Protocol. This trial protocol has been provided by the authors to give readers additional information about their work.

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1 Protocol This trial protocol has been provided by the authors to give readers additional information about their work. Protocol for: Reich K, Langley RG, Papp KA, et al. A 52-week trial comparing briakinumab with methotrexate in patients with psoriasis. N Engl J Med 2011;365:

2 1.0 Title Page CLINICAL STUDY PROTOCOL M A Phase 3, Multicenter, Randomized, Double-blind Study Comparing the Safety and Efficacy of ABT-874 to Methotrexate in Subjects with Moderate to Severe Chronic Plaque Psoriasis Incorporating Amendments 1, 2 and 3 Abbott Number / Investigational Product: ABT-874 Date: 04 May 2009 Development Phase: 3 Study Design: This is a randomized, double-blind, comparative trial. EudraCT Number: Investigator: Investigators information is on file at Abbott. Sponsor: Sponsor/Emergency Contact: Abbott, US 100 Abbott Park Road Abbott Park, IL Chin Lee, MD, MPH Associate Medical Director Abbott Laboratories Immunology Development Dept. NJ44 Bldg. AP6C Abbott Park Road Abbott Park, IL Abbott GmbH & Co.KG Knollstrasse Ludwigshafen, Germany Phone: (847) Fax: (847) This study will be conducted in compliance with the protocol, Good Clinical Practice and all other applicable regulatory requirements, including the archiving of essential documents. Confidential Information No use or disclosure outside Abbott is permitted without prior written authorization from Abbott. 1

3 1.1 Protocol Amendment: Summary of Changes The purpose of this amendment is to: Cover, Section 6.5: Adverse Event Reporting, and 7.0: Protocol Deviations Description: Update in Medical Monitor). Section 5.1: Overall Study Design: Description: 317 adult subjects with moderate to severe plaque psoriasis have been enrolled from 43 investigative sites in Europe and Canada. Section 5.2.2: Exclusion Criteria: Description: Clarification of Exclusion Criterion No. 11, which adds the opinion Abbott Medical Monitor to assess poorly controlled medical conditions. Section : Study Procedures: Description: revised to correct typographical errors. Section 5.4.1: Discontinuation of Individual Subjects: Laboratory parameters that require discontinuation of subjects has been further clarified. Section 5.5.1: Table 8: Oral Dose MTX/Placebo Adjustment Guidelines for Laboratory Abnormalities: Description: revised to correct typographical errors. Section : Storage and Disposition of Study Drugs: Description: Clarification to temperature excursions and reporting including use of IVRS/IWBS and the Abbott Temperature Excursion Monitoring system (ATEMS). Section : Preparation/Administration of Study Drug. Removal of statement "Subject will be provided with a diary to record date and time of injection, volume administered, and site of injection" as this is no longer valid. Section 5.5.4: Selection and Timing of Dose for Each Subject: Description: Removal of statement "at the Study Site" describing location of subject's first dose of methotrexate. Section 6.0: Adverse Events: Description: Criteria for interruption of study drug for elevated creatine kinase (CK) laboratory values has been added due 2

4 to several subjects in ABT-874 studies who have had transient increases in CK, which have decreased while continuing on study drug. Section 6.5: Adverse Event Reporting: Description: Change in Abbott Safety Reporting name, address, phone number, fax and addition of address. Section 6.6: Pregnancy: Description: Pregnancy in a subject must be reported to Immunology Safety Team. Section 8.0: Statistical Methods and Determination of Sample Size: Description: The definition of the intent-to-treat (ITT) population was modified based on a regulatory request to "all randomized subjects," dropping the requirement that the subjects received at least one dose/injection of study drug. For the analysis of demographics and baseline characteristics, the optional use of Fisher's exact test was added. An additional sensitivity analysis for the primary endpoint, using Fisher's exact test instead of the CMH test was added. Also, statistical power was revised. Appendix O: Correction of typographical error See Appendix S for an itemized list of all changes made to this protocol amendment. 3

5 2.0 Table of Contents 1.0 Title Page Protocol Amendment: Summary of Changes Table of Contents Introduction Study Objective Investigational Plan Overall Study Design and Plan: Description Selection of Study Population Inclusion Criteria Exclusion Criteria Prior and Concomitant Therapy Prior Therapy Concomitant Therapy Efficacy and Safety Assessments/Variables Efficacy and Safety Measurements Assessed and Flow Chart Study Procedures Drug Concentration Measurements Collection of Samples for Analysis Handling/Processing of Samples Disposition of Samples Measurement Methods Efficacy Variables Primary Variable Secondary Variables Safety Variables Pharmacokinetic Variables

6 5.4 Removal of Subjects from Therapy or Assessment Discontinuation of Individual Subjects Discontinuation of Entire Study Treatments Treatments Administered Dose Titration Management Identity of Investigational Products Packaging and Labeling Storage and Disposition of Study Drugs Preparation/Administration of Study Drug Method of Assigning Subjects to Treatment Groups Selection and Timing of Dose for Each Subject Blinding Treatment Compliance Drug Accountability Discussion and Justification of Study Design Discussion of Study Design and Choice of Control Groups Appropriateness of Measurements Suitability of Subject Population Selection of Doses in the Study Adverse Events Definitions Adverse Event Serious Adverse Events Adverse Event Severity Relationship to Study Drug Adverse Event Collection Period Adverse Event Reporting

7 6.6 Pregnancy Protocol Deviations Statistical Methods and Determination of Sample Size Statistical and Analytical Plans Analyzable Population Planned Methods of Statistical Analysis Demographics and Baseline (Week 0) Characteristics Statistical Analyses of Efficacy Primary Analysis of Efficacy Secondary Analysis of Efficacy Statistical Analyses of Safety Interim Analysis Pharmacokinetic Analyses Determination of Sample Size Randomization Methods Ethics Independent Ethics Committee (IEC) or Institutional Review Board (IRB) Ethical Conduct of the Study Subject Information and Consent Source Documents and Case Report Form Completion Source Documents Case Report Forms Data Collection Process Data Quality Assurance Use of Information and Publication Use of Information

