Clinical trial NCT06757426: Prospective Observational Study Evaluating the Safety and Efficacy of Immunomodulatory Therapies in Refractory Inflammatory and Autoimmune Diseases
Official title: Prospective Observational Study Evaluating the Safety and Efficacy of Immunomodulatory Therapies in Refractory Inflammatory and Autoimmune Diseases
Study type: OBSERVATIONAL
Overall status: NOT_YET_RECRUITING
Conditions: Autoimmune Diseases
Inflammatory Diseases
Keywords: autoimmune
inflamatory disease
Refraction
Lead sponsor: Groupe français d'étude des Maladies Inflammatoires de loeil
Sponsor class: OTHER
First posted: 2025-01-03
Enrollment: 80
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Patients with refractory inflammatory and autoimmune diseases

Brief summary: Inflammatory and/or autoimmune diseases represent a very broad group of diseases with highly variable clinical features, including - but not limited to - systemic connectivites and vasculitides. As these diseases are rare and heterogeneous, it is difficult to conduct randomized clinical trials in this setting. Refractory cases are therefore treated with drugs that are already available on the market for other indications in more frequent and clinically homogeneous diseases, such as inflammatory rheumatism and haematological malignancies.

Prescribing treatments from other specialties (e.g. rheumatology and oncohaematology) is a reality in the clinical practice of internists and immunologists, often representing an excellent solution for difficult-to-treat inflammatory and/or autoimmune diseases. As these molecules are prescribed without the availability of standardized data, it is essential to collect them prospectively to better characterize the efficacy and tolerability of these new therapeutic options in severe inflammatory and/or autoimmune diseases.

Detailed description: Inflammatory and/or autoimmune diseases represent a very broad group of diseases with highly variable clinical features, including - but not limited to - systemic connectivites and vasculitis. Individually, they are very rare diseases, generally estimated in terms of the number of cases per 100,000 or 1,000,000 inhabitants. However, if we consider all immune-mediated inflammatory diseases, it is estimated that they affect 4.5% of the world's population .

Despite their extreme heterogeneity in terms of clinical presentation, these diseases share several key pathogenic mechanisms. For example, over the past two decades, adaptive immunity has been successfully targeted with several monoclonal antibodies directed against B lymphocytes (e.g. rituximab, an anti-CD20) and co-stimulation between B and T lymphocytes (e.g. abatacept, a CTLA-4 agonist). Targeting cytokines common to several of these diseases has also proved effective in their management, in particular anti-TNF alpha and anti-IL-6, produced by cells of the innate and adaptive immune systems.

Although these molecules have ushered in a new era in the management of inflammatory and/or autoimmune diseases, not all patients are yet fully controlled, representing a major challenge in clinical practice.

Refractory cases are then treated with drugs that are already available on the market for other indications in more frequent and clinically homogeneous diseases, such as inflammatory rheumatism and haematological malignancies.

Certain therapeutic targets stand out. The first is the cytokine IL-17, which plays a crucial role in the polarization of T helper 17 (Th17) lymphocytes and orchestrates the adaptive response detectable in the blood and target tissues of various inflammatory and/or autoimmune diseases.

Another interesting modern strategy is the inhibition of the Janus kinase and signal transducer/activator of transcription (JAK/STAT) pathways, which act on several downstream cytokine receptors. The development of targeted oral therapies based on small molecules such as JAK inhibitors (JAKi) represents an effective means of simultaneously attenuating several downstream inflammatory pathways, and has enabled a paradigm shift in the treatment of various autoimmune and inflammatory conditions refractory to conventional therapy, with cortisone sparing as well.

Bispecific antibodies (BsAb) are a new class of drugs and one of the most promising immunotherapies for solid tumors and hematological malignancies. BsAbs combine the specificities of two therapeutic antibodies and simultaneously target different antigens or epitopes. They have attracted a great deal of interest over the past decade, thanks to their unique and versatile modes of action.

In summary, the prescription of commercially available treatments from other specialties (e.g. rheumatology and oncohaematology) is a reality in the clinical practice of internists and immunologists, often representing an excellent solution for difficult-to-treat inflammatory and/or autoimmune diseases. As these molecules are prescribed without the availability of standardized data, it is essential to collect them prospectively to better characterize the efficacy and tolerability of these new therapeutic options in inflammatory and/or autoimmune diseases.

Eligibility criteria: Inclusion Criteria:

1. Patients over 18 years
2. Enrolled in the French national social security system
3. Diagnosis of an inflammatory/autoimmune disease meeting internationally accepted classification criteria;
4. Clinical activity of their disease with biological and/or radiological signs, refractory to conventional therapeutic lines, requiring a new treatment as an addition or replacement according to clinical judgment.
5. No formal contraindication to the new therapeutic class.

