Focal Segmental Glomerulosclerosis, FSGS, MCD, Minimal Change Disease
Conditions
Keywords
Kidney Disease, Minimal Change Disease, Nephrotic Syndrome, Focal Segmental Glomerulosclerosis, FSGS
Brief summary
Adalimumab, a treatment which blocks tumor necrosis factor (TNF), was tested to see if it changed levels of urine biomarker levels, tissue inhibitor of metalloprotease-1 (TIMP1), and monocyte chemoattractant protein-1 (MCP1). Results may help develop individualized treatment options for future patients with TNF-driven focal segmental glomerulosclerosis (FSGS) or minimal change disease (MCD).
Interventions
DRUGadalimumab
Adalimumab will be dosed based on weight
Sponsors
University of Michigan
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
6 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Kidney biopsy confirmed Focal Segmental Glomerulosclerosis (FSGS) or Minimal Change Disease (MCD) * For Minimal Change Disease patients only, history of resistance to corticosteroid therapy * Increased urinary excretion of biomarkers of Tumor Necrosis Factor (TNF) activation (MCP1/Cr and/ or TIMP1/Cr) at study screening * eGFR\>30 ml/min/1.73 m2 at screening * Urine protein:creatinine ratio ≥1.5 g/g at screening * Weight \>15 kg * Stable therapy with angiotensin converting enzyme inhibitors, angiotensin receptor blockers, and oral immunosuppression agents for at least 30 days prior to enrollment * Birth control use in females of child bearing potential * Informed consent and assent if applicable
Exclusion criteria
* Kidney or other solid organ or bone marrow transplant recipient * Allergy or intolerance to investigational agent * Secondary Focal Segmental Glomerulosclerosis (FSGS) * Severe obesity * Live virus vaccine in the past 3 months * Malignancy, current or in the past 5 years * Active local or systemic bacterial, fungal or viral infection * Active or latent Hepatitis B, Hepatitis C, HIV, or tuberculosis * History of demyelinating disease, e.g. Multiple Sclerosis or Guillain-Barre * History of heart failure * Active liver disease * Systemic lupus erythematosus or ANA \> 1:80 * History of inflammatory bowel disease, e.g. ulcerative colitis or Crohns disease * Cyclophosphamide in past 90 days, Rituximab in the past 180 days * Pregnancy or nursing * Blood white blood cell count \<4,500/mm3; Hg \<9 g/dL; Platelet count \<150,000/mm3 at enrollment. - Use of an erythropoiesis stimulating agent will not be an exclusion criterion. * Concurrent use of interleukin-1 antagonist (Anakinra), other TNF blocking agent, methotrexate or abatacept * Diabetes Mellitus
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Urine MCP1/Cr Levels | 10 Weeks | MCP1 is an established marker of intra-renal TNF pathway activation. A reduction in MCP1 reflects a reduction in the activation of the TNF pathway in the kidney. Values were measured by enzyme-linked immunosorbent assay (ELISA) testing and standardized over serum creatinine. |
| Change in Urine TIMP1/Cr Levels | 10 Weeks | TIMP1 is an established marker of intra-renal TNF pathway activation. A reduction in TIMP1 reflects a reduction in the activation of the TNF pathway in the kidney. Values were measured by enzyme-linked immunosorbent assay (ELISA) testing and standardized over serum creatinine. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Adverse Events (AEs) | 14 weeks | AEs for this outcome measure were classified using the following definitions: * Mild: no or mild symptoms, and not requiring intervention * Moderate: with minimal or local intervention, and limiting age-appropriate activities * Severe: intervention necessary and limiting age-appropriate activities but not immediately life-threatening, and requiring hospitalization or prolongation of hospitalization * Serious AE: results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability/incapacity, pregnancy or congenital anomaly/birth defect. Some participants experienced multiple types of AE during the course of the trial. |
| Change in Estimated Glomerular Filtration Rate (eGFR) | 10 Weeks | eGFR is a measure of kidney functioning based on a blood sample and clinical information to calculate it. Normal kidney function is greater than 90 ml/min/1.73 m2. Result data is the percent change in eGFR following the intervention. The lower the number shows the greater decline in kidney function. |
| Change in Urine Protein Creatinine Ratio (UPCR) | 10 Weeks | UPCR is a measure of protein spillage from the kidney based on a urine specimen. Normal reference range is less than 0.03 mg/mg. Result is the percent change in UPCR following the intervention, with lower number showing less protein spilling from the kidney, reflecting better disease control. |
| Proportion of Participants Who Achieved Both a Nadir Urine Protein Creatinine Ratio (UPCR) of Less Than 1.5 g/g and at Least a 40% Reduction From Baseline | 10 Weeks | UPCR is a measure of protein spillage from the kidney based on a urine specimen. Normal reference range is less than 0.03 mg/mg. Result is the count of participants who simultaneously met the criteria of having both a raw UPCR value of less than 1.5 g/g and at least a 40% reduction from baseline. |
Countries
United States
Participant flow
Recruitment details
Recruitment Period: 2019-2023 Recruitment Sites: University of Michigan, Ann Arbor, MI; New York University Langone Health, New York, NY; Cleveland Clinic, Cleveland, OH; Levine Children's Hospital at Atrium Health, Charlotte, NC.