8 12.2 Publication Internet Sites Completion of the Study Investigator's Agreement Reference List List of Tables Table 1. Efficacy Results from M Table 2. Safety Results from M Table 3. Safety vs. Efficacy Assessor Duties...16 Table 4. Study Activities, Weeks Table 5. Study Activities, Weeks Table 6. Clinical Laboratory Tests...40 Table 7. Dose Escalation of Oral MTX/placebo...55 Table 8. Oral Dose MTX/Placebo Adjustment Guidelines for Laboratory Abnormalities...58 Table 9. Identity of Investigational Products for Subcutaneous Injection...59 Table 10. Identity of Investigational Products for Oral Administration...60 Table 11. NAPSI Score List of Figures Figure 1. Study Design...18 Figure 2. Oral Medication Blister Card...54 Figure 3. Adverse Event Collection...80 Figure 4. Fingernails List of Appendices Appendix A. List of Abbreviations and Definition of Terms

9 Appendix B. Appendix C. Appendix D. Appendix E. Appendix F. Appendix G. Documents Required Prior to Initiation of the Study Responsibilities of the Clinical Investigator US Center for Disease Control (CDC) Treatment Recommendations for Positive PPD Tuberculosis Information Treatment of Latent TB Infection Listing of Medications Contraindicated With MTX Broken Down by Absolute Contraindications and Relative Contraindications Psoriasis Area and Severity Index (PASI) and Assessment of Total Body Surface Area Physician's Global Assessment (PGA) Appendix H. Patient Reported Outcomes Questionnaires Appendix I. Dermatology Life Quality Index (DLQI) Appendix J. Appendix K. Appendix L. Patient's Global Assessment of Psoriasis-Severity Psoriasis-Related Pruritus Assessment Visual Analog Scale (VAS) for Plaque Psoriasis Pain Appendix M. EQ-5D Health Questionnaire Appendix N. Visual Analog Scale (VAS) for Psoriatic Arthritis Pain Appendix O. Examples of Class VI and Class VII Topical Corticosteroids Appendix P. Appendix Q. Appendix R. M Subject Instructions and Oral MTX/placebo Dosing Diary Nail Physician Global Assessment (NPGA) and Nail Psoriasis Severity Index (NAPSI) Subject Instructions and Dosing Diary for Oral Folic Acid/Placebo Appendix S. Protocol Amendment: List of Changes

10 3.0 Introduction Psoriasis is a chronic immunologic disease characterized by marked inflammation and thickening of the epidermis that results in thick, scaly plaques involving the skin. It affects 1% to 3% of the general population, with the highest disease prevalence in North America and Europe. 1 Psoriasis equally affects men and women, with peak onset of symptoms in young adults and again in the mid 50's. Genetic factors may predispose a person to psoriasis and psoriasis may be induced or exacerbated by exogenous triggers such as physical trauma, medications, infections and emotional stress. Psoriasis may be classified according to morphologic and clinical presentation: plaque psoriasis, guttate psoriasis, erythrodermic psoriasis, generalized pustular and localized pustular psoriasis, and inverse or intertriginous psoriasis. Plaque psoriasis is the most common form seen in 75% to80% of psoriasis patients. 2 Nail involvement is frequently associated and 30% or more of patients may have associated psoriatic arthritis (PsA). 3,4 Treatment depends on the extent and severity of disease. Topical corticosteroids are commonly used for mild to moderate cases. Other topical medications include keratolytic agents, anthralin, coal tar, vitamin D analogs, and retinoids. 5 For more widespread disease, phototherapy (ultraviolet B [UVB] or ultraviolet A and psoralen [PUVA]) is commonly used. Systemic therapy, including methotrexate (MTX), cyclosporine and synthetic retinoids are often effective in patients with moderate or severe disease. 6 Due to the potential adverse side effects of systemic agents, these medications are generally administered in rotation to avoid long-term or cumulative toxicities. 7 While effective, systemic therapies such as MTX are associated with long-term risks which have precluded more widespread and long-term use. The most commonly reported adverse reactions to the doses of MTX used in the treatment of psoriasis include malaise, gastrointestinal tract effects, headaches, leucopenia, thrombocytopenia, anemia, allergic pneumonitis/alveolitis, erythema, exanthema, and pruritis. 7,8,9 Of note, MTX has been associated with hepatic and hematopoietic abnormalities, therefore, laboratory monitoring 9

11 is required, and guidelines exist that recommend that liver biopsies be performed at specified cumulative dosage intervals of MTX in psoriasis patients. There is a lack of historical studies on the true efficacy response of MTX versus placebo in moderate to severe psoriasis patients. Nonetheless, MTX is approved in both the United States (US) and several European countries for the treatment of severe psoriasis. A complete description of the safety profile of MTX may be found in the approved package insert - Hexal Pharmaceuticals. 9 Due to the risk/benefit profiles of current systemic therapies, patients with moderate to severe plaque psoriasis are in need of new treatment options that are effective yet safe when used long term. The co-localization of activated dendritic cells, producing IL-23 and to a lesser extent IL 12 and activated Th1 memory cells in lesional psoriatic skin, suggest that the p40 subunit of IL-12/IL-23 is an attractive therapeutic target in psoriasis. 10 Indeed, published data have indicated that anti-il-12/il-23 p40 shows clinical efficacy in the treatment of plaque psoriasis. 11 Results from a phase 2 study in patients with moderate to severe psoriasis suggest that the anti-il-12/il-23 antibody ABT-874 may provide a significant alternative for this patient population. The clinical observations relating to disease pathology and underlying immune mechanisms and the pre-clinical data in animal models suggest that anti-il-12/il-23 p40 antibodies might be utilized for the treatment of autoimmune disorders. ABT-874 is a recombinant, full-length immunoglobulin with very high affinity for IL-12 and IL-23, and is the first member of this new class of IL-12/IL-23 antagonistic compounds to contain exclusively human sequences. Based on these observations, the clinical development of ABT-874 is considered promising. ABT-874 binds to human IL-12 and IL-23 and effectively neutralizes their bioactivity in vitro and in animal models (See Investigators' Brochure). The safety of ABT-874 has been demonstrated in single dose and repeated subcutaneous (SC) dose toxicity studies 10

