Clinical trial NCT01782664: A Dose Ranging Study to Evaluate the Safety and Efficacy of GSK2586184 in Patients With Chronic Plaque Psoriasis
Official title: A Multi-centre, Randomised, Double-blind, Placebo-controlled, Dose Ranging Study to Evaluate the Safety and Efficacy of GSK2586184 in Patients With Chronic Plaque Psoriasis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Psoriasis
Keywords: PASI
DLQI
GSK2586184
plaque-type psoriasis
PGA
inflammatory gene transcription
JAK-1 inhibitor
serum neopterin
skin biopsy
ACR response criteria
VAS itch score
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2013-02-04
Enrollment: 68
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: A multi-centre, randomised, dose ranging study to evaluate the safety and clinical efficacy of GSK2586184 in patients with chronic plaque psoriasis.

There will be 2 study cohorts (Cohorts A and B). Cohort A is the main study cohort, and this part of the study will be randomised, double-blind and placebo-controlled. Fifty-six subjects will be randomised in Cohort A: 14 subjects in each treatment group: 100 mg, 200 mg or 400 mg GSK2586184, or placebo. Cohort B is an exploratory, open-label investigation of the effect of 400 mg GSK2586184 on inflammatory gene expression in the skin and whole blood, and GSK2586184 concentrations in the skin. A maximum of 8 subjects will be included, and all subjects will take 400 mg GSK2586184.

In both Cohorts A and B, study medication will be administered orally (as tablets), twice daily, for up to 12 weeks.

Each subject will have 7 out-patient visits: Screening; Baseline \& Start of treatment; Week 2; Week 4; Week 8; Week 12; and Follow-up (Week 16)


Eligibility criteria: Inclusion Criteria:

* Otherwise healthy subjects with a diagnosis of moderate to severe plaque psoriasis defined by the following criteria:
* Diagnosed for at least 12 months before the first dose of study medication
* Psoriasis plaques cover \>=10% of body surface area.
* PASI score of \>=12, and PGA score of\>=3, and suitable for systemic or light therapy.
* Male or female, between 18 and 75 years of age inclusive.
* Female subjects of childbearing potential must agree to avoid pregnancy and male subjects must agree to avoid female partners becoming pregnant.
* Subjects must agree to use ultra violet (UV) light protection.
* Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.

Exclusion Criteria:

* Unable to refrain from the use of the following prescription and non-prescription drugs from the following periods before the first dose of study medication until completion of the follow-up visit:
* 12 weeks: alefacept, ustekinumab, adalimumab, etanercept, infliximab, or certolizumab pegol
* 4 weeks or 5 half-lives, whichever is longer:
* systemic medications for other medical conditions that are known to affect psoriasis, including but not limited to oral corticosteroids, cyclosporine, methotrexate, lithium, and beta-adrenergic blockers
* 7 days or 5 half-lives, whichever is longer:
* statins and other OATP and BCRP sensitive substrates (e.g. rapaglinide)
* any agent known to be a substrate of MATE1 and MATE2-K, which undergoes significant renal secretion (e.g. cimetidine)
* 3 weeks or 5 half-lives, whichever is longer:
* any agent known to be a strong CYP3A4 inhibitor or inducer
* 2 weeks: topical therapies that are known to affect psoriasis, including but not limited to corticosteroids, retinoids, vitamin D derivatives, tar and anthralin
* Other medications (including vitamins, herbal and dietary supplements) will be considered on a case-by-case basis, and will be allowed if in the opinion of the investigator the medication will not interfere with the study procedures or compromise subject safety.
* Phototherapy within 4 weeks before the first dose of study medication.
* A live vaccination within 4 weeks before the first dose of study medication, or a live vaccination planned during the course of the study (until completion of the follow-up visit).
* A major organ transplant (e.g. heart, lung, kidney, liver) or haematopoietic stem cell/marrow transplant.
* Significant unstable or uncontrolled acute or chronic disease unrelated to psoriasis (i.e. cardiovascular including uncontrolled hypertension, hypercholesterolemia, pulmonary, hematologic, gastrointestinal, hepatic, renal, neurological, malignancy or infectious diseases) which, in the opinion of the investigator, could confound the results of the study or put the subject at undue risk.
* A planned surgical procedure that, in the opinion of the investigator, makes the subject unsuitable for the study.
* A history of malignant neoplasm within the last 5 years, except for adequately treated cancers of the skin (basal or squamous cell) or carcinoma in situ of the uterine cervix.
* Acute or chronic infections, as follows:
* Known previous or active infection with Mycobacterium Tuberculosis
* Currently on any suppressive therapy for a chronic infection (such as pneumocystis, cytomegalovirus, herpes simplex virus, herpes zoster and atypical mycobacteria).
* Hospitalisation for treatment of infection within 60 days before first dose.
* Use of parenteral (IV or intramuscular) antibiotics (antibacterials, antivirals, antifungals, or antiparasitic agents) within 60 days before first dose.
* Unable to refrain from the consumption of grapefruit or grapefruit juice from 3 weeks before the first dose of study medication until 2 weeks after the last dose of study medication.
* History of sensitivity to any components of the study medications, or a history of drug or other allergy that, in the opinion of the investigator, contraindicates their participation.
* Serologic evidence of Hepatitis B (HB) infection based on the results of testing for HBsAg, anti-HBc antibody as follows: subjects positive for HBsAg are excluded; and subjects positive for anti-HBc antibody (regardless of anti-HBs antibody status) are excluded.
* Positive test for Hepatitis C antibody confirmed sample with a Hepatitis C RIBA immunoblot assay or equivalent. Subjects who are positive for Hepatitis C antibody, but negative when the Hepatitis C RIBA immunoblot assay or equivalent test is performed will be eligible to participate. Subjects who are positive for Hepatitis C antibody and have a positive or indeterminate result when the Hepatitis C RIBA immunoblot assay or equivalent test is performed will not be eligible to participate.
* A positive test for HIV antibody.
* Pregnant females as determined by a positive serum hCG test at screening, or a positive urine hCG test pre-dose on Day 1.
* Lactating females.
* Haemoglobin \<11 g/dL, haematocrit \<30%, WBC count (absolute) \<3 × 10\^9/L, neutrophils \<1.5 × 10\^9/L, platelets \<100 × 10\^9/L, lymphocytes \<1 x 10\^9/L.
* Current or history of renal disease, or estimated creatinine clearance \<60 mL/min/1.73m\^2 or serum creatinine \>1.5 ULN.
* Single QTc \> 450 msec; or QTc \> 480 msec in subjects with Bundle Branch Block.
* Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
* ALT \> 2xULN; alkaline phosphatase and bilirubin ≥ 1.5xULN (isolated bilirubin \>1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin \<35%).
* History of regular alcohol consumption within 6 months of the study defined as an average weekly intake of \>21 units for males or \>14 units for females. One unit is equivalent to 8 g of alcohol: a half-pint (\~240 ml) of beer, 1 glass (125 ml) of wine or 1 (25 ml) measure of spirits.
* The subject has participated in a clinical trial and has received an investigational product within 3 months before the first dose of study medication, or plans to take part in another clinical trial at the same time as participating in this clinical trial.

Primary outcomes:
measure: Percentage of Participants Who Had Achieved >=75% Improvement From Baseline in the Psoriasis Area Severity Index (PASI) Score at Week 12 (PASI 75)
timeFrame: Baseline and Week 12
measure: Percentage of Participants Who Had Achieved >=75% Improvement From Baseline in the Psoriasis Area Severity Index (PASI) Score at Week 12 (PASI 75)
timeFrame: Baseline and Week 12
Secondary outcomes:
measure: Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE)
timeFrame: From Baseline (Day 1) until the Follow-up visit (Day 112)
measure: Number of Participants With the Indicated Hematology Parameters Falling Outside of the Reference Range at Any Time Post-Baseline (BL) During Study
timeFrame: From BL (Day 1) until the Follow-up visit (Day 112)
measure: Number of Participants With the Indicated Clinical Chemistry Parameters Falling Outside the Reference Range at Any Time Post-Baseline (BL) During the Study
timeFrame: From Baseline (Day 1) until the Follow-up visit (Day 112)
measure: Number of Participants With the Systolic (S) and Diastolic (D) Blood Pressure (BP) Falling Outside the Clinical Concern Range at Any Time Post-baseline During the Study
timeFrame: From Baseline (Day 1) until the follow-up visit (Day 112)
measure: Number of Participants With the Heart Rate Falling Outside the Clinical Concern Range at Any Time Post-Baseline (BL) During the Study
timeFrame: From Baseline (Day 1) until the Follow-up visit (Day 112)
measure: Change From Baseline in Body Temperature
timeFrame: From Baseline (Day 1) until Week 16
measure: Number of Participants With the Indicated Maximum Change From Baseline in the Electrocardiogram (ECG) Findings
timeFrame: From Baseline (Day 1) until the Follow-up visit (Day 112)
measure: Change From Baseline (BL) in the PASI Score at Week 2, 4, 8 and 12
timeFrame: From Baseline (Day 1) until Week 12
measure: PASI Score at Week 2, 4, 8 and 12
timeFrame: Week 2, 4, 8 and 12
measure: Percentage of Participants Who Had a PASI Score With 50%, 75% and 90% Improvement From Baseline Until Week 12
timeFrame: From Baseline (Day 1) until Week 12
measure: Percentage of Participants Who Had a Physician Global Assessment (PGA) Score of 'Clear' (0) or 'Almost Clear' (1) at Weeks 2, 4, 8 and 12
timeFrame: Weeks 2, 4, 8 and 12
measure: Percentage of Participants in Each PGA Score Category at Weeks 2, 4, 8 and 12
timeFrame: Weeks 2, 4, 8 and 12
measure: Time to PASI 75
timeFrame: From Baseline (Day 1) until Week 12
measure: Time to PGA Score of 'Clear' (0) or 'Almost Clear' (1)
timeFrame: From Baseline (Day 1) until Week 12
measure: Change From Baseline in the Itch Visual Analogue Scale (VAS) Score at Week 2, 4, 8 and 12
timeFrame: From Baseline (Day 1) until Week 12
measure: Itch VAS Scores at Week 2, 4, 8 and 12
timeFrame: Week 2, 4, 8 and 12
measure: Change From Baseline of Dermatology Life Quality Index (DLQI) Score at Week 12
timeFrame: Baseline and Week 12
measure: Population Pharmacokinetic (PK) Derived Area Under the Concentration-time Curve From Time Zero (Pre-dose) to the Time of the Last Measureable Concentration (AUC(0-tau) of GSK2586184
timeFrame: Baseline (pre-dose), Day 14 (2 to 3 hour and 3 to 4 hour post-dose), Day 28 (4 to 6 hour and 6 to 8 hour post-dose), Day 56 (at anytime during clinical visit), Day 84 (1 sample to be taken at anytime during clinical visit)
measure: Clearance of GSK2586184
timeFrame: Baseline (pre-dose), Day 14 (2 to 3 hour and 3 to 4 hour post-dose), Day 28 (4 to 6 hour and 6 to 8 hour post-dose), Day 56 (at anytime during clinical visit), Day 84 (1 sample to be taken at anytime during clinical visit)
measure: Steady State Volume of Distribution (Vss) of GSK2586184
timeFrame: Baseline (pre-dose), Day 14 (2 to 3 hour and 3 to 4 hour post-dose), Day 28 (4 to 6 hour and 6 to 8 hour post-dose), Day 56 (at anytime during clinical visit), Day 84 (1 sample to be taken at anytime during clinical visit)
measure: Change From Baseline in Serum Neopterin Concentrations at Weeks 2, 4, 8 and 12
timeFrame: Baseline (pre-dose) and Weeks 2, 4, 8 and 12
Other outcomes:
Locations:
city: Stuttgart
country: Germany
facility: GSK Investigational Site
state: Baden-Wuerttemberg
city: Augsburg
country: Germany
facility: GSK Investigational Site
state: Bayern
city: Osnabrueck
country: Germany
facility: GSK Investigational Site
state: Niedersachsen
city: Essen
country: Germany
facility: GSK Investigational Site
state: Nordrhein-Westfalen
city: Muenster
country: Germany
facility: GSK Investigational Site
state: Nordrhein-Westfalen
city: Muenster
country: Germany
facility: GSK Investigational Site
state: Nordrhein-Westfalen
city: Witten
country: Germany
facility: GSK Investigational Site
state: Nordrhein-Westfalen
city: Berlin
country: Germany
facility: GSK Investigational Site
city: Berlin
country: Germany
facility: GSK Investigational Site
city: Berlin
country: Germany
facility: GSK Investigational Site
city: Hamburg
country: Germany
facility: GSK Investigational Site
city: Cardiff
country: United Kingdom
facility: GSK Investigational Site
city: London
country: United Kingdom
facility: GSK Investigational Site
city: London
country: United Kingdom
facility: GSK Investigational Site
city: Salford
country: United Kingdom
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References: