Study of Abatacept (BMS-188667) in Subjects With Active Rheumatoid Arthritis on Background Non-biologic DMARDS (Disease Modifying Antirheumatic Drugs) Who Have an Inadequate Response to Anti-TNF Therapy - Study Results

Study Type:	Interventional
Study Design:	Allocation: Non-Randomized; Endpoint Classification: Safety Study; Intervention Model: Parallel Assignment; Masking: Open Label; Primary Purpose: Treatment
Condition:	Rheumatoid Arthritis
Interventions:	Drug: Abatacept Drug: Non-biologic Disease Modifying Anti-Rheumatic Drug (DMARD) Drug: Anti-Tumor Necrosing Factor (TNF) Therapy

Participant Flow

Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
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Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Of 1286 participants enrolled in this study, 240 were not treated.

Reporting Groups

	Description
Short Term (ST) Abatacept (ABA)-Previous User	In participants who had previously used Tumor Necrosis Factor (TNF)-agonists, open-label abatacept was administered on Days 1, 15, and 29 and then once a month thereafter on a background of non-biologic Disease Modifying Anti-Rheumatic Drug (DMARD)s. Participants weighing < 60 kg received 500 mg, participants weighing 60 to 100 kg received 750 mg, and participants weighing > 100 kg received 1 gram of open-label abatacept by intravenous (IV) infusion.
ST-Current User	In participants currently using Tumor Necrosis Factor (TNF)-agonists, open-label abatacept was administered on Days 1, 15, and 29 and then once a month thereafter on a background of non-biologic Disease Modifying Anti-Rheumatic Drug (DMARD)s. Participants weighing < 60 kg received 500 mg, participants weighing 60 to 100 kg received 750 mg, and participants weighing > 100 kg received 1 gram of open-label abatacept by intravenous (IV) infusion.
Long-term ABA	Participants continued to receive the same 10 mg/kg weight-tiered dose of abatacept that they received in the initial short-term period.

Participant Flow for 2 periods

Period 1: Short-term Period

	Short Term (ST) Abatacept (ABA)-Previous User	ST-Current User
STARTED	449	597
COMPLETED	377	483
NOT COMPLETED	72	114
Death	1	1
Adverse Event	17	22
Lack of Efficacy	32	73
Lost to Follow-up	8	5
Withdrawal of Consent	7	9
Poor/Non-compliance	3	1
No Longer Meets Study Criteria	1	2
Participant Decision	1	0
Participant Chose Own Doctor	0	1
Investigator Decision-No Specific AE	1	0
Participant Had Lymphopenia	1	0

Period 2: Long-term Period

	Short Term (ST) Abatacept (ABA)-Previous User	ST-Current User	Long-term ABA
STARTED	0	0	530 ^[1]
COMPLETED	0	0	441
NOT COMPLETED	0	0	89
Death	0	0	1
Adverse Event	0	0	17
Lack of Efficacy	0	0	46
Lost to Follow-up	0	0	4
Withdrawal by Subject	0	0	16
Pregnancy	0	0	1
Poor/Non-compliance	0	0	2
Administrative Reason by Sponsor	0	0	1
Neurologist Recommendation	0	0	1

[1]	A large number did not continue due to a rollover from study drug to commercially available drug.

Baseline Characteristics

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Reporting Groups

	Description
ST Abatacept (ABA)-Previous User	In participants who had previously used Tumor Necrosis Factor (TNF)-agonists, open-label abatacept was administered on Days 1, 15, and 29 and then once a month thereafter on a background of non-biologic Disease Modifying Anti-Rheumatic Drug (DMARD)s. Participants weighing < 60 kg received 500 mg, participants weighing 60 to 100 kg received 750 mg, and participants weighing > 100 kg received 1 gram of open-label abatacept by intravenous (IV) infusion.
ST ABA-Current User	In participants currently using Tumor Necrosis Factor (TNF)-agonists, open-label abatacept was administered on Days 1, 15, and 29 and then once a month thereafter on a background of non-biologic Disease Modifying Anti-Rheumatic Drug (DMARD)s. Participants weighing < 60 kg received 500 mg, participants weighing 60 to 100 kg received 750 mg, and participants weighing > 100 kg received 1 gram of open-label abatacept by intravenous (IV) infusion.

Description

ST Abatacept (ABA)-Previous User

In participants who had previously used Tumor Necrosis Factor (TNF)-agonists, open-label abatacept was administered on Days 1, 15, and 29 and then once a month thereafter on a background of non-biologic Disease Modifying Anti-Rheumatic Drug (DMARD)s. Participants weighing < 60 kg received 500 mg, participants weighing 60 to 100 kg received 750 mg, and participants weighing > 100 kg received 1 gram of open-label abatacept by intravenous (IV) infusion.

ST ABA-Current User

In participants currently using Tumor Necrosis Factor (TNF)-agonists, open-label abatacept was administered on Days 1, 15, and 29 and then once a month thereafter on a background of non-biologic Disease Modifying Anti-Rheumatic Drug (DMARD)s. Participants weighing < 60 kg received 500 mg, participants weighing 60 to 100 kg received 750 mg, and participants weighing > 100 kg received 1 gram of open-label abatacept by intravenous (IV) infusion.

Baseline Measures

	ST Abatacept (ABA)-Previous User	ST ABA-Current User	Total
Number of Participants [units: participants]	449	597	1046
Age [units: years] Mean ± Standard Deviation	56.1 ± 12.5	53.2 ± 12.3	54.4 ± 12.4
Gender [units: participants]
Female	359	490	849
Male	90	107	197
Number of Tender Joints ^[1] [units: tender joints] Mean ± Standard Deviation	17.8 ± 5.9	17.8 ± 6.1	17.8 ± 6.0
Number of Swollen Joints ^[2] [units: swollen joints] Mean ± Standard Deviation	13.9 ± 5.6	13.5 ± 5.4	13.6 ± 5.5
Physical Function, Health Assessment Questionnaire Disability Index (HAQ-DI) ^[3] [units: units on a scale] Mean ± Standard Deviation	1.7 ± 0.6	1.7 ± 0.6	1.7 ± 0.6
hs-C-Reactive Protein (hs-CRP) Serum Levels ^[4] [units: mg/dL] Mean ± Standard Deviation	2.2 ± 3.0	2.1 ± 3.0	2.1 ± 3.0
Disease Activity Score (DAS) 28 (Using CRP Levels) ^[5] [units: units on a scale] Mean ± Standard Deviation	6.2 ± 0.7	6.2 ± 0.7	6.2 ± 0.7
Rheumatoid Factor (RF) Status ^[6] [units: participants]
Negative	138	215	353
Positive	292	349	641
Data Not Available	19	33	52

[1]	The mean number of tender joints was evaluated based on the number of tender joints in a standard 68 joint count.
[2]	The mean number of swollen joints was evaluated based on the number of swollen joints in a standard 66 joint count.
[3]	The HAQ-DI includes 20 questions to assess physical functions in 8 domains: dressing, arising, eating, walking, hygiene, reach, grip and common activities. The domain questions are evaluated on a 4-point scale: 0=without any difficulty, 1= with some difficulty, 2= with much difficulty, and 3= unable to do. HAQ-DI= sum of worst scores in each domain divided by the number of domains answered. HAQ-DI ranges from a minimum of 0 (no difficulty) to a maximum overall score of 3(unable to do).
[4]	hs-CRP is a acute phase reactant protein that is a clinical marker for Rheumatoid Arthritis (RA). Levels of hs-CRP can be used to determine DAS28.
[5]	The DAS28 (CRP) is a continuous disease measure which is a composite of 4 variables: the 28 tender joint count, the 28 swollen joint count, serum CRP level, and participant assessment of disease activity measure on a visual analogue scale. The DAS28 has numeric thresholds that define high disease activity (> 5.1), low disease activity (< 3.2) and remission (< 2.6). A clinically significant response= decrease in DAS28 score of >1.2 from baseline.
[6]	Rheumatoid factor (RF or RhF) is an autoantibody (antibody directed against an organism's own tissues) most relevant in rheumatoid arthritis. It is an antibody against the Fc portion of Immunoglobulin (Ig)G, which is itself an antibody. RF and IgG join to form immune complexes which contribute to the disease process.

Outcome Measures

Show All Outcome Measures

1. Primary:

Short-term Period: Number of Participants With Death, Serious Adverse Events (SAEs), Related SAEs, SAEs Leading to Discontinuations, AEs, Related AEs, or AEs Leading to Discontinuations [ Time Frame: Days 1-169 ]

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2. Primary:

Short-term Period: Number of Participants With AEs of Special Interest [ Time Frame: Days 1-169 ]

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3. Primary:

Short-term Period: Number of Participants With Hematology Laboratories Meeting Marked Abnormality (MA) Criteria [ Time Frame: Days 1-169 ]

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4. Primary:

Short-term Period: Number of Participants With Liver and Kidney Function Laboratories Meeting MA Criteria [ Time Frame: Days 1-169 ]

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5. Primary:

Short-term Period: Number of Participants With Electrolyte Laboratories Meeting MA Criteria [ Time Frame: Days 1-169 ]

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6. Primary:

Short-term Period: Number of Participants With Other Chemistry and Urinalysis Laboratories Meeting MA Criteria [ Time Frame: Days 1-169 ]

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7. Primary:

Short-term Period: Mean Change From Baseline in Systolic and Diastolic Blood Pressure [ Time Frame: Day 1 (Baseline) -Day 169 ]

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8. Primary:

Short-term Period: Number of Participants With Positive Anti-Abatacept or Anti-Cytotoxic T-Lymphocyte Antigen 4 (CTLA4) Responses by Enzyme-Linked Immunosorbant Assay (ELISA) [ Time Frame: Days 1-169 ]

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9. Primary:

Long-term Period: Number of Participants With Death, Serious Adverse Events (SAEs), Related SAEs, SAEs Leading to Discontinuations, AEs, Related AEs, or AEs Leading to Discontinuations [ Time Frame: From Day 169 through Day 813, including up to 56 days after the last dose of long-term period abatacept ]

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10. Primary:

Long-term Period: Number of Participants With AEs of Special Interest [ Time Frame: From Day 169 through Day 813, including up to 56 days after the last dose of long-term period abatacept ]

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11. Primary:

Long-term Period: Number of Participants With Hematology Laboratories Meeting Marked Abnormality (MA) Criteria [ Time Frame: From Day 169 through Day 813, including up to 56 days after the last dose of long-term period abatacept ]

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12. Primary:

Long-term Period: Number of Participants With Liver and Kidney Function Laboratories Meeting MA Criteria [ Time Frame: From Day 169 through Day 813, including up to 56 days after the last dose of long-term period abatacept ]

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13. Primary:

Long-term Period: Number of Participants With Electrolyte Laboratories Meeting MA Criteria [ Time Frame: From Day 169 through Day 813, including up to 56 days after the last dose of long-term period abatacept ]

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14. Primary:

Long-term Period: Number of Participants With Other Chemistry and Urinalysis Laboratories Meeting MA Criteria [ Time Frame: From Day 169 through Day 813, including up to 56 days after the last dose of long-term period abatacept ]

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15. Primary:

Long-term Period: Change From Baseline in Hemoglobin (HGB), Total Protein, and Albumin Over Time [ Time Frame: BL, Day 365, Day 729 ]

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16. Primary:

Long-term Period: Change From Baseline in Hematocrit Over Time [ Time Frame: BL, Day 365, Day 729 ]

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17. Primary:

