The Efficacy and Safety of Atacicept in Combination With Mycophenolate Mofetil Used to Treat Lupus Nephritis

• Sponsor: EMD Serono (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT00573157
• Collaborator: ZymoGenetics (Industry)
• Enrollment: 6
• Locations: 20
• Arms: 2
• Duration (Months): 16
• Patients Per Site: 0.3
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

The purpose of this study is to learn whether atacicept treatment leads to improvement in kidney function in subjects with active lupus nephritis in combination with mycophenolate mofetil (MMF) and corticosteroids. The study was sponsored by Merck Serono International; operational oversight was provided by ZymoGenetics.

Condition or Disease	Intervention/Treatment	Phase
Lupus Nephritis	Drug: Atacicept; Drug: Mycophenolate mofetil; Drug: Placebo; Drug: Corticosteroids	Phase 2/Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 6 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Phase 2/3, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety and Efficacy of Atacicept in Subjects With Lupus Nephritis in Combination With Mycophenolate Mofetil Therapy.
• Study Start Date: Dec 1, 2007
• Actual Primary Completion Date: Apr 1, 2009
• Actual Study Completion Date: Apr 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Atacicept Plus Mycophenolate mofetil Plus Corticosteroids	Drug: Atacicept; Atacicept will be administered at a dose of 150 milligram (mg) subcutaneously (SC) twice weekly for 4 weeks followed by maintenance dose of 150 mg SC once weekly for 48 weeks.; Drug: Mycophenolate mofetil; MMF will be administered orally with a starting dose of 500 mg twice daily for 1 week, will be increased to 1000 mg twice daily for 1 week, then it will be adjusted to 1500 mg or lower twice daily as per investigator's discretion.; Drug: Corticosteroids; High dose CS of 0.8 mg per kilogram per day or maximum of 60 mg per day prednisone or prednisone equivalent, whichever is less will be administered for 4 Weeks and will be tapered to 7.5 to 10 mg/day up to Week 12.
Placebo Comparator: Placebo Plus Mycophenolate mofetil Plus Corticosteroids	Drug: Mycophenolate mofetil; MMF will be administered orally with a starting dose of 500 mg twice daily for 1 week, will be increased to 1000 mg twice daily for 1 week, then it will be adjusted to 1500 mg or lower twice daily as per investigator's discretion.; Drug: Placebo; Placebo will be administered at a dose of 150 mg SC twice weekly for 4 weeks followed by 150 mg SC once weekly for 48 weeks.; Drug: Corticosteroids; High dose CS of 0.8 mg per kilogram per day or maximum of 60 mg per day prednisone or prednisone equivalent, whichever is less will be administered for 4 Weeks and will be tapered to 7.5 to 10 mg/day up to Week 12.

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With Confirmed Complete Renal Response (CRR), Partial Response, and Non-response [At Week 52]

   Complete renal response (CRR): from baseline, a return to within 10% of normal for renal function (assessed by calculated glomerular filtration rate [GFR]), improvement in proteinuria (urine protein/creatinine ratio <0.5) & resolution of hematuria. Partial response (PR): from baseline, a <= 10% worsening in renal function ( by calculated GFR); 50% improvement in proteinuria (assessed by urine protein/creatinine ratio) & resolution of hematuria, Non-response (NR): Neither criteria for CR or PR was met. Subjects were also deemed NR if they had treatment failure, regardless of CR or PR status. Subjects cannot be treatment failures. A response of CRR was confirmed if the Week 52 value is CRRand if the Week 48 value is CRR and at least 4 weeks apart from Week 52 /if the Week 48 value was missing/ less than 4 weeks from Week 52, then the Week 56 response must be CRR - if the Week 52 value was missing, then Week 48 and Week 56 must be CRR.

Secondary Outcome Measures

1. Percentage of Participants With Normalization of Renal Function [At Week 52]

2. Number of Participants With New Lupus Flares [At Week 52]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 16 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Diagnosis of systemic lupus erythematosus (SLE) satisfying at least 4 out of the 11 American College of Rheumatology (ACR) criteria (Appendix B)

• Renal biopsy performed consistent with active International Society of Nephrology/Renal Pathology Society (ISN/PRS) class III or IV lupus nephritis

Exclusion Criteria:

• Estimated glomerular filtration rate (GFR) less than or equal to (<=) 30 milliliter per minute (mL/min) per 1.73 square meter (m^2)

• Active central nervous system SLE deemed to be severe or progressive and/or associated with significant cognitive impairment

• Any treatment with MMF, azathioprine, or cyclophosphamide within the last 6 months, or known hypersensitivity to MMF or atacicept.

