Randomized Trial of 2 Antibody Induction Steroid Avoidance Protocols

• Sponsor: University of Miami (Other)
• Overall Status: Completed
• CT.gov ID: NCT01172418
• Collaborator: (none)
• Enrollment: 200
• Location: 1
• Arms: 2
• Duration (Months): 50.9
• Patients Per Site Per Month: 3.9

Study Details

Study Description

Brief Summary

The purpose of the present study is to determine which antibody induction regimen will result in a safer and more effective method to use with steroid avoidance in renal transplant recipients. Patients receiving either first cadaveric or non-HLA identical living donor kidney transplants will be preoperatively randomized into 2 groups.

Condition or Disease	Intervention/Treatment	Phase
Transplant; Failure, Kidney	Drug: Alemtuzumab; Drug: Daclizumab; Drug: Thymoglobulin	Phase 4

Detailed Description

Antibody Induction:

Group I: Our standard steroid avoidance protocol, i.e., 3 daily doses of 1 mg/kg of Thymoglobulin®, the first to be infused at surgery, accompanied by 2 doses of anti-CD25 humanized monoclonal antibody, the first also to be given at surgery, and the second 2 weeks later. (controls) Group II: A new steroid avoidance protocol in which 1 dose of 1 mg/kg of Thymoglobulin® is to be infused at surgery followed by 1 dose of alemtuzumab (Campath-1H) at 0.3 mg/kg within 24 hours. No further antibody therapy will be used.

In both groups, Prograf® maintenance therapy will be rapidly initiated (vide-infra) with a targeting dosage to 12 hour trough levels of 4 to 8 ng/ml.

In Group I, maintenance dosing Myfortic® will be targeted to 720 mg twice daily. In Group II, maintenance doses of Myfortic® will be targeted to 360 mg twice daily.

Steroids are to be given equivalently in both groups only during the first week postoperatively. The regimen consists of 500 mg/day of Solumedrol intravenously for 3 postoperative days followed by daily oral methylprednisolone or IV Solumedrol at 1 mg/kg per day, decreasing to 0.5 mg/kg per day during the remainder of the week primarily to avoid hypersensitivity reactions to the induction antibodies. No further steroid use is planned.

Study Design

• Study Type: Interventional
• Actual Enrollment: 200 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Prevention
• Official Title: Randomized Trial of 2 Antibody Induction Steroid Avoidance Protocols Accompanied by Maintenance Therapy With Prograf® and Myfortic®
• Study Start Date: Feb 1, 2006
• Actual Primary Completion Date: May 1, 2010
• Actual Study Completion Date: May 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Thymoglobulin and Daclizumab Group I: Our standard steroid avoidance protocol, i.e., 3 daily doses of 1 mg/kg of Thymoglobulin®, the first to be infused at surgery, accompanied by 2 doses of anti-CD25 humanized monoclonal antibody, the first also to be given at surgery, and the second 2 weeks later. (controls)	Drug: Daclizumab; Daclizumab used as part of combined induction.; Other Names: Zenapax (Daclizumab) ; Drug: Thymoglobulin; Thymoglobulin used as part of combined induction.; Other Names: rATG (rabbit antithymocyte globulin)
Experimental: Thymoglobulin and Alemtuzumab Group II: A new steroid avoidance protocol in which 1 dose of 1 mg/kg of Thymoglobulin® is to be infused at surgery followed by 1 dose of alemtuzumab (Campath-1H) at 0.3 mg/kg within 24 hours. No further antibody therapy will be used.	Drug: Alemtuzumab; Alemtuzumab used as part of combined Induction.; Other Names: Campath-1H (Alemtuzumab) ; Drug: Thymoglobulin; Thymoglobulin used as part of combined induction.; Other Names: rATG (rabbit antithymocyte globulin)

Outcome Measures

Primary Outcome Measures

1. Incidence of Acute Rejection at One Year Post-transplant [at one year post-transplant]

Secondary Outcome Measures

1. Graft Survival [at 1 year post-transplant]

2. Graft Survival [at 3 years post-transplant]

3. Patient Survival [at 1 year post-transplant]

4. Patient Survival [at 3 years post-transplant]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Patient has been fully informed and has signed a dated IRB approval informed consent form and is willing to follow study procedures for the extent of the study (12 months). Parent or legal guardian must provide written consent for patients <18 years of age.

2. Age 18-70 years

3. Weight > 40 kg

4. Primary renal allograft: living or deceased donor

5. Negative standard crossmatch for T cells. All deceased donor-recipient pairs matched for a minimum of 1 HLA DR antigen. (Standard at our center.)

6. Women of childbearing potential will be required to have a negative qualitative serum pregnancy test and agree to use an adequate method of contraception for the study duration.

7. Males and females are to be studied equivalently as they become available for transplantation using these criteria.

Exclusion Criteria:

• 1. Patient has previously received or is receiving an organ transplant other than a kidney.

1. Patient is receiving an ABO incompatible donor kidney. 3. Recipient or donor is seropositive for human immunodeficiency (HIV), Hepatitis C viruses, or Hepatitis B virus antigenemia.

