A Safety and Efficacy Study of Ustekinumab in Patients With Plaque Psoriasis Who Have Had an Inadequate Response to Methotrexate

This purpose of this study is to assess the safety of ustekinumab in psoriasis patients who receive ustekinumab following an inadequate response to methotrexate therapy. The study will provide information for doctors on how to manage the transfer from methotrexate to the biologic agent ustekinumab. The study is designed to compare two methods of transferring patients from methotrexate to ustekinumab. The two methods being compared are discontinuation of methotrexate with immediate initiation of ustekinumab versus initiation of ustekinumab with overlap and gradual dose reduction of methotrexate over 4 weeks.

Only limited data exist to guide physicians on transitioning patients onto biologic agents once conventional systemic agents have been found to be inadequate. Most Phase III regulatory studies for biologics, including ustekinumab, required washout periods of between one and three months between previous therapies and the start of study agent. Although advantageous from a methodological perspective, this approach does not appear to mirror real-world clinical practice, in which clinicians and patients are unwilling to go without treatment for extended periods. As a result, physicians appear to employ several arbitrary strategies when transitioning their patients. Two commonly used approaches are: Initiation of biologic therapy with immediate cessation of previous conventional systemic therapy or Initiation of biologic therapy with overlap and gradual reduction of previous conventional systemic therapy. Some physicians opt for the first strategy to minimise the risk of drug-drug interactions. Others opt for the second strategy to minimise the risk of symptomatic worsening between cessation of previous treatment and the onset of action of biologic agents. This study aims to compare safety, efficacy and quality of life outcomes associated with these two strategies, with follow-up for 52 weeks. The primary objective of this exploratory trial is to evaluate the comparative safety through week 12 of two treatment transition strategies in patients with inadequate response to methotrexate: discontinuation of methotrexate with immediate initiation of ustekinumab versus initiation of ustekinumab with overlap and gradual dose reduction of methotrexate over 4 weeks. Secondary objectives of the study include evaluating the safety, efficacy, and quality of life through Week 52. The focus of the trial is on estimation rather than on hypothesis testing and, therefore, no formal hypothesis testing is planned. The primary endpoint is the proportion of patients experiencing one or more treatment-emergent adverse events (AEs) through Week 12 within each treatment transition arm. All proportions will be accompanied by an estimated 95% confidence interval. This is a phase IIIB/IV multicentre, open label, two-arm, randomised study, lasting 56 weeks (including a screening period). The primary endpoint is assessed after 12 weeks of treatment (Week 12). All treated patients will be followed for safety and efficacy through Week 52. Patients will be stratified according to their body weight to ensure a similar distribution of patients \>100 kg between the two treatment arms. Approximately 4 weeks prior to study start, all patients who provide consent for participation will be screened according to the requirements of the inclusion and exclusion criteria. Patients who meet all of the inclusion criteria and none of the exclusion criteria will enter the study. During the Screening Phase, patients will continue their current treatment schedule and dose for methotrexate, with folic acid if prescribed. At Week 0, prior to the first dose of ustekinumab, patients will be randomised 1:1 to one of the two treatment arms described below. Patients will be stratified according to their baseline body weight (=\<100 kg or \>100 kg) to ensure a similar distribution of patients \>100 kg between the two treatment arms. Patients eligible for the study will be men and women aged 18 years or older with moderate to severe plaque psoriasis who have a Psoriasis Area and Severity Index (PASI) \>=10, who have failed or are intolerant to methotrexate therapy. Patients entering the study must be receiving methotrexate at a dose of 10-25 mg/week, and should have been receiving methotrexate for at least 8 weeks prior to screening. Approximately 576 patients will be included in the study from approximately 100 sites in 20 countries. In both treatment arms, Patients weighing ≤ 100 kg will receive ustekinumab 45 mg at Weeks 0, 4 and 16. Patients who achieve a PASI 75 response at Week 28 and 40 will continue receiving ustekinumab 45 mg at Week 28 and 40. Patients who fail to achieve PASI 75 response at Week 28 will receive ustekinumab 90 mg at Week 28 and 40. Patients who achieve a PASI 75 response at Week 28, but fail to achieve PASI 75 response at Week 40 will receive ustekinumab 90 mg at Week 40. Patients \> 100 kg will receive ustekinumab 90 mg at Weeks 0, 4, 16, 28 and 40, regardless of achievement of PASI 75 response. Consideration will be given to discontinuing treatment in these patients if they show no response at Week 28. At Week 0, all eligible patients will be randomised to one of the following treatment regimens. The methotrexate dose reduction regime will depend on the dose of methotrexate at screening. All patients will stop methotrexate regardless of the final dose after 4 overlapping weeks (Weeks 0, 1, 2 and 3). The last dose of methotrexate will be given within the 7 day period before the second dose of ustekinumab. Safety evaluations will include physical examination, body weight and waist circumference, pregnancy testing, vital signs, clinical laboratory testing with full blood analysis and biochemistry, skin assessment for suspicious malignant lesions, Tuberculosis (TB) assessment, adverse events review and collection. Efficacy evaluations, including Psoriasis Area Severity Index (PASI), Nail Psoriasis Severity Index (NAPSI) and Physician's Global Assessment (PGA), will be carried out. Evaluations to assess changes in quality of life, including the Dermatology Life Quality Index (DLQI), Hospital Anxiety Depression Score (HADS), EuroQol-5 dimensional questionnaire (EQ-5D) and Patient Benefit Index (PBI), will be carried out.

Eligibility Criteria:
Inclusion Criteria:

* Patients should have diagnosis of plaque-type psoriasis for at least 6 months prior to first administration of study agent (patients with concurrent psoriatic arthritis may be enrolled)
* Moderate-to-severe psoriasis scored as PASI \>= 10 at screening and at the time of first administration of ustekinumab
* Should currently receive (and have been receiving for at least 8 weeks directly prior to screening) systemic therapy with methotrexate at a dose of at least 10 mg/week but not exceeding 25 mg/week, with an inadequate response to this treatment (due to either efficacy or tolerability) and, in the judgment of the treating physician and patient, a treatment change is needed
* Women should take adequate birth control measures throughout the study and must agree to continue to use such birth control measures and not to become pregnant or plan to become pregnant for at least 15 weeks after the last dose of ustekinumab and for at least 6 months after the last dose of methotrexate
* Men must be using adequate birth control measures whilst receiving methotrexate and for 6 months after the last dose of methotrexate

Exclusion Criteria:

* Patients should not have non-plaque forms of psoriasis (eg, erythrodermic, guttate, or pustular)
* Should currently (and within 12 months) not receive ciclosporin, fumarates, PUVA, etanercept, efalizumab, infliximab, adalimumab or alefacept or other biologic or systemic therapy (and other therapy as indicated in the protocol)
* Women who are pregnant, breastfeeding, or planning pregnancy (both men and women) while enrolled in the study
* Have previously failed treatment with any therapeutic agent directly targeted at reducing IL-12 or IL-23, including, but not limited to, ustekinumab and ABT-874
* Active or latent Tuberculosis or other chronic or recurrent infectious disease
* Known history of lymphoproliferative disease
* Known malignancy or history of malignancy