• Any prior treatment with abatacept, rituximab, belimumab, or other B cell modulating agents.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Tulane University Hospital and Clinic Department of Internal Medicine	New Orleans,	Louisiana	United States
2	Northwest Louisiana Nephrology Research	Shreveport	Louisiana	United States	71101
3	Wayne State University Lupus Database Departments of Internal Medicine and Obstetrics & Gynecology Division of Rheumatology Wayne State University School of Medicine	Detroit	Michigan	United States
4	The Feinstein Institute for Medical Research	Manhasset	New York	United States	11030
5	Seligman Center for Advanced Therapeutics	New York	New York	United States	10003
6	Wake Forest University Health Sciences	Winston-Salem	North Carolina	United States	27109
7	Rheumatology Clinical Research Unit, Division of Rheumatology University Hospitals Case Medical Center	Beachwood	Ohio	United States	44122
8	University of Cincinnati College of Medicine	Cincinnati	Ohio	United States	45267
9	The Ohio State University Medical Center	Columbus	Ohio	United States	43210
10	Southwest Rheumatology and Research Group, LLC	Middleburg Heights	Ohio	United States	44130
11	1711 St. Julian Place	Columbia	South Carolina	United States	29204
12	ACME Research, LLC	Orangeburg	South Carolina	United States	29118
13	Institute of Rheumatology	Prague, 128 50		Czech Republic
14	Hospital Sultanah Bahiyah	Kedah		Malaysia
15	Hospital University Kebangsaan Malaysia	Kuala Lumpur		Malaysia
16	University of Malaya Medical Centre	Kuala Lumpur		Malaysia
17	Hospital Pulau Pinang	Pulau Pinang		Malaysia
18	Changi General Hospital	Singapore		Singapore
19	Singapore General Hospital	Singapore		Singapore
20	Kaohsiung Veterans General Hospital	Kaohsiung		Taiwan

Sponsors and Collaborators

• EMD Serono
• ZymoGenetics

Investigators

• Study Director: Medical Responsible, EMD Serono, Inc., a subsidiary of Merck KGaA, Darmstadt, Germany

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: EMD Serono
• ClinicalTrials.gov Identifier: NCT00573157
• Other Study ID Numbers: 28113; 493G01
• First Posted: Dec 14, 2007
• Last Update Posted: Mar 23, 2016
• Last Verified: Feb 1, 2016

• Keywords provided by EMD Serono: nephritis; atacicept
• Additional relevant MeSH terms: Nephritis; Lupus Nephritis; Mycophenolic Acid

Study Results

Participant Flow

Arm/Group Title	Atacicept Plus Mycophenolate Mofetil Plus Corticosteroids	Placebo Plus Mycophenolate Mofetil Plus Corticosteroids
Arm/Group Description	Atacicept was administered subcutaneously (SC) at a loading dose of 150 milligram (mg) twice weekly for 4 weeks followed by maintenance dose of 150 mg SC once weekly for 48 weeks. MMF was administered orally with a starting dose of 500 mg twice daily for 1 week, increased to 1000 mg twice daily for 1 week, then adjusted to 1500 mg or lower twice daily as per investigator's discretion. High dose corticosteroids (CS) of 0.8 mg per kilogram per day or maximum of 60 mg per day prednisone or prednisone equivalent, whichever was less was administered for 4 Weeks and tapered to 7.5 to 10 mg/day up to Week 12.	Placebo was administered SC at a loading dose of 150 mg twice weekly for 4 weeks followed by maintenance dose of 150 mg SC once weekly for 48 weeks. MMF was administered orally with a starting dose of 500 mg twice daily for 1 week, increased to 1000 mg twice daily for 1 week, then adjusted to 1500 mg or lower twice daily as per investigator's discretion. High dose CS of 0.8 mg per kilogram per day or maximum of 60 mg per day prednisone or prednisone equivalent, whichever was less was administered for 4 Weeks and tapered to 7.5 to 10 mg/day up to Week 12.
Period Title: Overall Study
STARTED	4	2
COMPLETED	0	0
NOT COMPLETED	4	2

