Clinical trial NCT02592798
Conditions: Nephrotic Syndrome Focal Segmental Glomerulosclerosis Minimal Change Disease
Sponsor: Bristol-Myers Squibb
Start date: 2016-03-09; Completion date: 2020-01-28
Enrollment: 36 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is evaluate if abatacept is effective and safe in decreasing the level of protein loss in the urine in patients with excessive loss of protein in the urine (nephrotic syndrome) due to either focal segmental glomerulosclerosis (FSGS) or minimal change disease (MCD). Candidates must have a prior kidney biopsy with either diagnosis. Another kidney biopsy will not be required as part of the study. Candidates must have failed or be intolerant of prior therapy for their kidney disease. The failed or intolerant therapy must include corticosteroids and at least one other drug. Candidates can be adults and children over the age of 6. Abatacept will be administered by venous infusion every 4 weeks.

Detailed description:

Arms: arm 1: * Double Blind Periods 1 and 2 (DB1 and DB2): Abatacept IV administered on Day 1, 15, 29 and then every 28 days until the end of the Double Blind Period.
* Open Label Period (OLE): Abatacept IV administered every 28 days arm 2: * Double Blind Periods 1 and 2 (DB1 and DB2): Normal Saline or Dextrose 5% in Water (D5W) administer on Day 1, 15, 29 and then every 28 days until the end of the Double Blind Period.
* Open Label Period (OLE): Abatacept IV administered every 28 days
Interventions: intervention 1: Abatacept intervention 2: Normal Saline intervention 3: D5W
Intervention descriptions: intervention 1: Abatacept IV administered on Day 1, 15, 29 and then every 28 days intervention 2: Normal Saline administer on Day 1, 15, 29 and then every 28 days intervention 3: Dextrose 5% in Water (D5W) administered on Day 1, 15, 29 and then every 28 days

Protocol documents:
Prot_000.pdf: 
Page:
1
Protocol Number:
IM101566
IND Number:
126,402
Ex-US
N/A
EUDRACT Number
2015-005450-36
Date:
05-Oct-2015
Revised Date:
18-Apr-2018
Clinical Protocol IM101566
A Phase II Randomized, Placebo-Controlled, Double-Blind, Parallel Arms, Pilot Study to 
Evaluate the Efficacy and Safety of Intravenous Abatacept in Treatment Resistant Nephrotic 
Syndrome (Focal Segmental Glomerulosclerosis/ Minimal Change Disease)
Revised Protocol Number: 02
Incorporates amendment(s): 02
Study Director/Medical Monitor
Michael Maldonado, MD
 
This document is the confidential and proprietary information of Bristol-Myers Squibb 
Company and its global affiliates (BMS). By reviewing this document, you agree to keep it 
confidential and to use and disclose it solely for the purpose of assessing whether your 
organization will participate in and/or the performance of the proposed BMS-sponsored 
study. Any permitted disclosures will be made only on a confidential "need to know" basis 
within your organization or to your independent ethics committee(s). Any other use, 
copying, disclosure or dissemination of this information is strictly prohibited unless 
expressly authorized in writing by BMS. Any supplemental information (eg, amendments) 
that may be added to this document is also confidential and proprietary to BMS and must 
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Date: 18-Apr-2018
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be kept in confidence in the same manner as the contents of this document. Any person 
who receives this document without due authorization from BMS is requested to return it 
to BMS or promptly destroy it. All other rights reserved. References to BMS in this 
protocol may apply to partners to which BMS has transferred obligations, eg, a Contract 
Research Organization (CRO).
Replace all previous version(s) of the protocol with this revised protocol and please provide a 
copy of this revised protocol to all study personnel under your supervision, and archive the 
previous versions.
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BMS-188667
abatacept
Revised Protocol No.: 02
Date: 18-Apr-2018
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DOCUMENT HISTORY
Document
Date of Issue
Summary of Change
Revised 
Protocol 02
18-Apr-2018
Incorporates Amendment 02.
Amendment 02
18-Apr-2018
Updated protocol title to delete “with Switchover.” Changed Period 1 to 
Double-Blind Period.  Added an option for early escape at Day 85 for 
pediatric subjects depending on investigator discretion (Day 57 UPCR 
>3 and assessment of clinical response). Deleted Period 2.  Replaced 
schematic with a new version reflecting the new study design.  Updated 
 efficacy assessments based on modification of 
the study design.  Deleted information on relapse.  Added adjustment of 
background treatment in the OLE.  Added treatment with systemic 
corticosteroids for adverse events limited to 2 weeks.  Added inhaled 
corticosteroids are permitted for the treatment of asthma, COPD, etc.  
Updated definition of serious breach. 
 
Revised 
Protocol 01
17-Apr-2017
Incorporates Amendment 01
Amendment 01
17-Apr-2017
Added EUDRACT number since the study is enrolling pediatric subjects.
Changed address and telephone for the Medical Monitor.  Changed 
address for Bristol Myers Squibb.  Decreased minimum eGFR at 
screening to 45 for subjects <18 years using the new Schwarz equation. 
Amended the Post Study Drug Access to indicate the post study drug will 
be available for subjects who demonstrate clinical benefit at the 
conclusion of the study.  Clarified description for treatment resistance 
and treatment intolerance.  Clarified language regarding treatment with 
an ACE or ARB.  Deleted detailed description on method of 
contraception from the body of the protocol and added Appendix 2.  
Updated numbering of other appendices.  Added exclusion for subjects 
who are post-renal transplantation, including relapsing post-transplant 
FSGS.  Clarified Restricted Treatment and Other Restrictions and 
Precautions.  Added the dose windows for Period 2.  Added sample 
collection for DNA and Additional Research.  Corrected to add CBC 
collection at Day 197 and Total Cholesterol and Triglycerides at Days 
169 and 197. Added pregnancy testing in open label.  Clarified exclusion 
criteria for BMI.
Original 
Protocol
05-Oct-2015
Not applicable
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Clinical Protocol
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BMS-188667
abatacept
SYNOPSIS
Clinical Protocol IM101566
Protocol Title: A Phase II Randomized, Placebo-Controlled, Double-Blind, Parallel Arms, Pilot Study to Evaluate 
the Efficacy and Safety of Intravenous Abatacept in Treatment Resistant Nephrotic Syndrome (Focal Segmental 
Glomerulosclerosis/ Minimal Change Disease).
Investigational Product(s), Dose and Mode of Administration, Duration of Treatment with Investigational 
Product(s): The study will utilize the IV abatacept formulation. Subjects randomized to abatacept treatment in the 
Double-Blind Period will be dosed as follows. Adults will use the weight-tiered dose: < 60 kg: 500 mg, 60 to 100 
kg: 750 mg, > 100 kg: 1000 mg; pediatric patients 6 to 17 years who weigh < 75 kg will receive:10 mg/kg and those 
who weigh 75 kg will follow adult dosing. 
Dosing is on Day 1, 15, 29 and then every 28 days for 113 days. Subject in the placebo arm will receive normal 
Saline or D5W following the same dosing schedule. In the open-label extension, subjects who enter will all receive 
age and weight-based IV abatacept every 28 days for 169 days.
Study Phase: II
Research Hypothesis: Subjects with treatment resistant nephrotic syndrome (TRNS) due to either focal segmental 
glomerulosclerosis (FSGS) or Minimal Change Disease (MCD) [TRNS (FSGS/MCD)] will demonstrate 
improvement in proteinuria when treated with abatacept.
Objectives:
Primary Objective: Demonstrate improvement in nephrotic range proteinuria to sub-nephrotic range while 
maintaining renal function following treatment with abatacept compared to placebo.

Demonstrate difference in percent of renal responders defined by composite renal index at Day 113.
Secondary Objectives:
1)
Assess improvement in change from baseline in the level of proteinuria following treatment with abatacept
compared to placebo.

Assess difference in mean change from baseline in UPCR at Day 113.
2)
Assess improvement in serum albumin levels following treatment with abatacept compared to placebo.

Assess difference in mean change from baseline in serum albumin at Day 113.
3)
Assess improvement in complete remission while maintaining renal function following treatment with abatacept 
compared to placebo.

Assess difference in percent of subjects achieving complete remission (UPCR 0.3) with preservation of 
eGFR at Day 113.
4)
Assess improvement in patient reported outcomes related to nephrotic syndrome.

Assess changes using the Patient Reported Outcomes Measurement Information System (PROMIS) at Day 
113.
5)
Assess the safety and immunogenicity of abatacept in subjects with TRNS.

Describe rates of AEs and SAEs and immunogenicity testing. 
6)
Assess the pharmacokinetics of abatacept in subjects with TRNS

Describe the pharmacokinetics of abatacept.
Study Design: This pilot study will randomize approximately 90 subjects 1:1 to intravenous (IV) abatacept or 
placebo in a double-blind (DB) fashion into a parallel arms. The trial will consist of 4 periods totaling ~17 months: 
the Screening Period will be 28 days (can be extended an additional 14 days to complete testing by repeating 
screening labs), a 16 week Double-Blind Treatment Period (parallel arms: IV abatacept vs placebo) with a possible 
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early escape at Day 85 for pediatric age subjects, a 168 day abatacept Open Label Extension Period (OLE), and a 6 
month Follow-up Period (see schematic).
Subjects will be recruited from approximately 25 sites in North America. Written informed consent will be provided 
by the subjects prior to undergoing any procedures during the screening phase. Randomization will be stratified by 
results of genotyping of APOL1 gene and age (< 18 and 18). 
The primary efficacy assessment, renal response, will be on Day 113 (end of the double-blind period). The rationale 
for allowing non-responders to enter the OLE and receive abatacept is to allow these non-responders who wish to 
determine if a longer exposure to abatacept with or without adjustment of background therapy could lead to a 
response, to do so. During the OLE the durability (ie, continuous response) and stability (ie, variability in the 
improvement in UPCR) of response will be determined by continuing to capture and describe the same study 
outcomes among responders. Adjustment of background therapy will also be allowed during the OLE at the 
discretion of the investigators and subjects to determine the relative contribution (or need) of these agents for renal 
responses.
Study Population: Subjects who enroll must meet the criteria for TRNS (FSGS/MCD). This includes the 
pathological findings of either FSGS (excluding collapsing FSGS, a sub-set of FSGS seen in both HIV and non-HIV 
infected subjects with a more severe presentation and poor prognosis) or MCD on the most recent renal biopsy. NS 
will be defined by a UPCR 3 (g/g or unitless). Subjects will need to have a minimal preserved renal function as 
measured by eGFR (45 for children and adults (mL/min/1.73m2) based on the CKD-EPI for adults and the new 
Schwartz equation for children). Treatment resistance will be defined as persistence of NS in spite of therapy with 
either corticosteroids (CS) or other accepted agents for the required period of time (listed in the inclusion criteria) or 
intolerance to any two of these agents. Subjects age 6 and older will be enrolled. Subjects receiving permitted 
background therapy at the time of enrollment may continue these as long as the dose has been stable for 4 weeks 
prior to randomization. Subjects will be required to use either an angiotensin-converting-enzyme inhibitor (ACEi) or 
an angiotensin receptor blocker (ARB) at stable doses during the course of the double-blind (DB) period unless 
intolerant. Management of hypertension and volume will follow standard of care. Subjects will be tested at 
screening for the SNPs associated with the high-risk APOL1 variants. Subjects will be allowed to opt-out of 
genotyping and still enroll. This will be used for stratification during randomization.
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Key Inclusion Criteria:

Male and female subjects ages 6 years

Subjects diagnosed with TRNS (FSGS/MCD)

Pathological findings of either FSGS (excluding collapsing FSGS) or MCD on the most recent renal biopsy 
(renal biopsies will not be part of this study). This will be confirmed by review of the pathology report 
(not slides) by a central pathologist

UPCR 3 at screening

Treatment resistant defined as:

Persistence of UPCR 3 in spite of therapy with any one of the following agents: corticosteroids (CS), 
calcineurin inhibitors (cyclosporine and tacrolimus), sirolimus, mycophenolate mofetil (MMF), 
mycophenolic acid (MPA) or cyclophosphamide

Duration of therapy: The duration of CS therapy required to determine treatment resistance will be 
6 weeks in subjects < 18 year of age and 12 weeks for subjects 18 years. For all other agents, the 
minimum duration of therapy will be 16 weeks, regardless of age

Intolerance to any two of these agents, regardless of duration of treatment or age

Subjects must be receiving either an angiotensin-converting-enzyme inhibitor (ACEi) or an angiotensin receptor 
blocker (ARB) at stable doses for at least 2 weeks prior to randomization unless intolerance is documented. 
Combined use of renin angiotensin system (RAS) inhibitors will not be allowed. If aldosterone inhibitors 
(spirolactone or eplerenone) or aliskiren (direct renin inhibitor) are used, they must also be at stable doses.

A minimal level of renal function at screening based on estimated glomerular filtration rate (eGFR) will be 
required (45 for both children and adults)

APOL1 Genotyping. Subjects will be genotyped for the APOL1 renal risk variants SNPs [Risk allele G1 
(rs73885319 and rs60910145) and risk allele G2 (rs71785313)]. Subjects with 2 copies of the high-risk APOL1
variants are in the APOL1 high-risk group which will be used for stratification at randomization. Genotyping 
during screening will not be necessary if results of previous testing are available. Subjects will be allowed to 
opt-out of genotyping for APOL1. Subjects who refuse genotyping will still be eligible to be randomized.

Concomitant medication. Subjects may enroll with or without the following background agents used to treat 
TRNS (FSGS/MCD): CS (low dose, prednisone or equivalent at doses 10 mg/day), calcineurin inhibitors 
(cyclosporine and tacrolimus), MMF or mycophenolic acid. Agents must be used at standard doses, must not 
have been started within 8 weeks of enrollment and must be stable for at least 4 weeks prior to randomization. 
No adjustment in doses of concomitant medications will be allowed during the double-blind period. Dose 
decrease or holds to address drug-related toxicity are allowed.
Key Exclusion Criteria:

Subjects with other causes of TRNS other than FSGS or MCD (eg, IgA nephropathy, obesity related 
glomerulopathy or membranous nephropathy)

Subjects with collapsing FSGS, also known as collapsing glomerulopathy

Subjects with systemic lupus erythematosus (SLE)

Subjects with diabetes mellitus, both type 1 and type 2

Subjects with clinically significant congestive heart failure (CHF; New York Heart Association [NYHA] 
Class III or Class IV)

Body mass index (BMI) > 40 for adults
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Study Drug: includes both Investigational [Medicinal] Products (IP/IMP) and Non-investigational 
[Medicinal] Products (Non-IP/Non-IMP) as listed:
Study Drug for IM101566
Medication 
Potency 
IP/Non-IP 
Intravenous Abatacept 
10 mg/kg
IP
Study Assessments: The primary outcome used will be a composite renal index which will be used to determine the 
rate of renal responders. Secondary endpoints will be determined by assessing complete remission (defined as 
UPCR 0.3 with preservation of eGFR), the change in patient reported outcomes (using PROMIS measures), 
change in height as determined by standard deviation score (HSDS; z-scores) for subjects < 18 years and laboratory 
assessments (serum albumin, serum total cholesterol and triglycerides). 
Statistical Considerations:
Sample Size: The study is planned to randomize 90 subjects to assess the primary endpoint of proportion subjects in 
Renal Response at Day 113 between the IV Abatacept and placebo arms. The randomization will be stratified by
Genotype (APOL1 high risk group vs Others) and Age (< 18 and 18).
Endpoints:
Primary Endpoint: The primary efficacy endpoint is the proportion of subjects in Renal Response at Day 113.
Secondary Efficacy Endpoint(s):

Mean change from baseline in UPCR at Day 113

Mean change from baseline in serum albumin at Day 113

Proportion of subjects achieving complete remission (UPCR 0.3 with eGFR: normal or 75% baseline 
if below normal at baseline) at Day 113

Mean change from baseline in PROMIS measures at Day 113
Safety Endpoints:

All adverse events (AEs, SAEs, AE leading to discontinuation, deaths)

AEs of interest (infections, malignancies, autoimmune disorders, infusional related reactions, renal-related 
events)

Laboratory test abnormalities
Immunogenicity Endpoint: Proportion of subjects with positive antibody response relative to baseline over time.
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Analyses:
Summary of Planned Efficacy Analyses
Measure of Interest
Analysis Method
Renal Response
Primary Analysis:
Using a logistic regression model that includes treatment arm, randomization stratification 
factor (Genotype, Age) and baseline UPCR as continuous variable and point estimate of 
adjusted ORs, corresponding 95% CI and p-value will be provided.
Differences in proportions: 
proportion of subjects 
achieving complete remission 
at Day 113
Secondary Efficacy Analysis:
Using a logistic regression model that includes treatment arm, stratification variables 
(Genotype and Age) and baseline UPCR as continuous variable and point estimate of 
adjusted ORs, corresponding 95% CI will be provided.
Difference in mean change 
from baseline in continuous 
endpoints (UPCR, Serum 
Albumin, 
 
Longitudinal (repeated measure) mixed model [including treatment group, baseline value of 
variable and randomization stratification factors (genotype and Age), time, and time by 
treatment interaction as fixed effects and subject as a random effect], adjusted mean, SE, 
95% CI for adjusted mean difference between treatment groups will be provided.
Safety Analyses
Significant physical examination findings, and clinical and laboratory test results will be listed. Summary statistics 
will be tabulated. Frequency distributions and individual listings of all adverse events will be generated. Changes 
from baseline in clinical laboratory test results will be summarized and listed. Frequencies of marked abnormal 
laboratory measures will also be provided. Safety analyses will be presented by treatment arms in the double-blind 
period.
Pharmacokinetic Analyses
Summary statistics will be tabulated by treatment for the pharmacokinetic parameters (Cmax, Tmax, and AUC) and 
by study days for Cmin. Geometric means and coefficients of variation will be presented for Cmin, Cmax, and 
AUC. Medians and ranges will be presented for Tmax.
 
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TABLE OF CONTENTS 
TITLE PAGE ................................................................................................................ 
DOCUMENT HISTORY .............................................................................................. 
SYNOPSIS .................................................................................................................... 
TABLE OF CONTENTS .............................................................................................. 
 
 
 
 
 
 
 
 
 
 
1.2 Research Hypothesis ......................................................................................... 
1.3 Objectives(s) ..................................................................................................... 
1.3.1 Primary Objectives .................................................................................. 
1.3.2 Secondary Objectives ............................................................................... 
 
 
1.5 Overall Risk/Benefit Assessment ..................................................................... 
2 ETHICAL CONSIDERATIONS ............................................................................... 
2.1 Good Clinical Practice ...................................................................................... 
2.2 Institutional Review Board/Independent Ethics Committee ............................. 
2.3 Informed Consent.............................................................................................. 
3 INVESTIGATIONAL PLAN .................................................................................... 
3.1 Study Design and Duration ............................................................................... 
3.1.1 Screening Period: .................................................................................... 
3.1.2 Double-Blind Period (Day 1 - Day 113): ................................................ 
3.1.3 Open Label Extension (Day 1 - Day 169): .............................................. 
3.1.4 Post-Treatment Follow-up Period ........................................................... 
3.2 Post Study Access to Therapy ........................................................................... 
3.3 Study Population ............................................................................................... 
3.3.1 Inclusion Criteria ..................................................................................... 
3.3.2 Exclusion Criteria .................................................................................... 
3.3.3 Women of Childbearing Potential ........................................................... 
 
 
 
 
 
 
 
 
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3.5 Discontinuation of Subjects following any Treatment with Study Drug .......... 
3.6 Post Study Drug Study Follow up .................................................................... 
3.6.1 Withdrawal of Consent ............................................................................ 
3.6.2 Lost to Follow-Up .................................................................................... 
4 STUDY DRUG .......................................................................................................... 
4.1 Investigational Product ..................................................................................... 
4.2 Non-investigational Product ............................................................................. 
4.3 Storage and Dispensing..................................................................................... 
4.4 Method of Assigning Subject Identification ..................................................... 
4.5 Selection and Timing of Dose for Each Subject ............................................... 
4.5.1 Abatacept Dosing ..................................................................................... 
4.5.1.1 Pediatric Subjects ........................................................................... 
4.5.1.2 Adult Subjects.................................................................................. 
4.5.2 Administration of Abatacept or Placebo .................................................. 
4.5.3 Dosing During the Open Label Extension ............................................... 
4.5.4 Dose Modifications .................................................................................. 
4.5.4.1 Dose Modifications in the Absence of Adverse Events ................... 
4.5.4.2 Dose Modifications Due to an Adverse Event ................................ 
4.6 Blinding/Unblinding ......................................................................................... 
4.7 Treatment Compliance ...................................................................................... 
4.8 Destruction of Study Drug ................................................................................ 
4.9 Return of Study Drug ........................................................................................ 
4.10 Retained Samples for Bioavailability/Bioequivalence ................................... 
5 STUDY ASSESSMENTS AND PROCEDURES ..................................................... 
5.1 Flow Chart/Time and Events Schedule ............................................................. 
5.1.1 Retesting During Screening or Lead-in Period ....................................... 
5.1.2 Study Materials ........................................................................................ 
5.2 Safety Assessments ........................................................................................... 
5.2.1 Imaging Assessment for the Study............................................................ 
5.2.2 Adverse Events of Special Interest ........................................................... 
5.2.3 Physical Examination .............................................................................. 
5.2.4 Chest X-ray .............................................................................................. 
5.2.5 Physical Measurements ........................................................................... 
5.2.6 Vital Signs ................................................................................................ 
5.2.7 Body Mass Index (BMI) ........................................................................... 
5.2.8 TB Screening ............................................................................................ 
5.2.9 Renal Biopsy History ............................................................................... 
5.2.10 Hospitalizations and Emergency Room (ER) Visits ............................... 
5.2.11 Laboratory Assessments ......................................................................... 
5.2.11.1 Hematology ................................................................................... 
5.2.11.2 Blood Chemistry............................................................................ 
5.2.11.3 Lipid Testing ................................................................................. 
5.2.11.4 Urinalysis ...................................................................................... 
5.2.11.5 Urine Testing ................................................................................ 
5.2.11.6 Estimated Glomerular Filtration Rate (eGFR) ............................. 
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5.2.11.7 Hepatitis Screening ....................................................................... 
5.2.11.8 Pregnancy Testing ........................................................................ 
5.2.11.9 HIV Testing ................................................................................... 
5.2.11.10 FSH Testing ................................................................................ 
5.2.11.11 Genetic Testing ........................................................................... 
 
5.3 Efficacy Assessments ........................................................................................ 
5.3.1 Primary Efficacy Assessment ................................................................... 
5.3.1.1 Renal Response ............................................................................... 
5.3.2 Secondary Efficacy Assessments .............................................................. 
5.3.2.1 Improvement in Proteinuria ............................................................ 
5.3.2.2 Improvement in Serum Albumin...................................................... 
5.3.2.3 Complete Remission ........................................................................ 
5.3.2.4 Patient Reported Outcomes Measurement Information System 
(PROMIS) ............................................................................................. 
 
 
 
5.4 Pharmacokinetic Assessments .......................................................................... 
5.4.1 Pharmacokinetic: Blood and Urine Sample Collection ........................... 
5.4.2 Pharmacokinetic Sample Processing, Labeling and Shipping ................ 
5.4.3 Pharmacokinetic Sample Analysis ........................................................... 
5.4.4 Pharmacokinetic Evaluation .................................................................... 
 
 
 
 
 
 
 
5.6 Outcomes Research Assessments ..................................................................... 
5.7 Other Assessments ............................................................................................ 
5.7.1 Immunogenicity Assessments ................................................................... 
5.7.2 Immunogenicity: Blood Sample Collection and Processing .................... 
5.7.3 Immunogenicity: Sample Analysis ........................................................... 
6 ADVERSE EVENTS ................................................................................................. 
6.1 Serious Adverse Events .................................................................................... 
6.1.1 Serious Adverse Event Collection and Reporting .................................... 
6.2 Nonserious Adverse Events .............................................................................. 
6.2.1 Nonserious Adverse Event Collection and Reporting .............................. 
6.3 Laboratory Test Result Abnormalities .............................................................. 
6.4 Pregnancy .......................................................................................................... 
6.5 Overdose ........................................................................................................... 
6.6 Potential Drug Induced Liver Injury (DILI) ..................................................... 
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6.7 Other Safety Considerations ............................................................................. 
7 DATA MONITORING COMMITTEE AND OTHER EXTERNAL COMMITTEES
................................................................................................................................. 
8 STATISTICAL CONSIDERATIONS....................................................................... 
8.1 Sample Size Determination ............................................................................... 
8.2 Populations for Analyses .................................................................................. 
8.3 Endpoints .......................................................................................................... 
8.3.1 Primary Endpoint(s) ................................................................................ 
8.3.2 Secondary Endpoint(s) ............................................................................. 
8.3.2.1 Secondary Efficacy Endpoints ........................................................ 
8.3.2.2 Safety Endpoints.............................................................................. 
8.3.2.3 Immunogenicity Endpoint ............................................................... 
 
8.4 Analyses ............................................................................................................ 
8.4.1 Demographics and Baseline Characteristics........................................... 
8.4.2 Efficacy Analyses ..................................................................................... 
8.4.2.1 Primary Efficacy Analysis: ............................................................. 
8.4.2.2 Secondary Efficacy Analyses .......................................................... 
8.4.3 Efficacy Analyses ..................................................................................... 
8.4.4 Safety Analyses......................................................................................... 
8.4.5 Pharmacokinetic Analyses ....................................................................... 
 
8.4.7 Outcomes Research Analyses .................................................................. 
8.5 Interim Analyses ............................................................................................... 
9 STUDY MANAGEMENT ........................................................................................ 
9.1 Compliance ....................................................................................................... 
9.1.1 Compliance with the Protocol and Protocol Revisions ........................... 
9.1.2 Monitoring ............................................................................................... 
9.1.2.1 Source Documentation .................................................................... 
9.1.3 Investigational Site Training.................................................................... 
9.2 Records ............................................................................................................. 
9.2.1 Records Retention .................................................................................... 
9.2.2 Study Drug Records ................................................................................. 
9.2.3 Case Report Forms .................................................................................. 
9.3 Clinical Study Report and Publications ............................................................ 
10 GLOSSARY OF TERMS ........................................................................................ 
11 LIST OF ABBREVIATIONS .................................................................................. 
 
APPENDIX 1 CENTRAL PATHOLOGY REVIEW .................................................. 
APPENDIX 2 METHODS OF CONTRACEPTION ................................................... 
APPENDIX 3 LABORATORY GUIDELINES: PATIENT STUDIES ...................... 
APPENDIX 4 PROMIS QUESTIONNAIRES (ADULT, PARENT PROXY, AND 
PEDIATRIC) .......................................................................................................... 
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1.2
Research Hypothesis 
Subjects with treatment resistant nephrotic syndrome (FSGS/MCD) will demonstrate 
improvement in proteinuria when treated with abatacept.
1.3
Objectives(s)
1.3.1
Primary Objectives
Demonstrate improvement in nephrotic range proteinuria to sub-nephrotic range while 
maintaining renal function following treatment with abatacept compared to placebo.

Demonstrate difference in percent of renal responders defined by composite renal index at 
Day 113.
1.3.2
Secondary Objectives
1) Assess improvement in change from baseline in the level of proteinuria following treatment 
with abatacept compared to placebo.

