Active Psoriatic Arthritis

The primary objective is to compare ixekizumab 80 mg Q2W and 80 mg Q4W versus placebo in the treatment of patients with active psoriatic arthritis (PsA) who are bDMARD-experienced, as measured by the percentage of patients achieving ACR20 response at Week 24. The major secondary objectives are to compare ixekizumab 80 mg Q2W and 80 mg Q4W versus placebo in the treatment of patients with PsA who are bDMARD-experienced based on the following measures:  Change from baseline to Week 24 in Health Assessment Questionnaire-Disability Index (HAQ-DI) scores.  ACR20 response rate at Week 12.  PASI 75 response rate at Week 12 (restricted to patients with baseline psoriatic lesion involving ≥3% body surface area [BSA]).  Change from baseline to Week 12 in Leeds Enthesitis Index (LEI) (restricted to patients with enthesitis at baseline).  Change from baseline to Week 12 in Itch Numeric Rating Scale (NRS) (restricted to patients with baseline psoriatic lesion(s) involving ≥3% BSA).  There are also a number of other secondary and exploratory objectives for this protocol.

Ixekizumab(LY2439821)

Ixekizumab

subcutaneous Injection

80

Efficacy: The following efficacy measures will be assessed in this study: ACR20; ACR50; ACR70; individual
components of the ACR core set including TJC (68 joint count), SJC (66 joint count), Patient’s Assessment of Pain
Visual Analog Scale (VAS), Patient’s Global Assessment of Disease Activity VAS, Physician’s Global
Assessment of Disease Activity VAS, Patient’s Assessment of Physical Function as measured by the HAQ-DI and
C-reactive protein (CRP); disease activity score with CRP (DAS28-CRP); Psoriatic Arthritic Response Criteria
(PsARC); Minimal Disease Activity (MDA) score; LEI, Leeds Dactylitis Index—Basic (LDI-B), Spondyloarthritis
Research Consortium of Canada (SPARCC); Bath Ankylosing Spondylitis Disease Activity Index (BASDAI);
PASI 75, PASI 90, PASI 100; static Physician Global Assessment (sPGA); percentage BSA; Nail Psoriasis
Severity Index (NAPSI); Composite Psoriatic Disease Activity Index (CPDAI); Modified Score for Assessment
and Quantification of Chronic Rheumatoid Affections of the Hands (mSACRAH).
Safety: The following safety measures will be assessed in this study: adverse events (AEs), serious adverse events
(SAEs), suspected unexpected serious adverse reactions (SUSARs), adverse events of special interest (AESI),
concomitant medications, sitting blood pressure (BP) and pulse, electrocardiograms (ECGs), physical evaluations,
chest x-ray and tuberculosis (TB) testing, urine pregnancy tests, and laboratory evaluations including, but not
limited to, chemistry, hematology, urinalysis, and immunogenicity testing (anti-drug antibodies [ADAs]).
Health Outcomes: The following health outcome measures will be assessed in this study: itch NRS, fatigue
severity NRS, Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36), Dermatology Life Quality
Index (DLQI), Ankylosing Spondylitis Quality of Life Questionnaire (ASQoL), health utility using the European
Quality of Life–5 Dimensions 5 Level (EQ-5D 5L), Work Productivity and Activity Impairment-Specific Health
Problem (WPAI-SHP), healthcare resource utilization, and Quick Inventory of Depressive Symptomatology-self
report, 16 items (QIDS–SR16).
Bioanalytical: Concentrations of immunoreactive ixekizumab in human serum as determined by a validated
method.
Pharmacokinetics: Serum concentration of ixekizumab and anti-ixekizumab antibodies, and associated time from
dose, will be obtained at selected visits using 4 sampling cohorts.
Pharmacodynamics: Efficacy endpoints such as ACR20 response rate and PASI, and safety endpoints such as
neutrophil counts.
Translational Medicine: A multifaceted approach will be employed to explore potential biomarkers in serum,
plasma, urine and whole blood ribonucleic acid (RNA) and deoxyribonucleic acid (DNA).

