Clinical Trials Register

Summary
EudraCT Number:	2012-001645-41
Sponsor's Protocol Code Number:	JAK115919
National Competent Authority:	Estonia - SAM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2012-11-27
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

Estonia - SAM

A.2

EudraCT number

2012-001645-41

A.3

Full title of the trial

An adaptive Phase II study to evaluate the efficacy, pharmacodynamics, safety and tolerability of GSK2586184 in patients with active systemic lupus erythematosus.

A.3.1

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

A study to assess the efficacy and safety of GSK2586184 in SLE

A.4.1

Sponsor's protocol code number

JAK115919

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	GlaxoSmithKline Research and Development Limited
B.1.3.4	Country	United Kingdom
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	GSK
B.4.2	Country	United Kingdom
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	GlaxoSmithKline
B.5.2	Functional name of contact point	Clinical Trials Helpdesk
B.5.3	Address:
B.5.3.1	Street Address	Iron Bridge Road
B.5.3.2	Town/ city	Uxbridge
B.5.3.3	Post code	UB11 1BU
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	+44 02089904466
B.5.5	Fax number	+44020 89901234
B.5.6	E-mail	GSKClinicalSupportHD@gsk.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	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	GSK2586184
D.3.2	Product code	GSK2586184
D.3.4	Pharmaceutical form	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	GSK2586184
D.3.9.1	CAS number	1206163-45-2
D.3.9.2	Current sponsor code	GSK2586184
D.3.9.3	Other descriptive name	N-(5-{4-[(3,3-dimethyl-1-azetidinyl)carbonyl]phenyl}[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide
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.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	No
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	GSK2586184
D.3.2	Product code	GSK2586184
D.3.4	Pharmaceutical form	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	GSK2586184
D.3.9.1	CAS number	1206163-45-2
D.3.9.2	Current sponsor code	GSK2586184
D.3.9.3	Other descriptive name	N-(5-{4-[(3,3-dimethyl-1-azetidinyl)carbonyl]phenyl}[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide
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	200
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	Tablet
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

Systemic Lupus Erythematosus

E.1.1.1

Medical condition in easily understood language

Systemic Lupus Erythematosus (chronic autoimmune disorder)

E.1.1.2

Therapeutic area

Body processes [G] - Bones and nerves physological processes [G11]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	16.0
E.1.2	Level	PT
E.1.2	Classification code	10042945
E.1.2	Term	Systemic lupus erythematosus
E.1.2	System Organ Class	10028395 - Musculoskeletal and connective tissue disorders

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

• To estimate the relationship between dose of GSK2586184 and pharmacodynamic effect on expression of selected messenger ribonucleic acid (mRNA) transcripts following 2 weeks of treatment in SLE patients
• To estimate the relationship between dose of GSK2586184 and clinical response as assessed by SELENA SLEDAI score following 12 weeks of treatment in SLE patients
• To evaluate the safety and tolerability of repeat doses of GSK2586184 in SLE patients.

E.2.2

Secondary objectives of the trial

• To estimate the relationship between dose of GSK2586184 and clinical response as assessed by the SRI following 12 weeks of treatment in SLE patients
• To estimate the relationship between dose of GSK2586184 and clinical response as assessed by the SLEDAI-2K and S2K RI-50 scores following 12 weeks of treatment in SLE patients
• To estimate the relationship between changes in the expression of selected mRNA transcripts following dosing with GSK2586184 and clinical response
• To assess the pharmacokinetics of GSK2586184 in SLE patients.
• To define the PK/PD relationship of JAK-1 inhibition on the interferon (IFN) transcriptional signature biomarker following 2 weeks of treatment.
• To define the PK/PD relationship of JAK-1 inhibition on clinical response parameters following 12 weeks of treatment.
• To estimate any impact of GSK2586184 treatment on patient reported outcomes