Long-term Period: Change From Baseline in Erythrocytes Over Time [ Time Frame: BL, Day 365, Day 729 ]

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18. Primary:

Long-term Period: Change From Baseline in Platelets (PLT) Over Time [ Time Frame: BL, Day 365, Day 729 ]

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19. Primary:

Long-term Period: Change From Baseline in White Blood Cells Over Time [ Time Frame: BL, Day 365, Day 729 ]

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20. Primary:

Long-term Period: Change From Baseline in Alkaline Phosphatase (ALP), Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT), and G-Glutamyl Transferase (GGT) Over Time [ Time Frame: BL, Day 365, Day 729 ]

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21. Primary:

Long-term Period: Change From Baseline in Bilirubin, Blood Urea Nitrogen (BUN), Creatinine, Calcium (Ca), Phosphorus (P), Serum Glucose (Glu), and Uric Acid Over Time [ Time Frame: BL, Day 365, Day 729 ]

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22. Primary:

LT; Change From Baseline in Sodium (Na), Potassium (K), Chloride (Cl) Over Time [ Time Frame: BL, Day 365, Day 729 ]

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23. Primary:

Long-term Period: Mean Sitting Systolic Blood Pressure (SBP) Over Time [ Time Frame: From Day 169 through Day 813, including up to 56 days after the last dose of long-term period abatacept ]

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24. Primary:

Long-term Period: Mean Sitting Diastolic Blood Pressure (DBP) Over Time [ Time Frame: From Day 169 through Day 813, including up to 56 days after the last dose of long-term period abatacept ]

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25. Primary:

Long-term Period: Mean Heart Rate (HR) Over Time [ Time Frame: From Day 169 through Day 813, including up to 56 days after the last dose of long-term period abatacept ]

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26. Primary:

Long-term Period: Mean Temperature (T) Over Time [ Time Frame: From Day 169 through Day 813, including up to 56 days after the last dose of long-term period abatacept ]

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27. Secondary:

Short-term Period: Number of Participants With Clinically Meaningful Improvement (CMI) in Disease Activity Score (DAS 28), Low Disease Activity (LDAS), or Remission at Day 169 [ Time Frame: BL, Day 169 ]

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28. Secondary:

Short-term Period: Mean Time-matched Baseline (Day 0) DAS 28 and DAS 28 for Post-Baseline Visits Through 6 Month Open-Label [ Time Frame: BL (Day 0), Day 15, Day 29, Day 57, Day 85, Day 113, Day 141, Day 169 ]

Show Outcome Measure 28

29. Secondary:

Short-term Period: Mean Time-matched Change From Baseline (Day 0) in DAS 28 Through 6 Month Open-Label [ Time Frame: BL (Day 0), Day 15, Day 29, Day 57, Day 85, Day 113, Day 141, Day 169 ]

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30. Secondary:

Short-term Period: Mean Change From Baseline to Day 169 in High Sensitivity C-Reactive Protein (Hs-CRP) [ Time Frame: BL, Day 169 ]

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31. Secondary:

Short-term Period: Mean Change From Baseline to Day 169 in Rheumatoid Factor (RF) [ Time Frame: BL, Day 169 ]

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32. Secondary:

Short-term Period: Mean Change From Baseline to Day 169 in the Health Assessment Questionnaire Disability Index (HAQ-DI) [ Time Frame: BL, Day 169 ]

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33. Secondary:

Short-term Period: Number of Participants Achieving a Clinically Meaningful HAQ Response [ Time Frame: BL, Day 169 ]

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34. Secondary:

Short-term Period: Mean Baseline Short Form 36 (SF-36) Quality of Life Physical Component Summary (PCS), Mental Component Summary (MCS), and SF-36 Individual Component Scores [ Time Frame: BL ]

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35. Secondary:

Short-term Period: Mean Change From Baseline to Day 169 in SF-36 PCS, MCS, and SF-36 Individual Component Scores [ Time Frame: BL, Day 169 ]