Baseline Characteristics

Arm/Group Title	Atacicept Plus Mycophenolate Mofetil Plus Corticosteroids	Placebo Plus Mycophenolate Mofetil Plus Corticosteroids	Total
Arm/Group Description	Atacicept was administered SC at a loading dose of 150 mg twice weekly for 4 weeks followed by maintenance dose of 150 mg SC once weekly for 48 weeks. MMF was administered orally with a starting dose of 500 mg twice daily for 1 week, increased to 1000 mg twice daily for 1 week, then adjusted to 1500 mg or lower twice daily as per investigator's discretion. High dose CS of 0.8 mg per kilogram per day or maximum of 60 mg per day prednisone or prednisone equivalent, whichever was less was administered for 4 Weeks and tapered to 7.5 to 10 mg/day up to Week 12.	Placebo was administered SC at a loading dose of 150 mg twice weekly for 4 weeks followed by maintenance dose of 150 mg SC once weekly for 48 weeks. MMF was administered orally with a starting dose of 500 mg twice daily for 1 week, increased to 1000 mg twice daily for 1 week, then adjusted to 1500 mg or lower twice daily as per investigator's discretion. High dose CS of 0.8 mg per kilogram per day or maximum of 60 mg per day prednisone or prednisone equivalent, whichever was less was administered for 4 Weeks and tapered to 7.5 to 10 mg/day up to Week 12.	Total of all reporting groups
Overall Participants	4	2	6
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	36.8 (11.3)	36.0 (25.5)	36.5 (14.4)
Sex: Female, Male (Count of Participants)
Female	3 75%	1 50%	4 66.7%
Male	1 25%	1 50%	2 33.3%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With Confirmed Complete Renal Response (CRR), Partial Response, and Non-response
Description	Complete renal response (CRR): from baseline, a return to within 10% of normal for renal function (assessed by calculated glomerular filtration rate [GFR]), improvement in proteinuria (urine protein/creatinine ratio <0.5) & resolution of hematuria. Partial response (PR): from baseline, a <= 10% worsening in renal function ( by calculated GFR); 50% improvement in proteinuria (assessed by urine protein/creatinine ratio) & resolution of hematuria, Non-response (NR): Neither criteria for CR or PR was met. Subjects were also deemed NR if they had treatment failure, regardless of CR or PR status. Subjects cannot be treatment failures. A response of CRR was confirmed if the Week 52 value is CRRand if the Week 48 value is CRR and at least 4 weeks apart from Week 52 /if the Week 48 value was missing/ less than 4 weeks from Week 52, then the Week 56 response must be CRR - if the Week 52 value was missing, then Week 48 and Week 56 must be CRR.
Time Frame	At Week 52

Outcome Measure Data

Analysis Population Description

Due to early termination of the study caused by unanticipated safety issues, the outcome measure was not assessed.

Arm/Group Title	Atacicept Plus Mycophenolate Mofetil Plus Corticosteroids	Placebo Plus Mycophenolate Mofetil Plus Corticosteroids
Arm/Group Description	Atacicept was administered SC at a loading dose of 150 mg twice weekly for 4 weeks followed by maintenance dose of 150 mg SC once weekly for 48 weeks. MMF was administered orally with a starting dose of 500 mg twice daily for 1 week, increased to 1000 mg twice daily for 1 week, then adjusted to 1500 mg or lower twice daily as per investigator's discretion. High dose CS of 0.8 mg per kilogram per day or maximum of 60 mg per day prednisone or prednisone equivalent, whichever was less was administered for 4 Weeks and tapered to 7.5 to 10 mg/day up to Week 12.	Placebo was administered SC at a loading dose of 150 mg twice weekly for 4 weeks followed by maintenance dose of 150 mg SC once weekly for 48 weeks. MMF was administered orally with a starting dose of 500 mg twice daily for 1 week, increased to 1000 mg twice daily for 1 week, then adjusted to 1500 mg or lower twice daily as per investigator's discretion. High dose CS of 0.8 mg per kilogram per day or maximum of 60 mg per day prednisone or prednisone equivalent, whichever was less was administered for 4 Weeks and tapered to 7.5 to 10 mg/day up to Week 12.
Measure Participants	0	0

2. Secondary Outcome

Title	Percentage of Participants With Normalization of Renal Function
Time Frame	At Week 52

Outcome Measure Data

Analysis Population Description

Due to early termination of the study caused by unanticipated safety issues, the outcome measure was not assessed.