12 conducted in primates at dose levels 20-fold (100 mg/kg) above the highest dose given in Phase 1 dose titration studies (5.0 mg/kg) up to nine months. ABT-874 has not produced any clinically significant effects on renal function, on the cardiovascular system, respiratory system, or Central Nervous System in these studies. There is no information concerning the safety of this drug in unborn children. ABT-874 was given to pregnant monkeys in low, moderate and high doses. One set of fetuses was examined two-thirds of the way through pregnancy; another set at the end of pregnancy. At least one of the female fetuses in each dose group showed a variation in external genitalia development when examined two-thirds through pregnancy and no variations, in any dose group, were seen in the female external genitalia of full term fetuses. Hormone measurements during pregnancy were normal. The efficacy, safety and tolerability of ABT-874 in psoriasis patients have been evaluated in a dose-finding Phase 2 trial (M05-736). This trial was a double-blind, randomized, placebo-controlled study in patients with moderate to severe chronic plaque psoriasis. A total of 180 patients were enrolled in the study and randomized to one of five regimens of ABT 874 or placebo for 12 weeks. The ABT-874 regimens included 200 mg, one dose at Week 0; 100 mg every other week; 200 mg every week for 4 weeks; 200 mg every other week; and 200 mg every week. The primary efficacy analysis compared the proportion of subjects with a 75% or greater reduction in Baseline (Week 0) Psoriasis Area and Severity Index (PASI) score at Week 12. Results of the primary efficacy analysis demonstrate that the proportion of patients achieving a 75% or greater reduction in PASI score was greater in all of the ABT-874 dosing groups tested when compared to placebo. All five of the ABT-874 dosing regimens achieved statistically significant differences compared to the placebo group (p<0.001). The efficacy results are summarized in the following Table 1. 11

13 Table 1. Efficacy Results from M Placebo N = 30 Proportion of Patients with PASI 75 Response at Week mg, 1 dose N = mg, eow N = mg, 4 doses N = mg, eow N = mg, ew N = % 63.3 %* 93.3 %* 90.0 %* 93.3 %* 90.0 %* * = p < vs. placebo eow = every other week ew = every week ABT-874 was well tolerated and no safety issues were identified. The safety results are summarized in Table 2. Table 2. Safety Results from M Placebo N = mg, one dose N = mg, eow N = mg, 4 doses N = mg, eow N = mg, ew N = 30 Adverse events 18 (60.0%) 18 (60.0%) 22 (73.3%) 21 (70.0%) 21 (70.0%) 19 (63.3%) Serious adverse events 1 (3.3%) 1 (3.3%) Adverse events leading to discontinuation 2 (6.7%) 1 (3.3%) Adverse events, infectious 7 (23.3%) 7 (23.3%) 9 (30.0%) 13 (43.3%) 13 (43.3%) 10 (33.3%) Adverse events, 1 (3.3%) (3.3%) 0 0 malignancies Deaths ABT-874 has been well tolerated in clinical trials conducted to date, including phase II studies in rheumatoid arthritis, Crohn's disease, psoriasis and multiple sclerosis. The most frequently reported treatment-emergent adverse events in the Phase II study of patients with chronic plaque psoriasis were injection site reaction, nasopharyngitis, upper respiratory tract infection and headache. This study, M10-255, is a pivotal Phase 3 study in adult subjects with moderate to severe chronic plaque psoriasis who are candidates for systemic therapy or phototherapy. The 12

14 goal of this study is to demonstrate that ABT-874 is superior to weekly administration of oral MTX. A detailed discussion of the pre-clinical toxicology, metabolism, pharmacology, and safety experience with ABT-874 can be found in the current Investigator's Brochure. 4.0 Study Objective The objectives of this study are to compare the short-term and long-term clinical efficacy, safety and tolerability of ABT-874 compared to MTX in the treatment of moderate to severe chronic plaque psoriasis over a 24 and 52-week period. 5.0 Investigational Plan 5.1 Overall Study Design and Plan: Description The study is a 52-week double-blind treatment study designed to evaluate the safety, tolerability, and clinical efficacy of one ABT-874 dosing regimen versus MTX in the treatment of adult subjects with moderate to severe plaque psoriasis. According to the original study plan, approximately 250 adult subjects with moderate to severe plaque psoriasis were to have been enrolled from approximately 60 investigative sites. As per Amendment 3, 317 adult subjects with moderate to severe plaque psoriasis have been enrolled from 43 investigative sites in Europe and Canada. At Week 0, subjects will be randomized 1:1 to receive one of the following doses of study medication: Treatment A (ABT-874 SC injection): 200 mg ABT-874 administered SC at Baseline (Week 0) and Week 4, followed by 100 mg ABT-874 SC at Week 8 and a maintenance dose of 100 mg ABT-874 SC every 4 weeks starting at Week 12 and continuing through Week 48; Treatment B (MTX capsules): 5-25 mg weekly dosing per titration schedule at Weeks Subjects in Treatment B will also receive oral folate, 5 mg weekly at Weeks

15 Subjects randomized to Treatment A, will receive two SC injections of ABT-874 at Week 0 and Week 4, followed by one SC injection of ABT-874 at Weeks 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48. To maintain the blind, subjects in Treatment A will also receive placebo capsules to match MTX and placebo tablets to match folate at Weeks Subjects randomized to Treatment B, will receive weekly capsules of MTX (weekly dose of 5-25 mg as per titration schedule) and weekly doses of 5 mg oral folate at Weeks To maintain the blind, subjects randomized to Treatment B will also receive two SC injections of placebo to match ABT-874 at Week 0 and Week 4 and one SC injection of placebo to match ABT-874 at Weeks 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48. At Week 24, subjects who have achieved PASI 75 AND PGA 0 or 1, will maintain current the MTX dose from Week 24 through Week 51. Adjust only for Laboratory Abnormalities, see Table 8. At Week 24, subjects who have not achieved a treatment success, defined as having achieved both PASI 75 AND PGA 0 or 1 will be discontinued from the study and are eligible to roll into the open label extension study M10-016, and receive treatment with subcutaneous injections of ABT-874 at a dose of 100 mg every four weeks. After Week 24, subjects who lose response defined as PASI < 50 AND PGA 3 will be discontinued from the study and are eligible to roll into the open label extension study M10-016, and receive treatment with subcutaneous injections of ABT-874 at a dose of 100 mg every four weeks. In order to maintain the study blind the Interactive Voice Response System (IVRS) and Interactive Web-Based System (IWBS) will be used to dispense the appropriate medication to subjects throughout the entire study. To reduce the potential for study Investigator bias, this blinded study will utilize separate Evaluating (Efficacy Assessor) and Treating (Safety Assessor) personnel, during the study. The Principal Investigator or designee will be the safety assessor and will be responsible for the review of clinical laboratory tests, physical exams, and Adverse Events (AEs). As the Principal 14

16 Investigator maintains overall responsibility for data integrity, the physician performing the role of safety assessor will have access to subject source documents (safety and efficacy), case report forms (CRFs) and electronic case report forms (ecrfs). The safety assessor will be responsible for the overall treatment of the subject and will review all safety and efficacy data. The safety assessor is also responsible for determining the appropriateness of all dose adjustments (e.g. increases and decreases) in oral MTX/placebo study medication, during the study. Primary consideration in determining dosage adjustments will made based on the review of clinical laboratory results, physical examination findings and AEs. At Weeks 10 and 16 the safety assessor will also use the PASI and PGA scores to determine the correct oral MTX/placebo dosing for a subject. Subjects demonstrating tolerability in their current oral MTX/placebo dosage but who do not have adequate PASI or PGA scores at Weeks 10 and 16 are eligible for oral MTX/placebo study medication dosage increase as outlined in Table 7. During the study, the safety assessor will be responsible for determining the appropriate dosage of oral MTX/placebo for a given subject in accordance with the protocol dosing guidelines outlined in Section The study site personnel will call subjects and instruct them on oral MTX/placebo dosing, once that visit's lab results and AEs have been reviewed by the safety assessor (approximately 2 to 3 days following the visit). All MTX/placebo will be taken orally. A qualified Investigator or designee from the site, deemed the efficacy assessor, will be responsible for performing the Physician's Global Assessments (PGAs) and PASI at all appropriate study visits. The efficacy assessor must provide proof of training and competency in PGA and PASI assessments prior to performing any study assessments. The site should make every attempt to have the same Investigator or designee perform these assessments throughout the study for each subject. The efficacy assessor must remain blinded to the clinical laboratory results and all subject safety data during the study. The efficacy assessor will not view or discuss any subject specific safety data with the safety assessor or any other site personnel. The efficacy assessor therefore cannot be the Principal Investigator. 15

17 Efficacy and safety measurements will be performed throughout this study (see Section 5.3). During the study, it is recommended that each study site have two designated back-up Investigators or designees, one as a back-up for the safety assessor and another as a back-up for the efficacy assessor. As MTX administration may impart characteristic changes in clinical laboratory profiles, the Principal Investigator is required to delegate the conduct of efficacy parameters (PASI, PGA) to another licensed physician or designee. The efficacy assessor shall not have access to or be responsible for the review of clinical laboratory results during the study. The efficacy assessor will not view or discuss any subject specific safety data with the safety assessor or any other site staff during the study. Specific duties to be performed by either the safety assessor or efficacy assessor are listed in Table 3. Table 3. Safety vs. Efficacy Assessor Duties Activity Safety Assessor Review Medical/ Surgical History Physical Exam Review CXR & ECG Lab Review NPGA, NAPSI PGA, PASI* Monitor Adverse Events and Concomitant Therapy X X X X X* X Efficacy Assessor X X * At Weeks 10 and 16, the safety assessor will also use the PGA and PASI scores to determine the correct oral MTX/placebo dosing for a subject. All injections of the study drug will be administered by the subject, their qualified authorized representative, or qualified site personnel throughout the course of the study. Efficacy and safety measurements will be performed throughout the study (see Section 5.3.1). 16

