Therapeutic Use of Tadekinig Alfa in Adult-onset Still's Disease

NCT02398435 | Completed Phase 2 DMC

• 1 other identifier: AOSD-2014-001
• Study Type: interventional
• Target: 23
• Locations: 3 countries
• Sites: 20

Brief Summary

The objective of this study is to assess safety, tolerability and early signs of efficacy of the investigational drug Tadekinig alfa in Adult-onset Still's disease, a rare polygenic auto-inflammatory disorder for which treatment remains empirical. This disease is characterized by a daily spiking fever, arthralgia / arthritis, and skin rashes with frequent components of sore throat, lymphadenopathies and neutrophilic leukocytosis. The etiology is unknown. In addition to the above-mentioned clinical features, the diagnosis includes some laboratory components that reflect the systemic inflammation: high erythro-sedimentation rate, C-reactive protein, high serum ferritin and high levels of interleukin 18 (IL-18). Tadekinig alfa is the drug name for recombinant human interleukin-18 binding protein (IL-18BP). This investigational drug was tested in healthy volunteers, psoriasis and rheumatoid arthritis patients in phase I studies. It demonstrated good safety and tolerability profile with only mild adverse events in the injection site.

Conditions

Still's Disease, Adult-Onset

Keywords

Auto-inflammatory disease; Still's disease; Arthritis Rheumatoid; IL-18; interleukin-18; IL-18 binding protein

Outcome Measures

Primary Outcomes (1)

• Safety (adverse events)

  Safety assessments will be reported all along the study. The data safety monitoring board will assess Safety at 3 weeks and 12 weeks of treatment.

  12 weeks after first administration

Secondary Outcomes (1)

• Efficacy 9 Efficacious dose at 3 weeks will be considered if normalisation of body temperature and decrease of C-reactive protein (CRP) by more or equal to 50 percent of baseline values are achieved.)

  12 weeks after first administration

Study Arms (2)

Cohort 80 mg

EXPERIMENTAL

Cohort 1 included 10 patients. Patients received Tadekinig alfa s.c with a dosage of 80mg. Safety assessments were conducted by data safety monitoring board. Non-responder patients were upscaled to next dose (160mg) after 3 weeks of treatment.

Biological: Tadekinig alfa (recombinant human IL-18 binding protein)

Cohort 160 mg

EXPERIMENTAL

Cohort 2 included 13 patients. all patients were treated with Tadekinig alfa s.c with a dosage of 160mg. Safety was evaluated by data safety monitoring board.

Biological: Tadekinig alfa (recombinant human IL-18 binding protein)

Interventions

Tadekinig alfa (recombinant human IL-18 binding protein) BIOLOGICAL

Patients received the study treatment three times a week subcutaneously.

