A Dose Ranging Study to Evaluate the Safety and Efficacy of GSK2586184 in Patients With Chronic Plaque Psoriasis

Phase 2

Completed

Conditions: Psoriasis

Interventions: Drug: 400 mg GSK2586184
Drug: 100 mg GSK2586184
Drug: 200 mg GSK2586184
Drug: Placebo

Registration Number: NCT01782664

Lead Sponsor: GlaxoSmithKline

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)

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 68

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
400 mg GSK2586184 (Cohort B)	400 mg GSK2586184	Subjects will take 400 mg GSK2586184 twice daily for up to 84 days
100 mg GSK2586184	100 mg GSK2586184	Subjects will be randomized to 100 mg GSK2586184 twice daily for up to 84 days
200 mg GSK2586184	200 mg GSK2586184	Subjects will be randomized to 200 mg GSK2586184 twice daily for up to 84 days
400 mg GSK2586184	400 mg GSK2586184	Subjects will be randomized to 400 mg GSK2586184 twice daily for up to 84 days
Placebo	Placebo	Subjects will be randomized to receive Placebo twice daily for up to 84 days

Primary Outcome Measures

Name	Time	Method
Percentage of Participants Who Had Achieved >=75% Improvement From Baseline in the Psoriasis Area Severity Index (PASI) Score at Week 12 (PASI 75)	Baseline and Week 12	PASI score was determined by evaluation of BSA covered by plaque psoriasis in 4 areas (head/neck, arms, trunk and legs with area score of 0.1, 0.2, 0.3 and 0.4 respectively). This test included combination of both degree of involvement (assessed as per the % of affected body area using a 7-point scale such that 0=0% involvement, 1=1-9%, 2=10-29%, 3=30-49%, 4=50-69%, 5=70-89% and 6=90-100%) and severity (evaluated individually using a 5-point scale that ranged as 0=No evidence of sign, 1=slight evidence, 2=moderate evidence, 3=marked evidence and 4=very marked, most severe evidence of sign) of erythema, induration and desquamation in each of the same 4 areas. PASI score ranges from 0(no psoriasis) to 72(worse psoriasis). Final PASI=(sum of severity score for each area)x(% body affected score x area score). Baseline=Day 1. Percentage of participants who achieved \>= 75% improvement from Baseline was reported with LOCF analysis.

Secondary Outcome Measures

Name	Time	Method
Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE)	From Baseline (Day 1) until the Follow-up visit (Day 112)	An AE is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. A SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability or incapacity, is a congenital anomaly or birth defect. Any SAEs assessed as related to study participation (e.g. study treatment, protocol-mandated procedures, invasive tests, or change in existing therapy) or related to a GSK product was recorded from the time a participant consents to participate in the study up to and including any follow-up contact.
Number of Participants With the Indicated Clinical Chemistry Parameters Falling Outside the Reference Range at Any Time Post-Baseline (BL) During the Study	From Baseline (Day 1) until the Follow-up visit (Day 112)	Safety and tolerability were assessed by measuring the clinical chemistry parameters such as creatinine and cystatin C. BL values were obtained at Day 1. The number of participants with the indicated hematology parameter data outside of the reference range (\> high or \< low) at any time post-BL, including unscheduled or scheduled assessments, are presented.
Number of Participants With the Heart Rate Falling Outside the Clinical Concern Range at Any Time Post-Baseline (BL) During the Study	From Baseline (Day 1) until the Follow-up visit (Day 112)	Vital sign monitoring included heart rate (HR) measurements. HR measurements were taken in supine position after 5 minutes of rest. The number of participants with HR outside the clinical concern range at any time post-BL are presented. HR "low" was any HR less than 40 beats per minute (bpm) and "high" was any HR greater than 110 bpm. The BL values were those values obtained at Day 1. Anytime post-BL assessments included any scheduled and unscheduled post-BL assessment.
Change From Baseline (BL) in the PASI Score at Week 2, 4, 8 and 12	From Baseline (Day 1) until Week 12	Psoriatic lesions were assessed using the PASI. PASI score was determined by evaluation of BSA covered by plaque psoriasis in 4 areas (head/neck, arms, trunk and legs with area score of 0.1, 0.2, 0.3 and 0.4 respectively). This test included combination of both degree of involvement (assessed as per the % of affected body area using a 7-point scale such that 0=0% involvement, 1=1-9%, 2=10-29%, 3=30-49%, 4=50-69%, 5=70-89% and 6=90-100%) and severity (evaluated individually using a 5-point scale that ranged as 0=No evidence of sign, 1=slight evidence, 2=moderate evidence, 3=marked evidence and 4=very marked, most severe evidence of sign) of erythema, induration and desquamation in each of the same 4 areas. PASI score ranges from 0(no psoriasis) to 72(worse psoriasis). Final PASI=(sum of severity score for each area)x(% body affected score x area score). Baseline=Day 1. The change from Baseline was the difference between post-Baseline and Baseline.
Change From Baseline in the Itch Visual Analogue Scale (VAS) Score at Week 2, 4, 8 and 12	From Baseline (Day 1) until Week 12	The visual analogue scale (VAS) was used to assess itch. The participants rated the intensity of itch over the past week by marking a line on a 100 millimeter(mm) (0 to 100 mm) long scale. A line placed on the extreme left, that is 0 mm indicated no noticeable itching sensation and extreme right that is 100 mm indicated maximum itching sensation. This scale has no subscales. The participant perception of their symptoms was measured using the VAS itch score. The Baseline value was the value obtained on Day 1. The change from Baseline was the difference between post-Baseline and Baseline.
Itch VAS Scores at Week 2, 4, 8 and 12	Week 2, 4, 8 and 12	The visual analogue scale (VAS) was used to assess itch. The participants rated the intensity of itch over the past week by marking a line on a 100 mm (0 to 100 mm) long scale. A line placed on the extreme left, that is 0 mm indicated no noticeable itching sensation and extreme right that is 100 mm indicated maximum itching sensation. This scale has no subscales. The participant perception of their symptoms was measured using the VAS itch score. Itch VAS scores at Week 2, 4, 8 and 12 are reported.
PASI Score at Week 2, 4, 8 and 12	Week 2, 4, 8 and 12	Psoriatic lesions were assessed using the PASI. PASI score was determined by evaluation of BSA covered by plaque psoriasis in 4 areas (head/neck, arms, trunk and legs with area score of 0.1, 0.2, 0.3 and 0.4 respectively). This test included combination of both degree of involvement (assessed as per the % of affected body area using a 7-point scale such that 0=0% involvement, 1=1-9%, 2=10-29%, 3=30-49%, 4=50-69%, 5=70-89% and 6=90-100%) and severity (evaluated individually using a 5-point scale that ranged as 0=No evidence of sign, 1=slight evidence, 2=moderate evidence, 3=marked evidence and 4=very marked, most severe evidence of sign) of erythema, induration and desquamation in each of the same 4 areas. PASI score ranges from 0(no psoriasis) to 72(worse psoriasis). Final PASI=(sum of severity score for each area)x(% body affected score x area score). Baseline=Day 1.
Time to PGA Score of 'Clear' (0) or 'Almost Clear' (1)	From Baseline (Day 1) until Week 12	The severity of psoriatic lesions over the whole body were assessed by the investigator using the PGA scoring system. A 0 to 6 point rating scale was used, as follows: 0 = Clear (no signs of psoriasis), 1 = Almost clear (slight elevation, scale and/or erythema), 2 = Mild (mild plaque elevation, scale and/or erythema), 3 = Mild to moderate (mild plaque elevation with moderate erythema and/or scale)4 = Moderate (moderate plaque elevation, scale and/or erythema), 5 = Moderate to severe (marked plaque elevation, scale and/or erythema), 6 = Severe (very marked plaque elevation, scale and/or erythema). The Baseline value was the value obtained on Day 1. The scores were reported with the last observation carried forward (LOCF) analysis.
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	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)	Blood samples were taken to measure plasma concentrations of GSK2586184. A two-compartment model with a three-compartment transit model was used to derive PK parameters.
Number of Participants With the Indicated Hematology Parameters Falling Outside of the Reference Range at Any Time Post-Baseline (BL) During Study	From BL (Day 1) until the Follow-up visit (Day 112)	Hematology parameters included: basophils, eosinophils, erythrocyte mean corpuscular hemoglobin (EMCHb) EMCHb concentration (EMCHbC), erythrocyte mean corpuscular volume (EMCV), erythrocyte sedimentation rate (ESR), erythrocytes, hematocrit (fraction 1), hemoglobin, leukocytes, lymphocytes, monocytes, neutrophils, segmented neutrophils, platelets, reticulocytes. BL values were obtained at Day 1. The number of participants with the indicated hematology parameters data outside of the reference range (with high and low) any time post-BL are presented. Anytime post-BL assessments included any scheduled and unscheduled post-BL assessment.
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	From Baseline (Day 1) until the follow-up visit (Day 112)	Vital sign monitoring included systolic and diastolic BP measurements. BP measurements were taken in the supine position after 5 minutes of rest. The number of participants with the SBP or DBP outside the clinical concern range at any time post-BL are presented. SBP "low" was measured as less than 85 millimeters of mercury (mmHg)and "high" was measured as greater than 160 mmHg. DBP "low" was measured as less than 45 mmHg and "high" was measured as greater than 100 mmHg. The BL values were those values obtained at Day 1. Anytime post-BL assessments included any scheduled and unscheduled post-BL assessment.
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	Weeks 2, 4, 8 and 12	The severity of psoriatic lesions over the whole body were assessed by the investigator using the PGA scoring system. A 0 to 6 point rating scale was used, as follows: 0 = Clear (no signs of psoriasis), 1 = Almost clear (slight elevation, scale and/or erythema), 2 = Mild (mild plaque elevation, scale and/or erythema), 3 = Mild to moderate (mild plaque elevation with moderate erythema and/or scale), 4 = Moderate (moderate plaque elevation, scale and/or erythema), 5 = Moderate to severe (marked plaque elevation, scale and/or erythema), 6 = Severe (very marked plaque elevation, scale and/or erythema). Higher scores indicated worse psoriasis. The Baseline value was the value obtained on Day 1. The scores were reported with the last observation carried forward (LOCF) analysis.
Percentage of Participants in Each PGA Score Category at Weeks 2, 4, 8 and 12	Weeks 2, 4, 8 and 12	The severity of psoriatic lesions over the whole body were assessed by the investigator using the PGA scoring system. A 0 to 6 point rating scale was used, as follows: 0 = Clear (no signs of psoriasis), 1 = Almost clear (slight elevation, scale and/or erythema), 2 = Mild (mild plaque elevation, scale and/or erythema), 3 = Mild to moderate (mild plaque elevation with moderate erythema and/or scale), 4 = Moderate (moderate plaque elevation, scale and/or erythema), 5 = Moderate to severe (marked plaque elevation, scale and/or erythema), 6 = Severe (very marked plaque elevation, scale and/or erythema). Higher scores indicated worse psoriasis. The Baseline value was the value obtained on Day 1. The scores were reported with the last observation carried forward (LOCF) analysis.
