Efficacy and Safety Study of Abatacept to Treat Lupus Nephritis

Study Description

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Brief Summary:

The purpose of this study is to evaluate (Abatacept) for treatment of lupus nephritis when used on a background of Cellcept (mycophenolate) and prednisone (corticosteroids)

Condition or disease	Intervention/treatment	Phase
Lupus Nephritis	Biological: BMS-188667; Drug: Mycophenolate mofetil; Drug: Prednisone; Biological: Placebo matching with BMS-188667	Phase 3

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	695 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:	Treatment
Official Title:	A Phase 3 Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of BMS-188667 (Abatacept) or Placebo on a Background of Mycophenolate Mofetil and Corticosteroids in the Treatment of Subjects With Active Class III or IV Lupus Nephritis
Actual Study Start Date :	January 22, 2013
Actual Primary Completion Date :	November 21, 2016
Estimated Study Completion Date :	May 18, 2018

Arms and Interventions

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Arm	Intervention/treatment
Experimental: BMS-188667 + Mycophenolate mofetil + Prednisone; BMS-188667 30 mg/kg injection by intravenous on Days 1,15, 29, and 57, followed by a weight-tiered dose approximating 10mg/kg injection by intravenous every 4 weeks, Mycophenolate mofetil 1.5 g tablet by mouth and Prednisone up to 60 mg tablet by mouth Daily for 104 weeks	Biological: BMS-188667; Other Name: Abatacept Drug: Mycophenolate mofetil; Other Name: Cellcept Drug: Prednisone
Placebo Comparator: Placebo + Mycophenolate mofetil + Prednisone; Placebo matching with BMS-188667 injection by intravenous on Days 1,15, 29, and 57, followed by every 4 weeks, Mycophenolate mofetil 1.5 g tablet by mouth and Prednisone up to 60 mg tablet by mouth Daily for 104 Weeks	Drug: Mycophenolate mofetil; Other Name: Cellcept Drug: Prednisone Biological: Placebo matching with BMS-188667

Outcome Measures

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Primary Outcome Measures :

1. Percentage of Participants in Complete Renal Response of Lupus Glomerulonephritis at Day 365 of the Double-blind Period [ Time Frame: 365 days ]
   Number of participants achieving CR was divided by the total number of participants in that arm and expressed as a percentage. Complete Response (CR) defined as: eGFR is normal or no <85% of the baseline; eGFR based on mean creatinine value from day 358 and 365. Proteinuria: UPCR<0.5 mg/mg. Urine sediment: No cellular casts. Corticosteroid dose: Daily dose must be no >10 mg prednisone or equiv. for at least 28 days prior to assessment. Participants with >10mg/day prednisone or equivalent for non-renal disease within 28 days prior to day 365 will be imputed as having achieved CR if the following are true: Met all criteria for CR at day 337 and all criteria for CR except corticosteroid dose at day 365; Investigator confirms increase in steroid dose is not related to renal disease. Adjusted odds ratio is estimated from logistic regression model which includes treatment group, baseline ACEi/ARBs use (Yes/No), race (Asian/ Black/Caucasian/Other) and baseline UPCR as a continuous variable.

Secondary Outcome Measures :

