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Trial to Evaluate Safety and Tolerability of Tacrolimus Extended-Release (Astagraf XL) in HLA Sensitized Kidney Transplant Recipients

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ClinicalTrials.gov Identifier: NCT03194321
Recruitment Status : Recruiting
First Posted : June 21, 2017
Last Update Posted : May 10, 2019
Sponsor:
Collaborator:
Astellas Pharma Inc
Information provided by (Responsible Party):
Stanley Jordan, MD, Cedars-Sinai Medical Center

Brief Summary:
The purpose of this study is to demonstrate the safety of tacrolimus extended-release in HLA sensitized (HS, defined as panel reactive antibody ≥ 30%), kidney transplant recipients after desensitization with intravenous immunoglobulin (IVIG) and rituximab +/- plasma exchange (PLEX) per the standard of care with alemtuzumab induction.

Condition or disease Intervention/treatment Phase
End Stage Renal Disease Drug: Tacrolimus Extended Release Oral Capsule Phase 4

Detailed Description:

The study will be a single center, pilot trial. It will be an open label, single-arm, non- controlled design. All HS kidney transplant recipients with a PRA ≥ 30%, age 18 and older, requiring desensitization may be included in the study. Initial desensitization protocol for LD or DD includes Intravenous Immunoglobulin (IVIG) 2g/kg (>70kg max 140g) given on day 0 (split over 2 days for peritoneal dialysis patients), rituximab 375mg/m2 (rounded to the nearest 100mg vial) given on day 15, and IVIG 2g/kg (>70kg max 140g ) given on day 30. Recipients for LD or DD who are unresponsive to IVIG/ritux (after 2 months for LD and after 6 months for DD) will require plasma exchange (PLEX) 5-7 sessions followed by IVIG 2g/kg (>70kg max 140g) and rituximab 375mg/m2. Patients will be receiving acetaminophen, antihistamine, and steroid as premedication for all infusions.

A total of 20 subjects will be enrolled in the study. Subjects will take part in the study until they are one year post-transplant. All subjects will require informed consent. At the time of screening, subjects will receive a physical exam and undergo lab testing. Alemtuzumab 30mg, will be administered subcutaneously to all subjects for induction immunosuppression immediately post-transplant. Maintenance immunosuppression will consist of tacrolimus extended-release, mycophenolate mofetil 500mg twice daily or mycophenolate sodium 360mg twice daily, and prednisone. Patients will receive antimicrobial prophylaxis per CSMC protocol. Lab tests and physical exams for safety will take place according to the evaluation schedule below. Safety will be assessed by the reporting of serious adverse events.

Tacrolimus trough level, complete metabolic panel, liver function panel, complete blood count with differential, DSA, and urinalysis with culture will be assessed according to the evaluation schedule below. Subjects will complete the study at one year post-transplant. Consent may be withdrawn by the study participant at any time. The investigator may also withdraw the study participant at any time if there are any safety concerns.

Desensitization includes Intravenous Immunoglobulin (IVIG) 2g/kg (>70kg max 140g) given on day 0 (split over 2 days for peritoneal dialysis patients), rituximab 375mg/m2 (rounded to the nearest 100mg vial) given on day 15, and IVIG 2g/kg (>70kg max 140g ) given on day 30. Patients will require plasma exchange (PLEX) 5-7 sessions if they have received desensitization in the past. In this case, patients will receive PLEX daily x 5-7 sessions followed by IVIG 2g/kg (>70kg max 140g) and rituximab 375mg/m2. Patients will be receiving acetaminophen, antihistamine, and steroid as premedication for all infusions.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Prospective, Pilot Trial to Evaluate Safety and Tolerability of Tacrolimus Extended-Release (Astagraf XL) in HLA Sensitized Kidney Transplant Recipients
Actual Study Start Date : September 11, 2017
Estimated Primary Completion Date : May 9, 2020
Estimated Study Completion Date : May 9, 2021

Resource links provided by the National Library of Medicine

Drug Information available for: Tacrolimus

Arm Intervention/treatment
Experimental: Tacrolimus extended release arm
All patients will receive tacrolimus extended-release adjusted to target trough levels, mycophenolate mofetil or mycophenolate sodium, and prednisone per CSMC practice.
Drug: Tacrolimus Extended Release Oral Capsule
Maintenance immunosuppression will consist of tacrolimus extended-release, mycophenolate mofetil 500mg twice daily or mycophenolate sodium 360mg twice daily, and prednisone.




