Tocilizumab in Active Moderate-severe Graves' Orbitopathy

NCT04876534 | Unknown Phase 2 DMC

• 1 other identifier: ML39921
• Study Type: interventional
• Target: 64
• Locations: 1 country
• Sites: 4

Brief Summary

To treat patientis with active moderate-severe GO with the anti-IL6 receptor monoclonal antibody tocilizubam with the purpose of assesing the efficacy of therapy on active GO and on the proportion of patiens with inactivation and reactivation of disease (Primary Objective) Effect of therapy on disease progression, improvement of QoL, the degree of residual disease after the inflammatory phase and safety of treatment (Secondary Objective)

Conditions

Graves Ophthalmopathy

Keywords

Graves' orbitopathy; Graves' disease; Tocilizumab; Hyperthyroidism; Thyroid's disease

Outcome Measures

Primary Outcomes (1)

• Desease inactivation

  Proportion of patients with CAS reduction of 3 points or disease inactivation (CAS\<4) at 12 and 24 weeks

  at 12 and 24 weeks

Secondary Outcomes (7)

• Desease improvement

  24 weeks

• Improvement of quality of life

  at 12 and 24 weeks

• Incident of adverse events in tocilizumab therapy

  from 0 to 12 weeks

• Immunological changes

  at 12, 24 and 36 and 48weeks of follow up

• Desease relapse

  at 24-48 weeks

Study Arms (2)

Tocilizumab

EXPERIMENTAL

32 patients with active moderate-severe GO treated with i.v. tocilizumab; Tocilizumab weight adjusted, 8 mg/kg, 1 intravenous infusion every four weeks (+/- 72 hours) for 12 weeks

Drug: Tocilizumab 20 Mg/mL Intravenous Solution

Methylprednisolone

ACTIVE COMPARATOR

32 patients with active moderate-severe GO treated with i.v. methylprednisolone; Methylprednisolone, 500 mg infusion weekly (+/- 48 hours) for 6 weeks, followed by 250 mg infusion weekly (+/- 48 hours) for another 6 weeks

Drug: MethylPREDNISolone Injectable Solution

Interventions

Tocilizumab 20 Mg/mL Intravenous Solution DRUG

Intravenous administration

Also known as: Actemra

Tocilizumab

MethylPREDNISolone Injectable Solution DRUG

Intravenous administration

Also known as: Solumedrol

Methylprednisolone

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Written informed consent
• Male or female, 18-75 years old
• Women of childbearing potential should use effective contraception (abstinence or use contraceptive methods with a failure rate of \<1%) throughout study and for a minimum of 6 months after study drug therapy and must have a negative serum pregnancy test at screening
• GO at first diagnosis or at the time of relapse of no more than 9 months' duration.
• Patients with moderate-severe active GO (clinical activity score 4/10 assessed at the end of the screening period) untreated or previously treated with i.v. steroids withdrawn for at least 3 months.
• Euthyroid for at least 6-8 weeks (serum free hormone concentrations within 20% of normal range), on either anti-thyroid medications (tyonamides) to control hyperthyroidism or L-thyroxine for replacement therapy for hypothyroidism.
• Patients will also be allowed to stay on propranolol treatment for the control of tachycardia.

You may not qualify if:

• Patients with sight-threatening Graves' orbitopathy (severe keratopathy, compression optic neuropathy and inflammatory optic neuropathy).
• Treatment with any biological therapy at any time.
• Previous oral or intravenous corticosteroid treatment in the last three months except for oral steroid not exceeding a cumulative dose of 1 gr.
• Plasmapheresis within 90 days prior to Day 0.
• Treatment with intravenous immunoglobulin.
• Azathioprine more than 100 mg/day within 30 days before screening.
• Administration of live vaccines given within 30 days prior to administration of (Day 0) or concurrently with tocilizumab (during study).
• Splenectomy.
• Subjects at risk of bleeding that threatens a vital organ.
• History of a major organ transplant or hematopoietic stem cell/marrow transplant.
• History of malignant neoplasm within the last 5 years, except for adequately treated cancers of the skin (basal or squamous cell) or carcinoma in situ of the uterine cervix.
• Required management of infections, as follows: currently on any suppressive therapy for a chronic infection, hospitalization for treatment of infection within 60 days before Day 0, use of parenteral antibiotics within 60 days before Day 0, use of oral antibiotics within 30 days before Day 0.
• Pregnancy.
• Patients with reproductive potential not willing to use an effective method of contraception throughout study and for a minimum of 6 months after study drug therapy
• Breast feeding.

