Safety in Immunomodulatory Functions of Alemtuzumab (Campath) in Pediatric Kidney Transplantation Recipients

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00240994
• Collaborator: Cooperative Clinical Trials in Pediatric Transplantation (Other)
• Enrollment: 35
• Locations: 4
• Arm: 1
• Duration (Months): 58
• Patients Per Site: 8.8
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the safety of alemtuzumab after kidney transplantation as part of a multitherapy regimen to prevent kidney graft loss and death and to avoid steroids and chronic use of calcineurin inhibitors in pediatric renal transplant recipients 1 to 20 years of age.

Condition or Disease	Intervention/Treatment	Phase
Kidney Failure, Chronic; Kidney Transplantation; Immunosuppression	Drug: Alemtuzumab; Drug: Tacrolimus; Drug: Mycophenolate mofetil; Drug: Sirolimus	Phase 2

Detailed Description

Kidney transplantation is widely considered to be the treatment of choice for children with End Stage Renal Disease (ESRD). Improvements in surgical techniques, donor selection, and immunosuppression practices, as well as the enhanced experience of specialized pediatric transplant teams, have all led to marked improvements in patient and kidney graft survival in infants and young children ages 1 to 10. However, young children now have more infections following transplant previously. Also, improved graft survival is not observed in pediatric renal transplant recipients 11 to 17 years of age. Some studies do indicate that the poor long term outcome of patient and kidney survival observed in this age group may be caused by noncompliance with immunosuppressive medications. Therefore, protocols that minimize the use of immunosuppressive medications while retaining kidney function are necessary for improving graft and patient survival in children. This study will evaluate the safety of a regimen containing alemtuzumab after kidney transplantation, followed by steroid avoidance and calcineurin inhibitor withdrawal in pediatric renal transplant recipients 1 to 20 years of age.

The accrual period is scheduled for 18 months. The study follow-up period will last 24 months. All participants enrolled will undergo this treatment schedule: 1.) All participants will receive intravenous alemtuzumab one day before transplantation and 1 day after transplantation. 2.) Mycophenolate mofetil (MMF) will be administered orally no later than 2 days after transplantation. 3.) Participants will begin to take oral tacrolimus twice a day 1 to 3 days after transplantation until Weeks 8 through 12 when 4.) Sirolimus will be initiated. 5.) Sirolimus and MMF will be taken orally until Month 24.

Blood collection will occur at baseline, 1 day before transplant, at Days 1 and 3, at Weeks 2, 4, 6, 8, 10, and at Months 3 through 24. Scheduled kidney (renal) biopsies will be performed at transplant, during Weeks 8 through 12, immediately before conversion to sirolimus, and at Months 6 and 24.

Study Design

• Study Type: Interventional
• Actual Enrollment: 35 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Prevention
• Official Title: A Phase II Exploratory Study to Determine the Safety and Study the Immunomodulatory Functions of Induction Therapy With Campath, Combined With Chronic Immunosuppression With Mycophenolate Mofetil and Sirolimus
• Study Start Date: Jan 1, 2005
• Actual Primary Completion Date: Nov 1, 2009
• Actual Study Completion Date: Nov 1, 2009

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Alemtuzumab (Campath) In this open-label, single-arm trial , participants will be administered a 0.3 mg/kg dose of alemtuzumab (Campath) intravenously one day prior to kidney transplantation and one day post kidney transplantation. Participants will then receive a maintenance immunosuppressive regimen of tacrolimus and mycophenolate mofetil (MMF) for 8 to 12 weeks, followed by sirolimus and MMF until 24 months post transplantation.

Drug: Alemtuzumab; Administered intravenously over a period of 2-3 hours. Two doses total, the first will be one day before transplant and the second will be on the day following transplantation. Pre-medication with methylprednisolone, acetaminophen, and Benadryl will be administered before each dose.; Other Names: Campath Campath- 1H ; Drug: Tacrolimus; Administered orally at a dose of 0.05-0.1 mg/kg twice daily, beginning 1-3 days following transplantation and continuing until weeks 8-12. Tacrolimus will be discontinued and a treatment regimen with sirolimus will be initiated between weeks 8-12 but some overlap with these medications is possible.; Other Names: Prograf ; Drug: Mycophenolate mofetil; Per recommendation; Other Names: CellCept ; Drug: Sirolimus; Administered by either liquid or tablet every 12 hours from month 6 until month 24. Dosage will vary throughout the treatment course.; Other Names: Rapamycin