Assess difference in mean change from baseline in UPCR at Day 113.
2) Assess improvement in serum albumin levels following treatment with abatacept compared 
to placebo.

Assess difference in mean change from baseline in serum albumin at Day 113.
3) Assess improvement in complete remission while maintaining renal function following 
treatment with abatacept compared to placebo.

Assess difference in percent of subjects achieving complete remission (UPCR 0.3) with 
preservation of eGFR at Day 113.
4) Assess improvement in patient reported outcomes related to nephrotic syndrome at Day 113.

Assess changes using the Patient Reported Outcomes Measurement Information System 
(PROMIS) at Day 113.
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5) Assess the safety and immunogenicity of abatacept in subjects with TRNS.

Describe rates of AEs and SAEs and immunogenicity testing.
6) Assess the pharmacokinetics of abatacept in subjects with TRNS.

Describe the pharmacokinetics of abatacept.
 
 
 
 
 
 
 
 
 
1.5
Overall Risk/Benefit Assessment
Subjects with TRNS (FSGS/MCD) with nephrotic syndrome are at significant risk of multiple 
complications, including increased susceptibility to infection, end-stage renal disease (ESRD) 
and increased mortality. TRNS (FSGS/MCD) impacts both children and adults. Clinical care 
depends on both immunomodulatory and nonimmunologic therapy aimed at reducing 
proteinuria, although there is no clear standard of care.8
IV abatacept has been studied primarily in autoimmune or immune-mediated diseases including 
rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), systemic lupus erythematosus, 
including lupus nephritis, Crohn’s disease, ulcerative colitis, acute graft-versus-host disease 
prevention (aGVHD) and ANCA-associated vasculitis.22,33,34 The major identified risk of 
abatacept is an increased incidence of infections. Consistent with its mechanism of action, the 
abatacept RA program identified both non-serious and serious infections, mainly bacterial [upper 
respiratory infections (URI’s), pneumonias] and viral (herpes simplex), as occurring more 
frequently in abatacept-treated subjects. Despite this identified risk, the majority of infections 
presented typically, responded appropriately to treatment, and there did not appear to be a major 
difference in outcome between abatacept and placebo. The risk for serious infections did not 
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increase in the open-label periods with increasing exposure. Opportunistic infections and 
tuberculosis (TB) were uncommon, although all subjects were screened for latent TB. The 
overall risk of malignancy for abatacept-treated subjects was comparable with placebo-treated 
subjects during the double-blind periods. The incidence of malignancy did not appear to be 
greater with increased exposure. An important caution is that the clinical studies contain neither 
sufficient numbers of subjects nor follow up of sufficient duration to assess long term treatment 
or to rule out increases in the risk of AEs with long latency, such as malignancy. Treatment with 
abatacept was associated with an excellent peri-infusional safety profile, no increased risk of 
autoimmunity, and was associated with a low level of immunogenicity which is not dependent
on use of concomitant therapy.
A significant co-factor in assessing the risk of therapy with IV abatacept is the use of 
concomitant therapies that also have immunomodulatory properties as they can contribute 
significantly to the risk of infections. Abatacept has been studied across multiple disease states 
with a wide variety of these agents including MMF, methotrexate and corticosteroids, both high 
and low doses, but rarely with calcineurin inhibitors (cyclosporine and tacrolimus).22,35,33,36,37
The potential risk of combining these agents can by mitigated by limiting which agents can be 
used concurrently, discontinuation prior to study entry or minimizing dosages.
There is more extensive experience in the use of IV abatacept in subjects age 18 and older. Most 
experience in the use of IV abatacept in younger subjects comes from subjects with JIA.22
Additional experience has been reported from both controlled studies and case series in other 
disease states including Type 1 diabetes, systemic onset JIA (soJIA), lupus nephritis, aGVHD 
and uveitis (refractory JIA-related and idiopathic).38,35,33,24,39,40 Most of this reported experience 
has been with the use of IV abatacept at the dose of 10 mg/kg every 28 days. One case series 
used higher doses of abatacept of up to 18 mg/kg in subjects with active soJIA with no 
associated safety signal.35 Clinical development of IV abatacept has been limited to age 6 and 
older due to immune system abnormalities seen in studies in juvenile rats exposed to abatacept 
and the unknown impact it may have on the developing human immune systems.22
The pharmacokinetic (PK) profile of IV abatacept in subjects with lupus nephritis with and 
without nephrotic syndrome has been studied.22 The presence of nephrotic range proteinuria can 
impact multiple PK parameters including decreasing the area under the concentration-time curve 
for a dosing interval [AUC(TAU)] and trough concentration (Cmin). These impacts were seen at 
both IV abatacept doses studied (30 mg/kg and ~10 mg/kg). More robust improvements in 
proteinuria were seen in abatacept dose groups, including the ~10 mg/kg dose, compared to 
placebo for subjects with baseline nephrotic range proteinuria (UPCR 3). Based on case reports 
and the more robust available clinical experience, especially in subjects age 17 and younger, the 
~10 mg/kg dose of abatacept seems the most appropriate initial dose to examine the safety and 
efficacy of IV abatacept in this mixed age population of subjects with TRNS (FSGS/MCD).
Abatacept is classified as a Pregnancy Category C with no adequate and well-controlled studies 
of ORENCIA use in pregnant women. There have been over 200 reports of abatacept exposure 
during pregnancy, both maternal and paternal.22 Impact on nursing mothers and infants is very 
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limited but there is theoretic concern with maternal-infant transmission which could impact live 
vaccination adversely. Women of childbearing potential will be required to practice effective 
contraception and undergo pregnancy testing throughout the study.
It is not known if all or even some of the subjects with TRNS (FSGS/MCD) who may respond to 
abatacept will require ongoing therapy to maintain the clinical response.
As an initial controlled study in a new disease state, a Data Monitoring Committee (DMC) will 
be created to provide oversight of safety and efficacy considerations in this study. The DMC will 
provide advice to BMS regarding actions the committee deems necessary for the continuing 
protection of subjects enrolled in the study. The DMC is charged with assessing such actions in 
light of an acceptable benefit/risk profile for abatacept. The creation of a DMC will help mitigate 
the risk associated with this pilot study.
Preclinical work and case reports suggest that a subset of patients with TRNS (FSGS/MCD) may 
benefit from treatment with IV abatacept. This subset includes both pediatric and adult age 
subjects. A greater safety experience in subjects age 17 and younger and the observed benefits on 
nephrotic range proteinuria in subjects with either active lupus nephritis or TRNS (FSGS/MCD) 
justifies the initial study of the approximately 10 mg/kg dose of IV abatacept in this pilot study 
in subjects with TRNS (FSGS/MCD). The risk associated with the use of abatacept, with or 
without concomitant immunomodulatory therapy, is acceptable for this group of subjects with 
high morbidity and risk of ESRD.
2
ETHICAL CONSIDERATIONS
2.1
Good Clinical Practice
This study will be conducted in accordance with Good Clinical Practice (GCP), as defined by the 
International Conference on Harmonisation (ICH) and in accordance with the ethical principles 
underlying European Union Directive 2001/20/EC and the United States Code of Federal 
Regulations, Title 21, Part 50 (21CFR50).
The study will be conducted in compliance with the protocol. The protocol and any amendments 
and the subject informed consent will receive Institutional Review Board/Independent Ethics 
Committee (IRB/IEC) approval/favorable opinion prior to initiation of the study.
All potential serious breaches must be reported to BMS immediately. A serious breach is a 
breach of the conditions and principles of Good Clinical Practice (GCP) (occurring in any 
country) in connection with the study or the protocol, which is likely to affect, to a significant 
degree, the safety or physical or mental integrity of 1 or more subjects of the study or the 
scientific value of the study.
Personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective tasks.
This study will not use the services of study personnel where sanctions have been invoked or 
where there has been scientific misconduct or fraud (eg, loss of medical licensure, debarment).
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2.2
Institutional Review Board/Independent Ethics Committee 
Before study initiation, the investigator must have written and dated approval/favorable opinion 
from the IRB/IEC for the protocol, consent form, subject recruitment materials 
(eg, advertisements), and any other written information to be provided to subjects. The 
investigator or BMS should also provide the IRB/IEC with a copy of the Investigator Brochure 
or product labeling information to be provided to subjects and any updates. 
The investigator or BMS should provide the IRB/IEC with reports, updates and other 
information (eg, expedited safety reports, amendments, and administrative letters) according to 
regulatory requirements or institution procedures.
2.3
Informed Consent
Investigators must ensure that subjects are clearly and fully informed about the purpose, potential 
risks, and other critical issues regarding clinical studies in which they volunteer to participate.
In situations where consent cannot be given to subjects, their legally acceptable representatives
(as per country guidelines) are clearly and fully informed about the purpose, potential risks, and 
other critical issues regarding clinical studies in which the subject volunteers to participate.
BMS will provide the investigator with an appropriate (ie, Global or Local) sample informed 
consent form which will include all elements required by ICH, GCP and applicable regulatory 
requirements. The sample informed consent form will adhere to the ethical principles that have 
their origin in the Declaration of Helsinki.
Investigators must:
1) Provide a copy of the consent form and written information about the study in the language 
in which the subject is most proficient prior to clinical study participation. The language 
must be non-technical and easily understood.
2) Allow time necessary for subject or subject’s legally acceptable representative to inquire 
about the details of the study.
3) Obtain an informed consent signed and personally dated by the subject or the subject’s 
legally acceptable representative and by the person who conducted the informed consent 
discussion.
4) Obtain the IRB/IEC’s written approval/favorable opinion of the written informed consent 
form and any other information to be provided to the subjects, prior to the beginning of the 
study, and after any revisions are completed for new information.
5) If informed consent is initially given by a subject’s legally acceptable representative or legal 
guardian, and the subject subsequently becomes capable of making and communicating his 
or her informed consent during the study, consent must additionally be obtained from the 
subject.
6) Revise the informed consent whenever important new information becomes available that is 
relevant to the subject’s consent. The investigator, or a person designated by the investigator, 
should fully inform the subject or the subject’s legally acceptable representative or legal 
guardian, of all pertinent aspects of the study and of any new information relevant to the 
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subject’s willingness to continue participation in the study. This communication should be 
documented.
The confidentiality of records that could identify subjects must be protected, respecting the 
privacy and confidentiality rules applicable to regulatory requirements, the subjects’ signed ICF 
and, in the US, the subjects’ signed HIPAA Authorization.
The consent form must also include a statement that BMS and regulatory authorities have direct 
access to subject records.
For minors, according to local legislation, one or both parents or a legally acceptable 
representative must be informed of the study procedures and must sign the informed consent 
form approved for the study prior to clinical study participation. The explicit wish of a minor,
who is capable of forming an opinion and assessing this information to refuse participation in, or 
to be withdrawn from, the clinical study at any time should be considered by the investigator. 
Minors who are judged to be of an age of reason must also give their written assent.
The rights, safety, and well-being of the study subjects are the most important considerations and 
should prevail over interests of science and society.
3
INVESTIGATIONAL PLAN
3.1
Study Design and Duration
The study will randomize approximately 90 subjects 1:1 to intravenous (IV) abatacept or placebo 
in a double-blind (DB) fashion into parallel arms. The trial will consist of 4 periods totaling ~17
months: the Screening Period will be 28 days (can be extended an additional 14 days to complete 
testing by repeating screening labs), a 16 week Double-Blind Treatment Period (parallel arms: 
IV abatacept vs placebo), a 168 day abatacept Open Label Extension Period (OLE), and a 6 
month Follow-up Period (see schematic). The primary efficacy assessment, renal response, will 
be on Day 113. This treatment time is based on case reports which suggest that subjects that 
respond to abatacept will do so in this time frame.11,12 On Day 113, all subjects who choose to
receive open label therapy with abatacept will enter the OLE.  The rationale for allowing non-
responders to enter the OLE and receive abatacept is to allow these non-responders who wish to 
determine if a longer exposure to abatacept with or without adjustment of background therapy 
could lead to a response, to do so. During the OLE the durability (ie, continuous response) and 
stability (ie, variability in the improvement in UPCR) of response will be determined by 
continuing to capture and describe the same study outcomes among responders. Adjustment of 
background therapy will also be allowed during the OLE at the discretion of the investigators 
and subjects to determine the relative contribution (or need) of these agents for renal responses.
The main purpose of the study is to decrease the level of proteinuria from a nephrotic range to a 
sub-nephrotic range in subjects with TRNS (FSGS/MCD). The endpoint used will capture a 
change in proteinuria that is clinically relevant without an associated negative impact on renal 
function [ie, change in estimated glomerular filtration rate (eGFR)] and which accounts for 
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varying degrees of baseline proteinuria.41,42 The primary outcome used will be a composite renal 
index which will be used to determine the rate of renal responders. Renal responders are defined 
as subjects who achieve a reduction of their baseline UPCR of 50% and to less than 3 with no 
worsening of baseline estimated glomerular filtration rate (eGFR: normal or 75% baseline if 
below normal at baseline). Secondary and exploratory endpoints will assess associated features 
of nephrotic syndrome and demonstrate improvements that support the primary endpoint. These 
will include complete remission (UPCR 0.3 with preservation of eGFR: normal or 75% 
baseline if below normal at baseline), patient reported outcomes (PROMIS measures), change in 
height as determined by standard deviation score (HSDS; z-scores) for subjects < 18 years and 
laboratory assessments (UPCR, serum albumin, serum total cholesterol and triglycerides).43,44,45
46
Subjects who enroll must meet the criteria for TRNS (FSGS/MCD). This includes the 
pathological findings of either FSGS (excluding collapsing FSGS, a sub-set of FSGS seen in 
both HIV and non-HIV infected subjects with a more severe presentation and poor prognosis) or 
MCD on the most recent renal biopsy (renal biopsies will not be performed as part of this study). 
This will be confirmed by review of the pathology report (not renal biopsy slides) by a central 
pathologist. 
NS will be defined by a UPCR 3 (g/g or unitless). Subjects will need to have a minimal 
preserved renal function as measured by eGFR (45 for children and adults (mL/min/1.73 m2) 
based on the CKD-EPI for adults and the new Schwartz equation for children).47,48
Treatment resistance will be defined as persistence of NS in spite of therapy with either CS or 
other accepted agents for the required period of time (listed in the inclusion criteria) or 
intolerance to any 2 of these agents. 
Subjects age 6 and older will be enrolled. While there are some differences in clinical 
characteristics and disease course between children and adults with TRNS (FSGS/MCD), the 
overall disease course and response to therapy is sufficiently similar so as to justify their 
inclusion in the same study that will test the same intervention (use of abatacept) with the same 
primary outcome (Renal Response).42,46 There is the option for an early escape on Day 85 only 
for pediatric age (18 years) as described below. Subjects receiving permitted background 
therapy at the time of enrollment may continue these as long as the dose has been stable for 4 
weeks prior to randomization. Subjects will be required to use either an angiotensin-converting-
enzyme inhibitor (ACEi) or an angiotensin receptor blocker (ARB) at stable doses during the 
course of the Double Blind period unless intolerant. Management of hypertension and volume 
will follow standard of care. All subjects will be asked, but not required, to be tested at screening 
for the SNPs associated with the high-risk APOL1 variants.7 The results will be used for 
stratification at randomization.
The study will utilize the IV abatacept formulation with doses previously established in studies 
with adults with RA and in pediatric patients with juvenile idiopathic arthritis and included in the 
current US Prescribing Information.2 Abatacept serum trough levels in subjects with nephrotic 
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syndrome due to lupus nephritis are lower than in non-nephrotic subjects receiving either the 
~10 mg/kg or ~30 mg/kg dose.24 Clinical efficacy was still seen in subjects with lupus nephritis 
at the ~10 mg/kg dosing level.13 Case reports demonstrating benefit in patients with TRNS 
(FSGS/MCD) was also reported at this dosing level.11,12 There is no clinical trial experience with 
IV abatacept doses of ~30 mg/kg in subjects less than 18 years of age. Therefore, a risk-benefit 
assessment suggests that the initial study including both pediatric and adult age subjects should 
be conducted at this dose level for which there is the most clinical experience, including safety 
data, in both age groups.
The study design schematic is presented in Figure 3.1-1.
Figure 3.1-1:
Study Design Schematic
3.1.1
Screening Period: 
Eligibility will be based on specified inclusion and exclusion criteria, medical history, disease 
activity and safety assessments. Randomization should occur within 28 days of signing the 
informed consent. This may be extended to 42 days to allow for screening results (eg, TB,
APOL1 SNP, UPCR and eGFR).
3.1.2
Double-Blind Period (Day 1 - Day 113):
On Day 1, subjects will be randomized to one of two blinded parallel treatment arms in a 
1:1 ratio:
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Abatacept IV
adults use weight-tiered dose:
< 60 kg: 
500 mg
60 to 100 kg: 
750 mg
> 100 kg: 
1000 mg
pediatric patients 6 to 17 years: 
< 75 kg: 10 mg/kg
75 kg follow adult dosing.
Placebo (Normal Saline or D5W following the same dosing schedule).
Dosing is on Day 1, 15, 29, and then every 28 days.
The duration of the Double-Blind Period is 113 days.
There is an option to Early Escape into the OLE on Day 85 for pediatric age subjects only (< 18 
years of age at randomization). The decision to Early Escape will be based on the Day 57 UPCR 
(> 3) and the assessment of clinical status on Day 85. If at the discretion of the investigator, in 
consultation with the subject (and their guardians), it is decided that the subject’s clinical status 
has worsened or not improved sufficiently based on both of these criteria, the Day 85 visit may 
be skipped. The subject would complete the Double-Blind Period Early Termination visit (Table 
5.1-2). The decision will then be made to either proceed to the OLE Day 1 visit (Table 5.1-3) or 
the Follow-up Visits (Table 5.1-4).
3.1.3
Open Label Extension (Day 1 - Day 169):
At the end of the Double Blind, there will be a 169 day open label extension (OLE). Subjects 
may enter this extension in 2 different manners. Subjects who reach the end of Double Blind will 
be able to volunteer to enter the OLE at the discretion of the investigators. Pediatric age subjects 
(6 to 17 years) who choose to Early Escape may then choose to enter the OLE.  This includes 
both responder and non-responders who wish to determine if a longer exposure to abatacept 
could lead to a response. Abatacept will be administered every 28 days starting on Day 1 of the 
OLE (Day 1 of the OLE will be Day 113 of the Double Blind Treatment Period), without a 
loading dose. Adjustment in background therapy is allowed but limited. This includes increases 
or decreases in doses, including discontinuation, or change from one permitted agent to another 
(3.4.1.2, Restricted Treatments During Double-Blind).
Subjects who do not wish to enter the OLE should receive appropriate standard of care following 
discontinuation of study drug.
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3.1.4
Post-Treatment Follow-up Period 
Subjects who discontinue treatment of study drug or complete the study and do not transition to 
commercial abatacept will have three follow-up visits over the 168 day Follow-up Period, to 
perform safety and laboratory assessments. 
Treatment codes will be provided to the investigators after completion of the study.
The start of the trial is defined as the date the first subject signs the informed consent. End of 
trial is defined as the last visit or scheduled procedure shown in the Time & Events schedule for 
the last subject. The study will continue beyond primary endpoint collection until the End of 
Trial.
3.2
Post Study Access to Therapy
At the conclusion of the study, participants who continue to demonstrate clinical benefit will be 
eligible to receive BMS supplied study treatment. Study treatment will be provided via an 
extension of the study, a rollover study requiring approval by responsible health authority and 
ethics committee or through another mechanism at the discretion of BMS. BMS reserves the 
right to terminate access to BMS supplied study treatment if any of the following occur: a) the 
study is terminated due to safety concerns; b) the development of abatacept for this indication is 
terminated for other reasons, including but not limited to lack of efficacy and/or not meeting the 
study objectives; c) the participant can obtain medication from a government sponsored or 
private health program. In all cases BMS will follow local regulation. 
3.3
Study Population
For entry into the study, the following criteria MUST be met.
3.3.1
Inclusion Criteria
1. Signed Written Informed Consent
a) Prior to study participation, written informed consent from subjects, or in the case of 
minors (< 18 years), written permission (informed consent) from parents, guardians, or 
legally acceptable representatives must be obtained according to local laws and 
regulations.
b) Assent from minor subjects should be obtained per local requirements.
2. Target Population
a) Subjects diagnosed with TRNS (FSGS/MCD).
i)
Pathological findings of either FSGS (excluding collapsing FSGS) or MCD on the 
most recent renal biopsy (renal biopsies will not be part of this study). This will be 
confirmed by review of the pathology report (not slides) by a central pathologist. The 
criteria for pathology review are in Appendix 1.
ii) UPCR 3 at screening.
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iii) Treatment Resistant or Treatment Intolerant
(1) Treatment resistant is defined as persistence of UPCR 3 in spite of therapy with 
any one of the following agents: corticosteroids (CS), calcineurin inhibitors 
(cyclosporine and tacrolimus), sirolimus, mycophenolate mofetil (MMF), 
mycophenolic acid (MPA), or cyclophosphamide. 
(a) Duration of therapy: The duration of CS therapy required to determine 
treatment resistance will be 6 weeks in subjects < 18 year of age and 12 weeks 
for subjects 18 years. For all other agents, the minimum duration of therapy 
will be 16 weeks, regardless of age.
(2) Intolerance to any 2 of these agents, regardless of duration of treatment or age.
b) Subjects must be receiving either an angiotensin-converting-enzyme inhibitor (ACEi) or 
an angiotensin receptor blocker (ARB) or have intolerance documented in the source 
documents maintained at the site.  If a subject is currently receiving an ACEi or ARB, the 
dose must be stable for at least 2 weeks, prior to randomization.  Combined use of renin-
angiotensin system (RAS) inhibitors will not be allowed. If aldosterone inhibitors 
(spirolactone or eplerenone) or aliskiren (direct renin inhibitor) are used, they must also 
be at stable doses.
c) A minimal level of renal function at screening based on estimated glomerular filtration 
rate (eGFR) will be required.
i)
45 for subjects < 18 years (new Schwartz equation).48
ii) 45 for subjects 18 years (CKD-EPI equation).47
d) APOL1 genotyping: Subjects will be genotyped for the APOL1 renal risk variants SNPs
[Risk allele G1 (rs73885319 and rs60910145) and risk allele G2 (rs71785313)]. Subjects 
with 2 copies of the high-risk APOL1 variants are in the APOL1 high-risk group which 
will be used for stratification at randomization. Genotyping during screening will not be 
necessary if results of previous testing are available. Subjects will be allowed to opt-out 
of genotyping for APOL1. Subjects who refuse genotyping will still be eligible to be 
randomized.
e) Concomitant Medication:
i)
Subjects may enroll with or without the following background agents used to treat 
TRNS (FSGS/MCD): 
(1) CS (low dose, prednisone or equivalent at doses 10 mg/day)
(2) calcineurin inhibitors (cyclosporine and tacrolimus)
(3) MMF
(4) MPA
ii) Agents must be used at standard doses, must not have been started within 8 weeks of 
enrollment 
iii) Agents must be stable for at least 4 weeks prior to randomization. 
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iv) No adjustment in doses of concomitant medications will be allowed during the 
double-blind period other than for dose reductions or holds to address drug-related 
toxicity.
f)
Subjects who had previously been treated with rituximab are allowed in the study if use 
had occurred more than 6 months prior to randomization and there are laboratory results 
indicating the presence of circulating B cells (CD19+).
g) Hypertension must be controlled and stable. Hypertension control is defined as a blood 
pressure (BP) 140/90 for subjects 18 years of age and < 95th percentile for subjects 
< 18 year of age by gender, age and height percentile.49
h) Changes in diuretic use should be avoided prior to the Day 113 assessment unless 
necessary to manage an adverse event.
i)
Treatment 
to 
manage 
dyslipidemia 
is 
allowed. 
HMG 
CoA 
reductase 
(hydroxymethylglutaryl CoA reductase) inhibitors or statins use must be stable 2 weeks 
prior to randomization and throughout the treatment periods.
j)
Subject Re-enrollment: This study permits the re-enrollment of a subject that has 
discontinued the study as a pre-treatment failure (ie, subject has not been randomized / 
has not been treated). If re-enrolled, the subject must be re-consented.
3. Age and Reproductive Status
a) Males and Females, ages 6 years.
b) Women of childbearing potential (WOCBP) must have a negative serum or urine 
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 
24 hours prior to the start of study drug.
c) Women must not be breastfeeding
d) Women of childbearing potential (WOCBP) must agree to follow instructions for 
method(s) of contraception for the duration of treatment
with study drug
(abatacept/placebo) plus 5 half-lives (70 days) plus 30 days (duration of ovulatory cycle) 
for a total of 100 days post-treatment completion.
e) Females who are not of childbearing potential must have documented proof that they are 
not of childbearing potential (eg, not experienced menarche, surgically sterile).
f)
Males who are sexually active with WOCBP must agree to follow instructions for 
method(s) of contraception for the duration of treatment with study drug
(abatacept/placebo) plus 5 half-lives of the study drug (70 days) plus 90 days (duration of 
sperm turnover) for a total of 160 days post-treatment completion. In addition, male 
subjects must be willing to refrain from sperm donation during this time. 
g) Azoospermic males are exempt from contraceptive requirements. WOCBP who are 
continuously not heterosexually active are also exempt from contraceptive requirements 
and still must undergo pregnancy testing as described in this section.
Investigators shall counsel WOCBP, and male subjects who are sexually active with WOCBP,
on the importance of pregnancy prevention and the implications of an unexpected pregnancy.
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Investigators shall advise on the use of highly effective methods of contraception (Appendix 2)
which have a failure rate of < 1% when used consistently and correctly.
3.3.2
Exclusion Criteria
1. Target Disease Exceptions
a) Subjects with other causes of TRNS other than FSGS or MCD (eg, IgA nephropathy, 
obesity related glomerulopathy or membranous nephropathy).
b) Subjects with collapsing FSGS, also known as collapsing glomerulopathy.
c) Subjects with systemic lupus erythematosus (SLE).
d) Subjects with diabetes mellitus, both type 1 and type 2.
e) Subjects with clinically significant congestive heart failure (CHF; New York Heart 
Association [NYHA] Class III or Class IV).
f)
Subjects post renal transplantation, including relapsing post-transplant FSGS.
2. Medical History and Concurrent Diseases
a) Subjects at risk for tuberculosis (TB) defined as follows:
i)
Current clinical, radiographic or laboratory evidence of active TB.
ii) Chest x-rays [PA (posterioranterior) and lateral] obtained within the 6 months prior to 
randomization will be permitted but the images must be available and reviewed by 
the investigator. TB testing (IFN-release assay or PPD) performed in the past month 
prior to randomization will be accepted; however, a copy of the report must be placed 
in the subject binder.
iii) A history of active TB 
iv) Subjects with a positive TB screening test indicative of latent TB will not be eligible 
for the study unless they have no evidence of current TB on chest x-ray at screening 
and they are actively being treated for TB with isoniazid (INH) or other therapy for 
latent TB given according to local health authority guidelines (eg, Center for Disease 
Control). Treatment regimens should be dictated by local guidelines as long as the 
treatment dose and duration meet or exceed local health authority guidelines. If 
permitted by local guidelines regarding treatment with biologic medications, subjects 
may be randomized prior to completion of treatment as long as they have completed 
at least 4 weeks of treatment and they have no evidence of current TB on chest x-ray 
at screening. 
b) Subjects with recent acute infection defined as:
i)
Any acute infection within 60 days prior to randomization
that required 
hospitalization or treatment with parenteral antibiotics.
ii) Any acute infection within 30 days prior to randomization that required oral 
antimicrobial or antiviral therapy.
c) Subjects with history of chronic or recurrent bacterial infection (such as chronic 
pyelonephritis, osteomyelitis, and bronchiectasis etc.) or evidence (as assessed by the 
Investigator) of active or latent bacterial or viral infections at the time of enrollment, 
including subjects with evidence of Human Immunodeficiency Virus (HIV) infection.
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d) Subjects with history of recurrent herpes zoster (more than 1 episode) or disseminated 
(more than 1 dermatome) herpes zoster or disseminated herpes simplex, or ophthalmic 
zoster will be excluded. Symptoms of herpes zoster or herpes simplex must have resolved 
more than 60 days prior to screening.
e) Subjects with history of primary immunodeficiency. 
f)
Subjects who have present or previous malignancies, except documented history of cured 
non-metastatic squamous or basal skin cell carcinoma, or cervical carcinoma in situ, with 
no recurrence in the 5 years prior to screening. Subjects who had screening procedure 
that is suspicious for malignancy, and in whom the possibility of malignancy cannot be 
reasonably excluded following additional clinical, laboratory or other diagnostic 
evaluations.
g) Current symptoms of severe, progressive, or uncontrolled renal, hepatic, hematological, 
gastrointestinal, pulmonary, psychiatric, cardiac, neurological, or cerebral disease 
including severe and uncontrolled infections, such as sepsis and opportunistic infections. 
Concomitant medical conditions that, in the opinion of the investigator, might place the 
subject at unacceptable risk for participation in this study.
h) Subjects who have received any live vaccines within 3 months of the study drug 
administration or are scheduled to receive live vaccines during the study. Study subjects 
should not be administered a live virus vaccine for a minimum of 3 months following the 
last dose of study medication. Subjects who are in close contact with others who have 
received a live vaccine may be enrolled at the investigator’s discretion.
i)
Subjects who have undergone a major surgical procedure within the 60 days prior to 
randomization.
j)
Subjects with a known current problem with drug or alcohol abuse history or known 
cirrhosis including alcoholic cirrhosis.
k) Subjects who have received prior treatment with abatacept or CTLA4Ig or other CTLA4 
therapies.
3. Physical and Laboratory Test Findings
a) Body mass index (BMI): > 40 in subjects years of age and 99% percentile for 
subjects < 18 years of age.
b) Hepatitis B surface antigen (HBsAg)-positive, or Hepatitis B core antibody 
(HBcAb)-positive subjects with detectable hepatitis B viral DNA
c) Hepatitis C antibody (HCAb)-positive subjects with detectable hepatitis C viral RNA
d) Hemoglobin (Hgb) < 8.5 g/dl
e) White Blood Count (WBC) < 3,000/mm3 (3 x 109/L)
f)
Platelets < 100,000/mm3 (100 x 109/L)
g) Serum ALT or AST > 2 times upper limit of normal.
h) Evidence of active cardiac or pulmonary disease on chest X-Ray (CXR).
i)
Any test results that, in the opinion of the investigator, might place the subject at 
unacceptable risk for participation in this study
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4. Allergies and Adverse Drug Reaction
a) Hypersensitivity to abatacept and/or its excipients.
5. Other Exclusion Criteria
a) Prisoners or subjects who are involuntarily incarcerated. (Note: under certain specific 
circumstances a person who has been imprisoned may be included or permitted to 
continue as a subject. Strict conditions apply and Bristol-Myers Squibb approval is 
required.)
b) Subjects who are compulsorily detained for treatment of either a psychiatric or physical 
(eg, infectious disease) illness
c) Subjects with a history or suspicion of unreliability, poor cooperation, or non-compliance 
with medical treatment.
Eligibility criteria for this study have been carefully considered to ensure the safety of the study 
subjects and that the results of the study can be used. It is imperative that subjects fully meet all 
eligibility criteria.
3.3.3
Women of Childbearing Potential
Women
of childbearing potential (WOCBP) is defined as any female who has 
experienced menarche and who has not undergone surgical sterilization (hysterectomy or 
bilateral oophorectomy) and is not postmenopausal. Menopause is defined as 12 months of 
amenorrhea in a woman over age 45 years in the absence of other biological or physiological 
causes. In addition, females under the age of 55 years must have a serum follicle stimulating 
hormone, (FSH) level > 40 mIU/mL to confirm menopause.
*Females treated with hormone replacement therapy, (HRT) are likely to have artificially 
suppressed FSH levels and may require a washout period in order to obtain a physiologic FSH 
level. The duration of the washout period is a function of the type of HRT used. The duration of 
the washout period below are suggested guidelines and the investigators should use their 
judgement in checking serum FSH levels. 

