Clinical trial NCT03194321: Trial to Evaluate Safety and Tolerability of Tacrolimus Extended-Release (Astagraf XL) in Human Leukocyte Antigen (HLA) Sensitized Kidney Transplant Recipients
Official title: A Prospective, Pilot Trial to Evaluate Safety and Tolerability of Tacrolimus Extended-Release (Astagraf XL) in HLA Sensitized Kidney Transplant Recipients
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: End Stage Renal Disease
Keywords: Highly-sensitized; Kidney transplantation; Desensitization
Lead sponsor: Cedars-Sinai Medical Center
Sponsor class: OTHER
Collaborators: name: Astellas Pharma Inc
First posted: 2017-06-21
Enrollment: 20
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Number of Participants With Treatment-related Adverse Events and Treatment Failure
timeFrame: 12 months
Secondary outcomes:
measure: Change in Donor Specific Antibodies (DSA) as Defined by the DSA Relative Intensity Score (RIS)
timeFrame: Transplant, 1 month, 3 months, 6 months, 9 months, and 12 months
measure: Tolerability as Defined by the Number of Subjects Discontinuing the Study Medication
timeFrame: 12 months
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Cedars Sinai Medical Center
state: California
Study officials:
References: