A Safety and Tolerability Study of Otelixizumab in Thyroid Eye Disease
Condition: Graves Ophthalmopathy
MeSH terms: Eye Diseases; Graves Ophthalmopathy
Intervention: Otelixizumab - low dose; Otelixizumab - medium low dose; Otelixizumab - medium high dose; Otelixizumab - high dose; Otelixizumab; Methylprednisolone
Intervention description: 8 day dose rising intravenous infusions of a low dose of otelixizumab; 8 day dose rising intravenous infusions of a medium low dose of otelixizumab; 8 day dose rising intravenous infusions of a medium high dose of otelixizumab; 8 day dose rising intravenous infusions of a high dose of otelixizumab; 8 day dose rising intravenous infusions of otelixizumab administered at a dose decided upon results from Part A.; Weekly intravenous infusions of methylprednisolone administered as 500 mg per week for 6 weeks and then 250 mg per week for 6 weeks
Intervention MeSH terms: Methylprednisolone; Methylprednisolone Acetate; Methylprednisolone Hemisuccinate; Prednisolone; Prednisolone acetate; Prednisolone hemisuccinate; Prednisolone phosphate
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Enrollment: 2.0
Sex: All
Minimum age: 18 Years
Maximum age: 75 Years
Healthy volunteers: No
Keywords: GSK2136525; Pharmacodynamics; Safety; Otelixizumab; Thyroid eye disease; Graves' ophthalmopathy; Repeat dose; Intravenous infusion; Tolerability; EUGOGO

Summary:

      The purpose of this study is to investigate the safety and tolerability of otelixizumab in
      patients with Graves' ophthalmopathy (thyroid eye disease). There is currently no alternative
      therapy available for this condition other than treatment with steroids, or radiotherapy and
      surgery. The study also includes a comparison of the current steroid treatment,
      methylprednisolone, with the proposed new otelixizumab treatment.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Male or female between 18 and 75 years of age inclusive

          -  A female subject is eligible to participate if she is of:

          -  Non-childbearing potential defined as pre-menopausal females with a documented tubal
             ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous
             amenorrhea [in questionable cases a blood sample with simultaneous follicle
             stimulating hormone (FSH) > 40 mIU/ml and estradiol <40 pg/ml (<140 pmol/L) is
             confirmatory].

          -  Child-bearing potential and agrees to use one of the agreed contraception methods
             listed in the protocol for an appropriate period of time to sufficiently minimize the
             risk of pregnancy at that point. Female subjects must agree to use contraception for
             at least 2 weeks prior to dosing and for at least 6 months after the last dose.

          -  Male subjects must agree to use one of the contraception methods listed in the
             protocol. This criterion must be followed from the time of the first dose of study
             medication until at least 60 days after the last dose.

          -  Blood test of liver function within normal range

          -  Body mass index within 18.5 - 35 kg/m2 inclusive

          -  Capable of giving informed consent and agreement to comply with the study restrictions

          -  12-lead ECG within normal limits

          -  fT4 blood levels within reference range for at least 2 months

          -  Active Graves' Ophthalmopathy (GO) with a Clinical Activity Score (CAS) of >/= 3 out
             of 7

          -  Moderately severe GO (as defined by EUGOGO guidelines)

          -  No previous immunosuppressive treatment for GO

          -  Subject is seropositive for EBV with <10,000 copies of EBV DNA per 10^6 lymphocytes
             (qPCR) or seronegative with no evidence of acute EBV infection (asymptomatic, negative
             EBV IgM and EBV viral load of <10,000 per 10^6 lymphocytes)

          -  The subject has no current or prior malignancy, other than non-melanoma skin cancer
             (subject must have had fewer than 5 occurrences of non-melanoma skin cancer, and the
             last occurrence must not be within 3 months of study entry)

        Exclusion Criteria:

          -  A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody
             result within 3 months of screening

          -  Current or chronic history of liver disease, or known hepatic or biliary abnormalities
             (with the exception of Gilbert's syndrome or asymptomatic gallstones)

          -  Positive pre-study drug/alcohol screen. A minimum list of drugs that will be screened
             for include amphetamines, barbiturates, cocaine, opiates, cannabinoids and
             benzodiazepines

          -  Positive test for HIV antibody

          -  Positive test for syphilis

          -  History of regular alcohol consumption within 6 months of the study defined as:

          -  an average weekly intake of greater than 21 units or an average daily intake of
             greater than 3 units (males), or

          -  an average weekly intake of greater than 14 units or an average daily intake of
             greater than 2 units (females)

          -  Participation in a clinical trial and has received an investigational product within
             the following time period prior to the first dosing day in the current study: 30 days,
             5 half-lives or twice the duration of the biological effect of the investigational
             product (whichever is longer) or planning to take any investigational drug for the
             planned duration of study participation (6 months after the last dose of study drug)

          -  Exposure to more than four new chemical entities within 12 months prior to the first
             dosing day

          -  History of sensitivity to any of the study medications, or components thereof or a
             history of drug or other allergy that, in the opinion of the investigator or GSK
             Medical Monitor, contraindicates their participation

          -  Where participation in the study would result in donation of blood or blood products
             in excess of 500 mL within a 56 day period

          -  Pregnant females as determined by positive (serum or urine) hCG test at screening or
             prior to dosing, or lactating females

          -  Currently receiving or has received corticosteroids or other immunosuppressive agents
             within the last 3 months

          -  Evidence of optic neuropathy and/or corneal breakdown

          -  Immunization with a vaccine within 30 days before the first dose of study drug or
             requires a vaccine within 30 days after the last dose of study drug

          -  A CD4+ lymphocyte count outside the range of 0.53 - 1.76 × 109/L during screening

          -  Significant systemic infection during the 6 weeks before the first dose of study drug

          -  Received a course of oral antibiotics within 2 weeks of dosing day one

          -  History of recurrent or chronic infection

          -  Subject has had a splenectomy

          -  Subjects with a screening chest X-ray suggestive of TB without documentation of
             adequate TB treatment

          -  Any major surgical procedure within the 8 weeks before signing the consent form, or
             planning to undergo any such surgery within the 3 months after the last dose of study
             drug

          -  Clinically significant cardiovascular and/or cerebrovascular disease

          -  Predisposition to thromboembolic disease, or thromboembolic event (excluding
             superficial) in past 12 months

          -  Uncontrolled medical conditions: Significant concurrent, uncontrolled medical
             condition including, but not limited to renal, hepatic, hematological,
             gastrointestinal, endocrine, pulmonary, neurological, cerebral psychiatric disease, or
             evidence of demyelinating disease

          -  A condition or situation that, in the investigator's judgment, is likely to cause the
             subject to be unable or unwilling to participate in study procedures or to complete
             all scheduled assessments

          -  Clinically significant abnormal laboratory values during the Screening period, other
             than those due to GO. Abnormal values are permitted if, upon re-test, the abnormality
             was resolved

          -  Unwillingness or inability to follow the procedures outlined in the protocol

          -  Mentally or legally incapacitated