1 week minimum for vaginal hormonal products (rings, creams, gels)

4 week minimum for transdermal products

8 week minimum for oral products
Other parenteral products may require washout periods as long as 6 months. If the serum FSH 
level is > 40 mIU/ml at any time during the washout period, the woman can be considered 
postmenopausal.
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3.5
Discontinuation of Subjects following any Treatment with Study Drug 
Subjects MUST discontinue investigational product (and non-investigational product at the 
discretion of the investigator) for any of the following reasons:

Subject’s request to stop study treatment

Any clinical adverse event (AE), laboratory abnormality or intercurrent illness which, in 
the opinion of the investigator, indicates that continued participation in the study is not in 
the best interest of the subject

Termination of the study by Bristol-Myers Squibb (BMS)

Loss of ability to freely provide consent through imprisonment or involuntarily
incarceration for treatment of either a psychiatric or physical (eg, infectious disease) 
illness

Unblinding a subject for any reason (emergency or non-emergency)

Use of prohibited medication

Missed two or more doses of investigational product for any reason during the Double 
Blind Period
In the case of pregnancy, the investigator must immediately notify the BMS Medical 
Monitor/designee of this event. In the event a normal healthy female becomes pregnant during a 
clinical trial, the study drug must be discontinued immediately. In most cases, the study drug will 
be permanently discontinued in an appropriate manner (eg, dose tapering if necessary for subject 
safety). Please call the BMS Medical Monitor within 24 hours of awareness of the pregnancy. If 
the investigator determines a possible favorable benefit/risk ratio that warrants continuation of 
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study drug, a discussion between the investigator and the BMS Medical Monitor/designee must 
occur.
All subjects who discontinue study drug should comply with protocol specified follow-up 
procedures as outlined in Section 5. The only exception to this requirement is when a subject 
withdraws consent for all study procedures including post-treatment study follow-up or loses the 
ability to consent freely (ie, is imprisoned or involuntarily incarcerated for the treatment of either 
a psychiatric or physical illness).
If study drug is discontinued prior to the subject’s completion of the study, the reason for the 
discontinuation must be documented in the subject’s medical records and entered on the 
appropriate case report form (CRF) page.
3.6
Post Study Drug Study Follow up
Subjects who discontinue study drug may continue to be followed.
3.6.1
Withdrawal of Consent
Subjects who request to discontinue study drug will remain in the study and must continue to be 
followed for protocol specified follow-up procedures. The only exception to this is when a 
subject specifically withdraws consent for any further contact with him/her or persons previously 
authorized by subject to provide this information. Subjects should notify the investigator of the 
decision to withdraw consent from future follow-up in writing, whenever possible. The 
withdrawal of consent should be explained in detail in the medical records by the investigator, as 
to whether the withdrawal is from further treatment with study drug only or also from study 
procedures and/or post treatment study follow-up, and entered on the appropriate CRF page. In 
the event that vital status (whether the subject is alive or dead) is being measured, publicly 
available information should be used to determine vital status only as appropriately directed in 
accordance with local law.
3.6.2
Lost to Follow-Up
All reasonable efforts must be made to locate subjects to determine and report their ongoing 
status. This includes follow-up with persons authorized by the subject as noted above. Lost to 
follow-up is defined by the inability to reach the subject after a minimum of three documented 
phone calls, faxes, or emails as well as lack of response by subject to one registered mail letter. 
All attempts should be documented in the subject’s medical records. If it is determined that the 
subject has died, the site will use permissible local methods to obtain the date and cause of death.
If investigator’s use of third-party representative to assist in the follow-up portion of the study 
has been included in the subject’s informed consent, then the investigator may use a 
Sponsor-retained third-party representative to assist site staff with obtaining subject’s contact 
information or other public vital status data necessary to complete the follow-up portion of the 
study. The site staff and representative will consult publicly available sources, such as public 
health registries and databases, in order to obtain updated contact information. If after all 
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attempts, the subject remains lost to follow-up, then the last known alive date as determined by 
the investigator should be reported and documented in the subject’s medical records.
4
STUDY DRUG
Study drug includes both Investigational [Medicinal] Product (IP/IMP) and Non-investigational 
[Medicinal] Product (Non-IP/Non-IMP) and can consist of the following:
Abatacept for Injection
Normal Saline or 5% Dextrose in Water (provided by the investigational site)
Table 4-1:
Study Drugs for IM101566
Product 
Description / Class 
and Dosage Form
Potency
IP/
Non-IMP
Blinded 
or Open 
Label
Packaging/
Appearance
Storage Conditions
(per label)
Abatacept for 
injection
250 mg 
per vial
IP
Open 
label
White to off-
white, whole or 
fragmented cake 
in a vial. Vials 
will be assembled
into boxes for 
shipping.
STORE REFRIGERATED, 
2-8 DEGREES C 
(36-46 DEGREES F); 
PROTECT FROM LIGHT.
4.1
Investigational Product
An investigational product, also known as investigational medicinal product in some regions, is 
defined a pharmaceutical form of an active substance or placebo being tested or used as a 
reference in a clinical study, including products already with a marketing authorization but used 
or assembled (formulated or packaged) differently than the authorized form, or used for an 
unauthorized indication, or when used to gain further information about the authorized form.
The investigational product should be stored in a secure area according to local regulations. It is 
the responsibility of the investigator to ensure that investigational product is only dispensed to 
study subjects. The investigational product must be dispensed only from official study sites by 
authorized personnel according to local regulations.
Further information with regard to preparation of abatacept for intravenous use will be provided 
separately in the IM101566 dosing procedure manual. For this study, placebo shall be considered 
an equal volume of diluent as used for active infusion admixture in either Dextrose 5% in Water 
or Normal Saline.
4.2
Non-investigational Product
Other medications used as support or escape medication for preventative, diagnostic, or 
therapeutic reasons, as components of the standard of care for a given diagnosis, may be
considered as non-investigational products. 
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4.3
Storage and Dispensing
The product storage manager should ensure that the study drug is stored in accordance with the 
environmental conditions (temperature, light, and humidity) as determined by BMS. If concerns 
regarding the quality or appearance of the study drug arise, the study drug should not be 
dispensed and contact BMS immediately.
Study drug not supplied by BMS will be stored in accordance with the package insert.
Investigational product documentation (whether supplied by BMS or not) must be maintained 
that includes all processes required to ensure drug is accurately administered. This includes 
documentation of drug storage, administration and, as applicable, storage temperatures, 
reconstitution, and use of required processes (eg, required diluents, administration sets).
4.4
Method of Assigning Subject Identification
At the time of enrollment, immediately after written informed consent is obtained and before 
performing any study-related procedures, each subject at a site will be assigned a unique 
sequential subject number beginning with 001, 002, 003, etc. for identification throughout the 
study. This subject number must not be reused for any other participant at the site. The 
physician/coordinator must contact the Central Randomization System to enroll each subject into 
a centralized database at the beginning of the study (Screening).
4.5
Selection and Timing of Dose for Each Subject
Subjects will be randomized to 1 of 2 treatment groups:

Abatacept intravenous infusions.

Placebo (D5W or Normal Saline) intravenous infusions.
Dosing for subjects 18 years and older will follow adult dosing rules. Dosing for subjects 
younger than 18 years will follow pediatric dosing rules.
4.5.1
Abatacept Dosing
4.5.1.1
Pediatric Subjects
Pediatric subjects receiving active abatacept will be dosed based on their weight at each visit 
following these rules:

Pediatric subjects weighing < 75 kg: 10 mg/kg intravenously. 

Pediatric subjects weighing 75 kg: or more should be administered abatacept following the 
adult intravenous dosing regimen, not to exceed a maximum dose of 1000 mg

75 to 100 kg: 750 mg

> 100 kg: 1000 mg
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4.5.1.2
Adult Subjects 
Adult subjects receiving active abatacept will be dosed based on their screening visit weight 
following these rules:

Subjects weighing < 60 kg will receive 500 mg

Subjects weighing 60 to 100 kg will receive 750 mg

Subjects weighing > 100 kg will receive 1000 mg.
4.5.2
Administration of Abatacept or Placebo
The Central Randomization System will confirm the subject’s body weight and age and assign 
the number of vials of abatacept to allocate for the visit. Subjects will receive doses of study 
medication at every treatment period visit (Days 1, 15, 29, 57 and 85 during Double Blind 
Period). 
Subjects who are randomized to receive placebo will be given either Dextrose 5% in Water 
(D5W) or Normal Saline (NS) at the discretion of the investigator. Placebo (NS or D5W) will be 
supplied by the investigative site.
A 3 day window is allowed for the dose on Day 15, a -3 and +7 day window is allowed for the 
dose on Day 29 and a 7 day window is allowed for doses thereafter. Infusions should occur at 
approximately the same time of day throughout the duration of the study. 
All doses of study medication will be administered intravenously in a fixed volume of 100 ml at 
a constant rate of flow over approximately 30 minutes. Please flush with D5W or NS at the end 
of the infusion to ensure that the administration line used to deliver the drug solution is 
adequately cleared; please refer to the infusion set’s manufacturer’s materials to determine the 
appropriate flush volume needed to assure delivery of the entire dosage. The infusion solution 
must be prepared by a qualified staff member and supplied to personnel administering the dose 
in a container not identifying the contents so as to maintain the blind. The infusion of the fully 
diluted abatacept/placebo must be completed within 24 hours of reconstitution of the vials. The 
fully diluted abatacept/placebo may be stored at room temperature or refrigerated at 2CtoC 
(36F to 46F) before use. The fully diluted solution should be discarded if not administered 
within 24 hours.
All intravenous infusions will be with the subject in the seated position. No adjustments will be 
made in treatment dose level or schedule. Subjects will be observed for adverse events and vital 
signs (seated blood pressure, heart rate, and temperature) from the start of each infusion 
(pre-dose and 60 minutes). There is a 5-minute window for vital sign collection. Subjects will 
be observed for a minimum of 1 hour from the start of the infusion. The observation period 
should be extended if clinically indicated.
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4.5.3
Dosing During the Open Label Extension 
Adult subjects who enter the Open Label Extension (OLE) following completion of the Double 
Blind will receive doses of study medication at every OLE period visit (OLE Days 1, 29, 57, 85, 
113, and 141) based on their OLE Day 1 visit weight. 
Pediatric subjects who enter the Open Label Extension (OLE) following completion of the 
Double Blind Period will receive doses of study medication at every OLE period visit (OLE 
Days 1, 29, 57, 85, 113, and 141) based on their weight at each visit. 
They will follow the same pediatric and adult dosing rules in Sections 4.5.1.1 and 4.5.1.2.
4.5.4
Dose Modifications
4.5.4.1
Dose Modifications in the Absence of Adverse Events
In the absence of adverse events deemed at least possibly related to study medication treatment, 
subjects should complete their scheduled IV infusions as prescribed by protocol. Dosing 
windows to adjust for the subject’s and/or the site personnel’s convenience are as follows. A 3 
day window beyond the target date is allowed for the Double Blind Period at Day 15, and a -3 
and +7 day window is allowed for Day 29. A 7 day window is allowed for all subsequent 
IV infusions.
4.5.4.2
Dose Modifications Due to an Adverse Event
If there is evidence of toxicity in abnormal laboratory tests or clinical adverse events that, in the 
judgment of the Investigator, could place the subject at increased risk, study drug administration 
should be interrupted and the investigator should notify BMS. Subjects may be considered 
eligible to receive further study medication treatment only if full resolution of the adverse event 
is documented. Under no circumstances should the dose of study drug be altered due to an 
adverse event.
The IV infusion dosing window may be extended if the delay is due to an adverse event and if 
the adverse event has completely resolved. For Day 15, the dose may be delayed up to 7 days. 
For all subsequent IV infusions, the dose may be delayed up to 14 days. If the adverse event has 
not resolved within these windows, the IV infusion scheduled for that visit should be skipped 
(missed one IV dose). For example, if the Day 57 dose could not be administered until the 
73rd day, the Day 57 dose should be skipped and the subject’s next dose would occur at the 
Day 85 visit. Only two missed doses are allowed in the Double Blind Period.
4.6
Blinding/Unblinding
Blinding of treatment assignment is critical to the integrity of this clinical study. However, in the 
event of a medical emergency or pregnancy in an individual subject in which knowledge of the 
investigational product is critical to the subject’s management, the blind for that subject may be 
broken by the investigator. The subject’s safety takes priority over any other considerations in 
determining if a treatment assignment should be unblinded.
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Before breaking the blind of an individual subject’s treatment, the investigator should determine
that the unblinded information is necessary, ie, that it will alter the subject’s immediate 
management. In many cases, particularly when the emergency is clearly not related to the 
investigational product, the problem may be properly managed by assuming that the subject is 
receiving active product. It is highly desirable that the decision to unblind treatment assignment 
be discussed with the Medical Monitor, but the investigator always has ultimate authority for the 
decision to unblind. The Principal Investigator should only call in for emergency unblinding 
AFTER the decision to discontinue the subject has been made.
For this study, the method of unblinding for emergency purposes is the Central Randomization 
System.
In cases of accidental unblinding, contact the Medical Monitor and ensure every attempt is made 
to preserve the blind.
Any request to unblind a subject for non-emergency purposes should be discussed with the 
Medical Monitor.
The BMS Bioanalytical Science Department or its designee will be unblinded to the randomized 
treatment assignments in order to accurately perform sample analysis for the PK and 
immunogenicity samples.
4.7
Treatment Compliance
All subjects are expected to receive study therapy as outlined in the protocol. Permitted dose 
modifications are described in Section 4.5.4. Conditions under which therapy must be 
discontinued due to non-compliance are outlined in Section 3.5. Randomized subjects failing to 
receive any infusion of study medication will be deemed pre-treatment drop-outs and will not be 
followed for further evaluation. Subjects receiving at least one dose of study medication will be 
followed for safety, efficacy, pharmacodynamics, pharmacokinetics and immunogenicity testing. 
Subjects who will be discontinued from the study will be evaluated as outlined in Section 5.1
(Flow Chart/Time and Event Schedule).
4.8
Destruction of Study Drug
For this study, study drugs (those supplied by BMS or sourced by the investigator) such as 
partially used study drug containers, vials and syringes may be destroyed on site. 
Any unused study drugs can only be destroyed after being inspected and reconciled by the 
responsible Study Monitor unless study drug containers must be immediately destroyed as 
required for safety, or to meet local regulations (eg, cytotoxics or biologics). 
On-site destruction is allowed provided the following minimal standards are met:

On-site disposal practices must not expose humans to risks from the drug.

On-site disposal practices and procedures are in agreement with applicable laws and 
regulations, including any special requirements for controlled or hazardous substances.
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
Written procedures for on-site disposal are available and followed. The procedures must be 
filed with the site’s SOPs and a copy provided to BMS upon request.

Records are maintained that allow for traceability of each container, including the date 
disposed of, quantity disposed, and identification of the person disposing the containers. The 
method of disposal, ie, incinerator, licensed sanitary landfill, or licensed waste disposal 
vendor must be documented.

Accountability and disposal records are complete, up-to-date, and available for the Monitor 
to review throughout the clinical trial period.
If conditions for destruction cannot be met the responsible Study Monitor will make 
arrangements for return of study drug.
It is the investigator’s responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable federal, state, local, 
and institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept.
4.9
Return of Study Drug
If study drug will not be destroyed upon completion or termination of the study, all unused 
and/or partially used study drug that was supplied by BMS must be returned to BMS. The return 
of study drug will be arranged by the responsible Study Monitor. 
It is the investigator’s responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable federal, state, local, 
and institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept.
4.10
Retained Samples for Bioavailability/Bioequivalence
Not Applicable.
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5
STUDY ASSESSMENTS AND PROCEDURES
5.1
Flow Chart/Time and Events Schedule 
Table 5.1-1:
Screening 
Procedure
Visit 1 
(all subjects)
Optional 
Visit 2 
(if Visit 1
occurred 
> 28 days
prior)
Notes
Eligibility Assessments
Informed Consent
X
Inclusion/Exclusion Criteria
X
X
Medical History
X
Renal Biopsy History
X
Review of the report by a central pathologist is required.
Prior Medication Review. Stabilize/Withdraw 
Prohibited Medication (if necessary)
X
X
Enroll Subject (contact Central Randomization 
System)
X
Safety Assessments
Physical Examination
X
Vital Signs
X
X
Seated BP, heart rate, temperature
Height, Standing
X
X
Weight
X
X
Body Mass Index
X
Chest X-ray
X
Not required if performed within 6 months of obtaining written 
informed consent and if documentation is on file.
Serious Adverse Events Assessment
X
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Table 5.1-1:
Screening 
Procedure
Visit 1 
(all subjects)
Optional 
Visit 2 
(if Visit 1
occurred 
> 28 days
prior)
Notes
Laboratory Tests
TB Screening
X
PPD or interferon gamma release assay. Testing performed locally.
CBC
X
X
Chemistry Panel
X
X
eGFR
X
X
X
Urine sample for protein/creatinine ratio (UPCR)
X
X
To be taken from a 24-hour urine collection. If not possible, then 
from a single voided specimen, preferably in the morning.
Urinalysis
X
Testing performed locally
Hepatitis B surface antigen
X
If positive, obtain HBV DNA
Hepatitis B core antibody
X
If positive, obtain HBV DNA
Hepatitis C antibody
X
If positive, obtain HCV RNA
HIV Testing
X
Testing performed locally if required.
Urine Pregnancy Test
X
X
Testing performed locally on WOCBP subjects only.
APOL1 Genotyping
X
This is not necessary if results of previous testing are available. 
Subjects will be able to opt-out of genotyping for APOL1.
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Table 5.1-2:
Double Blind Period
Visit Day 
Day 1
Day 15
Day 29
Day 57
Day 85a
Day 92
(PK Visit)
Day 99
(PK Visit)
Day 106
(PK Visit)
Day 113 or Early 
Termination
Notes
Contact Central 
Randomization System 
X
X
X
X
X
X
Outcomes Research Assessments
PROMIS Questionnaires
X
X
X
Safety Assessments
Adverse Event Monitoring
X
X
X
X
X
X
 
Targeted Physical Exam
X
X
X
X
X
X
Weight
X
X
X
X
X
X
 
Vital Signs
X
X
X
X
X
X
Seated BP, heart rate, temperature should be taken 
pre-dose and 60 minutes post-dose.
Emergency Room/ 
Hospitalization CRF
X
X
X
X
X
X
Laboratory Assessments
CBC
X
X
X
X
Chemistry panel 
X
X
X
X
X
X
eGFR
X
X
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Table 5.1-2:
Double Blind Period
Visit Day 
Day 1
Day 15
Day 29
Day 57
Day 85a
Day 92
(PK Visit)
Day 99
(PK Visit)
Day 106
(PK Visit)
Day 113 or Early 
Termination
Notes
 
X
X
X
Urine sample for 
protein/creatinine ratio
X
X
X
X
X
X
Taken from a 24-hour urine collection on Day 1 and 
113; if not possible, then from a single voided 
specimen.
Taken from a single voided specimen at all other time 
points. A single voided specimen is also required at 
Day 1 and Day 113. For single voids, morning 
collections are preferred.
Urinalysis
X
X
Testing performed locally.
Urine pregnancy test
X
X
X
X
X
X
Testing performed locally on WOCBP subjects only
 
 
 
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Table 5.1-2:
Double Blind Period
Visit Day 
Day 1
Day 15
Day 29
Day 57
Day 85a
Day 92
(PK Visit)
Day 99
(PK Visit)
Day 106
(PK Visit)
Day 113 or Early 
Termination
Notes
Pharmacokinetics and 
Immunogenicity
Pharmacokinetic Sampling in 
Blood
X*
X*
X*
X*
X*
X**
X**
X**
X
* The samples will be collected both prior to dosing 
and at the end of infusion.
** The samples will be collected during the PK visit.
All the PK assessments are specified in Section 5.4.1.
Pharmacokinetic Sampling in 
Urine
X
X
X
X
X
X
To be taken from a 24-hour urine collection on Day 1 
and 113; if not possible, then from a single voided 
specimen. From a single voided specimen at all other 
time points. A single voided specimen is also required 
at Day 1 and Day 113. For single voids, morning 
collections are preferred. The samples will be 
collected prior to dosing.
Immunogenicity anti-
Abatacept Ab testing
X
X
Clinical Supplies
Drug preparation by a 
pharmacist
X
X
X
X
X
Abatacept/placebo dosing
X
X
X
X
X
a Pediatric subjects may early escape at Day 85 at the discretion of investigator (and consultation with the subject’s guardian) based on criteria specified in 
Section 3.1.2.  In such situations, the Day 85 will be the Early Termination visit.
b If a subject does not consent to the use of their samples for additional research, their samples will be discarded after all protocol-specified testing has been 
completed (not to exceed 15 years).
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Table 5.1-3:
Open Label Extension
Visit Day (7 days)
Day 1
(Same day as 
last visit of the 
Double Blind 
Period)
Day 29
Day 57
Day 85
Day 113
Day 141
Day 169 or 
Early 
Termination
Notes
Contact Central Randomization 
System
X
X
X
X
X
X
X
Safety Assessments
Adverse Event Monitoring
X
X
X
X
X
X
Targeted Physical Exam
X
X
X
X
X
X
Weight
X
X
X
X
X
X
Vital Signs
X
X
X
X
X
X
Seated BP, heart rate, temperature should be taken 
pre-dose and 60 minutes post-dose.
X
X
X
X
X
X
 
Emergency Room/Hospitalization 
CRF
X
X
X
X
X
X
Laboratory Assessments
CBC
X
Chemistry panel
X
X
X
Total Cholesterol and Triglycerides, 
fasting
X
Urine sample for protein/creatinine 
ratio
X
X
X
X
X
X
To be taken from a single voided specimen. Morning 
collections are preferred.
eGFR
X
Urine pregnancy test
X
X
X
X
X
X
Testing performed locally on WOCBP subjects only
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Table 5.1-3:
Open Label Extension
Visit Day (7 days)
Day 1
(Same day as 
last visit of the 
Double Blind 
Period)
Day 29
Day 57
Day 85
Day 113
Day 141
Day 169 or 
Early 
Termination
Notes
Clinical Supplies
Drug preparation by a pharmacist
X
X
X
X
X
X
Abatacept dosing
X
X
X
X
X
X
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abatacept
Table 5.1-4:
Follow-Up Visits (after last dose)a
Visit (14 days)
56 Days after 
Last Dose
84 Days 
after Last 
Dose
168 Days 
after Last 
Dose
Notes
Adverse Event Monitoring
X
X
X
Targeted Physical Exam
X
X
X
Vital Signs
X
X
X
Seated BP, heart rate, temperature
Emergency Room/Hospitalization CRF
X
X
X
Laboratory Assessments
Urine pregnancy test
X
X
X
Testing performed locally on WOCBP subjects only
Immunogenicity anti-abatacept Ab testing
X
X
X
Pharmacokinetic Sampling in Blood
X
X
X
The sample will be stored until a decision is made that the 
testing will be needed.
a Testing will be required only if the subject is off abatacept treatment and does not transition to commercially available treatment with abatacept.
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5.1.1
Retesting During Screening or Lead-in Period
Retesting of laboratory parameters and/or other assessments within any single screening period 
will be permitted (in addition to any parameters that require a confirmatory value).
Any new result will override the previous result (ie, the most current result prior to 
Randomization) and is the value by which study inclusion will be assessed, as it represents the 
subject’s most current, clinical state.
5.1.2
Study Materials

