Clinical trial NCT04114188: Tacrolimus After rATG and Infliximab Induction Immunosuppression (RIMINI)
Official title: Tacrolimus After rATG and Infliximab Induction Immunosuppression (RIMINI)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Renal Transplant Rejection
Keywords: transplant medicine
Lead sponsor: Charite University, Berlin, Germany
Sponsor class: OTHER
Collaborators: name: Institut Klinické a Experimentální Medicíny
First posted: 2019-10-03
Enrollment: 68
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: This is a confidence-interval-estimation based early phase design, aiming to estimate a plausible range of the population treatment effect which is not bound to a formal hypothesis.
Primary purpose: TREATMENT

Brief summary: International multicenter open-label single-arm confidence-interval-estimation based Phase II clinical trial, aiming to estimate a plausible range of the proportion of patients experiencing efficacy failure in the population, to provide evidence for efficacy and safety of the induction regimen with rATG and infliximab and a go/no go rule for further clinical development.

Detailed description: A total of 75 patients will receive the proposed induction regimen, with expected 68 completers accounting for drop-outs and non-compliances with the protocol. If up to 27 out of the 68 completers experience efficacy failure, a progression into a larger trial will be considered justifiable. If the number of patients experiencing efficacy failure is between 28 and 34 out of 68, the merits of a larger non-inferiority design will be considered depending on the risk/benefit assessment. If more than 34 out of the 68 completers experience efficacy failure, a progression into a larger trial would be considered unjustifiable. 1st kidney transplant recipients (low risk: PRA/cPRA \< 20%, no DSA) will receive short rATG induction (2x1.5 mg/kg) given perioperatively and on first postoperative day. All patients will receive one shot Infliximab mAb at day 2. Since POD1, maintenance IS consists of Tac and tapered steroids therapy. All patients will be followed up for one year.

At the POD 0 the first rATG dose (1.5mg/kg) will be given according to the local practice and Methyprednisolon 500mg will be given before reperfusion. At the POD 1 patients will receive methylprednisolon 500mg i.v. followed by second rATG dose (1.5mg/kg). Infliximab 5mg/kg b.w. will be given in slow infusion on POD2. Tacrolimus will be given the first dose before surgery at dose 0.1 mg/kg and next from POD1 at 0.2mg/kg/day and doses adjusted according to blood trough levels (10-15 ng/mL, POD1-POD13, 5-8ng/mL POD 14-90, 4-6ng/mL POD \>90. Prednison (or appropriate dose of methylprednisolone) will be initiated POD 2 at a dose of 20mg/day and slowly tapered down to 5 mg at the POD 7 (POD2: 20mg, POD3: 15mg, POD4-5: 10mg, POD6-7: 7,5mg, \> POD7: 5mg).

Eligibility criteria: Inclusion Criteria:

1. Primary deceased-donor or living-donor kidney transplantation XML File Identifier: CJub4EkHas0e/mXDp2mGyZzEe9E= Page 22/33
2. Men and women (recipient) age \>18 years and \<70 years
3. Panel reactive antibody frequency/ calculated panel reactive antibody frequency (peak PRA/cPRA) \<20%
4. Written informed consent
5. Diagnosis of end stage renal disease
6. Women of Childbearing Potential (WOCBP) must be using a highly effective method of contraception (Pearl-Index \< 1) to avoid pregnancy throughout the study in such a manner that the risk of pregnancy is minimized. WOCBP include any female who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or is not postmenopausal \[defined as amenorrhea ≥ 12 consecutive months; or women on hormone replacement therapy (HRT) with documented serum follicle stimulating hormone (FSH) level \> 35 mIU/mL\]. WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 hours prior to the start of clinical trial. Male participants with pregnant or nonpregnant WOCBP partner must use condoms.

Exclusion Criteria:

1. Previous transplantation
2. Combined kidney transplantation with other organ
3. Subjects receiving an allograft from a donor older than 65 years with elevated serum creatinine levels and/or treated diabetes.
4. Immunosuppressive therapy up to 6 months before transplantation
5. Planned induction therapy with depletion agents
6. EBV seronegativity
7. HIV positivity
8. Leukopenia \< 3000 cells per microliter, thrombocytopenia \< 100 000 cells per microliter
9. Biological therapy history with ATG, OKT3, anti TNF agents
10. Tuberculosis history
11. Cancer history (skin non-melanoma cancer excluded)
12. Anti HCV positivity, HBsAg positivity or HBV DNA positivity
13. Detectable donor specific antibodies (DSA) by solid phase assay (Luminex®)
14. Subjects with a known hypersensibility to any of the drugs used in this protocol
15. Subjects who have used any investigational drug within 30 days prior to enrolment in this clinical trial
16. WOCBP who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period, women who are pregnant or breastfeeding or women with a positive pregnancy test on enrolment
17. Subjects who are legally detained in an official institution
18. All contraindications against study medication (including auxiliary substances)
19. Interactions with study medication
20. Current treatment with one of the following substances:

    cyclosporine, tacrolimus, mycophenolate mofetil, azathioprine, rituximab, prednisone
21. Patients unwilling to consent to saving and propagation of pseudonymized medical data and/or biological samples for study reasons
22. Chronic heart failure (NYHA III, IV) at transplantation
23. Participation in other clinical trials (pharmaceutical trials)
24. persons dependent of the sponsor, investigator or investigative site
25. positive Quantiferon test (for TBC)
26. live vaccine treatment 30 days prior to enrolment in this clinical trial

Primary outcomes:
measure: Composite endpoint of efficacy failure [(treated biopsy-proven acute rejection, graft loss, death, or loss to follow-up) and renal function (estimated glomerular filtration rate)] of the induction regimen
timeFrame: 12 months post transplantation
Secondary outcomes:
measure: Prevalence of biomarker signatures at 6, 12 months of follow-up.
timeFrame: 6, 12 months of follow-up
measure: Incidence of death by 12 months post-transplantation
timeFrame: 12 months post-transplantation
measure: Incidence of graft loss by 12 months post-transplantation
timeFrame: 12 months post-transplantation
measure: Incidence of metabolic and cardiovascular co-morbidity by 12 months post-transplantation
timeFrame: 12 months post-transplantation
measure: Proportion of subjects who remain on tacrolimus/steroids therapy at 12 months post-transplantation
timeFrame: 12 months post-transplantation
measure: Incidence of acute and chronic lesions assessed by the Banff 07 score in protocol biopsy at 12months post-transplantation
timeFrame: 12 months post-transplantation
measure: Incidence of discontinuation of study treatment
timeFrame: 12 month
measure: Donor specific antibody (DSA) at 12M
timeFrame: 12 months post-transplantation
measure: Overall safety of tacrolimus/steroids therapy immunosuppressive regimen measured by the occurrence of viral and bacterial infections, malignancies and autoimmunity.
timeFrame: 12 month
measure: Health-related quality of life using SF-36v2 questionnaires at baseline (pre Transplantation), Month 1, Month 3, Month 6, and Month 12
timeFrame: baseline (pre transplantation), Month 1, Month 3, Month 6, and Month12
measure: Assessment of patient-specific resource consumption using a trial specific questionnaire at initial discharge, Month 3, Month 6, Month 12, and in cases of repeated hospitalization
timeFrame: initial discharge, Month 3, Month 6, Month 12, and in cases of repeated hospitalization
measure: Health-related quality of life using EQ5D-5L questionnaires at baseline (pre Transplantation), Month 1, Month 3, Month 6, and Month 12
timeFrame: baseline (pre transplantation), Month 1, Month 3, Month 6, and Month12
Other outcomes:
Locations:
city: Berlin
country: Germany
facility: Charité University Medicine Berlin
Study officials:
affiliation: Charité-University Medicine (Berlin, Germany)
name: Reinke Reinke, PhD, MD
role: STUDY_CHAIR
affiliation: Institute for Clinical and Experimental Medicine
name: Ondrej Viklicky, PhD, MD
role: PRINCIPAL_INVESTIGATOR
References: