Subcutaneous Treatment In Randomized Subjects To Evaluate Safety And Efficacy In Generalized Lupus Erythematosus

Study Overview
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Brief Summary
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The objective of this study is to evaluate and compare efficacy of 3 dose levels of PF-04236921 to placebo in subjects with generalized lupus using a measure called the Systemic Lupus Erythematosus (SLE) Responder Index. The study will evaluate secondary and exploratory measures as well.

Official Title
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A Double-blind, Randomized, Placebo-controlled, Multicenter Dose-ranging Study To Evaluate The Efficacy And Safety Of Pf-04236921 In Subjects With Systemic Lupus Erythematosus (Sle)

Conditions
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Lupus Erythematosus, Systemic

Intervention / Treatment
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* Biological: PF-04236921
* Biological: PF-04236921
* Biological: PF-04236921
* Biological: PF-04236921


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female subjects between ages of 18 and 75 years old at time of signing consent. Have a clinical diagnosis of SLE according to 1997 update on the revised 1982 American College of Rheumatology (ACR) criteria. Have a unequivocally positive anti-nuclear antibody (ANA) test result. Active disease at screening defined by both: SLEDAI-2K score greater than or equal to 6 and BILAG Level A disease in more than or equal to 1 organ system (except renal or central nervous system) or BILAG B disease in more than or equal to 2 organ systems if no level A disease in present. Exclusion Criteria: Any prior history of treatment with PF-04236921, or anti-IL-6 agent; Have received any of the following within 364 days of day 1: a biologic investigational agent other than B cell targeted therapy; required 3 or more courses of systemic corticosteroids for concomitant conditions; history of previously untreated or current evidence of active or untreated latent infection with Tuberculosis (TB), evidence of prior untreated or currently active TB by chest radiography, residing with or frequent close contact with an individual with active TB.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: 10 mg of PF-04236921<br> | Biological: PF-04236921<br>* subcutaneous injection; administered at day 1, weeks 8, 16.<br>|
| Other: 50 mg of PF-04236921<br> | Biological: PF-04236921<br>* subcutaneous injection; administered at day 1, weeks 8, 16.<br>|
| Other: 200 mg of PF-04236921<br> | Biological: PF-04236921<br>* subcutaneous injection; administered at day 1, weeks 8, 16.<br>|
| Other: Placebo<br> | Biological: PF-04236921<br>* subcutaneous injection; administered at day 1, weeks 8, 16<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving Systemic Lupus Erythematosus (SLE) Responder Index (SRI) at Week 24 | SRI components include:Systemic Lupus Erythematosus Disease Activity Index 2000(SLEDAI-2K),British Isles Lupus Assessment Group(BILAG) 2004,Physician's Global Assessment(PhGA).Participants classified as responder if they did not meet definition of treatment failure and met all the following criteria: greater than or equal to(>=) 4 point reduction in SLEDAI-2K score; no new BILAG A organ domain score or 2 new BILAG B organ domain scores; no worsening (less than [<] 0.3 point increase) in PhGA score. Treatment failure: any new/increased use of corticosteroids,immunosuppressants/antimalarial drug, any death, hospitalization/treatment discontinuation due to SLE, any flare of lupus interfering with participation in study. SLEDAI-2K:assesses improvement in disease activity (range: 0 to 105; higher score = higher severity). BILAG:assesses disease extent, severity (range: A[severe] to E[no disease]). PhGA: assesses worsening in participant's general health status(range: 0[none] to 3[severe]). | Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving Systemic Lupus Erythematosus (SLE) Responder Index (SRI) at Week 4, 8, 12, 16, and 20 | SRI components include:SLEDAI-2K ,BILAG 2004, PhGA. Participants classified as responder if they did not meet definition of treatment failure and met all the following criteria: >=4 point reduction in SLEDAI-2K score; no new BILAG A organ domain score or 2 new BILAG B organ domain scores; no worsening (<0.3 point increase) in PhGA score. Treatment failure: any new/increased use of corticosteroids,immunosuppressants/antimalarial drug, any death, hospitalization/treatment discontinuation due to SLE, any flare of lupus interfering with participation in study. SLEDAI-2K: assesses improvement in disease activity (range: 0 to 105; higher score = higher severity). BILAG:assesses disease extent, severity (range: A [severe] to E [no disease]). PhGA: assesses worsening in participant's general health status(range: 0[none] to 3[severe]). | Week 4, 8, 12, 16, 20 | 