2. Patient has a current malignancy or a history of malignancy (within the past 5 years), except non-metastatic basal or squamous cell carcinoma of the skin that has been treated successfully, or carcinoma in situ of the cervix that has been treated successfully.

3. Patients with significant liver disease, defined as having during the past 28 days continuously elevated AST (SGOT) and/or ALT (SGPT) levels greater than 3 times the upper value of the normal range of this center.

4. Patient has uncontrolled concomitant infections and/or severe diarrhea, vomiting, active upper gastro-intestinal tract malabsorption or an active peptic ulcer or any other unstable medical condition that could interfere with study objectives.

5. Patient is currently participating in another clinical trial of an investigational drug in the 30 days prior to transplant.

6. Patient will be receiving any immunosuppressive agent other than those prescribed in the study.

7. Patient is unable to take medications orally or via nasogastric tube by the morning of the second day following completion of the transplant procedure (i.e., skin closure).

8. Patient is receiving or may require warfarin, fluvastatin, or herbal supplements during the study.

9. Concurrent use of astemizole, pimozide, cisapride, terfenadine, or ketoconazole.

10. Patient has a known hypersensitivity to tacrolimus, Thymoglobulin®, IL-2 receptor inhibitor monoclonal antibodies, alemtuzumab, sirolimus, MMF, Myfortic®, or corticosteroids.

11. Patient is pregnant or lactating. 14. Patients with a screening/baseline (or within 96 hours of transplant) total white blood cell count <4000/mm3; platelet count <100,000/mm3; fasting triglycerides >400 mg/dl (>4.6 mmol/L); fasting total cholesterol >300 mg/dl (>7.8 mmol/L); fasting HDL-cholesterol <30 mg/dl; fasting LDL-cholesterol >200 mg/dl.

12. Patient is unlikely to comply with the visits scheduled in the protocol. 16. Patient has any form of substance abuse, psychiatric disorder or a condition that, in the opinion of the investigator, may invalidate communication with the investigator.

13. If tacrolimus cannot be instituted for longer than 5 days postoperatively.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Miami Miller School of Medicine	Miami	Florida	United States	33136

Sponsors and Collaborators

• University of Miami

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: George W. Burke, Chief, Kidney and Kidney-Pancreas Transplantation, University of Miami
• ClinicalTrials.gov Identifier: NCT01172418
• Other Study ID Numbers: IRB #20057672
• First Posted: Jul 29, 2010
• Last Update Posted: Dec 8, 2017
• Last Verified: Nov 1, 2017

• Keywords provided by George W. Burke, Chief, Kidney and Kidney-Pancreas Transplantation, University of Miami: adult; primary kidney transplant recipient
• Additional relevant MeSH terms: Renal Insufficiency; Alemtuzumab; Thymoglobulin; Antilymphocyte Serum; Daclizumab

Study Results

Participant Flow

Arm/Group Title	Thymoglobulin and Daclizumab	Thymoglobulin and Alemtuzumab
Arm/Group Description	Group I: Our standard steroid avoidance protocol, i.e., 3 daily doses of 1 mg/kg of Thymoglobulin®, the first to be infused at surgery, accompanied by 2 doses of anti-CD25 humanized monoclonal antibody, the first also to be given at surgery, and the second 2 weeks later. (controls) Daclizumab: used in combination with Thymoglobulin as combined induction	Group II: A new steroid avoidance protocol in which 1 dose of 1 mg/kg of Thymoglobulin® is to be infused at surgery followed by 1 dose of alemtuzumab (Campath-1H) at 0.3 mg/kg within 24 hours. No further antibody therapy will be used. Alemtuzumab: used in conjunction with Thymoglobulin as combined Induction.
Period Title: Overall Study
STARTED	100	100
COMPLETED	100	100
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Thymoglobulin and Daclizumab	Thymoglobulin and Alemtuzumab	Total
Arm/Group Description	Group I: Our standard steroid avoidance protocol, i.e., 3 daily doses of 1 mg/kg of Thymoglobulin®, the first to be infused at surgery, accompanied by 2 doses of anti-CD25 humanized monoclonal antibody, the first also to be given at surgery, and the second 2 weeks later. (controls) Daclizumab: used in combination with Thymoglobulin as combined induction	Group II: A new steroid avoidance protocol in which 1 dose of 1 mg/kg of Thymoglobulin® is to be infused at surgery followed by 1 dose of alemtuzumab (Campath-1H) at 0.3 mg/kg within 24 hours. No further antibody therapy will be used. Alemtuzumab: used in conjunction with Thymoglobulin as combined Induction.	Total of all reporting groups
Overall Participants	100	100	200
Age (participants) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [participants]	49.9 (12) 49.9%	49.4 (13) 49.4%	49.65 (12.5) 24.8%
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	91 91%	87 87%	178 89%
>=65 years	9 9%	13 13%	22 11%
Sex: Female, Male (Count of Participants)
Female	28 28%	24 24%	52 26%
Male	72 72%	76 76%	148 74%
Region of Enrollment (participants) [Number]
United States	100 100%	100 100%	200 100%