Sponsors & Collaborators

• Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico: lead
• Mauriziano Umberto I Hospital: collaborator
• Istituto Auxologico Italiano: collaborator
• Azienda Ospedaliera "Sant'Andrea": collaborator
• Azienda Ospedaliero, Universitaria Pisana: collaborator

Study Sites (4)

Istituto Auxologico Italiano

Milan, MI, 20149, Italy

RECRUITING

Azienda Ospedaliero, Universitaria Pisana

Pisa, PI, 56126, Italy

RECRUITING

Azienda Ospedaliera "Sant'Andrea"

Roma, RM, 00189, Italy

RECRUITING

Mauriziano Umberto I Hospital

Torino, TO, 10128, Italy

RECRUITING

Related Publications (21)

• Bartalena L, Baldeschi L, Boboridis K, Eckstein A, Kahaly GJ, Marcocci C, Perros P, Salvi M, Wiersinga WM; European Group on Graves' Orbitopathy (EUGOGO). The 2016 European Thyroid Association/European Group on Graves' Orbitopathy Guidelines for the Management of Graves' Orbitopathy. Eur Thyroid J. 2016 Mar;5(1):9-26. doi: 10.1159/000443828. Epub 2016 Mar 2.

  PMID: 27099835 BACKGROUND

• Campi I, Vannucchi G, Salvi M. THERAPY OF ENDOCRINE DISEASE: Endocrine dilemma: management of Graves' orbitopathy. Eur J Endocrinol. 2016 Sep;175(3):R117-33. doi: 10.1530/EJE-15-1164. Epub 2016 Mar 31.

  PMID: 27032693 BACKGROUND

• Salvi M, Campi I. Medical Treatment of Graves' Orbitopathy. Horm Metab Res. 2015 Sep;47(10):779-88. doi: 10.1055/s-0035-1554721. Epub 2015 Sep 11.

  PMID: 26361263 BACKGROUND

• Campi I, Tosi D, Rossi S, Vannucchi G, Covelli D, Colombo F, Trombetta E, Porretti L, Vicentini L, Cantoni G, Curro N, Beck-Peccoz P, Bulfamante G, Salvi M. B Cell Activating Factor (BAFF) and BAFF Receptor Expression in Autoimmune and Nonautoimmune Thyroid Diseases. Thyroid. 2015 Sep;25(9):1043-9. doi: 10.1089/thy.2015.0029. Epub 2015 Aug 13.

  PMID: 26214745 BACKGROUND

• Salvi M, Vannucchi G, Curro N, Campi I, Covelli D, Dazzi D, Simonetta S, Guastella C, Pignataro L, Avignone S, Beck-Peccoz P. Efficacy of B-cell targeted therapy with rituximab in patients with active moderate to severe Graves' orbitopathy: a randomized controlled study. J Clin Endocrinol Metab. 2015 Feb;100(2):422-31. doi: 10.1210/jc.2014-3014. Epub 2014 Dec 15.

  PMID: 25494967 BACKGROUND

• Salvi M. Immunotherapy for Graves' ophthalmopathy. Curr Opin Endocrinol Diabetes Obes. 2014 Oct;21(5):409-14. doi: 10.1097/MED.0000000000000097.

  PMID: 25105999 BACKGROUND

• Curro N, Covelli D, Vannucchi G, Campi I, Pirola G, Simonetta S, Dazzi D, Guastella C, Pignataro L, Beck-Peccoz P, Ratiglia R, Salvi M. Therapeutic outcomes of high-dose intravenous steroids in the treatment of dysthyroid optic neuropathy. Thyroid. 2014 May;24(5):897-905. doi: 10.1089/thy.2013.0445. Epub 2014 Mar 6.

