Tocilizumab in Active Moderate-severe Graves' Orbitopathy

Description

1 Primary Endpoint:

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

1.2 Secondary Endpoints:

1. Proportion of patients improved at 24 weeks as assessed by the EUGOGO composite ophthalmic score (see below paragraph#5)
2. Improvement of quality of life according to the GO-QoL questionnaire at 12 and 24 weeks.
3. Safety of tocilizumab therapy in patients with GO compared to Methylprednisolone, evaluated on the basis of the following endpoints: Incidence and severity of adverse events, with severity determined according to NCI CTCAE v5.0,
4. Changes of serum TSH receptor binding and stimulating antibodies, anti-TPO antibodies and serum concentrations of IL-6 and sIL-6 receptor at 12, 24 and 36 and 48weeks of follow up.
5. Proportion of patients with disease reactivation (CAS > or =4) during follow-up at 24-48 weeks.
6. Quantification of signs of residual motility abnormalities by motility tests and orbital imaging
7. Number of rehabilitative surgical interventions at the end of follow-up

2.Study Design and Methods

Randomized, single blind (ophthalmologist), controlled study, IIb phase. The study will be conducted in 5 National centres dedicated to the management of Graves' orbitopathy

The present study will randomize GO patients, euthyroid for at least 6-8 weeks, to two

treatments

1. Tocilizumab weight adjusted, 8 mg/kg, 1 intravenous infusion every four weeks (+/- 72 hours) for 12 weeks
2. Methylprednisolone, 500 mg infusion weekly (+/- 48 hours) for 6 weeks, followed by 250 mg infusion weekly (+/- 48 hours) for another 6 weeks

The enrollment period is approximately 24 months

3.Phases of the study

• Screening phase (-4/-2 to 0 weeks): involves 1 to 2 visits
• Treatment phase (0 to 12 weeks): assessments at baseline and every 4 weeks
• Observation phase (12 to 24 weeks): assessments every 6 weeks
• Follow up (24 to 48 weeks): assessments every 12 weeks

Data from week 24 are used to determine primary and secondary endpoints

4.Definition of improvement, worsening or no change of the secondary end point criteria*

1. Improvement, when at least two of the following outcome measures improve in one eye, without deterioration in any of the measure in either eyes: a) reduction in palpebral aperture by at least 3 mm; b) reduction in any of the class 2 signs of NOSPECS by at least 2 grades; c) reduction of proptosis by at least 2 mm; d) improvement of 8 degrees in any duction or in diplopia (Gorman score); e) improvement in CAS by at least 2 points
2. Worsening, when optic neuropathy or two of the following occur: a) increase in palpebral aperture by at least 3 mm; b) increase in any of the class 2 signs of NOSPECS by at least 2 grades; c) increase of proptosis by at least 2 mm; d) deterioration of 8 degrees in any duction or in diplopia (Gorman score); e) worsening in CAS.
3. No change, when there are no changes or changes smaller than the above defined parameters
4. Study population

5.1 Withdrawal Rules

1. Should patients become affected with any of the conditions outlined as exclusion criteria during the study period or follow-up, they will be withdrawn from the study
2. Should patients require administration of any of the medications listed in the exclusion criteria, according to prohibited medication rules, they will be withdrawn from the study.
3. Other reasons for study withdrawal are:
4. refusal of continuing the study medication after having commenced it.
5. diagnosis of major cardiovascular diseases or neoplasia once treatment has started.
6. If patients present with a severe complication of GO, i.e. progression to dysthyroid optic neuropathy due to unresponsiveness to treatment, they will be considertreatment failure and will undergo urgent surgical orbital decompression.

Patients have the right to voluntarily withdraw from the study at any time for any reason. In addition, the investigator has the right to withdraw a patient from the study at any time. Reasons for withdrawal from the study may include, but are not limited to, the following:

Patient withdrawal of consent

Study termination or site closure

Patient non-compliance, defined as failure to comply with protocol requirements as determined by the investigator or Sponsor

Every effort should be made to obtain information on patients who withdraw from the study. The primary reason for withdrawal from the study should be documented on the appropriate eCRF. If a patient requests to be withdrawn from the study, this request must be documented in the source documents and signed by the investigator. Patients who withdraw from the study will not be replaced.

5.2 Study Arms

Arm 1: 32 patients with active moderate-severe GO treated with i.v. tocilizumab

Arm 2: 32 patients with active moderate-severe GO treated with i.v. methylprednisolone.

5.3 Study Medications and Dosing Regimen

Tocilizumab, the IMP-test, will be supplied and distribute by Roche packed and labelled.

Upon delivery to the site, site personnel should check for damage and verify proper identity, quantity, integrity of seals and temperature conditions. Site personnel should report any deviations or product complaints to the study monitor upon discovery.

For information on the formulation and handling of tocilizumab see the SmPC and Investigator's Brochure

Methylprednisolone is the IMP-comparator,

For information on the formulation, packaging, and handling of MP, see the SmPC.

Arm 1. Tocilizumab: i.v. infusion of, weight adjusted, 8 mg/kg of TCZ every four weeks (+/- 72 hours) for 12 weeks.

Arm 2. Methylprednisolone (MP): i.v. infusion of 500 mg of MP weekly (+/- 48 hours) for 6 weeks, followed by i.v. infusion of 250 mg of MP one a week (+/- 48 hours) for 6 weeks

5.4 Study duration

Duration of the study: 3 years (2 years for enrollment and one year for follow up)

5.5 Study Discontinuation

The Sponsor has the right to terminate this study at any time. Reasons for terminating the study may include, but are not limited to, the following:

The incidence or severity of adverse events in this or other studies indicates a potential health hazard to patients

Patient enrollment is unsatisfactory

The Sponsor will notify the investigator if the Sponsor decides to discontinue the study.

5.6 Site Discontinuation

The Sponsor has the right to close a site at any time. Reasons for closing a site may include, but are not limited to, the following:

Excessively slow recruitment

Poor protocol adherence

Inaccurate or incomplete data recording

Non-compliance with the International Council for Harmonisation (ICH) guideline for Good Clinical Practice

No study activity (i.e., all patients have completed the study and all obligations have been fulfilled)

6. Statistical considerations and sample size calculation A sample size of 64 patients is planned to provide at least an 80% power if 32 patients per treatment arm were included for an anticipated (improvement) responder rate of 68% in steroid and 95% in tocilizumab treated patients, with a two-tail significance of 0.05.

No patients stratification is planned The calculation is based on the available literature on the significant decrease of the after rituximab and steroid therapy and after tocilizumab and placebo.

64 patients with active GO will be enrolled and an interim analysis of results will be carried out after the first 32 patients (16 in arm 1 and 16 in arm 2) will reach the 24 week endpoint.

All enrolled patients receiving at least one dose of study medication and withdrawing from the study for any reason will be analyzed as non-responder in an ITT population for the 24 weeks primary endpoint.

Statistical Analysis: repeated measures ANOVA and Spearman or Pearson rank test for clinical activity and severity scores; Wilcoxon rank sum test to assess differences between treatment groups; chi-square for response and relapse rates.

An interim analysis of results will be carried out after the first 16 enrolled patients in both arms reach 24 week point), in order to eventually plan for another study perhaps employing s.c. TCZ .

Details