Abatacept With Methotrexate- Phase IIB

Phase 2

Completed

Conditions: Rheumatoid Arthritis

Interventions: Drug: Abatacept (BMS-188667)
Drug: Placebo

Registration Number: NCT00162266

Lead Sponsor: Bristol-Myers Squibb

Brief Summary: This study was conducted to assess the safety and tolerability of Abatacept combined with Methotrexate in participants with active rheumatoid arthritis (RA). The secondary objectives were to assess efficacy, pharmacodynamic marker activity, and immunogenicity of Abatacept combined with Methotrexate.

Detailed Description: All participants who completed the 12-month double-blind study period were eligible to continue in the open-label study. Participants received placebo, Abatacept 2 mg/kg, or Abatacept 10 mg/kg in the double-blind study. Participants receiving placebo in the double-blind study were switched 1:1 to continued treatment with placebo or Abatacept 2 mg/kg. Participants receiving Abatacept 2 mg/kg or Abatacept 10 mg/kg continued at the double-blind study dosage. After results from the double-blind period became available, all participants were switched to a weight-tiered 10 mg/kg dose of Abatacept.

Open label study design: Single group assignment, Single arm, Open label,

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 524

Inclusion Criteria

Double blind study phase:

Males or females (not nursing and not pregnant), at least 18 years of age. Women of child bearing potential (WOCBP) are eligible if they are practicing effective contraceptive measures
Subjects must meet the criteria of the American Rheumatism Association (1987) for the diagnosis of rheumatoid arthritis and the American College of Rheumatology (1991) functional classes I, II, or III
Subjects have been taking Methotrexate (10-30 mg weekly) for at least 6 months, and at a stable dose for 28 days prior to treatment
Washout/drug stabilization requirements (except Methotrexate) [Informed consent must be signed before making any changes in RA therapy if those changes are solely for the purpose of this study].
- Leflunomide or Infliximab have already been discontinued at least 60 days prior to enrollment (prior to signing of informed consent) and a total of 90 days prior to treatment. All other Disease Modifying Anti-Rheumatic Drugs (DMARDs) (except Methotrexate) have been withdrawn at least 28 days prior to treatment
- Oral corticosteroid treatment has been reduced to the equivalent of 10 mg or less prednisone daily and stabilized for at least 28 days prior to enrollment
Eligibility of subjects for the study is based on their disease activity and anti-rheumatic treatment at the initial visit:
- Methotrexate monotherapy: Subject is receiving only Methotrexate, steroids, Non-steroidal anti-inflammatory drugs (NSAIDs) and will not require washout
- Combination therapy: Subject is receiving Methotrexate in combination with another DMARD(s) and will require washout
At entry, Methotrexate monotherapy must have a disease activity:
- 10 or more swollen joints (66 joint count)
- 12 or more tender joints (68 joint count)
- C reactive protein (CRP) ≥.1 mg/dL (10 mg/L) at "Screening" visit
At entry, combination therapy must have a disease activity (if subject does not satisfy the above):
- 6 or more swollen joints (66 joint count)
- 8 or more tender joints (68 joint count)
- No restriction on C-reactive protein (CRP)
In addition

All subjects who were on combination therapy at entry must undergo a 28 day washout period of DMARDs other than Methotrexate. After the washout/drug stabilization and prior to randomization such subjects must have:
- 10 or more swollen joints (66 joint count)
- 12 or more tender joints (68 joint count)
- C reactive protein (CRP) ≥ 1 mg/dL (10 mg/L)
Subject is willing to participate in the study and willing to sign the informed consent

Open label study phase:

Participants that have completed the initial short term portion (double blind) of the study

Exclusion Criteria

Double blind study phase:

Subjects who have at any time received treatment with BMS-188667 (Abatacept)
Subjects who within 30 days of the Day 1 visit have received treatment with any investigational drug
Subjects with active vasculitis of a major organ system (except for subcutaneous rheumatoid nodules)
Current symptoms of severe, progressive, or uncontrolled renal, hepatic, hematological, gastrointestinal, pulmonary, cardiac, neurological, or cerebral disease. Concomitant medical conditions that in the opinion of the investigator might place the subject at unacceptable risk for participation in this study
Mammogram requiring further investigation or biopsies leading to the diagnosis of a clinically significant abnormality. Complete evaluation of lesion is required before initiation of dosing
Subjects with a history of cancer within the last five years (other than non-melanoma skin cell cancers cured by local resection)
Subjects who have a history of clinically significant drug or alcohol abuse, or admit to consumption of more than 1 alcoholic drink per day
Subjects with evidence (as assessed by the investigator) of active or latent bacterial or viral infections at the time of potential enrollment, including subjects with evidence of Human Immunodeficiency Virus (HIV) infection, or hepatitis B or C infection
Subjects with any serious or chronic infections such as pneumonia, pyelo-nephritis, renal infection, chest infection with bronchiectasis, or sinusitis in the previous 3 months
Subjects with active tuberculosis requiring treatment within the previous 3 years
Subjects with any opportunistic infections such as herpes zoster or cytomegalovirus (CMV) within the previous 2 months
Subjects with severe asthma defined as > 3 emergency room admissions in the last year or > 3 treatments with oral steroids for asthma in the last year
A history of either angioedema or anaphylaxis that was associated with a reaction to a drug
Subjects with the following laboratory values:
- Hemoglobin < 8.5 g/dL
- White blood cells < 3000/mm3
- Platelets < 100,000/mm3
- Serum creatinine > 2 times upper limit of normal
- Serum Alanine aminotransferase (ALAT) or Aspartate aminotransferase (ASAT) > 2 times upper limit of normal
- Any other lab values that in the opinion of the investigator might place the subject at unacceptable risk for participation in this study