Outcome Measures

Primary Outcome Measures

1. The Proportion of Participants With Graft Loss or Death Within 12 Months Post Kidney Transplantation [Up to one year post kidney transplantation procedure]

   Graft loss is defined as the need for dialysis for more than 30 days duration, allograft nephrectomy, or the decision to withdraw immunosuppression due to graft failure.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 1 Year to 20 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Between the ages of 1 to 20 (prior to 21st birthday)

• End Stage Renal Disease

• Necessity of kidney transplant

• First kidney transplant received from a living donor

• A living kidney donor identified

• No known contraindications to therapy with alemtuzumab

• Negative pregnancy test before study entry

• Willing to use approved methods of contraception for the duration of the study, 6 weeks after discontinuation of MMF, and 12 weeks after discontinuation of sirolimus

• Informed consent from participant, parent, or guardian

• Current vaccinations, including varicella-zoster (VZV) vaccine, before study enrollment

Exclusion Criteria:

• Recipient of a deceased donor kidney transplant

• Multiorgan transplant

• History of prior organ transplantation

• Participant sensitized to greater than 0% Panel Reactive Antibody (PRA) within 4 weeks before study enrollment. (If participant receives a blood transfusion status post PRA test, then the PRA must be repeated within 1 week of transplantation)

• Participants with human leukocyte antigen (HLA) identical living related donors

• History of primary focal segmented glomerulosclerosis

• History of other disorders requiring continuous maintenance steroids or calcineurin inhibitors

• Active systemic infection at time of transplant

• History of malignancy

• Infected with human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV)

• Contraindication to receive tacrolimus, sirolimus, MMF, or monoclonal antibody therapy

• Use of investigational drugs within 4 weeks before study enrollment

• Recipient of any licensed or investigational live attenuated vaccine(s) within 2 months before study enrollment

• Family history of high cholesterol

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California, San Francisco	San Francisco	California	United States	94143-0116
2	Children's Hospital, Boston	Boston	Massachusetts	United States	02115
3	Children's Hospital, Philadelphia	Philadelphia	Pennsylvania	United States	19104
4	Children's Hospital and Regional Medical Center, Seattle	Seattle	Washington	United States	98105

Sponsors and Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID)
• Cooperative Clinical Trials in Pediatric Transplantation

Investigators

• Study Chair: William Harmon, MD, Boston Children's Hospital

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• National Institute of Allergy and Infectious Diseases (NIAID)
• Division of Allergy, Immunology, and Transplantation (DAIT)

Publications

• Ciancio G, Burke GW, Gaynor JJ, Mattiazzi A, Roohipour R, Carreno MR, Roth D, Ruiz P, Kupin W, Rosen A, Esquenazi V, Tzakis AG, Miller J. The use of Campath-1H as induction therapy in renal transplantation: preliminary results. Transplantation. 2004 Aug 15;78(3):426-33.
• Kreis H, Cisterne JM, Land W, Wramner L, Squifflet JP, Abramowicz D, Campistol JM, Morales JM, Grinyo JM, Mourad G, Berthoux FC, Brattström C, Lebranchu Y, Vialtel P. Sirolimus in association with mycophenolate mofetil induction for the prevention of acute graft rejection in renal allograft recipients. Transplantation. 2000 Apr 15;69(7):1252-60.
• Rao V, Pirsch JD, Becker BN, Knechtle SJ. Sirolimus monotherapy following Campath-1H induction. Transplant Proc. 2003 May;35(3 Suppl):128S-130S.
• Watson CJ, Bradley JA, Friend PJ, Firth J, Taylor CJ, Bradley JR, Smith KG, Thiru S, Jamieson NV, Hale G, Waldmann H, Calne R. Alemtuzumab (CAMPATH 1H) induction therapy in cadaveric kidney transplantation--efficacy and safety at five years. Am J Transplant. 2005 Jun;5(6):1347-53.
• Wolff G, Strecker K, Vester U, Latta K, Ehrich JH. Non-compliance following renal transplantation in children and adolescents. Pediatr Nephrol. 1998 Nov;12(9):703-8. Review.

• Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
• ClinicalTrials.gov Identifier: NCT00240994
• Other Study ID Numbers: DAIT PC01
• First Posted: Oct 18, 2005
• Last Update Posted: Jan 2, 2017
• Last Verified: Nov 1, 2016

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID): End stage renal disease; Kidney transplantation; Renal transplantation; Kidney failure; Pediatric renal transplant recipients; Alemtuzumab; Campath; Mycophenolate mofetil; MMF; CellCept; Tacrolimus; Prograf; Sirolimus; Rapamycin
• Additional relevant MeSH terms: Renal Insufficiency; Kidney Failure, Chronic; Mycophenolic Acid; Sirolimus; Alemtuzumab; Tacrolimus

Study Results

Participant Flow

Recruitment Details	Four centers in the United States recruited 35 subjects between January 2005 and October 2007 who were less than 21 years of age and first time living-donor kidney allograft recipients.
Pre-assignment Detail	At a screening visit, participants underwent procedures to establish inclusion/exclusion criteria and then sign the informed consent form.

Arm/Group Title	Alemtuzumab (Campath)
Arm/Group Description	In this open-label, single-arm trial, participants were administered a 0.3 mg/kg dose of alemtuzumab intravenously one day prior to kidney transplantation and one day post kidney transplantation. Participants were then administered a maintenance immunosuppressive regimen of tacrolimus and mycophenolate mofetil (MMF) for 8 to 12 weeks, followed by sirolimus and MMF until 24 months post transplantation.
Period Title: Overall Study
STARTED	35
COMPLETED	32
NOT COMPLETED	3

Baseline Characteristics

Arm/Group Title	Alemtuzumab (Campath)
Arm/Group Description	In this open-label, single-arm trial, participants were administered a 0.3 mg/kg dose of alemtuzumab intravenously one day prior to kidney transplantation and one day post kidney transplantation. Participants were then administered a maintenance immunosuppressive regimen of tacrolimus and mycophenolate mofetil (MMF) for 8 to 12 weeks, followed by sirolimus and MMF until 24 months post transplantation.
Overall Participants	35
Age (years) [Mean (Standard Deviation) ]
Final status: Completed (N=22)	13.1 (5.0)
Final status: Discontinued Therapy (N=10)	9.8 (6.2)
Final status: Discontinued Study (N=3)	17.7 (2.4)
All Participants (N=35)	12.6 (5.5)
Gender (Count of Participants)
Female	20 57.1%
Male	15 42.9%
Region of Enrollment (participants) [Number]
United States	35 100%

Outcome Measures

1. Primary Outcome

Title	The Proportion of Participants With Graft Loss or Death Within 12 Months Post Kidney Transplantation
Description	Graft loss is defined as the need for dialysis for more than 30 days duration, allograft nephrectomy, or the decision to withdraw immunosuppression due to graft failure.
Time Frame	Up to one year post kidney transplantation procedure

