Clinical Trials Register

Summary
EudraCT Number:	2012-004987-23
Sponsor's Protocol Code Number:	CY4026
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2012-12-12
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

UK - MHRA

A.2

EudraCT number

2012-004987-23

A.3

Full title of the trial

A Phase IIb, multi-national, double-blind, randomised, placebo-controlled study to evaluate the safety, tolerability and efficacy of CK-2017357 in patients with amyotrophic lateral sclerosis (ALS)

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

A study in which patients suffering from amyotrophic lateral sclerosis (ALS) may be assigned randomly to receive either the treatment or placebo to look at how safe the product is, whether it has an effect and is easy to take.

A.4.1

Sponsor's protocol code number

CY4026

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT01709149

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Cytokinetics Inc
B.1.3.4	Country	United States
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Cytokinetics Inc
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Cytokinetics Inc
B.5.2	Functional name of contact point	Medical Affairs
B.5.3	Address:
B.5.3.1	Street Address	280 East Grand Avenue,
B.5.3.2	Town/ city	South San Francisco,
B.5.3.3	Post code	CA 94080
B.5.3.4	Country	United States
B.5.4	Telephone number	0016506242929
B.5.5	Fax number	0016506243010
B.5.6	E-mail	medicalaffairs@cytokinetics.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	Yes
D.2.5.1	Orphan drug designation number	EU/3/12/970
D.3 Description of the IMP
D.3.1	Product name	Tirasemtiv
D.3.2	Product code	CK2017357
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Tirasemtiv
D.3.9.1	CAS number	1005491-05-3
D.3.9.2	Current sponsor code	CK-2017357
D.3.9.3	Other descriptive name	6-ethynyl-1-(pentan-3-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	125
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Rilutek
D.2.1.1.2	Name of the Marketing Authorisation holder	Aventis Pharma S.A
D.2.1.2	Country which granted the Marketing Authorisation	European Union
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Riluzole
D.3.4	Pharmaceutical form	Capsule
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	RILUZOLE
D.3.9.1	CAS number	1744-22-5
D.3.9.4	EV Substance Code	SUB10319MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	50
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Film-coated tablet
D.8.4	Route of administration of the placebo	Oral use
D.8 Placebo: 2
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Capsule
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Amyotrophic lateral sclerosis

E.1.1.1

Medical condition in easily understood language

Amyotropic lateral sclerosis is a form of motor neurone disease where attacks of the nerve cells responsible for sending instructions to the muscles lead to weakness, muscle waste and paralysis.

E.1.1.2

Therapeutic area

Body processes [G] - Immune system processes [G12]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.1
E.1.2	Level	PT
E.1.2	Classification code	10002026
E.1.2	Term	Amyotrophic lateral sclerosis
E.1.2	System Organ Class	10029205 - Nervous system disorders

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

To assess the effect of CK-2017357 versus placebo on the ALSFRS-R total score when administered twice daily at each patients's maximum tolerated dose, up to a maximum of 500 mg daily.

E.2.2

Secondary objectives of the trial

Exploration of alternative methods to assess the effect of CK-2017357 versus placebo on the change from baseline in the ALSFRS-R score and to assess the effect of CK-2017357 versus placebo on certain measures of respitratory and skeletal muscle function.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Able to comprehend and willing to sign an informed consent form (ICF)
2. Male or female 18 years or older
3. A diagnosis of familial or sporadic ALS (defined as meeting the possible, laboratory probable, probable, or definite criteria for a diagnosis of ALS according to the World Federation of Neurology EI escorial criteria)
4. Upright Slow Vital Capacity (SVC) > 50% of predicted for age, height and sex
5. At least 4 of the 12 ALSFRS-R questions must be scored 2 or 3
6. Diminished but measurable maximum voluntary grip strength in at least one hand; i.e. between 10 and 50 pounds (females) and 10 and 70 pounds (males)
7. Able to swallow tablets without crushing, and in the opinion of the Investigator, is expected to do so for the duration of the study
8. A caregiver (if one is needed) who can and will observe and report the patient's status
9. Pre-study clinical laboratory findings within normal range, or if outside, of the normal range, deemed not clinically significant by the Investigator
10. Male patients must agree for the duration of the study and 10 weeks after the end of the study to use a condom during sexual intercourse with female partners who are of reporduction potential and to have female partners use an additional effective means of contraception (e.g. diaphragm plus spermicide, or oral contraceptives) or the male patients must agree to abstain from sexual intercourse during and for 10 weeks after the end of the study
11. Female patients must be post-menopausal (≥ 1 year) or sterilized, or, if of childbearing potential, not be breastfeeding, have a negative pregnancy test, have no intention to become pregnant during the course of the study, and use contraceptive drugs or devices as detailed in item 10 for the duration of the study and for 10 weeks after the end of the study.
12. Patients must be either on a stable dose of riluzole 50 mg twice daily for at least 30 dats prior to screening or have not taken riluzole for at least 30 days prior to screening and are willing not to begin riluzole use during the conduct of this study.