Pre-assignment details
Following consent, participants provided a urine sample to measure urinary monocyte chemoattractant protein-1 (uMCP-1) and urinary tissue inhibitor of metalloprotease-1 (uTIMP-1), two indicators of intra-renal tumor necrosis factor (TNF) pathway activation. Participants with present TNF activation were advanced to screening. Upon confirmation of eligibility, participants proceeded to the treatment phase.
Participants by arm
| Arm | Count |
|---|---|
| Adalimumab Adalimumab dose every other week (study weeks 0, 2, 4, 6, and 8), subcutaneously. Adalimumab will be dosed based on weight (20 mg for subjects weighing 15kg to \<30kg, or 40 mg for subjects \>30kg). | 7 |
| Total | 7 |
Baseline characteristics
| Characteristic | Adalimumab |
|---|---|
| Age, Continuous | 15.9 years |
| Race/Ethnicity, Customized Ethnicity Hispanic or Latino | 3 Participants |
| Race/Ethnicity, Customized Ethnicity Not Hispanic or Latino | 4 Participants |
| Race/Ethnicity, Customized Race Black or African American | 1 Participants |
| Race/Ethnicity, Customized Race Native Hawaiian or Other Pacific Islander | 1 Participants |
| Race/Ethnicity, Customized Race White | 5 Participants |
| Region of Enrollment United States | 7 participants |
| Sex: Female, Male Female | 5 Participants |
| Sex: Female, Male Male | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 7 |
| other Total, other adverse events | 5 / 7 |
| serious Total, serious adverse events | 1 / 7 |
Outcome results
Primary
Change in Urine MCP1/Cr Levels
MCP1 is an established marker of intra-renal TNF pathway activation. A reduction in MCP1 reflects a reduction in the activation of the TNF pathway in the kidney. Values were measured by enzyme-linked immunosorbent assay (ELISA) testing and standardized over serum creatinine.
Time frame: 10 Weeks
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Adalimumab | Change in Urine MCP1/Cr Levels | Baseline | 5.57 ng/mg |
| Adalimumab | Change in Urine MCP1/Cr Levels | Week 10 | 2.89 ng/mg |
Primary
Change in Urine TIMP1/Cr Levels
TIMP1 is an established marker of intra-renal TNF pathway activation. A reduction in TIMP1 reflects a reduction in the activation of the TNF pathway in the kidney. Values were measured by enzyme-linked immunosorbent assay (ELISA) testing and standardized over serum creatinine.
Time frame: 10 Weeks
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Adalimumab | Change in Urine TIMP1/Cr Levels | Baseline | 41.34 ng/mg |
| Adalimumab | Change in Urine TIMP1/Cr Levels | Week 10 | 31.36 ng/mg |
Secondary
Change in Estimated Glomerular Filtration Rate (eGFR)
eGFR is a measure of kidney functioning based on a blood sample and clinical information to calculate it. Normal kidney function is greater than 90 ml/min/1.73 m2. Result data is the percent change in eGFR following the intervention. The lower the number shows the greater decline in kidney function.
Time frame: 10 Weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Adalimumab | Change in Estimated Glomerular Filtration Rate (eGFR) | -28.90 Percent Change |
Secondary
Change in Urine Protein Creatinine Ratio (UPCR)
UPCR is a measure of protein spillage from the kidney based on a urine specimen. Normal reference range is less than 0.03 mg/mg. Result is the percent change in UPCR following the intervention, with lower number showing less protein spilling from the kidney, reflecting better disease control.
Time frame: 10 Weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Adalimumab | Change in Urine Protein Creatinine Ratio (UPCR) | -11.60 Percent Change |
Secondary
Incidence of Adverse Events (AEs)
AEs for this outcome measure were classified using the following definitions: * Mild: no or mild symptoms, and not requiring intervention * Moderate: with minimal or local intervention, and limiting age-appropriate activities * Severe: intervention necessary and limiting age-appropriate activities but not immediately life-threatening, and requiring hospitalization or prolongation of hospitalization * Serious AE: results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability/incapacity, pregnancy or congenital anomaly/birth defect. Some participants experienced multiple types of AE during the course of the trial.
Time frame: 14 weeks
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Adalimumab | Incidence of Adverse Events (AEs) | Mild AEs | 7 Adverse Event |
| Adalimumab | Incidence of Adverse Events (AEs) | Moderate AEs | 4 Adverse Event |
| Adalimumab | Incidence of Adverse Events (AEs) | Severe AEs | 1 Adverse Event |
| Adalimumab | Incidence of Adverse Events (AEs) | Serious AEs | 10 Adverse Event |
Secondary
Proportion of Participants Who Achieved Both a Nadir Urine Protein Creatinine Ratio (UPCR) of Less Than 1.5 g/g and at Least a 40% Reduction From Baseline
UPCR is a measure of protein spillage from the kidney based on a urine specimen. Normal reference range is less than 0.03 mg/mg. Result is the count of participants who simultaneously met the criteria of having both a raw UPCR value of less than 1.5 g/g and at least a 40% reduction from baseline.
Time frame: 10 Weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Adalimumab | Proportion of Participants Who Achieved Both a Nadir Urine Protein Creatinine Ratio (UPCR) of Less Than 1.5 g/g and at Least a 40% Reduction From Baseline | 2 Participants |