Tocilizumab for Renal Graft Inflammation

Sponsor
Flavio Vincenti (Other)
Overall Status
Completed
CT.gov ID
NCT02108600
Collaborator
(none)
33
Enrollment
1
Location
2
Arms
54.5
Actual Duration (Months)
0.6
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Randomized open label clinical trial in which 48 renal transplant recipients with inflammation in the 6 month allograft biopsy will either continue usual immunosuppression or receive monthly Actemra (Tocilizumab) infusions for 6 months in addition to usual immunosuppression.

Condition or DiseaseIntervention/TreatmentPhase
Phase 2

Detailed Description

This is a prospective randomized controlled study of kidney transplant recipients with SCI on 6-month surveillance kidney biopsies. SCI for the purpose of this study is defined as 10-50% total parenchymal mononuclear inflammation (Banff ti1-ti2) with <i2,t2 concurrent lesions.

After enrollment, study participants subjects will be randomized to group 1 (standard of care group) or group 2 (tocilizumab (TCZ) group). Block randomization will be performed by the UCSF investigational pharmacy using computer-generated random numbers. The pathologist will be blinded to the randomization.

Group 1 (standard of care group) will continue their usual immunosuppression and not receive any specific intervention.

Group 2 (TCZ group) will receive tocilizumab 8 mg/kg intravenously at four-week intervals for a total of 6 doses.In addition, they will continue their usual immunosuppressive regimen.

As noted above, both groups will continue their usual maintenance immunosuppression regimen. Therefore, recipients who are already receiving prednisone will continue it at 5 mg/day. Recipients on prednisone-free regimens will remain prednisone-free. Mycophenolate mofetil will be continued at the same dose as at the time of the biopsy. Tacrolimus dosing will be adjusted to aim for trough levels of 5-8 mcg/L.

The study period will be 12 months (6 months of therapy plus 6 months of extended follow up- see Study Schema). Any episodes of infections, renal allograft dysfunctions, rejections or other clinical events during the study period will be treated per the usual standard of care.

All participants will be seen by the study PI or co-investigator at monthly study visits. A focused history and physical exam will be performed, including queries for drug toxicities and signs/ symptom of infections. All participants will obtain laboratory tests at intervals of 4 weeks, consisting of a complete blood count, serum electrolytes, BUN and serum creatinine, fasting glucose, liver function tests and 12-hour trough tacrolimus levels. Lipid panels will be obtained at baseline, then every 12 weeks an at study termination.The outpatient electronic medical record will be queried twiceweekly by the study coordinator for any new laboratory results on study participants. Laboratory data on all study participants will be reviewed weekly by the study PI.

The 12-month surveillance biopsy will be performed at the end of therapy (6 months after study enrollment).

Study Design

Study Type:
Interventional
Actual Enrollment :
33 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Phase II Trial of the Efficacy and Safety of Tocilizumab for Treatment of Inflammation in the Renal Allograft
Actual Study Start Date :
Jun 1, 2014
Actual Primary Completion Date :
Dec 16, 2018
Actual Study Completion Date :
Dec 16, 2018

Arms and Interventions

ArmIntervention/Treatment
No Intervention: Standard of Care

Will continue usual immunosuppression and not receive any specific intervention.

Experimental: Tocilizumab (TCZ) Group

Will receive tocilizumab 8 mg/kg intravenously at four-week intervals for a total of 6 doses. In addition, will continue usual immunosuppressive regimen.

Drug: Tocilizumab
Will receive tocilizumab 8 mg/kg intravenously at four-week intervals for a total of 6 doses. In addition, will continue usual immunosuppressive regimen.

Outcome Measures

Primary Outcome Measures

  1. Change in Inflammation on Renal Allograft Biopsy From Baseline to 6 Months [Baseline and 6 months]

    Proportion of participants in each group who had a 1 point decrease in inflammation based on Banff scoring on renal allograft biopsy at 6 months compared to baseline. The Banff ti- score can be 0, 1, 2 or 3.

Secondary Outcome Measures

  1. Change in Urinary Cytokines [Baseline and 6 months]

    Change in urinary cytokines from baseline at 6 months.

  2. Development of Donor Specific Anti-HLA Antibodies [From baseline to 6 months]

    Proportion of participants who developed de novo DSA from baseline to 6 months

  3. Incidence of Acute Rejection [In the interval between baseline and 6 Months]

    Proportion of patients with acute rejection in each group

Eligibility Criteria

Criteria

Ages Eligible for Study:
18 Years to 70 Years
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
Inclusion Criteria:
  • All kidney transplant recipients with SCI on 6-month surveillance biopsy.