1. Percentage of Nephrotic Participants in CR of Lupus Glomerulonephritis at Day 365 of the Double-blind Period [ Time Frame: 365 days ]
   Number of participants achieving CR was divided by total participants in that arm, expressed as a percentage. Nephrotic is defined as screening UPCR >=3.0 mg/mg (>=339mg/mmol). CR is defined the following criteria: eGFR is normal or no <85% of the baseline value; eGFR is based on mean creatinine value from day 358 and 365. Proteinuria: UPCR<0.5 mg/mg. Urine sediment: No cellular casts. Corticosteroid dose: Daily dose must be no >10 mg prednisone or equivalent for at least 28 days prior. Subjects with >10mg/day prednisone or equivalent for non-renal disease within 28 days prior to day 365 will be imputed as CR if the following are true: Met all criteria for CR at day 337 and all criteria for CR except corticosteroid dose at day 365; Investigator confirms increase in steroid dose is not related to renal disease. Adjusted odds ratio is estimated from logistic regression model which includes treatment group, baseline ACEi/ARBs use, race and baseline UPCR as a continuous variable.
2. Adjusted Mean Change From Baseline in UPCR at Day 365 of the Double-blind Period in Nephrotic Participants [ Time Frame: Baseline and Day 365 ]
   Adjusted Mean Change from Baseline in Urine protein/creatinine ratio (UPCR) at Day 365 of the double-blind period in nephrotic participants
3. Adjusted Mean Change From Baseline in UPCR at Day 365 of the Double-blind Period in Overall Population [ Time Frame: Day 1 and Day 365 ]
   Adjusted Mean Change from Baseline in Urine protein/creatinine ratio (UPCR) at Day 365 of the double-blind period in the overall population
4. Adjusted Mean Change From Baseline in Disease Activity as Measured by BILAG 2004 Over Time During Year 1 of the Double-blind Period [ Time Frame: Day 1 to Day 365 ]
   Adjusted mean change from baseline in British Isles Lupus Assessment Group (BILAG) score over time during Year 1 of the double-blind period based on a repeated measure mixed model and presented at each visit in the first 12-month of the double-blind period. BILAG index measures disease activity in different organs/systems separately. BILAG score is calculated for each of 9 systems depending on the clinical features present and whether they are new (4 points), worse (3 points), the same (2 points), improving (1 point) or not present (0 points) in the last 4 weeks compared with previously. BILAG "A" represents the presence of serious features of lupus. BILAG "B" represents more moderate features of the disease. BILAG "C" includes only mild symptomatic features. BILAG "D" represents prior activity with no current symptoms due to active lupus. BILAG "E" represents an organ that has never been involved. Overall BILAG score ranges from 0-108, with higher scores reflecting a worse outcome.
5. Number of Participants With Any Adverse Events (AEs) [ Time Frame: From Day 1 up to 56 days post last dose in Year 1 of the double-blind period ]
   All AEs were coded and grouped into preferred terms (PT) by system organ class (SOC), using the Medical Dictionary for Regulatory Activities (MedDRA, version 19.1). Investigators determined the intensity of each AE as mild, moderate, severe, or very severe and assessed the relationship to study drug.
6. Number of Participants With Ranked Outcome of CR, PR, and No Response Throughout the Double-blind Period [ Time Frame: Day 729 ]
   Complete renal response (CR): defined as meeting ALL of the following criteria: eGFR normal OR no less than 85% of the baseline value; Urine protein/creatinine ratio (UPCR) < 0.5; Urine sediment: No cellular casts; Daily corticosteroid dose must be no greater than 10 mg prednisone or equivalent for at least 28 days prior to assessment. Partial renal response (PR): defined as meeting ALL of the following criteria: Subject does not meet criteria for CR; eGFR no less than 85% of the lesser of the values at screening or randomization (Day 1); UPCR < 0.5 OR 50% reduced from baseline and < 1 if baseline value was < 3, OR 50% reduced from baseline and < 3 if baseline value was greater than or equal to 3; Urine sediment: no cellular casts; daily corticosteroid dose no greater than 10 mg/day prednisone or prednisone equivalent for at least 28 days prior to assessment No renal response (NR): defined as not meeting criteria for CR or PR or withdrawn
7. Median Time to Complete Response (CR) During the Double-blind Period in All Participants [ Time Frame: Day 729 ]
   The estimate of median time to Complete Response (CR) is based on Kaplan-Meier analysis. Complete renal response (CR): defined as meeting ALL of the following criteria: eGFR normal OR no less than 85% of the baseline value; Urine protein/creatinine ratio (UPCR) < 0.5; Urine sediment: No cellular casts; Daily corticosteroid dose must be no greater than 10 mg prednisone or equivalent for at least 28 days prior to assessment.
8. Median Time to Complete Response (CR) During the Double-blind Period in Nephrotic Participants [ Time Frame: Day 729 ]
   The estimate of median time to Complete Response (CR) in nephrotic participants is based on Kaplan-Meier analysis. Complete renal response (CR): defined as meeting ALL of the following criteria: eGFR normal OR no less than 85% of the baseline value; Urine protein/creatinine ratio (UPCR) < 0.5; Urine sediment: No cellular casts; Daily corticosteroid dose must be no greater than 10 mg prednisone or equivalent for at least 28 days prior to assessment.
9. Median Time to Partial Response (PR) During the Double-blind Period in All Participants [ Time Frame: Day 729 ]
   The estimate of median time to Partial Response (PR) is based on Kaplan-Meier analysis. Partial renal response (PR): defined as meeting ALL of the following criteria: Subject does not meet criteria for CR; eGFR no less than 85% of the lesser of the values at screening or randomization (Day 1); UPCR < 0.5 OR 50% reduced from baseline and < 1 if baseline value was < 3, OR 50% reduced from baseline and < 3 if baseline value was 3; Urine sediment: no cellular casts; daily corticosteroid dose no greater than 10 mg/day prednisone or prednisone equivalent for at least 28 days prior to assessment
10. Median Time to Partial Response (PR) During the Double-blind Period in Nephrotic Participants [ Time Frame: Day 729 ]
    The estimate of median time to Partial Response (PR) in nephrotic participants is based on Kaplan-Meier analysis. Partial renal response (PR): defined as meeting ALL of the following criteria: Subject does not meet criteria for CR; eGFR no less than 85% of the lesser of the values at screening or randomization (Day 1); UPCR < 0.5 OR 50% reduced from baseline and < 1 if baseline value was < 3, OR 50% reduced from baseline and < 3 if baseline value was 3; Urine sediment: no cellular casts; daily corticosteroid dose no greater than 10 mg/day prednisone or prednisone equivalent for at least 28 days prior to assessment
11. Adjusted Mean Change From Baseline in UPCR Over Time [ Time Frame: Day 729 ]
    A repeated measure mixed model that included the baseline UPCR value, randomization stratification factors, time, and time by treatment interaction as fixed effects and subject as a random effect was used.
12. Median Percent Change From Baseline in UPCR Over Time [ Time Frame: Day 729 ]
    A repeated measure mixed model that included the baseline UPCR value, randomization stratification factors, time, and time by treatment interaction as fixed effects and subject as a random effect was used.
13. Adjusted Mean Change From Baseline in eGFR Over Time [ Time Frame: Day 729 ]
    Estimated glomerular filtration rate(eGFR), will be calculated by the CKD-EPI formula shown below.50 eGFR is expressed as mL/min per 1.73m2. For the purpose of this study lower limit of normal eGFR is defined as 90mL/min per 1.73m2 eGFR = 141 X min (Scr/k, 1)α X max (Scr/k, 1)-1.209 X 0.993Age X (1.018 [if female]) X (1.159 [if black]) Where Scr is serum creatinine (mg/dL), k is 0.7 for females and 0.9 for males, α is -0.329 for females and -0.411 for males, min indicates the minimum of Scr/k or 1, and max indicates the maximum of Scr/k or 1, age in years.
14. Time to First Sustained Change to No Response During the Double-blind Period [ Time Frame: Day 729 ]
    Sustained response defined as response present at 2 consecutive visits approximately 4 weeks apart. No renal response (NR): defined as not meeting criteria for CR or PR or withdrawn
15. Number of Participants With Sustained Change From Higher Level of Response to no Response During the Double-blind Period [ Time Frame: Day 729 ]
    Sustained change to no response is defined as going from CR (or PR) to NR and remaining in NR for at least 2 consecutive visits; visits should be approximately 4 weeks apart. This analysis will be based on time from response CR (or PR) to the first visit in which the no response (NR) was achieved and sustained to the next visit.
16. Adjusted Mean Change From Baseline in Disease Activity as Measured by BILAG 2004 Over Time During the Double-blind Period [ Time Frame: Day 1 to Day 729 ]
    BILAG index measures and reports disease activity in different organs/systems separately. The BILAG score is calculated for each of nine systems depending on the clinical features present and whether they are new (4 points), worse (3 points), the same (2 points), improving (1 point) or not present (0 points) in the last 4 weeks compared with previously. A BILAG "A" represents the presence of one or more serious features of lupus. A BILAG "B" represents more moderate features of the disease. A BILAG "C" includes only mild symptomatic features. A BILAG "D" represents only prior activity with no current symptoms due to active lupus. A BILAG "E" represents an organ that has never been involved.
17. Cmin (ug/mL): Trough Level Serum Concentration of Abatacept Prior to the Administration of the IV Infusion [ Time Frame: Days 1 to 365 ]
    Trough level serum concentration of abatacept prior to the administration of the IV infusion on Days 1 to 365
18. Cmax: Maximum Observed Serum Concentration Following Subjects Receiving Active Abatacept IV [ Time Frame: at 1 hour post Day 1 dose and 30 minutes post Day 337 dose ]
    Cmax: Maximum observed serum concentration following subjects receiving active abatacept IV
19. AUC (TAU): Area Under the Serum Concentration Time Curve Over a Dosing Interval [ Time Frame: Days 337 to 365 ]
    AUC (TAU): Area under the serum concentration time curve over a dosing interval between Days 337 to 365.
20. Summary Statistics for Systolic Blood Pressure [ Time Frame: Day 1 to Day 729 ]
    Summary statistics for systolic blood pressure
21. Summary Statistics for Diastolic Blood Pressure [ Time Frame: Day 1 to Day 729 ]
    Summary statistics for diastolic blood pressure
22. Summary Statistics for Heart Rate [ Time Frame: Day 1 to Day 729 ]
    Summary statistics for Heart Rate
23. Mean Change From Baseline in Laboratory Analytes During the Double-blind Period [ Time Frame: Day 1 to Day 729 ]
    Laboratory assessments were analyzed centrally, with the exception of pregnancy testing. Blood draws and urine collections were performed at visits specified in the protocol.
24. Number of Participants With Marked Hematology Laboratory Abnormalities During the Double Blind Period [ Time Frame: Day 729 ]