Instructions for completion of the eCRF pages

Pregnancy Prevention Information Sheet

Pregnancy Surveillance Forms

Source documents for outcomes research instruments

Drug Inventory Binder

Pharmacy Manual

Central Randomization System Worksheets

Laboratory test kits for all required testing
5.2
Safety Assessments
On Day 1, the results of all assessments must be reviewed to assure that eligibility requirements 
are met before contacting the Central Randomization System for the subject’s randomization 
assignment.
Subjects who terminate treatment early should complete the appropriate Early Termination Visit. 
The Early Termination Visit should be as soon as possible after the last dose of study 
medication. If a subject does not transition to treatment with commercial abatacept, the subject 
will be required to complete the Post Drug Follow-up Visits.
All assessments should be performed or administered prior to study drug administration unless 
otherwise indicated.
Only data for the procedures and assessments specified in this protocol should be submitted to 
BMS on a case report form. Additional procedures and assessments may be performed as part of 
standard of care; however, data for these assessments should remain in the subject’s medical 
record and should not be provided to BMS, unless specifically requested from BMS.
5.2.1
Imaging Assessment for the Study
Not Applicable.
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5.2.2
Adverse Events of Special Interest
As part of the safety evaluation, AEs that may be associated with the use of immunomodulatory 
drugs will be identified. Specific events within the categories of infection, autoimmune 
disorders, malignancies, infusion reactions, and renal-related events will be prospectively 
identified and classified as “AE of special interest.” These AE are a subset of all AEs and include 
serious and non-serious events.
5.2.3
Physical Examination
Physical examinations must be performed by a Doctor of Medicine (MD), Doctor of Osteopathy 
(DO), Physician Assistant (PA), or Nurse Practitioner (NP). 
The physical examination should include examination of the heart, lungs, abdomen, the lymph 
nodes, liver, spleen and skin. A physical examination may note any changes in the subject’s 
condition (body systems) since the last assessment and does not preclude examination of any 
other body systems as clinically indicated.
5.2.4
Chest X-ray
A posterior-anterior and lateral chest x-ray, performed during screening, is required for all 
subjects unless performed within 6 months prior to obtaining written informed consent and 
documentation of the earlier x-ray is on file. Investigators must ensure that the results of the 
chest x-ray satisfy criteria for eligibility. The chest x-ray result will be recorded on the 
appropriate page of the eCRF.
5.2.5
Physical Measurements
Weight is to be recorded at all visits noted in Section 5.1, Flow Chart/Time and Events Schedule.
Standing height is required for subjects  18 years only at the Screening Visit.
5.2.6
Vital Signs
Vital signs (seated blood pressure, heart rate, and temperature) will be recorded during every 
office visit and prior to and after dose administration is complete, when applicable. Blood 
pressure and heart rate should be measured after the subject has been seated quietly for at least 5 
minutes.
5.2.7
Body Mass Index (BMI)
Body mass index (BMI) will be used to exclude subjects who have obesity related 
glomerulopathy as the primary cause of the subject’s refractory proteinuria. (Exclusion Criteria 
Section 3.3.2, 3,a) Since BMI may fluctuate due to accumulated edema secondary to severe 
proteinuria and not be indicative of the role an elevated BMI may have played in the underlying 
disease process, subjects with an elevated BMI at screening may enroll, at the discretion of the 
investigator, if the high BMI is due to accumulated edema and the BMI was not known to be 
elevated at onset of disease. These factors must be documented in the study source documents at 
randomization.
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BMI will be calculated at screening for purposes of checking for the exclusion criteria. For BMI 
determination in children, follow the 2000 CDC Growth Charts (www.cdc.gov/growthcharts) by 
age and gender. 
For adults, BMI is calculated from the weight and standing height as follows:
BMI = body weight (kg) ÷ height (meters) squared
5.2.8
TB Screening
A chest x-ray and physical examination are considered part of the process to assess a subject’s 
eligibility. In addition to a chest x-ray that does not show any evidence or suspicion of latent TB, 
a tuberculin test will be performed and interpreted according to local country Health Authorities 
and/or Medical Society guidelines. Some guidelines have specific recommendations for subjects 
who are to receive biologics51,52,53 or immunosuppressant therapies (eg, RA experience with 
biologic agents), or who are immunocompromised and who have had prior BCG 
vaccination(s).54,55 Tuberculin skin testing is not contraindicated for persons who have been 
vaccinated with BCG. An interferon gamma release assay (eg, QuantiFERONGold or 
Tspot/ELISpot) is an acceptable alternative when skin testing for tuberculosis (ie, PPD) is not 
appropriate.
5.2.9
Renal Biopsy History
All subjects must have a biopsy report confirming the diagnosis of FSGS/MCD prior to 
enrollment in the study. The report will be reviewed by a central pathologist to confirm the 
diagnosis 
prior 
to 
the 
subject 
qualifying 
for 
randomization.
Light 
microscopy, 
immunofluorescence/immunohistochemistry and electron microscopy are required to fulfill 
pathologic enrollment criteria. The criteria for path review are found in Appendix 1.
5.2.10
Hospitalizations and Emergency Room (ER) Visits
Hospitalizations and ER visits will be recorded on the eCRF.
5.2.11
Laboratory Assessments
All laboratory assessments will be analyzed centrally except where noted.
Blood and/or urine samples will be obtained at all visits noted in Section 5.1, Flow Chart/Time 
and Events Schedule. Any laboratory test result that the investigator considers clinically relevant 
should be recorded on the appropriate Adverse Event page of the CRF (see Appendix 3).
5.2.11.1
Hematology
Hemoglobin
Hematocrit
Total WBC, including differential
Platelet count
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5.2.11.2
Blood Chemistry
Sodium 
Creatinine
Potassium 
Blood urea nitrogen (BUN)
Chloride 
Total bilirubin
Total Protein 
Alanine aminotransferase (ALT)
Albumin 
Aspartate aminotransferase (AST)
Calcium 
Gamma-glutamyltransferase (GGT)
Phosphorus 
Alkaline phosphatase
Glucose
hsCRP
Uric Acid
Cystatin C
 
5.2.11.4
Urinalysis
The urinalysis testing is performed locally.

pH

Protein

Glucose

Blood
5.2.11.5
Urine Testing
Urine Protein Creatinine Ratio (UPCR) will be determined from spot urine collections except for 
baseline and Day 113 in which 24-hour urine collections will be performed. If 24-hour 
collections are not possible, these samples will be determined from spot urine specimens. 
24-hour collections are preferable although they can be inconvenient for patients and are subject 
to incorrect collection. While spot urines have inherent biological variation, they are still suitable 
for study endpoint determination.56
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5.2.11.6
Estimated Glomerular Filtration Rate (eGFR)
eGFR will be calculated by the new Schwartz equation for subjects < 18 years and the CKD-EPI 
equation for subjects 18 years.
5.2.11.7
Hepatitis Screening
The results must be available on Day 1 prior to dosing.

Hepatitis B surface antigen, hepatitis B core antibody -- If positive, reflex HBV DNA testing 
must be performed.

Hepatitis C antibody. If positive, reflex HCV RNA testing must be performed
5.2.11.8
Pregnancy Testing
Urine pregnancy tests (minimum sensitivity 25 IU/L of -HCG) must be performed for all 
WOCBP within 24 hours prior to dosing for visits specified in Section 5.1, Flow Chart/Time and 
Events Schedule. Urine tests are the preferred method and must be performed unless serum is 
required by local requirements. A serum test must be performed centrally for confirmation of any 
positive urine test result. Urine tests can be processed locally. If any female subject becomes 
pregnant, she will stop receiving study treatment immediately and enter the Post Treatment 
Follow-up Period. A pregnancy surveillance form will be completed and submitted to 
Bristol-Myers Squibb. 
5.2.11.9
HIV Testing
HIV testing will be performed locally if required based on the judgment of the investigator.
5.2.11.10 FSH Testing
FSH testing must be performed to confirm menopause for female subjects under the age of 55. 
The female subject must have a serum FSH level > 40 mIU/ml in screening.
FSH testing will be performed for female subjects who become menopausal after entry into the 
study.
5.2.11.11 Genetic Testing
Genotyping for the APOL1 renal risk variants SNPs [Risk allele G1 (rs73885319 and 
rs60910145) and risk allele G2 (rs71785313)] will be requested for all subjects. Genotyping 
during screening will not be necessary if results of previous testing are available.  Subjects may 
opt out of testing.
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5.3
Efficacy Assessments
5.3.1
Primary Efficacy Assessment
Primary efficacy will be the renal response rate which will be determined using a composite 
renal index.
5.3.1.1
Renal Response
The renal response will be present if all the following criteria are met at Day 113:
PROTEINURIA:
Reduction of baseline UPCR of 50% and to less than 3.
RENAL FUNCTION:
No worsening of baseline (Study Day 1) estimated glomerular 
filtration rate (eGFR) defined as normal or 75% baseline value if 
below normal at baseline.
eGFR determination will be based on the CKD-EPI for adults and 
the new Schwartz equation for children.
Proteinuria assessment for primary and secondary endpoints will be obtained from 24 hour urine 
collections performed at baseline and Day 113. When a 24 hour collection is not possible, a 
single voided specimen (ie, spot urine) will be utilized, preferably in the morning.
5.3.2
Secondary Efficacy Assessments
5.3.2.1
Improvement in Proteinuria
Improvement in proteinuria will be determined by the change from baseline in the level of 
proteinuria as assessed by UPCR at Day 113.
5.3.2.2
Improvement in Serum Albumin
Improvement in serum albumin will be determined by the change from baseline in the level of 
serum albumin as assessed by UPCR at Day 113.
5.3.2.3
Complete Remission 
Complete remission will be present if all the following criteria are met at Day 113:
PROTEINURIA:
UPCR 0.3
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RENAL FUNCTION:
No worsening of baseline (Study Day 1) estimated glomerular 
filtration rate (eGFR) defined as normal or 75% baseline value if 
below normal at baseline.
eGFR determination will be based on the CKD-EPI for adults and 
the new Schwartz equation for children.
5.3.2.4
Patient Reported Outcomes Measurement Information System 
(PROMIS)
Improvement in patient reported outcomes related to nephrotic syndrome will be captured using 
age-appropriate PROMIS. For subjects below the age of 18, both the subjects and the 
parents/guardians will complete PROMIS.
 
 
5.4
Pharmacokinetic Assessments
5.4.1
Pharmacokinetic: Blood and Urine Sample Collection
Table 5.4.1-1 lists the sampling schedule to be followed for the assessment of pharmacokinetics 
(blood and urine) as well as the immunogenicity. 
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The actual date and time of sample collection must be recorded. The volume of urine collection 
must be recoded. Every effort should be made to collect PK samples as close to the protocol-
specified times as possible. 
Table 5.4.1-1:
Sampling Schedule
Study Day
Time 
(Relative to 
Dosing)
Hour
Time 
(Relative to 
Dosing)
Hour: Min
PK
Blood 
Sample
PK
Urine 
Samplea
Immunogenicity 
Sample
Double Blind
1
0 (predose)
00:00
X
X
X
1
0.5 (postdose)
0.5:00
X
X
15
0 (predose)
00:00
X
X
15
0.5 (postdose)
0.5:00
X
29
0 (predose)
00:00
X
X
29
0.5 (postdose)
0.5:00
X
57
0 (predose)
00:00
X
X
57
0.5 (postdose)
0.5:00
X
85
0 (predose)
00:00
X
X
85
0.5 (postdose)
0.5:00
X
92
168
168:00
X
99
336
336:00
X
106
504
504:00
X
113 (or Early 
Termination
0 (predose)
00:00
X
X
X
Follow-Up 
Visitsb
56 Days after 
Last Dose
1344
1344:00
X
X
84 Days after 
Last Dose
2016
2016:00
X
X
168 Days after 
Last Dose
4032
4032:00
X
X
a To be taken from a 24-hour urine collection on Day 1and Day 113. If not possible, the sample will be taken from 
a single voided specimen. Single voided specimens are to be taken at all other time points including Day 1 and 
Day 113. For single voids, morning collections are preferred.
b Only for subjects discontinuing use of abatacept (off study and not on commercial abatacept).
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5.4.2
Pharmacokinetic Sample Processing, Labeling and Shipping
Detailed instructions on processing, labeling, handling, storage, and shipping of PK specimens 
for analysis will be supplied to Investigators in a separate laboratory manual at or before the time 
of study initiation.
5.4.3
Pharmacokinetic Sample Analysis
A sensitive validated enzyme immunoassay (EIA) method will be used to measure 
concentrations of abatacept in serum and urine.  Samples collected in Period 2 from the previous 
protocol will still be analyzed.
5.4.4
Pharmacokinetic Evaluation
The pharmacokinetics of abatacept will be derived from serum concentration versus time data. 
Individual subject pharmacokinetic parameter values will be derived by non-compartmental 
methods and summarized. Urinary abatacept determinations will be obtained primarily for the 
purpose of determining whether abatacept is excreted in urine in the setting of proteinuria and 
whether the amount of abatacept found in urine is related to the level of ongoing proteinuria.
Volume of urine collection from single voids and the total volume of urine collection from 24-hr 
collections will be recorded so that amount of abatacept present in urine can be determined. The 
pharmacokinetic evaluations will be comprised of the following parameters:
Serum PK:

Cmin (g/mL): Trough level serum concentration of abatacept on Days 1, 15, 29, 57, 85, and 
113)

Cmax (g/mL): Peak serum concentration of abatacept on Day 85

Tmax (hr): Time to reach peak serum concentration of abatacept on Day 85

AUC (TAU) (g.h/mL): Area under the serum concentration time curve in a dosing interval 
between Days 85 and 113 (TAU) = 28 days) where TAU = 28 days
Urine PK:

Xu (g): Amount of abatacept excreted in urine
 
 
 
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5.6
Outcomes Research Assessments
The Patient Reported Outcomes Measurement Information System (PROMIS) will be used to 
capture patient reported outcomes relevant to subjects with nephrotic syndrome. The PROMIS 
project was established as part of the National Institutes of Health Roadmap Initiative to create 
item banks for both adults and children, which are publically available, efficient, precise, and 
valid across a variety of diseases to assess PROs (www.nihpromis.org).60
In this study, the static short forms (ie, containing a fixed set of items) will be used, eg, in 
pencil-and-paper format. This will bypass the need to use the computerized adaptive testing 
approach. The item banks chosen are based on prior experience with these items in nephrotic 
syndrome as well as on the characteristics of the disease condition.46,61 For subjects 17 and 
younger, both the subjects and their parent proxy will complete the appropriate static short 
forms.
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The following static short forms will be utilized from the following PROMIS items banks
(see Appendix 4).

For subjects 18 and older:

SF Physical Function v1.2 Form 8b 

SF Fatigue v1.0 Adult Form 8a 

SF Pain Interference v1.0 Adult Form 8a 

For subjects 8-17 and younger and their parent proxy:

SF Physical Function - Mobility v1.0 Peds Form 8a 

SF Fatigue v1.0 Peds Form 10a

SF Pain Interference v1.0 Peds Form 8a 

For subjects 6-7 and their parent proxy

SF Physical Function Mobility v1.0 Parent Proxy Form 8

SF Fatigue v1.0 Parent Proxy Form 10

SF Pain Interference v1.0 Parent Proxy Form 8
5.7
Other Assessments 
5.7.1
Immunogenicity Assessments
The immunogenic potential of the study medication will be assessed based on levels of 
antiabatacept antibodies.
5.7.2
Immunogenicity: Blood Sample Collection and Processing
The blood sampling schedule to be followed for the assessment of immunogenicity is shown in 
Table 5.4.1-1. Detailed instructions of immunogenicity specimens will be supplied to 
Investigators in a separate laboratory manual.
5.7.3
Immunogenicity: Sample Analysis
A validated, sensitive, electrochemiluminescence assay (ECL) method will be used to analyze
for the presence of anti-abatacept and anti-CTLA4-T antibodies in serum. Samples that are
confirmed positive for anti-CTLA4 antibodies with the ECL immunogenicity assay and has
abatacept serum concentrations below 1 μg/mL will be further analyzed with a validated, in 
vitro, cell-based bioassay to determine whether the sera contained abatacept neutralizing activity.
6
ADVERSE EVENTS
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a 
preexisting medical condition in a clinical investigation subject administered study drug and that 
does not necessarily have a causal relationship with this treatment. An AE can therefore be any 
unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, or disease 
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temporally associated with the use of study drug, whether or not considered related to the study 
drug.
The causal relationship to study drug is determined by a physician and should be used to assess 
all adverse events (AE). The causal relationship can be one of the following:
Related: There is a reasonable causal relationship between study drug administration and 
the AE.
Not related: There is not a reasonable causal relationship between study drug 
administration and the AE.
The term “reasonable causal relationship” means there is evidence to suggest a causal 
relationship.
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a subject. (In order to prevent reporting bias, subjects should not be 
questioned regarding the specific occurrence of one or more AEs.)
6.1
Serious Adverse Events
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose: 

results in death

is life-threatening (defined as an event in which the subject was at risk of death at the time of 
the event; it does not refer to an event which hypothetically might have caused death if it 
were more severe)

requires inpatient hospitalization or causes prolongation of existing hospitalization 
(see NOTE below)

results in persistent or significant disability/incapacity

is a congenital anomaly/birth defect

is an important medical event (defined as a medical event(s) that may not be immediately 
life-threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the subject or may require intervention [eg, medical, 
surgical] to prevent one of the other serious outcomes listed in the definition above.) 
Examples of such events include, but are not limited to, intensive treatment in an emergency 
room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do not 
result in hospitalization.) Potential drug induced liver injury (DILI) is also considered an 
important medical event. (See Section 6.6 for the definition of potential DILI.)
Suspected transmission of an infectious agent (eg, pathogenic or nonpathogenic) via the study 
drug is an SAE.
Although pregnancy, overdose, cancer, and potential drug induced liver injury (DILI) are not 
always serious by regulatory definition, these events must be handled as SAEs. (See 
Section 6.1.1 for reporting pregnancies).
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NOTE: 
The following hospitalizations are not considered SAEs in BMS clinical studies: 

a visit to the emergency room or other hospital department < 24 hours, that does not 
result in admission (unless considered an important medical or life-threatening event)

elective surgery, planned prior to signing consent

admissions as per protocol for a planned medical/surgical procedure

routine health assessment requiring admission for baseline/trending of health status 
(eg, routine colonoscopy)

medical/surgical admission other than to remedy ill health and planned prior to entry into 
the study. Appropriate documentation is required in these cases

admission encountered for another life circumstance that carries no bearing on health 
status and requires no medical/surgical intervention (eg, lack of housing, economic 
inadequacy, caregiver respite, family circumstances, administrative reason)

admission for administration of anticancer therapy in the absence of any other SAEs 
(applies to oncology protocols)
6.1.1
Serious Adverse Event Collection and Reporting
Section 5.5.1 in the Investigator Brochure (IB) represent the Reference Safety Information to 
determine expectedness of serious adverse events for expedited reporting. Following the 
subject’s written consent to participate in the study, all SAEs, whether related or not related to 
study drug, must be collected, including those thought to be associated with protocol-specified 
procedures. All SAEs must be collected that occur during the screening period and within
6 months of discontinuation of dosing. If applicable, SAEs must be collected that relate to any 
later protocol-specified procedure (eg, a follow-up skin biopsy). 
The investigator must report any SAE that occurs after these time periods and that is believed to 
be related to study drug or protocol-specified procedure. 
An SAE report must be completed for any event where doubt exists regarding its seriousness. 
If the investigator believes that an SAE is not related to study drug, but is potentially related to 
the conditions of the study (such as withdrawal of previous therapy or a complication of a study 
procedure), the relationship must be specified in the narrative section of the SAE Report Form.
SAEs, whether related or not related to study drug, and pregnancies must be reported to BMS 
(or designee) within 24 hours of awareness of the event. SAEs must be recorded on the SAE 
Report Form; pregnancies on a Pregnancy Surveillance Form (electronic or paper forms). The 
preferred method for SAE data reporting collection is through the eCRF. The paper 
SAE/pregnancy surveillance forms are only intended as a back-up option when the eCRF system 
is not functioning. In this case, the paper forms are to be transmitted via email or confirmed 
facsimile (fax) transmission to:
SAE Email Address: Refer to Contact Information list.
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SAE Facsimile Number: Refer to Contact Information list.
For studies capturing SAEs through electronic data capture (EDC), electronic submission is the 
required method for reporting. In the event the electronic system is unavailable for transmission, 
paper forms must be used and submitted immediately. When paper forms are used, the original 
paper forms are to remain on site.
SAE Telephone Contact (required for SAE and pregnancy reporting): Refer to Contact
Information list.
If only limited information is initially available, follow-up reports are required. (Note: Follow-up 
SAE reports must include the same investigator term(s) initially reported.) 
If an ongoing SAE changes in its intensity or relationship to study drug or if new information 
becomes available, the SAE report must be updated and submitted within 24 hours to BMS 
(or designee) using the same procedure used for transmitting the initial SAE report.
All SAEs must be followed to resolution or stabilization.
6.2
Nonserious Adverse Events
A nonserious adverse event is an AE not classified as serious.
6.2.1
Nonserious Adverse Event Collection and Reporting
The collection of nonserious AE information should begin at initiation of study drug. Nonserious 
AE information should also be collected from the start of a placebo lead-in period or other 
observational period intended to establish a baseline status for the subjects.
Nonserious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious (see Section 6.1.1). Follow-up is also required for nonserious AEs that cause 
interruption or discontinuation of study drug and for those present at the end of study treatment 
as appropriate. All identified nonserious AEs must be recorded and described on the nonserious 
AE page of the CRF (paper or electronic). 
Completion of supplemental CRFs may be requested for AEs and/or laboratory abnormalities 
that are reported/identified during the course of the study.
6.3
Laboratory Test Result Abnormalities
The following laboratory test result abnormalities should be captured on the nonserious AE CRF 
page or SAE Report Form (paper or electronic) as appropriate:

Any laboratory test result that is clinically significant or meets the definition of an SAE 

Any laboratory test result abnormality that required the subject to have study drug 
discontinued or interrupted

Any laboratory test result abnormality that required the subject to receive specific corrective 
therapy.
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It is expected that wherever possible, the clinical rather than laboratory term would be used by 
the reporting investigator (eg, anemia versus low hemoglobin value).
6.4
Pregnancy
If, following initiation of the study drug, it is subsequently discovered that a study subject is 
pregnant or may have been pregnant at the time of study exposure, including during at least 
5 half lives after product administration, the investigator must immediately notify the BMS 
Medical Monitor/designee of this event and complete and forward a Pregnancy Surveillance 
Form to BMS Designee within 24 hours of awareness of the event and in accordance with SAE 
reporting procedures described in Section 6.1.1.
In most cases, the study drug will be permanently discontinued in an appropriate manner 
(eg, dose tapering if necessary for subject safety). Please call the BMS Medical Monitor within 
24 hours of awareness of the pregnancy.
Protocol-required procedures for study discontinuation and follow-up must be performed on the 
subject.
The investigator must immediately notify the BMS (or designee) Medical Monitor of this event 
and complete and forward a Pregnancy Surveillance Form to BMS (or designee) within 24 hours 
of awareness of the event and in accordance with SAE reporting procedures described in 
Section 6.1.1. 
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome and, where applicable, offspring information must be reported on the Pregnancy 
Surveillance Form.
Any pregnancy that occurs in a female partner of a male study participant should be reported to 
BMS. Information on this pregnancy will be collected on the Pregnancy Surveillance Form.
6.5
Overdose
An overdose is defined as the accidental or intentional administration of any dose of a product 
that is considered both excessive and medically important. All occurrences of overdose must be 
reported as an SAE (see Section 6.1.1 for reporting details.).
6.6
Potential Drug Induced Liver Injury (DILI)
Specific criteria for identifying potential DILI have not been identified for this protocol. 
Standard medical practice in identifying and monitoring hepatic issues should be followed.
6.7
Other Safety Considerations
Any 
significant 
worsening
noted 
during 
interim 
or 
final 
physical 
examinations, 
electrocardiogram, x-ray filming, any other potential safety assessment required or not required 
by protocol should also be recorded as a nonserious or serious AE, as appropriate, and reported 
accordingly. 
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7
DATA MONITORING COMMITTEE AND OTHER EXTERNAL 
COMMITTEES
A Data Monitoring Committee (DMC) will be instituted to perform safety monitoring oversight. 
Details will be contained in the DMC Charter.
8
STATISTICAL CONSIDERATIONS
8.1
Sample Size Determination
This pilot study is planned to randomize approximately 90 subjects to assess the primary 
endpoint of proportion subjects in Renal Response at Day 113 between the IV Abatacept and 
placebo arms. The randomization will be stratified by Genotype for whom test results, obtained 
either prior to enrollment or at screening, are available (APOL1 high risk group vs Others) and 
Age (< 18 and 18).
A total of 90 subjects randomized in a 1:1 ratio to Abatacept vs placebo will yield approximately 
80% power to detect a treatment difference (delta) of 28% between the two treatment arms. This 
power estimate assumes a 2-sided alpha level of 5%, Renal Response rate of 40% and 12% in the 
IV Abatacept and Placebo arms respectively. The 12% estimate of Renal Response in the 
placebo arm was based on observed rate of Renal Response in the FONT II study42 which has a 
similar population that is proposed for the present study and expert opinion.
8.2
Populations for Analyses
Efficacy endpoints will be summarized according to the Intent-to-Treat (ITT) population and 
safety endpoints will be summarized according to the As Treated population. These populations 
are described below along with the Per-Protocol population and the Immunogenicity population.
Intent-to-Treat Analysis Population
The Intent-to-Treat (ITT) Analysis Population is defined to include all subjects randomized into 
the study for whom Case Report Form (CRF) data indicate that at least one dose of study 
medication (IV Abatacept or placebo) is administered during the Double-Blind Period.
All subjects who are randomized but never received study medication are to be excluded. Given 
the blinded nature of this study, it is reasonable to assume that subjects who discontinue prior to 
the receipt of study medication do so for reasons unrelated to study medication. 
Subjects are grouped according to the treatments to which they are randomized by the Central 
Randomization System (IV Abatacept vs placebo). 
ITT Analysis Population is also referred to as ‘All Randomized and Treated Subjects’. 
As-Treated Analysis Population
The As-Treated Analysis Population contain all subjects for whom CRF data indicate that at least 
one dose of study medication was administered during the Double-Blind Period. 
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Subjects are grouped according to the treatments to which they are randomized, except in cases 
where information is available, which indicate that a subject receives a different treatment for the 
entire course of the 16 week Double-Blind Period. In this case, the subject will be presented by 
the treatment they actually received. 
The As Treated Analysis Population will also be referred as ‘All Treated Subjects’. 
Per-Protocol Analysis Population
The Per-protocol Analysis Population is defined as a subset of the ITT Analysis Population 
which excludes subjects who have relevant protocol deviations during the 16 week double-blind 
period. A programmable list of relevant protocol deviations will be included in the Statistical 
Analysis Plan and approved prior to the database lock for the 16 week Double-Blind period.
The Per-protocol Analysis Population will only be used if more than 10% of the subjects in 
either treatment group have relevant protocol deviations. In such a case, the analysis of the 
primary efficacy endpoints will be repeated in the Per-protocol Analysis Population. 
Immunogenicity Analysis Population
The immunogenicity analysis population includes subjects who received at least 1 dose of 
abatacept and had an immunogenicity result available during the Double-Blind Period.
PK Analysis Population
The PK analysis population includes subjects who received at least 1 dose of abatacept and had a 
measurable concentration result available during the Double-Blind Period.
8.3
Endpoints
8.3.1
Primary Endpoint(s)
The primary efficacy endpoint is the proportion of subjects in Renal Response at Day 113. 
8.3.2
Secondary Endpoint(s)
8.3.2.1
Secondary Efficacy Endpoints

Mean change from baseline in UPRC at Day 113.

