ABC: Clarification of Abatacept Effects in SLE With Integrated Biologic and Clinical Approaches

• Sponsor: Oklahoma Medical Research Foundation (Other)
• Overall Status: Completed
• CT.gov ID: NCT02270957
• Collaborator: Bristol-Myers Squibb (Industry)
• Enrollment: 66
• Location: 1
• Arms: 2
• Actual Duration (Months): 95
• Patients Per Site Per Month: 0.7

Study Details

Study Description

Brief Summary

This is a randomized, double blind, placebo controlled trial of abatacept for the treatment of lupus arthritis and other manifestations of lupus. Patients with lupus and at least 3 tender and 3 swollen joints and </= 20 mg prednisone have other background immune suppressants withdrawn at entry. They can elect to receive up to a total of 320 mg depomedrol (in two or more injections) between the screening visit and the visit 2 months after dosing begins. Abatacept (125 mg) or placebo is administered in weekly subcutaneous doses. After 3 months of treatment patients who are not responding may elect to receive open label abatacept with or without additional standard of care therapies. Such patients are considered non responders. The primary endpoint is the British Isles Lupus Assessment Group Index (BILAG)-linked Combined Lupus Assessment (BICLA) which will require a clinically significant improvement in arthritis and other active features of lupus

Condition or Disease	Intervention/Treatment	Phase
Systemic Lupus Erythematosus	Biological: Abatacept; Other: Placebo	Phase 2

Detailed Description

Research Hypothesis: Abatacept is effective in lupus arthritis and this will be discernible in a small trial with robust endpoints which incorporates withdrawal of background immune suppressants

Study Schematic: Abatacept 125 mg or placebo will be given in a 1:1 randomization subcutaneously each week for six months. All patients may elect to continue six more months on open label Abatacept. Background Immune Suppressants will be withdrawn at any time between screening and the first dosing visit. At or after screening, patients may elect 40-160 mg depomedrol shots prn not to exceed 320 mg total up to and including the Month 2 Visit (two months after the first dosing visit) After that, additional steroids or immune suppressants, if necessary, will be allowed but the patient will be considered a non-responder in the primary endpoint at six months on that basis. At of after the 3 month visit patients with significant clinical flare may also elect to receive open label Abatacept but will be considered non-responders in the primary endpoint at six months.

Primary Objective: To compare response rates between Abatacept-Treated and Placebo-Treated Patients with active lupus arthritis in a trial designed with background immune suppressant withdrawal, limited steroid rescue, and a robust, discriminatory endpoint. The trial design and primary endpoint of response by BICLA (defined below) have been pre-tested by us for safety and ability to ensure placebo group non-response, underscoring our powering of the study. This will support a rational decision about further development of abatacept for SLE at minimal cost.

Secondary clinical outcome measures used as endpoints will include: SRI 4/5, changes in joint counts, SLEDAI, BILAG, CLASI, PGA, and LFA REAL measures.

The definitions of the clinical outcome measures are as follows: BICLA: BILAG-based Combined Lupus Assessment, This is defined as British Isles Lupus Assessment Group (BILAG) index scores that were severe at entry (BILAG A scores) improving to a moderate (BILAG B) level (or better) and all features that were moderate at entry improving to a mild level (BILAG C scores) or resolved (BILAG D scores) without increase in any other BILAG feature or SLEDAI scoring (see SLEDAI definition below), as well as no more than 10% worsening in a Physician's Global Assessment or any additional treatments after the protocolized baseline rescue (e.g. no new SLE treatments after the two month visit). SLEDAI stands for the Systemic Lupus Erythematosis Disease Activity Index. SRI 4/5 is defined as SLEDAI improvement by at least 4 points (or 5 points respectively), no increase in BILAG-measured disease activity and no more than 10% worsening in a Physician's Global Assessment (PGA). CLASI stands for the Cutaneous Lupus Erythematosus Disease Area and Severity Index. PGA stands for Physician's Global Assessment. LFA REAL stands for the Lupus Foundation of America Rapid Evaluation of the Activity of Lupus. This instrument is in a pilot phase but will be tested in the ABC study.

PK and immunogenicity studies will also be performed to help in interpretation of outcomes. Novel biologic discovery will be integrated into the clinical trial to support both pre-specified and exploratory biomarker discovery. Data will be generated that might be used to help select more appropriate patient subsets for future trials and, along with PK data, help to guide optimal dosing strategies. Optimizing patient selection and dosing are important goals for further increasing demonstrable effect size in trials by increasing the response rates in the treatment group.

