Acute Interstitial Nephritis, Acute Kidney Injury
Conditions
Keywords
acute kidney injury, acute interstitial nephritis, checkpoint nephritis
Brief summary
This is a multi-center, 1:1 randomized pilot study examining the efficacy and safety of infliximab 5mg/kg x 1 paired with 2 weeks of prednisone 1mg/kg per day for 2 weeks versus standard-of-care glucocorticoid therapy (prednisone 1mg/kg/day x 2 weeks followed by a 4 week taper) on the rate and speed of renal recovery from immune checkpoint inhibitor-associated AKI.
Detailed description
Data to guide treatment of immune-checkpoint inhibitor associated acute kidney injury (ICI-AKI) are limited, with current guidelines recommending 4-8 weeks of glucocorticoids (GCs). However, GCs have numerous side effects and can attenuate the anti-tumor response induced by ICI therapy, commonly leads to adverse events, and can delay anti-cancer therapy. Infliximab is an FDA-approved monoclonal antibody that inhibits tumor necrosis factor-α and is used to treat a variety of autoimmune diseases, as well as steroid-refractory extrarenal immune-related adverse events. A strong biologic rationale exists for its use in patients with ICI-AKI, and case reports suggest some benefit in steroid-refractory ICI-AKI; however, there are no randomized clinical trial (RCT) data to guide the upfront use of infliximab in ICI-AKI. This is a multi-center, 1:1 randomized pilot study examining the efficacy of infliximab in increasing the rate, speed, and durability of renal recovery when compared to standard of care prednisone which is current standard of care in patients receiving ICIs. The primary outcome is the rate of sustained renal recovery at 12 weeks. Key secondary outcomes include time-to-sustained renal recovery, time-to-ICI-AKI recurrence, and time-to-rechallenge with anti-cancer therapy. Additionally, we will characterize the safety profile of infliximab, as well a 6- vs. 2-week course of GCs, using the Glucocorticoid Toxicity Index.
Interventions
DRUGInfliximab
Infliximab 5mg/kg x 1 and prednisone 1mg/kg per day (rounded to the nearest 10mg) x 2 weeks
DRUGPrednisone
Prednisone 1mg/kg per day for 2 weeks (rounded to the nearest 10mg, maximum 100mg/day) followed by a 4-week taper, tapered by 0.2mg/kg/day per week.
DRUGprednisone (oral)
Prednisone 1mg/kg per day for two weeks (Rounded do the nearest 10mg and maximum dose of 100mg per day)
Sponsors
Massachusetts General Hospital
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age ≥18 years. * Acute kidney injury (AKI), defined as ≥1.5-fold increase in serum creatinine compared to baseline. Baseline is defined as the closest serum creatinine value prior to immune checkpoint inhibitor initiation (ICI). * Receipt of ICI in the 180 days preceding AKI onset. * AKI due to ICI-AIN, based on either a kidney biopsy or clinical adjudication by the treating team. * Ability of the patient to understand the study and willingness to sign the written informed consent form.
Exclusion criteria
* Any condition requiring high dose glucocorticoids (GCs) (\>10 mg/day prednisone equivalents) or other immunosuppressants, such as infliximab, tocilizumab, mycophenolate mofetil, B cell depletion, or calcineurin inhibitors, within 14 days preceding screening * Evidence of any uncontrolled infection, including Tuberculosis (must have no evidence of active or latent TB determined by clinical history and negative interferon gamma release assay within the last 12 months or at screening); Hepatitis B (based on AntiSAg and HBV DNA negative within the last 12 months or at screening. Patients with Isolated Anti-HBcore positivity must agree to antiviral prophylaxis with entecavir for 6 months after receiving infliximab); Hepatitis C (must have no uncontrolled active infection evidenced by negative HCV antibody or HCV RNA within the last 12 months or at screening, and reflex testing must be performed for any patient with HCV antibody positivity); Patients with known HIV must be on stable disease antiretroviral therapy ≥12 weeks with a negative viral load \[\<50 copies/mL\] at screening and CD4 count ≥ 350 cells/uL) measured within the last 12 months. * History of hypersensitivity to infliximab or murine proteins. * Moderate-severe (New York Heart Association class III/IV) heart failure or recent decompensation. * Any active or uncontrolled hepatitis (immune-mediated, viral, or drug-induced) defined as AST or ALT \> 3 × ULN or Total bilirubin \> 1.5 × ULN in the 14 days preceding screening. (Participants with Gilbert syndrome can be enrolled with elevated total bilirubin if their direct bilirubin is not \> ULN) * History of demyelinating disease (e.g., multiple sclerosis) or optic neuritis. * Uncontrolled or recurrent serious infections (e.g., untreated abscess, active sepsis), requirement for oral or intravenous antibiotics, at screening. * Receipt of any live vaccine in the 28 days preceding screening * Kidney biopsy showing primary lesion other than acute interstitial nephritis * Life expectancy \<12 weeks in the opinion of the investigator * Unable to tolerate study procedures, including IV insertion. * Contraindication to GCs, including but not limited to, uncontrolled diabetes mellitus with inability to safely manage expected steroid-induced hyperglycemia, severe and active psychiatric disease requiring ongoing titration of psychiatric medications, active peptic ulcer disease, severe osteoporosis or high fracture risk, or other investigator-determined conditions where systemic GC or infliximab would pose unacceptable risk in the judgment of the investigator. * Vulnerable populations including children, prisoners, neonates and pregnant or breastfeeding patients
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Acute kidney injury recovery at 12 weeks | 12 weeks | The proportion of patients achieving AKI recovery within 12 weeks is defined as return of serum creatinine to less than 1.5-fold baseline creatinine within the need for ongoing immunosuppression. (Active immunosuppression is defined as currently receiving \>10mg/day of prednisone equivalent or having received any non-glucocorticoid immunosuppressant within the last 2 weeks). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to AKI recovery | 24 weeks | Time to AKI recovered is defined as the time in days to meeting criteria for AKI recovery as defined in the primary outcome. |
| Time to ICI-AKI recurrence | 24 weeks | Time to ICI-AKI recurrence is defined as \>= 1.5-fold rise in serum creatinine compared to the lowest serum creatinine achieved while receiving immunosuppression, occurring within 24 weeks following randomization and without a clear alternative more likely cause of AKI. |
| Change in serum creatinine | 24 weeks | Change from enrollment to follow-up serum creatinine |
| Tumor response | 24 weeks | Tumor response is determined using the RECIST 1.1 criteria, a widely accepted 4-category scale (complete response, partial response, stable disease, and disease progression). |
| Progression free survival | 24 weeks | Progression-free survival is defined as survival to 24 weeks with complete response, partial response, or stable disease |
| Overall survival | 24 weeks | Overall survival at 24 weeks |
| Adverse events leading to treatment discontinuation | 6 weeks | Summary of any adverse event that leads to treatment discontinuation |
| Adverse events of special interest | 30 days after completing study treatment | Adverse events of infliximab inclusion infusion reaction, serious infection, headach, hepatotoxicity, serum sickness, autoimmune phenomenon, rash, new malignancy, congestive heart failure, neurotoxicity. |
| Serious adverse events (SAE) | Up to 30 days after completing study treatment | An SAE is defined as an adverse event that meets any of the following criteria 1) results in death, 2) is life threatening, 3) requires or prolongs hospitalization, 4) results in persistent or significant disability/incapacity. |
| Glucocorticoid toxicity index | 6 weeks | The Glucocorticoid Toxicity Index (GTI) is a validated clinician-assessed instrument designed to prospectively quantify changes in glucocorticoid-associated morbidity over time. The GTI evaluates toxicity across multiple domains, including body mass index, glucose tolerance, blood pressure, lipid metabolism, myopathy, bone health, skin toxicity, neuropsychiatric effects, infection, ocular complications, and patient-reported symptoms. GTI will be assessed at baseline and at week 6. Higher GTI scores reflect greater glucocorticoid-associated toxicity, whereas improvements in score indicate a reduction in steroid-related adverse effects. |
Countries
United States
Contacts
CONTACTMeghan E Sise, MD
PRINCIPAL_INVESTIGATORMeghan E Sise, MD
Massachusetts General Hospital
PRINCIPAL_INVESTIGATORDavid Leaf, MD
Brigham and Women's Hospital
Outcome results
None listed