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36. Secondary:

Short-term Period: Mean Baseline Fatigue Visual Analog Scale (VAS) [ Time Frame: BL ]

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37. Secondary:

Short-term Period: Mean Change From Baseline to Day 169 in Fatigue Visual Analog Scale (VAS) [ Time Frame: BL, Day 169 ]

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38. Secondary:

Long-term Period: Number of Participants With Clinically Meaningful Improvement in DAS 28, Low Disease Activity, or Remission Over Time [ Time Frame: BL, Days 365, 449, 533, 617, 729, 813 ]

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39. Secondary:

Long-term Period: Mean Time-matched Baseline (Day 0) DAS 28 and DAS 28 for Post-Baseline Visits Over the Long Term [ Time Frame: BL (Day 0), Days 365, 449, 533, 617, 729, 813 ]

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40. Secondary:

Long-term Period: Mean Time-matched Change From Baseline (Day 0) in DAS 28 Over The Long Term [ Time Frame: BL (Day 0), Days 365, 449, 533, 617, 729, 813 ]

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41. Secondary:

Long-term Period: Mean Time-matched Baseline (Day 0) Number of Tender Joints and Number of Tender Joints for Post-Baseline Visits Over the Long Term [ Time Frame: BL (Day 0), Days 365, 449, 533, 617, 729, 813 ]

Show Outcome Measure 41

42. Secondary:

Long-term Period: Mean Time-matched Change From Baseline (Day 0) in Number of Tender Joints Over the Long Term [ Time Frame: BL (Day 0), Days 365, 449, 533, 617, 729, 813 ]

Show Outcome Measure 42

43. Secondary:

Long-term Period: Mean Time-matched Baseline (Day 0) Number of Swollen Joints And Post-Baseline Number of Swollen Joints Over the Long Term [ Time Frame: BL (Day 0), Days 365, 449, 533, 617, 729, 813 ]

Show Outcome Measure 43

44. Secondary:

Long-term Period: Mean Time-Matched Change From Baseline (Day 0) in Number of Swollen Joints Over the Long Term [ Time Frame: BL (Day 0), Days 365, 449, 533, 617, 729, 813 ]

Show Outcome Measure 44

45. Secondary:

Long-term Period: Mean Time-matched Baseline (Day 0) Hs-CRP Levels and Hs-CRP Levels for Post-Baseline Over the Long Term [ Time Frame: BL (Day 0), Days 365, 449, 533, 617, 729, 813 ]

Show Outcome Measure 45

46. Secondary:

Long-term Period: Mean Time-matched Change From Baseline (Day 0) in Hs-CRP Level Over the Long Term [ Time Frame: BL (Day 0), Days 365, 449, 533, 617, 729, 813 ]

Show Outcome Measure 46

47. Secondary:

Long-term Period: Mean Time-matched Baseline (Day 0) Visual Analog Scale (VAS) and VAS for Post-Baseline Visits Over the Long Term [ Time Frame: BL (Day 0), Days 365, 449, 533, 617, 729, 813 ]

Show Outcome Measure 47

48. Secondary:

Long-term Period: Mean Time-matched Change From Baseline (Day 0) in VAS Over the Long Term [ Time Frame: BL (Day 0), Days 365, 449, 533, 617, 729, 813 ]

Show Outcome Measure 48

49. Secondary:

Long-term Period: Mean Time-matched Baseline (Day 0) HAQ-DI and HAQ-DI Component Scores For Participant Cohorts at Each Corresponding Post-baseline Visit Over the Long Term [ Time Frame: BL (Day 0) ]

Show Outcome Measure 49

50. Secondary:

Long-term Period: Mean HAQ-DI and HAQ-DI Component Scores For Participant Cohorts at Post-baseline Visits Over the Long Term [ Time Frame: Days 365, 449, 533, 617, 729, 813 ]