Mean change from baseline in serum albumin at Day 113

Proportion of subjects achieving complete remission (UPCR 0.3 with eGFR: normal or 
75% baseline if below normal at baseline) at Day 113.

Mean change from baseline in PROMIS measures at Day 113.
8.3.2.2
Safety Endpoints

All adverse events (AEs, SAEs, AEs leading to discontinuation, deaths, etc.)

AEs of interest (infections, malignancies, autoimmune disorders, infusional related reactions, 
renal-related events)
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
Laboratory test abnormalities
8.3.2.3
Immunogenicity Endpoint

Proportion of subjects with positive antibody response relative to baseline over time.
 
8.4
Analyses
8.4.1
Demographics and Baseline Characteristics
Frequency distributions and summary statistics of all demographic variables and baseline 
characteristics will be presented by treatment arm using the ITT population.
8.4.2
Efficacy Analyses
The analysis for the double-blind period will be performed once all subjects complete the Double 
Blind Period Day 113 visit assessment or discontinue prematurely. The double-blind analysis 
will include the analysis of the primary efficacy endpoint and all other efficacy endpoints on 
subjects who were treated in the Double-Blind Period. 
8.4.2.1
Primary Efficacy Analysis: 
The primary comparison of proportion of subjects in renal response at Day 113 at the end of the 
Double Blind period between IV Abatacept and Placebo arm will be assessed using a logistic 
regression model. To account for randomization stratification, the logistic regression model will 
adjust for baseline UPCR and the randomization stratification variables of Genotype (APOL1
high risk group vs Others) and Age (< 18 vs 18). Point estimate of the adjusted Odds Ratios 
(OR) of the odds of achieving Renal Response in the IV Abatacept arm compared to the Placebo 
arm, corresponding 95% CI and p-value will be provided. Unadjusted point estimate of the 
proportion of renal response in each treatment arm and corresponding 95% CI will also be 
provided. All subjects who discontinue prematurely prior to reaching the primary endpoint,
Day 113, assessment visit will be considered as not achieving response in the primary analysis. 
A sensitivity analysis of the primary endpoint will be performed using a logistic regression 
model that does not adjust for the 2 stratification factors. Analysis of the renal response by 
APOL1 and Age subgroups will also be performed to assess differences in renal response within 
each category of stratification variables by treatment arm; details of any additional analyses to 
assess these differences will be provided in the Statistical Analysis Plan. The efficacy analysis 
will be performed based on the ITT population.
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8.4.2.2
Secondary Efficacy Analyses
In addition to the primary efficacy endpoint, analyses related to the secondary efficacy objectives 
will also be included in the double-blind analysis. The secondary efficacy assessment of change 
from baseline in UPRC at Day 113 will be assessed using a longitudinal (repeated measure) 
mixed model including treatment arm, baseline value UPRC and randomization stratification 
factors (genotype and Age), time (study days in which UPRC is measured), and time by 
treatment interaction as fixed effects and subject as a random effect. Adjusted mean, SE, 95% CI 
for adjusted mean difference between treatment arms will be provided. A similar mixed model 
will also be used to assess the change from baseline in serum albumin at Day 113. The model 
will include treatment group, baseline value serum albumin value and randomization 
stratification factors (genotype and age), time (study days in which serum albumin is measured), 
and time by treatment interaction as fixed effects and subject as a random effect. Adjusted mean, 
SE, 95% CI for adjusted mean difference between treatment arms will also be provided. 
The secondary efficacy endpoint of proportion of subjects achieving complete remission (UPCR 
0.3 with eGFR: normal or 75% baseline if below normal at baseline) at Day 113 will be 
assessed using a logistic regression model similar to the one used for the primary efficacy 
endpoint. The logistic regression model will include treatment arm, stratification variables 
(Genotype and Age) and baseline UPCR as continuous variable and point estimate of adjusted 
ORs, corresponding 95% CI will be provided. 
A summary of the analysis methods to be used for the analysis of the primary, secondary and 
exploratory efficacy endpoints are presented in Table 8.4.3-1 below. Further details on the 
primary and secondary analyses along with exploratory evaluations, any additional sensitivity 
analyses and data handling details regarding issues such as missing data are provided in the 
Statistical Analysis Plan.
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8.4.3
Efficacy Analyses
Table 8.4.3-1:
Summary of Planned Efficacy Analyses
Measure of Interest
Analysis Method
Renal Response
Primary Analysis:
Using a logistic regression model that includes treatment arm, randomization 
stratification factor (Genotype, Age) and baseline UPCR as continuous 
variable and point estimate of adjusted ORs, corresponding 95% CI and p-
value will be provided.
Differences in proportions: 
proportion of subjects achieving 
complete remission at Day 113
Secondary Efficacy Analysis:
Using a logistic regression model that includes treatment arm, stratification 
variables (Genotype and Age) and baseline UPCR as continuous variable and 
point estimate of adjusted ORs, corresponding 95% CI will be provided.
Difference in mean change from 
baseline in continuous endpoints 
(UPCR, Serum Albumin,
 
Longitudinal (repeated measure) mixed model [including treatment group, 
baseline value of variable and randomization stratification factors (genotype 
and age), time, and time by treatment interaction as fixed effects and subject 
as a random effect], adjusted mean, SE, 95% CI for adjusted mean difference 
between treatment groups will be provided.
8.4.4
Safety Analyses
Significant physical examination findings, and clinical and laboratory test results will be listed. 
Summary statistics will be tabulated. Frequency distributions and individual listings of all 
adverse events will be generated. Changes from baseline in clinical laboratory test results will be 
summarized and listed. Frequencies of marked abnormal laboratory measures will also be 
provided. Safety analyses will be presented by treatment arms in the Double Blind Period.
8.4.5
Pharmacokinetic Analyses
Summary statistics will be tabulated by age group (<years and 18 years) for the 
pharmacokinetic parameters (Cmax, Tmax, and AUC) and by age group and study day for Cmin. 
Geometric means and coefficients of variation will be presented for Cmin, Cmax and AUC. 
Medians and ranges will be presented for Tmax. The amount of abatacept excreted in urine (Xu) 
will be summarized by collection time.
 
 
8.4.7
Outcomes Research Analyses
Descriptive summary statistics for changes in patient reported outcomes of physical function, 
fatigue and pain interference from baseline over time during the Double-Blind Period for the 
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PROMIS static short forms will be provided by age group (for subjects 18 and older: SF Physical 
Function v1.2 8b, SF Fatigue v1.0 Adult 8a and SF Pain Interference v1.0 Adult 8a; for subjects 
17 and younger and their parent proxy: SF Physical Function - Mobility v1.0 Peds 8a, SF Fatigue 
v1.0 Peds 10a and SF Pain Interference v1.0 Peds 8a). Results for adults and pediatric subjects 
will be reported separately. The results for subjects 17 and younger will also be reported 
separately from their parent proxy form results. The mean change from baseline in these 
measures will be presented based on an analysis of covariance (ANCOVA) model.
8.5
Interim Analyses
No formal interim analysis is planned for this study. Analyses for the DMC reporting will be 
detailed in the DMC analysis plan for the study.
9
STUDY MANAGEMENT
9.1
Compliance
9.1.1
Compliance with the Protocol and Protocol Revisions
The study shall be conducted as described in this approved protocol. All revisions to the protocol 
must be discussed with, and be prepared by, BMS. The investigator should not implement any 
deviation or change to the protocol without prior review and documented approval/favorable 
opinion from the IRB/IEC of an amendment, except where necessary to eliminate an immediate 
hazard(s) to study subjects. 
If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) prior 
to obtaining IRB/IEC approval/favorable opinion, as soon as possible the deviation or change 
will be submitted to:

IRB/IEC for review and approval/favorable opinion

BMS

Regulatory Authority(ies), if required by local regulations
Documentation of approval signed by the chairperson or designee of the IRB(s)/IEC(s) must be 
sent to BMS.
If an amendment substantially alters the study design or increases the potential risk to the 
subject: (1) the consent form must be revised and submitted to the IRB(s)/IEC(s) for review and 
approval/favorable opinion; (2) the revised form must be used to obtain consent from subjects 
currently enrolled in the study if they are affected by the amendment; and (3) the new form must 
be used to obtain consent from new subjects prior to enrollment.
If the revision is done via an administrative letter, investigators must inform their IRB(s)/IEC(s).
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9.1.2
Monitoring
BMS representatives will review data centrally to identify potential issues to determine a 
schedule of on-site visits for targeted review of study records.
Representatives of BMS must be allowed to visit all study site locations periodically to assess the 
data quality and study integrity. On site they will review study records and directly compare 
them with source documents, discuss the conduct of the study with the investigator, and verify 
that the facilities remain acceptable. Certain CRF pages and/or electronic files may serve as the 
source documents.
In addition, the study may be evaluated by BMS internal auditors and government inspectors 
who must be allowed access to CRFs, source documents, other study files, and study facilities. 
BMS audit reports will be kept confidential.
The investigator must notify BMS promptly of any inspections scheduled by regulatory 
authorities, and promptly forward copies of inspection reports to BMS. 
9.1.2.1
Source Documentation
The Investigator is responsible for ensuring that the source data are accurate, legible, 
contemporaneous, original and attributable, whether the data are hand-written on paper or 
entered electronically. If source data are created (first entered), modified, maintained, archived, 
retrieved, or transmitted electronically via computerized systems (and/or any other kind of 
electronic devices) as part of regulated clinical trial activities, such systems must be compliant 
with all applicable laws and regulations governing use of electronic records and/or electronic 
signatures. Such systems may include, but are not limited to, electronic medical/health records 
(EMRs/EHRs), adverse event tracking/reporting, protocol required assessments, and/or drug 
accountability records.
When paper records from such systems are used in place of electronic format to perform 
regulated activities, such paper records should be certified copies. A certified copy consists of a 
copy of original information that has been verified, as indicated by a dated signature, as an exact 
copy having all of the same attributes and information as the original. 
9.1.3
Investigational Site Training
Bristol-Myers Squibb will provide quality investigational staff training prior to study initiation. 
Training topics will include but are not limited to: GCP, AE reporting, study details and 
procedure, electronic CRFs, study documentation, informed consent, and enrollment of WOCBP.
9.2
Records
9.2.1
Records Retention
The investigator must retain all study records and source documents for the maximum period 
required by applicable regulations and guidelines, or institution procedures, or for the period 
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specified by BMS, whichever is longer. The investigator must contact BMS prior to destroying 
any records associated with the study.
BMS will notify the investigator when the study records are no longer needed.
If the investigator withdraws from the study (eg, relocation, retirement), the records shall be 
transferred to a mutually agreed upon designee (eg, another investigator, IRB). Notice of such 
transfer will be given in writing to BMS.
9.2.2
Study Drug Records 
It is the responsibility of the investigator to ensure that a current disposition record of study drug 
(inventoried and dispensed) is maintained at the study site to include investigational product
Records or logs must comply with applicable regulations and guidelines and should include:

amount received and placed in storage area

amount currently in storage area

label identification number or batch number 

amount dispensed to and returned by each subject, including unique subject identifiers

amount transferred to another area/site for dispensing or storage

nonstudy disposition (eg, lost, wasted) 

amount destroyed at study site, if applicable

amount returned to BMS

retain samples for bioavailability/bioequivalence, if applicable

dates and initials of person responsible for Investigational Product dispensing/accountability, 
as per the Delegation of Authority Form.
BMS will provide forms to facilitate inventory control if the investigational site does not have an 
established system that meets these requirements.
9.2.3
Case Report Forms
An investigator is required to prepare and maintain adequate and accurate case histories designed 
to record all observations and other data pertinent to the investigation on each individual treated 
or entered as a control in the investigation. Data that are derived from source documents and 
reported on the CRF must be consistent with the source documents or the discrepancies must be 
explained. Additional clinical information may be collected and analyzed in an effort to enhance 
understanding of product safety. CRFs may be requested for AEs and/or laboratory abnormalities 
that are reported or identified during the course of the study.
For sites using the BMS electronic data capture tool, electronic CRFs will be prepared for all 
data collection fields except for fields specific to SAEs and pregnancy, which will be reported on 
the paper or electronic SAE form and Pregnancy Surveillance form, respectively. If electronic 
SAE form is not available, a paper SAE form can be used. Spaces may be left blank only in those 
circumstances permitted by study-specific CRF completion guidelines provided by BMS. 
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The confidentiality of records that could identify subjects must be protected, respecting the 
privacy and confidentiality rules in accordance with the applicable regulatory requirement(s).
The investigator will maintain a signature sheet to document signatures and initials of all persons 
authorized to make entries and/or corrections on CRFs. 
The completed CRF, including any paper or electronic SAE/pregnancy CRFs, must be promptly 
reviewed, signed, and dated by the investigator or qualified physician who is a subinvestigator
and who is delegated this task on the Delegation of Authority Form. For electronic CRFs, review 
and approval/signature is completed electronically through the BMS electronic data capture tool.
The investigator must retain a copy of the CRFs including records of the changes and 
corrections.
Each individual electronically signing electronic CRFs must meet BMS training requirements 
and must only access the BMS electronic data capture tool using the unique user account 
provided by BMS. User accounts are not to be shared or reassigned to other individuals.
9.3
Clinical Study Report and Publications
A Signatory Investigator must be selected to sign the clinical study report. 
For this protocol, the Signatory Investigator will be selected as appropriate based on the 
following criteria:

Study Steering Committee chair or their designee

Subject recruitment (eg, among the top quartile of enrollers)

Involvement in trial design
The data collected during this study are confidential and proprietary to BMS. Any publications 
or abstracts arising from this study must adhere to the publication requirements set forth in the 
clinical trial agreement (CTA) governing [Study site or Investigator] participation in the study. 
These requirements include, but are not limited to, submitting proposed publications to BMS at 
the earliest practicable time prior to submission or presentation and otherwise within the time 
period set forth in the CTA.
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10
GLOSSARY OF TERMS
Term
Definition
Complete Abstinence
Complete Abstinence is defined as complete avoidance of heterosexual 
intercourse and is an acceptable form of contraception for all study drugs. This 
also means that abstinence is the preferred and usual lifestyle of the patient. 
This does not mean periodic abstinence (eg, calendar, ovulation, 
symptothermal, profession of abstinence for entry into a clinical trial, post-
ovulation methods) and withdrawal, which are not acceptable methods of 
contraception. Women must continue to have pregnancy tests. Acceptable 
alternate methods of highly or less effective contraception’s must be discussed 
in the event that the subject chooses to forego complete abstinence.
Renal Responder
Renal responders are defined as subjects who achieve a reduction of their 
baseline UPCR of 50% and to less than 3 with no worsening of baseline 
estimated glomerular filtration rate (eGFR: normal or 75% baseline if below 
normal at baseline).
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11
LIST OF ABBREVIATIONS
Term
Definition
ACEi
angiotensin-converting-enzyme inhibitor
ACTH
adrenocorticotropic hormone
AE
adverse event
aGVHD
Acute graft-versus-host disease
ALT
alanine aminotransferase
ARB
angiotensin receptor blocker
AST
aspartate aminotransferase
AUC
area under the concentration-time curve
-HCG
beta-human chorionic gonadotrophin
BMI
body mass index
BMS
Bristol-Myers Squibb
BP
blood pressure
BUN
blood urea nitrogen
C
Celsius
CBC
complete blood count
CDC ACIP
The Center for Disease Control Advisory Committee on Immunization 
Practices
CFR
Code of Federal Regulations 
CHF
Congestive heart failure
CI
confidence interval
CKD-EPI
Chronic Kidney Disease - Epidemiology
C1-
chloride
cm
centimeter
Cmax
Peak serum concentration of abatacept
Cmin
Trough level serum concentration of abatacept
CRF
Case Report Form, paper or electronic
CS
corticoseroids
CTA
Clinical trial agreement
CXR
Chest X-ray
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Term
Definition
DB
Double-blind
DILI
Drug induced liver injury
dL
deciliter
DMC
Data Monitoring Committee
DNA
Deoxyribonucleic acid
D5W
5% Dextrose in Water
ECL
electrochemiluminescence
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
eg
exempli gratia (for example)
eGFR
Estimated glomerular filtration rate
EIA
enzyme immunoassay
ELISA
Enzyme-linked immunoabsorbent assay
EMRs/EHRs
electronic medical/health records 
ER
Emergency room
ESRD
End stage renal disease
F
Fahrenheit
FDA
Food and Drug Administration
FSGS
Focal Segmental Glomerulosclerosis
FSH
follicle stimulating hormone
g
gram
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
GFR
glomerular filtration rate
h
hour
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
Hgb
hemoglobin
HIPAA
Health Insurance Portability and Accountability Act
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Term
Definition
HIV
Human Immunodeficiency Virus
HRT
hormone replacement therapy
hsCRP
High sensitivity C-reactive protein
HSDS
height standard deviation score
IB
Investigator Brochure
ICD
International Classification of Diseases
ICF
Informed consent
ICH
International Conference on Harmonisation 
ie
id est (that is)
IEC
Independent Ethics Committee
IFN-
Interferon gamma release assay
Ig
immunoglobulin
IMP
investigational medicinal products
IND
Investigational New Drug Exemption
INH
isoniazid
IP
Investigational product
IRB
Institutional Review Board
ITT
Intent-to-Treat
IU
International Unit
IUD
Intrauterine device
IUS
Intrauterine-hormonal releasing system
IV
intravenous
kg
kilogram
JIA
Juvenile idiopathic arthritis
L
liter
LAM
lactation amenorrhea method
ln
natural logarithm
LN
Lupus nephritis
LPLV
Last patient last visit
MCD
Minimal Change Disease
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Term
Definition
mg
milligram
min
minute
mL
milliliter
MMF
mycophenolate mofetil
mmHg
millimeters of mercury
MPA
mycophenolic acid
MTD
maximum tolerated dose
g
microgram
N
number of subjects or observations
N/A
not applicable
ng
nanogram
Non-IMP
non-investigational medicinal product
NS
Nephrotic Syndrome
NSAID
nonsteroidal anti-inflammatory drug
NYHA
New York Heart Association
OLE
Open Label Extension
OR
Odds ratio
PA
posterioranterior
PD
pharmacodynamics
PEF
Peak expiratory flow
pJIA
Polyarticular juvenile idiopathic arthritis
PK
pharmacokinetics
PPD
Purified protein derivative
PROMIS
Patient Reported Outcomes Measurement Information System
RA
Rheumatoid arthritis
RAS
Renin-angiotensin system
RBC
red blood cell
RNA
Ribonucleic acid
SAE
serious adverse event
SD
standard deviation
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Term
Definition
SLE
Systemic lupus erythematosus
SNPs
single nucleotide polymorphisms
SOP
Standard Operating Procedures
Subj
subject
t
temperature
T
time
TAO
Trial Access Online, the BMS implementation of an EDC capability
TB
tuberculosis
Tmax
Time to reach peak serum concentration of abatacept
TRNS
Treatment Resistant Nephrotic Syndrome
ULN
Upper limit normal
UPCR
Urine Protein to Creatinine Ratio
UR
urinary recovery
URI
Upper respiratory infections
WBC
white blood cell
WHO
World Health Organization
WOCBP
women of childbearing potential
Xu
Amount of abatacept excreted in urine
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APPENDIX 1
CENTRAL PATHOLOGY REVIEW
CENTRAL PATHOLOGY REVIEW SOURCE DOCUMENT
FOCAL SEGMENTAL GLOMERULOSCLEROSIS
Page 1 of 2
Site #
Subject #
Date of Kidney Biopsy 
Report 
(DD-MMM-YYYY)
Date Sent to Central 
Reader
(DD-MMM-YYYY)
Instructions: LM, IF/IHC, and EM are required to fulfill pathologic enrollment criteria for 
FSGS.
Check Response
Inclusion Criteria
__ Yes
__ No

LM: Minimum sample requirement is 5 or more glomeruli for LM in 
the LM/IF/IHC/EM sections combined.  At least one glomerulus in 
combined tissue for LM/IF/IHC/EM with segmental sclerosis (with or 
without hyalinosis) or consolidation described in the Columbia FSGS 
Classification System (excluding collapsing variant) or as described 
for infantile/childhood “diffuse mesangial sclerosis”. If yes, classify 
as:
__
NOS variant
__
Tip variant
__
Perihilar variant
__
Cellular variant
__
“Diffuse mesangial sclerosis” using CureGN criteria
__
Indeterminate (insufficient for confident classification)
__ Yes
__ No

IF/IHC: <1+ glomerular staining for IgG and IgA; and ≤ 1+ 
glomerular IgM, C3 and C1q (on a scale of 0-3 or 0-4) (except in 
areas of hyalinosis or sclerosis). Note: >1+ staining for C1q reflexes 
case to C1qN enrollment.
__ Yes
__ No

EM: Absence of immune complex-type electron dense deposits other 
than small segmental mesangial dense deposits (except in cases 
reflexed to C1qN).
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CENTRAL PATHOLOGY REVIEW SOURCE DOCUMENT
FOCAL SEGMENTAL GLOMERULOSCLEROSIS
Page 2 of 2
Check Response
Exclusion Criteria:
__ Yes
__ No

LM/IF/IHC/EM findings indicative of other glomerular disease 
[including collapsing FSGS (collapsing glomerulopathy)]
__ Yes
__ No

IF/IHC: ≥1+ glomerular staining for IgG and IgA, and >1+ glomerular 
IgM, C3 and C1q (on a scale of 0-3 or 0-4) (except in areas of 
hyalinosis or sclerosis). Note: >1+ staining for C1q reflexes case to 
C1qN enrollment.
__ Yes
__ No

EM: Widespread well-defined immune complex-type electron dense 
deposits (except in cases reflexed to C1qN).
Non-Excluding Pathology Findings:
__

LM: Mild mesangial hypercellularity or concurrent features of 
arterionephrosclerosis.
Check Response
Assessment of Central Pathology Reader
__ Yes
__ No

Pathology entry criteria for FSGS fulfilled
Date of Assessment (DD-MMM-YYYY) _______________ 
Assessor Initials: __________
__

Reflexed to C1q nephropathy
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CENTRAL PATHOLOGY REVIEW SOURCE DOCUMENT
MINIMAL CHANGE DISEASE
Page 1 of 2
Site #
Subject #
Date of Kidney Biopsy 
Report 
(DD-MMM-YYYY)
Date Sent to Central 
Reader
(DD-MMM-YYYY)
Instructions: LM, IF/IHC and EM are required to fulfill pathologic enrollment criteria for 
MCD.
Check 
Response
Inclusion Criteria
__ Yes
__ No

LM: Ten or more nonsclerotic glomeruli must be available for examination 
in LM/IF/IHC/EM. Histologically unremarkable glomeruli except for 
mesangial hypercellularity and globally sclerotic obsolescent glomeruli. 
Note: Any amount of mesangial hypercellularity will be allowed and scored 
later
__ Yes
__ No

IF/IHC: <1+ glomerular staining for IgG and IgA and ≤ 1+ glomerular C3 
and C1q (on a scale of 0-3 or 0-4). Any intensity of IgM staining is allowed 
and the intensity scored later. Note: >1+ staining for C1q reflexes case to 
C1qN enrollment.
__ Yes
__ No

EM: Absence of immune complex-type electron dense deposits (except in 
cases reflexed to C1qN). Any degree of foot process effacement is allowed, 
however, if there is minimal or no foot process effacement, clinical/laboratory 
features must strongly support a diagnosis of MCD in the patient (e.g. 
substantial proteinuria at some point in the course of disease).
Check 
Response
Exclusion Criteria:
__ Yes
__ No

LM/IF/IHC/EM findings indicative of other glomerular disease.
__ Yes
__ No

IF/IHC: ≥1+ glomerular staining for IgG, and IgA, and >1+ glomerular C3 
or C1q (on a scale of 0-3 or 0-4). Note: >1+ staining for C1q reflexes case to 
C1qN enrollment.
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CENTRAL PATHOLOGY REVIEW SOURCE DOCUMENT
MINIMAL CHANGE DISEASE
Page 2 of 2
Check 
Response
Exclusion Criteria
__ Yes
__ No

EM: Immune complex-type electron dense deposits (except in cases reflexed to 
C1qN).
Check 
Response
Non-Excluding Pathology Findings:
__

LM:
Globally sclerotic glomeruli, mild mesangial hypercellularity,
or
concurrent features of arterionephrosclerosis
Check 
Response
Assessment of Central Pathology Reader
__ Yes
__ No

Pathology entry criteria for MCD fulfilled
Date of Assessment (DD-MMM-YYYY) _______________
Assessor Initials: __________
__

Reflexed to C1q nephropathy
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CENTRAL PATHOLOGY REVIEW SOURCE DOCUMENT
C1q Nephropathy 
Site #
Subject #
Date of Kidney Biopsy 
Report 
(DD-MMM-YYYY)
Date Sent to Central 
Reader
(DD-MMM-YYYY)
Check 
Response
Inclusion Criteria:
__ MCD
__ FSGS

LM: Light microscopic findings fulfilling CureGN criteria for minimal 
change disease or focal segmental glomerulosclerosis (excluding collapsing 
variant). If yes for FSGS, classify as follows:
__
NOS variant
__
Tip variant
__
Perihilar variant
__
Cellular variant
__
Indeterminate (insufficient for confident classification)
__ Yes
__ No

IF/IHC: >1+ staining for C1q with any amount of staining for IgG, IgA, 
IgM and C3 (on a scale of 0-3 or 0-4).
__ Yes
__ No

EM: Mesangial immune complex-type electron dense deposits with or 
without scattered subendothelial and subepithelial deposits.
Check 
Response
Exclusion Criteria:
__ Yes
__ No

LM/IF/IHC/EM findings indicative of glomerular disease other than MCD 
or FSGS, especially lupus GN.
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Check 
Response 
Non-Excluding Pathology Findings:
__

