Safety, Pharmacodynamics and Pharmacokinetics of GSK2136525 Repeat Dose in Rheumatoid Arthritis

NCT01077531 | Terminated Phase 1

• 1 other identifier: 111601
• Study Type: interventional
• Target: 12
• Locations: 3 countries
• Sites: 7

Brief Summary

The assessment of otelixizumab in rheumatoid arthritis subjects will provide safety, tolerability, pharmacodynamic and pharmacokinetic information which will enable the identification of appropriate safe and well-tolerated dosage regimens to be used in clinical efficacy studies. This study will consist of a screening phase, followed by a treatment period where four cohorts of subjects will receive 5 daily intravenous infusions of otelixizumab. The cumulative dose will increase in each successive cohort and infusion rates can be adjusted based on signs and symptoms of cytokine release syndrome and to ensure the specified maximum infusion rate is not exceeded. Serial blood samples will be obtained for clinical laboratory testing, determination of pharmacodynamic markers, serum otelixizumab PK parameters, exploratory biomarkers and immunogenicity. Safety and pharmacodynamic data from the previous cohort(s) will be evaluated prior to dosing subsequent cohorts to ensure safety. Adverse events, laboratory values, vital signs and ECG's will be monitored closely during this study. All subjects in the study will undergo long-term follow-up out to 48 months to monitor patient safety.

Conditions

Arthritis, Rheumatoid

Keywords

Rheumatoid arthritis; intravenous infusion; long-term followup

Outcome Measures

Primary Outcomes (3)

• Safety and tolerability of multiple doses of otelixizumab: adverse events, ECGs, laboratory safety results, Epstein-Barr Virous viral load, JCV detection.

  48 months

• Saturation and modulation of CD3/TCR complex on peripheral blood T cells

  Six months

• Individual absolute and percentage circulating peripheral T lymphocytes and CD4+ and CD8+ subset counts

  Six months

Secondary Outcomes (3)

• Serum concentrations of otelixizumab and PK parameters

  Five days

• Individual absolute and percentage circulating Treg as measured by foxP3+ and CD4 + foxP3+ subsets

  Six months

• Anti-otelixizumab antibody titres and whether detected antibodies are neutralising

  Three months

Study Arms (2)

Otelixizumab

ACTIVE COMPARATOR

Otelixizumab (GSK2136525) is a humanised, aglycosyl, non-mitogenic, anti CD3 monoclonal antibody (MAb).

Drug: Otelixizumab

Placebo

PLACEBO COMPARATOR

Matching placebo for intravenous infusion

Drug: Matching placebo

Interventions

Otelixizumab DRUG

Otelixizumab injection for intravenous infusion. Otelixizumab (GSK2136525) is a humanised, aglycosyl, non-mitogenic, anti CD3 monoclonal antibody (MAb).

Otelixizumab

Matching placebo DRUG

Matching placebo for intravenous infusion

Placebo

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (7)

GSK Investigational Site

Moscow, 115522, Russia

Location

GSK Investigational Site

Moscow, 119121, Russia

Location

GSK Investigational Site

Yaroslavl, 150003, Russia

Location

GSK Investigational Site

Santander, 39008, Spain

Location

GSK Investigational Site

Santiago de Compostela, 15706, Spain

Location

GSK Investigational Site

Cambridge, Cambridgeshire, CB2 0QQ, United Kingdom

Location

GSK Investigational Site

Newcastle, Northumberland, NE1 4LP, United Kingdom

Location

Related Links

• Researchers can use this site to request access to anonymised patient level data and/or supporting documents from clinical studies to conduct further research.

MeSH Terms

Conditions

Arthritis, Rheumatoid

Interventions

otelixizumab

Condition Hierarchy (Ancestors)

Arthritis; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Skin and Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 25, 2010
• First Posted: March 1, 2010
• Study Start: April 28, 2010
• Primary Completion: March 19, 2013
• Study Completion: March 19, 2013
• Last Updated: June 8, 2017

Record last verified: 2017-06

Data Sharing

• IPD Sharing: Will share

Locations

GB (2); RU (3); ES (2)