Exclusion Criteria:

1. Pregnancy or breast-feeding (for women of childbearing potential, a negative serum pregnancy test will be required);
2. History of severe immunosuppression, HIV or HBsAg positive.
3. Positive QuantiFERON test result (QFT-TBGIn-Tube) for active tuberculosis (latent tuberculosis under treatment may be included).
4. Have received live vaccines in the 3 months preceding the start of treatment.
5. History of malignant tumor within the last 5 years.
6. Severe renal insufficiency (creatinine clearance \<30mL/min/1.73m²)
7. Liver dysfunction defined by aspartate transaminase (AST) or alanine transaminase (ALT) levels ≥ 5 times the upper limit of normal.
8. Blood count abnormality:

   * Platelets \< 50 x 103/mm3
   * Neutropenia \< 1000/mm3
   * Hemoglobin \< 8 g/dL

Primary outcomes:
measure: proportion of complete remission from the disease at week 24
timeFrame: week 24
Secondary outcomes:
measure: Evaluate the proportion of patients in clinical, biological or radiological remission
timeFrame: week 12 and week 48
measure: Cumulative incidence of relapse (i.e., recurrence of clinical symptoms associated with biological and/or radiological inflammatory activity following complete remission)
timeFrame: weeks 12, 24, 36 and 52
measure: Cumulative incidence of remission according to primary endpoint definitions
timeFrame: weeks 12, 36 and 52
measure: Evaluate changes in median disease-specific activity scores
timeFrame: weeks 12, 24, 36 and 52
measure: Cumulative prednisone dose
timeFrame: weeks 12, 24, 36 and 52
measure: Cumulative incidence of serious adverse events (i.e., those requiring hospitalization or death) at weeks 12, 24, 36 and 52
timeFrame: weeks 12, 24, 36 and 52
measure: Evolution of circulating immune cell populations & cytokines under treatment
timeFrame: Weeks 0, 1, 2, 4, 12, 24, and 52
Other outcomes:
Locations:
city: Paris
country: France
facility: APHP_Hopital Lariboisière
state: Ile De France
city: Paris
country: France
facility: APHP_Hôpital St Antoine
state: Ile De France
city: Paris
country: France
facility: APHP_ Hôpital Pitié-Salpêtrière
state: Ile De France
city: Paris
country: France
facility: APHP_Hôpital Bichat
state: Ile De France
city: Paris
country: France
facility: APHP_Hopital Ambroise Paré
state: Ile De France
city: Aix-en-provence
country: France
facility: Clinique Axium - Aix-en-provence
city: Blois
country: France
facility: CH Simone Veil de BLOIS
city: Caen
country: France
facility: CHU Caen Normandie
city: Le Mans
country: France
facility: CH du Mans
city: Marseille
country: France
facility: APHM_Hôpital La Conception
city: Marseille
country: France
facility: APHM_Hôpital Nord
city: Melun
country: France
facility: GHSIF Melun
city: Montfermeil
country: France
facility: GHI Le Raincy Montfermeil
city: Nantes
country: France
facility: CHU Nantes - Hotel-Dieu
city: Rouen
country: France
facility: CHU Rouen_Hôpital Charles Nicolle
city: Saint-Exupéry
country: France
facility: Clinique Saint-Exupéry
city: Tours
country: France
facility: CHRU de Tours_Hôpital Bretenneau
Study officials:
References:
citation: Venhoff N, Schmidt WA, Bergner R, Rech J, Unger L, Tony HP, Finzel S, Andreica I, Kofler DM, Weiner SM, Lamprecht P, Schulze-Koops H, App C, Pournara E, Mendelson MH, Sieder C, Maricos M, Thiel J. Safety and efficacy of secukinumab in patients with giant cell arteritis (TitAIN): a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Rheumatol. 2023 Jun;5(6):e341-e350. doi: 10.1016/S2665-9913(23)00101-7.
citation: Klein C, Brinkmann U, Reichert JM, Kontermann RE. The present and future of bispecific antibodies for cancer therapy. Nat Rev Drug Discov. 2024 Apr;23(4):301-319. doi: 10.1038/s41573-024-00896-6. Epub 2024 Mar 6.
citation: Hayter SM, Cook MC. Updated assessment of the prevalence, spectrum and case definition of autoimmune disease. Autoimmun Rev. 2012 Aug;11(10):754-65. doi: 10.1016/j.autrev.2012.02.001. Epub 2012 Feb 23.
citation: Watts RA, Hatemi G, Burns JC, Mohammad AJ. Global epidemiology of vasculitis. Nat Rev Rheumatol. 2022 Jan;18(1):22-34. doi: 10.1038/s41584-021-00718-8. Epub 2021 Dec 1.