LM: Globally sclerotic glomeruli, mild mesangial hypercellularity or 
concurrent features of arterionephrosclerosis
Check 
Response
Assessment of Central Pathology Reader
__ Yes
__ No

Pathology entry criteria for C1qN fulfilled
Date of Assessment (DD-MMM-YYYY) _______________
Assessor Initials: __________
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APPENDIX 2
METHODS OF CONTRACEPTION
At a minimum, subjects must agree to use one highly effective method of contraception as listed 
below:
HIGHLY EFFECTIVE METHODS OF CONTRACEPTION
Highly effective methods of contraception have a failure rate of < 1% when used consistently 
and correctly. WOCBP and female partners of male subjects, who are WOCBP, are expected to 
use one of the highly effective methods of contraception listed below. Male subjects must inform 
their female partners who are WOCBP of the contraceptive requirements of the protocol and are 
expected to adhere to using contraception with their partner. Contraception methods are as 
follows:
1) Progestogen only hormonal contraception associated with inhibition of ovulation.
2) Hormonal methods of contraception including oral contraceptive pills containing combined 
estrogen + progesterone, vaginal ring, injectables, implants and intrauterine devices (IUDs) 
such as Mirena
3) Nonhormonal IUDs, such as ParaGard
4) Bilateral tubal occlusion
5) Vasectomised partner with documented azoospermia 90 days after procedure
a) Vasectomised partner is a highly effective birth control method provided that partner is 
the sole sexual partner of the WOCBP trial participant and that the vasectomised partner 
has received medical assessment of the surgical success.
6) Intrauterine hormone-releasing system (IUS).
7) Complete abstinence
a) Complete abstinence is defined as the complete avoidance of heterosexual intercourse 
(refer to Glossary of Terms)
b) Complete abstinence is an acceptable form of contraception for all study drugs and must 
be used throughout the duration of the study treatment (plus 5 half-lives of the 
investigational drug plus 30 days).
c) It is not necessary to use any other method of contraception when complete abstinence is 
elected.
d) Subjects who choose complete abstinence must continue to have pregnancy tests, as 
specified in Section 6.4.
e) Acceptable alternate methods of highly effective contraception must be discussed in the 
event that the subject chooses to forego complete abstinence.
f)
The reliability of sexual abstinence needs to be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the subject.
Local laws and regulations may require use of alternative and/or additional contraception 
methods.
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UNACCEPTABLE METHODS OF CONTRACEPTION
1) Periodic abstinence (calendar, symptothermal, post-ovulation methods)
2) Withdrawal (coitus interruptus)
3) Spermicide only
4) Lactation amenorrhea method (LAM)
 
 
 
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APPENDIX 3
LABORATORY GUIDELINES: PATIENT STUDIES 
Laboratory test results, which meet these criteria, and the Investigator feels is clinically relevant 
should be described on the Adverse Event Form. Those which are judged to be SERIOUS events 
require the completion of a Serious Adverse Event Form (see Sections 6.1.1 and 6.3).
[NOTE:  LLN = lower limit of normal; ULN = upper limit of normal.]
albumin - < 0.9xLLN or if pretreatment value is < LLN, < 0.75x pretreatment
alkaline phosphatase - >2 x ULN; or if pretreatment > ULN, 3x pretreatment value
basophils (%) - > 3% if 0-1% pretreatment, > 3x pretreatment value if pretreatment > 1%
bilirubin
a.
direct - > 1.5x ULN, or if pretreatment above ULN, > 2x pretreatment
b. total - > 2x upper limit of normal, or if pretreatment above ULN, > 4 x pretreatment 
value
blasts - > 0
blood urea nitrogen (BUN) - > 2x pretreatment
calcium - < 0.8x LLN or > 1.2x ULN; < 0.75x pretreatment if pretreatment below LLN, or 
> 1.25x pretreatment if pretreatment above ULN; > ULN if < LLN pretreatment, or < LLN if 
> ULN pretreatment
chloride - < 0.9x LLN or > 1.1x ULN; or < 0.9x pretreatment if pretreatment below LLN, or 
> 1.1x pretreatment if pretreatment above ULN; > ULN if < LLN pretreatment, or < LLN if 
> ULN pretreatment
creatinine - >1.5x pretreatment value
eosinophils (%) - > 3x pretreatment and > 8% if pretreatment normal; if pretreatment > ULN, 
> 3 x pretreatment
erythrocytes - < 0.75x pretreatment value
estimated glomerular filtration rate (eGFR):  0.5x pre-treatment
glucose - < 0.8x LLN or >1.5x ULN; if pretreatment < LLN then < 0.8x pretreatment; if 
pretreatment > ULN then >2x pretreatment; < LLN if > ULN pretreatment, or > ULN if < LLN 
pretreatment
hematocrit - < 0.75x pretreatment
hemoglobin - > 3 g/dL decrease from pretreatment value
lactic dehydrogenase (LDH) - > 1.5x ULN; if pretreatment value is above ULN, > 3x 
pretreatment value
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leukocyte (WBC) count - < 0.75 x LLN or >1.25x ULN; <0.8x pretreatment if pretreatment 
< LLN or > 1.2x pretreatment if pretreatment > ULN; > ULN if pretreatment < LLN or < LLN if 
> ULN pretreatment
lymphocytes (%) - < 0.5x LLN or > 2.0 x ULN, or < 0.5x pretreatment if below LLN 
pretreatment; > 2.0x pretreatment if above ULN pretreatment. > ULN if < LLN pretreatment, or 
< LLN if > ULN pretreatment
monocytes (%) - > 2x ULN; >2x pretreatment if pretreatment above ULN
neutrophil count (neutrophils+bands) - < 0.67x pretreatment if pretreatment < 1000/mm3; 
otherwise, < 1000/mm3.
phosphate - < 0.75 x LLN or > 1.25x ULN; < 0.67x pretreatment value if below LLN 
pretreatment, or > 1.33x pretreatment if above ULN pretreatment; > ULN if < LLN pretreatment, 
or < LLN if >ULN pretreatment
platelet count - < 0.67x LLN or > 1.5 x ULN; if below normal pretreatment, < 0.5x pretreatment 
value and < 100,000/mm3
potassium - < 0.9x LLN or > 1.1x ULN; < 0.9x pretreatment if pretreatment below LLN, or 
> 1.1x pretreatment if pretreatment above ULN; > ULN if < LLN pretreatment, or < LLN if 
> ULN pretreatment
protein, total - < 0.9x LLN or > 1.1x ULN; < 0.9 x pretreatment if below LLN pretreatment, or 
> 1.1x ULN if above ULN pretreatment; > ULN if < LLN pretreatment, or < LLN if > ULN 
pretreatment
SGOT and SGPT (ASAT and ALAT) - > 3 x upper limit of normal; if pretreatment above 
ULN, > 4x pretreatment value
sodium - < 0.95x LLN or > 1.05x ULN; < 0.95x pretreatment if below LLN pretreatment, 
> 1.05x pretreatment if above ULN pretreatment; > ULN if < LLN pretreatment, or < LLN if 
> ULN pretreatment
uric acid - > 1.5x ULN; if pretreatment above ULN, > 2x pretreatment value
urinalysis
a) urinary protein - > 1 gram/24 hours and 2x pretreatment value
b) urinary RBC - > 5/HPF or, > 4x pretreatment if pretreatment value 5/HPF
c) urinary WBC - > 5/HPF or, > 4x pretreatment if 5/HPF pretreatment
d) creatinine clearance (glomerular filtration rate) - < 0.67x pretreatment value
e) urine dipstick measurements:  Protein, blood, sugar, and acetone- 2+, or if 
1+ pretreatment, 2x pretreatment. Do not evaluate protein if quantitative protein 
determination done
stool hemoccult - positive if negative pretreatment
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APPENDIX 4
PROMIS QUESTIONNAIRES (ADULT, PARENT PROXY, AND 
PEDIATRIC)
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SAP_001.pdf: 
Official Title of Study: 
A Phase II Randomized, Placebo-Controlled, Double-Blind, Parallel Arms, Pilot Study to 
Evaluate the Efficacy and Safety of Intravenous Abatacept in Treatment Resistant Nephrotic 
Syndrome (Focal Segmental Glomerulosclerosis/ Minimal Change Disease) 
 
NCT Number: NCT02592798 
 
Document Date (Date in which document was last revised): November 06, 2018 
 


STATISTICAL ANALYSIS PLAN
FOR TREATMENT RESISTANT NEPHROTIC SYNDROME
A PHASE II RANDOMIZED, PLACEBO-CONTROLLED, DOUBLE-BLIND, 
PARALLEL ARMS, PILOT STUDY TO EVALUATE THE EFFICACY AND SAFETY OF 
INTRAVENOUS ABATACEPT INTREATMENT RESISTANT NEPHROTIC 
SYNDROME (FOCAL SEGMENTAL GLOMERULOSCLEROSIS/ MINIMAL CHANGE)
PROTOCOL(S) IM101566
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Statistical Analysis Plan
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BMS-188667
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TABLE OF CONTENTS
STATISTICAL ANALYSIS PLAN FOR TREATMENT RESISTANT NEPHROTIC 
SYNDROME ...........................................................................................................1
TABLE OF CONTENTS............................................................................................................2
LIST OF TABLES......................................................................................................................4
2
STUDY DESCRIPTION ..........................................................................................7
2.1
Study Design ............................................................................................................7
2.2
Treatment Assignment..............................................................................................8
2.3
Blinding and Unblinding...........................................................................................8
2.4
Protocol Amendments...............................................................................................9
2.5
Safety Monitoring...................................................................................................10
3
OBJECTIVES ........................................................................................................10
3.1
Primary Objective...................................................................................................10
3.2
Secondary Objectives .............................................................................................10
4
ENDPOINTS..........................................................................................................11
4.1
Primary Endpoint....................................................................................................11
4.2
Secondary Efficacy Endpoints ................................................................................11
4.3
Safety Endpoints.....................................................................................................11
4.4
Laboratory test abnormalities.Immunogenicity Endpoints.......................................12
5
SAMPLE SIZE AND POWER...............................................................................12
6
STUDY PERIODS, TREATMENT REGIMENS AND POPULATIONS 
FOR ANALYSES ..................................................................................................12
6.1
Study Periods..........................................................................................................12
6.2
Treatment Regimens...............................................................................................13
6.3
Populations for Analyses ........................................................................................14
6.3.1
Intent-to-Treat Analysis Population........................................................................14
6.3.2
As-Treated Analysis Population..............................................................................14
6.3.3
Per-Protocol Analysis Population...........................................................................14
6.3.4
Immunogenicity Analysis Population ......................................................................15
6.3.5
PK Analysis Population..........................................................................................15
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STATISTICAL ANALYSES..................................................................................15
7.1
General Methods ....................................................................................................15
7.2
Study Conduct........................................................................................................16
7.3
Study Population ....................................................................................................16
7.3.1
Subject Disposition.................................................................................................16
7.3.2
Demographic and Baseline Disease Characteristics...............................................17
7.3.3
Medical History and Prior Medication ...................................................................17
7.4
Extent of Exposure .................................................................................................18
7.4.1
Study Therapy.........................................................................................................18
7.4.2
Discontinuations from Study Medication.................................................................19
7.4.3
Treatment Compliance............................................................................................20
7.5
Efficacy..................................................................................................................20
7.5.1
Analysis of Primary Efficacy Endpoint....................................................................21
7.5.2
Sensitivity Analysis .................................................................................................21
7.5.3
Analysis of Secondary Efficacy Endpoints...............................................................21
7.5.4
Analysis of Exploratory Efficacy Endpoints ............................................................23
7.5.5
Subgroup Analysis..................................................................................................24
7.6
Safety.....................................................................................................................25
7.6.1
Adverse Events .......................................................................................................25
7.6.2
Adverse Events of Interest.......................................................................................26
7.6.2.1
Renal Related Events..............................................................................................26
7.6.2.2
Infections................................................................................................................26
7.6.2.3
Malignancy.............................................................................................................27
7.6.2.4
Autoimmune Disorders ...........................................................................................27
7.6.2.5
Infusional Reactions ...............................................................................................27
7.6.3
Incidence Rate Analyses .........................................................................................27
7.6.4
Multiple Adverse Events .........................................................................................28
7.6.4.1
EudraCT Summaries...............................................................................................28
7.6.5
Laboratory Data.....................................................................................................29
7.6.6
Vital Signs ..............................................................................................................30
7.7
Other Analyses .......................................................................................................30
7.7.1
Immunogenicity ......................................................................................................30
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7.7.2
Pharmacokinetic Endpoints....................................................................................31
8
CONVENTIONS....................................................................................................31
8.1
Definitions..............................................................................................................31
8.1.1
Renal Response.......................................................................................................31
8.1.2
Complete remission ................................................................................................32
8.1.3
Prednisone or Prednisone Equivalent Use..............................................................32
8.2
Determination of Responders..................................................................................33
8.3
Baseline Measurements ..........................................................................................34
8.4
Missing Measurements ...........................................................................................34
8.5
Multiple Measurements ..........................................................................................34
8.6
Day Ranges for Analysis Time Points.....................................................................34
9
CONTENT OF REPORTS .....................................................................................40
APPENDIX 1
DOCUMENT HISTORY .......................................................................41
APPENDIX 2
RELEVANT PROTOCOL DEVIATIONS.............................................42
APPENDIX 3
CLINICAL REPORTS CONTENT........................................................43
LIST OF TABLES
Table 2.4-1:
Protocol Amendment................................................................................9
Table 7.5.5-1:
Subgroup of Interest of the Primary Efficacy Assessment of Renal 
Response ................................................................................................24
Table 7.6.5-1:
Definitions of Analytes Cut Points..........................................................29
Table 8.6-1:
Day Ranges for Components of Renal Response, Component of 
Completed Remission and Outcomes Research Assessments at 
Every Scheduled Visit During the Double-Blind Period and OLE 
Period.....................................................................................................35
Table 8.6-2:
For Subjects who Completed Period 1 and Entered Period 2 prior 
to the Protocol Revision..........................................................................35
Table 8.6-3:
Day Ranges for Laboratory Assessments at Every Scheduled Visit 
During the Double-Blind Period and OLE Period ...................................36
Table 8.6-4:
For Subjects who Completed Period 1 and Entered Period 2 prior 
to the Protocol Revision..........................................................................37
Table 8.6-5:
Day Ranges for Immunogenicity Assessments at Every Scheduled 
Visit During the Double -Blind Period and Follow-Up Period ................39
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Table 8.6-6:
For Subjects who Completed Period 1 and Entered Period 2 prior 
to the Protocol Revision..........................................................................39
Table 9-1:
Document History ..................................................................................41
Table 9-2:
Safety Analysis by Period.......................................................................43
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Research Hypothesis:
Subjects with treatment resistant nephrotic syndrome (TRNS) due to either focal segmental 
glomerulosclerosis (FSGS) or Minimal Change Disease (MCD) [(TRNS (FSGS/MCD] will 
demonstrate improvement in proteinuria when treated with abatacept.
Schedule of Analyses:
There are two planned analysis in this study; one at the end of double-blind treatment period and 
the other at the end of study 
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•
Double-blind period analysis: This analysis will be performed for the double-blind period 
when all subjects complete their Day 113 visit assessment or discontinue prematurely prior to 
Day 113. At the time of the first analysis the data will be unblinded. This analysis will include 
primary endpoint and secondary endpoints.
•
End of study analysis: A second analysis will be performed at the end of the study when all 
subjects complete their open label extension (OLE) and follow-up period or discontinue 
prematurely.
This statistical analysis plan will describe the analysis to be performed at the end of the double-
blind period and at the end of the study.
Prior to Protocol Amendment 2, the study design had a blinded-study drug period that was twice 
as long as the current double-blind period and was divided into 2 periods of equal length, known 
as Period 1 and Period 2, so that randomized subjects could switch blinded therapy. The current 
design eliminates Period 2 and renames the previous Period 1 as the double-blind period.
This modification does not impact the primary nor secondary study objectives. It does impact the 
exploratory objectives which addressed persistence of response and onset of response during 
Period 2, these are now eliminated.
For subjects who completed Period 1 and entered Period 2 prior to the protocol revision, the 
Period 1 data will be analyzed as part of the double-blind period since study execution during this 
timeframe is unchanged, the Period 2 data will only be listed. Period 2 data won’t be part of any
summaries except for safety summaries at the end of the study on the cumulative abatacept safety 
period.
2
STUDY DESCRIPTION
2.1
Study Design
This is a phase II randomized, placebo-controlled, double-blind, parallel arm design study to 
evaluate the efficacy and safety of intravenous abatacept in treatment resistant nephrotic syndrome 
(Focal Segmental Glomerulosclerosis / Minimal Change) in adult and pediatric subjects.
This pilot study will randomize approximately 90 subjects 1:1 to intravenous (IV) abatacept or 
placebo in a double-blind (DB) fashion. The randomization will be stratified by Genotype for 
whom test results, obtained either prior to enrollment or at screening, are available (APOL1 high 
risk group vs. Others) and Age (< 18 y and ≥18 y).
The trial will consist of 4 periods: the screening period will be 28 days (can be extended an 
additional 14 days to complete testing by repeating screening labs), a 16 week double-blind 
treatment period (parallel arms: IV abatacept vs. IV placebo), a 168 day abatacept open label 
extension period (OLE), and a 6 month follow-up period.
Subjects randomized to abatacept treatment in the double-blind period will be dosed as follows. 
Adults will use the weight-tiered dose: < 60kg: 500mg, 60 to 100kg: 750mg, > 100kg: 1000mg; 
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pediatric patients 6 to 17 years who weigh < 75kg will receive:10mg/kg and those who weigh 
≥75kg will follow adult dosing. Dosing is on Day 1, 15, 29, 57, 85. Subject in the placebo arm 
will receive normal Saline or D5W following the same dosing schedule. In the OLE, subjects who 
enter will all receive age and weight-based IV abatacept every 28 days for 169 days.
The primary efficacy assessment, renal response (defined in Section 8.1.1), will be on Day 113. 
On Day 113, all subjects who choose to receive open label therapy with abatacept will enter the 
OLE. During the OLE, the durability (i.e., continuity of response) and stability (i.e., the change in
urine protein/creatinine ratio (UPCR)) of response will be determined by continuing to capture and 
describe the same study outcomes among responders. Adjustment of background therapy will also 
be allowed during the OLE at the discretion of the investigators and subjects to determine the 
relative contribution (or need) of these agents for renal responses.
2.2
Treatment Assignment
Subjects are randomized in a 1:1 ratio within each of the strata to the abatacept or placebo treatment 
arms across all sites in the double-blind period. The randomization will be stratified by Genotype 
for whom test results, obtained either prior to enrollment or at screening, are available (APOL1 
high risk group vs. Others) and Age (< 18 y and ≥18 y). Subjects who refuse genotyping will be 
considered as in the “Others” Genotype group.
2.3
Blinding and Unblinding
The subjects and clinical assessor(s) are not aware of which treatment is being administered to the 
subjects enrolled in the study. The pharmacist (or qualified drug preparation person) will be 
unblinded to study medication (abatacept or placebo).
The pharmacist (or qualified drug preparation person) will know the scheduled assignments and 
prepare the appropriate dose of active - abatacept or placebo accordingly. The prepared drug must 
be supplied to study personnel in a manner such that neither study personnel nor subjects will be 
aware of whether they receive active drug or placebo.
Blinding is critical to the integrity of this clinical drug trial. However, in the event of a medical 
emergency or pregnancy in an individual subject, in which knowledge of the investigational 
product is critical to the subject's management, the blind for that subject may be broken by the 
treating physician.
Before breaking the blind of an individual subject's blinded treatment, the Investigator should 
determine that the information is necessary, i.e., that it will alter the subject's immediate 
management. In many cases, particularly when the emergency is clearly not investigational 
product-related, the problem may be properly managed by assuming that the subject is receiving 
active product without the need for unblinding.
BMS personnel will be blinded to treatment assignment until all subjects have completed Day 113
and the database is locked for primary analysis.
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The following individuals will have access to the treatment code during the study:
•
As described in the DMC Charter, the members of the independent data monitoring committee 
(DMC) and the external reporting statistician will be partially unblinded with a right to fully 
unblind treatment codes if necessary to enable review of the emerging data.
•
Personnel charged with generating and maintaining randomization files, packaging study 
medication, and operating the IVRS will also have access to treatment codes.
•
Bioanalytical Scientist or its designate will be unblinded to the randomized treatment 
assignments in order to minimize unnecessary PK analysis of samples from control group 
subjects. A single pharmacokinetist in Discovery Medicine and Clinical Pharmacology may
be unblinded in order to prepare preliminary summaries of pharmacokinetic, 
pharmacodynamics, and safety data, as needed (for example by the Data Monitoring 
Committee) before randomization codes will be broken after final database lock. These 
summaries will not reveal individual subjects’ treatment assignments.
2.4
Protocol Amendments
The protocol currently has two amendments. The table below summarizes the main purpose of the 
amendments.
Table 2.4-1:
Protocol Amendment
Amendment 
No.
Amendment 
Date
Main Purpose of Amendment
1
17-Apr-2017
Added EUDRACT number since the study is enrolling pediatric 
subjects. Changed address and telephone for the Medical Monitor. 
Changed address for Bristol Myers Squibb. Decreased minimum eGFR 
at screening to ≤45 for subjects < 18 years using the new Schwarz 
equation. Amended the Post Study Drug Access to indicate the post 
study drug will be available for subjects who demonstrate clinical 
benefit at the conclusion of the study. Clarified description for 
treatment resistance and treatment intolerance. Clarified language 
regarding treatment with an ACE or ARB. Deleted detailed description 
on method of contraception from the body of the protocol and added 
APPENDIX 2. Updated numbering of other appendices. Added 
exclusion for subjects who are post-renal transplantation, including 
relapsing post-transplant FSGS. Clarified Restricted Treatment and 
Other Restrictions and Precautions. Added the dose windows for 
Period 2. Added sample collection for DNA and Additional Research. 
Corrected to add CBC collection at Day 197 and 
 
. Added pregnancy testing in open 
label. Clarified exclusion criteria for BMI.
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Table 2.4-1:
Protocol Amendment
Amendment 
No.
Amendment 
Date
Main Purpose of Amendment
2
13-Apr-2018
Updated protocol title to delete “with Switchover”. Changed Period 1 
to double-blind period. Added an option for early escape at Day 85 for 
pediatric subjects depending on investigator discretion (Day 57 UPCR 
> 3 and assessment of clinical response). Deleted Period 2. Replaced 
schematic with a new version reflecting the new study design. Updated 
 efficacy assessments based on 
modification of the study design. Deleted information on relapse.
Added adjustment of background treatment in the OLE. Added 
treatment with systemic corticosteroids for adverse events limited to 
± 2 weeks. Added inhaled corticosteroids are permitted for the 
treatment of asthma, COPD, etc. Updated definition of serious breach.
2.5
Safety Monitoring
An external independent DMC was formed and charged with periodic monitoring of key safety 
data. The DMC makes any necessary recommendations regarding the conduct of the study. The 
contents and methods of safety data reports to the DMC are outlined in the Charter of that 
Committee.
3
OBJECTIVES
3.1
Primary Objective
Demonstrate improvement in nephrotic range proteinuria to sub-nephrotic range while maintaining 
renal function following treatment with abatacept compared to placebo.
•
Demonstrate difference in percent of renal responders defined by composite renal index
Response (defined in Section 8.1.1) at Day 113.
3.2
Secondary Objectives
1) Assess improvement in change from baseline in the level of proteinuria following treatment 
with abatacept compared to placebo.
•
Assess difference in mean change from baseline in Urine Protein/Creatinine Ratio (UPCR) at 
Day 113.
2) Assess improvement in serum albumin levels following treatment with abatacept compared to 
placebo.
•
Assess difference in mean change from baseline in serum albumin at Day 113.
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3) Assess improvement in complete remission while maintaining renal function following 
treatment with abatacept compared to placebo.
•
Assess difference in percent of subjects achieving complete remission (UPCR ≤0.3) with 
preservation of eGFR at Day 113.
4)
Assess improvement in patient reported outcomes related to nephrotic syndrome.
•
Assess changes using the Patient Reported Outcomes Measurement Information System 
(PROMIS) at Day 113.
5)
Assess the safety and immunogenicity of abatacept in subjects with TRNS.
•
Describe rates of AEs and SAEs and immunogenicity testing.
6)
Assess the pharmacokinetics of abatacept in subjects with TRNS
•
Describe the pharmacokinetics of abatacept.
 
4
ENDPOINTS
4.1
Primary Endpoint
•
The primary efficacy endpoint is the proportion of subjects in Renal Response (defined in 
Section 8.1.1) at Day 113.
4.2
Secondary Efficacy Endpoints
•
Mean change from baseline in UPCR at Day 113.
•
Mean change from baseline in serum albumin at Day 113.
•
Proportion of subjects achieving complete remission (UPCR ≤0.3 with eGFR: normal or
≥75% of baseline value if below normal at baseline) at Day 113.
•
Mean change from baseline in PROMIS measures at Day 113.
4.3
Safety Endpoints
•
All adverse events (AEs, SAEs, AEs leading to discontinuation, deaths, etc.).
•
AEs of interest (infections, malignancies, autoimmune disorders, infusional related reactions, 
renal-related events).
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4.4
Laboratory test abnormalities.Immunogenicity Endpoints
•
Proportion of subjects with positive antibody response relative to baseline over time.
 