    LLN= Lower limit of normals ULN= Upper limit of normals Pre RX = Baseline value HEMOGLOBIN g/L 4.0 HB >3 G/DL DECREASE FROM PRE RX HEMATOCRIT vol 6.3 HCT <0.75X PRE RX ERYTHROCYTES x10*12 c/L 5.2 RBC <0.75X PRE RX PLATELET COUNT x10*9 c/L 5.0 PLAT <0.67X LLN OR >1.5X ULN, OR IF PRE RX<LLN THEN USE 0.5X PRE RX AND <100,000/MM3 LEUKOCYTES x10*9 c/L 6.2 WBC <0.75X LLN OR >1.25X ULN, OR IF PRE RX<LLN THEN USE <0.8X PRE RX OR >ULN, OR IF PRE RX>ULN THEN USE >1.2X PRE RX OR <LLN EOSINOPHILS (ABSOLUTE) x10*9 c/L 8.3 EOSA IF VALUE > .750 X10*3 c/uL BASOPHILS (ABSOLUTE) x10*9 c/L 8.3 BASOA IF VALUE > 400/MM3 MONOCYTES (ABSOLUTE) x10*9 c/L 8.3 MONOA IF VALUE > 2000/MM3 LYMPHOCYTES (ABSOLUTE) x10*9 c/L 8.3 LYMPA IF VALUE < .750 X10*3 c/uL OR IF VALUE > 7.50 X10*3 c/uL
25. Number of Participants With Marked Liver and Kidney Function Laboratory Abnormalities During the Double Blind Period [ Time Frame: Day 729 ]
    LLN= Lower limit of normals ULN= Upper limit of normals Pre RX = Baseline value ALKALINE PHOSPHATASE (ALP) U/L 5.0 ALP >2X ULN, OR IF PRE RX>ULN THEN USE >3X PRE RX ASPARTATE AMINOTRANSFERASE (AST) U/L 5.0 AST >3X ULN, OR IF PRE RX>ULN THEN USE >4X PRE RX ALANINE AMINOTRANSFERASE (ALT) U/L 5.0 ALT >3X ULN, OR IF PRE RX>ULN THEN USE >4X PRE RX G-GLUTAMYL TRANSFERASE (GGT) U/L 5.0 GGT >2X ULN, OR IF PRE RX>ULN THEN USE >3X PRE RX BILIRUBIN, TOTAL umol/L 5.1 TBILI >2X ULN, OR IF PRE RX>ULN THEN USE >4X PRE RX BILIRUBIN, DIRECT umol/L 5.1 DBILI >1.5X ULN, OR IF PRE RX>ULN THEN USE >2X PRE RX BLOOD UREA NITROGEN mmol/L 5.1 BUN >2X PRE RX CREATININE umol/L 5.0 CREAT >1.5X PRE RX
26. Number of Participants With Marked Electrolyte Laboratory Abnormalities During the Double Blind Period [ Time Frame: Day 729 ]
    LLN= Lower limit of normals ULN= Upper limit of normals Pre RX = Baseline value SODIUM, SERUM mmol/L 4.0 NA <0.95X LLN OR >1.05X ULN, OR IF PRE RX<LLN THEN USE <0.95X PRE RX OR >ULN, OR IF PRE RX>ULN THEN USE >1.05X PRE RX OR <LLN POTASSIUM, SERUM mmol/L 4.1 K <0.9X LLN OR >1.1X ULN, OR IF PRE RX<LLN THEN USE <0.9X PRE RX OR >ULN, OR IF PRE RX>ULN THEN USE >1.1X PRE RX OR <LLN CHLORIDE, SERUM mmol/L 5.0 CL <0.9X LLN OR >1.1X ULN, OR IF PRE RX<LLN THEN USE <0.9X PRE RX OR >ULN, OR IF PRE RX>ULN THEN USE >1.1X PRE RX OR <LLN
27. Number of Participants With Marked Urinalysis Laboratory Abnormalities During the Double Blind Period [ Time Frame: Day 729 ]
    LLN= Lower limit of normals ULN= Upper limit of normals Pre RX = Baseline value PROTEIN, URINE Unknown UPRO IF MISSING PRE THEN USE >=2, OR IF VALUE >=4, OR IF PRE RX =0 OR 0.5 THEN USE >=2, OR IF PRE RX =1 THEN USE >=3, OR IF PRE RX =2 OR 3 THEN USE >=4 GLUCOSE, URINE N/A UGLU IF MISSING PRE THEN USE >=2, OR IF VALUE >=4, OR IF PRE RX =0 OR 0.5 THEN USE >=2, OR IF PRE RX =1 THEN USE >=3, OR IF PRE RX =2 OR 3 THEN USE >=4 BLOOD, URINE N/A UBLD IF MISSING PRE THEN USE >=2, OR IF VALUE >=4, OR IF PRE RX =0 OR 0.5 THEN USE >=2, OR IF PRE RX =1 THEN USE >=3, OR IF PRE RX =2 OR 3 THEN USE >=4 RBC, URINE hpf 5.0 URBC IF MISSING PRE THEN USE >=2, OR IF VALUE >=4, OR IF PRE RX =0 OR 0.5 THEN USE >=2, OR IF PRE RX =1 THEN USE >=3, OR IF PRE RX =2 OR 3 THEN USE >=4 WBC, URINE hpf 5.0 UWBC IF MISSING PRE THEN USE >=2, OR IF VALUE >=4, OR IF PRE RX =0 OR 0.5 THEN USE >=2, OR IF PRE RX =1 THEN USE >=3, OR IF PRE RX =2 OR 3 THEN USE >=4
28. Number of Participants With Other Marked Chemistry Laboratory Abnormalities During the Double Blind Period [ Time Frame: Day 729 ]
    LLN= Lower limit of normals ULN= Upper limit of normals Pre RX = Baseline value CALCIUM, TOTAL mmol/L 5.2 CA <0.8X LLN OR >1.2X ULN, OR IF PRE RX<LLN THEN USE <0.75X PRE RX OR >ULN, OR IF PRE RX>ULN THEN USE >1.25X PRE RX OR <LLN PHOSPHORUS, INORGANIC mmol/L 5.2 PHOS <0.75X LLN OR >1.25X ULN, OR IF PRE RX<LLN THEN USE <0.67X PRE RX OR >ULN GLUCOSE, SERUM mmol/L 4.1 GLUC <65 mg/dL, OR >220 mg/dL PROTEIN, TOTAL g/L 5.0 TPRO <0.9X LLN OR >1.1X ULN, OR IF PRE RX<LLN THEN USE 0.9X PRE RX OR >ULN, OR IF PRE RX>ULN THEN USE 1.1X PRE RX OR <LLN ALBUMIN g/L 3.0 ALB <0.9X LLN, OR IF PRE RX<LLN THEN USE <0.75X PRE RX CHOLESTEROL, TOTAL (TC) mmol/L 5.2 CHOL >2X PRE R

