Eculizumab Therapy for Chronic Complement-Mediated Injury in Kidney Transplantation

• Sponsor: Sanjay Kulkarni (Other)
• Overall Status: Completed
• CT.gov ID: NCT01327573
• Collaborator: Alexion Pharmaceuticals (Industry)
• Enrollment: 16
• Location: 1
• Arms: 2
• Duration (Months): 47.1
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

This study is designed to assess the effectiveness of eculizumab in recipients of kidney transplantation with donor-specific antibodies (DSA) and worsening kidney function and to assess if eculizumab improves endothelial cell injury in the kidney.

The investigators hypothesize that complement inhibition with eculizumab will reduce allograft injury, resulting from less complement-mediated injury of endothelial cells and less endothelial cell activation.

Condition or Disease	Intervention/Treatment	Phase
Kidney; Complications, Allograft	Drug: eculizumab	Phase 1

Detailed Description

This study will address the clinical challenge that currently exists in the management of kidney transplant recipients who have developed de novo DSA, have deteriorating graft function, yet have no established treatment alternative.

This is a randomized, open-label, pilot intervention trial. Post transplant patients with deteriorating renal function (defined as 20% reduction in GFR) will be screened for the development of DSA and biopsied for the presence of C4d deposition. All patients with DSA and those meeting inclusion/exclusion criteria will undergo protocol renal biopsy and will be assessed for C4d deposition. Participants will be randomized to treatment with eculizumab plus standard of care (SOC) or SOC only. Randomization will be stratified by C4d status (C4d+/C4d-) with 10 subjects (7 eculizumab, 3 SOC only) in each stratum.

Eculizumab is an antibody that has been developed to inhibit the complement protein C5.

Eculizumab will be delivered via IV according to the following schedule:

• Eculizumab Induction 600mg IV every 7 days for 4 doses

• Eculizumab 900mg IV 7 days later

• Eculizumab Maintenance 900mg IV every 14 days for total of 26 weeks

Study Design

• Study Type: Interventional
• Actual Enrollment: 16 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Eculizumab Therapy for Chronic Complement-Mediated Injury in Kidney Transplantation: A Randomized, Open-Label, Pilot Intervention Trial
• Study Start Date: Mar 1, 2011
• Actual Primary Completion Date: Feb 1, 2015
• Actual Study Completion Date: Feb 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Eculizumab eculizumab will be given in addition to standard immunosuppression regimen (oral tacrolimus or equivalent, MMF [mycophenolate mofetil ], prednisone)	Drug: eculizumab; Eculizumab Induction 600mg IV every 7 days for 4 doses Eculizumab 900mg IV 7 days later Eculizumab Maintenance 900mg IV every 14 days for total of 26 weeks; Other Names: h5G1.1-mAb Soliris
No Intervention: no additional therapy patients in this arm will receive standard immunosuppression regimen (oral tacrolimus or equivalent, MMF, prednisone only, no additional therapy

Outcome Measures

Primary Outcome Measures

1. Baseline eGFR (Estimated Glomerular Filtration Rate) [Baseline]

2. Estimated Glomerular Filtration Rate (eGFR) at Months 2,3,4,5,6 [Months 2,3,4,5,6]

   Primary statistical analysis of change from baseline was conducted with mixed effects modeling providing calculated estimates.

3. Group Difference Percentage Change in 6-month Estimated Glomerular Filtration Rate (eGFR) [6 months]

   These data were calculated by mean 6-month eGFR minus baseline mean eGFR divided by baseline eGFR. Presented below are the between groups results. These results were derived from the results in the outcome "Estimated Glomerular Filtration Rate (eGFR) at Months 2,3,4,5,6".

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Kidney transplant recipients greater than 6 months from the date of transplant

• Must be on standard immunosuppression: tacrolimus, mycophenolate mofetil, prednisone and have stable tacrolimus trough levels over past 3 months

• Deteriorating renal function, as defined by 20% reduction in GFR (MDRD calculation)

• Presence of DSA, as defined as MFI > 1100

• Renal biopsy demonstrating no diffuse, irreversible end-stage organ injury (i.e. stage IV Fibrosis)

• Renal biopsy demonstrating C4d deposition (stratum 1) or no C4d deposition (stratum 2)

Exclusion Criteria:

• History of CMV, BK, HSV or other viral infections

• History of chronic, recurrent bacterial infections

• Evidence of tubulitis on renal biopsy or other morphological features of acute cellular rejection or acute humoral rejection

• Renal biopsy demonstrating diffuse, irreversible end-stage organ injury

• Absolute GFR < 25 (MDRD calculation)

• Inability to provide informed consent

• History of poor vascular access

• Refusal to use double barrier contraception during study participation

• Patients actively enrolled in other clinical trials

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Yale University	New Haven	Connecticut	United States	06520

Sponsors and Collaborators

• Sanjay Kulkarni
• Alexion Pharmaceuticals

Investigators

• Principal Investigator: Sanjay Kulkarni, MD, Yale University

Study Documents (Full-Text)

None provided.

