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

• Register: EUCTR
• Last refreshed on: 1 December 2014
• Main ID: EUCTR2012-001645-41-DE
• Date of registration: 16/10/2012
• Prospective Registration: Yes
• Primary sponsor: GlaxoSmithKline Research and Development Limited
• Public title: A study to assess the efficacy and safety of GSK2586184 in SLE
• Scientific title: An adaptive Phase II study to evaluate the efficacy, pharmacodynamics, safety and tolerability of GSK2586184 in patients with active systemic lupus erythematosus.
• Date of first enrolment: 19/02/2013
• Target sample size: 250
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2012-001645-41
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: no Cross over: no Other: yes Other trial design description: Adaptive If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no Number of treatment arms in the trial: 5

Countries of recruitment

Argentina, Brazil, Chile, Czech Republic, Estonia, Germany, Greece, Hong Kong, Hungary, India, Korea, Republic of, Mexico, Peru, Poland, Russian Federation, South Africa, Spain, Sweden, Thailand

Contacts

• Name: Clinical Trials Helpdesk
• Affiliation: GlaxoSmithKline

• Name: Clinical Trials Helpdesk
• Affiliation: GlaxoSmithKline

Key inclusion & exclusion criteria

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 antimalarial 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 antimalarial 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
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.


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Body processes [G] - Bones and nerves physological processes [G11]

Systemic Lupus Erythematosus
MedDRA version: 16.0 Level: PT Classification code 10042945 Term: Systemic lupus erythematosus System Organ Class: 10028395 - Musculoskeletal and connective tissue disorders

Intervention(s)

Product Name: GSK2586184
Product Code: GSK2586184
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: GSK2586184
CAS Number: 1206163-45-2
Current Sponsor code: GSK2586184
Other descriptive name: N-(5-{4-[(3,3-dimethyl-1-azetidinyl)carbonyl]phenyl}[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 50-
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Product Name: GSK2586184
Product Code: GSK2586184
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: GSK2586184
CAS Number: 1206163-45-2
Current Sponsor code: GSK2586184
Other descriptive name: N-(5-{4-[(3,3-dimethyl-1-azetidinyl)carbonyl]phenyl}[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 200-
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Primary Outcome(s)

Secondary Objective: • 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

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.

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)

Main Objective: • 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.

Secondary Outcome(s)

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.

Timepoint(s) of evaluation of this end point: Secondary endpoints 1 through 6 will be evaluated during the 12 week treatment period.

Secondary ID(s)

JAK115919

Source(s) of Monetary Support

GSK