Inclusion Criteria
Patients are eligible to be included in the study only if they meet all of the following criteria:
[1] Are male or female patients 18 years or older.
[1a] Male patients agree to use a reliable method of birth control during the study.
[1b] Female patients:
Are women of childbearing potential who test negative for pregnancy and agree to
use a reliable method of birth control or remain abstinent during the study and for at
least 12 weeks following the last dose of investigational product, whichever is longer.
Methods of contraception considered acceptable when used properly include oral
contraceptives, contraceptive patch, injectable or implantable contraceptives,
intrauterine device, vaginal ring, diaphragm with contraceptive gel, or condom with
contraceptive foam.
-orAre women of non-childbearing potential, defined as:
Women who have had surgical sterilization (hysterectomy, bilateral oophorectomy, or
tubal ligation);
-orWomen who are ≥60 years of age;
-orWomen ≥40 and <60 years of age who have had a cessation of menses for
≥12 months and a follicle-stimulating hormone (FSH) test confirming
non-childbearing potential (≥40 mIU/mL).
[2] Have a diagnosis of active PsA for at least 6 months (based on a detailed medical history
provided by the patient, and a physical exam by the Study Investigator, and/or other
evidence such as that provided by joint x-rays, that establishes a history consistent with a
diagnosis of active PsA of at least 6 months duration) and currently meet the Classification
for Psoriatic Arthritis (CASPAR) criteria (Attachment 4).
[3] Have active PsA defined as the presence of at least 3/68 tender and at least 3/66 swollen
joints, as determined by the Tender and Swollen Joint Count Assessment Form (Attachment
5) at Visit 1 (Screening) and Visit 2 (Week 0, baseline).
[4] Have been treated with 1 or more cDMARDs (MTX, sulfasalazine, leflunomide, or
hydroxychloroquine).
[5] Have had prior treatment with at least 1 and not more than 2 TNF inhibitors. The subject
must have discontinued at least 1 TNF inhibitor due to either an inadequate response (based
on a minimum of 12 weeks on therapy) or documented intolerance.
[6] Have active psoriatic skin lesions (plaque) or a documented history of plaque Ps.
[7] Have given written informed consent approved by Lilly, or its designee, and IRB/ERB
governing the site.