18 Blood samples for serum anti-drug antibodies (ADA) measurement will be collected prior to dosing at Baseline (Week 0), Weeks 8, 12, 16, 24, 32, 40, 48, 52, or at the time of Early Termination from the study, if applicable (see Section 5.3.2). Blood samples for measurement of serum ABT-874 concentration will be collected prior to dosing at Baseline (Week 0), Weeks 2, 4, 8, 12, 16, 24, 32, 40, 48, 52, or at the time of Early Termination from the study, if applicable (see Section 5.3.2). During the study subjects will be evaluated monthly to assess safety, tolerability, and changes in PGA and PASI scores. Subjects who successfully complete this study will be eligible to receive treatment with ABT-874 in the open-label extension study M Subjects who discontinue from this study prematurely (for reasons other than loss of response to treatment) will not be eligible for the open label extension study M Subjects will not be eligible to enter the open-label study (M10-016) prior to Week 24. For subjects who do not enter the open-label study (M10-016), site personnel will contact all subjects approximately 45 days following drug discontinuation to determine the occurrence of adverse events and changes in concomitant medications, and urine pregnancy test, if applicable. 17

19 The study design is shown in Figure 1. Figure 1. Study Design Screening N=250 Treatment A: 200 mg ABT-874 at Weeks 0 & 4, followed by 100 mg ABT-874 at Week 8 and a maintenance dose of 100 mg ABT-874 every 4 weeks at Wks (N=125) Treatment B: MTX (5-25 mg) weekly, per titration schedule at Wks 0-23 adjusted for safety and efficacy 1 (N=125) Endpoint: PGA & PASI response at Wk 24 Endpoint: PGA & PASI response at Wk 52 Baseline (Week 0) Week 24 2,3 Week day Follow Up Call, after discontinuation of study drug 1. At Week 24, subjects who have achieved PASI 75 AND PGA 0 or 1, will maintain current the MTX dose from Week 24 through Week 51. Adjust only for Laboratory Abnormalities, see Table At Week 24, subjects who have not achieved a PASI 75 OR PGA 0 or 1 will be eligible to roll into the open label extension study M10-016, and receive treatment with subcutaneous injections of ABT-874 at a dose of 100 mg every four weeks. 3. After Week 24, subjects who lose response defined as PASI <50 AND PGA >3 will be eligible to roll into the open label extension study M10-016, and receive treatment with subcutaneous injections of ABT-874 at a dose of 100 mg every four weeks. 5.2 Selection of Study Population Subjects will be adult men and women who meet all of the inclusion criteria and none of the exclusion criteria specified in Sections and Section of this protocol. Subjects meeting all of the following criteria will be eligible for study participation: 18

20 5.2.1 Inclusion Criteria 1. Males and females 18 years of age and over. 2. Clinical diagnosis of psoriasis for at least 6 months as determined by subject interview of his/her medical history and confirmation of diagnosis through physical examination by the Principal Investigator. 3. Stable plaque psoriasis for at least 2 months before Screening and at Baseline (Week 0) visits as determined by subject interview of his/her medical history. 4. Moderate to severe plaque psoriasis defined by 10% Body Surface Area (BSA) involvement at the Baseline (Week 0) visit. 5. PGA of at least moderate disease (defined as PGA 3) at the Baseline (Week 0) visit. 6. PASI score of 12 at the Baseline (Week 0) visit. 7. Subject is a candidate for systemic therapy or phototherapy and has active psoriasis despite treatment with topical agents. 8. Women are eligible to participate in the study if they meet one of the following criteria: Women of childbearing potential must undergo monthly pregnancy testing during the study and agree to use two of the following methods of contraception throughout the study and for 6 months after the last dose of study drug: Oral contraceptives; Transdermal contraceptives; Injectable or implantable methods; Intrauterine devices; and 19

21 Barrier methods (diaphragm with spermicide, condom with spermicide). Subjects using oral or parenteral forms of contraceptives must have been practicing birth control for at least three months prior to study drug administration. Women who are postmenopausal (for at least one year), sterile, or hysterectomized; Women who have undergone tubal ligation will be required to undergo monthly pregnancy testing during the duration of the study and agree to use a second form of contraception which includes: Oral contraceptives; Transdermal contraceptives; Injectable or implantable methods; Intrauterine devices; and Barrier methods (diaphragm with spermicide, or condom with spermicide). 9. Sexually active male subjects (including males who have had a vasectomy) are able to participate in the study if they use effective contraception (i.e. condoms with spermicide) during the study and 6 months after study completion. 10. Subject is judged to be in good general health as determined by the Principal Investigator based upon the results of medical history, laboratory profile, physical examination, chest X-ray (CXR), and 12-lead electrocardiogram (ECG) performed at Screening. 11. Able and willing to give written informed consent and to comply with the requirements of this study protocol. 20

22 5.2.2 Exclusion Criteria 1. Previous exposure to systemic anti-il-12 therapy, including ABT Subject has previous exposure to MTX. 3. Diagnosis of erythrodermic psoriasis, generalized or localized pustular psoriasis, medication-induced or medication-exacerbated psoriasis, or new onset guttate psoriasis. 4. Diagnosis of other active skin diseases or skin infections (bacterial, fungal, or viral) that may interfere with evaluation of psoriasis. 5. History of an allergic reaction or significant sensitivity to constituents of study drug (See Section 5.5.2). 6. Cannot discontinue topical therapies for the treatment of psoriasis such as corticosteroids, vitamin D analogs, or retinoids at least 2 weeks prior to the Baseline (Week 0) visit and during the study. Subjects are allowed to use: Shampoos that contain no corticosteroid; Bland (without beta or alpha hydroxy acids) emollients; Low potency (Class VI or Class VII) topical corticosteroids on the palms, soles, face, inframammary area, and groin only. See Appendix O for a listing of examples of Class VI or VII topical corticosteroids. 7. Cannot avoid UVB phototherapy for at least 2 weeks prior to the Baseline (Week 0) visit and during the study. 8. Cannot avoid PUVA phototherapy for at least 4 weeks prior to the Baseline (Week 0) visit and during the study. 9. Cannot discontinue systemic therapies for the treatment of psoriasis, or systemic therapies known to improve psoriasis, during the study: 21