Open label study phase:

Participants must continue to meet inclusion/exclusion criteria as in the short term (double blind) phase of the protocol except subjects who have receiving other than Abatacept

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Abatacept (2 mg/kg) - Double blind	Abatacept (BMS-188667)	-
Abatacept (10 mg/Kg) - Open Label	Abatacept (BMS-188667)	-
Abatacept (10 mg/kg) - Double blind	Abatacept (BMS-188667)	-
Placebo - Double blind	Placebo	-

Primary Outcome Measures

Name	Time	Method
Number of Responders to American College of Rheumatology 20% Improvement Criteria (ACR 20) at Day 180 of the Double-Blind (DB) Period	Day 180	ACR 20 response requires a participant to have a 20% reduction in the number of swollen and tender joints, and a reduction of 20% in three of the following five parameters: physician global assessment of disease, participant global assessment of disease, participant assessment of pain, C-reactive protein or erythrocyte sedimentation rate, and degree of disability in Health Assessment Questionnaire score. A participant achieved a sustained ACR 20 response if the participant had ACR 20 observed for at least 2 consecutive study visits.
Participants Receiving Concomitant Disease Modifying Rheumatic Drugs and Biologics in Open-Label (OL) Period	Day 360 to Day 3,060	The number of participants receiving concomitant rheumatoid arthritis treatment with disease modifying rheumatic drugs and/or biologics.
Number of Participants Experiencing Adverse Events (AEs) and Serious Adverse Events (SAEs) in OL Period	Day 360 to Day 3060	AE=any new untoward medical occurrence or worsening of a pre-existing medical condition which does not necessarily have a causal relationship with treatment.SAE=any untoward medical occurrence that at any dose: results in death, is life-threatening, requires inpatient hospitalization or causes prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, results in development of drug dependency or drug abuse, is an important medical event. Related AE/SAE=Certain,Probable,Possible,or Missing relationship to drug.
Baseline Serum Immunoglobulin A (IgA) Over Time in OL Period	Baseline (Day 0) and Days 360, 720,1080, 1440, and 1800	Time-matched baseline (Day 0) values and post-baseline values were presented for each post-baseline visit and represent only that cohort of participants with measurements available at that post-baseline assessment. Mean Change from Baseline data for these cohorts are presented in Outcome Measure 6.
Number of Participants With Electrolyte Values Meeting Marked Abnormality Criteria in OL Period	Day 360 to Day 3060
Number of Participants With Glucose, Protein, Metabolites, and Urinalysis Values Meeting Marked Abnormality Criteria in OL Period	Day 360 to Day 3060
Number of Participants With AEs of Special Interest in OL Period	Day 360 to Day 3060	AEs were defined as any new untoward medical occurrence or worsening of a pre- existing medical condition which does not necessarily have a causal relationship with this treatment. AEs of special interest were those which may be associated with the use of immunomodulatory agents or infusion of therapeutic proteins. Acute infusional AEs were defined as those that occurred within 1 hour after the start of the infusion. Peri-Infusional AEs were defined as those that occurred within 24 hours after the start of the infusion.
Mean Change From Baseline (BL) in IgA Over Time in OL Period	Baseline (Day 0) and Days 360, 720, 1080, 1440, and 1800	Blood samples for immunoglobulin assessments were obtained to determine change from baseline in serum IgA. Baseline data for these time-matched cohorts are presented in Outcome Measure 5.
Baseline Immunoglobulin G (IgG) Over Time in OL Period	Baseline (Day 0) and Days 360, 720, 1080, 1440 and 1800	Time-matched baseline (Day 0) values and post-baseline vales were presented for each post-baseline visit and represent only that cohort of participants with measurements available at that post-baseline assessment. Mean Change from Baseline data for these cohorts are presented in Outcome Measure 8.
Mean Change From Baseline (BL) in IgG Over Time in OL Period	Baseline (Day 0) and Days 360, 720, 1080, 1440, and 1800	Blood samples for immunoglobulin assessments were obtained to determine change from baseline in serum IgG. Baseline data for these cohorts are presented in Outcome Measure 7.
Baseline Immunoglobulin M (IgM) Over Time in OL Period	Baseline (Day 0) and Days 360, 720,1080,1440, and 1800	Time-matched baseline (Day 0) values and post-baseline values were presented for each post-baseline visit and represent only that cohort of participants with measurements available at that post-baseline assessment. Mean Change from Baseline data for these cohorts are presented in Outcome Measure 10.
Mean Change From Baseline (BL) in IgM in OL Period	Baseline (Day 0) and Days 360, 720, 1080, 1440, and 1800	Blood samples for immunoglobulin assessments were obtained to determine change from baseline in serum IgM. Baseline data for these time-matched cohorts are presented in Outcome Measure 9.
Number of Participants With Liver and Kidney Function Values Meeting Marked Abnormality Criteria in OL Period	Day 360 to Day 3060
Number of Participants With Hematology Values Meeting Marked Abnormality Criteria in OL Period	Day 360 to Day 3060

