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Interferon Alfa Therapy Based on Th17 Profile in Membranous Nephropathy (ALPHAGEM)

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ClinicalTrials.gov Identifier: NCT05941845
Recruitment Status : Not yet recruiting
First Posted : July 12, 2023
Last Update Posted : July 12, 2023
Sponsor:
Information provided by (Responsible Party):
Centre Hospitalier Universitaire de Nice

Study Description
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Brief Summary:
Membranous Nephropathy (MN) is a renal autoimmune disease mediated by autoantibodies. Current management is based on the use of immunosuppressive therapies. MN patients with a pro-inflammatory Th17 cytokine profile have a 10.5-fold increased risk of disease relapse. Interferon-based immunomodulatory therapies are effective in blocking the production of cytokines in the Th17 pathway avoiding an increased risk of infection, unlike immunosuppressive treatments. To date, these treatments have not been evaluated in the management of MN. The aims of the ALPHAGEM project are to monitor the immunological activity of the disease before and after 6 months of personalized interferon-alfa treatment in MN patients.

Condition or disease Intervention/treatment Phase
Membranous Nephropathy Drug: Peginterferon Alfa-2A 180 MCG/ML Injectable Solution Phase 2

Detailed Description:
Membranous Nephropathy (MN) is a renal autoimmune disease mediated by autoantibodies, in particular the anti-phospholipase A2 receptor antibodies (anti-PLA2R1). The development of these autoantibodies is the consequence of a genetic predisposition, environmental factors and a dysregulation of the immune response, with increased production of pro-inflammatory Th2 and Th17 cytokines. Current management is based on the use of immunosuppressive therapies to induce immunological remission, which precedes clinical remission. Disease relapse may occur in 5-28% of patients, and may be complicated by long-term renal failure. MN patients with a pro-inflammatory Th17 cytokine profile have a 10.5-fold increased risk of disease relapse. Rituximab induces the regulatory T pathway, but has no impact on the Th17 pathway. Interferon-based immunomodulatory therapies are effective in blocking the production of cytokines in the Th17 pathway avoiding an increased risk of infection, unlike immunosuppressive treatments. These treatments have been used for many years in the management of autoimmune diseases (such as multiple sclerosis for interferon beta) and viral infectious diseases (such as chronic hepatitis B for interferon alfa), affections where the Th17 pathway plays a key pathophysiological role. To date, these treatments have not been evaluated in the management of MN. The aims of the ALPHAGEM project are to monitor the immunological activity of the disease before and after 6 months of personalized interferon-alfa treatment in MN patients with immunological relapse and a Th17-type cytokine profile, and to assess drug tolerance.
Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 5 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Study of Immunological Activity After Personalized Immunomodulatory Therapy Regulating the Th17 Pathway in Patients With Membranous Nephropathy
Estimated Study Start Date : July 24, 2023
Estimated Primary Completion Date : January 24, 2025
Estimated Study Completion Date : July 24, 2025

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Kidney Diseases

Arms and Interventions
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Arm Intervention/treatment
Experimental: 6-month interferon alfa treatment Drug: Peginterferon Alfa-2A 180 MCG/ML Injectable Solution

Injections will be carried out on the Nephrology day hospitalization ward. The injections follows a personalized administration schedule: all enrolled patients will receive an injection of Pegasys® at Week 0.

Patients with a persistent Th17 profile (cytokine profile showing IL-17A levels greater than 73 pg/ml) at Week 2 will receive a new dose of Pegasys®, followed by a monthly cytokine profile. In the case of a persistent Th17 profile, 2 injections will be given two weeks apart.

In patients with no Th17 profile at Week 2, no Pegasys® injections will be performed at this time. Cytokine profiles will be performed monthly, and in the case of a persistent Th17 profile, 1 injection will be performed.

In total, patients will receive a minimum of one injection and a maximum of 13 injections of 180 µg (1 injection every two weeks for 24 weeks).