More Information

Publications

• Al-Lamki RS, Bradley JR, Pober JS. Endothelial cells in allograft rejection. Transplantation. 2008 Nov 27;86(10):1340-8. doi: 10.1097/TP.0b013e3181891d8b. Review.
• Brodsky RA, Young NS, Antonioli E, Risitano AM, Schrezenmeier H, Schubert J, Gaya A, Coyle L, de Castro C, Fu CL, Maciejewski JP, Bessler M, Kroon HA, Rother RP, Hillmen P. Multicenter phase 3 study of the complement inhibitor eculizumab for the treatment of patients with paroxysmal nocturnal hemoglobinuria. Blood. 2008 Feb 15;111(4):1840-7. Epub 2007 Nov 30.
• Davin JC, Gracchi V, Bouts A, Groothoff J, Strain L, Goodship T. Maintenance of kidney function following treatment with eculizumab and discontinuation of plasma exchange after a third kidney transplant for atypical hemolytic uremic syndrome associated with a CFH mutation. Am J Kidney Dis. 2010 Apr;55(4):708-11. doi: 10.1053/j.ajkd.2009.08.011. Epub 2009 Oct 25.
• Terasaki PI, Ozawa M. Predicting kidney graft failure by HLA antibodies: a prospective trial. Am J Transplant. 2004 Mar;4(3):438-43.
• Worthington JE, McEwen A, McWilliam LJ, Picton ML, Martin S. Association between C4d staining in renal transplant biopsies, production of donor-specific HLA antibodies, and graft outcome. Transplantation. 2007 Feb 27;83(4):398-403.

• Responsible Party: Sanjay Kulkarni, Associate Professor, Yale University
• ClinicalTrials.gov Identifier: NCT01327573
• Other Study ID Numbers: 100700716
• First Posted: Apr 1, 2011
• Last Update Posted: Aug 12, 2019
• Last Verified: Jul 1, 2019

• Keywords provided by Sanjay Kulkarni, Associate Professor, Yale University: chronic kidney allograft injury; complement protein; eculizumab; Kidney transplantation
• Additional relevant MeSH terms: Eculizumab

Study Results

Participant Flow

Arm/Group Title	Eculizumab	no Additional Therapy
Arm/Group Description	eculizumab will be given in addition to standard immunosuppression regimen (oral tacrolimus or equivalent, MMF [mycophenolate mofetil ], prednisone) eculizumab: • Eculizumab Induction 600mg IV every 7 days for 4 doses Eculizumab 900mg IV 7 days later Eculizumab Maintenance 900mg IV every 14 days for total of 26 weeks	patients in this arm will receive standard immunosuppression regimen (oral tacrolimus or equivalent, MMF, prednisone only, no additional therapy
Period Title: Overall Study
STARTED	11	5
Received Treatment/Control as Allocated	10	5
COMPLETED	8	4
NOT COMPLETED	3	1

Baseline Characteristics

Arm/Group Title	Eculizumab	no Additional Therapy	Total
Arm/Group Description	eculizumab will be given in addition to standard immunosuppression regimen (oral tacrolimus or equivalent, MMF [mycophenolate mofetil ], prednisone) eculizumab: • Eculizumab Induction 600mg IV every 7 days for 4 doses Eculizumab 900mg IV 7 days later Eculizumab Maintenance 900mg IV every 14 days for total of 26 weeks	patients in this arm will receive standard immunosuppression regimen (oral tacrolimus or equivalent, MMF, prednisone only, no additional therapy	Total of all reporting groups
Overall Participants	10	5	15
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	38	44	43
Sex: Female, Male (Count of Participants)
Female	3 30%	3 60%	6 40%
Male	7 70%	2 40%	9 60%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	1 10%	2 40%	3 20%
White	6 60%	2 40%	8 53.3%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	3 30%	1 20%	4 26.7%
Region of Enrollment (participants) [Number]
United States	10 100%	5 100%	15 100%
C4d Status at Randomization (participants) [Number]
Positive	5 50%	1 20%	6 40%
Negative	5 50%	4 80%	9 60%
Baseline DSA (Donor Specific Antibody) MFI (mean fluorescent intensity) (MFI) [Median (Full Range) ]
Median (Full Range) [MFI]	5,000	3,100	4,600