Secondary Outcome Measures

Name	Time	Method
Number of ACR 20 Responders in DB Period	Days 15, 30, 60, 90, 120, 150,180, 240, 300, and 360	ACR 20 response requires a participant to have a 20% reduction in the number of swollen and tender joints, and a reduction of 20% in three of the following five parameters: physician global assessment of disease, participant global assessment of disease, participant assessment of pain, C-reactive protein or erythrocyte sedimentation rate, and degree of disability in HAQ score. A participant achieved a sustained ACR 20 response if the participant had ACR 20 observed for at least 2 consecutive study visits.
Number of ACR 50 Responders in DB Period	Day 15; Day 30; Day 60; Day 90; Day 120; Day 150; Day 180; Day 240; Day 300; Day 360	ACR 50 response requires a participant to have a 50% reduction in the number of swollen and tender joints, and a reduction of 50% in three of the following five parameters: physician global assessment of disease, participant global assessment of disease, participant assessment of pain, C-reactive protein or erythrocyte sedimentation rate, and degree of disability in HAQ score. A participant achieved a sustained ACR 50 response if the participant had ACR 50 observed for at least 2 consecutive study visits.
Pharmacodynamic Measure: Mean Changes From Baseline in Rheumatoid Factor at Day 180 and Day 360	Baseline, Day 180, Day 360
Pharmacodynamic Measure: Mean Changes From Baseline in Interleukin-6 at Day 180 and Day 360	Baseline, Day 180, Day 360
Pharmacodynamic Measure: Mean Changes From Baseline in Plasma Soluble Interleukin-2 Receptor (sIL-2R) at Day 180 and Day 360	Baseline, Day 180, Day 360
Pharmacodynamic Measure: Mean Changes From Baseline in E-Selectin at Day 180 and Day 360	Baseline, Day 180, Day 360
Pharmacodynamic Measure: Mean Changes From Baseline in Soluble Inter-Cellular Adhesion Molecule 1 (sICAM-1) at Day 180 and Day 360	Baseline, Day 180, Day 360
Pharmacodynamic Measure: Mean Changes From Baseline in Tumor Necrosis Factor (TNF)-Alpha at Day 180 and Day 360	Baseline, Day 180, Day 360
Adjusted Mean Percent Changes From Baseline in the Modified Health Assessment Questionnaire (mHAQ) at Day 180 and Day 360	Baseline, Day 180, Day 360	A shortened version of the Health Assessment Questionnaire (HAQ), which uses only 8 instead of the 20 original items and is used to assess motor performance in everyday activities, such as dressing, turning a faucet on/off, and getting in and out of a car. Percent change from baseline = (baseline - post baseline value) / baseline value x 100.
Number of Participants With At Least One New Active Joint (Tender Joints and Swollen Joints) at Day 180 and Day 360	Day 180, Day 360
Participants Who Experienced Death, Adverse Events (AEs), Serious AEs (SAEs), and Discontinuations During the Double-Blind Period	From the start of study through the end of the double-blind period (at 12 months)	AE: any new untoward medical occurrence/worsening of pre-existing medical condition, whether or not related to study drug. SAE: any AE that resulted in death; was life threatening; resulted in persistent/significant disability/incapacity; resulted in/prolonged an existing in-patient hospitalization; was a congenital anomaly/birth defect; or was an overdose. Participants who discontinued the study due to any AEs were recorded. Related events include those that were considered by the investigator to be certain, probable, or possibly related to study drug.
Participants With Laboratory Abnormalities Meeting the Marked Abnormality Criteria for Selected Blood Chemistry Values During Double-Blind Therapy	From the start of study up to 60 days post the end of the 12-month double-blind period
Participants With Laboratory Abnormalities Meeting the Marked Abnormality Criteria for Selected Hematologic Values During Double-Blind Therapy	From the start of study up to 60 days post the end of the 12-month double-blind period
Number of Participants Who Discontinued Due to Lack of Efficacy in the DB and OL Periods	Day 1 to Day 360 (Double-Blind Period), Day 361 to Day 3060 (Open-Label Period)
Immunogenicity Data: Anti-CTLA4Ig Antibodies With Immunoglobulin (IG) Region	Baseline, Days 30, 90, 180, 270, 360
Number of ACR 70 Responders in DB Period	Day 15; Day 30; Day 60; Day 90; Day 120; Day 150; Day 180; Day 240; Day 300; Day 360	ACR 70 response requires a participant to have a 70% reduction in the number of swollen and tender joints, and a reduction of 70% in three of the following five parameters: physician global assessment of disease, participant global assessment of disease, participant assessment of pain, C-reactive protein or erythrocyte sedimentation rate, and degree of disability in HAQ score. A participant achieved a sustained ACR 70 response if the participant had ACR 70 observed for at least 2 consecutive study visits.