23 Systemic (investigational or marketed) therapies must be discontinued at least 4 weeks prior to the Baseline (Week 0) visit except for biologics, which must be discontinued at least 12 weeks prior to Baseline (Week 0). Investigational chemical agents (except for biologics) must be discontinued at least 30 days or 5 half-lives, prior to the Baseline (Week 0) visit (whichever is longer). 10. Subject is taking or requires oral or injectable corticosteroids during the study. Inhaled corticosteroids for stable medical conditions are allowed. 11. Poorly controlled medical condition, such as uncontrolled diabetes with documented history of recurrent infections, unstable ischemic heart disease, congestive heart failure, recent cerebrovascular accidents and any other condition, which, in the opinion of the Investigator or the Abbott Medical Monitor, would put the subject at risk by participation in the study. 12. Subject has a history of clinically significant hematologic (e.g. severe anemia, leukopenia, thrombocytopenia), renal or liver disease (e.g. fibrosis, cirrhosis, hepatitis). 13. Subject has infection or risk factors for severe infections, for example: Excessive immunosuppression or other factors associated with it, including human immunodeficiency virus infection; Severe, recurrent, or persistent infections such as Hepatitis B or C; Active tuberculous disease; Evidence of latent tuberculosis (TB) infection demonstrated by Purified Protein Derivative (PPD) 5 mm of induration and/or CXR findings suggestive of latent TB; EXCEPT if prophylactic treatment, as recommended by local guidelines, is initiated prior to administration of study drug or there is documentation that the subject has received prophylactic treatment for TB previously, see Appendix D (US Center for Disease Control [CDC] Treatment 22

24 Recommendations for Positive PPD Tuberculosis Information - Treatment of Latent TB Infection); Any other significant infection requiring hospitalization or intravenous (IV) antibiotics in the month prior to Screening; Infection requiring treatment with antibiotics in the two weeks prior to Screening; Subject has received vaccination with Bacille Calmette-Guérin (BCG) within 12 months prior to Screening; Subject has received vaccination with a live viral agent one month prior to Screening or will require vaccination during study participation including up to one month after the last dose of study drug. 14. History of malignancies other than successfully treated basal cell carcinoma, nonmetastatic cutaneous squamous cell carcinoma or cervical carcinoma in situ. 15. History of major immunologic reaction (such as serum sickness or anaphylactoid reaction) to an Immunoglobulin G containing agent (such as IV gamma globulin, a fusion protein, or monoclonal antibody). 16. Exacerbation of asthma requiring hospitalization in the ten years prior to Screening (subjects with asthma not requiring hospitalization should be discussed with the Medical Monitor prior to Baseline [Week 0]). 17. Female subject who is pregnant or breast-feeding or considering becoming pregnant during the study or for six months after study completion. 18. Screening clinical laboratory analyses show any of the following abnormal results: Hemoglobin (Hgb) < 10 g/dl in females or < 12 g/dl in males; White blood cell (WBC) count < /L; Platelet count < /L; 23

25 Serum aspartate transaminase (AST) or alanine transaminase (ALT) 1.5 upper limits of normal (ULN); Serum total bilirubin 1.5 mg/dl ( 26 µmol/l); or Serum creatinine > 1.6 mg/dl (> 141 µmol/l). 19. Recent history of substance abuse or psychiatric illness that could preclude compliance with the protocol. 20. Subject has a known allergic hypersensitivity to MTX. 21. Subjects with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption. 22. For any reason, subject is considered by the Principal Investigator to be an unsuitable candidate to receive ABT Prior and Concomitant Therapy Prior Therapy Any medication (including, but not limited to, over-the-counter medicines such as aspirin, antacids, vitamins, mineral supplements and herbal preparations) that the subject is receiving at the time of screening/enrollment, or receives during the study, must be entered into the appropriate electronic case report forms (ecrf) along with the reason for use, dates of administration and dosages. Any prescribed treatments for psoriasis prior to study entry and treatments for psoriasis since initial diagnosis (as determined through medical history records or through subject interview) will be entered into the ecrf. Study drug administration will be documented in a separate section of the ecrf Concomitant Therapy Any medication that the subject receives during the study must be recorded. Vaccines administered to the subject should be listed as a concomitant medication. During the course of the study, subjects may continue treatment with medicated shampoos that do 24

26 not contain corticosteroids, bland (without beta or alpha hydroxy acids) emollients, or Class VI or VII low-potency topical corticosteroids on the palms, soles, face, inframammary area and groin only (see Appendix O). Application of these topical therapies for psoriasis, however, should not occur within 24 hours of a study visit so as not to interfere with clinical assessments for psoriasis. Vaccination with a live viral agent is not permitted one month prior to dosing with ABT-874, during the study and for one month after the last dose of study medication. Section (exclusion criteria 6 through 10) provides guidance on medications or therapies for psoriasis that should not be used during the study. Medications that may have potential for drug interaction with MTX (relative contraindicated medications, see Appendix E) should be administered with caution and careful monitoring and after discussion with the Medical Monitor. Such medications include but are not limited to: Phenytoin, tetracycline, nonsteroidal anti-inflammatory drugs (NSAIDs) and salicylates. Please refer to Appendix E for medications that should not be used during the study as they are absolutely contraindicated in association with MTX. Such medications include but are not limited to: Sulfonamides, including Trimethoprim-sulfamethoxazole/co-trimoxazole Leflunomide Additionally, any drug whose Summary of Product Characteristics (SPC) mentions a possible interaction with MTX should be discussed with the Medical Monitor before being used in the study. 25