Arm/Group Title	Atacicept Plus Mycophenolate Mofetil Plus Corticosteroids	Placebo Plus Mycophenolate Mofetil Plus Corticosteroids
Arm/Group Description	Atacicept was administered SC at a loading dose of 150 mg twice weekly for 4 weeks followed by maintenance dose of 150 mg SC once weekly for 48 weeks. MMF was administered orally with a starting dose of 500 mg twice daily for 1 week, increased to 1000 mg twice daily for 1 week, then adjusted to 1500 mg or lower twice daily as per investigator's discretion. High dose CS of 0.8 mg per kilogram per day or maximum of 60 mg per day prednisone or prednisone equivalent, whichever was less was administered for 4 Weeks and tapered to 7.5 to 10 mg/day up to Week 12.	Placebo was administered SC at a loading dose of 150 mg twice weekly for 4 weeks followed by maintenance dose of 150 mg SC once weekly for 48 weeks. MMF was administered orally with a starting dose of 500 mg twice daily for 1 week, increased to 1000 mg twice daily for 1 week, then adjusted to 1500 mg or lower twice daily as per investigator's discretion. High dose CS of 0.8 mg per kilogram per day or maximum of 60 mg per day prednisone or prednisone equivalent, whichever was less was administered for 4 Weeks and tapered to 7.5 to 10 mg/day up to Week 12.
Measure Participants	0	0

3. Secondary Outcome

Title	Number of Participants With New Lupus Flares
Time Frame	At Week 52

Outcome Measure Data

Analysis Population Description

Due to early termination of the study caused by unanticipated safety issues, the outcome measure was not assessed.

Arm/Group Title	Atacicept Plus Mycophenolate Mofetil Plus Corticosteroids	Placebo Plus Mycophenolate Mofetil Plus Corticosteroids
Arm/Group Description	Atacicept was administered SC at a loading dose of 150 mg twice weekly for 4 weeks followed by maintenance dose of 150 mg SC once weekly for 48 weeks. MMF was administered orally with a starting dose of 500 mg twice daily for 1 week, increased to 1000 mg twice daily for 1 week, then adjusted to 1500 mg or lower twice daily as per investigator's discretion. High dose CS of 0.8 mg per kilogram per day or maximum of 60 mg per day prednisone or prednisone equivalent, whichever was less was administered for 4 Weeks and tapered to 7.5 to 10 mg/day up to Week 12.	Placebo was administered SC at a loading dose of 150 mg twice weekly for 4 weeks followed by maintenance dose of 150 mg SC once weekly for 48 weeks. MMF was administered orally with a starting dose of 500 mg twice daily for 1 week, increased to 1000 mg twice daily for 1 week, then adjusted to 1500 mg or lower twice daily as per investigator's discretion. High dose CS of 0.8 mg per kilogram per day or maximum of 60 mg per day prednisone or prednisone equivalent, whichever was less was administered for 4 Weeks and tapered to 7.5 to 10 mg/day up to Week 12.
Measure Participants	0	0