ACR Numeric Values (ACR-N)	Day 15; Day 30; Day 60; Day 90; Day 120; Day 150; Day 180; Day 240; Day 300; Day 360	The ACR-N is calculated for each participant by taking the lowest percentage improvement in (1) swollen joint count or (2) tender joint count or (3) the median of the remaining 5 components of the ACR response (participant's assessment of disease activity; participant's global assessment of pain; physician's assessment of disease activity; participant's assessment of physical function; an acute phase reactant value - CRP). Negative numbers indicate worsening.
ACR-N Area Under The Curve (AUC) on Day 180 and Day 360	Baseline and Day 180; Baseline and Day 360	The AUC for ACR-N is the measure of the area under the curve of the mean change from baseline in ACR-N. The trapezoidal rule was used to compute the AUC. The ACR-N AUC was compared between the two abatacept treatment groups and the placebo group using an analysis of variance (ANOVA) for 6- and 12-month data (Day 180 and Day 360). This allowed for the assessment of subject response throughout the study. See Measure Description in Outcome Measure 18 for a definition of ACR-N.
Individual Components of ACR Criteria--Mean Percentage Change From Baseline at Day 180	Baseline, Day 180	Percentage change = 100\*(Baseline value - value at specific visit) / Baseline value. The American College of Rheumatology (ACR) response criteria, based on a core set of variables which includes a tender joint count, a swollen joint count, patient-reported pain scale (Subject Assessment of Physical Function \[SAPF\]), patient and physician global assessments of disease activity (Subject Global Assessment \[SGA\] and Physician Global Assessment \[PGA\]), patient assessment of functional ability, and an acute phase reactant (C-Reactive Protein \[CRP\])
Individual Components of ACR Criteria--Mean Percentage Change From Baseline at Day 360	Baseline, Day 360	Percentage change = 100\*(Baseline value - value at specific visit) / Baseline value. The American College of Rheumatology (ACR) response criteria, based on a core set of variables which includes a tender joint count, a swollen joint count, patient-reported pain scale (Subject Assessment of Physical Function \[SAPF\]), patient and physician global assessments of disease activity (Subject Global Assessment \[SGA\] and Physician Global Assessment \[PGA\]), patient assessment of functional ability, and an acute phase reactant (C-Reactive Protein \[CRP\])
Mean Changes From Baseline in the Short Form 36 (SF-36) Physical and Mental Health Component Summary Scores (PCS and MCS) at Day 180 and Day 360	Baseline, Day 180, Day 360	SF-36 measures health-related quality of life across multiple disease states. It has 36 questions with 8 subscale scores and 2 summary scores: PCS=physical functioning, role-physical, bodily pain, and general health; MCS=vitality, social functioning, role-emotional, and mental health. Scoring is done for both subscores and summary scores. For both, 0=worst score (or quality of life) and 100=best score.
Immunogenicity Data: Anti-CTLA4Ig Antibodies Without IG Region	Baseline, Days 30, 90, 180, 270, 360
Immunogenicity Data: Categories of Post Baseline Value to Baseline Value (VA/PRE) Ratios and Number of Participants With Sero-conversion (Anti-CTLA4Ig Antibodies With IG Region)	Baseline, Days 30, 90, 180, 270, 360	Number of participants with ratio of VA/PRE \<=3, \<3 to \<=9, and \>9. Ratios greater than 9 are incidences of Anti-CTLA4Ig sero-conversion.
Immunogenicity Data: Categories of Post Baseline Value to Baseline Value (VA/PRE) Ratios and Number of Participants With Sero-conversion(Anti-CTLA4Ig Antibodies Without IG Region)	Baseline, Days 30, 90, 180, 270, 360	Number of participants with ratio of VA/PRE \<=3, \<3 to \<=9, and \>9. Ratios greater than 9 are incidences of Anti-CTLA4Ig sero-conversion.
Number of ACR 20 Responders in OL Period	Days 360, 450, 540, 630, 720, 810, 900, 1080, 1350, 1440, 1530, 1620, 1710, 1800, 1980, 2160, 2340, 2520, 2700, 2880, and 3060	ACR 20 response requires a participant to have a 20% reduction in the number of swollen and tender joints, and a reduction of 20% in three of the following five parameters: physician global assessment of disease, participant global assessment of disease, participant assessment of pain, C-reactive protein or erythrocyte sedimentation rate, and degree of disability in Health Assessment Questionnaire score. A participant achieved a sustained ACR 20 response if the participant had ACR 20 observed for at least 2 consecutive study visits.