Exclusion Criteria
Patients will be excluded from study enrollment if they meet any of the following criteria:
[8] Are currently receiving treatment with any biologic or small molecule therapy for PsA or
Ps, including investigational therapies (such as, but not limited to, a TNF inhibitor, IL-1
receptor antagonists, IL-6 inhibitor, anti-IL-12/23p40, T cell or B cell targeted therapies,
PDE4 inhibitors, or JAK inhibitors), or have received denosumab.
[9] Have previously completed or withdrawn from this study or any other study investigating
ixekizumab or other IL-17 inhibitors, eg, anti-IL-17 or anti-IL-17 receptor (anti-IL-17R)
monoclonal antibodies.
[10] Have a history of drug-induced Ps.
[11] Have received treatment with IL-17 or IL12/23 targeted MAb therapy.
[12] Concurrent or recent use of any biologic agent within the following washout periods:
etanercept <28 days; infliximab, adalimumab, certolizumab pegol, or alefacept <60 days;
golimumab <90 days; rituximab <12 months; or any other biologic agent or small molecule
<5 half-lives prior to baseline (Week 0; Visit 2).
[13] Have used DMARDs other than MTX, leflunomide, sulfasalazine, or hydroxychloroquine
(for example, gold salts, cyclosporine, azathioprine, dapsone, 6-mercaptopurine,
mycophenolate mofetil, or any other immunosuppressive agents) in the 8 weeks prior to
baseline (Week 0, Visit 2).
Have discontinued MTX or sulfasalazine within the 8 weeks prior to baseline, or
hydroxychloroquine within 12 weeks prior to baseline.
If taking MTX, leflunomide, sulfasalazine, or hydroxychloroquine must have been treated
for at least 12 weeks prior to baseline and on a stable dose for at least 8 weeks prior to
baseline, as follows: oral or parenteral MTX = 10 to 25 mg/week, leflunomide =
20 mg/day, sulfasalazine = up to 3 g/day, or hydroxychloroquine = up to 400 mg/day. The
dose of these allowed concomitant medications must remain unchanged throughout the
Double-Blind Treatment Period (Period 2) of the study, unless changes are required for
safety issues, or for rescue therapy at Week 16. Local standard of care should be followed
for concomitant administration of folic acid with MTX.
[14] Are receiving treatment with more than 1 conventional DMARD (MTX, leflunomide,
sulfasalazine, or hydroxychloroquine) at study entry. Note: Under no circumstances will
simultaneous use of MTX and leflunomide be allowed at any time during the study for
safety reasons.
[15] Have discontinued leflunomide within 4 weeks prior to baseline or have received
leflunomide from 4 to 12 weeks prior to baseline (Week 0, Visit 2) and have not undergone
a drug elimination procedure.
[16] Use of oral corticosteroids at average daily doses of >10 mg/day of prednisone or its
equivalent, or use of variable doses of any oral corticosteroids, within 4 weeks prior to
baseline (Week 0, Visit 2).
[17] Have received any parenteral glucocorticoid administered by intraarticular, intramuscular,
or intravenous (IV) injection within 6 weeks prior to baseline (Week 0, Visit 2), or for
whom a parenteral injection of glucocorticosteroids is anticipated during the Double-Blind
Treatment Period (Period 2) of the study.
[18] Concomitant use of NSAIDs, including cyclooxygenase-2 (COX-2) inhibitors, unless the
patient is on a stable dose for at least 2 weeks prior to baseline (Week 0, Visit 2).
[19] Use of any opiate analgesic at average daily doses of >30 mg/day of morphine or its
equivalent or use of variable doses of any opiate analgesic within 6 weeks prior to baseline
(Week 0, Visit 2).
[20] Have received systemic non-biologic Ps therapy other than DMARDs or corticosteroids as
indicated above (including, but not limited to, oral psoralens and ultraviolet A [PUVA]
light therapy, oral retinoids, thioguanine, hydroxyurea, fumaric acid derivatives, or
1, 25 dihydroxy vitamin D3 and analogues) or phototherapy (including either oral and
topical PUVA, ultraviolet B [UVB] or self-treatment with tanning beds or therapeutic
sunbathing) within 4 weeks prior to baseline (Week 0, Visit 2);
OR had topical Ps treatment within the previous 2 weeks prior to baseline (Week 0,
Visit 2).
Exceptions: weak potency (WHO Group 1 classification) topical steroids will be
permitted.
[21] For those patients with plaque Ps, cannot avoid use of tanning booths for at least 4 weeks
prior to baseline (Week 0, Visit 2) and during the study.
[22] Have a known allergy or hypersensitivity to any biologic therapy that would pose an
unacceptable risk to the patient if participating in this study.
[23] Have ever received natalizumab or other agents that target alpha-4-integrin.
[24] Had a live vaccination within 12 weeks prior to baseline (Week 0, Visit 2), or intend to
have a live vaccination during the course of the study, or within 12 weeks of completing
treatment in this study, or have participated in a vaccine clinical study within 12 weeks
prior to baseline. Investigators should review the vaccination status of their patients and
follow the local guidelines for adult vaccination with non-live vaccines intended to prevent
infectious disease prior to therapy.
Note: Killed/inactive or subunit vaccines are expected to be safe; however, their efficacy
with concomitant ixekizumab treatment is unknown.
[25] Had a vaccination with Bacillus Calmette-Guérin (BCG) within 12 months prior to baseline
(Week 0, Visit 2), or intend to have this vaccination with BCG during the course of the
study, or within 12 months of completing treatment in this study.
[26] Have a diagnosis of other inflammatory arthritic syndromes such as RA, ankylosing
spondylitis, reactive arthritis, or enteropathic arthritis.
[27] Have active Crohn’s disease or active ulcerative colitis.
[28] Have diagnosis of fibromyalgia.
[29] Have a chronic pain condition that would confound evaluation of the patient.
[30] Have evidence of active vasculitis or uveitis.
[31] Have had surgical treatment of a joint within 8 weeks prior to baseline or will require such
up to Week 24.
[32] Have had any major surgery within 8 weeks prior to baseline, or will require such during
the study that in the opinion of the investigator and in consultation with Lilly or its
designee would pose an unacceptable risk to the patient.
[33] Have current or a history of lymphoproliferative disease.
[34] Have diagnosis or history of malignant disease within the 5 years prior to baseline
(Week 0, Visit 2). Note: Patients with successfully treated basal-cell carcinoma (no more
