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Tocilizumab Treatment in Graves´ Ophthalmopathy (Graves´ Orbitopathy or Thyroid Eye Disease) (GRC)

Primary Purpose

Thyroid Associated Ophthalmopathies, Graves´ Ophthalmopathy, Thyroid Eye Disease

Status
Completed
Phase
Phase 3
Locations
Spain
Study Type
Interventional
Intervention
Tocilizumab (RoActemra®)
Sterile 0.9% Sodium Chloride
Sponsored by
Hospital Clinico Universitario de Santiago
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Thyroid Associated Ophthalmopathies focused on measuring Graves´ orbitopathy, Graves´ ophthalmopathy, Thyroid eye disease, Thyroid-associated ophthalmopathy, Tocilizumab, EUGOGO, CAS

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Principal Inclusion Criteria:

Patients diagnosed GO with CAS ≥ 4 and an index of severity, according EUGOGO guidelines, 1. moderately to severely or 2. sight-threatening GO, after receiving corticosteroid pulse treatment due to:

  • Poor response to intravenous corticosteroid pulses Or
  • Recurrence of the GO, after treatment with intravenous corticosteroids

Exclusion Criteria:

  • Orbital decompression surgery needed immediately
  • Active smoker
  • Patients who could need treatment with radioactive iodine or thyroidectomy during the study
  • Pregnant patient or patient who is planning to become pregnant during the study
  • History of chronic recurrent or active infection
  • History of intestinal ulceration or diverticulitis
  • Patients with a history of chronic liver disease or liver disorders: Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) above 5 times upper limit of normal (ULN)
  • History of HIV, hepatitis C or hepatitis B Positive
  • Neutrophil count < 0.5 × 109/L or a platelet count < 50×103/μL
  • Simultaneous use or contraindications to the use of immunosuppressive agents
  • A treatment with another investigational drug within four weeks of selection or five half-lives of study drug
  • Cardiovascular or cerebrovascular disease clinically significant
  • Uncontrolled diabetes mellitus
  • Use of corticosteroids during four weeks before to inclusion period
  • History of reactions or anaphylactic allergic severe human monoclonal antibodies, humanized or murine
  • Uncontrolled pathologies, whose exacerbations are treated with corticosteroids

Sites / Locations

  • Hospital Clínico de Santiago
  • Hospital Santa Creu i Sant Pau
  • Hospital Clínico San Carlos
  • Hospital Universitario Ramón y Cajal
  • Centro Oftalmológico Moreiras
  • Hospital Universitario Virgen del Rocío
  • Hospital Universitario Virgen Macarena
  • Hospital Universitario La Fe
  • Hospital Clínico Universitario Lozano Blesa

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Tocilizumab

Sterile 0.9% Sodium Chloride

Arm Description

Outcomes

Primary Outcome Measures

Drug efficacy will be established as a decrease in CAS (clinical activity score) by 2 or more points in a scale of 10.

Secondary Outcome Measures

Clinical response of patients who respond to treatment with tocilizumab
Evaluate the patients quality of life associated with tocilizumab treatment, using SF-36
Determine time to recurrence during follow-up period
Safety as adverse events reported

Full Information

First Posted
February 16, 2011
Last Updated
January 19, 2016
Sponsor
Hospital Clinico Universitario de Santiago
Collaborators
Fundación Ramón Domínguez
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1. Study Identification

Unique Protocol Identification Number
NCT01297699
Brief Title
Tocilizumab Treatment in Graves´ Ophthalmopathy (Graves´ Orbitopathy or Thyroid Eye Disease)
Acronym
GRC
Official Title
Clinical Trial Phase III, Parallel Group, Randomized, Placebo-controlled, Double-blind, Multicenter Study to Evaluate the Efficacy and Safety of Tocilizumab Administration in Patients With Moderate-to-severe or Sight-threatening Graves' Ophthalmopathy (GO), That Had Not Responded Adequately to Treatment With Intravenous Corticoid Pulses.
Study Type
Interventional

2. Study Status

Record Verification Date
January 2016
Overall Recruitment Status
Completed
Study Start Date
March 2012 (undefined)
Primary Completion Date
October 2015 (Actual)
Study Completion Date
December 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Hospital Clinico Universitario de Santiago
Collaborators
Fundación Ramón Domínguez

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
The purpose is to investigate tocilizumab administration in patients with moderately to severely or sight-threatening GO (Graves' ophthalmopathy) without response to treatment with corticoid intravenous pulses. Currently, these patients only have surgery as therapeutic alternative. The principal aim of this study is to evaluate efficacy and safety of tocilizumab treatment in order to provide a better alternative to surgery for this patients.
Detailed Description
Thyroid orbitopathy or Graves´orbitopathy (GO) is manifested for inflammation of the orbital and periorbital soft tissues. Ten percent of patients with GO will have long-term serious eye problems. The cause of the GO is complex. Autoreactive T cells recognize an autoantigen, the TSH receptor present in the orbit and thyroid follicular cell, secrete cytokines (IL-6), which stimulate the fibroblasts to synthesize glycosaminoglycan, which draws liquid produce periorbital edema and muscle, causing exophthalmos. This approach suggests that inhibition of IL-6 can be an effective treatment for this problem on the basis that tocilizumab specifically binds to the receptors of the IL-6, both soluble and membrane-bound. Tocilizumab has been shown to inhibit signaling mediated for IL-6Rm IL-6Rs.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Thyroid Associated Ophthalmopathies, Graves´ Ophthalmopathy, Thyroid Eye Disease
Keywords
Graves´ orbitopathy, Graves´ ophthalmopathy, Thyroid eye disease, Thyroid-associated ophthalmopathy, Tocilizumab, EUGOGO, CAS