Number of ACR 50 Responders in the OL Period	Days 360, 450, 540, 630, 720, 810, 900, 1080, 1350, 1440, 1530, 1620, 1710, 1800, 1980, 2160, 2340, 2520, 2700, 2880, and 3060	ACR 50 response requires a participant to have a 50% reduction in the number of swollen and tender joints, and a reduction of 50% in three of the following five parameters: physician global assessment of disease, participant global assessment of disease, participant assessment of pain, C-reactive protein or erythrocyte sedimentation rate, and degree of disability in HAQ score. A participant achieved a sustained ACR 50 response if the participant had ACR 50 observed for at least 2 consecutive study visits.
Number of ACR 70 Responders in the OL Period	Days 360, 450, 540, 630, 720, 810, 900, 1080, 1350, 1440, 1530, 1620, 1710, 1800, 1980, 2160, 2340, 2520, 2700, 2880, and 3060	ACR 70 response requires a participant to have a 70% reduction in the number of swollen and tender joints, and a reduction of 70% in 3 of the following 5 parameters: physician global assessment of disease, participant global assessment of disease, participant assessment of pain, C-reactive protein or erythrocyte sedimentation rate, and degree of disability in HAQ score. A participant achieved a sustained ACR 70 response if the participant had ACR 70 observed for at least 2 consecutive study visits.
Number of Participants With a Clinically Meaningful Improvement on the Modified Health Assessment Questionnaire (mHAQ) in OL Period	Days 360, 720,1080, 1440, 1800, 2160, 2520, 2880, and 3060	The mHAQ is a self-administered questionnaire composed of 20 questions that assess physical functions in 8 domains: dressing, arising, eating, walking, hygiene, reach, grip, and common activities. The answers are graded on a 4-point scale: 0=without any difficulty, 1=with some difficulty, 2=with much difficulty, and 3=unable to do. The HAQ disease index is a weighted sum of the scale scores, with a higher score indicating poorer function. A clinically meaningful improvement was defined as a reduction from baseline in mHAQ score of at least 0.30 units.
Baseline Level of Serum Rheumatoid Factor Over Time in OL Period	Baseline (Day 0) and Days 360, 720,1080, 1440, 1800, 2160, 2520, 2880, and 3060	Serum evaluations were carried out to determine participant baseline rheumatoid factor serum concentration. Time-matched baseline(Day 0) values and post-baseline vales were presented for each post-baseline visit and represent only that cohort of participants with measurements available at that post-baseline assessment.
Mean Change From Baseline in Serum Rheumatoid Factor Level Over Time in OL Period	Baseline (Day 0) and Days 360, 720,1080, 1440, 1800, 2160, 2520, 2880, and 3060	Serum evaluations were carried out to determine participant change from baseline in rheumatoid factor serum concentration. Mean change from baseline = value at post-baseline OL time point-value and baseline OL time point.
Mean Baseline Soluble Serum Interleukin-2 Receptor Level (sIL2-r) Over Time in OL Period	Baseline (Day 0) and Days 360, 720,1080, 1440, 1800, 2160, 2520, 2880, and 3060	Serum evaluations were carried out to determine participant serum levels of sIL2-r at baseline. Time-matched baseline (Day 0) values and post-baseline vales were presented for each post-baseline visit and represent only that cohort of participants with measurements available at that post-baseline assessment.
Mean Change From Baseline in sIL2-r Over Time in OL Period	Baseline (Day 0) and Days 360, 720, 1080, 1440, and 1800	Serum evaluations were carried out to determine participant serum levels of sIL2-r. Mean change from baseline=value at post-baseline OL time point-value and baseline OL time point.
Mean Baseline Serum C-Reactive Protein Level Over Time in OL Period	Baseline (Day 0) and Days 360, 720, 1080,1440,1800, 2160, 2520, 2880, 3060	Serum evaluations were carried out to evaluate participant serum CRP concentrations at baseline. Time-matched BL (Day 0) values and post-BL vales were presented for each post-BL visit and represent only that cohort of participants with measurements available at that post-BL assessment.
Mean Change From Baseline in Level of C Reactive Protein Over Time in OL Period	Baseline (Day 0) and Days 360, 720, 1080, 1440, 1800, 2160, 2520, 2880, 3060	Serum evaluations were carried out to evaluate participant concentrations of serum C reactive protein. Mean change from baseline=value at post-baseline OL time point-value and baseline OL time point.
Mean Baseline Physical Component Summary (PCS) of the Short-Form 36 (SF-36) Over Time in OL Period	Baseline (Day 0) and Days 360, 720, 1080, 1440, 1800, 2160, 2880, and 3060	SF-36 = PCS \& MCS \& 8 individual indices (physical function, role-physical, bodily pain, general health, vitality, social functioning, role-emotional, \& mental health). Subscales were scored using norm-based methods that standardized scores to a mean of 50 \& a standard deviation of 10 in the general population. Scores range from 0 to 100, with a higher score indicating better quality of life. Time-matched BL \& post-BL values are presented for each post-BL visit \& represent only that cohort with measurements available at that assessment. Change from BL data are presented in Outcome Measure 50.