This study will be performed as a double blind, randomized, placebo-controlled clinical trial with 1:1 randomization of patients to abatacept 125 mg weekly subcutaneous dose or placebo, with the withdrawal of background immune suppressants. Limited steroid rescue is allowed between the screening visit and the Month 2 visit per protocol. Additional standard of care rescue medications may be used after that as needed but will define non-response at the primary endpoint date of six months. Flaring patients may elect to receive open label abatacept at Month 3 but will also be defined as non-responders in the primary endpoint. All patients may elect to receive open label abatacept for an additional six months after the primary endpoint date, with two follow up visits (2 and 4 months post medication withdrawal) to assess withdrawal effects and to complete the safety assessments.

Accrual Goal: This study will continue to recruit until we achieve the goal of 60 patients who complete study visits through the 6 month endpoint.

Correlative Studies: Extensive exploratory protocol-specific and ancillary immune pharmacodynamic studies, focusing first on changes in IFN alpha, BLyS and other B Cell pathways. A major focus will also be on T Cell pathways with a focus on T suppressor/TH17 dichotomy after treatment with abatacept. A responder analysis will be performed in order to generate hypotheses useful for selecting appropriate patients for this treatment and optimizing dosing strategies.

Adverse Events, Serious Adverse Events and Adverse Events of special interest (infusion reactions and infections) will be collected and described. Stopping Rules: Patients may be withdrawn by the investigator for non-compliance or safety. All patients terminating before six months will be considered non responders in the primary analysis. Use of off protocol immune suppressants will not necessarily dictate withdrawal but will determine non-responder status. A DSMB board of at least two physicians (four are currently participating) will review data and may stop the study if needed.

Study Design

• Study Type: Interventional
• Actual Enrollment: 66 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Clarification of Abatacept Effects in SLE With Integrated Biologic and Clinical Approaches (The ABC Study)
• Actual Study Start Date: Jan 1, 2014
• Actual Primary Completion Date: Dec 1, 2018
• Actual Study Completion Date: Dec 1, 2021

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Abatacept Patients receive Abatacept 125 mg subcutaneously weekly for six months. An optional continuation up until 12 months is allowed. Background immune suppressants are withdrawn at the beginning of the study and the option of depomedrol up to 320 mg total (in divided doses) is allowed at any time up through the visit 2 months after study medication is started. After this additional rescue is allowed with any standard of care treatment and/or open label abatacept (since patients are blinded) but this additional rescue will define non-response in the primary endpoint at six months.	Biological: Abatacept; Other Names: Orencia
Placebo Comparator: Placebo Patients receive placebo instead of Abatacept in a double blind fashion. Otherwise participation is the same, including that at the time of treatment failure they may elect any standard of care treatment and/or to begin taking open label abatacept but this rescue will define non-response in the primary endpoint at six months.	Other: Placebo

Outcome Measures

Primary Outcome Measures

1. British Isles Lupus Assessment Group Index-based Combined Lupus Assessment (BICLA) [6 months]

   The British Isles Lupus Assessment Group Index is a scoring system for progress of disease activity over the prior month with a scoring system that rates each organ system as "A" or severe, "B" or moderate, "C" or mild vs no activity in the past month. To meet the BICLA endpoint requires all baseline severe features (BILAG A) improving to moderate (BILAG B), mild or resolved, and all baseline BILAG B features improving to mild or resolved without increase in any other feature on either the BILAG or a different measure called the SLEDAI (SLE Disease Activity Index). Furthermore there must be no increase in Physician's Global Assessment or any rescue medications after the month 2 visit. Only those meeting all of these criteria meet the primary endpoint.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Signed Written Informed Consent

2. Four 1997 revised ACR Classification Criteria for SLE

3. Active polyarticular arthritis meeting at minimum BILAG 2004 B definition with a minimum of 3 tender and 3 swollen joints observed at the screening visit

4. Men and women 18 to 70 years of age.

5. Women of childbearing potential and men with partners of childbearing potential must use an acceptable method of birth control throughout the study

6. Women of childbearing potential must have a negative urine pregnancy test at screening and Study Day 1 (baseline visit) and may not be breast feeding

Exclusion Criteria:

1. Current severe, organ-threatening disease (e.g. acute nephritis appropriate for induction therapy, CNS lupus (excepting chorea, cranial neuropathy, and resolving optic neuritis) or any lupus condition requiring cyclophosphamide, biologic therapy, or IV bolus steroids of >/= 500 mg.