Adverse Events

Time Frame	From the first dose of trial medication to 24-Week follow-up after last dose of trial medication.
Adverse Event Reporting Description	A Serious adverse event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect.
Arm/Group Title	Atacicept Plus Mycophenolate Mofetil Plus Corticosteroids		Placebo Plus Mycophenolate Mofetil Plus Corticosteroids
Arm/Group Description	Atacicept was administered SC at a loading dose of 150 mg twice weekly for 4 weeks followed by maintenance dose of 150 mg SC once weekly for 48 weeks. MMF was administered orally with a starting dose of 500 mg twice daily for 1 week, increased to 1000 mg twice daily for 1 week, then adjusted to 1500 mg or lower twice daily as per investigator's discretion. High dose CS of 0.8 mg per kilogram per day or maximum of 60 mg per day prednisone or prednisone equivalent, whichever was less was administered for 4 Weeks and tapered to 7.5 to 10 mg/day up to Week 12.		Placebo was administered SC at a loading dose of 150 mg twice weekly for 4 weeks followed by maintenance dose of 150 mg SC once weekly for 48 weeks. MMF was administered orally with a starting dose of 500 mg twice daily for 1 week, increased to 1000 mg twice daily for 1 week, then adjusted to 1500 mg or lower twice daily as per investigator's discretion. High dose CS of 0.8 mg per kilogram per day or maximum of 60 mg per day prednisone or prednisone equivalent, whichever was less was administered for 4 Weeks and tapered to 7.5 to 10 mg/day up to Week 12.
All Cause Mortality
	Atacicept Plus Mycophenolate Mofetil Plus Corticosteroids		Placebo Plus Mycophenolate Mofetil Plus Corticosteroids
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Atacicept Plus Mycophenolate Mofetil Plus Corticosteroids		Placebo Plus Mycophenolate Mofetil Plus Corticosteroids
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/4 (75%)		0/2 (0%)
Blood and lymphatic system disorders
Anaemia	1/4 (25%)		0/2 (0%)
Infections and infestations
Empyema	1/4 (25%)		0/2 (0%)
Pneumonia	1/4 (25%)		0/2 (0%)
Pneumonia legionella	1/4 (25%)		0/2 (0%)
Sepsis	1/4 (25%)		0/2 (0%)
Nervous system disorders
Syncope	1/4 (25%)		0/2 (0%)
Renal and urinary disorders
Renal failure acute	1/4 (25%)		0/2 (0%)
Respiratory, thoracic and mediastinal disorders
Pneumothorax	1/4 (25%)		0/2 (0%)
Pulmonary embolism	1/4 (25%)		0/2 (0%)
Vascular disorders
Hypertensive crisis	1/4 (25%)		0/2 (0%)
Other (Not Including Serious) Adverse Events
	Atacicept Plus Mycophenolate Mofetil Plus Corticosteroids		Placebo Plus Mycophenolate Mofetil Plus Corticosteroids
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/4 (100%)		1/2 (50%)
Blood and lymphatic system disorders
Anaemia	1/4 (25%)		0/2 (0%)
Haemolytic anaemia	1/4 (25%)		0/2 (0%)
Thrombotic microangiopathy	1/4 (25%)		0/2 (0%)
Cardiac disorders
Tachycardia	1/4 (25%)		1/2 (50%)
Atrial fibrillation	1/4 (25%)		0/2 (0%)
Palpitations	0/4 (0%)		1/2 (50%)
Eye disorders
Dry eye	1/4 (25%)		0/2 (0%)
Gastrointestinal disorders
Nausea	1/4 (25%)		1/2 (50%)
Abdominal pain	0/4 (0%)		1/2 (50%)
Diarrhoea	1/4 (25%)		0/2 (0%)
Rectal haemorrhage	1/4 (25%)		0/2 (0%)
Vomiting	1/4 (25%)		0/2 (0%)
General disorders
Injection site erythema	1/4 (25%)		0/2 (0%)
Injection site haematoma	0/4 (0%)		1/2 (50%)
Injection site pain	1/4 (25%)		0/2 (0%)
Oedema	1/4 (25%)		0/2 (0%)
Oedema peripheral	1/4 (25%)		0/2 (0%)
Pyrexia	1/4 (25%)		0/2 (0%)
Immune system disorders
Hypogammaglobulinaemia	2/4 (50%)		0/2 (0%)
Infections and infestations
Influenza	1/4 (25%)		0/2 (0%)
Injury, poisoning and procedural complications
Contusion	1/4 (25%)		0/2 (0%)
Renal haematoma	1/4 (25%)		0/2 (0%)
Wrist fracture	1/4 (25%)		0/2 (0%)
Investigations
Blood immunoglobulin G decreased	1/4 (25%)		0/2 (0%)
Metabolism and nutrition disorders
Hypokalaemia	2/4 (50%)		0/2 (0%)
Anorexia	1/4 (25%)		0/2 (0%)
Hypoalbuminaemia	1/4 (25%)		0/2 (0%)
Hypophosphataemia	1/4 (25%)		0/2 (0%)
Type 2 diabetes mellitus	1/4 (25%)		0/2 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	0/4 (0%)		1/2 (50%)
Pain in extremity	1/4 (25%)		0/2 (0%)
Nervous system disorders
Dysgeusia	0/4 (0%)		1/2 (50%)
Tremor	1/4 (25%)		0/2 (0%)
Psychiatric disorders
Insomnia	1/4 (25%)		0/2 (0%)
Mood altered	1/4 (25%)		0/2 (0%)
Renal and urinary disorders
Dysuria	1/4 (25%)		0/2 (0%)
Renal failure acute	1/4 (25%)		0/2 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	1/4 (25%)		0/2 (0%)
Epistaxis	1/4 (25%)		0/2 (0%)
Oropharyngeal pain	1/4 (25%)		0/2 (0%)
Skin and subcutaneous tissue disorders
Acne	1/4 (25%)		0/2 (0%)
Leukocytoclastic vasculitis	0/4 (0%)		1/2 (50%)
Rash	0/4 (0%)		1/2 (50%)
Vascular disorders
Hypertension	1/4 (25%)		0/2 (0%)

Limitations/Caveats

The study was terminated due to unanticipated safety issues.

More Information

Certain Agreements

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

Prior to publishing results, Institution and Principal Investigator (PI) must first provide Sponsor with a copy of proposed publication for review at least 30 days prior to submission. If Institution and PI do not agree to modification, they shall so notify Sponsor and postpone submission for additional 60 days to allow Sponsor to seek legal remedies or file patent applications. There is a need for coordinated approach to any publication of results from sites for any multi-site study.