5
SAMPLE SIZE AND POWER
This pilot study is planned to randomize approximately 90 subjects to assess the primary endpoint 
of proportion subjects in Renal Response at Day 113 between the abatacept and placebo arms. The 
randomization will be stratified by Genotype for whom test results, obtained either prior to 
enrollment or at screening, are available (APOL1 high risk group vs. Others) and Age (< 18 y and 
≥18 y).
A total of 90 subjects randomized in a 1:1 ratio to abatacept vs. placebo will yield approximately
80% power to detect a treatment difference (delta) of 28% between the two treatment arms. This 
power estimate assumes a 2-sided alpha level of 5%, and Renal Response rate of 40% and 12% in 
the abatacept and placebo arms respectively. The 12% estimate of Renal Response in the placebo 
arm was based on observed rate of Renal Response in the FONT II study3 which has a similar 
population that is proposed for the present study and expert opinion.
6
STUDY PERIODS, TREATMENT REGIMENS AND POPULATIONS FOR 
ANALYSES
6.1
Study Periods
In this study, there are four study periods: screening period, double-blind period (DB), open label
extension period (OLE), and follow-up period.
The following analysis periods defined below are for analysis purposes. The definitions below 
indicate the data to be included in the analysis of each specified period. Subjects discontinued 
during a specified period (DB or OLE) will be considered on-treatment for 56 and 42 days after 
the last dosing in that period for safety and efficacy analysis respectively. Follow-up period data 
will be included in one of the analysis periods depending on the time of completing the study.
Screening Period: Starts with the day of enrolment and ends prior or on the day of first dose of 
study medication (abatacept or placebo).
Double-Blind Period: Starts with the first dosing of double-blind study medication and ends 56/42
days (for safety/efficacy analysis) after the last dose of the double-blind period or the first dosing 
of OLE, whichever is earlier.
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For subjects who completed Period 1 and entered Period 2 prior to Protocol Amendment 2, 
includes data from first dose date in Period 1 up to the first dose in Period 2.
Open Label Extension Period (OLE): Starts with the first dosing in the OLE and ends 56/42 (for 
safety/efficacy analysis) days after the last dose in the OLE.
Cumulative Abatacept Safety Period: Starts at the time of the first dose of abatacept (either in 
the double-blind period for the subjects randomized to abatacept or in the OLE for the subjects 
randomized to placebo) and continues up to 56 days post last dose of abatacept for safety (AE and 
laboratory summaries). The last abatacept dose can be last dose in double-blind period for subjects 
not treated in the OLE.
For subjects who completed Period 1 and entered Period 2 prior to the protocol revision:
•
For subjects on abatacept during Period 1:
‒
For subjects who do not enter OLE period: starts with the first dosing of Period 1 and ends 
56 days after the last dosing of Period 1.
‒
For subjects who enter OLE period: starts with the first dosing of Period 1 and ends 
56 days after the last dosing of Period 1 combined with OLE period that starts with the first 
dosing in the OLE period and ends 56 days after the last dosing in the OLE period.
•
For subjects on placebo during Period 1:
‒
For subjects who do not enter OLE period: starts with the first dosing of Period 2 and ends 
56 days after the last dosing of Period 2.
‒
For subjects who enter OLE period: starts with the first dosing of Period 2 and ends 
56 days after the last dosing of OLE period. If a subject’s first dosing in OLE period is 
more than 56 days from last dosing in Period 2, the duration after 56 days from last dosing 
in Period 2 to the first dosing in OLE will be excluded.
6.2
Treatment Regimens
There are two treatment groups: abatacept IV or placebo IV. Abatacept IV will be dosed based on 
age group and weight as follows:
•
Adults (≥18 years):
‒
< 60kg: 500mg
‒
60 - 100kg: 750mg
‒
> 100kg: 1000mg
•
Pediatric (6-17 years):
‒
< 75kg: 10mg/kg
‒
≥75kg follow adult dosing
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6.3
Populations for Analyses
Efficacy endpoints will be summarized according to the Intent-to-Treat (ITT) population and 
safety endpoints will be summarized according to the As-Treated population. These populations 
are described below along with the Per-Protocol population, Immunogenicity population and the 
Pharmacokinetic population
6.3.1
Intent-to-Treat Analysis Population
The Intent-to-Treat (ITT) Analysis Population is defined to include all subjects randomized into 
the study for whom Case Report Form (CRF) data indicate that at least one dose of study 
medication (abatacept or placebo) was administered during the double-blind period.
All subjects who were randomized but never received study medication are to be excluded. Given 
the blinded nature of this study, it is reasonable to assume that subjects who discontinue prior to 
the receipt of study medication do so for reasons unrelated to study medication.
Subjects are grouped according to the treatments to which they are randomized by Interactive 
Response System (IxRS).
ITT Analysis Population is also referred to as ‘All Randomized and Treated Subjects’.
6.3.2
As-Treated Analysis Population
The As-Treated Analysis Population contains all subjects for whom CRF data indicate that at least 
one dose of study medication was administered during double-blind period.
Subjects are grouped according to the treatments to which they are randomized, except in cases 
where information is available, which indicate that a subject received a different treatment for the 
entire course of the 16 week double-blind period. In this case, the subject will be presented by the 
treatment they actually received.
The As Treated Analysis Population will also be referred as ‘All Treated Subjects’.
6.3.3
Per-Protocol Analysis Population
The Per-Protocol Analysis Population is defined as a subset of the ITT Analysis Population which 
excludes subjects who have relevant protocol deviations during the 16 week double-blind period.
A programmable list of relevant protocol deviations is provided in APPENDIX 1.
The Per-Protocol Analysis Population will only be used if more than 10% of the subjects in either 
treatment group have relevant protocol deviations. In such a case, the analysis of the primary 
efficacy endpoints will be repeated in the Per-Protocol Analysis Population.
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6.3.4
Immunogenicity Analysis Population
The Immunogenicity Analysis Population includes subjects who received at least 1 dose of
abatacept and had an immunogenicity result available during the double-blind period.
6.3.5
PK Analysis Population
The PK Analysis Population includes subjects who received at least 1 dose of abatacept and had a
measurable concentration result available during the double-blind period.
7
STATISTICAL ANALYSES
The randomization is stratified by Genotype (APOL1 high risk group vs. Others) and Age (< 18 y
and ≥18 y). Therefore genotype and age, which will obtained from IxRS data, will be included as 
stratification factors in some of the efficacy analyses described below. The analyses to be 
performed at the end of study on OLE period is outlined in Section 9.
7.1
General Methods
All construction of CIs for differences in response rates between treatment groups will be based 
on minimum risk weights4 to account for randomization stratification factors, unless otherwise 
noted. All construction of CIs for response rates within treatment group will be based on normal 
approximation, unless otherwise noted.
All construction of CIs for continuous measures will be based on a mixed effects model which 
includes treatment group, baseline value of variable, randomization stratification factors, time, 
time by treatment interaction, and baseline value by time interaction as fixed effects and subject 
as a random effect. An unstructured covariance matrix will be used to model the correlation of the 
repeated measures within each subject. The SAS procedure PROC MIXED will be used with the 
restricted maximum likelihood (REML) method for estimation and the denominator degrees of 
freedom will be calculated according to the Kenward Roger method. In case of non-convergence 
of the preferred longitudinal model, memory space issues or other computational issues the 
following back-up models are defined:
•
In the first backup model, the repeated statement will specify a spatial power covariance matrix 
and intercept and slope will be specified as random effects on a subject level.
•
In the second backup model, the model will not include terms for the interaction between the
baseline variable and time.
Unless otherwise specified, summary statistics will include the following:
•
Summary statistics for continuous variables will include means, standard deviations, median, 
quartiles, minima and maxima.
•
Summary statistics for qualitative or discrete variables will include the count and percentage.
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7.2
Study Conduct
Relevant protocol deviations, which could have major impact on the interpretation of the primary 
efficacy endpoint of the study results, will be identified prior to the unblinding the database for all 
subjects who are randomized and receive double-blind medication. Relevant protocol deviation 
criteria are listed in APPENDIX 1.
All relevant protocol deviations, pre-randomization and during double-blind period, will be listed 
and summarized by treatment arm. The per-protocol analysis population will exclude subjects with 
at least 1 relevant protocol deviation. Relevant protocol deviations will not be assessed for the 
OLE analysis.
7.3
Study Population
Summary statistics of data pertaining to subject disposition, demographics, baseline
characteristics, and medical history will be tabulated and displayed by randomized treatment arm.
No statistical test will be carried out for comparison of any baseline measurement among treatment 
groups.
7.3.1
Subject Disposition
The number of subjects enrolled into the study, and the number of subjects enrolled but not 
randomized together with the reasons for not being randomized will be summarized. The reasons 
for not being randomized will be taken from the CRF pre-randomization status page.
Enrollment at each site and by age group (adult and pediatric) will be summarized as specified in 
EudraCT requirements.
The disposition of subjects during the double-blind period will include the number of subjects 
randomized, the number of subjects who are randomized and treated, the number of subjects who 
are randomized but not treated, the number of subjects who complete the double-blind period and 
the number of subjects who discontinue the double-blind period together with the reasons for 
discontinuation.
For subjects who completed Period 1 and entered Period 2 prior to the protocol revision, the 
number of subjects who complete Period 2 and the number of subjects who discontinue the Period 
2 together with the reasons for discontinuation will be summarized.
The number of subjects who enter the OLE, the number of subjects who complete the OLE and 
the number of subjects who discontinue the OLE together with the reasons for discontinuation will 
be summarized.
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7.3.2
Demographic and Baseline Disease Characteristics
Demographic and baseline disease characteristics will be summarized using the ITT Analysis
Population for pediatric patients (< 18 y), adult patients (≥18 y) and overall in separate summaries.
Continuous variables will be summarized using means and standard deviations, and categorical 
variables will be summarized using frequency distributions. Summaries will be presented by 
randomized treatment group.
The following demographic and baseline characteristics will be summarized:
•
Age
•
Age group (18 - 64 y, ≥65 years for adults and 6 -< 18 y for pediatric subjects)
•
Gender
•
Race
•
Ethnicity
•
Weight by age group (pediatric and adult)
•
Weight group (< 60, 60 - 100, > 100kg for adult and < 75, 75 - 100, > 100kg for pediatric)
•
Height (pediatric only)
•
BMI
•
Randomization Strata (APOL1 high risk group vs. Others)
•
Serum albumin at baseline (g/dL)
•
Estimated Glomerular Filtration Rate at baseline (mL/min/1.73m2)
•
Urine protein/creatinine ratio at baseline (mg/mg)
•
Diagnosis (FSGS versus MCD)
7.3.3
Medical History and Prior Medication
General medical history will be summarized by each body system for the ITT Analysis Population.
Prior medications are defined as medications a subject started to take prior to the first infusion of 
double-blind study medication. Prior medications will be summarized for each treatment arm by 
drug class and generic name for the ITT Analysis Population.
Medications of special interest to TRNS (FSGS/MCD) include corticosteroids (CS) (prednisone 
or equivalent), calcineurin inhibitors (cyclosporine and tacrolimus), sirolimus, mycophenolate 
mofetil (MMF), mycophenolic acid (MPA), or cyclophosphamide. A summary of prior 
medications of special interest will be provided for each treatment group.
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7.4
Extent of Exposure
7.4.1
Study Therapy
Extent of exposure to double-blind study drug will be summarized using the As Treated Analysis
Population in two ways:
•
Number of infusions.
•
Number of days a subject is known to be on study drug ignoring dosing interruptions.
The number of infusions subjects received will be based on the study medication page of the CRF 
when an infusion date is present.
The number of days the subject is known to be on study drug (exposure to study drug) during each
period is calculated as:
Double-blind period:
•
Discontinued subjects during double-blind period and subjects completed double-blind period 
but do not continue into the OLE:
Exposure in days = (date of last study medication in the double-blind period - date of first study 
medication in the double-blind period + 1) + 56.
•
Subjects continuing in the OLE:
Exposure in days = (date of first study medication in OLE - date of first study medication in double-
blind period) - adjustment.
Adjustment is the period after 56 days from last study medication from double-blind period to the 
first study medication in OLE.
•
Subjects who completed Period 1 and entered Period 2 prior to the protocol revision:
Exposure = (date of first study medication in Period 2 - date of first study medication in Period 1) 
- adjustment.
Adjustment is the period after 56 days from last study medication from Period 1 to the first study 
medication in Period 2.
OLE period:
Exposure = (date of last study medication in OLE - date of first study medication in OLE + 1) 
+ 56.
Cumulative abatacept safety period:
•
Subjects treated with abatacept and discontinuing before entering the OLE:
Exposure in double-blind period = (date of last study medication in double-blind period - date of 
first study medication in double-blind period + 1) + 56.
•
Subjects treated with abatacept and continuing in the OLE, it is the sum of the following:
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Exposure in double-blind period = (date of first study medication in OLE - date of first study 
medication in double-blind period) - adjustment.
Exposure in OLE = (date of last study medication in OLE - date of first study medication in OLE 
+ 1) + 56.
For subjects randomized to placebo, the date of first abatacept study medication is the date of first 
study medication in OLE. For subjects randomized to abatacept, the date of first abatacept study 
medication is the date of first double-blind period.
•
Subjects who completed Period 1 and entered Period 2 prior to the protocol revision:
‒
For subjects on abatacept during Period 1 and entering OLE period, it is the sum of the 
following:
♦Exposure in Period 1 = (date of first study medication in Period 2- date of first study 
medication in Period 1 + 1) +56.
♦Exposure in OLE = (date of last study medication in OLE - date of first study 
medication in OLE + 1) + 56.
‒
For subjects on abatacept during Period 2, it is the sum of the following:
♦Exposure in Period 2 = (date of first study medication in OLE period - date of first 
study medication in Period 2) - adjustment. Adjustment is the period after 56 days from 
last study medication from Period 2 to the first study medication in OLE.
♦Exposure in OLE = (date of last study medication in OLE - date of first study 
medication in OLE + 1) + 56.
‒
For subjects on abatacept during Period 2 and not entering OLE:
♦Exposure in Period 2 = (date of last study medication in Period 2 - date of first study 
medication in Period 2 + 1) + 56.
The offset of 56 days is the length of 2 regular dosing cycles and represents approximately 4 times 
the half-life of abatacept in humans.
Summaries of exposure to study drug will show the distribution of the number of infusions and
days on drug, together with the means, standard deviations, medians, minima and maxima, by
treatment group.
7.4.2
Discontinuations from Study Medication
Discontinuation from study medication is defined as subject’s termination of the study medication 
(abatacept or placebo) without resumption prior to study completion. A subject will be considered 
as discontinued from study period if and only if the subject status CRF page indicates he/she did 
not complete that specific study period. The summary of discontinuations is provided in 
Section 7.3.1.
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7.4.3
Treatment Compliance
The number of subjects with missed infusions in the double-blind period (excluding missed 
infusions due to premature discontinuation from study) will be summarized by treatment group 
and number of missed infusions. An interruption of infusion on a particular day will not be counted 
as a ‘missed’ infusion. This summary will be performed with the ITT Analysis Population. A 
listing of all missed infusions indicating the period will be also provided.
 
 
 
 
 
 
 
 
 
