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Donor-Alloantigen-Reactive Regulatory T Cell (darTreg) Therapy in Renal Transplantation (The ONE Study ) (DART)

Primary Purpose

Kidney Disease

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
darTreg infusion
Sponsored by
University of California, San Francisco
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Kidney Disease

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria: (organ donor eligibility)

  1. Eligible for live kidney donation
  2. At least 18 years of age
  3. An ABO blood type compatible with the organ recipient
  4. Willing and able to provide a blood sample for The ONE Study IM (Immune Monitoring) Subproject
  5. Willing to provide personal and medical/biological data for the trial analysis
  6. Eligible to give blood for B cell source prior to organ donation
  7. Signed and dated written informed consent*. *For subjects unable to read and/or write, oral informed consent observed by an independent witness is acceptable if the subject has fully understood oral information given by the Investigator. The witness should sign the consent form on behalf of the subject.

In signing the donor information sheet/informed consent form (DIS/ICF), organ donors agree to undergo phlebotomy to provide donor B cells for the production of darTreg, to provide a blood sample for the IM Subproject, and permit access to their medical records for the collection of specified demographic and medical/biological data for the trial.

Organ Recipient eligibility:

A prospective kidney transplant recipient is eligible for enrollment into the study if all of the following inclusion criteria apply:

  1. Chronic renal insufficiency necessitating kidney transplantation and approved to receive a primary kidney allograft from a living donor
  2. At least 18 years of age
  3. Able to commence the immunosuppressive regimen at the protocol-specified time point
  4. Willing and able to participate in The ONE Study IM and HEC (Health-Economics Subproject) subprojects
  5. Adequate venous access to support leukapheresis
  6. Signed and dated written informed consent*.

    • For patients unable to read and/or write, oral informed consent observed by an independent witness is acceptable if the patient has fully understood oral information given by the Investigator. The witness should sign the consent form on behalf of the patient.

Exclusion Criteria: (organ donor)

If a prospective donor fulfills any of the following criteria, they are ineligible for the trial:

  1. Genetically identical to the prospective organ recipient at the HLA (human leukocyte antigen) loci (0-0-0 mismatch)
  2. CMV-positive and donating to a CMV-negative recipient
  3. Exposure to any investigational agents at the time of kidney donation, or within 28 days prior to kidney donation
  4. Any form of substance abuse, psychiatric disorder, or other condition that, in the opinion of the Investigator, may invalidate communication with the Investigator and/or designated study personnel
  5. Subjects unable to freely give their informed consent (e.g. individuals under legal guardianship).

Exclusion criteria (organ recipient)

  1. Patient has previously received any tissue or organ transplant other than the planned kidney graft
  2. Known contraindication to the protocol-specified treatments / medications
  3. Genetically identical to the prospective organ donor at the HLA (human leukocyte antigen) loci (0-0-0 mismatch)
  4. PRA (panel reactive antibody) grade > 40% within 6 months prior to enrollment
  5. Previous treatment with any desensitization procedure (with or without IVIg)
  6. Concomitant malignancy or history of malignancy within 5 years prior to planned study entry (excluding successfully-treated non-metastatic basal/squamous cell carcinoma of the skin)
  7. Evidence of significant local or systemic infection
  8. HIV-positive, EBV-negative or suffering chronic viral hepatitis
  9. CMV-negative and receiving a kidney from a CMV-positive donor
  10. Significant liver disease, defined as persistently elevated AST (aspartate aminotransferase) and/or ALT(alanine aminotransferase) levels > 2 x ULN (Upper Limit of Normal range)
  11. Malignant or pre-malignant hematological conditions
  12. Neutrophils < 1000/μl ; platelets < 100,000/μl
  13. Regulatory T cells present in peripheral blood at <30/µL
  14. Any uncontrolled medical condition or concurrent disease that could interfere with the study objectives
  15. Any condition which, in the judgment of the Investigator, would place the subject at undue risk
  16. Ongoing treatment with systemic immunosuppressive drugs at study entry
  17. Patients who have received anti-T cell therapy within 30 days prior to transplant surgery
  18. Participation in another clinical trial during the study or within 28 days prior to planned study entry
  19. Female patients of reproductive potential with a positive pregnancy test at enrollment
  20. Female patients who are breast-feeding
  21. All female patients of reproductive potential* UNLESS the patient is willing to use an acceptable birth control for the duration of the study unless the patient chooses abstinence (she chooses to avoid heterosexual intercourse completely) (See Table 2. Acceptable Contraception Methods for Females of Reproductive Potential)
  22. Male patients unwilling to use a reliable and effective form of contraception for 3 months after darTreg dosing
  23. Psychological, familial, sociological or geographical factors potentially hampering compliance with the study protocol and follow-up visit schedule
  24. Any form of substance abuse, psychiatric disorder, or other condition that, in the opinion of the Investigator, may invalidate communication with the Investigator and/or designated study personnel
  25. Patients unable to freely give their informed consent (e.g. individuals under legal guardianship).