Outcome Measure Data

Analysis Population Description

Intent-to-treat

Arm/Group Title	Alemtuzumab (Campath)
Arm/Group Description	In this open-label, single-arm trial, participants were administered a 0.3 mg/kg dose of alemtuzumab intravenously one day prior to kidney transplantation and one day post kidney transplantation. Participants were then administered a maintenance immunosuppressive regimen of tacrolimus and mycophenolate mofetil (MMF) for 8 to 12 weeks, followed by sirolimus and MMF until 24 months post transplantation.
Measure Participants	35
Number [Proportion of participants]	0.057 0.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alemtuzumab (Campath)
	Comments	The proportion of participants with graft loss or death within 12 months post kidney transplantation is descriptively summarized with a 95% confidence interval using an exact binomial method.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Proportion with graft loss or death
	Estimated Value	.057
	Confidence Interval	(2-Sided) 95%; 0.007 to 0.192
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	From beginning of study to end of study
Adverse Event Reporting Description	This study graded the severity of adverse events experienced by the study participants according to criteria set forth in the National Cancer Institute's Common Terminology Criteria for Adverse Events Version 3.0 (June 10, 2003)
Arm/Group Title	Alemtuzumab (Campath)
Arm/Group Description	In this open-label, single-arm trial , participants were administered a 0.3 mg/kg dose of alemtuzumab intravenously one day prior to kidney transplantation and one day post kidney transplantation. Participants were then administered a maintenance immunosuppressive regimen of tacrolimus and mycophenolate mofetil (MMF) for 8 to 12 weeks, followed by sirolimus and MMF until 24 months post transplantation.
All Cause Mortality
	Alemtuzumab (Campath)
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Alemtuzumab (Campath)
	Affected / at Risk (%)	# Events
Total	25/35 (71.4%)
Blood and lymphatic system disorders
Anaemia	1/35 (2.9%)	1
Leukopenia	1/35 (2.9%)	1
Neutropenia	4/35 (11.4%)	4
Thrombotic microangiopathy	1/35 (2.9%)	1
Gastrointestinal disorders
Abdominal compartment syndrome	1/35 (2.9%)	1
Abdominal pain	1/35 (2.9%)	1
Ascites	1/35 (2.9%)	2
Diarrhoea	4/35 (11.4%)	4
Mouth ulceration	1/35 (2.9%)	1
General disorders
Adverse drug reaction	1/35 (2.9%)	1
Oedema	1/35 (2.9%)	1
Pyrexia	5/35 (14.3%)	5
Immune system disorders
Graft loss	2/35 (5.7%)	2
Hypersensitivity	1/35 (2.9%)	1
Kidney transplant rejection	2/35 (5.7%)	2
Transplant rejection	3/35 (8.6%)	4
Infections and infestations
Adenovirus infection	1/35 (2.9%)	1
Arthritis bacterial	1/35 (2.9%)	1
Bacterial pyelonephritis	1/35 (2.9%)	1
Catheter site cellulitis	1/35 (2.9%)	1
Cellulitis	1/35 (2.9%)	1
Central line infection	1/35 (2.9%)	1
Gastroenteritis	3/35 (8.6%)	4
Herpes simplex	1/35 (2.9%)	2
Influenza	1/35 (2.9%)	1
Klebsiella infection	1/35 (2.9%)	1
Lobar pneumonia	1/35 (2.9%)	1
Pneumonia	2/35 (5.7%)	2
Pyelonephritis	2/35 (5.7%)	3
Rhinovirus infection	1/35 (2.9%)	1
Urinary tract infection	1/35 (2.9%)	2
Injury, poisoning and procedural complications
Arteriovenous fistula occlusion	1/35 (2.9%)	1
Arteriovenous fistula thrombosis	1/35 (2.9%)	1
Post procedural haemorrhage	1/35 (2.9%)	1
Investigations
Blood creatinine increased	4/35 (11.4%)	6
Blood culture positive	1/35 (2.9%)	1
Metabolism and nutrition disorders
Dehydration	2/35 (5.7%)	2
Hypervolaemia	1/35 (2.9%)	1
Musculoskeletal and connective tissue disorders
Epiphyseal disorder	1/35 (2.9%)	1
Tenosynovitis	1/35 (2.9%)	1
Nervous system disorders
Grand mal convulsion	1/35 (2.9%)	1