27 Contact the Abbott Medical Monitor identified in Section 6.5 if there are any questions regarding concomitant or prior therapies. 5.3 Efficacy and Safety Assessments/Variables Efficacy and Safety Measurements Assessed and Flow Chart Study procedures for efficacy and safety will be performed as summarized in the schedule of assessments presented in Table 4 and Table 5. Clinical laboratory tests results should be received from the central laboratory within 2 to 3 days of the subject visit. Starting at Week 1 and for each visit thereafter, the safety assessor will review the clinical laboratory results and provide oral MTX/placebo dosing instructions to subjects by telephone. At Weeks 10 and 16 the PASI and PGA assessments recorded by the efficacy assessor will be used in conjunction with the clinical laboratory test results in the determination of oral MTX/placebo dosing. The maximum participation of a subject in this study is projected to be 52 weeks plus the length of the Screening period and, for those subjects not rolling into the open-label study, a 45-day follow-up telephone call. This will consist of: Screening period: No more than 28 Days Treatment Period: Weeks 0-52 Follow-Up Telephone Call: 45 Days after the last dose of study medication Visits after Baseline (Week 0) should be completed within a +/- 3-day window of the schedule. If the subject prematurely withdraws from the study, the assessments for the Early Termination visit for that treatment period should be conducted. 26

28 Table 4. Study Activities, Weeks 0-12 Activity Informed Consent Inclusion/Exclusion Criteria Medical/Surgical/Medication History Screening X X X Baseline (Week 0) X c Week 1 Week 2 Week 4 Week 8 Week 10 Week 12 Early Termination Visit Physical Exam d X X CXR & ECG e X Unscheduled Visit a Vital Signs f /Weight/Height g X X X X X X X X X X Alcohol and Nicotine Use % BSA psoriasis assessment X X TB testing Hepatitis B & C serology ANA/reflex Anti-dsDNA antibody X X X X C-reactive Protein X X X Lipid Profile h X X X Serum Folate X ADA i X X X X ABT-874 PK i X X X X X X X Telephone Follow-Up 45 days after last dose b 27

29 Table 4. Study Activities, Weeks 0-12 (Continued) Early Termination Visit Telephone Follow-Up 45 days after last dose b Activity Screening Baseline (Week 0) Week 1 Week 2 Week 4 Week 8 Week 10 Week 12 Unscheduled Visit a Urine/Serum Pregnancy Tests j X X X X X X X Hematology k X X X X X X X X X X Chemistry l X X X X X X X X X X Urinalysis m X X X X X X X X DLQI X X X Patient's Global Assessment of Psoriasis-Severity X X X X X X X Psoriasis Related Pruritus X X X X X X X VAS for Plaque Ps Pain X X X X X X X EQ-5D Health Questionnaire X X X VAS for PsA Pain X X X X X X X PGA & PASI n X X X X X X X X X X NPGA & NAPSI o X X X X X X Telephone Subject p +2-3 d +2-3 d +2-3 d +2-3 d +2-3 d +2-3 d +2-3 d Monitor Adverse Events and Concomitant therapy X X X X X X X X X X Patient Drug Accountability X X X X X X X X X 28

30 Table 4. Study Activities, Weeks 0-12 (Continued) Activity Screening Baseline (Week 0) Week 1 Week 2 Week 4 Week 8 Week 10 Week 12 Dispense ABT-874/Placebo X X X X Dispense Oral Folic X X X X Acid/Placebo Dispense Oral MTX/placebo X X X X Early Termination Visit Unscheduled Visit a Telephone Follow-Up 45 days after last dose b Randomization X a. An unscheduled visit for laboratory assessments and determination of AEs will be scheduled for 2 weeks following a dose escalation in oral MTX/placebo study medication provided a standard study visit has not been scheduled or as deemed appropriate by the safety assessor (e.g. to follow-up with AEs or abnormal labs). Assessments listed will be done if deemed appropriate by the safety assessor. Other assessments may also be done if appropriate. b. Site personnel will contact all subjects approximately 45 days following drug discontinuation to determine the occurrence of adverse events, changes in concomitant medications, and a urine pregnancy test, if applicable. c. Update medical history information to assure subject eligibility, at the baseline visit. d. A full physical examination will be performed at Screening, Week 52, or Early Termination, if applicable. A symptom-directed physical examination should be performed at all other visits if, in the opinion of the Investigator, it is warranted by the subject's AE status or on review of symptoms. e. Subject will have a repeat ECG or CXR if in the Investigator's opinion, clinically significant AEs develop during the study that warrant a repeat. f. Vital signs should be taken just prior to dosing. g. Height at Screening only. h. Standard lipid profile will include total cholesterol, triglycerides, HDL, Calculated LDL and Cholesterol/HDL Ratio. Requires a 12-hour fast. i. Blood samples will be drawn prior to administration of injections. 29

31 Table 4. Study Activities, Weeks 0-12 (Continued) j. Serum pregnancy test at Screening; urine pregnancy test at all other indicated visits. Serum pregnancy test to be done if any urine pregnancy test is positive, including the pregnancy test at the 45-day follow-up call. Urine pregnancy test to be performed at home at the time of the 45-day telephone follow-up call. The results of this test will be conveyed to the site verbally. k. Hematocrit, hemoglobin, red blood cell count, white blood cell count, differential, platelet count. l. Sodium, potassium, chloride, CO2, glucose, creatinine, calcium, inorganic phosphorus, magnesium, uric acid, AST, ALT, total bilirubin, alkaline phosphatase, albumin, creatine kinase, total protein, BUN. m. Specific gravity, ph, protein, blood, glucose, bilirubin, ketones, nitrite (microscopic analysis will be done if urinalysis is abnormal). n. PGA, PASI assessments to be performed by the qualified blinded efficacy assessor. Site should make every attempt to have the same qualified efficacy assessor conduct these assessments throughout the study for any given subject. o. Any subjects that have a score of "None" for NPGA or "0" for NAPSI will not have these assessments at any subsequent visit throughout the study. Any subject currently with artificial nail products or removal of artificial nail products within 9 months of the study will not have these assessments at any time throughout the study. p. The study site personnel will call subjects and instruct them on oral MTX/placebo dosing, once that visit's lab results and AEs have been reviewed by the safety assessor (approximately 2 to 3 days after the study visit). 30