    • Females of reproductive potential include girls who have entered puberty and all women who have a uterus and have not passed through menopause. Menopause is the permanent end of menstruation and fertility. Menopause should be clinically confirmed by a patient's healthcare practitioner. Some commonly used diagnostic criteria include 1) 12 months of spontaneous amenorrhea (not amenorrhea induced by a medical condition or medical therapy) or 2) postsurgical from a bilateral oophorectomy.

Exclusion Criteria B (organ recipient)

Below are exclusion criteria to be assessed post-transplantation and prior to darTreg infusion. Subjects who meet any of these criteria should not receive a darTreg-infusion:

  1. Unacceptable darTreg product.
  2. Delayed graft function (requiring dialysis post-transplant).
  3. Requiring oxygen supplementation to keep capillary oxygen saturations >95%.
  4. Any medical or technical complications (e.g. myocardial infarction, urine leak, wound dehiscence, pneumonia, ongoing fevers, etc.) that in the judgment of the investigators or responsible clinician would put the subject at undue risk.-

Sites / Locations

  • University of California San Francisco - Transplant Department. 513 Parnassus Ave HSE 504

Arms of the Study

Arm 1

Arm 2

Arm Type

Other

Other

Arm Label

Cohort 1

Cohort 2

Arm Description

3 subjects treated with a target dose of 300 million darTreg with the possibility of expanding to 5 patients if safety signals should require additional patients be observed at the 300 million dose. The first subject in each dosing cohort will be monitored for 4 weeks after darTreg infusion. Following the 4 week observation period, the study team will conduct a thorough review of all available data to ensure that there are no safety signals and to make a determination about proceeding with additional patients.

The second cohort will comprise a minimum of 3 and up to 5 subjects treated at a target dose of 900 million darTreg, depending on how many patients were required to be treated in lower dose group. The first subject in each dosing cohort will be monitored for 4 weeks after darTreg infusion. Following the 4 week observation period, the study team will conduct a thorough review of all available data to ensure that there are no safety signals and to make a determination about proceeding with additional patients.

Outcomes

Primary Outcome Measures

Incidence of biopsy-confirmed acute rejection (BCAR) following renal transplantation.
Explore the immunomodulatory potential, safety and tolerability of a single infusion of darTregs as adjunct immunosuppressive treatment through the incidence of biopsy-confirmed acute rejection (BCAR) within 60 weeks following renal transplantation.

Secondary Outcome Measures

Time to first acute rejection episode
Severity of acute rejection episodes
severity of acute rejection episodes based on response to treatment and histological scoring
Total immunosuppressive burden at 60 weeks post-transplantation
Total immunosuppressive burden assessed at last study visit
Prevention of chronic graft dysfunction (chronic rejection or IF/TA)
chronic graft dysfunction assessed by clinical (impairment of GFR) and histopathological (Banff staging) measures
Incidence of post-transplant dialysis, inclusion on the transplant waiting list or re-transplantation following graft loss through rejection
Avoidance of drug-related complications by immunosuppressant reduction
Assessed by the incidence of reported adverse drug reactions
Biochemical disturbances caused by cell infusion
Assessed by Incidence of acute toxicities associated with infusion of the cell product
Over-suppression of the immune system assessed by the incidence of major and/or opportunistic infections especially CMV (cytomegalovirus ), EBV (Epstein-Barr virus) and polyoma virus
Incidence of neoplasia
Incidence of patients treated for subclinical acute rejection

Full Information

First Posted
September 11, 2014
Last Updated
October 10, 2018
Sponsor
University of California, San Francisco
Collaborators
Seventh Framework Programme
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1. Study Identification

Unique Protocol Identification Number
NCT02244801
Brief Title
Donor-Alloantigen-Reactive Regulatory T Cell (darTreg) Therapy in Renal Transplantation (The ONE Study )
Acronym
DART
Official Title
Donor-Alloantigen-Reactive Regulatory T Cell (darTreg) Therapy in Renal Transplantation: A ONE Study Clinical Trial
Study Type
Interventional

2. Study Status

Record Verification Date
October 2018
Overall Recruitment Status
Completed
Study Start Date
April 2015 (Actual)
Primary Completion Date
September 2017 (Actual)
Study Completion Date
August 28, 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of California, San Francisco
Collaborators
Seventh Framework Programme

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This Phase I pilot study will evaluate the safety, and tolerability of darTreg infusion for adult, de novo, living donor renal transplant recipients.
Detailed Description
A single-center, open-label, dose-escalation pilot trial of a single infusion of darTregs in two dosing cohorts. This study is an independent single-center clinical trial. However, the organizational and mechanistic infrastructure of the study will be provided by the ONE Study project, a European Union funded collaborative project, whose objective is to assess distinct purified hematopoietic immunoregulatory cells as clinical therapies in solid organ transplantation. This study is one of multiple clinical trials within the framework of The ONE Study project, based on the same general design.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Kidney Disease