Outcome Measures

1. Primary Outcome

Title	Baseline eGFR (Estimated Glomerular Filtration Rate)
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Eculizumab	no Additional Therapy
Arm/Group Description	eculizumab will be given in addition to standard immunosuppression regimen (oral tacrolimus or equivalent, MMF [mycophenolate mofetil ], prednisone) eculizumab: • Eculizumab Induction 600mg IV every 7 days for 4 doses Eculizumab 900mg IV 7 days later Eculizumab Maintenance 900mg IV every 14 days for total of 26 weeks	patients in this arm will receive standard immunosuppression regimen (oral tacrolimus or equivalent, MMF, prednisone only, no additional therapy
Measure Participants	10	5
Mean (95% Confidence Interval) [mL/min/1.73 m2]	30.04	30.04

2. Primary Outcome

Title	Estimated Glomerular Filtration Rate (eGFR) at Months 2,3,4,5,6
Description	Primary statistical analysis of change from baseline was conducted with mixed effects modeling providing calculated estimates.
Time Frame	Months 2,3,4,5,6

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Eculizumab	no Additional Therapy
Arm/Group Description	eculizumab will be given in addition to standard immunosuppression regimen (oral tacrolimus or equivalent, MMF [mycophenolate mofetil ], prednisone) eculizumab: • Eculizumab Induction 600mg IV every 7 days for 4 doses Eculizumab 900mg IV 7 days later Eculizumab Maintenance 900mg IV every 14 days for total of 26 weeks	patients in this arm will receive standard immunosuppression regimen (oral tacrolimus or equivalent, MMF, prednisone only, no additional therapy
Measure Participants	10	5
Month 2	29.34	31.34
Month 3	29.56	30.68
Month 4	29.78	30.02
Month 5	29.99	29.35
Month 6	30.21	28.69

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Eculizumab, no Additional Therapy
	Comments	Analysis used eGFR, group, time, and group-by-time variables.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.09
	Comments	This p-value was for the overall slope difference between groups (i.e. the interaction between group and time). Significance level was set at 0.1 a priori.
	Method	Mixed effects model analysis
	Comments

3. Primary Outcome

Title	Group Difference Percentage Change in 6-month Estimated Glomerular Filtration Rate (eGFR)
Description	These data were calculated by mean 6-month eGFR minus baseline mean eGFR divided by baseline eGFR. Presented below are the between groups results. These results were derived from the results in the outcome "Estimated Glomerular Filtration Rate (eGFR) at Months 2,3,4,5,6".
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

These are the between groups percent change that represents the difference between groups when controlling for baseline. Outcome measure #2 provides the data by treatment arm where these data are derived.

Arm/Group Title	Between Groups Difference
Arm/Group Description	These are the percent change between group differences derived from the Estimated Glomerular Filtration Rate (eGFR) at Months 2,3,4,5,6 outcome.
Measure Participants	16
Month 2	6.66
Month 3	3.73
Month 4	0.80
Month 5	-2.13
Month 6	-5.06

Adverse Events

Arm/Group Title	Eculizumab		no Additional Therapy
Arm/Group Description	eculizumab will be given in addition to standard immunosuppression regimen (oral tacrolimus or equivalent, MMF [mycophenolate mofetil ], prednisone) eculizumab: • Eculizumab Induction 600mg IV every 7 days for 4 doses Eculizumab 900mg IV 7 days later Eculizumab Maintenance 900mg IV every 14 days for total of 26 weeks		patients in this arm will receive standard immunosuppression regimen (oral tacrolimus or equivalent, MMF, prednisone only, no additional therapy
All Cause Mortality
	Eculizumab		no Additional Therapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Eculizumab		no Additional Therapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/10 (40%)		3/5 (60%)
Infections and infestations
Bacterial Infection	1/10 (10%)	1	1/5 (20%)	1
Viral Infection	1/10 (10%)	1	1/5 (20%)	1
Renal and urinary disorders
Graft Failure	2/10 (20%)	2	1/5 (20%)	1
Other (Not Including Serious) Adverse Events
	Eculizumab		no Additional Therapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/10 (20%)		0/5 (0%)
Blood and lymphatic system disorders
Anemia	1/10 (10%)	1	0/5 (0%)	0
Infections and infestations
Viral Infection	1/10 (10%)	1	0/5 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.