  PMID: 24417307 BACKGROUND

• Vannucchi G, Covelli D, Campi I, Origo D, Curro N, Cirello V, Dazzi D, Beck-Peccoz P, Salvi M. The therapeutic outcome to intravenous steroid therapy for active Graves' orbitopathy is influenced by the time of response but not polymorphisms of the glucocorticoid receptor. Eur J Endocrinol. 2013 Nov 22;170(1):55-61. doi: 10.1530/EJE-13-0611. Print 2014 Jan.

  PMID: 24128430 BACKGROUND

• Salvi M, Vannucchi G, Beck-Peccoz P. Potential utility of rituximab for Graves' orbitopathy. J Clin Endocrinol Metab. 2013 Nov;98(11):4291-9. doi: 10.1210/jc.2013-1804. Epub 2013 Sep 5.

  PMID: 24009135 BACKGROUND

• Vannucchi G, Covelli D, Curro N, Dazzi D, Maffini A, Campi I, Bonara P, Guastella C, Pignataro L, Ratiglia R, Beck-Peccoz P, Salvi M. Serum BAFF concentrations in patients with Graves' disease and orbitopathy before and after immunosuppressive therapy. J Clin Endocrinol Metab. 2012 May;97(5):E755-9. doi: 10.1210/jc.2011-2614. Epub 2012 Mar 7.

  PMID: 22399512 BACKGROUND

• Salvi M, Vannucchi G, Curro N, Introna M, Rossi S, Bonara P, Covelli D, Dazzi D, Guastella C, Pignataro L, Ratiglia R, Golay J, Beck-Peccoz P. Small dose of rituximab for graves orbitopathy: new insights into the mechanism of action. Arch Ophthalmol. 2012 Jan;130(1):122-4. doi: 10.1001/archopthalmol.2011.1215. No abstract available.

  PMID: 22232486 BACKGROUND

• Salvi M, Vannucchi G, Campi I, Curro N, Dazzi D, Simonetta S, Bonara P, Rossi S, Sina C, Guastella C, Ratiglia R, Beck-Peccoz P. Treatment of Graves' disease and associated ophthalmopathy with the anti-CD20 monoclonal antibody rituximab: an open study. Eur J Endocrinol. 2007 Jan;156(1):33-40. doi: 10.1530/eje.1.02325.

  PMID: 17218723 BACKGROUND

• Vannucchi G, Campi I, Bonomi M, Covelli D, Dazzi D, Curro N, Simonetta S, Bonara P, Persani L, Guastella C, Wall J, Beck-Peccoz P, Salvi M. Rituximab treatment in patients with active Graves' orbitopathy: effects on proinflammatory and humoral immune reactions. Clin Exp Immunol. 2010 Sep;161(3):436-43. doi: 10.1111/j.1365-2249.2010.04191.x.

  PMID: 20529087 BACKGROUND

• Salvi M, Vannucchi G, Campi I, Curro N, Simonetta S, Covelli D, Pignataro L, Guastella C, Rossi S, Bonara P, Dazzi D, Ratiglia R, Beck-Peccoz P. Rituximab treatment in a patient with severe thyroid-associated ophthalmopathy: effects on orbital lymphocytic infiltrates. Clin Immunol. 2009 May;131(2):360-5. doi: 10.1016/j.clim.2008.12.005. Epub 2009 Feb 4.

  PMID: 19195932 BACKGROUND

• Yanaba K, Bouaziz JD, Matsushita T, Magro CM, St Clair EW, Tedder TF. B-lymphocyte contributions to human autoimmune disease. Immunol Rev. 2008 Jun;223:284-99. doi: 10.1111/j.1600-065X.2008.00646.x.

  PMID: 18613843 BACKGROUND

• Rowland SL, Leahy KF, Halverson R, Torres RM, Pelanda R. BAFF receptor signaling aids the differentiation of immature B cells into transitional B cells following tonic BCR signaling. J Immunol. 2010 Oct 15;185(8):4570-81. doi: 10.4049/jimmunol.1001708. Epub 2010 Sep 22.

  PMID: 20861359 BACKGROUND

• Moore PA, Belvedere O, Orr A, Pieri K, LaFleur DW, Feng P, Soppet D, Charters M, Gentz R, Parmelee D, Li Y, Galperina O, Giri J, Roschke V, Nardelli B, Carrell J, Sosnovtseva S, Greenfield W, Ruben SM, Olsen HS, Fikes J, Hilbert DM. BLyS: member of the tumor necrosis factor family and B lymphocyte stimulator. Science. 1999 Jul 9;285(5425):260-3. doi: 10.1126/science.285.5425.260.

  PMID: 10398604 BACKGROUND

• Gilbert JA, Kalled SL, Moorhead J, Hess DM, Rennert P, Li Z, Khan MZ, Banga JP. Treatment of autoimmune hyperthyroidism in a murine model of Graves' disease with tumor necrosis factor-family ligand inhibitors suggests a key role for B cell activating factor in disease pathology. Endocrinology. 2006 Oct;147(10):4561-8. doi: 10.1210/en.2006-0507. Epub 2006 Jun 22.

  PMID: 16794009 BACKGROUND

• Salvi M, Girasole G, Pedrazzoni M, Passeri M, Giuliani N, Minelli R, Braverman LE, Roti E. Increased serum concentrations of interleukin-6 (IL-6) and soluble IL-6 receptor in patients with Graves' disease. J Clin Endocrinol Metab. 1996 Aug;81(8):2976-9. doi: 10.1210/jcem.81.8.8768861.

  PMID: 8768861 BACKGROUND

• Campi I, Vannucchi GM, Minetti AM, Dazzi D, Avignone S, Covelli D, Curro N, Ratiglia R, Guastella C, Pignataro L, Beck-Peccoz P, Salvi M. A quantitative method for assessing the degree of axial proptosis in relation to orbital tissue involvement in Graves' orbitopathy. Ophthalmology. 2013 May;120(5):1092-8. doi: 10.1016/j.ophtha.2012.10.041. Epub 2013 Feb 8.

  PMID: 23399378 BACKGROUND

• Perez-Moreiras JV, Gomez-Reino JJ, Maneiro JR, Perez-Pampin E, Romo Lopez A, Rodriguez Alvarez FM, Castillo Laguarta JM, Del Estad Cabello A, Gessa Sorroche M, Espana Gregori E, Sales-Sanz M; Tocilizumab in Graves Orbitopathy Study Group. Efficacy of Tocilizumab in Patients With Moderate-to-Severe Corticosteroid-Resistant Graves Orbitopathy: A Randomized Clinical Trial. Am J Ophthalmol. 2018 Nov;195:181-190. doi: 10.1016/j.ajo.2018.07.038. Epub 2018 Aug 4.

  PMID: 30081019 BACKGROUND

MeSH Terms

Conditions

Graves Ophthalmopathy; Graves Disease; Hyperthyroidism

Interventions

tocilizumab; Methylprednisolone Hemisuccinate

Condition Hierarchy (Ancestors)

Eye Diseases, Hereditary; Eye Diseases; Exophthalmos; Orbital Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Goiter; Thyroid Diseases; Endocrine System Diseases; Autoimmune Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Methylprednisolone; Prednisolone; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds

Study Officials

• Mario MS Salvi, MD

  Fondazione IRCCS "Cà Granda" Ospedale Maggiore Policlinico

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Mario MS Salvi, MD

CONTACT

+39 025-503-3332; mario.salvi@policlinico.mi.it

Ilaria IM Muller, MD,PhD

CONTACT

+39 025-503-3332; ilaria.muller@unimi.it

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: CARE PROVIDER
• Masking Details: The ophthalmologist assessing the ophthalmic changes is blinded to the patient's treatment
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 32 patients with active moderate-severe GO treated with i.v. tocilizumab; 32 patients with active moderate-severe GO treated with i.v. methylprednisolone.

Study Record Dates

• First Submitted: May 3, 2021
• First Posted: May 6, 2021
• Study Start: December 18, 2019
• Primary Completion: December 18, 2022
• Study Completion: December 18, 2023
• Last Updated: August 4, 2022

Record last verified: 2022-08

Data Sharing

• IPD Sharing: Will not share

Locations

IT (4)