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
6 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Cohort 1
Arm Type
Other
Arm Description
3 subjects treated with a target dose of 300 million darTreg with the possibility of expanding to 5 patients if safety signals should require additional patients be observed at the 300 million dose. The first subject in each dosing cohort will be monitored for 4 weeks after darTreg infusion. Following the 4 week observation period, the study team will conduct a thorough review of all available data to ensure that there are no safety signals and to make a determination about proceeding with additional patients.
Arm Title
Cohort 2
Arm Type
Other
Arm Description
The second cohort will comprise a minimum of 3 and up to 5 subjects treated at a target dose of 900 million darTreg, depending on how many patients were required to be treated in lower dose group. The first subject in each dosing cohort will be monitored for 4 weeks after darTreg infusion. Following the 4 week observation period, the study team will conduct a thorough review of all available data to ensure that there are no safety signals and to make a determination about proceeding with additional patients.
Intervention Type
Drug
Intervention Name(s)
darTreg infusion
Other Intervention Name(s)
darTregs
Intervention Description
The first subject in each dosing cohort will be monitored for 4 weeks after darTreg infusion. Following the 4 week observation period, the study team will conduct a thorough review of all available data to ensure that there are no safety signals and to make a determination about proceeding with additional patients. sBc production for darTreg manufacturing for the second subject in each cohort may be initiated but the second subject may not undergo leukapheresis until the safety review is complete. Once the last subject in the first cohort reaches week 4 post-infusion, the DSMB will conduct a thorough review of all available data to make a determination about proceeding with additional patients at the lower dose or proceeding to the second dosing cohort. sBc production for darTreg manufacturing for the subsequent subject may be initiated but the patient may not undergo leukapheresis until the DSMB( Data Safety and Monitoring Board ) has approved enrollment of subsequent subjects.
Primary Outcome Measure Information:
Title
Incidence of biopsy-confirmed acute rejection (BCAR) following renal transplantation.
Description
Explore the immunomodulatory potential, safety and tolerability of a single infusion of darTregs as adjunct immunosuppressive treatment through the incidence of biopsy-confirmed acute rejection (BCAR) within 60 weeks following renal transplantation.
Time Frame
60 weeks post renal transplantation
Secondary Outcome Measure Information:
Title
Time to first acute rejection episode
Time Frame
60 weeks post renal transplantation
Title
Severity of acute rejection episodes
Description
severity of acute rejection episodes based on response to treatment and histological scoring
Time Frame
60 weeks post renal transplantation
Title
Total immunosuppressive burden at 60 weeks post-transplantation
Description
Total immunosuppressive burden assessed at last study visit
Time Frame
60 weeks post renal transplantation
Title
Prevention of chronic graft dysfunction (chronic rejection or IF/TA)
Description
chronic graft dysfunction assessed by clinical (impairment of GFR) and histopathological (Banff staging) measures
Time Frame
60 weeks post renal transplantation
Title
Incidence of post-transplant dialysis, inclusion on the transplant waiting list or re-transplantation following graft loss through rejection
Time Frame
60 weeks post renal transplantation
Title
Avoidance of drug-related complications by immunosuppressant reduction
Description
Assessed by the incidence of reported adverse drug reactions
Time Frame
60 weeks post renal transplantation
Title
Biochemical disturbances caused by cell infusion
Description
Assessed by Incidence of acute toxicities associated with infusion of the cell product
Time Frame
1 week
Title
Over-suppression of the immune system assessed by the incidence of major and/or opportunistic infections especially CMV (cytomegalovirus ), EBV (Epstein-Barr virus) and polyoma virus
Time Frame
60 weeks post renal transplantation
Title
Incidence of neoplasia
Time Frame
60 weeks post renal transplantation
Title
Incidence of patients treated for subclinical acute rejection
Time Frame
60 weeks post transplantation
Other Pre-specified Outcome Measures:
Title
Incidence of malignancies arising directly from darTreg infusion
Time Frame
60 weeks
Title
incidence of autoimmune disorders
Time Frame
60 weeks post transplantation
Title
A Health-Economics Subproject will evaluate the health-related qualify-of-life of trail patients using patient-reported outcome measures
Time Frame
60 weeks post transplantation

