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

Psoriasis Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01782664
• Other study ID #: 116679
• Status: Completed
• Phase: Phase 2
• First received: January 31, 2013
• Last updated: November 18, 2016
• Start date: March 2013
• Est. completion date: March 2014

Study information

• Verified date: November 2016
• Source: GlaxoSmithKline
• Contact: n/a
• Is FDA regulated: No
• Health authority: United Kingdom: Medicines and Healthcare Products Regulatory AgencyGermany: Bundesinstitut für Arzneimittel und Medizinprodukte
• Study type: Interventional

Clinical Trial 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)

Recruitment information / eligibility

• Status: Completed
• Enrollment: 68
• Est. completion date: March 2014
• Est. primary completion date: March 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 75 Years

Eligibility

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

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Psoriasis

Intervention

Drug:
• 100 mg GSK2586184
100 mg GSK2586184 to be taken twice daily with food (as tablets) for up to 84 days.
• 200 mg GSK2586184
200 mg GSK2586184 to be taken twice daily with food (as tablets) for up to 84 days.
• 400 mg GSK2586184
400 mg GSK2586184 to be taken twice daily with food (as tablets) for up to 84 days.
• Placebo
Placebo tablets to be taken twice daily with food for up to 84 days.

Locations

Country	Name	City	State
Germany	GSK Investigational Site	Augsburg	Bayern
Germany	GSK Investigational Site	Berlin
Germany	GSK Investigational Site	Berlin
Germany	GSK Investigational Site	Berlin
Germany	GSK Investigational Site	Essen	Nordrhein-Westfalen
Germany	GSK Investigational Site	Hamburg
Germany	GSK Investigational Site	Muenster	Nordrhein-Westfalen
Germany	GSK Investigational Site	Muenster	Nordrhein-Westfalen
Germany	GSK Investigational Site	Osnabrueck	Niedersachsen
Germany	GSK Investigational Site	Stuttgart	Baden-Wuerttemberg
Germany	GSK Investigational Site	Witten	Nordrhein-Westfalen
United Kingdom	GSK Investigational Site	Cardiff
United Kingdom	GSK Investigational Site	London
United Kingdom	GSK Investigational Site	London
United Kingdom	GSK Investigational Site	Salford

Sponsors (1)

Lead Sponsor	Collaborator
GlaxoSmithKline

Countries where clinical trial is conducted

Germany,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	The proportion of subjects who achieve >=75% improvement from baseline in PASI score at Week 12 (PASI 75)	The Psoriasis Area Severity Index (PASI) assessment will be performed by the investigator or a suitably trained delegate. The lesions on each area of the body will be assessed for redness, thickness, and scaling.	Baseline and Week 12	No
Secondary	Safety and tolerability of twice-daily doses of GSK2586184	To be assessed by adverse event reporting, laboratory safety data, vital signs, and 12-lead ECG monitoring.	Up to Week 16	No
Secondary	Change from baseline and actual PASI scores at Weeks 2, 4, 8 and 12	See above for description of PASI scoring.	Baseline and Weeks 2, 4, 8 and 12.	No
Secondary	The proportion of subjects who achieve >=50% and >=90% improvement from baseline in PASI score at Weeks 2, 4, 8 and 12 (PASI 50 and PASI 90)	See above for description of PASI scoring.	Baseline and Weeks 2, 4, 8 and 12.	No
Secondary	The proportion of subjects who achieve >=75% improvement from baseline in PASI score at Weeks 2, 4 and 8 (PASI 75).	See above for description of PASI scoring.	Baseline and Weeks 2, 4 and 8.	No
Secondary	Time to PASI 75.	See above for description of PASI scoring.	Up to Week 16	No
Secondary	The proportion of subjects in each PGA score category at Weeks 2, 4, 8 and 12	The Physician Global Assessment (PGA) will be performed by the investigator or a suitably trained delegate. It is a global lesion score, and subjects will be scored using the following categories: 0 = Clear, 1 = Almost clear, 2 = Mild, 3 = Mild to moderate, 4 = Moderate, 5 = Moderate to severe, 6 = Severe.	Weeks 2, 4, 8 and 12	No
Secondary	The proportion of subjects who have a PGA score of 'clear' (0) or 'almost clear' (1) at Weeks 2, 4, 8 and 12.	See above for description of PGA scoring.	Weeks 2, 4, 8 and 12	No
Secondary	Time to PGA score of 'clear' (0) or 'almost clear' (1)	See above for description of PGA scoring.	Up to Week 16	No
Secondary	Change from baseline and actual VAS itch score	A visual analogue scale will be used to assess any change in itch.	Baseline and Weeks 2, 4, 8 and 12	No
Secondary	Change from baseline of Dermatology Life Quality Index (DLQI) score	The DLQI is a validated questionnaire, which will be used to assess any change in quality of life.	Baseline and Week 12	No
Secondary	Plasma concentrations and derived pharmacokinetic parameters of GSK2586184	Pharmacokinetic (PK) parameters will be calculated following repeat doses of GSK2586184, including area under the concentration-time curve over the dosing interval (AUC(0-tau)), apparent clearance (CL/F), apparent volume of distribution (V/F) and maximum plasma concentration (Cmax).	Baseline (pre-dose), Week 2 (pre-dose, 23 h, 34 h post-dose), Week 4 (46 h, 68 h post-dose), Week 8 and Week 12	No
Secondary	Change from baseline of neopterin concentrations	Blood samples will be taken to measure serum neopterin concentrations	Baseline and Weeks 2, 4, 8 and 12	No

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