Clinical trial NCT01077531 (phase 1, status: terminated)
Conditions: arthritis, rheumatoid
ICD codes: M06.9, M05.9, M06.08, M06.00, M06.011, M06.012, M06.019
Drugs: otelixizumab, matching placebo
SMILES: CC1=CC(O)=CC(C)=C1Cl
Reason stopped: 
    the risk-benefit ratio for patients has changed since we initiated the study, and that the
    study in its current form cannot be justified
  
Eligibility criteria:

        Inclusion Criteria:

          -  Male or female subjects between 18 and 75 years of age inclusive.

          -  Female subjects of: a. 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]. Females on hormone replacement therapy (HRT) and whose
             menopausal status is in doubt will be required to use one of the contraception methods
             in Section 8.1 if they wish to continue their HRT during the study. Otherwise, they
             must discontinue HRT to allow confirmation of post-menopausal status prior to study
             enrollment. For most forms of HRT, at least 2-4 weeks will elapse between the
             cessation of therapy and the blood draw; this interval depends on the type and dosage
             of HRT. Following confirmation of their post-menopausal status, they can resume use of
             HRT during the study without use of a contraceptive method. b. Child-bearing potential
             and agrees to use one of the contraception methods listed in Section 8.1 of 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 60 days after the last dose.

          -  Male subjects must agree to use one of the contraception methods listed in Section 8.1
             of 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.

          -  Body mass index within the range 18.5 - 35 kg/m2 inclusive.

          -  Capable of giving written informed consent, which includes compliance with the
             requirements and restrictions listed in the consent form and willing and able to
             follow the procedures outlined in the protocol.

          -  A 12-lead ECG at pre-study screening measured in triplicate, which in the opinion of
             the Principal Investigator or physician designee has no abnormalities that will
             compromise safety in this study. QTcB < 450 msec; or QTc < 480 msec in subjects with
             Bundle Branch Block.

          -  The subject has a diagnosis of RA according to the revised 1987 criteria of the
             American College of Rheumatology.

          -  The subject tests positive for Rheumatoid factor.

          -  The subject has active disease with at least 3 swollen and 3 tender joints, early
             morning joint stiffness ≥ 30 minutes and a serum CRP>5mg/L (3 out of 4) at screening.

          -  The subject has ACR functional class I-III.

          -  The subject has persistent disease activity in spite of therapy with at least one
             DMARD.

          -  The subject has not previously received otelixizumab or any other anti-CD3 monoclonal
             antibody, e.g., OKT3 (muromonab or Orthoclone), ChAglyCD3, or hOKT3γ1 (ala ala), and
             is willing to refrain from using any such antibody for 2 years after the last dose of
             study drug unless invited to participate in possible future studies with otelixizumab.

          -  If taking methotrexate, the patient must have been taking methotrexate for at least 12
             weeks and to be on a stable dose of methotrexate (7.5-25 mg/week) for at least four
             weeks prior to dosing and be willing to remain on this up to 12 weeks after last dose
             of the investigational product in this study unless change required for clinical
             management of disease activity or safety.

          -  If sulfasalazine is being taken, the patient must have been taking sulfasalazine for
             at least 12 weeks and to be on a stable dose within local treatment guidelines for at
             least 4 weeks prior to dosing and be willing to remain on this dose for at least 12
             weeks after the last dose of study drug unless change required for clinical management
             of disease activity or safety.

          -  If leflunomide is being taken, the patient must have been receiving this DMARD for at
             least 6 months prior to dosing with otelixizumab and the DMARD dose has been stable
             dose within local treatment guidelines for 12 weeks prior to dosing with study drug.

          -  Patients on glucocorticoids e.g. prednisolone (≤10mg/day), must be on stable dosing
             regimens for at least 4 weeks prior to dosing and be willing to remain on this regime
             for at least 12 weeks after the last dose of study drug.

          -  PRN use is acceptable for NSAIDS and COX-2 inhibitors within local treatment
             guidelines.