Cohort 160 mg; Cohort 80 mg

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients aged 18 years and older, diagnosed as AoSD based on the presence of the Yamaguchi criteria with active disease (see appendix 2), irrespective of the continuation of the permitted treatment mentioned below
• Patients with active disease will be considered if they exhibit at least two of the Yamaguchi's major criteria (see appendix 2) at the screening visit plus at least either fever or elevation of markers of inflammation (CRP ≥ 10 mg/L).
• Patients that have been exposed to NSAIDS, Prednisone (at least 5mg/day for ≥1 month) and/or synthetic sDMARDs (methotrexate at a dose of at least 10mg/day for ≥ 3 months) without response to treatment or with incomplete response to treatment
• Women of childbearing potential with negative pregnancy test at screening, V3, V4, V5 and V6 and that agree to follow highly effective birth control recommendations during the study and until 1 month after the end of the treatment. Birth control methods that are considered as highly effective are either: combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation, progestogen-only hormonal contraception associated with inhibition of ovulation, intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, vasectomized partner or sexual abstinence.
• In each case of delayed menstrual period (over one month between menstruations, confirmation of absence of pregnancy is strongly recommended. This recommendation also applies to women of child bearing potential with infrequent or irregular menstrual cycles.
• As regards the duration of contraception after the study, taking into account the median half-life of Tadekinig alfa of almost 40h, 5 half-lives represent duration of 200 hours. In order to be on the safe side, a post-study contraception duration of - Patients can maintain treatment with stable doses of Non-Steroidal anti-inflammatory Drugs (NSAIDs), Prednisone (stable dose of Prednisone of at least 5mg/day), and sDMARDs during Tadekinig alfa treatment (methotrexate at a dose of at least 10mg/week). Specifically baseline levels of prednisone treatment can be maintained or tapered (due to patient improvement), any requirement for prednisone increase during treatment will be considered a treatment failure.
• Ability to understand and willingness to sign a written informed consent
• Previous treatments with biologicals are allowed if the following wash-out periods are respected: one week for anakinra, two weeks for etanercept, and 6 weeks for, adalimumab, certolizumab, golimumab, tocilizumab, abatacept and 8 weeks for infliximab. Previous rituximab administration will require 6 months of washout and normal B-cell counts and previous treatment with canakinumab will require 6 months of washout.

You may not qualify if:

• Patients with a first episode of AoSD with less than one month of therapy with Prednisone or sDMARDs
• Patients with active or chronic infections (i.e. Tuberculosis (TB), HIV, HBV \& HCV)
• Patients suffering from inherited immunodefinciency diseases
• Patients suffering from immune-mediated inflammatory diseases, including RA, SLE, etc. or spondylarthropathies, or inflammatory bowel disease.
• Patients with white blood cell counts below 2'500 cells/mm3
• Concomitantly treated with biologicals
• Inability to understand and unwilling to sign a written informed consent
• Any acute or chronic life-threatening disease: Such as cancer, and irreversible organ failures of heart, liver, lung and kidney (creatinine not higher than 1.5 X upper limit of normal).
• Patients having received adalimumab, certolizumab, golimumab, tocilizumab, abatacept within 6 weeks, infliximab within 8 weeks, canakinumab within 6 months, etanercept within 2 weeks, or anakinra 1 week prior to the start of Tadekinig alfa will not be enrolled into the study. Patients that have received rituximab within 6 months and/or have persistent low B-cell counts will not be eligible for enrolment.
• Subject who cannot be expected to comply with the study procedures
• Currently participating or having participated in another clinical trial during the last 4 weeks prior to the beginning of this study.
• Patients with no social security coverage
• Patients with a history of severe hypersensitivity reactions

Sponsors & Collaborators

• AB2 Bio Ltd.: lead

Study Sites (20)

Hôpital Pellegrin

Bordeaux, 33076, France

Location

CHRU de Lille - Hôpital Claude Huriez

Lille, 59037, France

Location

Hôpital de la Croix Rousse

Lyon, 69317, France

Location

CHRU de Montpellier

Montpellier, 34090, France

Location

CHU de Nantes - Hôtel Dieu

Nantes, 44093, France

Location

CHU Paris-GH La Pitié Salpêtrière-Charles Foix - Hôpital Pitié-Salpêtrière

Paris, 75651, France

Location

Strasbourg University Hospital

Strasbourg, France

Location

Innere Medizin II - Rheumatologie Schlosspark-Klinik

Berlin, 14059, Germany

Location

Medizinische Klinik - Rheumatologie und Klinische

Berlin, Germany

Location

Universitätsklinikum Erlangen

Erlangen, 91054, Germany

Location

Asklepios Klinik Altona

Hamburg, 22763, Germany

Location

St. Elisabeth Gruppe GmbH Katholische Kliniken Rhein-Ruhr Rheumazentrum Ruhrgebiet