| Percentage of Participants Achieving Modified Systemic Lupus Erythematosus (SLE) Responder Index (SRI) at Week 4, 8, 12, 16, 20, and 24 | SRI components include: modified SLEDAI-2K (SLEDAI-2K without standard parameters Low complement and Leukopenia), BILAG 2004, PhGA. Participants classified as responder if they did not meet definition of treatment failure and met all the following criteria: >=4 point reduction in SLEDAI-2K score; no new BILAG A organ domain score or 2 new BILAG B organ domain scores; no worsening (<0.3 point increase) in PhGA score. Treatment failure: any new/increased use of corticosteroids, immunosuppressants/antimalarial drug, any death, hospitalization/treatment discontinuation due to SLE, any flare of lupus interfering with participation in study. Modified SLEDAI-2K: assesses improvement in disease activity (range: 0 to 102; higher score = higher severity). BILAG: assesses disease extent, severity (range: A [severe] to E [no disease]). PhGA: assesses worsening in participant's general health status (range: 0[none] to 3[severe]). | Week 4, 8, 12, 16, 20, 24 | 
| Percentage of Participants Achieving British Isles Lupus Assessment Group-based Composite Lupus Assessment (BICLA) Response at Week 4, 8, 12, 16, 20, and 24 | BICLA include: BILAG-2004, SLEDAI-2K, PhGA of disease activity. Participants classified as responder if they did not meet the definition of treatment failure and met all the following criteria: BILAG-2004 improvement (all A scores at baseline improved to B/C/D and all B scores improved to C or D); no worsening in disease activity (no new BILAG-2004 A scores or =<1 new B score); no worsening of total SLEDAI-2K score; no significant deterioration (<10 percent [%] worsening) in analogue PhGA. Treatment failure: any new/increased use of corticosteroids,immunosuppressants/antimalarial, any death, hospitalization/treatment discontinuation due to SLE, any flare of lupus interfering with participation in study. BILAG:assesses disease extent, severity (range: A[severe] to E[no disease]). SLEDAI-2K:assesses improvement in disease activity (range: 0 to 105; higher score = higher severity). PhGA: assesses worsening in participant's general health status(range: 0[none] to 3[severe]). | Week 4, 8, 12, 16, 20, 24 | 
| Percentage of Participants Achieving Pre-defined Criteria for Systemic Lupus Erythematosus (SLE) Responder Index (SRI) Components at Week 24 | SRI components include: SLEDAI-2K, BILAG 2004 and PhGA. Participants classified as responder if they did not meet definition of treatment failure and met all the following criteria: >=4 point reduction in SLEDAI-2K score; no new BILAG A organ domain score or 2 new BILAG B organ domain scores; no worsening(<0.3 point increase) in PhGA score. Treatment failure: any new/increased use of corticosteroids, immunosuppressants/antimalarial drug, any death, hospitalization/treatment discontinuation due to SLE, any flare of lupus interfering with participation in study. SLEDAI-2K: assesses improvement in disease activity(range: 0 to 105; higher score = higher severity). BILAG: assesses disease extent, severity (range: A[severe] to E [no disease]). PhGA: assesses worsening in participant's general health status (range: 0[none] to 3[severe]). Model percent estimates reported only for 'Reduction in SLEDAI Score','No Worsening in PhGA' categories; for remaining categories, raw percentages reported | Week 24 | 
| Number of Participants With Clinically Significant Laboratory Tests Results | Pre-defined criteria were established for each laboratory test to define the values that would be identified as of potential clinical importance. Laboratory values included Alanine Aminotransferase (ALT) [>5.0 - 10.0*Upper limit of normal range (ULN)], Albumin [<26-20 gram per liter (g/L)/ <20 g/L], Amylase [>2.0 - 5.0*ULN], Aspartate Aminotransferase (AST) [>5.0 - 10.0*ULN], Creatine Kinase (CK) [>5.0 - 10.0* ULN/ >10.0*ULN], Glucose (Hyperglycemia) [>13.9 - 27.8 millimoles/liter (mmol/L)], Hemoglobin (HGB) [<80 - 65 g/L/ <65 g/L], Lipase [>2.0 - 5.0*ULN], Lymphocytes (Lymph.)(Absolute [Abs]) [<0.5 - 0.2*10^3/microliter (UL)/ <0.2*10^3/UL], Platelets [<50-25*10^3/UL/ <25*10^3/UL], potassium (low) [<3.0 - 2.5 mmol/L], Sodium (low) [<130 - 120 mmol/L], Total Neutrophils (TN) (Abs) [<1.0 - 0.5*10^3/UL/ <0.5*10^3/UL], Triglycerides [>5.7 - 11.4 mmol/L], White Blood Cell Count (WBC) [<2.0 - 1.0*10^3/UL/ <1.0*10^3/UL]. | Baseline up to Week 52 | 
| Number of Participants Who Discontinued Due to Adverse Events | An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Number of participants who discontinued due to adverse events were reported. | Baseline up to Week 52 | 
| Number of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs) | An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent are events between first dose of study drug and up to Week 52 that were absent before treatment or that worsened relative to pretreatment state. Number of participants with treatment-emergent AEs or SAEs (excluding infectious AEs or SAEs and injection site reactions) were reported. AEs include both SAEs and non-SAEs. | Baseline up to Week 52 | 
| Number of Participants With Treatment-Emergent Infectious Adverse Events (AEs) or Serious Adverse Events (SAEs) | An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent are events between first dose of study drug and up to Week 52 that were absent before treatment or that worsened relative to pretreatment state. Number of participants with treatment-emergent infectious AEs or SAEs were reported. AEs include both SAEs and non-SAEs. | Baseline up to Week 52 | 
| Number of Participants With Potentially Clinically Important (PCI) Electrocardiogram (ECG) Findings | Criteria for potentially clinically important (PCI) findings in ECG were defined as: heart rate <=40 beats per minute (bpm) or >=120 bpm; PR interval >=220 millisecond (msec); QT interval >=480 msec; QRS interval >=120 msec; QT interval corrected using the Fridericia formula (QTcF) >=500msec; no sinus rhythm. | Baseline up to Week 52 | 
| Number of Participants With Potentially Clinically Important Vital Signs Findings | Criteria for PCI findings in vital signs were defined as: sitting systolic blood pressure (Increase from baseline >=20 millimeter of mercury (mm Hg) and >=160 mm Hg or a decrease from baseline >=20 mm Hg and <=90 mm Hg) and sitting diastolic blood pressure (increase from baseline >=15 mm Hg and >=90 mm Hg or decrease from baseline >=15 mm Hg and <=60 mm Hg), pulse rate (increase from baseline >=15 beats/min and >=120 beats/min or decrease from baseline >=15 beats/min and <=50 beats /min), body temperature (increase of >=2 degree Fahrenheit (F) and temperature >=101 degree F) and weight (change of >=7% in body weight) | Baseline up to Week 52 | 
| Number of Participants With Anti-drug Antibodies (ADAs) and Neutralizing Antibodies (Nabs) | Human serum samples were analyzed for the presence or absence of anti-PF-04236921 antibodies. A positive ADA sample was further tested for neutralizing antibodies using a validated assay. | Baseline up to Week 52 | 
| Serum Concentration of PF-04236921 | Serum PF-04236921 concentrations over time were summarized. | Day 1, Week 2, 4, 6, 8, 12, 16, 20, 24 | 
| Percentage of Participants With Corticosteroid Dose Reduced by Both Greater Than or Equal to (>=) 25 Percent (%) From Baseline and Less Than or Equal to (<=) 7.5 Milligrams Per Day (mg/Day) | Participants were given supplemental corticosteroids at baseline to control disease activity, if necessary. The steroid taper was based on participant's symptoms. Participants recorded their steroid usage on a diary card. Least Observation Carried Forward (LOCF) method was used to impute missing data. | Week 12, 16, 20, 24 | 
| Percentage of Participants With Normalized Serological Activity | Serologic activity was to be assessed in the subgroup of participants who had positive serologic activity at baseline. | Baseline up to Week 24 | 
| Patient Global Visual Analog Scale (VAS) Scores at Baseline | Participants assessed their disease activity using a 100 millimeter (mm) VAS. Participants answered the following question Considering all the ways your disease affects you, how are you feeling today? Response was recorded by placing a mark on the scale between 0 (very well) and 100 (extremely bad). | Baseline | 
| Change From Baseline in Patient Global Visual Analog Scale (VAS) at Week 2, 4, 6, 8, 12, 16, 20 and 24 | Participants assessed their disease activity using a 100 mm VAS. Participants answered the following question Considering all the ways your disease affects you, how are you feeling today? Response was recorded by placing a mark on the scale between 0 (very well) and 100 (extremely bad). | Baseline, Week 2, 4, 6, 8, 12, 16, 20, 24 | 