Other Name: Pegasys®, interferon alfa


Outcome Measures
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Primary Outcome Measures :
  1. Membranous nephropathy immunological activity monitoring over 6-month interferon alfa treatment [ Time Frame: 18 months ]
    Intra-individual variation in anti-PLA2R1 antibody titer (ELISA titer in RU/mL), before and after 6 months of treatment with IFN alfa


Secondary Outcome Measures :
  1. Nephrotic syndrome monitoring over 6-month interferon alfa treatment [ Time Frame: Baseline to Week 24 ]
    Intra-individual variation in proteinuria (g/g) under IFN alfa and stable symptomatic treatment

  2. Nephrotic syndrome monitoring over 6-month interferon alfa treatment [ Time Frame: Baseline to Week 24 ]
    Intra-individual variation in albuminemia (g/L) under IFN alfa and stable symptomatic treatment

  3. Immune response monitoring over 6-month interferon alfa treatment [ Time Frame: Baseline to Week 24 ]
    Intra-individual variation in cytokine profile (assay of 8 cytokines in pg/ml: IL-12p70; IL-17A; IL-4; IL-5; IL-1β; IL-10; IFNα; IL-6) before and after 6 months of personalized treatment with IFN alfa

  4. Immune response monitoring over 6-month interferon alfa treatment [ Time Frame: Baseline to Week 24 ]
    Intra-individual variation in cytokine profile (assay of 1 cytokine in UI/ml: IFNγ) before and after 6 months of personalized treatment with IFN alfa

  5. Clinical Tolerance monitoring over 6-month interferon alfa treatment [ Time Frame: At Week 52 ]
    Percentage of Participants with clinical Adverse Events (AEs)

  6. Biological Tolerance monitoring over 6-month interferon alfa treatment [ Time Frame: At Week 52 ]
    Percentage of Participants with biological Adverse Events (AEs)


Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Age 18 and above
  2. Diagnosis of membranous nephropathy PLA2R1 antibodies-mediated
  3. Immunological relapse (defined as an increase in anti-PLA2R1 antibody titer > 14 RU/mL after a phase of anti-PLA2R1 antibody negativation, i.e. immunological remission)
  4. Plasma IL-17A levels > 73 pg/mL after non-specific stimulation of peripheral blood immune cells
  5. Symptomatic anti-proteinuric treatment at a stable, maximum-tolerated dosage;
  6. Patients with: (i) a platelet count≥ 90,000 cells/mm3; (ii) a neutrophil count ≥ 1500 cells/mm3; and (iii) appropriately monitored normal thyroid function (TSH and T4) at screening

Exclusion Criteria:

  1. Immunosuppressive treatment for MN in the 6 months before screening
  2. Secondary MN (associated with cancer, infectious disease, autoimmune or iatrogenic disease)
  3. Active nephrotic syndrome defined according to KDIGO guidelines by proteinuria > 3.5 g/day (or 3.5 g/g urine sample) and albuminemia < 30 g/L
  4. Absence of previous immunological (anti-PLA2R1 antibodies < 14 RU/mL in ELISA or negative indirect immunofluorescence) and clinical (partial or complete) remission
  5. Patients with a history of thrombosis or treated with anticoagulants
  6. Pregnancy or breastfeeding
  7. Cancer in treatment
  8. Pre-existing retinopathy
  9. Active and severe infections
  10. Severe liver failure or cirrhosis
  11. Pre-existing severe heart failure
  12. Pre-existing psychiatric disorder or patient at risk of anxiety or depression (HAD Score > 11)
  13. Patients who use or abuse substances
  14. Hypersensitivity to active substance or excipients of study treatment
Contacts and Locations
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Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05941845


Contacts
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Contact: Maxime TEISSEYRE, MD +33492038828 teisseyre.m@chu-nice.fr
Contact: Céline FERNANDEZ, MsC +33492038828 fernandez.c3@chu-nice.fr

Locations
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France
CHU de NICE
Nice, France
Contact: Céline FERNANDEZ    +33492038828    fernandez.c3@chu-nice.fr   
Sponsors and Collaborators
Centre Hospitalier Universitaire de Nice
More Information
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Responsible Party: Centre Hospitalier Universitaire de Nice
ClinicalTrials.gov Identifier: NCT05941845    
Other Study ID Numbers: 22-AOIP-03
First Posted: July 12, 2023    Key Record Dates
Last Update Posted: July 12, 2023
Last Verified: June 2023
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: Not planed

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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
Keywords provided by Centre Hospitalier Universitaire de Nice:
Membranous nephropathy
Immunomodulatory therapy
Interferon alpha
Interleukine 17-A (IL-17A)
Personalized medicine
Additional relevant MeSH terms:
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Kidney Diseases
Glomerulonephritis, Membranous
Urologic Diseases
Female Urogenital Diseases
Female Urogenital Diseases and Pregnancy Complications
Urogenital Diseases
Male Urogenital Diseases
Glomerulonephritis
Nephritis
Autoimmune Diseases
 Immune System Diseases
Interferons
Interferon-alpha
Peginterferon alfa-2a
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Immunologic Factors
Physiological Effects of Drugs