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
32 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Tocilizumab
Arm Type
Experimental
Arm Title
Sterile 0.9% Sodium Chloride
Arm Type
Placebo Comparator
Intervention Type
Drug
Intervention Name(s)
Tocilizumab (RoActemra®)
Intervention Description
Single intravenous infusion of tocilizumab (8 mg/kg); every 4 weeks during 16 weeks.
Intervention Type
Drug
Intervention Name(s)
Sterile 0.9% Sodium Chloride
Intervention Description
Single intravenous dip infusion of a sterile 0.9% sodium chloride, every four weeks during 16 weeks.
Primary Outcome Measure Information:
Title
Drug efficacy will be established as a decrease in CAS (clinical activity score) by 2 or more points in a scale of 10.
Time Frame
It will be measured before treatment (week -4 / 0), after treatment (week 16) and after the end of the follow-up (week 40).
Secondary Outcome Measure Information:
Title
Clinical response of patients who respond to treatment with tocilizumab
Time Frame
It will be analyzed before treatment (week -4 / 0), after treatment (week 16) and once to follow up (week 40).
Title
Evaluate the patients quality of life associated with tocilizumab treatment, using SF-36
Time Frame
It will be analyzed before treatment (week -4 / 0), after treatment (week 16) and once to follow up (week 40).
Title
Determine time to recurrence during follow-up period
Time Frame
It is measured on a weeks-time scale assessed by the physician during patient follow-up visits.
Title
Safety as adverse events reported
Time Frame
12 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Principal Inclusion Criteria: Patients diagnosed GO with CAS ≥ 4 and an index of severity, according EUGOGO guidelines, 1. moderately to severely or 2. sight-threatening GO, after receiving corticosteroid pulse treatment due to: Poor response to intravenous corticosteroid pulses Or Recurrence of the GO, after treatment with intravenous corticosteroids Exclusion Criteria: Orbital decompression surgery needed immediately Active smoker Patients who could need treatment with radioactive iodine or thyroidectomy during the study Pregnant patient or patient who is planning to become pregnant during the study History of chronic recurrent or active infection History of intestinal ulceration or diverticulitis Patients with a history of chronic liver disease or liver disorders: Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) above 5 times upper limit of normal (ULN) History of HIV, hepatitis C or hepatitis B Positive Neutrophil count < 0.5 × 109/L or a platelet count < 50×103/μL Simultaneous use or contraindications to the use of immunosuppressive agents A treatment with another investigational drug within four weeks of selection or five half-lives of study drug Cardiovascular or cerebrovascular disease clinically significant Uncontrolled diabetes mellitus Use of corticosteroids during four weeks before to inclusion period History of reactions or anaphylactic allergic severe human monoclonal antibodies, humanized or murine Uncontrolled pathologies, whose exacerbations are treated with corticosteroids
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Juan Jesús Gómez-Reino Carnota, MD, PhD
Organizational Affiliation
Hospital Clínico de Santiago
Official's Role
Study Chair
First Name & Middle Initial & Last Name & Degree
Jóse V. Pérez Moreiras, MD, PhD
Organizational Affiliation
Centro Oftalmológico Moreiras
Official's Role
Principal Investigator
Facility Information:
Facility Name
Hospital Clínico de Santiago
City
Santiago de Compostela
State/Province
A Coruña
ZIP/Postal Code
15706
Country
Spain
Facility Name
Hospital Santa Creu i Sant Pau
City
Barcelona
Country
Spain
Facility Name
Hospital Clínico San Carlos
City
Madrid
Country
Spain
Facility Name
Hospital Universitario Ramón y Cajal
City
Madrid
Country
Spain
Facility Name
Centro Oftalmológico Moreiras
City
Santiago de Compostela
Country
Spain
Facility Name
Hospital Universitario Virgen del Rocío
City
Sevilla
Country
Spain
Facility Name
Hospital Universitario Virgen Macarena
City
Sevilla
Country
Spain
Facility Name
Hospital Universitario La Fe
City
Valencia
Country
Spain
Facility Name
Hospital Clínico Universitario Lozano Blesa
City
Zaragoza
Country
Spain

12. IPD Sharing Statement

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Tocilizumab Treatment in Graves´ Ophthalmopathy (Graves´ Orbitopathy or Thyroid Eye Disease)

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