E.4

Principal exclusion criteria

1. Any use of non-invasive positive pressure ventilation (NIPPV, e.g. CPAP or BiPAP) for any protion of the day, or mechanical ventilation via tracheostomy, or on any form of oxygen supplementation.
2. Patients with a diaphragm pacing system (DPS) at study entry or who anticipates DPS placement during the course of the study.
3. Body Mass Index (BMI) of 19.0 kg/m² or lower
4. Unwilling to discontinue tizanidine and theophylline-containing medications during the study participation
5. Serum chloride < 100 mmol/dl
6. Neurological impairment due to a condition other than ALS, including a history of TIA within the past year
7. Presence at screening of any medically significant cardiac, pulmonary, GI, musculoskeletal or psychiatric illness that might interfere with the patient's ability to comply with study procedures or that might confound the interpretation of clinical safety or efficacy data, including, but not limited to:
a. Poorly controlled hypertension
b. NYHA Class II or greater congestive heart failure
c. Clinically significant ECG abnormalities
d. Chronic obstructive pulmonary disease or asthma requiring frequent use of bronchodilator medications
e. History of sleep apnea requiring CPAP or oxygen supplementation
f. GI disorder that might impair absorption of study drug from the gastorintestinal tract
g. History of significant liver disease defined by bilirubin > 2 times the upper limit of normal (ULN) or alanine transferase (ALT) or aspartate aminotransferase (AST) > 3 times the ULN on repeat testing
h. Poorly controlled diabetes mellitus
i. History of vertigo within 3 months of study entry
j. History of syncope without an explainable or treated cause
k. History of untreated intracranial aneurysm or poorly controlled seizure disorder
l. Amputation of a limb
m. Cognitive impairment, related to ALS or otherwise, sufficient to impair the patient's ability to understand and/or comply with study procedures and giving informed consent
n. Cancer with metatstic potential (other than basal cell carcinoma, carcinoma in situ of cervix, or squamous cell carcinoma of the skin excised with clean margins) daignosed and treated within the last 2 years
o. Any other condition, impairment or social circumstance that, in the opinion of the Investigator, would render the patient not suitable to participate in the study.
p. Patient judged to be actively suicidal and a suicide risk by the Investigator.
8. Has taken any investigational study drug within 30 days or 5 half-lives of the prior agent, whichever is greater, prior to dosing.
9. Previously received CK-2017357 in any previous trial

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint is the change from baseline to the average of the ALSFRS-R total score obtained at Visits 6 and 7 (i.e. after approximately 8 and 12 weeks of double-blind treatment)

E.5.1.1

Timepoint(s) of evaluation of this end point

After 8-12 weeks of double-blind treatment

E.5.2

Secondary end point(s)

1. ALSFRS-R enpoints for secondary analyses
2. Respiratory function
- Maximum Voluntary Ventilation (MVV)
- Sniff Nasal Inspiratory Pressure (SNIP)
- Slow Vital Capacity (SVC)
3. Skeletal muscle function
- Handgrip strength and fatigability
-Maximum handgrip strenth
-Sub-maximum handgrip fatigue
-Muscle strength by hand-held dynamometry (HDD) as determined by the megascore of:
-Elbow flexion (bilateral)
- Wrist extension (bilateral)
- Knee extension (bilateral)
-Ankle dorsiflexion (bilateral)

E.5.2.1

Timepoint(s) of evaluation of this end point

At visit 5, 6, 7, 8 and follow-up

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Canada

United States

E.8.7

Trial has a data monitoring committee

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

Last visit last subject

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

700

F.1.3

Elderly (>=65 years)

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

280

F.4.2.2

In the whole clinical trial

700

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

None but patients currently taking riluzole can resume their prescribed dose of riluzole (50 mg twice daily) starting the day after their last dose of study drug.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2013-01-23

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-01-24

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2014-03-21

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