2. Subjects who are incapable of understanding or completing study-related assessments.

3. Subjects with any condition, whether or not related to SLE, which, in the opinion of the investigator, might place a subject at unacceptable risk for participation in the study.

4. Subjects with a history of cancer in the last 5 years, other than non-melanoma skin cell cancers cured by local resection or carcinoma in situ.

5. Subjects who currently abuse drugs or alcohol.

6. Subjects with acute herpes zoster or cytomegalovirus (CMV) within 2 months of screening.

7. Subjects who have received any live vaccines within 3 months of first dose.

8. Subjects with any serious bacterial infection within the last 3 months, unless treated and resolved with antibiotics, or any chronic bacterial infection (eg, chronic pyelonephritis, osteomyelitis, or bronchiectasis).

9. Subjects at risk for tuberculosis (TB).

10. Subjects known to be positive for hepatitis B surface antigen or hepatitis C unless negative by PCR or RIBA

11. Acute hemolytic anemia with hemoglobin < 7.0 g/dL or known change in Hg by 2.0 g/dL within four months

12. WBC < 2500/mm3 (< 3 x 109/L) unless due to chronic stable lupus activity

13. Platelets < 40,000/mm3 (< 3 x 109/L) (If less than 100,000 must have been stable (within a range of 10,000/mm3 ) within two months of screening or in two tests during the screening period.

14. Serum creatinine > 2 times the ULN

15. Serum ALT or AST > 2.5 times the ULN

16. Any other laboratory test results that, in the opinion of the investigator, might place a subject at unacceptable risk for participation in the study.

17. Known allergy/sensitivity to the study agent or carrier.

18. Treatment with investigational drug within 28 days (or 5 terminal half-lives) of the Day 1 dose.

19. Cyclophosphamide within 3 months of Day 1 or bolus IV steroids >/=500 mg within 1 month

20. Prednisone > 20 mg qd after the screening visit

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Oklahoma Medical Research Foundation	Oklahoma City	Oklahoma	United States	73104

Sponsors and Collaborators

• Oklahoma Medical Research Foundation
• Bristol-Myers Squibb

Investigators

• Study Director: Joan T Merrill, MD, Oklahoma Medical Research Foundation

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jan 8, 2016

More Information

Publications

None provided.

• Responsible Party: Oklahoma Medical Research Foundation
• ClinicalTrials.gov Identifier: NCT02270957
• Other Study ID Numbers: OMRF 13-38
• First Posted: Oct 22, 2014
• Last Update Posted: Jan 26, 2022
• Last Verified: Jan 1, 2022

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Additional relevant MeSH terms: Lupus Erythematosus, Systemic; Abatacept

Study Results

Participant Flow

Arm/Group Title	Abatacept	Placebo
Arm/Group Description	Patients receive Abatacept 125 mg subcutaneously weekly for six months. An optional continuation up until 12 months is allowed. Background immune suppressants are withdrawn at the beginning of the study and the option of depomedrol up to 320 mg total (in divided doses) is allowed at any time up through the visit 2 months after study medication is started. After this additional rescue is allowed with any standard of care treatment and/or open label abatacept (since patients are blinded) but this additional rescue will define non-response in the primary endpoint at six months. Abatacept	Patients receive Placebo but at the time they meet non-response criteria they may elect open label abatacept or any standard of care to treat their SLE
Period Title: Overall Study
STARTED	31	35
COMPLETED	27	31
NOT COMPLETED	4	4

Baseline Characteristics

Arm/Group Title	Abatacept	Placebo	Total
Arm/Group Description	Patients receive Abatacept 125 mg subcutaneously weekly for six months. An optional continuation up until 12 months is allowed. Background immune suppressants are withdrawn at the beginning of the study and the option of depomedrol up to 320 mg total (in divided doses) is allowed at any time up through the visit 2 months after study medication is started. After this additional rescue is allowed with any standard of care treatment and/or open label abatacept (since patients are blinded) but this additional rescue will define non-response in the primary endpoint at six months. Abatacept	Patients receive Placebo. At any time that they meet non-response criteria (primary endpoint) they may elect to be treated with any standard of care medication or open label abatacept Placebo	Total of all reporting groups
Overall Participants	31	35	66
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	43.8 (10.9)	46.9 (11.9)	45.4 (11.5)
Sex: Female, Male (Count of Participants)
Female	29 93.5%	34 97.1%	63 95.5%
Male	2 6.5%	1 2.9%	3 4.5%
Race/Ethnicity, Customized (Count of Participants)
Caucasian	17 54.8%	26 74.3%	43 65.2%
African	8 25.8%	6 17.1%	14 21.2%
Asian	0 0%	0 0%	0 0%
Native American/Alaskan Native	6 19.4%	3 8.6%	9 13.6%
Region of Enrollment (participants) [Number]
United States	31 100%	35 100%	66 100%
anti-dsDNA positive (participants) [Number]
Number [participants]	5 16.1%	12 34.3%	17 25.8%
low complement (participants) [Number]
Number [participants]	5 16.1%	9 25.7%	14 21.2%
Number with at least one BILAG "B" score (Count of Participants)
Count of Participants [Participants]	31 100%	35 100%	66 100%

