Protocol I1F-MC-RHBS;A 52-Week Multicenter, Randomized, Blinded, Parallel Group Study Comparing the Efficacy and Safety of Ixekizumab to Ustekinumab in Patients with Moderate to Severe Plaque Psoriasis

Psoriasis is a relatively common chronic inflammatory skin disease,
characterized by the formation of red, thick, scaly plaques on the skin, which
is often accompanied by itching. Overall, patients' quality of life, work
productivity and sleep can be severely impacted by this condition. The
currently available treatments are topical therapy, phototherapy and systemic
therapy. The first two are not sufficiently effective in patients with moderate
to severe psoriasis. Systemic therapy seems to be more promising, but most
conventional drugs have limited applicability due to toxicity and side effects.
Biological agents show higher rates of improvement, but still the rate of
improvement is limited and treatment is often discontinued due to side effects,
such loss of efficacy. Increasing levels of clearance result in greater
improvements in quality of life. The greatest benefit is expected with at least
90% response and complete clearance of plaques. IL-17A was recently identified
as an important factor in the formation of psoriasis. Ixekizumab (LY2439821) is
a humanized immunoglobulin G subclass (IgG4) monoclonal antibody (MAb) designed
and engineered to selectively inhibit IL-17A (IL-17A).

Previous phase 3 studies with ixekizumab have demonstrated positive
benefit/risk profiles. 80 mg ixekixumab every two weeks yielded better outcomes
than every 4 weeks in the initial treatment period.

Ustekinumab is currently considered one of the most effective drugs for the
treatment of moderate-to-severe psoriasis.
The purpose of Study I1F-MC-RHBS (RHBS) is to compare the efficacy and safety
of ixekizumab 80 mg Q2W (12-week induction regimen) followed by Q4W
(maintenance regimen) to ustekinumab in patients with moderate-to-severe
psoriasis over 52 weeks of treatment.

The primary objectives of this study are to assess whether 80 mg ixekizumab
every 2 weeks (Q2W) is:
• noninferior to ustekinumab at Week 12 in the treatment of patients with
moderate-to-severe plaque psoriasis as measured by proportion of patients
achieving 90% improvement in Psoriasis Area and Severity Index (PASI; PASI 90),
and then
• superior to ustekinumab at Week 12 in the treatment of patients with
moderate-to-severe plaque psoriasis as measured by proportion of patients
achieving PASI 90
The key secondary objectives of this study are to compare the following
efficacy and health outcomes measures between ixekizumab Q2W and ustekinumab at
the 12-week study time point:
• proportion of patients achieving a >=75% improvement in PASI from baseline
(PASI 75)
• proportion of patients achieving a 100% improvement in PASI from baseline
(PASI 100)
• binary proportion of patients achieving an sPGA of 0 [remission]
• proportion of patients with a static Physician Global Assessment (sPGA)
(0,1) with at least a 2-point improvement from baseline
• proportion of patients achieving dermatology-specific quality of life
index (DLQI) (0,1)
• proportion of patients reaching Itch Numeric Rating Scale (NRS) responder
definition (decrease of
4 points in the Itch NRS in patients with baseline score >=4 points)
• change from baseline in Itch NRS
• change from baseline in Skin Pain visual analog scale (VAS)

Study I1F-MC-RHBS is a Phase 3b, multicenter, randomized, blinded,
double-dummy, active-comparator, and parallel-group study examining the effect
on PASI 90 measured at 12 weeks for ixekizumab versus ustekinumab and
subsequent time points for up to 52 weeks in patients with moderate-to-severe
psoriasis.
The following treatment groups will be assessed in this study:
• Ixekizumab 80 mg, subcutaneous (SC) injection. After a starting dose of
160 mg (two 80-mg SC injections) at randomization (Week 0), 80 mg will be
self-injected SC Q2W, starting at Week 2 until Week 12, and then Q4W thereafter.
• Ustekinumab: 45 mg SC injection for patients <100 kg AND 90 mg SC
injection for patients >100 kg.
Injection at randomization (Week 0), at Week 4, and then Q12W thereafter (Weeks
16, 28, and 48). The study will consist of 4 periods:
• Period 1: Screening Period lasting up to 35 days before Period 2
• Period 2: Induction Period from Week 0 (baseline) up to Week 12
• Period 3: Maintenance Period from Week 12 up to Week 52
• Period 4: Post-Treatment Follow-Up Period occurring from last treatment
period visit or EarlyTermination Visit (ETV) for a minimum of 12 weeks
following that visit

Investigational Product, Dosage, and Mode of Administration or Intervention:
80 mg ixekizumab: A starting dose of 160 mg (Week 0) will be given as a 2 SC
injections, followed by 80 mg given as 1 SC injection Q2W (Weeks 2, 4, 6, 8,
10, and 12), and then 80 mg given as 1 SC injection Q4W (Weeks 16, 20, 24, 28,
32, 36, 40, 44, and 48).

Reference Therapy, Dose, and Mode of Administration or Comparative Intervention:
45 mg ustekinumab (for patients <=100 kg): A 45-mg dose of ustekinumab (Week 0
and Week 4) will be given as 1 SC injection, and then Q12W (Weeks 16, 28, and
40) thereafter.
Or 90 mg ustekinumab (for patients >100 kg): A 90-mg dose of ustekinumab (Week
0 and Week 4) will be given as 1 SC injection, and then Q12W (Weeks 16, 28,
and 40) thereafter.
Planned Duration of Treatment:
Up to 52 weeks for ixekizumab over 4 Periods (Screening Period: up to 35 days
before Period 2; Induction Period:
12 weeks; Maintenance Period: 40 weeks; and Post-Treatment Follow-Up Period:
12 weeks after the date of the patient*s ETV or last regularly scheduled
visit).

There are several risks involved with the study drug. The most common side
effects associated with ixekizumab are: Runny nose and sore throat; cold
symptoms; Upper respiratory tract infection; Injection site reaction;Headache;
Worsening of rheumatoid arthritis; Urinary tract infection; Sinus irritation;
Injection site pain; Injection site redness; Diarrhea; Back pain; Bronchitis;
High blood pressure; Dizziness; Joint pain; Cough; Nausea; Vertigo.
The comparator, Ustekinumab can have side effect. The subject undergo a number
of study procedures, such as filling out questionnaires, blood draws,
subcutaneous injections, x rays and genetic testing. These procedures may also
be accompanied by certain risks. The combination of treatments and the
procedures may also have other unknown risks. These risks are desribed in the
informed consent form.

Subjects taking part in this study suffer from moderate to severe psoriasis.
Most established therapies show limited improvements and/or have side effects.
By inhibiting IL-17A a larger and long-lasting effect may be obtained. Previous
studies with ixekizumab showed positive benefit/risks. In addition, this study
has no placebo-only group, so patient will always receive a treatment. The
comparator is currently considered one of the most effective drugs for this
condition.