Tumor Necrosis Factor Inhibition in Focal Segmental Glomerulosclerosis and Treatment Resistant Minimal Change Disease

Precision Medicine Proof of Concept for Tumor Necrosis Factor Inhibition in Focal Segmental Glomerulosclerosis and Treatment Resistant Minimal Change Disease

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).

Study Overview

• Status: Completed
• Conditions: Focal Segmental Glomerulosclerosis; Minimal Change Disease; FSGS; MCD
• Intervention / Treatment: Drug: adalimumab

• Study Type: Interventional
• Enrollment (Actual): 7
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • The University of Michigan
  • New York
    • New York, New York, United States, 10016
      • New York University
  • North Carolina
    • Charlotte, North Carolina, United States, 28207
      • Levine Children's Hospital/Atrium Health
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Foundation

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 years to 70 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: adalimumab; Adalimumab dose every other week (study weeks 0, 2, 4, 6, and 8), subcutaneously	Drug: adalimumab; Adalimumab will be dosed based on weight; Other Names: Humira

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	10 Weeks
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.	10 Weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	14 weeks
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.	10 Weeks
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.	10 Weeks
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.	10 Weeks

Collaborators and Investigators

• Sponsor: University of Michigan
• Investigators: Study Director: Zubin Modi, MD, University of Michigan

Study record dates

Study Major Dates

• Study Start (Actual): October 2, 2019
• Primary Completion (Actual): September 5, 2023
• Study Completion (Actual): October 3, 2023

Study Registration Dates

• First Submitted: July 2, 2019
• First Submitted That Met QC Criteria: July 2, 2019
• First Posted (Actual): July 5, 2019

Study Record Updates

• Last Update Posted (Actual): October 30, 2024
• Last Update Submitted That Met QC Criteria: October 3, 2024
• Last Verified: October 1, 2024

More Information

Terms related to this study

• Keywords: Kidney Disease; Nephrotic Syndrome; FSGS; Focal Segmental Glomerulosclerosis; Minimal Change Disease
• Additional Relevant MeSH Terms: Urogenital Diseases; Pathologic Processes; Male Urogenital Diseases; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Glomerulonephritis; Nephritis; Nephrosis; Necrosis; Glomerulosclerosis, Focal Segmental; Nephrosis, Lipoid; Tumor Necrosis Factor Inhibitors; Anti-Inflammatory Agents; Antirheumatic Agents; Adalimumab
• Other Study ID Numbers: HUM00147018

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

This trial will follow the publication and data sharing policies of the NEPTUNE study, www.NEPTUNE-study.org

Request for ancillary studies should be submitted through the project contact and will be reviewed by the project steering committee.

After the study is completed, data will be submitted to the Nephrotic Syndrome Study Network (NEPTUNE), an NIH funded consortium. Proposals to access the data will then be submitted via the NEPTUNE Ancillary Studies program (NEPTUNE-study.org). Following closure of NEPTUNE, the trial data will convey with the NEPTUNE date to the NIH/NIDDK repository and can be accessed through this mechanism following approval.

• IPD Sharing Time Frame: At the latest, data will be shared with the NEPTUNE Data Analysis and Coordinating Center at the time of publication of final results or 24 months after transfer of samples or raw data sets.

IPD Sharing Access Criteria

While this study is open data requests from this study will need to seek approval from the trial steering committee.

Once the data is transferred to the NEPTUNE study, all study data will become part of the aggregate NEPTUNE data and available to NEPTUNE participant sites and other requesting third parties upon request. Subsequent access to these data will be governed by the NIH Office of Rare Diseases (ORD) data sharing policies.

• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

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