Outcome Measures

1. Primary Outcome

Title	British Isles Lupus Assessment Group Index-based Combined Lupus Assessment (BICLA)
Description	The British Isles Lupus Assessment Group Index is a scoring system for progress of disease activity over the prior month with a scoring system that rates each organ system as "A" or severe, "B" or moderate, "C" or mild vs no activity in the past month. To meet the BICLA endpoint requires all baseline severe features (BILAG A) improving to moderate (BILAG B), mild or resolved, and all baseline BILAG B features improving to mild or resolved without increase in any other feature on either the BILAG or a different measure called the SLEDAI (SLE Disease Activity Index). Furthermore there must be no increase in Physician's Global Assessment or any rescue medications after the month 2 visit. Only those meeting all of these criteria meet the primary endpoint.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

Full Analysis Set: All Randomized Patients

Arm/Group Title	Abatacept	Placebo
Arm/Group Description	Patients receive Abatacept 125 mg subcutaneously weekly for six months. An optional continuation up until 12 months is allowed. Background immune suppressants are withdrawn at the beginning of the study and the option of depomedrol up to 320 mg total (in divided doses) is allowed at any time up through the visit 2 months after study medication is started. After this additional rescue is allowed with any standard of care treatment and/or open label abatacept (since patients are blinded) but this additional rescue will define non-response in the primary endpoint at six months. Abatacept	Patients receive Abatacept 125 mg subcutaneously weekly for six months. An optional continuation up until 12 months is allowed. Background immune suppressants are withdrawn at the beginning of the study and the option of depomedrol up to 320 mg total (in divided doses) is allowed at any time up through the visit 2 months after study medication is started. After this additional rescue is allowed with any standard of care treatment and/or open label abatacept (since patients are blinded) but this additional rescue will define non-response in the primary endpoint at six months. Placebo
Measure Participants	31	35
Count of Participants [Participants]	8 25.8%	8 22.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Abatacept, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	>0.999
	Comments
	Method	Chi-squared
	Comments

2. Post-Hoc Outcome

Title	SLE Responder Index-4 (SRI-4)
Description	Comparing the endpoint date at six months to Baseline, there must be a 4 point decreased in SLEDAI score (SLEDAI is defined as the SLE Disease Activity Index). The SLEDAI is a discontinuous scale in which each type of sign or symptom of active SLE is assigned a fixed number of points. Although the scale includes possible signs or symptoms adding up to more than 100 points it is rare for any (even very severe) patient to ever have a total score > 20. To meet the SLE Responder Index endpoint, There must also be no worsening of BILAG (British Isles Lupus Assessment Group Index (described in the primary endpoint section) and no worsening of PGA (a visual analogue scale reflecting physicians global assessment) by more than 10% of the scale. To meet this endpoint there must also be no new or increased medication initiated after Baseline other than the steroid rescues up to Month 2.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	Abatacept	Placebo
Arm/Group Description	Patients receive Abatacept 125 mg subcutaneously weekly for six months. An optional continuation up until 12 months is allowed. Background immune suppressants are withdrawn at the beginning of the study and the option of depomedrol up to 320 mg total (in divided doses) is allowed at any time up through the visit 2 months after study medication is started. After this additional rescue is allowed with any standard of care treatment and/or open label abatacept (since patients are blinded) but this additional rescue will define non-response in the primary endpoint at six months. Abatacept	Patients receive Placebo but if the primary endpoint is met as "non-response" at any time they may elect any standard of care treatment or may initiate abatacept open label. Placebo
Measure Participants	31	35
Count of Participants [Participants]	9 29%	8 22.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Abatacept, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.587
	Comments
	Method	Chi-squared
	Comments