  • Maintenance immunosuppression regimens containing tacrolimus and MMF with or without prednisone.

  • Ability to provide written informed consent for the study.

  • Men and women of reproductive potential must agree to use an acceptable method of birth control during treatment and for six months after completion of treatment.

Exclusion Criteria:
General:

• Major surgery (including joint surgery) within 8 weeks prior to screening or planned major surgery within 6 months following randomization.

Excluded Previous or Concomitant Therapy:
  • Treatment with any investigational agent within 4 weeks (or 5 half-lives of the investigational drug, whichever is longer) of screening.

  • Previous treatment with any cell-depleting therapies, including investigational agents or approved therapies, some examples are CAMPATH, anti-CD4, anti-CD5, anti-CD3, anti-CD19 and anti-CD20, except Thymoglobulin.

  • Treatment with intravenous gamma globulin, plasmapheresis or Prosorba column within 6 months of baseline.

  • Immunization with a live/attenuated vaccine within 4 weeks prior to baseline.

  • Previous treatment with TCZ (an exception to this criterion may be granted for single dose exposure upon application to the sponsor on a case-by-case basis).

  • Any previous treatment with alkylating agents such as chlorambucil, or with total lymphoid irradiation.

Exclusions for General Safety:
  • Presence of acute cellular (Banff Type 1-3) or antibody-mediated rejection on 6-month surveillance biopsy or on biopsies for-cause in the previous 6 months.

  • History of positive urine or serum screening for BK virus (defined as a quantitative BK virus PCR in urine > 0.5 million copies/ml or any detectable BK viremia) within the first 6 months post-transplant.

  • History of severe allergic or anaphylactic reactions to human, humanized or murine monoclonal antibodies.

  • Evidence of serious uncontrolled concomitant cardiovascular, nervous system, pulmonary (including obstructive pulmonary disease), renal, hepatic, endocrine (include uncontrolled diabetes mellitus) or gastrointestinal disease (including diverticulitis, ulcerative colitis, or Crohn's disease.)

  • Current liver disease as determined by principal investigator unless related to primary disease under investigation.

  • Known active current or history of recurrent bacterial, viral, fungal, mycobacterial or other infections (including but not limited to tuberculosis and atypical mycobacterial disease, Hepatitis B and C, and herpes zoster, but excluding fungal infections of nail beds).

  • Any major episode of infection requiring hospitalization or treatment with IV antibiotics within 4 weeks of screening or oral antibiotics within 2 weeks prior to screening.

  • Active TB requiring treatment within the previous 3 years. Patients should be screened for latent TB and, if positive, treated following local practice guidelines prior to initiating TCZ. Patients treated for tuberculosis with no recurrence in 3 years are permitted. (Appendix 8).

  • Primary or secondary immunodeficiency (history of or currently active) unless related to primary disease under investigation.

  • Evidence of active malignant disease, malignancies diagnosed within the previous 10 years (including hematological malignancies and solid tumors, except basal and squamous cell carcinoma of the skin or carcinoma in situ of the cervix uteri that has been excised and cured), or breast cancer diagnosed within the previous 20 years unless related to primary disease under investigation.

  • Pregnant women or nursing (breast feeding) mothers.

  • Patients with reproductive potential not willing to use an effective method of contraception.

  • History of alcohol, drug or chemical abuse within 1 year prior to screening.

  • Patients with lack of peripheral venous access.

Laboratory Exclusion criteria (at screening):
  • Serum creatinine > 1.6 mg/dL (141 µmol/L) in female patients and > 1.9 mg/dL (168 µmol/L) in male patients. Patients with serum creatinine values exceeding limits may be eligible for the study if their estimated glomerular filtration rates (GFR) are >30 ml/min/1.73 m2.

  • Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 1.5 times upper limit of normal (ULN)

  • Total Bilirubin > 1.5 times ULN

  • Platelet count < 100 x 109/L (100,000/mm3)

  • Hemoglobin < 85 g/L (8.5 g/dL; 5.3 mmol/L)

  • White Blood Cells < 3.0 x 109/L (3000/mm3)

  • Absolute Neutrophil Count < 2.0 x 109/L (2000/mm3)

  • Absolute Lymphocyte Count < 0.5 x 109/L (500/mm3)

  • Positive Hepatitis BsAg, or Hepatitis C antibody

Contacts and Locations

Locations

SiteCityStateCountryPostal Code
1University of California, San FranciscoSan FranciscoCaliforniaUnited States94143

Sponsors and Collaborators

  • Flavio Vincenti

Investigators

  • Principal Investigator: Flavio Vincenti, MD, University of California, San Francisco

Study Documents (Full-Text)

More Information

Publications

Responsible Party:
Flavio Vincenti, Clinical Professor, University of California, San Francisco
ClinicalTrials.gov Identifier:
NCT02108600
Other Study ID Numbers:
  • ML29092
First Posted:
Apr 9, 2014
Last Update Posted:
Mar 9, 2021
Last Verified:
Mar 1, 2021
Individual Participant Data (IPD) Sharing Statement:
No
Plan to Share IPD:
No
Keywords provided by Flavio Vincenti, Clinical Professor, University of California, San Francisco
Additional relevant MeSH terms:

Study Results

Participant Flow

Recruitment Details
Pre-assignment Detail
Arm/Group TitleStandard of CareTocilizumab (TCZ) Group
Arm/Group DescriptionWill continue usual immunosuppression and not receive any specific intervention.Will receive tocilizumab 8 mg/kg intravenously at four-week intervals for a total of 6 doses. In addition, will continue usual immunosuppressive regimen. Tocilizumab: Will receive tocilizumab 8 mg/kg intravenously at four-week intervals for a total of 6 doses. In addition, will continue usual immunosuppressive regimen.
Period Title: Overall Study
STARTED1716
COMPLETED1415
NOT COMPLETED31

Baseline Characteristics

Arm/Group TitleStandard of CareTocilizumab (TCZ) GroupTotal
Arm/Group DescriptionWill continue usual immunosuppression and not receive any specific intervention.Will receive tocilizumab 8 mg/kg intravenously at four-week intervals for a total of 6 doses. In addition, will continue usual immunosuppressive regimen. Tocilizumab: Will receive tocilizumab 8 mg/kg intravenously at four-week intervals for a total of 6 doses. In addition, will continue usual immunosuppressive regTotal of all reporting groups
Overall Participants141630
Age (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]
51.5
53.5
52
Sex: Female, Male (Count of Participants)
Female
6
42.9%
7
43.8%
13
43.3%
Male
8
57.1%
9
56.3%
17
56.7%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native
0
0%
0
0%
0
0%
Asian
2
14.3%
2
12.5%
4
13.3%
Native Hawaiian or Other Pacific Islander
1
7.1%
0
0%
1
3.3%
Black or African American
1
7.1%
0
0%
1
3.3%
White
10
71.4%
14
87.5%
24
80%
More than one race
0
0%
0
0%
0
0%
Unknown or Not Reported
0
0%
0
0%
0
0%
Region of Enrollment (participants) [Number]
United States
14
100%
16
100%
30
100%

Outcome Measures

1. Primary Outcome
TitleChange in Inflammation on Renal Allograft Biopsy From Baseline to 6 Months
DescriptionProportion of participants in each group who had a 1 point decrease in inflammation based on Banff scoring on renal allograft biopsy at 6 months compared to baseline. The Banff ti- score can be 0, 1, 2 or 3.
Time FrameBaseline and 6 months

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group TitleStandard of CareTocilizumab (TCZ) Group
Arm/Group DescriptionWill continue usual immunosuppression and not receive any specific intervention.Will receive tocilizumab 8 mg/kg intravenously at four-week intervals for a total of 6 doses. In addition, will continue usual immunosuppressive regimen. Tocilizumab: Will receive tocilizumab 8 mg/kg intravenously at four-week intervals for a total of 6 doses. In addition, will continue usual immunosuppressive regimen.
Measure Participants1416
Count of Participants [Participants]
3
21.4%
10
62.5%
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Standard of Care, Tocilizumab (TCZ) Group
Comments
Type of Statistical Test Other
Comments
Statistical Test of Hypothesisp-Value0.033
Comments
MethodFisher Exact
Comments
2. Secondary Outcome
TitleChange in Urinary Cytokines
DescriptionChange in urinary cytokines from baseline at 6 months.
Time FrameBaseline and 6 months

