TocIlizumab in Chronic Antibody-mediated Rejection in Kidney Transplant Recipients (INTERCEPT)

A Randomized Controlled Open-label Multi-center Study to Assess the Efficacy of TCZ in Treatment of Chronic Active Antibody-mediated Rejection in Kidney Transplant Recipients

This multi-center study is an investigator-driven randomized controlled parallel group open-label clinical trial designed to evaluate the efficacy of addition of anti-IL-6 antibody tocilizumab (TCZ) to the standard of care (SOC) treatment as compared to the SOC alone in reducing the decline of graft function in kidney transplant recipients with chronic antibody-mediated rejection (cAMR). A total of 50 recipients will be allocated to receive either TCZ (n=25) added to the standard of care (SOC) or SOC alone (n=25) for a period of 24 months. Patients will be followed for an additional 12 months. Protocol kidney graft biopsies will be performed at baseline, at 12 and 24 months. The primary outcome is the mean rate of change in graft function as assessed by estimated glomerular filtration rate (eGFR) slope from baseline to 24 months after start of treatment.

Study Overview

• Status: Recruiting
• Conditions: Antibody-mediated Rejection
• Intervention / Treatment: Drug: Tocilizumab

• Study Type: Interventional
• Enrollment (Anticipated): 50
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Seema Baid-Agrawal, MD; Phone Number: +4631-342 10 00; Email: seema.baid-agrawal@vgregion.se
• Study Contact Backup: Name: Marie Felldin, MD, PhD; Phone Number: +4631-342 10 00; Email: marie.felldin@surgery.gu.se

Study Locations

• Sweden
  • Stockholm, Sweden, SE-141 86
    • Not yet recruiting
    • Karolinksa University Hospital
    • Contact: Lars Wennberg, MD, PhD; Phone Number: +46 8 5858 2554; Email: lars.wennberg@sll.se
    • Sub-Investigator: Dan-Mikael Hauzenberger, MD, PhD
    • Sub-Investigator: Annika Wernerson, MD,PhD
  • Uppsala, Sweden, 751 85
    • Not yet recruiting
    • Uppsala University Hospital
    • Contact: Tomas Lorant, MD, PhD; Phone Number: +46 18 611 7080; Email: Tomas.Lorant@surgsci.uu.se
    • Contact: Bengt Felldström, MD, PhD; Email: bengt.fellstrom@medsci.uu.se
  • Vastra Gotaland Regioin
    • Gothenburg, Vastra Gotaland Regioin, Sweden
      • Recruiting
      • Transplant Center, Sahlgrenska University Hospital
      • Contact: Seema Baid-Agrawal, MD; Phone Number: 031-342 10 00; Email: seema.baid-agrawal@vgregion.se
      • Contact: Marie Felldin, MD, PhD; Phone Number: 031-342 10 00; Email: marie.felldin@surgery.gu.se
      • Sub-Investigator: Jana Ekberg, MD
      • Sub-Investigator: Lars Mjornstedt, MD, PhD
      • Sub-Investigator: Per Lindnér, MD, PhD
      • Sub-Investigator: Marie Felldin, MD, PhD
      • Sub-Investigator: Lillian Streichart, MD
      • Sub-Investigator: Annette Lennerling, RN, PhD
      • Sub-Investigator: Verena Bröcker, MD
      • Sub-Investigator: Johan Mölne, MD, PhD
      • Sub-Investigator: Jan Holgersson, MD, PhD
      • Sub-Investigator: Jenny Nyström, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 98 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. The subject has given their written informed consent to participate in the study
2. Recipient of living donor or deceased donor kidney transplant
3. Age ≥18 years
4. At least 12 months post-transplantation at randomization
5. Biopsy-proven diagnosis of cAMR according to the Banff 2017 criteria in index biopsy
6. eGFR ≥20 ml/min/1.73 m2
7. Epstein-Barr Virus (EBV) IgG-positive

8. For female participants of childbearing potential:

   • use of adequate contraception and a negative pregnancy test

9. Subject known to have COVID-19 previously must meet all of the following conditions:

   • Asymptomatic for at least 1 month before the start of screening
   • Re-established on background immunosuppressants for at least 1 month prior to the randomization

Exclusion Criteria:

1. Inability to tolerate any of the SOC treatment- tacrolimus, mycophenolate acid (MPA) or prednisolone
2. Recipient of multi-organ transplants
3. De novo or recurrent renal disease that, in the Investigator's opinion, could adversely influence the current allograft
4. Active viral infections such as BK virus (BKV), cytomegalovirus (CMV), EBV, COVID-19, hepatitis C virus (HCV) or hepatitis B virus (HBV) infections based on polymerase chain reaction (PCR) testing
5. Ongoing serious infections as per Investigator's opinion
6. History of recurrent infections requiring hospitalization
7. History of tuberculosis (TB)
8. Active TB or latent TB (positive QuantiFERON-TB-Gold test, Chest X-ray)
9. Abnormal liver function tests alanine transaminase (ALT), aspartate transaminase (AST), bilirubin > 1.5 x upper limit of normal)
10. Other significant liver disease as per Investigator's opinion
11. Neutropenia (<2 x109/L) or thrombocytopenia (<100 x109/L)
12. Signs of post-transplant lymphoproliferative disorder
13. Signs of malignancy. Exceptions are basal cell carcinoma/squamous cell carcinoma or non-malignant melanoma
14. History of malignancy, unless subject has been considered to have fully recovered from malignancy since > 2 years, without any signs of relapse
15. History of diverticulitis, inflammatory bowel disease or gastrointestinal perforation
16. Active alcohol or illicit substance abuse
17. Serious medical or psychiatric illness likely to interfere with participation in the study as per Investigator's opinion
18. Mental inability, reluctance or language difficulties that result in difficulty understanding the meaning of study participation
19. Woman of childbearing potential who is unwilling/unable to use an acceptable method to avoid pregnancy for the entire study period and for up to 8 weeks after the last dose of study drug
20. Woman with a positive pregnancy test or who is pregnant or breastfeeding
21. Current or recent (within last 3 months) participation in another clinical drug trial