Time to PASI 75	From Baseline (Day 1) until Week 12	PASI 75 was \>= 75% improvement from Baseline in PASI score. Psoriatic lesions were assessed by the investigator using a PASI score. PASI score was determined by evaluation of BSA covered by plaque psoriasis in 4 areas (head/neck, arms, trunk and legs with area score of 0.1, 0.2, 0.3 and 0.4 respectively). This test included combination of both degree of involvement (assessed as per the % of affected body area using a 7-point scale such that 0=0% involvement, 1=1-9%, 2=10-29%, 3=30-49%, 4=50-69%, 5=70-89% and 6=90-100%) and severity (evaluated individually using a 5-point scale that ranged as 0=No evidence of sign, 1=slight evidence, 2=moderate evidence, 3=marked evidence and 4=very marked, most severe evidence of sign) of erythema, induration and desquamation in each of the same 4 areas. PASI score ranges from 0(no psoriasis) to 72(worse psoriasis). Final PASI=(sum of severity score for each area)x(% body affected score x area score). Baseline was Day 1.
Change From Baseline in Body Temperature	From Baseline (Day 1) until Week 16	Vital sign monitoring included body temperature measurements. Body temperature measurements were taken in the supine position after 5 minutes of rest. Baseline is defined as the last result on or before the day of first dose. Change from Baseline was determined by subtracting the indicated time point value minus the Baseline value.
Percentage of Participants Who Had a PASI Score With 50%, 75% and 90% Improvement From Baseline Until Week 12	From Baseline (Day 1) until Week 12	Psoriatic lesions were assessed using the PASI. PASI score was determined by evaluation of BSA covered by plaque psoriasis in 4 areas (head/neck, arms, trunk and legs with area score of 0.1, 0.2, 0.3 and 0.4 respectively). This test included combination of both degree of involvement (assessed as per the % of affected body area using a 7-point scale such that 0=0% involvement, 1=1-9%, 2=10-29%, 3=30-49%, 4=50-69%, 5=70-89% and 6=90-100%) and severity (evaluated individually using a 5-point scale that ranged as 0=No evidence of sign, 1=slight evidence, 2=moderate evidence, 3=marked evidence and 4=very marked, most severe evidence of sign) of erythema, induration and desquamation in each of the same 4 areas. PASI score ranges from 0(no psoriasis) to 72(worse psoriasis). Final PASI=(sum of severity score for each area)x(% body affected score x area score). Baseline was Day 1.
Clearance of GSK2586184	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)	Blood samples were taken to measure plasma concentrations of GSK2586184. A two-compartment model with a three-compartment transit model was used to derive PK parameters.
Steady State Volume of Distribution (Vss) of GSK2586184	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)	Blood samples were taken to measure plasma concentrations of GSK2586184. A two-compartment model with a three-compartment transit model was used to derive PK parameters.
Number of Participants With the Indicated Maximum Change From Baseline in the Electrocardiogram (ECG) Findings	From Baseline (Day 1) until the Follow-up visit (Day 112)	ECG measurements were obtained using single 12-lead ECGs with the participant in a supine position after resting in this position for at least 10 minutes. The Baseline values were those values obtained Pre-dose on Day 1. The change from Baseline was the difference between post-Baseline and Baseline. The QT intervals (milliseconds \[msec\]) corrected for heart rate using Bazett's formula (QTcB) and Fridericia's formula (QTcF) are reported.
Change From Baseline of Dermatology Life Quality Index (DLQI) Score at Week 12	Baseline and Week 12	The DLQI was used to assess a participant's health-related quality of life. Participants completed the questionnaire to evaluate how their psoriasis affected their life over the week before the assessment took place. Each of the 10 questions was scored out of 0-3 as; 0 = Not at all, 1 = A little, 2 = A lot and 3 = Very much. The total score for the DLQI was calculated by adding up all the individual scores for each question resulting in a minimum of 0 and a maximum of 30. Higher score indicated worsening of participant's quality of life. The Baseline value was the value obtained on Day 1. The change from Baseline was the difference between post-Baseline and Baseline.
Change From Baseline in Serum Neopterin Concentrations at Weeks 2, 4, 8 and 12	Baseline (pre-dose) and Weeks 2, 4, 8 and 12	Serum Neopterin is a marker of psoriatic disease activity. Blood samples were collected for estimation of serum neoprotein concentration. Baseline was Day 1. The change from Baseline was the difference between post-Baseline and Baseline.