than 3), squamous-cell carcinoma of the skin (no more than 2) within the 5 years prior to
baseline may participate in the study.
[35] Presence of significant uncontrolled cerebrocardiovascular (for example, myocardial
infarction [MI], unstable angina, unstable arterial hypertension, moderate-to-severe
[NYHA class III/IV] heart failure, or cerebrovascular accident), respiratory, hepatic, renal,
gastrointestinal, endocrine, hematologic, neurologic or neuropsychiatric disorders,
abnormal laboratory values or illicit drug use (including cannabinoids, whether legalized or
not) at screening that in the opinion of the investigator pose an unacceptable risk to the
patient if participating in the study or of interfering with the interpretation of data.
[36] Have a history of uncompensated heart failure, fluid overload, or MI, or evidence of
new-onset ischemic heart disease or other serious cardiac disease, within 12 weeks prior to
baseline (Week 0, Visit 2).
[37] Have history of a suicide attempt, have a score of 3 on Item 12 (Thoughts of Death or
Suicide) on the QIDS-SR16 at screening (Visit 1) or at baseline (Week 0, Visit 2), or are
clinically judged by the investigator to be at risk for suicide.
[38] Had a serious infection (for example, pneumonia, cellulitis), have been hospitalized, or
have received IV antibiotics for an infection, within 12 weeks prior to baseline (Week 0,
Visit 2), or had a serious bone or joint infection within 24 weeks prior to baseline, or have
ever had an infection of an artificial joint, or are immunocompromised to an extent such
that participation in the study would pose an unacceptable risk to the patient.
[39] Have or had an opportunistic infection characteristic of an immunocompromised host,
and/or that occurs with increased incidence in an immunocompromised host (including, but
not limited to, Pneumocystis jirovecii pneumonia, histoplasmosis, coccidioidomycosis, or
cryptococcosis); or have a known immunodeficiency.
[40] Have or had a herpes zoster or any other clinically apparent varicella-zoster virus infection
within 12 weeks of baseline (Week 0, Visit 2).
[41] Have evidence or suspicion of active or latent TB (refer to Section 10.3.2.2 for details on
determining full TB exclusion criteria).
[42] Have any other active or recent infection other than mentioned above within 4 weeks of
baseline (Week 0, Visit 2) that, in the opinion of the investigator, would pose an
unacceptable risk to the patient if participating in the study; these patients may be
rescreened once ≥4 weeks after documented resolution of symptoms.
[43] Have a body temperature ≥38°C (100.5°F) at baseline (Week 0, Visit 2); these patients may
be rescreened once ≥4 weeks after documented resolution of elevated temperature.
[44] Have uncontrolled arterial hypertension characterized by a sitting systolic BP >160 mm Hg
or diastolic BP >100 mm Hg at baseline (Week 0, Visit 2).
Note: Determined by 2 consecutive elevated readings. If an initial sitting BP reading
exceeds this limit, the BP may be repeated once after the patient has rested sitting for
≥10 minutes. If the repeat value is less than the criterion limits, the second value may be
accepted.
[45] Are positive for human immunodeficiency virus serology (HIV), ie, positive for human
immunodeficiency virus antibody (HIV Ab).
[46] Have evidence of or test positive for hepatitis B by any of the following criteria: 1)
positive for hepatitis B surface antigen (HBsAg+); 2) positive for anti-hepatitis B core
antibody (HBcAb+) and negative for anti-hepatitis B surface antibody (HBsAb–); 3)
positive for HBcAb+ and positive for anti-hepatitis B surface antibody (HBsAb+) with a
concentration of HBsAb <200 mIU/mL; or 4) HBcAb+, HBsAb+ (regardless of HBsAb
level), and positive for serum hepatitis B virus (HBV) DNA.
(Note: Patients who are negative for hepatitis B surface antigen (HBsAg–), HBcAb+,
HBsAb+ with a concentration of HBsAb ≥200 mIU/mL, and negative for serum HBV
DNA may participate in the study. Patients who meet these criteria at screening must be
monitored during the study as detailed in Section 10.3.3.3).
[47] Have evidence of or test positive for hepatitis C virus (HCV). A positive test for HCV is
defined as: positive for hepatitis C antibody and positive via a confirmatory test for HCV
(for example, HCV polymerase chain reaction).
[48] Have clinical laboratory test results at screening that are outside the normal reference range
for the population and are considered clinically significant, and/or have any of the
following specific abnormalities:
[48a]Neutrophil count <1500 cells/L
[48b]Lymphocyte count <800 cells/L
[48c]Platelet count <100,000 cells/L
[48d]Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2.5 times the
upper limit of normal (ULN).
[48e]Total white blood cell (WBC) count <3000 cells/L
[48f] Hemoglobin <8.5 g/dL (85.0 g/L) for male patients and <8.0 g/dL (80 g/L) for female
patients
[48g]Serum creatinine >2.0 mg/dL (177mol/L).
Note: Laboratory tests should not be repeated unless there is a technical error or clinical
reason to believe a result may be erroneous.
[49] Have electrocardiogram (ECG) abnormalities that are considered clinically significant and
would pose an unacceptable risk to the patient if participating in the study.
[50] Have any other condition that precludes the patient from following and completing the
protocol, in the opinion of the investigator.
[51] Have donated blood of more than 1 pint within the last 4 weeks, or intend to donate blood
during the course of the study.
[52] Are women who are lactating or breastfeeding.
[53] Are investigator site personnel directly affiliated with this study and/or their immediate
families. Immediate family is defined as a spouse, parent, child, or sibling, whether
biological or legally adopted.
[54] Are Lilly employees or its designee or are employees of third-party organizations (TPOs)
involved in the study.
[55] Are currently enrolled in a clinical trial involving an investigational product or
nonapproved use of a drug or device (other than the investigational product used in this
study), or concurrently enrolled in any other type of medical research judged not to be
scientifically or medically compatible with this study.
[56] Have been discontinued from a clinical trial involving an investigational product or
nonapproved use of a drug or device within the last 4 weeks or a period of at least
5 half-lives of the last administration of the drug, whichever is longer.