| Change From Baseline in European Quality of Life 5 Dimensions Questionnaire (EQ-5D) at Week 4, 8, 12, 16, 20 and 24 | EQ-5D is a standardized, participant-administered measure of health outcome. It provides a descriptive profile for 5 dimensions (mobility, self-care, usual activities, pain/discomfort, anxiety/depression), using 3 levels (no, moderate, or extreme problems) and a single index value characterizing current health status using a 100-point VAS (0= worst imaginable health state, 100= best imaginable health state). | Baseline, Week 4, 8, 12, 16, 20, 24 | 
| Thirty Six-Item Short-Form Health Survey (SF-36) Physical Component Score (PCS) and Mental Component Score (MCS) at Baseline | SF-36 is a standardized survey evaluating 8 aspects of functional health and well-being: physical and social functioning, physical and emotional role limitations, bodily pain, general health, vitality, mental health. These 8 aspects can also be summarized as PCS and mental component score MCS. The score for each aspect and PCS/MCS is an average of the individual question scores, which are scaled 0-100 (100=highest level of functioning). LOCF method was used to impute missing values. | Baseline | 
| Change From Baseline in 36-Item Short-Form Health Survey (SF-36) PCS and MCS at Week 4, 8, 12, 16, 20 and 24 | SF-36 is a standardized survey evaluating 8 aspects of functional health and well-being: physical and social functioning, physical and emotional role limitations, bodily pain, general health, vitality, mental health. These 8 aspects can also be summarized as physical component score (PCS) and mental component score (MCS). The score for each aspect and PCS/MCS is an average of the individual question scores, which are scaled 0-100 (100=highest level of functioning). LOCF method was used to impute missing values. | Baseline, Week 4, 8, 12, 16, 20, 24 | 
| Change From Baseline in Vitality Scores at Week 4, 8, 12, 16, 20 and 24 | SF-36 is a standardized survey evaluating 8 aspects of functional health and well being: physical and social functioning, physical and emotional role limitations, bodily pain, general health, vitality, mental health. Vitality sub-score is a component of SF-36 Health Survey Questionnaire and assesses energy and fatigue. The vitality score ranged from 0-100 (100=highest level of functioning). LOCF method was used to impute missing values. | Baseline, Week 4, 8, 12, 16, 20, 24 | 
| Change From Baseline in Short Form-6 Dimension (SF-6D) at Week 4, 8, 12, 16, 20 and 24 | The SF-6D focuses on seven of the eight health domains covered by the SF-36 Health Survey: physical functioning, role participation (combined role-physical and role-emotional), social functioning, bodily pain, mental health, and vitality. The SF-6D is an attempt to derive a single index from the SF-36 Health Survey for use in economic evaluation studies. As such, it represents a summary score based on a subset of the SF-36 data. Consequently, in lieu of the SF-6D, PCS and MCS SF-36 results are being provided. The score for each aspect and PCS/MCS is an average of the individual question scores, which are scaled 0-100 (100=highest level of functioning). LOCF method was used to impute missing values. | Baseline, Week 4, 8, 12, 16, 20, 24 | 
| Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) Score at Baseline | FACIT-F is a 13-item questionnaire. Participants scored each item on a 5-point scale: 0 (not at all) to 4 (very much). Larger the participant's response to the questions (with the exception of 2 negatively stated), greater was the participant's fatigue. For all questions, except for the 2 negatively stated ones, the code was reversed and a new score was calculated as (4 minus the participant's response). The sum of all responses resulted in the FACIT-Fatigue score for a total possible score of 0 (worse score) to 52 (better score). | Baseline | 
| Change From Baseline in Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) Score at Week 4, 8, 12, 16, 20 and 24 | FACIT-F is a 13-item questionnaire. Participants scored each item on a 5-point scale: 0 (not at all) to 4 (very much). Larger the participant's response to the questions (with the exception of 2 negatively stated), greater was the participant's fatigue. For all questions, except for the 2 negatively stated ones, the code was reversed and a new score was calculated as (4 minus the participant's response). The sum of all responses resulted in the FACIT-Fatigue score for a total possible score of 0 (worse score) to 52 (better score). LOCF method was used to impute missing values. | Baseline, Week 4, 8, 12, 16, 20, 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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double-blind, placebo-controlled, multicenter, dose-ranging, efficacy, safety, lupus.