Herne, 44649, Germany

Location

Universitätsklinikum Jena Klinik für Innere Medizin III Rheumatologie/Osteologie

Jena, 07747, Germany

Location

Klinik Kirchheim

Kirchheim unter Teck, 73230, Germany

Location

Universitätsklinikum Schleswig-Holstein - Campus Lübeck

Lübeck, 23538, Germany

Location

UNIVERSITÄTSMEDIZIN der Johannes-Gutenberg-Universität Mainz I. Medizinische Klinik und Poliklinik Rheumatologie

Mainz, 55131, Germany

Location

LMU München

München, 80336, Germany

Location

Hôpitaux Universitaires de Genève - HUG

Geneva, Switzerland

Location

CHUV hospital

Lausanne, Switzerland

Location

Immunologie-Zentrum de Zürich

Zurich, Switzerland

Location

Related Publications (7)

• Bagnari V, Colina M, Ciancio G, Govoni M, Trotta F. Adult-onset Still's disease. Rheumatol Int. 2010 May;30(7):855-62. doi: 10.1007/s00296-009-1291-y. Epub 2009 Dec 18.

  PMID: 20020138 BACKGROUND

• Bywaters EG. Still's disease in the adult. Ann Rheum Dis. 1971 Mar;30(2):121-33. doi: 10.1136/ard.30.2.121. No abstract available.

  PMID: 5315135 BACKGROUND

• Efthimiou P, Kontzias A, Ward CM, Ogden NS. Adult-onset Still's disease: can recent advances in our understanding of its pathogenesis lead to targeted therapy? Nat Clin Pract Rheumatol. 2007 Jun;3(6):328-35. doi: 10.1038/ncprheum0510.

  PMID: 17538564 BACKGROUND

• Fautrel B. Adult-onset Still disease. Best Pract Res Clin Rheumatol. 2008 Oct;22(5):773-92. doi: 10.1016/j.berh.2008.08.006.

  PMID: 19028363 BACKGROUND

• Kawashima M, Yamamura M, Taniai M, Yamauchi H, Tanimoto T, Kurimoto M, Miyawaki S, Amano T, Takeuchi T, Makino H. Levels of interleukin-18 and its binding inhibitors in the blood circulation of patients with adult-onset Still's disease. Arthritis Rheum. 2001 Mar;44(3):550-60. doi: 10.1002/1529-0131(200103)44:33.0.CO;2-5.

  PMID: 11263769 BACKGROUND

• Yamaguchi M, Ohta A, Tsunematsu T, Kasukawa R, Mizushima Y, Kashiwagi H, Kashiwazaki S, Tanimoto K, Matsumoto Y, Ota T, et al. Preliminary criteria for classification of adult Still's disease. J Rheumatol. 1992 Mar;19(3):424-30.

  PMID: 1578458 BACKGROUND

• Gabay C, Fautrel B, Rech J, Spertini F, Feist E, Kotter I, Hachulla E, Morel J, Schaeverbeke T, Hamidou MA, Martin T, Hellmich B, Lamprecht P, Schulze-Koops H, Courvoisier DS, Sleight A, Schiffrin EJ. Open-label, multicentre, dose-escalating phase II clinical trial on the safety and efficacy of tadekinig alfa (IL-18BP) in adult-onset Still's disease. Ann Rheum Dis. 2018 Jun;77(6):840-847. doi: 10.1136/annrheumdis-2017-212608. Epub 2018 Feb 22.

  PMID: 29472362 DERIVED

MeSH Terms

Conditions

Still's Disease, Adult-Onset; Arthritis, Juvenile; Arthritis, Rheumatoid

Condition Hierarchy (Ancestors)

Arthritis; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Skin and Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases

Study Officials

• Cem Gabay, Prof.

  Hospital University of Geneva

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 23, 2015
• First Posted: March 25, 2015
• Study Start: February 1, 2015
• Primary Completion: June 1, 2016
• Study Completion: July 1, 2016
• Last Updated: December 6, 2016

Record last verified: 2016-08

Locations

CH (3); DE (10); FR (7)