A Multicenter, Randomized, Double-Blind, Placebo-Controlled 16 Week Study Followed by Long Term Evaluation of Efficacy and Safety of Ixekizumab (LY2439821) in TNFi-Experienced Patients with Radiographic Axial Spondyloarthritis

Patients are eligible to be included in the study only if they meet all of the following criteria at
screening or as specified:;Type of Patient and Disease Characteristics;[1] Have an established diagnosis of rad-axSpA with sacroiliitis defined radiographically according to the mNY criteria (van der Linden et al. 1984) based on central reading: sacroiliitis grade >=2 bilaterally or grades 3 to 4 unilaterally.;AND;At least 1 SpA feature, according to ASAS criteria (Rudwaleit et al. 2009; Sieper et al. 2009), listed in Appendix 5.;[2] Patients have a history of back pain >=3 months with age at onset <45 years.;[3] Have active rad-axSpA defined as BASDAI >=4 and total back pain >=4 (Sieper et al. 2009, Box 25 Spinal Pain) on an NRS at screening and baseline.;[4] Have had prior treatment with at least 1 and not more than 2 TNF inhibitors. The patient must have discontinued at least 1 TNF inhibitor due to either intolerance or an inadequate response (defined as: In the opinion of the investigator, the patient had an inadequate response to at least 12 weeks of treatment with a TNF inhibitor at an adequate dose). Note: The following washout periods prior to baseline randomization must be followed: etanercept >=28 days; infliximab, adalimumab, or certolizumab pegol >=60 days; golimumab >=90 days.;[5] Must have had an inadequate response, as determined by the investigator, to 2 or more NSAIDs at the therapeutic dose range for a total duration of at least 4 weeks OR have a history of intolerance to NSAIDs.;[6] Patients must have a history of prior therapy for axSpA of at least 12 weeks prior to screening. Examples of prior therapy may include but are not limited to physical therapy, NSAID, and TNF inhibitor treatment.;[7] If taking NSAIDs or cyclooxygenase-2 (COX-2) inhibitors, the dose must be stable for at least 2 weeks prior to baseline randomization.;Patient Characteristics;[8] Are ambulatory male or female patients >=18 years of age at time of screening.;[9] Must agree to use a reliable method of birth control:
-* If a male patient, patient agrees to use a reliable method of birth control during the study and for at least 12 weeks following the last dose of investigational product, whichever is longer. Methods of birth control include, but are not limited to, condoms with spermicide and male
sterilization.;OR
-* If a female patient is a woman of childbearing potential who tests negative for pregnancy and agrees 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 include, but are not limited to: oral contraceptives, contraceptive patch, injectable or implantable contraceptives, intrauterine device, vaginal ring, diaphragm with contraceptive gel, or condom with contraceptive foam.;OR;- If a female patient is a woman of nonchildbearing potential, she must test negative for pregnancy and is not required to use any method of birth control. Non childbearing potential is defined as:
- Women who have had surgical sterilization (hysterectomy or bilateral oophorectomy or tubal ligation)
or
- women who are >=60 years of age
or
- Women >=40 and <60 years of age who have had a cessation of menses for >=12 months and a follicle stimulating hormone (FSH) test confirming nonchildbearing potential (>=40 mIU/mL or
>=40 IU/L).;Informed Consent;[10] Have given written informed consent approved by Lilly, or its designee, and the Investigational Review Board (IRB)/Ethical Review Board (ERB) governing the site.

Patients will be excluded from study enrollment if they meet any of the following criteria at
screening or as specified:;Medical Conditions;[11] Have total ankylosis of the spine, as assessed locally, based on lateral radiographs of the cervical and lumbar spine.;[12] Have a history of other systemic inflammatory diseases that might confound the evaluations of benefit from ixekizumab therapy (such as, but not limited to, lupus, vasculitis, or RA), or other chronic pain conditions (such as, but not limited to, fibromyalgia). Note: Patients with psoriasis that do not require systemic treatment, such as, but not limited to, oral agents or biologic therapies, can be included provided these patients fulfill the entry criteria.;[13] Have active Crohn*s disease (CD) or active ulcerative colitis (UC). Note: Patients may be enrolled if they have had a history of inflammatory bowel disease, including CD and UC, but have had no exacerbation for >=6 months prior to baseline randomization and, if currently on treatment, must be on stable treatment for >=6 months prior to baseline randomization.;[14] Have evidence of active anterior uveitis (an acute episode) within the last 42 days prior to baseline randomization.;[15] Have current or a history of lymphoproliferative disease, or signs or symptoms of lymphoproliferative disease, within 5 years prior to baseline randomization; or have active or history of malignant disease within 5 years prior to baseline randomization.;[16] Have a history of fluid overload, myocardial infarction (MI), uncompensated heart failure, or evidence of new-onset ischemic heart disease, or in the opinion of the investigator, other serious cardiac disease, within 12 weeks prior to baseline randomization.;[17] Presence of significant uncontrolled cerebrocardiovascular events (for example, unstable angina, unstable arterial hypertension, moderate-to-severe heart failure [New York Heart Association class III/IV], or cerebrovascular accident) 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.;[18] Presence of any comorbid respiratory, hepatic, renal, gastrointestinal, endocrine, hematologic disorders, 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.;[19] Presence of any neurologic or neuropsychiatric disorders at screening that, in the opinion of the investigator, poses an unacceptable risk to the patient if participating in the study or of interfering with the interpretation of data.;[20] Presence of significant uncontrolled neuropsychiatric disorder; have recent history (30 days within screening visit [Visit 1] and any time between screening visit [Visit 1] and baseline randomization [Visit 2]) of a suicide attempt; or have a score of 3 on Item 12 (Thoughts of Death or Suicide) of the Quick Inventory of Depressive Symptomatology-self report (16 items) (QIDSSR16)
at screening or baseline randomization; or are clinically judged by the investigator to be at risk for suicide.;[21] Have presence or personal history or family history (1st degree relative) of demyelinating disorder. Note: 1st degree means child, parent, or sibling, provided a blood relationship exists.;[22] Patients who have:
* in the past 12 weeks prior to baseline randomization:
o had a serious infection (for example, pneumonia, cellulitis),
o have been hospitalized for an infection,
o or have received intravenous (IV) antibiotics for an infection,
or in the past 24 weeks prior to baseline randomization had a serious
bone or joint infection
* or have ever had,
o an infection of an artificial joint,
o an infection that occurs with increased incidence in an immunocompromised host (including, but not limited to, Pneumocystis jirovecii pneumonia, symptomatic histoplasmosis, or coccidioidomycosis);[23] Have a known immunodeficiency or are immunocompromised to an extent such that participation in the study would pose an unacceptable risk to the patient.;[24] Have or had a herpes zoster or any other clinically apparent varicella-zoster virus infection within 12 weeks of baseline randomization.;[25] Have any other active or recent infection within 4 weeks of baseline randomization that, in the opinion of the investigator, would pose an unacceptable risk to the patient if participating in the study. Note: These patients may be rescreened one time >=4 weeks after resolution of symptoms.;[26] Have a known allergy or hypersensitivity to any biologic therapy that would pose an unacceptable risk to the patient if participating in this study.;[27] Have had surgical treatment of a joint that is to be assessed in the study within 8 weeks prior to baseline randomization or will require surgical treatment of a joint that is to be assessed in the study during the first 16 weeks of the trial.;[28] Have had any major surgery within 8 weeks prior to baseline randomization or will require major surgery 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. Prior/Concurrent Therapy or Clinical Trial Experience;[29] Have received cDMARDs, and/or other therapies such as, but not limited to: gold salts, cyclosporine, azathioprine, dapsone, 6-mercaptopurine, mycophenolate mofetil, or any other immunosuppressive agents within 4 weeks prior to baseline randomization. Exception: MTX (oral or parenteral up to 25 mg/week), sulfasalazine (up to 3 g/day), or hydroxychloroquine (up to 400 mg/day) may be allowed IF at stable dose for at least 4 weeks prior to baseline randomization;AND;if used, must not be in any combination with other cDMARDs. Note: If MTX is used, local standard of care is to be followed for concomitant administration of folic acid with MTX.;[30] Use of oral corticosteroids >10 mg/day prednisone or its equivalent. Note: If patients are taking prednisone or its equivalent and the dose is <=10 mg/day, the dose must be stable for at least 4 weeks prior to baseline randomization.;[31] Have received any prior, or are currently receiving, treatment with biologic or other immunomodulatory agents, including investigational therapies (such as but not limited to Janus kinase (JAK) inhibitors, IL-1, IL-6 , IL-23, IL-17 [including ixekizumab], IL-17R, T cell, or B cell targeted therapies). Note: Previous TNF inhibitor therapy is permitted.;[32] Are currently enrolled in, have participated, or discontinued from a clinical trial involving an investigational product or nonapproved use of a drug or device within the last 30 days prior to screening or a period of at least 5 halflives of the last administration of the drug, whichever is longer.
Note: Investigational products that are biologic or other immunomodulatory agents are not permitted, regardless of washout period (described in criterion
above).;[33] Are currently enrolled in any other clinical trial involving an investigational product or any other type of medical research judged not to be scientifically or medically compatible with this study.;[34] Have received prior, or are currently receiving, treatment with denosumab.;[35] Have received any parenteral glucocorticoid administered by intra-articular, intramuscular, or IV injection within 6 weeks prior to baseline randomization, or for whom a parenteral injection of glucocorticosteroids is anticipated during the Blinded Treatment Dosing Period (Period 2) of the study.;[36] Use of any opiate analgesic at average daily doses >30 mg/day of morphine or its equivalent, or use of variable doses of any opiate analgesic within 6 weeks prior to baseline randomization.;[37] Had a live vaccination within 12 weeks prior to baseline randomization, 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 randomization.
Investigators are to review the vaccination status of their patients and follow the local guidelines for adult vaccination with nonlive 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.;[38] Had a vaccination with Bacillus Calmette-Guérin (BCG) within 12 months prior to baseline randomization, or intend to have this vaccination with BCG during the course of the study or within 12 months of completing treatment in this study.;Diagnostics Assessments;[39] Have a body temperature >=38°C (100.5°F) at baseline randomization. Note: These patients may be rescreened one time >=4 weeks after documented resolution of elevated temperature.;[40] Have evidence or suspicion of active or latent TB (refer to Section 5.3 of the protocol for rescreening and Section 8.4.6 of the protocol for details on determining full TB exclusion criterion).;[41] Are positive for human immunodeficiency virus serology (HIV); that is, positive for human immunodeficiency virus antibody (HIVAb).;[42] Have evidence of or test positive for hepatitis B virus (HBV) by testing positive for: 1) HBV surface antigen (HBsAg+), OR 2) anti-hepatitis B core antibody positive (HBcAb+) and are HBV DNA positive. Note: Patients who are HBcAb+ and HBV DNA negative may be enrolled in the study. Patients who meet these criteria at screening will be identified by the central laboratory and monitored during the study as detailed in Section 8.4.10.2. of the protocol.;[43] Have evidence of or test positive for hepatitis C virus (HCV). A positive test for HCV is defined as: 1) positive for hepatitis C antibody (anti-HCV Ab) and 2) positive via a confirmatory test for HCV (for example, HCV-polymerase chain reaction).;[44] Have electrocardiogram (ECG) abnormalities that are considered clinically significant and would pose an unacceptable risk to the patient if participating in the study.;Laboratory tests may not be repeated unless there is a technical error or clinical reason to
believe a result may need to be retested within the screening period. Laboratory tests can be
repeated a maximum of 1 time, and results must be received and reviewed prior to
randomization. For eligibility, the most recent lab panel must not meet any of the following
criteria:;[45] At screening, have a neutrophil count <1500 cells/µL (<1.50x103/µL or <1.50 GI/L).;[46] At screening, have a lymphocyte count <800 cells/µL (<0.80x103/µL or <0.80 GI/L).;[47] At screening, have a platelet count <100,000 cells/µL (<100x103/µL or <100 GI/L).;[48] At screening, have aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2.5 times the upper limit of normal (>2.5xULN).;[49] At screening, have a total white blood cell (WBC) count <3000 cells/µL (<3.00x103/µL or <3.00 GI/L).;[50] At screening, have hemoglobin <8.5 g/dL (85.0 g/L) for male patients and <8.0 g/dL (80 g/L) for female patients.
[51] Have other clinical laboratory test results at screening that are outside the normal reference range for the population and are considered clinically significant, per investigator assessment.;Other Exclusions;[52] Have donated blood >450 mL within the last 4 weeks prior to screening, or intend to donate blood during the course of the study. Note: Patients who have donated blood may be rescreened one time >=4 weeks have passed since initial screening.;[53] Are women who are lactating or breastfeeding.;[54] 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.;[55] Are Lilly employees or its designee or are employees of third-party organizations involved in the study.;[56] Are unwilling or unable to comply with the use of a data collection device to directly record data from the patient.;[57] Have any other condition that precludes the patient from following and completing the protocol, in the opinion of the investigator.;pregnant women