Antibody-Mediated Rejection (AMR)
Conditions
Keywords
Drug Therapy, TAK-079
Brief summary
Antibody-mediated rejection (AMR) is a major cause of worsening kidney function after a kidney transplant (kidney allograft dysfunction) and can lead to kidney failure. AMR happens when the kidney recipient's immune system makes antibodies that attack the donor kidney. Antibodies are proteins made by the immune system to recognize foreign cells. Over time, this attack can damage kidney tissue and cause the transplant to fail. Because AMR can be serious, there is a need for treatments that are safe, work well, and are supported by good evidence. The main aim of this study is to find out how safe mezagitamab is and how well adults with AMR tolerate it compared with placebo. A placebo looks like medicine but has no active ingredients. The study will also look at whether mezagitamab helps to control inflammation in the transplanted kidney and helps keep kidney function stable, compared with placebo. Participants will be placed by chance in 1 of the 3 treatment groups in equal numbers. Two groups will receive mezagitamab in two different doses. One group will receive placebo. This means that out of every 3 participants, 2 will receive mezagitamab and 1 will receive placebo. During the study, participants will visit their study clinic several times.
Interventions
DRUGMezagitamab
Mezagitamab subcutaneous (SC) injection.
DRUGPlacebo
Mezagitamab-matching placebo SC injection.
Sponsors
Takeda
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
Key inclusion criteria: 1. The participant aged 18 to 80 years. 2. The participant must have a biopsy-confirmed diagnosis of active or chronic active late AMR (defined as greater than \[\>\] 6 month after kidney transplant) without concurrent definitive TCMR (Grade 1a and above) as defined by the 2022 Banff classification. 3. Biopsy within 30 days prior to screening, or performed during screening period within protocol-defined window. 4. If the participant has received treatment for rejection, then the repeat biopsy and donor specific antibody (DSA) testing must have been performed at least 6 weeks after stopping the treatment. 5. The participant with either human leukocyte antigen (HLA) class I and/or II DSA. 6. eGFR \> 30 milliliters per minute per 1.73 square meters (mL/min/1.73m\^2). Key
Exclusion criteria
1. The participant has blood type A, B, AB, or O (ABO) incompatible transplant. 2. The participant has a history of multiple organ transplants, including en bloc and dual kidney transplants. 3. Participant likely to require renal replacement therapy within the subsequent 30 days. 4. Participants who have received an anti-cluster of differentiation 38 (CD38) therapy in the last 1 year or have past history of failing to achieve AMR resolution despite treatment with an anti-CD38 therapy. 5. The participant has received any previous treatment with other immunosuppressant or immunomodulatory therapy: a) Within 6 months of signing the informed consent form (ICF) as listed below: * Complement system inhibitors (such as, eculizumab). * Proteasome inhibitors (such as, bortezomib). * Interleukin-6 (IL-6)/IL-6R antibody (such as, tocilizumab). * Anti-cluster of differentiation 20 (CD20) antibody (such as, rituximab). b) Within 6 weeks of signing the ICF as listed below: * Intravenous immunoglobulin (IVIG) or subcutaneous immunoglobulin (SCIG) or plasmapheresis 6. The participant has active infection with hepatitis B virus, hepatitis C virus (HCV), or human immunodeficiency virus (HIV). 7. Participant with serious infection within 2 weeks or with opportunistic infection within 2 months prior to signing ICF. Participant with active or untreated tuberculosis, or those with high suspicion of tuberculosis are also excluded. 8. History of malignancy (including myelodysplastic syndrome) within 5 years of signing the ICF, except for adequately treated non-melanoma skin cancer, superficial bladder cancer, and curatively treated cervical carcinoma-in-situ. Key Note: Other protocol specified inclusion and