 
7.5
Efficacy
The primary and secondary efficacy analyses (defined in section 7.5.2 and 7.5.4) will be performed 
using the ITT Analysis Population by treatment group assigned at randomization during the 
double-blind period. The primary analysis will be repeated using the PP analysis population if 
more than 10% of subjects in any treatment group meet the criteria for a relevant protocol 
deviation. All other efficacy analyses will be performed using the ITT Analysis Population, unless 
otherwise specified.
The efficacy analysis in this analysis plan is mainly focused on the double-blind period.
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7.5.1
Analysis of Primary Efficacy Endpoint
The primary objective of the study is the comparison of renal response, defined by composite renal 
index, at Day 113 at the end of double-blind period between abatacept and placebo arms. The 
definition and computation method for renal response is provided in Section 8.1.1.
The primary comparison of proportion of subjects in renal response at Day 113 at the end of
double-blind period between abatacept and placebo arms will be assessed using a logistic 
regression model. The logistic regression model will adjust for baseline UPCR, baseline eGFR and 
the randomization stratification variables of Genotype (APOL1 high risk group vs. Others) and 
Age (< 18 y vs. ≥18 y). Point estimate of the adjusted Odds Ratios (OR) of the odds of achieving 
renal response in the abatacept arm compared to the placebo arm, corresponding 95% CI and 
p-value, will be provided. Unadjusted point estimate of the proportion of renal response in each 
treatment arm and corresponding 95% CI will also be provided. All subjects who discontinue 
prematurely prior to reaching the primary endpoint, and subjects with missing data for response at
Day 113 assessment visit, will be considered as not achieving response in the primary analysis.
The primary analysis will be based on the ITT Analysis Population.
7.5.2
Sensitivity Analysis
Since the balance intended in the stratification by Genotype (APOL1 high risk group vs. Others) 
may be impacted by the number of subjects who choose to refuse genotyping and consequently 
considered in the “Others” Genotype group, sensitivity analysis of the primary endpoint will be 
performed. The sensitivity analysis will use a logistic regression model that does not adjust for the 
stratification factor of Genotype based on the ITT Analysis Population. The comparison between 
the proportion of subjects in renal response at Day 113 at the end of double-blind period in
abatacept and placebo arm will be assessed using a logistic regression model adjusting only for
Age (< 18 y vs. ≥18 y), baseline UPCR and baseline eGFR. Point estimate of the adjusted Odds 
Ratios (OR) of the odds of achieving renal response in the abatacept arm compared to the placebo 
arm, corresponding 95% will be provided. As in the primary analysis, all subjects who discontinue 
prematurely prior to reaching the primary endpoint, Day 113 assessment visit and subjects with 
missing data for response at Day 113 assessment visit, will be considered as not achieving response 
in the primary analysis.
7.5.3
Analysis of Secondary Efficacy Endpoints
•
Mean change from baseline in UPCR at Day 113: Longitudinal (repeated measure) mixed 
model will be used to assess this endpoint. The model will include treatment group, UPCR 
baseline value and randomization stratification factors (genotype and age), time, baseline value
by time interaction, time by treatment interaction as fixed effects and subject as a random 
effect. An unstructured covariance matrix will be used to model the correlation of the repeated 
measures within each subject. The SAS procedure PROC MIXED will be used with the 
restricted maximum likelihood (REML) method for estimation and the denominator degrees 
of freedom will be calculated according to the Kenward Roger method. Adjusted mean change 
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from baseline by treatment groups and associated standard errors (SE) will be presented as 
well as treatment differences versus placebo with 95% confidence intervals. A summary will 
be provided, presenting the mean change from baseline in UPCR at each time point in double-
blind period as described above. In addition:
‒
Summary of mean change from baseline in UPCR at each time point during double-blind 
period and OLE will be provided. This summary will be descriptive without adjusting for
stratification or baseline factors.
‒
Graphs of median percent change from baseline in UPCR during all periods will be 
presented.
•
Protein excretion determinations from 24 hour urine collections are considered to be more 
reliable than those obtained from spot urine collections. This is due primarily to the variability 
in the protein loss over the course of the day in chronic kidney diseases (CKD). This variability 
may not be similar between different forms of CKD. To help determine the degree of variability 
that may exist in subjects with TRNS (FSGS/MCD), UPCR are to be taken from a 24-hour 
urine collection on Day 1 and 113; if not possible, then from a single voided specimen. To 
assess the relationship between the two measurements a correlation analysis will be performed 
between the two measurements as an exploratory analysis. The analysis will be performed if 
more than 50% of subjects have both 24-hour collection and single voided specimen paired. 
The correlation between the 24-hour UPCR and single-void UPCR will be examined using the 
Pearson correlation coefficient or Kendall’s Tau if either measure is not normally distributed; 
the estimate of the correlation coefficient and corresponding 95% CI will be provided; all 
subjects will be combined into one group for this analysis.
•
Mean change from baseline in serum albumin at Day 113. A similar mixed model used in the 
above secondary endpoint will be applied for this endpoint. Adjusted mean change from 
baseline by treatment group and associated standard errors (SE) will be presented as well as 
treatment differences versus placebo with 95% confidence intervals will be provided. A 
summary will be provided, presenting the mean change from baseline in serum albumin at each 
time point in double-blind period as described above.
‒
Additional summary of mean change from baseline in serum albumin at each time point 
during OLE will be provided. This summary will be descriptive without adjusting to 
stratification or baseline factors and will be presented by treatment arm.
•
The proportion of subjects achieving complete remission (defined in Section 8.1.2: UPCR 
≤0.3 with eGFR normal or ≥75% baseline if below normal at baseline) at Day 113: the 
comparison in proportion of subjects achieving complete remission between the abatacept and 
placebo arms will be assessed using a logistic regression model. To account for randomization 
stratification, the logistic regression model will adjust for the randomization stratification
variables of genotype and age in addition to adjusting for baseline UPCR and baseline eGFR. 
Point estimate of the adjusted Odds Ratios (OR) of the odds of achieving complete remission 
in the IV abatacept arm compared to the placebo arm, corresponding 95% CI, will be provided.
•
Mean change from baseline in PROMIS measures at Day 113. Descriptive summary statistics 
for changes in patient reported outcomes of physical function, fatigue and pain improvement 
from baseline over time during double-blind period for the PROMIS static short forms will be 
provided by age group.
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‒
For subjects 18 years and older: SF Physical Function v1.2 8b, SF Fatigue v1.0 Adult 8a 
and SF Pain Interference v1.0 Adult 8a.
‒
For younger than 18 years and their parent proxy: SF Physical Function - Mobility v1.0 
Peds 8a, SF Fatigue v1.0 Peds 10a and SF Pain Interference v1.0 Peds 8a.
Results for adults and pediatric subjects will be reported separately. The results for subjects 
younger than 18 years will also be reported separately from their parent proxy form results. 
The mean change from baseline in these measures will be presented, for each age group
(< 18 y, ≥18 y), by treatment group based on Longitudinal (repeated measure) mixed model.
The treatment differences in adjusted mean changes from baseline, along with the 
corresponding 95% two-sided CI, will be based on Longitudinal (repeated measure) mixed 
model and will be presented at each scheduled visit in double-blind period. The model will 
include baseline value of variable, genotype, time, time by treatment interaction, and baseline 
value by time interaction as fixed effects and subject as a random effect.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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7.5.5
Subgroup Analysis
All analyses described in this section will be performed on the ITT Analysis Population. 
Table 7.5.5-1 shows the subgroups of interest for analyses of the primary efficacy endpoint of 
renal response. If the value of the grouping variable cannot be determined for a subject, the subject 
will be excluded from the corresponding subgroup analysis. Only subgroups consisting of 10% or 
more of the total study population will be considered.
Table 7.5.5-1:
Subgroup of Interest of the Primary Efficacy Assessment of Renal 
Response
Subgroup Factor
Categories
APOL1
High Risk
Other
Age
Pediatric (< 18 years)
Adult (≥18 years)
Gender
Male
Female
Race
Caucasian
Black
Asian
Others
Baseline UPCR
Baseline UPCR < 6mg/mg
6mg/mg ≤Baseline UPCR < 9mg/mg
Baseline UPCR ≥9mg/mg
Diagnosis
FSGS
MCD
The proportion of subjects who achieve renal response, defined by composite renal index, at Day 
113 at the end of double-blind period in abatacept and placebo arm will be summarized using point 
estimates and 95% confidence interval for each treatment group by subgroup. The difference in 
proportions between treatment groups for each subgroup will be provided by point estimate and 2-
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sided 95% confidence interval using normal approximation, without any adjustments for strata, if 
the number of events in each individual treatment group is at least 5. Otherwise, confidence 
intervals using an exact method will be provided.
7.6
Safety
Analysis of all safety data will follow the BMS standard safety data conventions and supplements 
to the standard conventions for the abatacept programs5.
The evaluation of drug safety is based primarily on clinical AEs, vital signs and laboratory 
abnormalities reported during the study. All safety presentation will be based on the As Treated 
Analysis Population by treatment group. Unless otherwise specified adverse events and laboratory 
abnormalities will be summarized for double-blind period, cumulative abatacept safety period and 
OLE period as described in APPENDIX 2. The definition of each period is provided in 
Section 6.1.
Frequency and individual listings of all AEs will be generated. Changes in clinical laboratory test 
results from baseline will be summarized. Laboratory marked abnormality using pre-defined 
abnormality criteria will also be descriptively summarized. There will be no statistical testing of 
group difference with respect to frequencies of AEs or laboratory marked abnormalities.
7.6.1
Adverse Events
Adverse events are recorded by the investigators on the Serious and Non-Serious Adverse Event 
page(s) of the CRF. All investigators are required to report the nature, the onset and resolution 
date, intensity, action taken, treatment required for event, and to express their opinion regarding 
the relationship between the AE and the study medication.
All AEs are coded and grouped into Preferred Terms (PT) by System Organ Class (SOC), using 
the Medical Dictionary for Regulatory Activities (MedDRA). Listings and summaries will be 
based on the resulting SOCs and PTs.
All reported AEs and SAEs will be listed, indicating the subject ID, treatment group, age, gender, 
race, day of onset relative to start of dosing, resolution date, investigator-assessment of relationship 
to study drug, investigator-assessment of intensity of event, action taken regarding study drug and 
whether treatment was required for the event.
All adverse events with an outcome of death will be listed.
Selected AE summaries will be generated for the double-blind period and cumulative abatacept 
safety period which include SAEs, AEs leading to study drug discontinuation, most common 
related AEs (reported in at least 2% of subjects) and most common (serious or non-serious) AEs 
(reported in at least 5% of subjects).
AE summaries by age group (adults versus pediatrics) will be presented for serious AEs, AEs 
leading to study drug discontinuation, most common related AEs (reported in at least 2% of 
subjects in any treatment group for each age group separately).
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Summary information (the number and percent of subjects) regarding AEs (for serious or non-
serious events) will be tabulated by SOC, PT and treatment group for:
•
Serious adverse events (SAE).
•
AEs leading to study drug discontinuation.
•
AEs related to study drug.
•
Related events categorized by intensity.
•
Most common related AEs (reported in at least 2% of subjects in any treatment group).
•
AEs by intensity.
•
All AEs (serious or non-serious).
•
Most common (serious or non-serious) AEs (reported in at least 5% of subjects in any treatment 
group).
•
Serious adverse events and related serious adverse events with death as an outcome following 
EudraCT requirements.
Laboratory AEs are laboratory results identified by the Investigator as AEs and thus reported on 
the AE pages of the CRF. Any such AE will be included in the respective AE summaries.
7.6.2
Adverse Events of Interest
7.6.2.1
Renal Related Events
All reported renal-related events during treatment will be summarized by preferred term and
treatment group. Renal-related events will be defined using the MedDRA Maintenance and 
Support Services Organization (MSSO) Chronic Kidney Disease Structured MedDRA Query 
(SMQ), MSSO Embolic and Thrombotic Disease SMQ, and BMS custom Renal Supplement 
SMQ. The listing will include all renal-related events up to the database lock.
7.6.2.2
Infections
All reported infections and infestations within the SOC: Infections and infestations occurring 
during treatment will be summarized by preferred term and treatment group. The listing will 
include all reported infections and infestations up to the database lock. Summary of infections and 
infestations AEs by intensity will also be summarized. A Kaplan-Meier plot of time to first serious 
infection during treatment will also be presented by treatment group.
In addition to the SOC of infections and infestations, all events in the cSMQ of Opportunistic 
Infections will be summarized by preferred term and treatment group. The listing will include all 
reported events up to the database lock.
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7.6.2.3
Malignancy
All events in the MSSO malignancies SMQ list will be summarized. These events will be 
summarized by preferred term and treatment group. The listing will include all reported events up 
to the database lock.
7.6.2.4
Autoimmune Disorders
The frequency of pre-specified autoimmune disorders, defined using a BMS custom Autoimmune 
Disorder SMQ will be provided. Autoimmune disorders will also be summarized by intensity. All 
reported autoimmune disorders reported up to the database lock will be listed.
7.6.2.5
Infusional Reactions
1) Peri-infusional AEs of interest are defined as those AEs occurring within the first 24 hours 
after the start of each study drug infusion that are included in the pre-specified MedDRA list 
of peri-infusional events of interest.
2) Acute infusional AEs of interest are defined as those AEs occurring within the first hour after 
the start of each study drug infusion that are included in the pre-specified MedDRA list of peri-
infusional events of interest.
The pre-specified MedDRA code of peri-infusional AEs of interest will be provided prior to 
database lock and will be included in the CSR.
3) Other peri-infusional AEs are defined as other AEs occurring during the first 24 hours after 
the start of each study drug infusion but not included in the pre-specified list of peri-infusional
AEs defined in 1) above.
The number and percent of subjects experiencing the infusional AEs defined in 1) above through 
3) above will be summarized by SOC, PT and treatment group. The distribution of the infusional 
AEs of interest by intensity will also be provided except for the AEs defined in C above. All 
reported peri-infusional AEs of interest reported up to the database lock will be listed.
7.6.3
Incidence Rate Analyses
Incidence rate is defined as the quotient of number of subjects with event and exposure (patient-
years), where the exposure (patient-years) is the sum over all subjects’ exposure during a pre-
specified study period (censored at the time of the first occurrence of event) divided by 365. The 
resulting incidence rate is multiplied by 100 to express the rate per 100 p-y. Incidence rates per 
100 p-y and associated 95% Poisson confidence intervals will be calculated for each treatment 
group.
Incidence rate analyses will be performed for SAEs, Renal Related AEs, Opportunistic Infections, 
Malignancy and Autoimmune disorders, the point estimate and 95% CI of incidence rate (per 
100 patient-years) of each endpoint will be provided by system organ class and preferred term, 
separately for each treatment group.
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The analyses will be performed for events that occurred in double-blind period up to 56 days post 
last dose in double-blind period or first dose date in OLE whichever is earlier.
For subjects who completed Period 1 and entered Period 2 prior to Protocol Amendment 2, the 
analyses will be performed for events that occurred in Period 1 up to the first dose in Period 2.
7.6.4
Multiple Adverse Events
Several descriptive summaries of adverse events that takes into account the number of occurrences 
that an AE was reported by individual patients will be provided. In order to prepare these 
summaries, the CRF data will be processed according to standard BMS algorithms to categorize 
each line of patient data as a new occurrence or a continuation of an existing event. This 
determination will be based upon onset and resolution dates. Each line of patient data will represent 
the maximum severity observed as well as the last known assessed relationship to study medication 
by the investigator.
This data will be presented as the rate per 100 years of patient exposure. Exposure to study 
medication will be calculated according to approved standard BMS algorithms as well.
As an example, if 5 patients report 7 unique episodes of headache and had a combined cumulative 
exposure of 20 years to study medication, the incidence rate is reported as 7/20 *(100) or 35 cases 
per 100 patient years of exposure.
For adverse events with multiple occurrences, the following will be provided:
•
A table showing the total number and rate (exposure adjusted) of occurrences for general AEs 
occurring in at least 5% of the subjects treated. AEs will be organized by System Organ Class 
(SOC) and Preferred Term (PT), and reported by and treatment group.
•
A listing displaying the unique instances of all AEs (i.e., after duplicates have been eliminated 
and overlapping and contiguous occurrences of the same event have been collapsed).
No formal comparisons are made between treatments. No formal statistical testing will be 
performed, only summary statistics of adverse events with multiple occurrences for double-blind 
period, cumulative abatacept safety period and OLE period as described in APPENDIX 2 will be 
provided.
7.6.4.1
EudraCT Summaries
Exposure adjusted adverse event summaries including multiple occurrences of unique adverse 
events for EudraCT reporting requirements will be presented by treatment group in the cumulative 
abatacept safety period. These summaries include serious adverse events, drug related serious 
adverse events and non-serious adverse events using a global cutoff of 5 percent.
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7.6.5
Laboratory Data
Safety summaries based on laboratory test results include evaluation of laboratory abnormalities 
and changes in laboratory test values from baseline (baseline definition is provided in Section 8.3).
Laboratory abnormalities will be summarized by treatment group for double-blind period and 
cumulative abatacept safety period as described in Section 7.6.
Laboratory abnormalities are identified using a pre-defined set of marked abnormality (MA) 
criteria (listed in Safety Data Convention). The frequency of subjects with laboratory MAs during 
treatment based on pre-specified criteria will be tabulated by treatment group, for each analyte.
Laboratory measurements and their changes from baseline will be summarized by study day and
treatment group, for protocol specified analytes. Subjects who have laboratory measures at 
baseline and corresponding measure on at least one scheduled visit following administration of 
study drug will be included in the laboratory analyte assessment. Note that not all subjects have 
laboratory determinations for all analytes at all visits, and therefore the sample size may vary from 
analyte to analyte at each time point.
In addition shift tables for the following laboratory tests will be provided. The categorical 
classifications of these tests will be determined based on the cut points specified below and cross-
tabulation of classification between baseline and each of the scheduled visits will be presented by 
treatment group.
Selected laboratory safety summaries will be generated for the double-blind period and the 
cumulative abatacept safety period separately as described in APPENDIX 2.
Table 7.6.5-1:
Definitions of Analytes Cut Points
Analytes (Test Code)
Cut Point
Platelet Count (PLAT)
< 100 x 10ଽc/L
≥100 x 10ଽc/L
Alanine Aminotransferase (ALT)
< 3 x ULN
3 - ≤5 x ULN
> 5 x ULN
Aspartate Aminotransferase (AST)
< 3 x ULN
3 - ≤5 x ULN
> 5 x ULN
Neutrophils (absolute)
< 0.5 x 10ଽc/L
0.5 x 10ଽc/L - ≤15 x 10ଽc/L
≥15 x 10ଽc/L
G-Glutamyl Transferase (GGT)
< 3 x ULN
3 - ≤5 x ULN
> 5 x ULN
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Table 7.6.5-1:
Definitions of Analytes Cut Points
Analytes (Test Code)
Cut Point
Serum albumin
≤ULNA (normal)
> ULNA (abnormal)
eGFR
< 60mL/min/1.73m²
60 - 89mL/min/1.73m²
≥90mL/min/1.73m²
7.6.6
Vital Signs
Summary statistics for vital sign measurements (seated systolic BP, seated diastolic BP, heart rate 
and body temperature) will be presented at study baseline, and prior and after infusion by 
scheduled visit and treatment group. At the end of the study report, summary statistics of vital 
signs measurements collected during OLE will be provided.
7.7
Other Analyses
7.7.1
Immunogenicity
Serum for anti-abatacept antibody titers are drawn at Days 1 and 113 during the double-blind 
period and at Day 56, 84 and 168 during the follow-up period. For this assay, for all summaries 
and listings unless specified otherwise, a positive relative to baseline immunogenicity response for 
‘CTLA4 and possibly Ig’, ‘Ig and/or Junction Region’, respectively, is defined as:
•
A missing baseline immunogenicity measurement and a positive laboratory reported 
immunogenicity response post-baseline.
•
A negative laboratory reported baseline immunogenicity response and a positive laboratory 
reported immunogenicity response post-baseline.
•
A positive laboratory reported baseline immunogenicity response and a positive laboratory 
reported immunogenicity response post-baseline that has a titer value strictly greater than the 
baseline titer value.
This definition will be applied for each antibody-reactivity separately.
All other ECL immunogenicity measurements will be classified as lack of positive (relative to 
baseline) immunogenicity response or negative immunogenicity response.
The number (and percentage) of subjects with positive samples relative to baseline will be 
provided. These summaries will be provided by antibody specificity, and overall. These summaries 
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will include frequencies by scheduled visit (including on-treatment, off-treatment and overall) and 
by treatment group and age group. The Day 1 measurement will be the baseline measurement for 
all subjects.
Immunogenicity during the follow up period will be analyzed as above and will be provided at the 
end of study report.
7.7.2
Pharmacokinetic Endpoints
Serum PK:
•
Cmin (ȣg/mL): Trough level serum concentration of abatacept on Days 1, 15, 29, 57, 85 and
113 will be tabulated by age group and study day. Geometric means and coefficients of 
variation will be presented.
•
Cmax (ȣg/mL): Maximum observed serum concentration on Day 85 in subjects receiving 
abatacept IV will be obtained and tabulated by age group. Geometric means and coefficients 
of variation will be presented.
•
Tmax (h): Time to reach peak serum concentration of abatacept will be obtained and tabulated 
by age group. Medians and ranges will be presented by age group.
•
AUC (TAU) (ȣg͌h/mL): Area under the serum concentration time curve over a dosing 
interval between Days 85 and 113 will be tabulated by age group. Geometric means and 
coefficients of variation will be presented.
•
Urine PK: Xu (ȣg): Amount of abatacept excreted in urine for Days 1, 15, 29, 57, 85 and 113 
will be tabulated by age group. Geometric means and coefficients of variation will be 
presented.
8
CONVENTIONS
8.1
Definitions
8.1.1
Renal Response
The renal response at a specific time point will be present if all the following criteria (composite 
renal index) are met at that time point:
PROTEINURIA: Reduction of baseline UPCR of ≥50% and to less than 3.
RENAL FUNCTION: No worsening of baseline (Study Day 1) estimated glomerular filtration rate 
(eGFR) defined as within normal range if normal at baseline or ≥75% baseline value if below 
normal at baseline.
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eGFR determination will be based on the CKD-EPI6 for adults and the new Schwartz equation7
for children.
The CKD-EPI formula will be used to determine the eGFR for the adults and will be expressed as 
mL/min per 1.73m2. The CKD-EPI formula is:
eGFR = 141 × min(Scr/k,1)α × max(Scr/k,1)-1.209 × 0.993Age × (1.018 [if female])
                                                                                                   × (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.
The new Schwartz formula for use in children to determine eGFR, also expressed as mL/min per 
1.73m2, is:
eGFR = 39.1[height(m)/Scr(mg/dl)]0.516 × [1.8/cystatinC(mg/L)]0.294 × [30/BUN(mg/dl)]0.169 ×
[1.099]gender × [height (m)/1.4]0.188
Gender = 1 if male and 0 if female
Normal eGFR is defined as eGFR equal or greater than the lower limit of normal (LLN) eGFR. 
For this study, the LLN eGFR for both adults and children is defined as 90mL/min per 1.73m2.
Proteinuria assessment for primary and secondary endpoints will be obtained from 24 hour urine 
collections performed at baseline and Day 113. When a 24 hour collection is not possible, a single 
voided specimen (i.e., spot urine) will be utilized, preferably in the morning. For all other time 
points, the assessment will require a single void spot urine.
8.1.2
Complete remission
Complete remission at a specific time point will be present if all the following criteria are met at 
that time point:
PROTEINURIA: UPCR ≤0.3.
RENAL FUNCTION: No worsening of baseline (Study Day 1) estimated glomerular filtration rate 
(eGFR) defined as within normal range if normal at baseline, or ≥75% baseline value if below 
normal at baseline.
eGFR determination will be based on the CKD-EPI for adults and the new Schwartz equation for 
children as indicated in Section 8.1.1 above.
8.1.3
Prednisone or Prednisone Equivalent Use
Systemic prednisone or prednisone equivalent medication (oral, intramuscular or intravenous) will 
consist of the following generic names of CS on the CRF page. Before unblinding a final review 
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of all medications will be performed to identify all prednisone equivalent medications and dose 
conversion if there is any.
•
Prednisolone
•
Prednisone
•
Deflazacort
•
Methylprednisolone
•
Dexamethasone
•
Hydrocortisone
•
Betamethasone
The conversions of dosages of the prednisone equivalents are as follows:
•
1mg of prednisolone = 1mg of prednisone
•
1mg of deflazocort = 0.83mg of prednisone
•
1mg of methylprednisolone = 1.25mg of prednisone
•
1mg of dexamethasone = 6.67mg of prednisone
•
1mg of hydrocortisone = 0.25mg of prednisone
•
1mg of Betamethasone = 8.33mg of prednisone
For subjects who discontinued the double-blind period early, the last prednisone dose reported will 
be carried to Day 113.
Prednisone use at each scheduled infusion visit:
•
Day 1: the total daily dose at Day 1.
•
Day 15: average daily dose in mg from one day after Day 1 to the infusion date of Day 15.
•
Day 29: average daily dose in mg from one day after infusion date of Day 15 to the infusion 
date of Day 29.
•
Day 57 to Day 113: average daily dose in mg from one day after the date of prior infusion to 
the date of current infusion.
•
If a scheduled infusion is missed, the target day will be used for the visit when calculating the 
average total daily dose at this visit.
8.2
Determination of Responders
For analyses of treatment differences in the proportions of subjects achieving a renal response or 
complete remission at specific time point, a conservative approach will be taken for subjects who 
prematurely discontinue prior to achieving the efficacy endpoint. That is, regardless of treatment 
group, these discontinued subjects will be considered as non-responders. Subjects with any 
missing renal response component will also be considered as non-responders.
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8.3
Baseline Measurements
For all outcome measures, unless otherwise specified, the baseline value is the last assessment 
taken prior to the first infusion of double-blind treatment. In general, this is the assessment taken 
on or just before the administration of study medication (Day 1). For some variables that are also 
measured during screening such as vital signs and laboratory data, if Day 1 assessments are 
unavailable, then screening assessments will be used as baseline measurements. Adult BMI will 
be calculated from the screening height and the Day 1 weight while the pediatric BMI will be 
calculated from the Day 1 height and weight.
8.4
Missing Measurements
For determination of renal response, handling of missing values is addressed in Section 8.2. For 
the analysis of individual components of other outcome research endpoints (Adult: SF Physical 
Function v1.2 8b, SF Fatigue v1.0 Adult 8a and SF Pain Interference v1.0 Adult 8a, Pediatric: SF 
Physical Function - Mobility v1.0 Peds 8a, SF Fatigue v1.0 Peds 10a and SF Pain Interference 
v1.0 Peds 8a), other efficacy measures and biomarkers, missing values will not be imputed. See 
the Safety Analysis Guidelines and Safety Data Conventions for the CTLA4IG program 
(Referenced earlier) for conventions related to the handling of missing or partial dates and the 
determination of appropriate default values in such cases and in particular for concomitant 
medication dose start-dates and end-dates and AE onset dates. All of these rules also apply when 
deriving efficacy data sets.
8.5
Multiple Measurements
When lab samples are inadvertently taken or analyzed multiple times, this produces multiple 
measures for the same date (and time in the case of labs) for the same subject.
In such cases, the average of such multiple assessments or lab results will be used for this time
point for this subject.
When clinical measurements are assessed multiple times at the same date for the same subject, the 
record with the latest ‘last change time stamp’ will be used for this time point for this subject.
8.6
Day Ranges for Analysis Time Points
Subjects do not always adhere strictly to the visit schedule timing in the protocol. Therefore the 
designation of visits during treatment will be based on the day of evaluation relative to the study 
(day of first infusion = study Day 1) rather than the nominal visit recorded in the case report form 
(CRF). Mutually exclusive relative day windows are defined in the following table to provide 
derived visits that correspond to the post-baseline time points specified in the protocol.
Designation of visits for efficacy assessments and outcomes research performed at every scheduled 
visit is tabulated in Table 8.6-1.
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Table 8.6-1:
Day Ranges for Components of Renal Response, Component of 
Completed Remission and Outcomes Research Assessments at Every 
Scheduled Visit During the Double-Blind Period and OLE Period
Visit
Target Day
Component of 
Renal Response/ 
Complete
Remission (UPCR, 
eGFR)
eGFR (Provided 
by Lab)
Outcomes 
Research Day 
Ranges
Double-blind period
Screening 
< 1
< 1
< 1
< 1
Day 1 (Baseline)
1
1
1
1
Day 15
15
8 - 22
Day 29
29
23 - 43
Day 57
57
44 - 71
Day 85
85
72 - 99
2 - 99
Day 113*
113
100 - 127
50 - 177
100 - 127
OLE period
Day 141
141
128 - 155
Day 169
169
156 - 183
Day 197
197
184 - 211
Day 225
225
212 - 239
Day 253
253
240 - 267
Day 281
281
268 - 295
* Day 113 assessment for subjects continuing in OLE, the upper inclusive limit of this window is the first infusion in 
OLE or 42 days after last dose in double-blind period, whichever comes earlier. Assessments within 42 days after last 
dose in double-blind period are included for subjects discontinuing during double-blind period.
For subjects who completed Period 1 and entered Period 2 prior to the protocol revision:
Table 8.6-2:
For Subjects who Completed Period 1 and Entered Period 2 prior 
to the Protocol Revision
Visit
Target Day
Component of 
Renal Response/ 
Complete 
Remission (UPCR, 
eGFR)
eGFR (Provided 
by Lab)
Outcomes 
Research Day 
Ranges
Double-blind 
(Period 1 and 
Period 2)
Screening 
< 1
< 1
< 1
< 1
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Table 8.6-2:
For Subjects who Completed Period 1 and Entered Period 2 prior 
to the Protocol Revision
Visit
Target Day
Component of 
Renal Response/ 
Complete 
Remission (UPCR, 
eGFR)
eGFR (Provided 
by Lab)
Outcomes 
Research Day 
Ranges
Day 1 (Baseline)
1
1
1
1
Day 15
15
8 - 22
Day 29
29
23 - 43
Day 57
57
44 - 71
Day 85
85
72 - 99
2 - 99
Day 113*
113
100 - 120
50 - 141
100 - 127
Day 128
128
121 - 134
Day 141
141
135 - 155
Day 169
169
156 - 183-
142 - 183
Day 197
197
184 - 211
184 - 211
Day 225*
225
212 - 239
212 - 239
OLE period
Day 253
253
240 - 267
Day 281
281
268 - 295
Day 309
309
296 - 323
Day 337
337
324 - 351
Day 365
365
352 - 379
Day 393
393
380 - 407
* Day 113 assessment for subjects continuing in Period 2, the upper inclusive limit of this window is the first infusion 
in Period 2 or 42 days after last dose in Period 1, whichever comes earlier. Day 113 assessment extends 42 days after 
last dose in Period 1 for subjects discontinuing during Period 1. Similarly, Day 225 assessment for subjects continuing 
in OLE, the upper inclusive limit of this window is the first infusion in OLE or 42 days after last dose in Period 2, 
whichever comes earlier. Assessments within 42 days after last dose in Period 2 are included for subjects discontinuing 
during Period 2.
Table 8.6-3:
Day Ranges for Laboratory Assessments at Every Scheduled Visit 
During the Double-Blind Period and OLE Period
Visit
Target Day
Chemistry
CBC
Total Cholesterol and 
Triglycerides, fasting
Double-blind period
Screening 
< 1
< 1
< 1
< 1
Day 1 (Baseline)
1
1
1
1
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Table 8.6-3:
Day Ranges for Laboratory Assessments at Every Scheduled Visit 
During the Double-Blind Period and OLE Period
Visit
Target Day
Chemistry
CBC
Total Cholesterol and 
Triglycerides, fasting
Day 15
15
8 - 22
Day 29
29
23 - 43
15- 57
Day 57
57
44 - 71
28 - 56
Day 85
85
72 - 99
58 - 99
Day 113*
113
100 - 141
100 - 197
57 - 197
OLE period
Day 169
169
142 - 197
Day 225
225
198 - 253
Day 281
281
254 - 309
198 - 309
198 - 309
* Day 113 assessment for subjects continuing in OLE, the upper inclusive limit of this window is the first infusion in 
OLE or 42 days after last dose in double-blind period, whichever comes earlier. Assessments within 42 days after last 
dose in double-blind period are included for subjects discontinuing during double-blind period.
For subjects who completed Period 1 and entered Period 2 prior to the protocol revision:
Table 8.6-4:
For Subjects who Completed Period 1 and Entered Period 2 prior 
to the Protocol Revision
Visit
Target Day
Chemistry 
CBC
Total Cholesterol and 
Triglycerides, fasting
Double-blind (Period 1 and 
Period 2)
Screening 
< 1
< 1
< 1
< 1
Day 1 (Baseline)
1
1
1
1
Day 15
15
8 - 22
Day 29
29
23 - 43
15 - 57
Day 57
57
44 - 71
28 - 56
Day 85
85
72 - 99
58 - 99
Day 113*
113
100 - 120
100 - 141
57 - 169
Day 128
128
121 - 134
Day 141
141
135 - 155
Day 169
169
156 - 183-
142 - 197
Day 197
197
184 - 211
Day 225*
225
212 - 253
198 - 309
170 - 309
OLE period
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Table 8.6-4:
For Subjects who Completed Period 1 and Entered Period 2 prior 
to the Protocol Revision
Visit
Target Day
Chemistry 
CBC
Total Cholesterol and 
Triglycerides, fasting
Day 281
281
254 - 309
Day 337
337
310 - 365
Day 393
393
366 - 421
310 - 421
310 - 421
* Day 113 assessment for subjects continuing in Period 2, the upper inclusive limit of this window is the first infusion 
in Period 2 or 42 days after last dose in Period 1, whichever comes earlier. Day 113 assessment extends 42days after 
last dose in Period 1 for subjects discontinuing during Period 1. Similarly, Day 225 assessment for subjects continuing 
in OLE, the upper inclusive limit of this window is the first infusion in OLE or 42 days after last dose in Period 2, 
whichever comes earlier. Assessments within 42 days after last dose in Period 2 are included for subjects discontinuing 
during Period 2.
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Table 8.6-5:
Day Ranges for Immunogenicity Assessments at Every Scheduled 
Visit During the Double -Blind Period and Follow-Up Period
Visit
Target Day
Immunogenicity Day Ranges*
Double-blind period
Day 1 (Baseline)
1
≤1
Day 113
113
8 - 169*
Follow-up period
Day 56
56
1 - 70
Day 84
84
71 - 126
Day 168
168
127 - 168
* For Day 113 assessment, the upper inclusive limit of this window is the first infusion in OLE or 56 days after last 
dose in double-blind period, whichever comes earlier.
For subjects who completed Period 1 and entered Period 2 prior to the protocol revision:
Table 8.6-6:
For Subjects who Completed Period 1 and Entered Period 2 prior 
to the Protocol Revision
Visit
Target Day
Immunogenicity Day Ranges*
Double-blind period
Day 1 (Baseline)
1
≤1
Day 113
113
8 - 169*
Day 225
225
170 - 281
Follow-up period
Day 56
56
1 - 70
Day 84
84
71 - 126
Day 168
168
127 - 168
*For Day 113 assessment, the upper inclusive limit of this window is the first infusion in Period 2 or 56 days after last 
dose in Period 1, whichever comes earlier
If a subject has more than one visit where a measurement is recorded within a window, the 
measurement closest to the target day will be used. In case of two visits being equidistant from the 
target, the later measurement will be used in the analyses. Exceptions to these rules apply to
immunogenicity, where the least favorable value (toward a positive response) in the window will 
be used.
For subjects who discontinue from study therapy prematurely, assessments performed after the last 
infusion of study drug will be included in the efficacy and safety data sets provided that these 
assessments are made within 42 and 56 days respectively of the last infusion.
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9
CONTENT OF REPORTS
The results of this study will be presented in a standard BMS Clinical Study Report (CSR). Prior 
to completion of the CSR an Initial Data Assessment will be prepared briefly identifying the key 
results and any unanticipated findings that are unusual for a study within this program. Prior to 
completion of the Initial Data Assessment, a meeting for the Initial Data Assessment of study 
results will be held after database lock and unblinding. Attendees at this meeting will review 
efficacy and safety summaries and listings and will identify key results that should be highlighted 
in the Initial Data Assessment and CSR.
At the end of the study, when all subjects complete the follow-up period or discontinue 
prematurely, a final closeout report will be prepared. The reports will be mainly presenting safety 
summaries based on the OLE and the cumulative period. It will include the following summaries
and the associated listings indicated in the respective sections in this analysis plan:
•
Subject Disposition.
•
Exposure summaries presented in Section 7.4.
•
Efficacy: Changes from baseline in UPCR and serum albumin.
•
Adverse Events:
‒
Serious adverse events (SAE).
‒
AEs leading to study drug discontinuation.
‒
AEs related to study drug.
‒
Related events categorized by intensity.
‒
Most common related AEs (reported in at least 2% of subjects in any treatment group).
‒
AEs by intensity.
‒
All AEs (serious or non-serious).
‒
Most common (serious or non-serious) AEs (reported in at least 5% of subjects in any 
treatment group).
‒
Serious adverse events and related serious adverse events with death as an outcome 
following EudraCT requirements.
‒
Multiple AEs summaries including the required EudraCT summaries in Section 7.6.4.1
(based on cumulative abatacept safety period).
•
Laboratory Summaries:
‒
Laboratory abnormalities.
‒
Shift tables.
•
Vital Signs based on OLE period only.
•
Immunogenicity.
•
Pharmacokinetics.
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APPENDIX 1
DOCUMENT HISTORY
Table 9-1:
Document History
Version
Statistician
Date
Notes/Revisions
1.0
16 January 2018
Original version
2.0
13 September 2018
Incorporates Protocol Amendment 2
- Period 2 is eliminated and the previous Period 1 is 
renamed as the double-blind period.
-
 
- For subjects who completed Period 1 and entered 
Period 2 prior to the protocol revision, the Period 1 is 
analyzed as part of the double-blind, the Period 2 data are 
only listed. Period 2 data are not part of any summaries 
except for safety summaries at the end of the study on the 
cumulative abatacept safety period.
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APPENDIX 2
RELEVANT PROTOCOL DEVIATIONS
Pre Randomization:
•
UPCR < 2.7 at screening.
•
eGFR below the following level at screening:
‒
50 for subjects < 18 years (new Schwartz equation).
‒
50 for subjects ≥18 years (CKD-EPI equation).
•
Body mass index (BMI): > 45 in subjects ≥18 years of age and ≥99% percentile for subjects 
< 18 years of age at screening.
•
Hemoglobin (Hgb) < 7.0g/dl at screening.
•
White Blood Count (WBC) < 2,000/mm3 (2 x 109/L) at screening.
•
Platelets < 75,000/mm3 (75 x 109/L) at screening.
•
Serum ALT or AST > 3 times upper limit of normal at screening.
•
Subjects systemically using any of CS (low dose, prednisone or equivalent at doses 
≤15mg/day), calcineurin inhibitors (cyclosporine and tacrolimus), MMF and MPA for 
treatment of TRNS (use for other medical indications [e.g. asthma] is allowed), satisfying any 
of the following:
‒
Started using one of the above agents within 8 weeks of enrollment.
‒
Not using the standard dose or
‒
Have not been on stable dose for at least 4 weeks prior to randomization.
Post Randomization:
•
FSGS or MCD diagnosis not confirmed by a pathology report.
•
Use of prohibited medication:
‒
Any systemic immunosuppressive or immunomodulator per protocol including, but not 
limited to cyclophosphamide, methotrexate, belimumab, azathioprine, leflunomide, 
rituximab, experimental therapies, everolimus, sirolimus, corticotropin injection gel 
(ACTH) or plasmapheresis.
‒
Combined use of two or more renin-angiotensin system (RAS) inhibitors.
•
Missed two or more doses of investigational product for any reason during double-blind period.
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APPENDIX 3
CLINICAL REPORTS CONTENT
Table 9-2:
Safety Analysis by Period
End of Double-Blind 
Period CSR
End of Study 
CSR
Double-Blind Period
Cumulative 
Abatacept 
Safety Period
OLE 
Period 
Serious Adverse Events
X
X
X
AEs leading to study drug 
discontinuation
X
X
X
AEs related to study drug
X
X
X
Related events categorized by 
intensity
X
X
X
Most common related AEs (reported 
in at least 2% of subjects in any 
treatment group)
X
X
X
All AEs (serious or non-serious)
X
X
X
AEs by intensity
X
X
X
Most common (serious or non-
serious) AEs (reported in at least 
5% of subjects in any treatment 
group)
X
X
X
Serious adverse events and related 
serious adverse events with death as 
an outcome (EudraCT)
X
AEs of Special Interest (Renal 
Related Events, Infections, 
Malignancy, Autoimmune Disorder, 
Infusional Reactions)
X
X
Multiple Adverse Events
X
X
EudraCT summaries - Exposure 
adjusted summaries
X
Laboratory abnormalities
X
X
X
Laboratory Shift Tables
X
X
X
Mean Change from Baseline in Lab 
Parameters
X
Vital Signs
X
X
Immunogenicity
X
X
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