Primary Outcome Measures :
  1. Number of participants with treatment-related adverse events and treatment failure. [ Time Frame: 12 months ]
    The primary objective is to determine the safety of tacrolimus extended-release in HS kidney transplant recipients after desensitization with IVIG and rituximab +/- PLEX per the standard of care and alemtuzumab induction. This will be measured by the rate of serious adverse events (SAEs) and treatment failure. Treatment failure is defined as a composite of biopsy proven acute rejection (BPAR), graft failure, or death. BPAR is defined as ≥ Banff 1A using the Banff 2007 criteria.


Secondary Outcome Measures :
  1. 1. Change in donor specific antibodies (DSA) as defined by the DSA relative intensity score [ Time Frame: 12 months ]
    To observe the change in DSA as defined by the DSA relative intensity score (RIS) defined by: 0 points for no DSA, 2 points for each weak DSA (MFI <5,000), 5 points for each moderate DSA (MFI 5,000 -10,000), and 10 points for each strong DSA (MFI >10,000)

  2. 2. Tolerability as defined by the number of subjects discontinuing the study medication [ Time Frame: 12 months ]
    To observe the tolerability as defined by the number of subjects discontinuing the study medication



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Recipient of a deceased or living donor kidney allograft
  2. Patients must have undergone desensitization with IVIG and rituximab with or without plasma exchange prior to transplant or be administered IVIG and rituximab peri-operatively (within seven days of transplant) post-transplant
  3. Age 18 and over
  4. Able to understand and provide informed consent
  5. Calculated PRA (CPRA)> 30% demonstrated on 3 consecutive samples. The methodology to measure PRA includes FLOW and Luminex Single Antigen Assay.
  6. At transplant, patient must have an acceptable crossmatch (as defined as T-or B- FCMX ≤ 225 MCS) from non-HLA identical donor. Negative crossmatch is Tpronase FCMX <70; T- FCMX <50 and Bpronase FCMX <130; B-FCMX <100.

Exclusion Criteria:

  1. Recipients of a dual simultaneous kidney/liver, kidney/heart, kidney/lung, or kidney/pancreas transplant
  2. History of hypersensitivity to any of the study drugs or to drugs of similar chemical classes
  3. Patients being treated with drugs that are strong inducers or inhibitors of cytochrome P450 3A4
  4. Patients with a clinically significant systemic infection within 30 days prior to transplant
  5. Patients who have any surgical or medical condition that may affect absorption of drug, such as severe diarrhea, active peptic ulcer disease, or uncontrolled diabetes mellitus, which in the opinion of the investigator, might significantly alter the absorption, distribution, metabolism and/or excretion of study medication
  6. Women of childbearing potential who are either pregnant, lactating, planning to become pregnant during this trial, or with a positive serum or urine pregnancy test. Women of childbearing potential must be willing to agree to contraceptive practices.
  7. Patients who are PCR positive for Hep B, Hep C, or HIV.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03194321


Contacts
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Contact: Noriko Ammerman, PharmD 312488186 noriko.ammerman@cshs.org

Locations
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United States, California
Cedars Sinai Medical Center Recruiting
Los Angeles, California, United States, 90048
Contact: Noriko Ammerman, PharmD    310-248-8186    noriko.ammerman@cshs.org   
Principal Investigator: Stanley Jordan, MD         
Sponsors and Collaborators
Cedars-Sinai Medical Center
Astellas Pharma Inc

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Responsible Party: Stanley Jordan, MD, Director, Nephrology & Transplant Immunology, Cedars-Sinai Medical Center
ClinicalTrials.gov Identifier: NCT03194321     History of Changes
Other Study ID Numbers: Pro00043132
First Posted: June 21, 2017    Key Record Dates
Last Update Posted: May 10, 2019
Last Verified: May 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Kidney Failure, Chronic
Kidney Diseases
Urologic Diseases
Renal Insufficiency, Chronic
Renal Insufficiency
Tacrolimus
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Calcineurin Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action