Psychiatric disorders
Depressed mood	1/35 (2.9%)	1
Renal and urinary disorders
Anuria	1/35 (2.9%)	1
Glomerulonephritis focal	1/35 (2.9%)	1
Pelvi-ureteric obstruction	1/35 (2.9%)	1
Proteinuria	1/35 (2.9%)	1
Renal failure	1/35 (2.9%)	1
Urinoma	1/35 (2.9%)	1
Reproductive system and breast disorders
Epididymitis	1/35 (2.9%)	1
Respiratory, thoracic and mediastinal disorders
Asthma	1/35 (2.9%)	2
Pneumothorax	1/35 (2.9%)	1
Respiratory distress	1/35 (2.9%)	1
Skin and subcutaneous tissue disorders
Skin disorder	1/35 (2.9%)	2
Skin lesion	1/35 (2.9%)	1
Urticaria	1/35 (2.9%)	1
Surgical and medical procedures
Gastrostomy closure	1/35 (2.9%)	1
Suture removal	1/35 (2.9%)	1
Vascular disorders
Hypotension	1/35 (2.9%)	1
Other (Not Including Serious) Adverse Events
	Alemtuzumab (Campath)
	Affected / at Risk (%)	# Events
Total	34/35 (97.1%)
Blood and lymphatic system disorders
Anaemia	20/35 (57.1%)	35
Leukopenia	23/35 (65.7%)	70
Lymphopenia	4/35 (11.4%)	6
Neutropenia	14/35 (40%)	26
Gastrointestinal disorders
Abdominal pain	4/35 (11.4%)	4
Anal ulcer	2/35 (5.7%)	3
Diarrhoea	12/35 (34.3%)	15
Mouth ulceration	5/35 (14.3%)	11
Nausea	3/35 (8.6%)	4
Stomatitis	2/35 (5.7%)	2
Vomiting	3/35 (8.6%)	3
General disorders
Fatigue	2/35 (5.7%)	2
Infusion related reaction	4/35 (11.4%)	4
Oedema peripheral	3/35 (8.6%)	4
Pain	2/35 (5.7%)	2
Pyrexia	7/35 (20%)	9
Immune system disorders
Cytokine release syndrome	3/35 (8.6%)	3
Transplant rejection	2/35 (5.7%)	3
Infections and infestations
Bronchitis	2/35 (5.7%)	2
Bronchitis acute	2/35 (5.7%)	2
Cellulitis	2/35 (5.7%)	2
Chronic sinusitis	2/35 (5.7%)	2
Cystitis klebsiella	4/35 (11.4%)	8
Ear infection	2/35 (5.7%)	3
Gastroenteritis	2/35 (5.7%)	2
Impetigo	2/35 (5.7%)	2
Nasopharyngitis	2/35 (5.7%)	2
Otitis media	2/35 (5.7%)	2
Sinusitis	7/35 (20%)	10
Upper respiratory tract infection	3/35 (8.6%)	3
Urinary tract infection	5/35 (14.3%)	8
Urinary tract infection enterococcal	3/35 (8.6%)	6
Viraemia	3/35 (8.6%)	4
Injury, poisoning and procedural complications
Anaemia postoperative	2/35 (5.7%)	2
Post procedural pain	2/35 (5.7%)	2
Investigations
Blood cholesterol increased	2/35 (5.7%)	2
Blood creatine phosphokinase increased	3/35 (8.6%)	3
Blood creatinine increased	5/35 (14.3%)	7
Blood parathyroid hormone increased	3/35 (8.6%)	3
Blood pressure increased	2/35 (5.7%)	2
Epstein-Barr virus antibody positive	3/35 (8.6%)	3
Haematocrit decreased	2/35 (5.7%)	2
Haemoglobin decreased	5/35 (14.3%)	9
Neutrophil count decreased	2/35 (5.7%)	3
Transferrin saturation decreased	2/35 (5.7%)	2
Weight increased	3/35 (8.6%)	3
Metabolism and nutrition disorders
Dehydration	3/35 (8.6%)	3
Food intolerance	2/35 (5.7%)	2
Hypercalcaemia	3/35 (8.6%)	3
Hypercholesterolaemia	2/35 (5.7%)	2
Hyperglycaemia	4/35 (11.4%)	5
Hyperkalaemia	6/35 (17.1%)	7
Hyperlipidaemia	8/35 (22.9%)	8
Hypertriglyceridaemia	3/35 (8.6%)	3
Hypoalbuminaemia	6/35 (17.1%)	7
Hypocalcaemia	3/35 (8.6%)	3
Hypokalaemia	5/35 (14.3%)	8
Hypomagnesaemia	3/35 (8.6%)	3
Hypophosphataemia	9/35 (25.7%)	11
Musculoskeletal and connective tissue disorders
Arthralgia	2/35 (5.7%)	2
Pain in extremity	3/35 (8.6%)	4
Nervous system disorders
Headache	2/35 (5.7%)	2
Migraine	2/35 (5.7%)	2
Psychiatric disorders
Anxiety	3/35 (8.6%)	4
Depression	3/35 (8.6%)	3
Insomnia	2/35 (5.7%)	2
Panic attack	2/35 (5.7%)	2
Renal and urinary disorders
Haematuria	4/35 (11.4%)	4
Hydronephrosis	3/35 (8.6%)	3
Hypercalciuria	2/35 (5.7%)	2
Proteinuria	5/35 (14.3%)	7
Respiratory, thoracic and mediastinal disorders
Pharyngolaryngeal pain	4/35 (11.4%)	5
Skin and subcutaneous tissue disorders
Pruritus	2/35 (5.7%)	2
Rash	2/35 (5.7%)	3
Vascular disorders
Hypertension	16/35 (45.7%)	18

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.