A Study to Evaluate the Effects of Multiple Doses of CK-2017357 in Patients With Amyotrophic Lateral Sclerosis (ALS)

Study Overview
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Brief Summary
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The study will generate data on safety, tolerability and pharmacokinetics after multiple daily doses of CK-2017357 in patients with ALS. Patients will be randomized into one of four different treatment groups, receiving daily oral doses of either placebo, 125 mg, 250 mg, or 375 mg of CK-2017357 for 14 days.

Detailed Description
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In Part A, approximately 24 patients will be randomized to one of four different treatment groups. After a 7-day washout of riluzole, patients in each treatment group will receive daily oral doses of placebo, 125 mg, 250 mg, or 375 mg of CK-2017357 for 14 days. Patients will take daily doses of CK-2017357 or placebo (Day 1 through Day 14) and will return to the study site on Day 2, Day 8 and Day 15. All patients will return for a follow-up visit 7 days (± 2 days) after their last dose. In Part B, approximately additional 24 patients will be randomized to one of four different treatment groups as in Part A. Patients in Part B will be required to decrease their riluzole dose to 50 mg once a day (QD) for 7 days prior to randomization. After this 7 day period, patients will take riluzole at 50 mg QD concurrently with their morning dose of blinded study drug.

Official Title
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A Phase II, Double-Blind, Randomized, Placebo-Controlled Study to Evaluate the Effects of Multiple Doses of CK-2017357 in Patients With Amyotrophic Lateral Sclerosis (ALS)

Conditions
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Amyotrophic Lateral Sclerosis

Intervention / Treatment
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* Drug: Placebo (Part A)
* Drug: CK-2017357 (Part A)
* Drug: CK-2017357 (Part A)
* Drug: CK-2017357 (Part A)
* Drug: Riluzole 50 MG (Part B)
* Drug: Placebo (Part B)
* Drug: CK-2017357 (Part B)
* Drug: CK-2017357 (Part B)
* Drug: CK-2017357 (Part B)


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Able to comprehend and willing to sign an Informed Consent Form (ICF) Males or females 18 years of age or older A diagnosis of familial or sporadic ALS (defined as meeting the possible, laboratory-supported probable, probable, or definite criteria for a diagnosis of ALS according to the World Federation of Neurology El Escorial criteria) Maximum voluntary grip strength in at least one hand between 10 & 40 pounds (females) and 10 & 60 pounds (males) Upright Slow Vital Capacity (SVC) >50% of predicted for age, height, and sex Able to swallow tablets with water Willing and able to remain off riluzole for 4 weeks (Part A only) Currently taking and tolerating a stable dose of 50 mg BID riluzole (Part B only) Willing and able to reduce daily dose of riluzole to 50 mg for 4 weeks (Part B only) Willing and able to refrain from caffeine-containing products during study participation Willing and able to remain off warfarin and theophylline-containing medications during study participation Has a caregiver who is capable of observing and reporting patient status, and also assisting in the proper use of nocturnal oximetry equipment Able to perform pulmonary function tests Key Exclusion Criteria: Life expectancy <3 months Participation in any trial in which receipt of investigational study drug occurred within 30 days or 5 half-lives of the prior agent, whichever is greater, prior to dosing Any prior treatment with CK-2017357 Use of non-invasive positive pressure ventilation (NIPPV) for any part of the day or night Other protocol-defined inclusion/exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Matching Placebo<br> | Drug: Placebo (Part A)<br>* Placebo tablets once daily for 14 days (Part A)<br>Drug: Riluzole 50 MG (Part B)<br>* One 50 mg tablet once daily for 14 days (Part B)<br>Drug: Placebo (Part B)<br>* Placebo tablets once daily for 14 days (Part B)<br>|
| Experimental: Active Drug Low Dose (CK-2017357 125 mg)<br> | Drug: Placebo (Part A)<br>* Placebo tablets once daily for 14 days (Part A)<br>Drug: CK-2017357 (Part A)<br>* One 125 mg CK-2017357 tablet once daily for 14 days (Part A)<br>* Other names: tirasemtiv;Drug: Riluzole 50 MG (Part B)<br>* One 50 mg tablet once daily for 14 days (Part B)<br>Drug: Placebo (Part B)<br>* Placebo tablets once daily for 14 days (Part B)<br>Drug: CK-2017357 (Part B)<br>* One 125 mg tablet once daily for 14 days (Part B)<br>* Other names: tirasemtiv;|
| Experimental: Active Drug Mid Dose (CK-2017357 250 mg)<br> | Drug: Placebo (Part A)<br>* Placebo tablets once daily for 14 days (Part A)<br>Drug: CK-2017357 (Part A)<br>* Two 125 mg CK-2017357 tablets once daily for 14 days (Part A)<br>* Other names: tirasemtiv;Drug: Riluzole 50 MG (Part B)<br>* One 50 mg tablet once daily for 14 days (Part B)<br>Drug: Placebo (Part B)<br>* Placebo tablets once daily for 14 days (Part B)<br>Drug: CK-2017357 (Part B)<br>* Two 125 mg tablets once daily for 14 days (Part B)<br>* Other names: tirasemtiv;|
| Experimental: Active Drug High Dose (CK-2017357 375 mg)<br> | Drug: CK-2017357 (Part A)<br>* Three 125 mg CK-2017357 tablets once daily for 14 days (Part A)<br>* Other names: tirasemtiv;Drug: Riluzole 50 MG (Part B)<br>* One 50 mg tablet once daily for 14 days (Part B)<br>Drug: CK-2017357 (Part B)<br>* Three 125 mg tablets once daily for 14 days (Part B)<br>* Other names: tirasemtiv;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants with Adverse Events as a Measure of Safety and Tolerability | Safety and tolerability of CK-2017357 after multiple oral doses to steady state in patients with ALS | 21 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) | An instrument for evaluating the functional status of patients with ALS. Minimum score is 0 and maximum score is 40. The higher the score the more function is retained. | 21 days | 
| Measurement of Grip Strength and Handgrip Fatigue | Measured using the DynEx Electronic Hand Dynamometer. Patients asked to squeeze the device with the maximum possible force to establish the maximum voluntary contraction. Handgrip fatigue is then measured. Patient is asked to squeeze the device until they can no longer stay above 60% of target or 120 seconds. | 21 days | 
| Measurement of muscle strength | Muscle strength is measured using Hand Held Dynamometry. A series of assessments are done on different muscle groups. | 21 days | 
| Measurement of Slow Vital Capacity (SVC) | SVC will be measured using the ndd EasyOne Spirometer System at Screening, Day -7, Day 1, Day 2, Day 8, Day 15 and at the Follow-Up Visit | 21 days | 
| Measurement of Sniff Nasal Inspiratory Pressure (SNIP) | SNIP will be measured using the Micro Medical Respiratory Pressure Meter (MicroRPM) at Screening, Day -7, Day 1, Day 2, Day 8, Day 15 and at the Follow-Up Visit | 21 days | 
| Measurement of Maximum Voluntary Ventilation (MVV) | MVV will be measured using the EasyOne Spirometer System at Screening, Day -7, Day 1, Day 2, Day 8, Day 15 and at the Follow-Up Visit | 21 days | 
| Patient global assessment | Patients will be asked to assess whether they feel the same, better or worse as compared to how they felt at pre-dose on Day 1 | 15 days | 
| Investigator global assessment | Investigator will assess whether the patient appears the same, better or worse as compared to the patient's status at pre-dose on Day 1. | 15 days |