32 Table 5. Study Activities, Weeks Final Visit/ Week 52 Early Termination Visit Week Week Week Week Week Week Week Week Week Activity Vital Signs c /Weight X X X X X X X X X X X X Physical Exam d X X CXR & ECG e ANA/reflex Anti-dsDNA antibody X X C-reactive Protein X X X X Lipid Profile f X X X X ADA g X X X X X X X ABT-874 PK g X X X X X X X Unscheduled Visit a Telephone Follow-Up 45 days after last dose b Urine/Serum Pregnancy Tests h X X X X X X X X X X X X Hematology i X X X X X X X X X X X X Chemistry j X X X X X X X X X X X X Urinalysis k X X X X X X DLQI X X X X Patient's Global Assessment of Psoriasis-Severity X X X X X X 31

33 Table 5. Study Activities, Weeks (Continued) Final Visit/ Week 52 Early Termination Visit Activity Week 16 Week 20 Week 24 Week 28 Week 32 Week 36 Week 40 Week 44 Week 48 Unscheduled Visit a Psoriasis Related Pruritus X X X X X X VAS for Plaque Ps Pain X X X X X X EQ-5D Health Questionnaire X X X X VAS for PsA Pain X X X X X X PGA & PASI l X X X X X X X X X X X X NPGA & NAPSI X X X X X X X X X X X X Telephone Subject m +2-3 d +2-3 d +2-3 d +2-3 d +2-3 d +2-3 d +2-3 d +2-3 d +2-3 d +2-3 d Monitor Adverse Events and Concomitant therapy Telephone Follow-Up 45 days after last dose b X X X X X X X X X X X X X Patient Drug Accountability X X X X X X X X X X X X Dispense ABT-874/Placebo X X X X X X X X X Dispense Oral Folic Acid/ Placebo X X X X X X X X X Dispense Oral MTX/placebo X X X X X X X X X 32

34 Table 5. Study Activities, Weeks (Continued) a. An unscheduled visit for laboratory assessments and determination of AEs will be scheduled for 2 weeks following a dose escalation in oral MTX/placebo study medication provided a standard study visit has not been scheduled or as deemed appropriate by the safety assessor (e.g. to follow-up with AEs or abnormal labs). Assessments listed will be done if deemed appropriate by the safety assessor. Other assessments may also be done if appropriate. b. Site personnel will contact all subjects approximately 45 days following drug discontinuation to determine the occurrence of adverse events, changes in concomitant medications, and a urine pregnancy test, if applicable. c. Vital signs should be taken just prior to dosing. d. A full physical examination will be performed at Screening, Week 52or Early Termination, if applicable. A symptom-directed physical examination should be performed at all other visits if, in the opinion of the Investigator, it is warranted by the subject's AE status or on review of symptoms. e. Subject will have a repeat ECG or CXR if in the Investigator's opinion, clinically significant AEs develop during the study that warrant a repeat. f. Standard lipid profile will include total cholesterol, triglycerides, HDL, Calculated LDL and Cholesterol/HDL Ratio. Requires a 12-hour fast. g. Blood samples will be drawn prior to administration of injections. h. Serum pregnancy test at Screening; urine pregnancy test at all other indicated visits. Serum pregnancy test to be done if any urine pregnancy test is positive, including the pregnancy test at the time of the 45-day follow-up call. Urine pregnancy test to be performed at home at the 45-day telephone follow-up call. The results of this test will be conveyed to the site verbally. i. Hematocrit, hemoglobin, red blood cell count, white blood cell count, differential, platelet count. j. Sodium, potassium, chloride, CO2, glucose, creatinine, calcium, inorganic phosphorus, magnesium, uric acid, AST, ALT, total bilirubin, alkaline phosphatase, albumin, creatine kinase, total protein, BUN. k. Specific gravity, ph, protein, blood, glucose, bilirubin, ketones, nitrite (microscopic analysis will be done if urinalysis is abnormal). l. PGA, PASI assessments to be performed by the qualified blinded efficacy assessor. Site should make every attempt to have the same qualified efficacy assessor conduct these assessments throughout the study for any given subject. m. The study site personnel will call subjects and instruct them on oral MTX/placebo dosing, once that visit's lab results and AEs have been reviewed by the safety assessor (approximately 2 to 3 days after the study visit). 33

35 Study Procedures The study procedures outlined in Table 4 and Table 5, are discussed in detail in this section, with the exception of the collection of AE information (discussed in Section 6.0). ecrfs and paper CRFs (subject questionnaires) will be used to capture all appropriate study data. Informed Consent Signed informed consent will be obtained from the subject before any study procedures are undertaken and before any medications are withheld from the subject in order to participate in this study. For those subjects in need of a 12-week washout period, the screening period should begin when additional screening procedures are performed, other than the signing of the informed consent. Details on obtaining informed consent and documentation are provided in Section 9.3. Medical History A complete medical history (which includes psoriasis related and non-psoriasis related medical and surgical history), including history of tobacco and alcohol use as well as inclusion/exclusion criteria, will be obtained from each subject during the Screening visit. Medical history will be reviewed and updated at the Baseline (Week 0) visit to ensure that the subject remains qualified for the study. All previous prescription medications or physician-administered treatments for psoriasis ever received will be recorded with the earliest start date; latest end date; maximum dose ever received, where required; frequency; response; and reason for discontinuation of treatment. Medication (prescription and over-the-counter) use during the study will be recorded. 34