Outcome Measure Data

Analysis Population Description
The urine samples were not adequate for analysis and therefore this outcome was not analyzed.
Arm/Group TitleStandard of CareTocilizumab (TCZ) Group
Arm/Group DescriptionWill continue usual immunosuppression and not receive any specific intervention.Will receive tocilizumab 8 mg/kg intravenously at four-week intervals for a total of 6 doses. In addition, will continue usual immunosuppressive regimen. Tocilizumab: Will receive tocilizumab 8 mg/kg intravenously at four-week intervals for a total of 6 doses. In addition, will continue usual immunosuppressive regimen.
Measure Participants00
3. Secondary Outcome
TitleDevelopment of Donor Specific Anti-HLA Antibodies
DescriptionProportion of participants who developed de novo DSA from baseline to 6 months
Time FrameFrom baseline to 6 months

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group TitleStandard of CareTocilizumab (TCZ) Group
Arm/Group DescriptionWill continue usual immunosuppression and not receive any specific intervention.Will receive tocilizumab 8 mg/kg intravenously at four-week intervals for a total of 6 doses. In addition, will continue usual immunosuppressive regimen. Tocilizumab: Will receive tocilizumab 8 mg/kg intravenously at four-week intervals for a total of 6 doses. In addition, will continue usual immunosuppressive regimen.
Measure Participants1416
Count of Participants [Participants]
0
0%
0
0%
4. Secondary Outcome
TitleIncidence of Acute Rejection
DescriptionProportion of patients with acute rejection in each group
Time FrameIn the interval between baseline and 6 Months

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group TitleStandard of CareTocilizumab (TCZ) Group
Arm/Group DescriptionWill continue usual immunosuppression and not receive any specific intervention.Will receive tocilizumab 8 mg/kg intravenously at four-week intervals for a total of 6 doses. In addition, will continue usual immunosuppressive regimen. Tocilizumab: Will receive tocilizumab 8 mg/kg intravenously at four-week intervals for a total of 6 doses. In addition, will continue usual immunosuppressive regimen.
Measure Participants1416
Count of Participants [Participants]
0
0%
0
0%

Adverse Events

Time Frame1 year
Adverse Event Reporting Description used Common Terminology Criteria for Adverse Events (CTCAE) grades
Arm/Group TitleStandard of CareTocilizumab (TCZ) Group
Arm/Group DescriptionWill continue usual immunosuppression and not receive any specific intervention.Will receive tocilizumab 8 mg/kg intravenously at four-week intervals for a total of 6 doses. In addition, will continue usual immunosuppressive regimen. Tocilizumab: Will receive tocilizumab 8 mg/kg intravenously at four-week intervals for a total of 6 doses. In addition, will continue usual immunosuppressive regimen.
All Cause Mortality
Standard of CareTocilizumab (TCZ) Group
Affected / at Risk (%)# EventsAffected / at Risk (%)# Events
Total0/14 (0%) 0/16 (0%)
Serious Adverse Events
Standard of CareTocilizumab (TCZ) Group
Affected / at Risk (%)# EventsAffected / at Risk (%)# Events
Total0/14 (0%) 3/16 (18.8%)
Infections and infestations
sepsis0/14 (0%) 01/16 (6.3%) 1
pyelonephritis0/14 (0%) 01/16 (6.3%) 1
Renal and urinary disorders
subcapsular hematoma0/14 (0%) 01/16 (6.3%) 1
Other (Not Including Serious) Adverse Events
Standard of CareTocilizumab (TCZ) Group
Affected / at Risk (%)# EventsAffected / at Risk (%)# Events
Total0/14 (0%) 2/16 (12.5%)
Infections and infestations
pneumonia0/14 (0%) 01/16 (6.3%) 1
skin infection0/14 (0%) 01/16 (6.3%) 1

Limitations/Caveats

The study could not meet its recruitment target of 48 subjects, and consequently, is underpowered statistically. Additionally, the urine samples were inadequate, leading to inability to perform urine cytokine measurements.

More Information

Certain Agreements

All Principal Investigators ARE 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.

Results Point of Contact

Name/TitleSindhu Chandran
OrganizationUniversity of California, San Francisco
Phone4153538374
Emailsindhu.chandran@ucsf.edu
Responsible Party:
Flavio Vincenti, Clinical Professor, University of California, San Francisco
ClinicalTrials.gov Identifier:
NCT02108600
Other Study ID Numbers:
  • ML29092
First Posted:
Apr 9, 2014
Last Update Posted:
Mar 9, 2021
Last Verified:
Mar 1, 2021