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: (organ donor eligibility) Eligible for live kidney donation At least 18 years of age An ABO blood type compatible with the organ recipient Willing and able to provide a blood sample for The ONE Study IM (Immune Monitoring) Subproject Willing to provide personal and medical/biological data for the trial analysis Eligible to give blood for B cell source prior to organ donation Signed and dated written informed consent*. *For subjects unable to read and/or write, oral informed consent observed by an independent witness is acceptable if the subject has fully understood oral information given by the Investigator. The witness should sign the consent form on behalf of the subject. In signing the donor information sheet/informed consent form (DIS/ICF), organ donors agree to undergo phlebotomy to provide donor B cells for the production of darTreg, to provide a blood sample for the IM Subproject, and permit access to their medical records for the collection of specified demographic and medical/biological data for the trial. Organ Recipient eligibility: A prospective kidney transplant recipient is eligible for enrollment into the study if all of the following inclusion criteria apply: Chronic renal insufficiency necessitating kidney transplantation and approved to receive a primary kidney allograft from a living donor At least 18 years of age Able to commence the immunosuppressive regimen at the protocol-specified time point Willing and able to participate in The ONE Study IM and HEC (Health-Economics Subproject) subprojects Adequate venous access to support leukapheresis Signed and dated written informed consent*. For patients unable to read and/or write, oral informed consent observed by an independent witness is acceptable if the patient has fully understood oral information given by the Investigator. The witness should sign the consent form on behalf of the patient. Exclusion Criteria: (organ donor) If a prospective donor fulfills any of the following criteria, they are ineligible for the trial: Genetically identical to the prospective organ recipient at the HLA (human leukocyte antigen) loci (0-0-0 mismatch) CMV-positive and donating to a CMV-negative recipient Exposure to any investigational agents at the time of kidney donation, or within 28 days prior to kidney donation Any form of substance abuse, psychiatric disorder, or other condition that, in the opinion of the Investigator, may invalidate communication with the Investigator and/or designated study personnel Subjects unable to freely give their informed consent (e.g. individuals under legal guardianship). Exclusion criteria (organ recipient) Patient has previously received any tissue or organ transplant other than the planned kidney graft Known contraindication to the protocol-specified treatments / medications Genetically identical to the prospective organ donor at the HLA (human leukocyte antigen) loci (0-0-0 mismatch) PRA (panel reactive antibody) grade > 40% within 6 months prior to enrollment Previous treatment with any desensitization procedure (with or without IVIg) Concomitant malignancy or history of malignancy within 5 years prior to planned study entry (excluding successfully-treated non-metastatic basal/squamous cell carcinoma of the skin) Evidence of significant local or systemic infection HIV-positive, EBV-negative or suffering chronic viral hepatitis CMV-negative and receiving a kidney from a CMV-positive donor Significant liver disease, defined as persistently elevated AST (aspartate aminotransferase) and/or ALT(alanine aminotransferase) levels > 2 x ULN (Upper Limit of Normal range) Malignant or pre-malignant hematological conditions Neutrophils < 1000/μl ; platelets < 100,000/μl Regulatory T cells present in peripheral blood at <30/µL Any uncontrolled medical condition or concurrent disease that could interfere with the study objectives Any condition which, in the judgment of the Investigator, would place the subject at undue risk Ongoing treatment with systemic immunosuppressive drugs at study entry Patients who have received anti-T cell therapy within 30 days prior to transplant surgery Participation in another clinical trial during the study or within 28 days prior to planned study entry Female patients of reproductive potential with a positive pregnancy test at enrollment Female patients who are breast-feeding All female patients of reproductive potential* UNLESS the patient is willing to use an acceptable birth control for the duration of the study unless the patient chooses abstinence (she chooses to avoid heterosexual intercourse completely) (See Table 2. Acceptable Contraception Methods for Females of Reproductive Potential) Male patients unwilling to use a reliable and effective form of contraception for 3 months after darTreg dosing Psychological, familial, sociological or geographical factors potentially hampering compliance with the study protocol and follow-up visit schedule Any form of substance abuse, psychiatric disorder, or other condition that, in the opinion of the Investigator, may invalidate communication with the Investigator and/or designated study personnel Patients unable to freely give their informed consent (e.g. individuals under legal guardianship). Females of reproductive potential include girls who have entered puberty and all women who have a uterus and have not passed through menopause. Menopause is the permanent end of menstruation and fertility. Menopause should be clinically confirmed by a patient's healthcare practitioner. Some commonly used diagnostic criteria include 1) 12 months of spontaneous amenorrhea (not amenorrhea induced by a medical condition or medical therapy) or 2) postsurgical from a bilateral oophorectomy. Exclusion Criteria B (organ recipient) Below are exclusion criteria to be assessed post-transplantation and prior to darTreg infusion. Subjects who meet any of these criteria should not receive a darTreg-infusion: Unacceptable darTreg product. Delayed graft function (requiring dialysis post-transplant). Requiring oxygen supplementation to keep capillary oxygen saturations >95%. Any medical or technical complications (e.g. myocardial infarction, urine leak, wound dehiscence, pneumonia, ongoing fevers, etc.) that in the judgment of the investigators or responsible clinician would put the subject at undue risk.-
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Sang-Mo Kang, M.D.
Organizational Affiliation
University of California, San Francisco
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of California San Francisco - Transplant Department. 513 Parnassus Ave HSE 504
City
San Francisco
State/Province
California
ZIP/Postal Code
94143
Country
United States

12. IPD Sharing Statement

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Donor-Alloantigen-Reactive Regulatory T Cell (darTreg) Therapy in Renal Transplantation (The ONE Study )

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