3. Post-Hoc Outcome

Title	4 Point Improvement in the SLE Disease Activity Index (SLEDAI)
Description	The SLEDAI is a discontinuous scoring system that weights disease activity not by severity of individual symptoms but by the weighting of organs. This makes it less robust for comparing one group of patients to another, but it is quite useful to gave numbers of patients with improvement, since to lower the score a rigorous improvement must be documented
Time Frame	Comparison of Baseline to 6 months

Outcome Measure Data

Analysis Population Description

Full Analysis Set of all randomized patients

Arm/Group Title	Abatacept	Placebo
Arm/Group Description	Patients receive Abatacept 125 mg subcutaneously weekly for six months. An optional continuation up until 12 months is allowed. Background immune suppressants are withdrawn at the beginning of the study and the option of depomedrol up to 320 mg total (in divided doses) is allowed at any time up through the visit 2 months after study medication is started. After this additional rescue is allowed with any standard of care treatment and/or open label abatacept (since patients are blinded) but this additional rescue will define non-response in the primary endpoint at six months. Abatacept	Patients receive Abatacept 125 mg subcutaneously weekly for six months. An optional continuation up until 12 months is allowed. Background immune suppressants are withdrawn at the beginning of the study and the option of depomedrol up to 320 mg total (in divided doses) is allowed at any time up through the visit 2 months after study medication is started. After this additional rescue is allowed with any standard of care treatment and/or open label abatacept (since patients are blinded) but this additional rescue will define non-response in the primary endpoint at six months. Placebo
Measure Participants	31	35
Count of Participants [Participants]	9 29%	8 22.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Abatacept, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.587
	Comments	None of the endpoints were met in any pre-specified unbiased Full Analysis Set analysis
	Method	Chi-squared
	Comments

Adverse Events

Time Frame	12 months
Arm/Group Title	Abatacept		Placebo
Arm/Group Description	Patients receive Abatacept 125 mg subcutaneously weekly for six months.		Patients receive Placebo subcutaneously weekly for six months.
All Cause Mortality
	Abatacept		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/31 (0%)		0/35 (0%)
Serious Adverse Events
	Abatacept		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/31 (19.4%)		4/35 (11.4%)
Blood and lymphatic system disorders
sickle cell crisis	1/31 (3.2%)	1	0/35 (0%)	0
Cardiac disorders
cardiac valve dysfunction	0/31 (0%)	0	1/35 (2.9%)	1
Gastrointestinal disorders
gastroenteritis	1/31 (3.2%)	1	0/35 (0%)	0
cholecystitis	1/31 (3.2%)	1	0/35 (0%)	0
Infections and infestations
viral syndrome	1/31 (3.2%)	1	1/35 (2.9%)	1
Musculoskeletal and connective tissue disorders
fracture	1/31 (3.2%)	1	0/35 (0%)	0
Psychiatric disorders
suicidal ideation	1/31 (3.2%)	1	0/35 (0%)	0
Renal and urinary disorders
Acute renal failure	0/31 (0%)	0	1/35 (2.9%)	1
blocked ureter	0/31 (0%)	0	1/35 (2.9%)	1
Respiratory, thoracic and mediastinal disorders
respiratory compromise	0/31 (0%)	0	1/35 (2.9%)	1
Social circumstances
opiate overdose	0/31 (0%)	0	1/35 (2.9%)	1
Other (Not Including Serious) Adverse Events
	Abatacept		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	29/31 (93.5%)		35/35 (100%)
Ear and labyrinth disorders
otitis media	1/31 (3.2%)	1	4/35 (11.4%)	5
Gastrointestinal disorders
gastroenteritis	17/31 (54.8%)	18	11/35 (31.4%)	11
Infections and infestations
oral candida	0/31 (0%)	0	8/35 (22.9%)	8
urinary tract infection	5/31 (16.1%)	7	17/35 (48.6%)	24
upper respiratory infection	15/31 (48.4%)	20	16/35 (45.7%)	27
influenza	1/31 (3.2%)	1	3/35 (8.6%)	4
sinusitis	4/31 (12.9%)	4	8/35 (22.9%)	14
vaginal yeast infestation	1/31 (3.2%)	1	5/35 (14.3%)	7
Injury, poisoning and procedural complications
injection site reaction	4/31 (12.9%)	4	3/35 (8.6%)	4
Respiratory, thoracic and mediastinal disorders
bronchitis	5/31 (16.1%)	5	4/35 (11.4%)	5
Skin and subcutaneous tissue disorders
rash	2/31 (6.5%)	2	4/35 (11.4%)	6

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.