Show Outcome Measure 50

51. Secondary:

Long-term Period: Mean Time-matched Change From Baseline (Day 0) in HAQ-DI and HAQ-DI Components For Participant Cohorts at Each Corresponding Post-baseline Visit Over the Long Term [ Time Frame: BL (Day 0), Days 365, 449, 533, 617, 729, 813 ]

Show Outcome Measure 51

52. Secondary:

Long-term Period: Number of Participants Achieving Clinically Meaningful HAQ Response Over Time [ Time Frame: BL, Days 365, 449, 533, 617, 729, 813 ]

Show Outcome Measure 52

53. Secondary:

Long-term Period: Mean Time-matched Baseline (Day 0) SF-36 PCS, MCS, and SF-36 Individual Component Scores For Participant Cohorts at Each Corresponding Post-baseline Visit Over the Long Term [ Time Frame: BL (Day 0) ]

Show Outcome Measure 53

54. Secondary:

Long-term Period: Mean SF-36 PCS, MCS, and SF-36 Individual Component Scores For Participant Cohorts at Each Post-baseline Visits Over the Long Term [ Time Frame: Days 365 and 729 ]

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55. Secondary:

Long-term Period: Mean Time-matched Change From Baseline (Day 0) in SF-36 PCS, MCS, and SF-36 Individual Component Scores For Participant Cohorts at Each Corresponding Post-baseline Visit Over the Long Term [ Time Frame: BL (Day 0), Days 365, 729 ]

Show Outcome Measure 55

56. Secondary:

LT; Number of Participants With Positive Anti-Abatacept or Anti-Cytotoxic T-Lymphocyte Antigen 4 (CTLA4) Responses by ELISA [ Time Frame: Days 1-813 ]

Show Outcome Measure 56

Serious Adverse Events

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Other Adverse Events

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More Information

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Certain Agreements:

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The agreement is:

	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description: Bristol-Myers Squibb Co. agreements with investigators vary; constant is our right to embargo communications regarding trial results prior to public release for a period ≤60 days from submittal for review. We will not prohibit investigators from publishing, but will prohibit the disclosure of previously undisclosed confidential information other than study results, and request postponement of single-center publications until after disclosure of the clinical trial's primary publication.

Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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Results Point of Contact:

Name/Title: BMS Study Director
Organization: Bristol-Myers Squibb
e-mail: Clinical.Trials@bms.com

Publications:

Schiff M, Pritchard C, Huffstutter JE, Rodriguez-Valverde V, Durez P, Zhou X, Li T, Bahrt K, Kelly S, Le Bars M, Genovese MC. The 6-month safety and efficacy of abatacept in patients with rheumatoid arthritis who underwent a washout after anti-tumour necrosis factor therapy or were directly switched to abatacept: the ARRIVE trial. Ann Rheum Dis. 2009 Nov;68(11):1708-14. Epub 2008 Dec 15.

Publications automatically indexed to this study:

Hassett AL, Li T, Buyske S, Savage SV, Gignac MA. The multi-faceted assessment of independence in patients with rheumatoid arthritis: preliminary validation from the ATTAIN study. Curr Med Res Opin. 2008 May;24(5):1443-53. Epub 2008 Apr 9.

Genovese MC, Schiff M, Luggen M, Becker JC, Aranda R, Teng J, Li T, Schmidely N, Le Bars M, Dougados M. Efficacy and safety of the selective co-stimulation modulator abatacept following 2 years of treatment in patients with rheumatoid arthritis and an inadequate response to anti-tumour necrosis factor therapy. Ann Rheum Dis. 2008 Apr;67(4):547-54. Epub 2007 Oct 5.

Responsible Party:	Bristol-Myers Squibb
ClinicalTrials.gov Identifier:	NCT00124982 History of Changes
Other Study ID Numbers:	IM101-064
Study First Received:	June 30, 2005
Results First Received:	February 18, 2011
Last Updated:	November 4, 2011
Health Authority:	United States: Food and Drug Administration