A Phase 3, Multicenter, Randomized, Double-Blind, Parallel-Group, Placebo- And Active-Controlled Study Followed By A Placebo-Controlled Maintenance Period And Open-Label Follow-Up To Evaluate The Efficacy And Safety Of Certolizumab Pegol In Subjects With Moderate To Severe Chronic Plaque Psoriasis

(Protocol v1.0 25Jul2014 p.13-14)
Psoriasis (PSO) is a common, chronic inflammatory disease characterized by a
series of linked cellular changes in the skin: hyperplasia of epidermal
keratinocytes, vascular hyperplasia and ectasia, and infiltration of T
lymphocytes, neutrophils, and other types of leucocytes in affected skin.
Though the pathophysiology of PSO is not fully understood, the importance of
T-cells and inflammatory cytokines has been demonstrated by the clinical
benefit provided by therapies directed at these targets.
Psoriasis affects approximately 3% of the adult US population and its onset can
begin at any age. Although its onset can occur at any age and has been reported
even at, or near, birth, it is unusual before late adolescence and most
patients develop the disease in the third decade of life.
The prevalence of PSO varies widely and ranges from about 1% in South America
to up to about 2.5% in parts of Europe. It is rare in West African blacks and
displays low incidence in Japanese and Eskimo populations.
Various forms of PSO exist including plaque, guttate, inverse, pustular, and
erythrodermic. Plaque PSO is the most common, comprising approximately 80% to
90% of all cases. Approximately 17% of those with PSO have moderate to severe
disease.
Increased severity of the disease tends to be correlated with a strong family
history, earlier onset of the disease (eg, in the late teens) and is often
manifested by more extensive involvement of the skin (ie, greater body surface
area). In addition to the impact on skin, PSO has a multitude of psychosocial
and emotional effects on patients, including increased selfconsciousness,
frustration, fatigue, depression, and suicidal ideation.
As a result, patients frequently report sleeping problems, difficulties at
work, problems interacting with family
members, disrupted leisure activities, and sexual difficulties. [...]

Therapy for patients with PSO varies according to the severity of disease.
Limited or mild disease is often treated with topical therapies, such as
corticosteroids and vitamin D analogs, and phototherapy. Patients with more
severe disease are often treated with photochemotherapy, cyclosporine,
methotrexate (MTX), or biologic agents, such as TNF inhibitors and IL12/23
inhibitors. The effectiveness of TNF inhibitors in the treatment of PSO has
been demonstrated in many Phase 3 clinical trials and has led to FDA approval
of multiple TNF inhibitors for use in patients with moderate to severe chronic
plaque PSO.
The efficacy of TNFα inhibitors in treating PSO has been attributed to their
inhibition of Th17 T cells. Different from the traditional systemic drugs that
impact the entire immune system, biologics target specific parts of the immune
system. The efficacy and safety of these molecules is now well established and
accepted in the management of the disease, yet a recent study has shown that
patients who switched to a different TNFα inhibitor as a result of secondary
loss of efficacy, adverse events (AEs), or intolerance were more likely to
reach a PASI75 response than those who switched as a result of primary
inefficacy. Data consistently demonstrate that >50% of severely affected
patients are dissatisfied with current treatments and up to 30% of severe
patients are not receiving treatment in accordance with accepted therapy
guidelines.

(Protocol v1.0 25Jul2014 p.18)
The primary objective of the study is to compare the efficacy of certolizumab
pegol (CZP) administered subcutaneously at the doses of CZP 400mg every two
weeks and CZP 200mg every two weeks after a loading dose of CZP 400mg every two
weeks at Weeks 0, 2, and 4 to Placebo (PBO) in the treatment of moderate to
severe chronic plaque PSO.

The secondary objectives of the study are to compare the efficacy of CZP
administered subcutaneously at the doses of CZP 400mg every two weeks and CZP
200mg every two weeks after a loading dose of CZP 400mg every two weeks at
Weeks 0, 2, and 4 to ETN administered
subcutaneously bi-weekly at a cumulative weekly dose of 100mg in the treatment
of moderate to severe chronic plaque PSO, to assess the optimal initial
treatment dose for the treatment of moderate to severe chronic plaque PSO, to
assess the optimal maintenance dose for the treatment of moderate to severe
chronic plaque PSO and to assess the safety and tolerability of CZP.

Other objectives of the study are to demonstrate the effect of CZP on aspects
of the disease, such as:
- Improvement of skin related quality of life (DLQI)
- Health status as measured by the EQ-5D 3L
- Productivity as measured by the WPAI-SHP
- Fatigue as measured by the FASca
- Psoriatic nail disease (target nail) as measured by mNAPSI in subjects with
nail disease at Baseline
- Assess the safety and efficacy of long-term use of CZP

(Protocol v1.0 25Jul2014 p.20)
The study is a double-blind, parallel-group, randomized, placebo- and
active-controlled, multicenter study with a double-blind, placebo-controlled
maintenance period.
The study includes 5 periods: Screening, Initial Treatment (Double-blind,
Placebo- and Activecontrolled), Maintenance Treatment (Placebo-controlled),
Open-label Treatment and Post Study Safety Follow-up.

(Protocol v1.0 25Jul2014 p.18)
Possibilities for intervention are:
- CZP 200mg: CZP administered subcutaneously at the dose of CZP 400mg once
every two weeks the first three visits (loading dose) followed by CZP 200mg
once every two weeks subcutaneously
- CZP 400mg: CZP administered subcutaneously at the dose of CZP 400mg once
every two weeks
- ETN: ETN administered subcutaneously at 50mg twice weekly
- PBO: PBO administered subcutaneously once every two weeks

(Protocol v1.0 25Jul2014 p.14-15)
The efficacy of TNFα inhibitors in treating PSO has been attributed to their
inhibition of Th17 T cells. Different from the traditional systemic drugs that
impact the entire immune system, biologics target specific parts of the immune
system. The efficacy and safety of these molecules is now well established and
accepted in the management of the disease, yet a recent study has shown that
patients who switched to a different TNFα inhibitor as a result of secondary
loss of efficacy, adverse events (AEs), or intolerance were more likely to
reach a PASI75 response than those who switched as a result of primary
inefficacy. Data consistently demonstrate that >50% of severely affected
patients are dissatisfied with current treatments and up to 30% of severe
patients are not receiving treatment in accordance with accepted therapy
guidelines.
[...]
Certolizumab pegol is an inhibitor of TNFα, which is a pro-inflammatory
cytokine with multiple biologic actions. A unique feature of CZP among TNF
antgonists is the lack of an Fc (fragment crystallizable) region, thereby the
molecule cannot initiate potential Fc-mediated effects such as
complement-mediated cytotoxicity or antibody dependent, cell-mediated
cytotoxicity.
Cimzia has been studied for the treatment of inflammatory diseases, such as
Crohn*s disease (CD), including pediatrics; rheumatoid arthritis (RA);
psoriatic arthritis (PsA); axial spondyloarthritis (axSpA), including
ankylosing spondylitis (AS); and is currently being studied in juvenile
idiopathic arthritis (JIA). Certolizumab pegol has also been evaluated in two
Phase 2 studies in subjects with PSO. As of 30 Apr 2013, the clinical
development program for CZP includes a total of 70 completed or ongoing
clinical studies, with 2 completed studies in moderate to severe chronic plaque
PSO (C87040 and C87044). Various doses and regimens have been assessed in these
programs.
In all studies to date, CZP has been shown to have an acceptable safety profile
and was well tolerated by subjects with CD, RA, PsA, axSpA, and PSO.