PHASE 3, MULTICENTER, RANDOMIZED, DOUBLE BLIND, PARALLEL GROUP, PLACEBO CONTROLLED STUDY TO EVALUATE THE EFFICACY AND SAFETY OF CERTOLIZUMAB PEGOL IN SUBJECTS WITH ADULT ONSET ACTIVE AND PROGRESSIVE PSORIATIC ARTHRITIS (PSA)

Psoriatic arthritis is an inflammatory arthritis that occurs in up to one-third
of patients with PSO and is usually diagnosed years after, but sometimes
before, the skin disease appears. More than 50% of patients with PsA experience
progressive, erosive arthritis that is often accompanied by pain, fatigue, and
functional impairment. The combination of joint and skin manifestations of PsA
can have a profound impact on patient function, well-being, and health-related
quality of life (HRQoL). The functional impairments are also associated with
significant direct health care costs and substantial work-related disability,
including a lower rate of employment.
Clinical manifestations of PsA include joint inflammation, enthesitis,
dactylitis, and psoriatic skin lesions. Clinical features that may distinguish
PsA from rheumatoid arthritis (RA) include asymmetry of joint involvement,
initial oligoarticular involvement, enthesial inflammation, iritis, and
infrequent presence of rheumatoid factor. Factors relevant to the assessment of
disease activity and severity of peripheral arthritis in PsA patients include:
1. The extent of synovitis, with polyarticular disease (* 4 involved joints) a
marker for more severe disease and impaired outcome than oligoarticular disease
(< 4 involved joints)
2. The presence of joint damage, indicated by periarticular erosions, which is
indicative of more severe disease and predictive of further damage
3. Impairment of functional status. The oligo- and polyarticular patterns of
PsA (with or without spinal involvement) constitute the predominant forms and
therefore will be the target populations for the proposed clinical study.
Therapeutic approaches for PsA have focused on a similar immunopathologic
etiology underlying both RA and PsA. Treatment for PsA traditionally has
included nonsteroidal anti-inflammatory drugs (NSAIDs), and data support their
efficacy in the treatment of signs and symptoms of peripheral arthritis. The
efficacy of oral or parenteral corticosteroids for peripheral arthritis in PsA
has not been examined formally, although they are commonly used in clinical
practice. Some data are available to support the use of DMARDs, ie,
sulfasalazine (SSZ), leflunomide, MTX, and cyclosporine, in providing a small
to medium degree of improvement in the clinical signs and symptoms, but not
joint damage, of PsA. The evidence has been negative for oral and injectable
gold.
Four TNF*-antagonists (infliximab [IFX], etanercept [ETN], adalimumab [ADA],
and golimumab [GOL]) are currently registered in the United States (USA) and
three (IFX, ETN, and ADA) are also registered in Europe for the treatment of
PsA. Tumor necrosis factor-antagonists substantially improve the signs and
symptoms of peripheral arthritis in PsA and accompanying psoriatic skin
disease. In addition, all have demonstrated improvement in functional status
and HRQoL. Moreover, the first 3 agents have demonstrated attenuation of the
progression of joint damage as assessed radiographically. For reasons of loss
or lack of efficacy or intolerance to currently available TNF-antagonists,
there remains a need for additional TNF-antagonists as therapeutic options for
patients with PsA, as observational data support that failure of an initial
TNF-antagonist does not preclude the response to another one (Conti et al,
2007).
Certolizumab pegol is a humanized Fab* conjugated to PEG with specificity for
human TNF*. Certolizumab pegol has demonstrated efficacy in clinical studies of
Crohn*s disease (CD), PSO, and RA. The objective of this study is to
demonstrate the effects of CZP in the treatment of PsA in adult patients with
active and progressive PsA. Certolizumab pegol has been approved by the Food
and Drug Administration for reducing signs and symptoms of CD and for the
treatment of moderate to severe active RA in adult patients. Two dose regimens
of CZP have been selected for this study, reflecting 2 different frequencies of
administration: each active group will receive 3 loading doses of CZP 400mg
administered sc at Weeks 0, 2, and 4 followed by either 200mg Q2W or 400mg Q4W.
Furthermore, ADA, ETN, and GOL, the 3 commercially available sc TNF-antagonists
for the treatment of PsA, have identical studied and commercial dosing regimens
in PsA and RA, with similar efficacy and safety profiles in both PsA and RA.
Therefore, the proposed CZP dosing regimens for this study were selected on the
basis that these doses of CZP were efficacious for the treatment of RA in
clinical trials, are the current recommended dosing regimens for RA in the USA,
and would be expected to have similar efficacy in PsA.

Certolizumab pegol is a humanized Fab* conjugated to PEG with specificity for
human TNF*. Certolizumab pegol has demonstrated efficacy in clinical studies of
Crohn*s disease (CD), PSO, and RA. The objective of this study is to
demonstrate the effects of CZP in the treatment of PsA in adult patients with
active and progressive PsA. Certolizumab pegol has been approved by the Food
and Drug Administration for reducing signs and symptoms of CD and for the
treatment of moderate to severe active RA in adult patients. Two dose regimens
of CZP have been selected for this study, reflecting 2 different frequencies of
administration: each active group will receive 3 loading doses of CZP 400mg
administered sc at Weeks 0, 2, and 4 followed by either 200mg Q2W or 400mg Q4W.
Furthermore, ADA, ETN, and GOL, the 3 commercially available sc TNF-antagonists
for the treatment of PsA, have identical studied and commercial dosing regimens
in PsA and RA, with similar efficacy and safety profiles in both PsA and RA.
Therefore, the proposed CZP dosing regimens for this study were selected on the
basis that these doses of CZP were efficacious for the treatment of RA in
clinical trials, are the current recommended dosing regimens for RA in the USA,
and would be expected to have similar efficacy in PsA.

Study PsA001 is a multicenter, randomized, double-blind, parallel-group,
placebo-controlled
clinical study to evaluate the efficacy and safety of CZP in adult subjects
with active and
progressive PsA. The study includes 5 periods:

Period 1
Screening period of 1 to 5 weeks in order to obtain laboratory data, to verify
that the doses of MTX, NSAIDs, and corticosteroids, if used, are stable, and to
enable washout of any medications not permitted for use during the study.

Period 2 * Week 0 to Week 24: Double-blind, placebo-controlled
Eligible subjects will be allocated to the following study treatments in a
1:1:1 ratio:
- CZP administered sc at the dose of CZP 400mg Q2W at Weeks 0, 2 and 4 followed
by CZP 200mg Q2W sc (starting at Week 6)
- CZP administered sc at the dose of CZP 400mg Q2W at Weeks 0, 2 and 4 followed
by CZP 400mg Q4W sc (starting at Week 8)
- Placebo
Study treatments (including placebo) will be administered by dedicated
unblinded trained site personnel at Weeks 0, 2, 4, 6, 8, 10, 12, 14, 16, 18,
20, and 22.
After the Week 24 Visit of the last subject, the database will be locked and a
first interim study report will be written. Limited UCB personnel will become
unblinded for the purposes of the data analysis but the Investigator and the
subject will remain blind to treatment assignments. All subjects will switch to
active treatment after Week 24.

Period 3 * Week 24 to Week 48: Dose-blind for the subjects and the
Investigators, no placebo
Subjects originally randomized to placebo will be re-randomized in a 1:1 ratio
to receive 3 loading doses of CZP sc 400mg at Weeks 24, 26, and 28 followed by
either CZP 200mg Q2W or CZP 400mg Q4W from Week 30 onward.
All subjects originally randomized to CZP will continue to receive the
treatment regimen they were assigned to at randomization (CZP 200mg Q2W or CZP
400mg Q4W sc).
Study treatments will be administered by dedicated unblinded trained site
personnel according to the injection scheme. All subjects will be trained on
self-administration at Weeks 26 and 28. Subjects will self-administer 1
injection at home Q4W starting from Week 30.
After the Week 48 Visit of the last subject, the database will be locked and a
second interim study report will be written.

Period 4 * Week 48 to Week 158: Open-label
Subjects will continue to receive the same dose regimen of CZP that they
received during Period 3. After Week 48, only subjects randomized to CZP 200mg
Q2W will self-administer CZP 200mg (one-1mL sc injection) Q4W at home. All
other injections will be administered preferably by self-administration during
scheduled visits.
The last dosing visit will be at Week 156. The final study assessments are
performed at Week 158.

Period 5 * Week 158 to Week 166: Safety Follow-Up
All subjects, including those withdrawn from study treatment, will have a
Safety Follow-Up Visit 10 weeks after their last dose of study medication.

Subjects will receive treatment with Certolizumab by injections of 1 ml
syringes.

For each subject the study will last up to the maximum of 171 weeks, consisting
of the following periods:

- A screening period that lasts up to 5 weeks
- A double blind placebo controlled treatment period of 24 weeks
- A dose blind treatment period of 24 weeks
- An open label treatment period of 110 weeks
- A safety follow up visit 10 weeks after the last dose of study medication.

During these visits the subjects will undergo:

- Physical Examination
- Vital signs/function tests
- Questionnaires about general condition, disease and related problems
- Tuberculosis test
- Vena punction (max 25 ml per visit)
- Subcutaneous injection (max 1 ml per visit)
- X-ray of chest, hands and feet