Outcome Measures

1. Primary Outcome

Title	Incidence of Acute Rejection at One Year Post-transplant
Time Frame	at one year post-transplant

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Thymoglobulin and Daclizumab	Thymoglobulin and Alemtuzumab
Arm/Group Description	Group I: Our standard steroid avoidance protocol, i.e., 3 daily doses of 1 mg/kg of Thymoglobulin®, the first to be infused at surgery, accompanied by 2 doses of anti-CD25 humanized monoclonal antibody, the first also to be given at surgery, and the second 2 weeks later. (controls) Daclizumab: used in combination with Thymoglobulin as combined induction	Group II: A new steroid avoidance protocol in which 1 dose of 1 mg/kg of Thymoglobulin® is to be infused at surgery followed by 1 dose of alemtuzumab (Campath-1H) at 0.3 mg/kg within 24 hours. No further antibody therapy will be used. Alemtuzumab: used in conjunction with Thymoglobulin as combined Induction.
Measure Participants	100	100
Number [percentage of patients having BPAR]	14	13

2. Secondary Outcome

Title	Graft Survival
Time Frame	at 1 year post-transplant

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Thymoglobulin and Daclizumab	Thymoglobulin and Alemtuzumab
Arm/Group Description
Measure Participants	100	100
Number (95% Confidence Interval) [actuarial percentage of participants]	92.9 92.9%	92.0 92%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Thymoglobulin and Daclizumab, Thymoglobulin and Alemtuzumab
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.78
	Comments
	Method	Log Rank
	Comments

3. Secondary Outcome

Title	Graft Survival
Time Frame	at 3 years post-transplant

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Thymoglobulin and Daclizumab	Thymoglobulin and Alemtuzumab
Arm/Group Description
Measure Participants	100	100
Number (95% Confidence Interval) [actuarial percentage of participants]	90.9 90.9%	86.9 86.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Thymoglobulin and Daclizumab, Thymoglobulin and Alemtuzumab
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.37
	Comments
	Method	Log Rank
	Comments

4. Secondary Outcome

Title	Patient Survival
Time Frame	at 1 year post-transplant

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Thymoglobulin and Daclizumab	Thymoglobulin and Alemtuzumab
Arm/Group Description
Measure Participants	100	100
Number (95% Confidence Interval) [actuarial percentage of participants]	96.9 96.9%	97 97%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Thymoglobulin and Daclizumab, Thymoglobulin and Alemtuzumab
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.99
	Comments
	Method	Log Rank
	Comments

5. Secondary Outcome

Title	Patient Survival
Time Frame	at 3 years post-transplant

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Thymoglobulin and Daclizumab	Thymoglobulin and Alemtuzumab
Arm/Group Description
Measure Participants	100	100
Number (95% Confidence Interval) [actuarial percentage of participants]	95.9 95.9%	91.8 91.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Thymoglobulin and Daclizumab, Thymoglobulin and Alemtuzumab
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.25
	Comments
	Method	Log Rank
	Comments

Adverse Events

Adverse Event Reporting Description	Total Numbers at Risk for Serious Adverse Events (100+100=200) and Other Adverse Events (75+70=145) were inconsistent, because in order to determine how many study participants developed NODAT (new onset diabetes after transplant), study participants having pre-transplant diabetes (25 in Groups I, and 30 in Group II) were excluded.
Arm/Group Title	Thymoglobulin and Daclizumab		Thymoglobulin and Alemtuzumab
Arm/Group Description	Group I: Our standard steroid avoidance protocol, i.e., 3 daily doses of 1 mg/kg of Thymoglobulin®, the first to be infused at surgery, accompanied by 2 doses of anti-CD25 humanized monoclonal antibody, the first also to be given at surgery, and the second 2 weeks later. (controls) Daclizumab: used in combination with Thymoglobulin as combined induction		Group II: A new steroid avoidance protocol in which 1 dose of 1 mg/kg of Thymoglobulin® is to be infused at surgery followed by 1 dose of alemtuzumab (Campath-1H) at 0.3 mg/kg within 24 hours. No further antibody therapy will be used. Alemtuzumab: used in conjunction with Thymoglobulin as combined Induction.
All Cause Mortality
	Thymoglobulin and Daclizumab		Thymoglobulin and Alemtuzumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Thymoglobulin and Daclizumab		Thymoglobulin and Alemtuzumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	29/100 (29%)		25/100 (25%)
Infections and infestations
Patients who developed an infection that required hospitalization	29/100 (29%)		25/100 (25%)
Other (Not Including Serious) Adverse Events
	Thymoglobulin and Daclizumab		Thymoglobulin and Alemtuzumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/75 (10.7%)		8/70 (11.4%)
Endocrine disorders
occurrence of NODAT in patients without pretransplant diabetes	8/75 (10.7%)	8	8/70 (11.4%)	8

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.