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

For additional information please contact the BMS Lupus Nephritis Clinical Trial Matching Service at 855-56-LUPUS. Please visit www.BMSStudyConnect.com for more information on clinical trial participation.

Note: Subjects > 16 are eligible for enrollment at selected centers

Inclusion Criteria:

• Potential subjects must have active lupus nephritis
• Biopsy within 12 months prior to screening visit indicating active Class 3 or 4 proliferative lupus glomerulonephritis (lupus effecting your kidney)
• Urine protein creatinine ratio (UPCR) ≥ 1 at Screening
• Serum creatinine ≤ 3 mg/dL (ie, ≤ 265 micromol/L)

• There must also be evidence of active disease within 3 months of Screening, based on at least one of the following:

  • Worsening of lupus nephritis OR
  • UPCR ≥ 3 at Screening OR
  • Active urine sediment OR
  • Biopsy within 3 months prior to screening visit indicating active Class 3 or Class 4 active proliferative lupus glomerulonephritis

Inclusion Criteria for the Long-Term Extension Period:

• Signed Written Informed Consent
• Subjects who achieve a complete or partial renal response after completing 2 years of double-blind treatment

Exclusion Criteria:

• Systemic Lupus Erythematosus (SLE) must be the primary/main autoimmune diagnosis
• Current symptoms of severe, progressive, or uncontrolled non-SLE related renal, hepatic, hematological, gastrointestinal, pulmonary, cardiac, neurological, or cerebral disease, or other concomitant medical conditions that, in the opinion of the Investigator, might place the subject at unacceptable risk for participation in this study
• Significant active Central nervous system (CNS) lupus with the exception of fatigue or mild stable cognitive
• Subjects who are diagnosed as end-stage renal disease or whose kidney damage is too significant and irreversible

Contacts and Locations

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Sponsors and Collaborators

Bristol-Myers Squibb

Investigators

Study Director:	Bristol-Myers Squibb	Bristol-Myers Squibb

More Information

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Additional Information:

BMS Clinical Trial Information 

FDA Safety Alerts and Recalls 

BMS Clinical Trial Patient Recruiting 

Investigator Inquiry Form 

Responsible Party:	Bristol-Myers Squibb
ClinicalTrials.gov Identifier:	NCT01714817 History of Changes
Other Study ID Numbers:	IM101-291; 2012-000714-11 ( EudraCT Number )
First Posted:	October 26, 2012
Results First Posted:	December 21, 2017
Last Update Posted:	April 2, 2018
Last Verified:	March 2018

Additional relevant MeSH terms:

Nephritis; Lupus Nephritis; Kidney Diseases; Urologic Diseases; Glomerulonephritis; Lupus Erythematosus, Systemic; Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases; Prednisone; Mycophenolic Acid; Abatacept; Anti-Inflammatory Agents; Glucocorticoids; Hormones

Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs; Antineoplastic Agents, Hormonal; Antineoplastic Agents; Antibiotics, Antineoplastic; Antibiotics, Antitubercular; Antitubercular Agents; Anti-Bacterial Agents; Anti-Infective Agents; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Immunosuppressive Agents; Immunologic Factors; Antirheumatic Agents