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Arms A, B, and C: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Up to Week 70 | An adverse event (AE) is any untoward medical occurrence in a clinical trial participant, temporally associated with the use of the trial intervention, whether or not the occurrence is considered related to the trial intervention. An AE can be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of the trial intervention. TEAEs are defined as AEs with start dates at the time of or following the first exposure to investigational medicinal product (IMP). |
| Arms A, B, and C: Number of Participants With Related TEAEs | Up to Week 70 | A related AE is an AE that is considered related to the IMP. Related TEAEs are defined as related AEs with start dates at the time of or following the first exposure to IMP. |
| Arms A, B, and C: Number of Participants With Serious Adverse Events (SAEs) | Up to Week 70 | An SAE is any untoward medical occurrence that results in death, is life threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity or is a congenital anomaly/birth defect. |
| Arms A, B, and C: Number of Participants With AEs of Special Interest | Up to Week 70 | AEs of special interest are AEs that are considered specific to the IMP. |
| Arms A, B, and C: Number of Participants With AE Leading to Treatment Discontinuation | Up to Week 70 | — |
| Arms A, B, and C: Number of Participants With Clinically Significant Abnormal Laboratory Test Results and Vital Signs | Up to Week 70 | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Arms A, B, and C: Percentage of Participants With Achievement of Biopsy-Proven Histologic Resolution of AMR Activity at Weeks 24 and 48 | Weeks 24 and 48 | Achievement of biopsy-proven histological resolution of AMR activity will be assessed by the 2022 Banff classification criteria. The Banff 2022 Classification provides a standardized framework for evaluating kidney transplant biopsies using lesion scoring. |
| Arms A, B, and C: Microvascular Inflammation (MVI) Score in Biopsy Samples at Weeks 24 and 48 | Weeks 24 and 48 | MVI is an important marker of allograft loss and is defined as the sum of glomerulitis and peritubular capillaritis scores (g+ptc) on kidney histology. |
| Arms A, B, and C: Percentage of Participants Who Achieve a MVI Score of 0 at Weeks 24 and 48 | Weeks 24 and 48 | — |
| Arms A, B, and C: Change From Baseline in MVI score at Weeks 24 and 48 | Baseline, Weeks 24 and 48 | — |
| Arms A, B, and C: Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at Weeks 24, 48 and 70 | Baseline, Weeks 24, 48 and 70 | eGFR is a measure of kidney function calculated from serum creatinine using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. |
| Arms A, B, and C: Change From Baseline in Donor-Derived Cell-Free DNA (dd-cfDNA) at Weeks 24, 48 and 70 | Baseline, Weeks 24, 48 and 70 | dd-cfDNA are DNA fragments released from injured donor cells. It serves as a noninvasive, quantitative method that reflects allograft injury and is associated with AMR activity in kidney transplant recipients. |
| Arms A, B, and C: Change From Baseline in Urine Protein Creatinine Ratio (UPCR) at Weeks 24, 48 and 70 | Baseline, Weeks 24, 48 and 70 | UPCR is a measure of protein excretion calculated from a urine sample, as the ratio of urine protein to creatinine, and used to assess kidney function. |
| Arm B: Percentage of Participants With Achievement of Biopsy-Proven Histologic Resolution of AMR Activity at Week 70 | Week 70 | — |
| Arm B: MVI Score in Biopsy Samples at Week 70 | Week 70 | — |
| Arm B: Percentage of Participants Who Achieve a MVI Score of 0 at Week 70 | Week 70 | — |
| Arm B: Change From Baseline in MVI score at Week 70 | Week 70 | — |
| Arms A, B, and C: Percentage of Participants With T-Cell Mediated Rejection (TCMR) by Biopsy at Weeks 24 and 48 | Weeks 24 and 48 | — |
| Arm B: Percentage of Participants With TCMR by Biopsy at Week 70 | Week 70 | — |
| Arms A and B: Serum Concentration of Mezagitamab | Pre-dose and at multiple time points post-dose up to Week 70 | — |
| Arms A, B and C: Number of Participants With Anti-Drug Antibody | Pre-dose and at multiple time points post-dose up to Week 70 | — |
| Arms A, B and C: Number of Participants With Neutralizing Antibody | Pre-dose and at multiple time points post-dose up to Week 70 | — |
Contacts
CONTACTTakeda Contact
STUDY_DIRECTORStudy Director
Takeda
Outcome results
None listed