Mean Change From Baseline (BL) in the Physical Component Summary (PCS) of the SF-36 Over Time in OL Period	Baseline (Day 0) and Days 360, 720, 1080, 1440, 1800, 2160, 2880, and 3060	The SF-36 consists of 2 summaries, the PCS and the MCS, and 8 individual indexes. The MCS addresses 4 of the 8 individual indices: vitality, social functioning, role-emotional, and mental health. The scores range from 0 to 100, with a higher score indicating better quality of life. Mean change from baseline=value at post-baseline OL time point-value and baseline OL time point. Baseline data for these time-matched cohorts are presented in Outcome Measure 49.
Mean Baseline Mental Component Summary (MCS) of the SF-36 Over Time in OL Period	Baseline (Day 0) and Days 360, 720, 1080, 1440, 1800, 2160, 2880, and 3060	SF-36=PCS, MCS, \& 8 individual indices. MCS addresses 4 of the 8 indices: vitality, social functioning, role-emotional, \& mental health. Subscales were scored using norm-based methods that standardized the scores to a mean of 50 \& a standard deviation of 10 in the general population. Scores range from 0 to 100, with a higher score indicating better quality of life. Time-matched baseline (Day 0) values \& post-baseline (BL) values are presented for each post-BL visit \& represent only that cohort with measurements available at that post-BL assessment. See Outcome Measure 51 for Change from BL.
Mean Change From Baseline (BL) in the MCS of the SF-36 Over Time in OL Period	Baseline (Day 0) and Days 360, 450, 540, 630, 720, 810, 900, 1080, 1350, 1440, 1530, 1620, 1710, 1800, 1980, 2160, 2340, 2520, 2700, 2880, and 3060	The SF-36 consists of 2 summaries, the PCS and the MCS, and 8 individual indexes. The MCS addresses 4 of the 8 individual indices: vitality, social functioning, role-emotional, and mental health. The scores range from 0 to 100, with a higher score indicating better quality of life. Mean change from baseline=value at post-baseline OL time point-value and baseline OL time point. Baseline data for these time-matched cohorts are presented in Outcome Measure 51.
Mean Baseline (BL) Physical Functioning Domain of the SF-36 Over Time in OL Period	Baseline (Day 0) and Days 360, 720, 1080, 1440, 1800, 2160, 2520, 2880, and 3060	SF-36 = PCS \& MCS \& 8 individual indices (physical function, role-physical, bodily pain, general health, vitality, social functioning, role-emotional, \& mental health). Subscales were scored using norm-based methods that standardized scores to a mean of 50 \& a standard deviation of 10 in the general population. Scores range from 0 to 100, with a higher score indicating better quality of life. Time-matched BL \& post-BL values are presented for each post-BL visit \& represent only that cohort with measurements available at that assessment. Change from BL data are presented in Outcome Measure 54.
Mean Change From Baseline (BL) in the Physical Functioning Domain of the SF-36 Over Time in OL Period	Baseline (Day 0) and Days 360, 720, 1080, 1440, 1800, 2160, 2520, 2880, and 3060	SF-36=2 summaries (PCS \& MCS) \& 8 individual indices including physical function, role-physical, bodily pain, general health, vitality, social functioning, role-emotional, \& mental health. All subscales were scored using norm-based methods that standardized the scores to a mean of 50 \& a standard deviation of 10 in the general population. The scores range from 0 to 100, with a higher score indicating better quality of life. Mean change from BL = value at post-BL OL time point-value and BL OL time point. Baseline data for these time-matched cohorts are presented in Outcome Measure 53.
Mean Baseline Role-Physical Domain of the SF-36 Over Time in OL Period	Baseline (Day 0) and Days 360, 720, 1080, 1440, 1800, 2160, 2520, 2880, and 3060	SF-36 = PCS \& MCS \& 8 individual indices (physical function, role-physical, bodily pain, general health, vitality, social functioning, role-emotional, \& mental health). Subscales were scored using norm-based methods that standardized scores to a mean of 50 \& a standard deviation of 10 in the general population. Scores range from 0 to 100, with a higher score indicating better quality of life. Time-matched BL \& post-BL values are presented for each post-BL visit \& represent only that cohort with measurements available at that assessment. Change from BL data are presented in Outcome Measure 56.
