| Eligibility |
Inclusion Criteria:
A subject will be eligible for inclusion in this study only if all of the following
criteria apply:
1. Male or female subjects between 18 and 75 years of age inclusive.
2. A female subject is eligible to participate if she is of:
1. 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 8.1.1 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.
2. Child-bearing potential and agrees to use one of the contraception methods listed
in Section 8.1.1 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 two weeks prior to dosing and for at least 60 days after the last
dose.
3. Male subjects must agree to use one of the contraception methods listed in Section
8.1.2. This criterion must be followed from the time of the first dose of study
medication until at least 60 days after the last dose of otelixizumab or two months
after adalimumab (Cohort 6 only).
4. Body mass index within the range 18.5 - 35 kg/m^2 inclusive
5. 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.
6. 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.
7. No significant and/or active disease in any body system. Examples of significant
diseases include but are not limited to: coronary artery disease, congestive heart
failure, uncontrolled hypertension, emphysema, seizure disorder, chronic infectious
disease ( e.g., chronic renal infection, chronic chest infection with bronchiectasis,
tuberculosis (TB) or latent tuberculosis, hepatitis B and C).
8. The subject has a diagnosis of RA according to the revised 1987 criteria of the
American College of Rheumatology
9. The subject tests positive for Rheumatoid factor
10. The subject has not previously received otelixizumab or any other anti-CD3 monoclonal
antibody, e.g., OKT3 (muromonab or Orthoclone), ChAglyCD3, or hOKT3?1 (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.
11. 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 dose until day 28 of the study
unless change required for clinical management of disease activity or safety.
12. 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 four weeks prior to dosing and be willing to remain on this dose until day 28 of
the study unless change required for clinical management of disease activity or
safety.
13. If leflunomide is being taken, the patient must have been receiving this DMARD for at
least six months prior to dosing with otelixizumab and the DMARD dose has been stable
dose within local treatment guidelines for four weeks prior to dosing with study drug
and be willing to remain on this dose until day 28 of the study unless change required
for clinical management of disease activity or safety.
14. Patients on glucocorticoids e.g. prednisolone (=10mg/day), must be on stable dosing
regimens for at least four weeks prior to dosing and be willing to remain on this dose
until day 28 of the study.
15. PRN use is acceptable for NSAIDS and COX-2 inhibitors within local treatment
guidelines. Chronic NSAID/COX-2 inhibitor use is not permitted.
16. The subject is seropositive for EBV with <10,000 copies of EBV DNA per 106 lymphocytes
(qPCR) or seronegative with no evidence of recent EBV exposure (EBV IgM negative and
no clinical symptoms suggestive of acute infection)
17. 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 subject will not be eligible for inclusion in this study if any of the following criteria
apply:
1. Subjects with a history of significant systemic involvement secondary to RA (e.g.,
vasculitis, pulmonary fibrosis, or Felty's syndrome)
2. 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.
3. 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.
4. A positive test for HIV antibody or risk factors which predispose subject to HIV
infection.
5. A positive test for syphilis according to local guidelines.
6. 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.
7. 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, five half-lives or twice the duration of the biological effect of the
investigational product (whichever is longer) or planning to take any investigational
drug within six months of the last dose of study drug
8. The subject is currently receiving or has received an anti-rheumatic biological
therapy within the following specified periods prior to dosing:
Within four weeks:
- Glucocorticoid unless given in doses equivalent to <=10 mg of prednisolone/day
- Intramuscular. or i.v. corticosteroids
- Live/attenuated vaccinations
- Cyclosporine
- Etanercept
- Anakinra
Within eight weeks:
- Infliximab
- Rituximab
- Abatacept
9. 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).
10. Previous or current exposure to adalimumab.
11. Exposure to more than four new chemical entities within 12 months prior to the first
dosing day.
12. 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.
13. Where participation in the study would result in donation of blood or blood products
in excess of 600 mL within a 56 day period.
14. Pregnant females as determined by positive (serum or urine) hCG test at screening or
prior to dosing, or lactating females.
15. The subject has received immunization with a vaccine within four weeks before the
first dose of study medication or requires a vaccine within 30 days after the last
dose of study medication.
16. A CD4+ lymphocyte count outside the range of (0.53 - 1.76 × 10^9 )/L during Screening.
17. 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).
18. The subject has received a course of oral antibiotics within 2 weeks of dosing day
one.
19. History of recurrent or chronic infection.
20. The subject has had a splenectomy.
21. 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).
Cohort 6 are required to undergo radiographic screening with CXR, this is optional
according to local guidelines for all other cohorts.
22. 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.
23. Positive plasma / white cell JC virus (JCV) PCR (either compartment)
24. 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.
25. Predisposition to thromboembolic disease, or thromboembolic event (excluding
superficial) in past 12 months.
26. Has clinically significant cardiovascular and/or cerebrovascular disease, including
but not limited to:
- Previous history of stroke or transient ischaemic attack
- Active unstable coronary artery disease within the last 6 months
- Documented myocardial infarction in the 1 year prior to screening
- Any cardiac surgery including percutaneous transluminal coronary angioplasty,
coronary
artery bypass grafting within a year prior to screening
- Unstable angina
- Clinically significant arrhythmia or valvular heart disease within previous year
- Congestive heart failure with New York Heart Association Class II to IV symptoms.
Class I is acceptable.
- Untreated hypertension with systolic pressure greater than 160mmHg, and/or
diastolic pressure greater than 95 mmHg.
27. 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
28. Liver Function Tests must not be outside the range: aspartate aminotransferase (AST)
and alanine aminotransferase (ALT) < 2x upper limit of normal (ULN); alkaline
phosphatase and bilirubin = 1.5x ULN (isolated bilirubin > 1.5x ULN is acceptable if
bilirubin is fractionated and direct bilirubin < 35%).
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