GAMECHANgER-1 trial: Suppressor cells for dialysis patients to help get a kidney transplant
- Conditions
- End-stage renal failure patients awaiting transplantation with antibodies against human leukocyte antigensUrological and Genital Diseases
- Registration Number
- ISRCTN14582152
- Lead Sponsor
- King's College London
- Brief Summary
2023 Protocol article in https://pubmed.ncbi.nlm.nih.gov/37118685/ (added 02/05/2023)
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Ongoing
- Sex
- All
- Target Recruitment
- 56
Current participant inclusion criteria as of 23/02/2022:
Part 1:
1. Adult (aged =18 years) dialysis patients on the renal transplant/deceased donor waiting list with HLA Ab and a CRF =50%
2. HLA Ab specificities corresponding to available PURE HLA protein
3. Able to give written informed consent
4. Female participants of childbearing potential* and male participants whose partner is of childbearing potential must be willing to consent that they or their partner use highly effective** contraception during Part 2 of the trial
Part 2:
Additional inclusion criteria will be confirmed:
1. Dual Fluorospot assay result to PURE HLA proteins that indicates anti-donor reactivity without evidence of suppression by CD25+ cells – the assay will most likely have been performed as part of part 1 assessment but may have been performed as part of a separate observational study, within the time frame of this study
2. Female participants of childbearing potential* and male participants whose partner is of childbearing potential must be willing to reconfirm that they or their partner use highly effective** contraception during Part 2 of the trial
*Female patients of childbearing potential are female patients who have experienced menarche and who are not post-menopausal or permanently sterilised (eg. By tubal occlusion, hysterectomny, bilateral salpingectomy). ‘Postmenopausal’ is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. However in the absence of 12 months of amenorrhea, confirmation with more than one FSH measurement is required.
**Highly effective methods of birth control are those with a failure rate <1% per year when employed consistently and correctly (e.g. hormonal contraception, some intrauterine devices, vasectomised partner, total abstinence). Hormonal contraception must be associated with inhibition of ovulation. Abstinence will be evaluated in the context of the usual lifestyle of the recipient. Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhoea method (LAM) are not acceptable methods of contraception. A female participant with a vasectomised partner must confirm that the vasectomised partner is the only sexual partner and that surgical success of the vasectomy has been medically confirmed.
All females of childbearing potential and males whose partner is of childbearing potential must be willing to use such methods if going into Part 2 and continue to use them to the end of phase 2 follow-up.
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Previous inclusion criteria as of 28/07/2021:
Part 1:
1. Adult (=18yrs) dialysis patients on the renal transplant/deceased donor waiting list with HLA Ab and a CRF =50%
2. HLA Ab specificities corresponding to available PURE HLA protein
3. Able to give written informed consent
4. Female participants of childbearing potential* and male participants whose partner is of childbearing potential must be willing to consent that they or their partner use highly effective** contraception during Part 2 of the trial
Part 2:
Additional inclusion criteria will be confirmed:
1. Dual fluorospot assay result to PURE HLA proteins that indicates anti-donor reactivity without evidence of suppression by CD25+ cells – the assa
Current participant exclusion criteria as of 23/02/2022:
Part 1
1. Living donor kidney transplant planned
2. Listed as a recipient of multi-organ transplants (i.e. combined kidney and pancreas)
3. Known HIV+ or previous HCV or HBV. If no HIV, HCV, or HBV tests within 5 years, these will be performed post-consent
4. Patient involved in other clinical trials of investigational medicinal products.
5. Active infection or history of recurrent infection. Recurrent infection defined as more than 2 confirmed infections requiring either antibiotics, antivirals, antifungals, or hospitalisation in the 6 months prior to consent.
6. Female patients of childbearing potential with a positive pregnancy test at enrolment
7. Female patients who are breastfeeding.
8. Hypersensitivity to IMP or to any of the excipients.
9. Known contraindication to the protocol-specified treatments or procedures
10. Severe liver impairment, defined as =Grade 3 or severely elevated ALT, AST, or total bilirubin, on bloods done within the last 3 months
11. ECG abnormalities suggesting active myocardial ischaemia or (potentially) malignant ventricular arrhythmia: ECG to have been performed within the last 3 months.
12. Patients, who in the opinion of the PI, have a medical condition, or other relevant psychological, familial or social factor that may jeopardise their health, compliance, or influence the trial integrity in any way.
Part 2
The following exclusion criteria will be re-checked at a screening visit prior to the patient entering Part 2:
1. Living donor kidney transplant planned
2. Patient involved in other clinical trials of investigational medicinal products.
3. Active infection or history of recurrent infection. Recurrent infection defined as more than 2 confirmed infections requiring either antibiotics, antivirals, antifungals or hospitalisation in 6 months prior to entering into Part 2.
4. Female patients of childbearing potential with a positive pregnancy test in the week prior to leukapheresis
5. Female patients who are breastfeeding.
6. Hypersensitivity to IMP or to any of the excipients.
7. Known contraindication to the protocol-specified treatments or procedures
8. Severe liver impairment, defined as =Grade 3 or severely elevated ALT, AST, or total bilirubin on bloods done within the last 3 months
9. ECG abnormalities suggesting active myocardial ischaemia or (potentially) malignant ventricular arrhythmia: ECG to have been performed within the last 3 months.
10. Patients, who in the opinion of the PI, have a medical condition, or other relevant psychological, familial, or social factor that may jeopardise their health, compliance, or influence the trial integrity in any way.
_____
Previous exclusion criteria as of 28/07/2021:
Part 1
1. Living donor kidney transplant planned
2. Listed as recipient of multi-organ transplants (i.e. combined kidney and pancreas)
3. Known HIV+ or previous HCV or HBV. If no HIV, HCV or HBV tests within 5 years, these will be performed post-consent
4. Patient involved in other clinical trials of investigational medicinal products.
5. Active infection or history of recurrent infection or allergy to DMSO. Recurrent infection defined as more than 2 confirmed infections requiring either antibiotics, antivirals, antifungals or hospitalisation in 6 months prior to consent.
6. Female patients of childbearing potential with a positive pregnancy test at enrolment
7. Female patients who are breastfeeding
Pa
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method The proportion of Treg-treated patients that show suppressed memory responses to specific purified HLA (chosen to match HLA Ab profiles), measured by IL-17/IFNgamma dual fluorospot, for 2 months post-treatment, in comparison to that seen in the baseline immunomonitoring group prior to intervention. Production of only one cytokine (positive at enrolment) needs to be suppressed. This will be assessed 2 months after Treg treatment in all patients in Part 2.
- Secondary Outcome Measures
Name Time Method 1. The proportion of sensitised dialysis patients with unregulated T & B cell anti-HLA responses<br>assessed using IFN/IL-17 dual colour Fluorospot assays at end of Part 1.<br>2. The duration of suppression of HLA-specific responses by Tregs assessed using IFN/IL-17 dual colour Fluorospot assays after 12 months post-treatment.<br>3. The adverse events associated with Treg therapy through reporting any untoward medical occurrence by all participants of the trial.<br><br>Secondary exploratory mechanistic endpoints:<br>4. Changes in Treg number and phenotype comparing baseline to post-Treg treatment assessed after 12 months post-treatment follow-up completed for each patient.<br>5. The changes in HLA Ab profiles measured by Luminex assessed after 12 months post-treatment follow-up completed for each patient.