Mean Change From Baseline (BL) in the Role-Physical Domain of the SF-36 Over Time in OL Period	Baseline (Day 0) and Days 360, 720, 1080, 1440, 1800, 2160, 2520, 2880, and 3060	SF-36=2 summaries (PCS \& MCS) \& 8 individual indices including physical function, role-physical, bodily pain, general health, vitality, social functioning, role-emotional, \& mental health. All subscales were scored using norm-based methods that standardized the scores to a mean of 50 \& a standard deviation of 10 in the general population. The scores range from 0 to 100, with a higher score indicating better quality of life. Mean change from BL = value at post-BL OL time point-value and BL OL time point. Baseline data for these time-matched cohorts are presented in Outcome Measure 55.
Mean Baseline Bodily Pain Domain of the SF-36 Over Time in OL Period	Baseline (Day 0) and Days 360, 720, 1080, 1440, 1800, 2160, 2520, 2880, and 3060	SF-36 = PCS \& MCS \& 8 individual indices (physical function, role-physical, bodily pain, general health, vitality, social functioning, role-emotional, \& mental health). Subscales were scored using norm-based methods that standardized scores to a mean of 50 \& a standard deviation of 10 in the general population. Scores range from 0 to 100, with a higher score indicating better quality of life. Time-matched BL \& post-BL values are presented for each post-BL visit \& represent only that cohort with measurements available at that assessment. Change from BL data are presented in Outcome Measure 58.
Mean Change From BL in the Bodily Pain Domain of the SF-36 Over Time in OL Period	BL (Day 0); Day 360; Day 720; Day 1,080; Day 1,440; Day 1,800; Day 2,160; Day 2,520; Day 2,880; Day 3,060	SF-36=2 summaries (PCS \& MCS) \& 8 individual indices including physical function, role-physical, bodily pain, general health, vitality, social functioning, role-emotional, \& mental health. All subscales were scored using norm-based methods that standardized the scores to a mean of 50 \& a standard deviation of 10 in the general population. The scores range from 0 to 100, with a higher score indicating better quality of life. Mean change from BL = value at post-BL OL time point-value and BL OL time point. Baseline data for these time-matched cohorts are presented in Outcome Measure 57.
Mean BL General Health Domain of the SF-36 Over Time in OL Period	Baseline (Day 0) and Days 360, 720, 1080, 1440, 1800, 2160, 2520, 2880, and 3060	SF-36 = PCS \& MCS \& 8 individual indices (physical function, role-physical, bodily pain, general health, vitality, social functioning, role-emotional, \& mental health). Subscales were scored using norm-based methods that standardized scores to a mean of 50 \& a standard deviation of 10 in the general population. Scores range from 0 to 100, with a higher score indicating better quality of life. Time-matched BL \& post-BL values are presented for each post-BL visit \& represent only that cohort with measurements available at that assessment. Change from BL data are presented in Outcome Measure 60.
Mean Change From Baseline (BL) in the General Health Domain of the SF-36 Over Time in OL Period	Baseline (Day 0) and Days 360, 720, 1080, 1440, 1800, 2160, 2520, 2880, and 3060	SF-36=2 summaries (PCS \& MCS) \& 8 individual indices including physical function, role-physical, bodily pain, general health, vitality, social functioning, role-emotional, \& mental health. All subscales were scored using norm-based methods that standardized the scores to a mean of 50 \& a standard deviation of 10 in the general population. The scores range from 0 to 100, with a higher score indicating better quality of life. Mean change from BL = value at post-BL OL time point-value and BL OL time point. Baseline data for these time-matched cohorts are presented in Outcome Measure 59.
Mean Baseline Vitality Domain of the SF-36 Over Time in OL Period	Baseline (Day 0) and Days 360, 720, 1080, 1440, 1800, 2160, 2520, 2880, and 3060	SF-36 = PCS \& MCS \& 8 individual indices (physical function, role-physical, bodily pain, general health, vitality, social functioning, role-emotional, \& mental health). Subscales were scored using norm-based methods that standardized scores to a mean of 50 \& a standard deviation of 10 in the general population. Scores range from 0 to 100, with a higher score indicating better quality of life. Time-matched BL \& post-BL values are presented for each post-BL visit \& represent only that cohort with measurements available at that assessment. Change from BL data are presented in Outcome Measure 62.
Mean Change From Baseline (BL) in the Vitality Domain of the SF-36 Over Time in OL Period	Baseline (Day 0) and Days 360, 720, 1080, 1440, 1800, 2160, 2520, 2880, and 3060	SF-36=2 summaries (PCS \& MCS) \& 8 individual indices including physical function, role-physical, bodily pain, general health, vitality, social functioning, role-emotional, \& mental health. All subscales were scored using norm-based methods that standardized the scores to a mean of 50 \& a standard deviation of 10 in the general population. The scores range from 0 to 100, with a higher score indicating better quality of life. Mean change from BL = value at post-BL OL time point-value and BL OL time point. Baseline data for these time-matched cohorts are presented in Outcome Measure 61.
