| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Skin and Connective Tissue Diseases [C17] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 17.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10050577 |
| E.1.2 | Term | Psoriatic plaque |
| E.1.2 | System Organ Class | 100000004858 |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
To estimate the relationship between dose of GSK2586184 and clinical response as assessed by PASI score after 12 weeks of
treatment in patients with moderate to severe plaque-type psoriasis. |
|
| E.2.2 | Secondary objectives of the trial |
- To assess the safety and tolerability of twice daily doses of
GSK2586184 in patients with moderate to severe plaque type
psoriasis.
- To investigate the efficacy of twice daily doses of GSK2586184 in
patients with moderate to severe plaque-type psoriasis, using the PASI score and PGA.
- To investigate the time taken to achieve an improvement in psoriasis disease activity please see protocol section 2 for further information.
- To investigate the effect of twice daily doses of GSK2586184 on the itch response in patients with moderate to severe plaque type psoriasis.
- To investigate the effect of twice daily doses of GSK2586184 on the quality of life of patients with moderate to severe plaque type psoriasis.
- To assess the plasma pharmacokinetics of twice daily doses of
GSK2586184 in patients with moderate to severe plaque type psoriasis.
- To investigate the effect of twice daily doses of GSK2586184 on serum neopterin concentrations. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Subjects with a diagnosis of moderate to severe plaque psoriasis for at least 12 months before the first dose of study medication, who are otherwise healthy.
Diagnosis of moderate to severe plaque psoriasis:
• Psoriasis plaques cover ≥10% of body surface area.
• PASI score of ≥12, and PGA score of ≥3, and suitable for systemic or light therapy.
• Cohort B only: Identification of a target lesion (≥2 cm²) on the trunk or extremities. The target lesion will be used for skin biopsies. Lesions on palms, soles, knees, elbows and intertriginous areas will not be used as the target lesion site.
• Subjects with psoriasis and concomitant joint involvement (psoriatic arthritis) only: Subjects who have had a diagnosis of active psoriatic arthritis will be included in the exploratory assessment of the effect of GSK2586184 on their joint disease using the ACR response criteria. Otherwise healthy as determined by a responsible and experienced physician, based on a medical evaluation including medical history, physical examination, laboratory tests and cardiac monitoring. A subject with a clinical abnormality or laboratory parameters outside the reference range for the population being studied may be included only if the investigator agrees that the finding is unlikely to introduce
additional risk factors and will not interfere with the study procedures. Specific laboratory parameter exclusion criteria are listed in Section 4.2.2 of the protocol.
2. Male or female, between 18 and 75 years of age inclusive, at the time of signing the informed consent.
3. A female subject is eligible to participate if she is of:
• Non-childbearing potential defined as:
• pre-menopausal females with a documented tubal ligation or hysterectomy;
or
• postmenopausal defined as 12 months of spontaneous amenorrhea. In questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) > 40 MlU/ml and estradiol < 40 pg/ml (<147 pmol/L) is confirmatory).
Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use acceptable contraception methods, as listed in Section 7.1 of the protocol, if they wish to continue their HRT during the study.
Otherwise, they must discontinue HRT to allow confirmation of postmenopausal status before study enrollment. For most forms of HRT, at least 2−4 weeks should elapse between the cessation of therapy and the blood draw; this interval depends on the type and dosage of HRT. Following confirmation of their post-menopausal status, they can resume use of HRT during the study without use of a contraceptive method.
• Child-bearing potential and agrees to use acceptable contraception methods, as listed in Section 7.1 of the protocol, for at least 1 month before the start of dosing to sufficiently minimise the risk of pregnancy at that point. Female subjects must agree to use contraception until at least 2 weeks after their last dose.
4. Subjects must agree to use UV light protection as described in Section 7.3 of the protocol.
5. Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form. |
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| E.4 | Principal exclusion criteria |
1. 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:
• 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 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.
2. Phototherapy within 4 weeks before the first dose of study medication.
3. 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).
4. A major organ transplant (e.g. heart, lung, kidney, liver) or haematopoietic stem cell/marrow transplant.
5. Significant unstable or uncontrolled acute or chronic disease unrelated to psoriasis which, in the opinion of the investigator, could confound the results of the study or put the subject at undue risk. View protocol for further information.
6. A planned surgical procedure that, in the opinion of the investigator, makes the subject unsuitable for the study.
7. 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.
8. 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.
9. 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.
10. 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.
11. Serologic evidence of Hepatitis B (HB) infection based on the results of testing for HBsAg, anti-HBc antibody. View protocol for further information.
12. Positive test for Hepatitis C antibody confirmed on the same sample with a Hepatitis C RIBA immunoblot assay or equivalent test. Please view protocol for further information.
13. A positive test for HIV antibody.
14. Pregnant females as determined by a positive serum hCG test at screening, or a positive urine hCG test pre-dose on Day 1.
15. Lactating females.
16. Haemoglobin <11 g/dL, haematocrit <30%, WBC count (absolute) <3 × 109/L, neutrophils <1.5 × 109/L, platelets <100 × 109/L, lymphocytes <1 x 109/L.
17. Current or history of renal disease, or estimated creatinine clearance <60 mL/min/1.73m2 or serum creatinine >1.5 ULN.
18. Single QTc > 450 msec; or QTc > 480 msec in subjects with Bundle Branch Block.
19. Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
20. ALT > 2xULN; alkaline phosphatase and bilirubin ≥ 1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).
21. 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. View protocol for further information.
22. 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.
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The proportion of subjects who achieve ≥ 75% improvement from baseline in PASI score at Week 12 (PASI 75). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| PASI: screening, baseline, Weeks 2, 4, 8, 12 and follow-up |
|
| E.5.2 | Secondary end point(s) |
- Adverse event reporting, Laboratory safety data (including serum
creatinine and cystatin C, and haematology parameters)
Vital signs (blood pressure, heart rate, body temperature), 12-lead ECG monitoring.
- Change from baseline and actual PASI scores at Weeks 2, 4, 8 and 12.
- 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), and the proportion of subjects who achieve ≥ 75% improvement from baseline in PASI score at Weeks 2, 4 and 8 (PASI 75).
- The proportion of subjects who have a PGA score of ‘clear’ (0) or ‘almost clear’ (1) at Weeks 2, 4, 8 and 12.
- The proportion of subjects in each PGA score category at Weeks 2, 4, 8 and 12.
- Time to PASI 75.
- Time to PGA score of ‘clear’ (0) or ‘almost clear’ (1).
- Change from baseline and actual VAS itch score at Weeks 2, 4, 8 and 12.
- Change from baseline of DLQI score at Week 12.
- Plasma concentrations and derived pharmacokinetic parameters of GSK2586184.
- Change from baseline of neopterin concentrations at Weeks 2, 4, 8 and 12. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
SAE reporting from signature of consent form until follow-up, and AE reporting from start of treatment to follow-up
Laboratory safety tests and vital signs:
screening, baseline, Weeks 2, 4, 8, 12
and follow-up 12-lead ECG:
screening, baseline, Weeks 4 and 12,
and follow-up PASI and PGA:
screening, baseline, Weeks 2, 4, 8, 12
and follow-up Itch VAS:
baseline, Weeks 2, 4, 8, and 12 DLQI:
screening, baseline, Week 12
and follow-up Plasma pharmacokinetic samples:
baseline, Weeks 2, 4, 8, and 12 Serum neopterin samples: baseline, Weeks 2, 4, 8, 12 and follow-up
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|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| 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 | 9 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 15 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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