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

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

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 (also known as ritux) +/- plasma exchange (PLEX) per the standard of care with alemtuzumab induction.

Study Overview

• Status: Completed
• Conditions: End Stage Renal Disease
• Intervention / Treatment: Drug: Tacrolimus Extended-Release Oral Capsule

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 Panel Reactive Antibodies (PRA) ≥ 30%, age 18 and older, requiring desensitization may be included in the study. Initial desensitization protocol for living donor (LD) or deceased donor (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 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 Cedars-Sinai Medical Center (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, Donor Specific Antibodies (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 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.

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90048
      • Cedars Sinai Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Recipient of a deceased or living donor kidney allograft
2. Patients must have undergone desensitization with intravenous immunoglobulin (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 Panel Reactive Antibodies (CPRA)> 30% demonstrated on 3 consecutive samples. The methodology to measure polymerase chain reaction (PCR) includes FLOW and Luminex Single Antigen Assay.
6. At transplant, patient must have an acceptable crossmatch (as defined as T-or B- Flow Cytometry Crossmatch (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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Treatment-related Adverse Events and Treatment Failure	To determine the safety of tacrolimus extended-release in HS kidney transplant recipients after desensitization with intravenous immunoglobulin (IVIG) and rituximab +/- plasma exchange (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.	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Donor Specific Antibodies (DSA) as Defined by the DSA Relative Intensity Score (RIS)	To observe the change in DSA as defined by the DSA RIS, which is 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).	Transplant, 1 month, 3 months, 6 months, 9 months, and 12 months
Tolerability as Defined by the Number of Subjects Discontinuing the Study Medication	To observe the tolerability as defined by the number of subjects discontinuing the study medication.	12 months

Collaborators and Investigators

• Sponsor: Cedars-Sinai Medical Center
• Collaborators: Astellas Pharma Inc

Study record dates

Study Major Dates

• Study Start (ACTUAL): September 11, 2017
• Primary Completion (ACTUAL): October 27, 2020
• Study Completion (ACTUAL): October 27, 2020

Study Registration Dates

• First Submitted: May 24, 2017
• First Submitted That Met QC Criteria: June 19, 2017
• First Posted (ACTUAL): June 21, 2017

Study Record Updates

• Last Update Posted (ACTUAL): January 19, 2022
• Last Update Submitted That Met QC Criteria: January 7, 2022
• Last Verified: January 1, 2022

More Information

Terms related to this study

• Keywords: Highly-sensitized; Kidney transplantation; Desensitization
• Additional Relevant MeSH Terms: Kidney Diseases; Urologic Diseases; Renal Insufficiency; Renal Insufficiency, Chronic; Kidney Failure, Chronic; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Immunosuppressive Agents; Immunologic Factors; Calcineurin Inhibitors; Tacrolimus
• Other Study ID Numbers: PRO00043132

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No