gravis

Eligibility Criteria

18 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • UCSF - Fresno
  • University of California - Irvine
  • California Pacific Medical Center
  • Stanford University
  • Hospital for Special Care
  • The University of Kansas Medical Center
  • Johns Hopkins
  • Neurocare Center for Research
  • University of North Carolina
  • Duke University
  • Drexel University College of Medicine
  • West Penn Allegheny Health System
  • Baylor College of Medicine
  • University of Texas Health Science Center
  • University of Virginia Health System

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm Type

Experimental

Experimental

Experimental

Experimental

Experimental

Experimental

Arm Label

Treatment Sequence 1

Treatment Sequence 2

Treatment Sequence 3

Treatment Sequence 4

Treatment Sequence 5

Treatment Sequence 6

Arm Description

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

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

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

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

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

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

Outcomes

Primary Outcome Measures

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.
Pulmonary Function Test (VC in liters)
Forced Vital Capacity
Manual Muscle Test (MMT)
Sum of strength or function values assessed by physician on the neck, shoulder, hip and ankle

Secondary Outcome Measures

Characterize dose and plasma concentrations of CK-2017357 and QMG
Characterize dose and plasma concentrations of CK-2017357 and Forced Vital Capacity (FVC)
Characterize dose and plasma concentrations of CK-2017357 and Manual Muscle Test (MMT)
Number of patients with adverse events
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
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
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

Full Information

First Posted
December 28, 2010
Last Updated
September 18, 2019
Sponsor
Cytokinetics
Collaborators
National Institute of Neurological Disorders and Stroke (NINDS)
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1. Study Identification

Unique Protocol Identification Number
NCT01268280
Brief Title
Pharmacodynamic Study of CK-2017357 in Patients With Generalized Myasthenia Gravis
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
Study Type
Interventional

2. Study Status

Record Verification Date
September 2019
Overall Recruitment Status
Terminated
Why Stopped
Closed after complete treatment of 32 patients after 21 months' recruitment.
Study Start Date
December 2010 (undefined)
Primary Completion Date
October 2012 (Actual)
Study Completion Date
October 2012 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Cytokinetics
Collaborators
National Institute of Neurological Disorders and Stroke (NINDS)

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Myasthenia Gravis

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Crossover Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
32 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Treatment Sequence 1
Arm Type
Experimental
Arm Description
Dosing Period 1 Placebo; Dosing Period 2 CK-2017357 250 mg; Dosing Period 3 CK-2017357 500 mg
Arm Title
Treatment Sequence 2
Arm Type
Experimental
Arm Description
Dosing Period 1 Placebo; Dosing Period 2 CK-2017357 500 mg; Dosing Period 3 CK-2017357 250 mg
Arm Title
Treatment Sequence 3
Arm Type
Experimental
Arm Description
Dosing Period 1 CK-2017357 250 mg; Dosing Period 2 Placebo; Dosing Period 3 CK-2017357 500 mg
Arm Title
Treatment Sequence 4
Arm Type
Experimental
Arm Description
Dosing Period 1 CK-2017357 250 mg; Dosing Period 2 CK-2017357 500 mg; Dosing Period 3 Placebo
Arm Title
Treatment Sequence 5
Arm Type
Experimental
Arm Description
Dosing Period 1 CK-2017357 500 mg; Dosing Period 2 Placebo; Dosing Period 3 CK-2017357 250 mg
Arm Title
Treatment Sequence 6
Arm Type
Experimental
Arm Description
Dosing Period 1 CK-2017357 500 mg; Dosing Period 2 CK-2017357 250 mg; Dosing Period 3 Placebo
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Matching placebo in capsules administered as a single oral dose.
Intervention Type
Drug
Intervention Name(s)
250 mg CK-2017357
Other Intervention Name(s)
tirasemtiv
Intervention Description
250 mg CK-2017357 in capsules administered as a single oral dose.
Intervention Type
Drug
Intervention Name(s)
500 mg CK-2017357
Other Intervention Name(s)
tirasemitiv
Intervention Description
500 mg CK-2017357 in capsules administered as a single oral dose.
Primary Outcome Measure Information:
Title
Quantitative Myasthenia Gravis score (QMG)
Description
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.
Time Frame
1 day
Title
Pulmonary Function Test (VC in liters)
Description
Forced Vital Capacity
Time Frame
1 day
Title
Manual Muscle Test (MMT)
Description
Sum of strength or function values assessed by physician on the neck, shoulder, hip and ankle
Time Frame
1 day
Secondary Outcome Measure Information:
Title
Characterize dose and plasma concentrations of CK-2017357 and QMG
Time Frame
2 days
Title
Characterize dose and plasma concentrations of CK-2017357 and Forced Vital Capacity (FVC)
Time Frame
2 days
Title
Characterize dose and plasma concentrations of CK-2017357 and Manual Muscle Test (MMT)
Time Frame
2 days
Title
Number of patients with adverse events
Time Frame
4 weeks
Title
Modified MG Symptom Score
Description
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
Time Frame
2 days
Title
Patient Global Assessment
Description
Patients answer a single question as to whether they feel the same, better or worse as compared to how they felt pre-dose
Time Frame
2 days
Title
Investigator Global Assessment
Description
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
Time Frame
2 days

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
No
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Andrew Wolff, MD, FACC
Organizational Affiliation
Cytokinetics, Inc.
Official's Role
Study Director
Facility Information:
Facility Name
UCSF - Fresno
City
Fresno
State/Province
California
ZIP/Postal Code
93721
Country
United States
Facility Name
University of California - Irvine
City
Orange
State/Province
California
ZIP/Postal Code
92868
Country
United States
Facility Name
California Pacific Medical Center
City
San Francisco
State/Province
California
ZIP/Postal Code
94115
Country
United States
Facility Name
Stanford University
City
Stanford
State/Province
California
ZIP/Postal Code
94305
Country
United States
Facility Name
Hospital for Special Care
City
New Britain
State/Province
Connecticut
ZIP/Postal Code
06053
Country
United States
Facility Name
The University of Kansas Medical Center
City
Kansas City
State/Province
Kansas
ZIP/Postal Code
26506
Country
United States
Facility Name
Johns Hopkins
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21205
Country
United States
Facility Name
Neurocare Center for Research
City
Newton
State/Province
Massachusetts
ZIP/Postal Code
02459
Country
United States
Facility Name
University of North Carolina
City
Chapel Hill
State/Province
North Carolina
ZIP/Postal Code
27599
Country
United States
Facility Name
Duke University
City
Durham
State/Province
North Carolina
ZIP/Postal Code
27710
Country
United States
Facility Name
Drexel University College of Medicine
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19107
Country
United States
Facility Name
West Penn Allegheny Health System
City
Pittsburgh
State/Province
Pennsylvania
ZIP/Postal Code
15212
Country
United States
Facility Name
Baylor College of Medicine
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Facility Name
University of Texas Health Science Center
City
San Antonio
State/Province
Texas
ZIP/Postal Code
78229
Country
United States
Facility Name
University of Virginia Health System
City
Charlottesville
State/Province
Virginia
ZIP/Postal Code
22908
Country
United States

12. IPD Sharing Statement

Citations:
Citation
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
Results Reference
result

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

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