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Arm A: Standard of care (SOC) + tocilizumab (TCZ); SOC, as below + TCZ (162 mg every week, subcuataneous administration)	Drug: Tocilizumab; Tocilizumab is a recombinant humanized monoclonal antibody directed against the human interleukin-6 (IL-6) receptor; Other Names: RoActemra
No Intervention: Arm B: SOC; Tacrolimus (target concentration 6 ±1 µg/L) + MPA (1.5-2 g/day as tolerated) + prednisolone (not less than 5 mg/day), all oral administration

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from baseline in eGFR at 24 months	Comparison of eGFR decline (eGFR slope) from baseline at 24 months after start of treatment in the two arms. The eGFR will be assessed by measured creatinine values using MDRD formula in mL/min/1.73m^2. MDRD formula is based on age, sex, ethnicity, and serum creatinine (in mg/dl) and eGFR values are calculated as follows: GFR in mL/min per 1.73 m^2 = 175 x Serum Cr^1.154 x age^-0.203 x 1.212 (if patient is black) x 0.742 (if female).	Baseline and 24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Donor-specific anti-HLA antibodies (DSA)	Change in DSA from baseline based on luminex assessments every 12 months	baseline and up to 36 months
Incidence of adverse and serious events related to TCZ treatment	Assessments of incidence of any side effects including infectious complications associated with TCZ therapy	up to 25 months
Histologic changes in protocol biopsy	Histologic changes at 12 and 24 months will be compared with those in the baseline biopsies. If the criteria for cAMR are no longer fulfilled in the follow-up biopsies, response to therapy is assumed. The response will be assessed as a yes/no categorical variable. In all biopsies, which still meet the required criteria for cAMR, means of individual Banff lesion scores will be compared between the baseline biopsy and the 12- and 24-months biopsies	baseline and up to 24 months
Changes in proteinuria	Assessed by urine albumin creatinine ratio (UACR) at baseline and every 12 months	baseline and up to 36 months
Renal function assessed by measured GFR (mGFR)	Changes from baseline in renal function as assessed by mGFR using iohexol clearance	baseline and up to 36 months
Renal function assessed by eGFR	Changes from baseline in renal function at 12 and 36 months after start of treatment, as assessed by eGFR (CKD-EPI)	baseline and up to 36 months
Patient survival	Incidence of patient survival at 12, 24 and 36 months after start of treatment	up to 36 months
Death-censored graft survival	Incidence of death-censored graft survival at 12, 24 and 36 months after start of treatment	up to 36 months
Possible change in experienced transplant-specific well-being and symptom burden	Assessed using a validated self-reported questionnaires at baseline and every 12 months	upto 36 months
Possible change in experienced perceived threat of the risk of graft rejection	Assessed using a validated self-reported questionnaires at baseline and every 12 months	upto 36 months
Possible change in adherence to immunosuppressive medications	Assessed using a validated self-reported questionnaires at baseline and every 12 months	upto 36 months

Collaborators and Investigators

• Sponsor: Vastra Gotaland Region
• Collaborators: Karolinska University Hospital; The Swedish Research Council; Uppsala University Hospital
• Investigators: Principal Investigator: Seema Baid-Agrawal, MD, Transplant Center, Sahlgrenska University Hospital, Gothenburg, Sweden; Principal Investigator: Lars Wennberg, MD, PhD, Transplant Center, Karolinska University Hospital, Stockholm, Sweden; Principal Investigator: Tomas Lorant, MD, PhD, Transplant Center, Uppsala University Hospital, Uppsala, Sweden

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2022
• Primary Completion (Anticipated): October 1, 2025
• Study Completion (Anticipated): December 1, 2026

Study Registration Dates

• First Submitted: September 3, 2020
• First Submitted That Met QC Criteria: September 22, 2020
• First Posted (Actual): September 24, 2020

Study Record Updates

• Last Update Posted (Actual): February 17, 2022
• Last Update Submitted That Met QC Criteria: February 16, 2022
• Last Verified: February 1, 2022

More Information

Terms related to this study

• Keywords: Adherence; Chronic rejection; Kidney transplant; Antibody-mediated rejection; Graft function; Donor specific antibodies (DSA); Transplant-specific well-being
• Other Study ID Numbers: 2019-004302-10

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No