          -  The subject is seropositive for EBV with <10,000 copies of EBV DNA per 106 lymphocytes
             (qPCR) or seronegative with no evidence of acute EBV infection (asymptomatic, negative
             EBV IgM and EBV viral load of <10,000 per 106 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:

          -  Subjects with a history of significant systemic involvement secondary to RA (e.g.,
             vasculitis, pulmonary fibrosis, or Felty's syndrome).

          -  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.

          -  The subject has a positive pre-study drug/alcohol screen. A minimum list of drugs that
             will be screened for include amphetamines, barbiturates, cocaine, opiates,
             cannabinoids and benzodiazepines.

          -  A positive test for HIV antibody.

          -  A positive EIA 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 defined as an average weekly intake of greater than 14 units
             or an average daily intake of greater than 2 units (females). One unit is equivalent
             to a half-pint (220mL) of beer or 1 (25ml) measure of spirits or 1 glass (125ml) of
             wine.

          -  The subject has participated 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).

          -  Previous or current exposure to biologic cell-depleting anti-rheumatic therapies,
             including investigational compounds (e.g. anti-CD11a, anti-CD-20, anti-CD22,
             anti-BLyS/BAFF, anti-CD3, anti-CD5, anti-CD52).

          -  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.

          -  The subject is currently receiving or has received an anti-rheumatic biological
             therapy within the following specified periods prior to dosing: Within 4 weeks:
             Glucocorticoid unless given in doses equivalent to ≤10 mg of prednisolone/day;
             Intramuscular. or i.v. corticosteroids; Live/attenuated vaccinations; Cyclosporine;
             Etanercept, within 8 weeks: Rituximab; Infliximab; Adalimumab or other subcutaneous
             anti-TNF/TNF-Rc therapy; Anakinra; Abatacept; Tocilizumab; Certolizumab, within 24
             weeks: Anti-cancer therapy (e.g. alkylating agents, anti-metabolites, purine
             analogues, monoclonal antibodies).

          -  The subject has received immunization with a vaccine within 4 weeks 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.

          -  The subject has had a significant systemic infection during the 6 weeks before the
             first dose of study drug (e.g., infection requiring hospitalization, major surgery, or
             IV antibiotics to resolve); other infections, e.g., bronchitis, sinusitis, localized
             cellulitis, candidiasis, or urinary tract infections, must be assessed on a
             case-by-case basis by the investigator regarding whether they are serious enough to
             warrant exclusion).

          -  The subject has received a course of oral antibiotics within 2 weeks of dosing day
             one.

          -  History of recurrent or chronic infection.

          -  The subject has had a splenectomy.

          -  Subjects with a screening chest X-ray suggestive of TB without documentation of
             adequate TB treatment will be excluded. Screening for latent TB infection using
             intradermal injection of tuberculin (e.g. the Mantoux test or equivalent) should be
             conducted in accordance with local guidelines. The tuberculin skin test results should
             be evaluated according to the criteria for immunocompromised subjects. Subjects with a
             positive skin tuberculin test should be excluded if the investigator judges the
             patient to be at risk of latent TB infection.

          -  The subject has undergone 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.

          -  Has clinically significant cardiovascular and/or cerebrovascular disease including,
             but not limited to: Previous history of stroke or transient ischemic attack; Active,
             unstable coronary heart disease within the past 6 months; Documented myocardial
             infarction within a year of screening; Any cardiac surgery including percutaneous
             transluminal coronary angioplasty or coronary artery bypass graft surgery within a
             year prior to screening; Unstable angina; Clinically significant arrhythmia or
             valvular heart disease within the past year; Congestive heart failure with New York
             Heart Association Class II to Class IV symptoms. Class I is acceptable; Untreated
             hypertension, with systolic pressure greater than 160mm Hg and/or diastolic pressure
             greater than 95mm Hg.

          -  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.

          -  Positive plasma / white cell JC virus (JCV) PCR (either compartment).

          -  The subject has 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.

          -  The subject has clinically significant abnormal laboratory values during the Screening
             period, other than those due to RA. Abnormal values are permitted if, upon re-test,
             the abnormality was resolved (ALT <2xULN, AST <2xULN).