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Subjects eligible for enrolment in the study must meet all of the following criteria:
1. Age and Gender: Male or female between 18 and 75 years of age inclusive, at the time of signing the informed consent.
2. SLE classification: Have a clinical diagnosis of SLE according to the American College of Rheumatology (ACR) classification criteria, with 4 or more of the 11 ACR criteria present, serially or simultaneously during any interval or observation.
3. Severity of disease: Have clinically active SLE disease defined as a SELENA SLEDAI score ≥8 at screening during the 35-day screen period.
4. Auto antibodies: Are serologically active having unequivocally positive antinuclear antibody (ANA) or anti-double stranded DNA (anti-dsDNA) antibody test results from 2 independent time points as follows:
• Positive test results from 2 independent time points within the study screening period. Screening results must be based on the study’s central laboratory results. A positive test is defined as a positive ANA test equivalent to a titre ≥1:80 as defined in the central laboratory manual and/or a positive anti-dsDNA (≥30 IU/mL) serum antibody.
OR
• One positive historical test result and 1 positive test result for either ANA or anti-dsDNA during the screening period.
Historical documentation of a positive test of ANA (e.g., ANA by HEp-2 titre) or anti-dsDNA antibody (e.g., anti-dsDNA by Farr assay) must include the date and type of the test, the name of the testing laboratory, numerical reference range, and a key that explains values provided as positive vs. negative OR negative,
equivocal/borderline positive). Only unequivocally positive values as defined in the laboratory’s reference range are acceptable; borderline values will not be accepted.
5. Treatment for SLE: patient stable on either no treatment or on a stable dose of corticosteroids (≤15mg/day prednisone or prednisone equivalent or less) stable for a minimum of 30 days prior to screening and through to Day 0/Randomisation and /or an anti-malarial therapy[hydroxychloroquine (≤400mg daily dose) or chloroquine (≤ 500mg daily dose) or quinacrine ( ≤100mg daily dose)]for a minimum of 60 days prior to the Day 0/Randomisation Visit. Subjects receiving azathioprine (≤ 2mg/kg/day or ≤ 150mg/day, whichever is greater) or mycophenolate mofetil (≤ 1.5g/day), or MTX (≤20mg/week), either alone or in addition to steroids and / or an anti-malarial therapy as described above, if they have been on a stable dose of azathioprine OR
mycophenolate mofetil OR MTX for a minimum of 90 days prior to the Day 0 /Randomisation Visit.
For those subjects on alternating day dosing of steroids, use the average of 2 daily doses to calculate the average daily steroid dose.
6. ECG: Single QTc, < 450 msec; or QTc < 480 msec in subjects with Bundle Branch Block.
7. Prevention of Pregnancy:
Females: A female subject is eligible to participate if she is not pregnant, as confirmed by a negative serum human chorionic gonadotrophin (hCG) test, or lactating and at least one of the following conditions applies: Please refer to page 41 bullet point 7 of the study protocol for details.
8. Informed consent: Capable of giving written informed consent, including confirmation that the subject is not mentally or legally incapacitated, and compliance with the requirements and restrictions listed in the consent form.
French subjects: In France, a subject will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category.

E.4

Principal exclusion criteria

Subjects meeting any of the following criteria must not be enrolled in the study:
1. Kidney Disease
2. CNS Disease
3. Alcohol Abuse
4. Substance Abuse
5. Hepatitis B
6. Hepatitis C
7. HIV
8. Previous investigational product exposure
9. Previous and current medication
10. Prior biological therapies
11. Transplantation
12. Uncontrolled Other Diseases
13. Surgery and Other Conditions
14. Cancer
15. Infections
16. Mycobacterium Tuberculosis
17. Haematology
18. Serum immunoglobulin (Ig) levels
19. Liver Function Tests
20. Other laboratory abnormalities
21. Drug sensitivity
22. Blood donation
* Please refer to the study protocol section 5.3 Exclusion Criteria pages 43-44 for further details.

E.5 End points

E.5.1

Primary end point(s)

1. Interferon transcriptional signature biomarker expression over time (Interim Analysis 1, Primary Endpoint)
2. SELENA SLEDAI score over time (Interim Analysis 2, 3 and final analysis, Primary Endpoint)
3. Change from baseline for blood pressure, heart rate and temperature over time.
4. Change from baseline in clinical chemistry and hematology parameters over time.
5. Number and severity of adverse events during the study period.

E.5.1.1

Timepoint(s) of evaluation of this end point

* Primary endpoints 1 to 5 will be evaluated during the 12 week treatment period.
* Primary endpoint 1 is the key decision making pharmacodynamic endpoint at Interim Analysis 1 after the first 25 subjects have been treated for 2 weeks
* Primary endpoint 2 is the key decision making clinical efficacy primary endpoint at Interim Analyses 2 and 3 (if conducted)

E.5.2

Secondary end point(s)

1. SRI Response Rate over time. Response is defined as:
≥ 4 point reduction from baseline in the SELENA SLEDAI score,
AND
No worsening (increase of <0.30 points from baseline) in Physicians Global Assessment (PGA)
AND
No new British Isles Lupus Assessment Group (BILAG) A organ domain score or 2 new BILAG B organ domain scores compared with baseline.
To evaluate the response over time, the percentage of subjects achieving a response on the composite endpoint, and each of the components of this endpoint, will be presented by visit.
2. Change from baseline in SLEDAI-2K score and the S2K RI-50 score during 12 weeks of treatment with GSK2586184
3. Individual plasma concentrations of GSK2586184 and data permitting, summary PK parameters.
4. Mean change from baseline in Short Form-36 Health Survey (SF-36) score (8 domains) at Week 12.
5. Mean change from baseline in Brief Fatigue Inventory (BFI) score (9 items) at Weeks 2, 4, 6, 8, 10 and 12.
6. Mean change from baseline in Brief Pain Inventory (BPI) (short form) score (15 items) at weeks 2, 4, 6, 8, 10 and 12.

E.5.2.1

Timepoint(s) of evaluation of this end point

Secondary endpoints 1 through 6 will be evaluated during the 12 week treatment period.

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

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

E.6.10

Pharmacogenetic

Yes

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

tolerability of GSK2586184 in adult patients with active SLE.

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

Yes

E.8.1.7.1

Other trial design description

Adaptive

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

Argentina

Brazil

Chile

Hong Kong

Korea, Republic of

Peru

South Africa

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

LSLV

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

E.8.9.2

In all countries concerned by the trial days

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:

175

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

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

137

F.4.2.2

In the whole clinical trial

250

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)

The investigator is responsible for ensuring that consideration has been given to the poststudy
care of the patient’s medical condition whether or not GSK is providing specific post study treatment.

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

2012-12-28

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-12-20

P. End of Trial
P.	End of Trial Status	Completed

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