An exploratory trial to assess naturalistic safety and efficacy outcomes in patients trasitioned to ustekinumab from previous methotrexate therapy

Psoriasis is a chronic, immunologically-mediated inflammatory skin disease of
unknown aetiology. The most common form is plaque psoriasis, characterised by
symmetrically distributed, well-demarcated, scaly, erythematous plaques. Areas
of the body that are frequently involved include the scalp, elbows, knees, and
genitalia. Psoriatic lesions can cause pain, itching, and bleeding, and these
physical discomforts combined with the potential psychological effects of the
disease may interfere with everyday activities and negatively impact an
individuals quality of life. Psoriasis has an impact similar to other major
medical conditions on health-related quality of life (Rapp et al, 1999) and may
be associated with a higher rate of depression (Gupta and Gupta, 1998). There
is an unmet need for effective psoriasis therapies. Despite the large number of
therapies available for the treatment of psoriasis, some agents are limited in
efficacy, and many provide only temporary relief. Many patients require
ultraviolet phototherapy or systemic therapies, which are often associated with
toxicities precluding long-term use. Currently, no treatments for psoriasis
produce a curative response for the condition, including newer biological
therapies. Thus, more effective and safer treatments that offer a longer
duration of therapy are continually sought to fill this unmet therapeutic need.

Primary Objective: 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: Secondary objectives of the study include evaluating the
safety, efficacy, and quality of life outcomes through Week 52.

This is a phase IIIb/IV, multicentre, open label, two-arm, randomised study,
lasting 56 weeks (including screening). The primary endpoint will be 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.

In both treatment arms, patients weighing <=100 kg will receive ustekinumab 45
mg (0.5 ml) by subcutaneous injection at Weeks 0, 4 and every 12 weeks
thereafter until Week 40. In both treatment arms, patients weighing >100 kg
will receive ustekinumab 90 mg (1 ml) in two subcutaneous injections at Weeks
0, 4 and every 12 weeks thereafter until Week 40. The ustekinumab dose will be
determined according to body weight recorded at randomisation and will remain
the same for the duration of the trial. At Week 0, all eligible patients will
be randomised to one of the following treatment regimens:

Arm 1: Immediate cessation of methotrexate therapy and administration of
subcutaneous ustekinumab at Weeks 0, 4, and every 12 weeks thereafter until
Week 40 (last dose of ustekinumab).

Arm 2: Gradual reduction of methotrexate therapy over a maximum of 4 weeks (see
suggested *Gradual Reduction regimes in the table below) and administration of
subcutaneous ustekinumab at Weeks 0, 4, and every 12 weeks thereafter until
Week 40 (last dose of ustekinumab). Gradual Reduction of Methotrexate Dose in
Arm 2 The methotrexate dose reduction regime will depend on the dose of
methotrexate at baseline.

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 approximately 1 week before the second dose of ustekinumab. As
methotrexate is taken once a week, patients in this group will preferably be
given their second dose of ustekinumab on the same day of Week 4 that they
normally take their methotrexate.

Follow up of patients will be 52 weeks at maximum during the trial. (exclusive
of screenings period). After screening and randomisation patiënts will come
every 2 weeks. After week 4 the next visit will take place and the next visit
will be after 8 weeks; than another visit will be performed after 4 weeks and
thereafter 1 visit every 3 months.
Patiënts receive subcutaneous injections, which will be administered by an
expereinced trial nurse.

Risks: Methotrexate is a registered medication on the market with known
side-effects. Ustekinumab is generally well tolerated by patients with
psoriasis, but is a drug which influences the way the immune system of the body
fights infections. In subjects who participated in earlier trials with
Ustekinumab, infections of the upper respiratory tract were relatively often
observed. Other infections which were observed were urinary tract infections or
flue. Serious infections which led to hospital admission for medical
observation and/or treatment were also observed in earlier trials with
Ustekinumab. Allergic reactions might occur as well as reactions at the
injection site.
The patient will have an extensive screening investigation, before
randomization will take place. During the trial the patient will be followed-up
intensively. Risks of blooddrawing are minimal.