Mean Baseline Social Functioning Domain of the SF-36 Over Time in OL Period	Baseline (Day 0) and Days 360, 720, 1080, 1440, 1800, 2160, 2520, 2880, and 3060	SF-36 = PCS \& MCS \& 8 individual indices (physical function, role-physical, bodily pain, general health, vitality, social functioning, role-emotional, \& mental health). Subscales were scored using norm-based methods that standardized scores to a mean of 50 \& a standard deviation of 10 in the general population. Scores range from 0 to 100, with a higher score indicating better quality of life. Time-matched BL \& post-BL values are presented for each post-BL visit \& represent only that cohort with measurements available at that assessment. Change from BL data are presented in Outcome Measure 64.
Mean Change From Baseline (BL) in the Social Functioning Domain of the SF-36 Over Time in OL Period	Baseline (Day 0) and Days 360, 720, 1080, 1440, 1800, 2160, 2520, 2880, and 3060	SF-36=2 summaries (PCS \& MCS) \& 8 individual indices including physical function, role-physical, bodily pain, general health, vitality, social functioning, role-emotional, \& mental health. All subscales were scored using norm-based methods that standardized the scores to a mean of 50 \& a standard deviation of 10 in the general population. The scores range from 0 to 100, with a higher score indicating better quality of life. Mean change from BL = value at post-BL OL time point-value and BL OL time point. Baseline data for these time-matched cohorts are presented in Outcome Measure 63.
Mean Baseline Role-Emotional Domain of the SF-36 Over Time in OL Period	Baseline (Day 0) and Days 360, 720, 1080, 1440, 1800, 2160, 2520, 2880, and 3060	SF-36 = PCS \& MCS \& 8 individual indices (physical function, role-physical, bodily pain, general health, vitality, social functioning, role-emotional, \& mental health). Subscales were scored using norm-based methods that standardized scores to a mean of 50 \& a standard deviation of 10 in the general population. Scores range from 0 to 100, with a higher score indicating better quality of life. Time-matched BL \& post-BL values are presented for each post-BL visit \& represent only that cohort with measurements available at that assessment. Change from BL data are presented in Outcome Measure 66.
Mean Change From Baseline (BL) in the Role-Emotional Domain of the SF-36 Over Time in OL Period	Baseline (Day 0) and Days 360, 720, 1080, 1440, 1800, 2160, 2520, 2880, and 3060	SF-36=2 summaries (PCS \& MCS) \& 8 individual indices including physical function, role-physical, bodily pain, general health, vitality, social functioning, role-emotional, \& mental health. All subscales were scored using norm-based methods that standardized the scores to a mean of 50 \& a standard deviation of 10 in the general population. The scores range from 0 to 100, with a higher score indicating better quality of life. Mean change from BL = value at post-BL OL time point-value and BL OL time point. Baseline data for these time-matched cohorts are presented in Outcome Measure 65.
Mean Baseline Mental Health Domain of the SF-36 Over Time in OL Period	Baseline (Day 0) and Days 360, 720, 1080, 1440, 1800, 2160, 2520, 2880, and 3060	SF-36 = PCS \& MCS \& 8 individual indices (physical function, role-physical, bodily pain, general health, vitality, social functioning, role-emotional, \& mental health). Subscales were scored using norm-based methods that standardized scores to a mean of 50 \& a standard deviation of 10 in the general population. Scores range from 0 to 100, with a higher score indicating better quality of life. Time-matched BL \& post-BL values are presented for each post-BL visit \& represent only that cohort with measurements available at that assessment. Change from BL data are presented in Outcome Measure 68.
Mean Change From Baseline (BL) in the Mental Health Domain of the SF-36 Over Time in OL Period	Baseline (Day 0) and Days 360, 720, 1080, 1440, 1800, 2160, 2520, 2880, and 3060	SF-36=2 summaries (PCS \& MCS) \& 8 individual indices including physical function, role-physical, bodily pain, general health, vitality, social functioning, role-emotional, \& mental health. All subscales were scored using norm-based methods that standardized the scores to a mean of 50 \& a standard deviation of 10 in the general population. The scores range from 0 to 100, with a higher score indicating better quality of life. Mean change from BL = value at post-BL OL time point-value and BL OL time point. Baseline data for these time-matched cohorts are presented in Outcome Measure 67.