Clinical Trials/NCT00674635

NCT00674635

Completed

Phase 2

A Randomized, Double-blind, Placebo-controlled, Bayesian Adaptive Dose Finding Study to Investigate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single and Repeat Intravenous Infusions GSK315234A in Patients With Active Rheumatoid Arthritis (RA)

GlaxoSmithKline1 site in 1 country135 target enrollmentApril 2008

ConditionsArthritis, Rheumatoid

InterventionsPlacebo GSK3152314A

DrugsGSK3152314A Placebo

Overview

Phase: Phase 2
Intervention: Placebo
Conditions: Arthritis, Rheumatoid
Sponsor: GlaxoSmithKline
Enrollment: 135
Locations: 1
Primary Endpoint: • To assess the safety and tolerability of GSK315234A after single and repeat intravenous infusions in subjects with active rheumatoid arthritis on a background of methotrexate.
Status: Completed
Last Updated: 9 years ago

Overview Investigators Eligibility Criteria Arms & Interventions Outcomes Sites Similar Trials

Overview

Brief Summary

This is a randomized, double-blinded, placebo-controlled adaptive, dose finding study to investigate the safety, tolerability, PK, PD and efficacy of single and repeat intravenous infusions of GSK315243A in patients with active rheumatoid arthritis. The study is divided into 2 parts: Part A is an adaptive, dose finding phase which will provide safety, tolerability, PK and PD on single intravenous infusions. Part B is a repeat dose phase which will provide safety, tolerability, PK, PD and efficacy following repeat intravenous infusions of a selected dose level.

Registry

clinicaltrials.gov

Start Date

April 2008

End Date

December 2010

Last Updated

9 years ago

Study Type

Interventional

Study Design

Parallel

Sex

All

Investigators

Sponsor

GlaxoSmithKline

Responsible Party

Sponsor

Eligibility Criteria

Inclusion Criteria

•Males or females between 18 and 75 years of age, inclusive.
•All subjects must use acceptable contraception (as defined in the study restriction section) to ensure that no pregnancies occur during the course of the study and for at least 12 weeks after dosing for males and for 32 weeks after dosing for females (see Section 7.1 on contraception for more details).
•Body mass index within the range 18.5 - 35 kg/m2 inclusive, in addition to a weight range of 55 - 95kg.
•The subject must be capable of giving informed consent and can comply with the study requirements and timetable.
•The subject must have a diagnosis of RA according to the revised 1987 criteria of the American College of Rheumatology (ACR) (see Appendix 2).
•The subject must have a DAS28 disease activity score of greater than 4.2 at screening and pre-dose.
•The subject must have a CRP serum level of \>/0.5mg/dl or an ESR level 28mm/hour at screening and pre-dose
•The subject has NOT received any biological therapy in the past, including biologicals for the treatment of rheumatoid arthritis
•The subject must have liver function tests including alanine transaminase (ALT) and aspartate transaminase (AST) within 1.5 times the upper limit of normal (ULN) and alkaline phosphatase (ALP) within 3 times ULN at screening. The patient must also have total bilirubin within the ULN at screening.
•The subject must have received at least 3 months of methotrexate and must be on a stable dose of methotrexate (up to 25 mg/week) for at least 8 weeks prior to screening and be willing to remain on this dose throughout the study.

Exclusion Criteria

•Any clinically relevant abnormality identified on the screening medical assessment, laboratory examination (e.g. haematology parameter outside the normal limits), or ECG (12 Lead or Holter).
•The subject has a positive Hepatitis B surface antigen or Hepatitis C antibody result at screening.
•The subject has a history of elevated liver function tests on more than one occasion (ALT, AST and ALP \> 3 x Upper Limit of Normal (ULN); total bilirubin \> 1.5 x ULN) in the past 6 months.
•Previous exposure or past infection caused by Mycobacterium tuberculosis
•The subject has an acute infection.
•The subject has a history of repeated, chronic or opportunistic infections that, in the opinion of the investigator and/or GSK medical monitor, places the subject at an unacceptable risk as a participant in this trial.
•The subject has a history of malignancy, except for surgically cured basal cell carcinoma or females with cured cervical carcinoma (\> 2 yrs prior).
•The subject has a history of human immunodeficiency virus (HIV) or other immunodeficiency disease.
•The subject whose calculated creatinine clearance is less than 50ml/min
•The subject has significant cardiac, pulmonary, metabolic, renal, hepatic or gastrointestinal conditions that, in the opinion of the investigator and/or GSK medical monitor, places the subject at an unacceptable risk as a participant in this trial.

Arms & Interventions

Placebo

matching placebo

Intervention: Placebo

GSK315234A

Part A single IV dose; Part B 3 repeat IV dose at Day 1, Day 28 and Day 56; Part C single SC dose

Intervention: GSK3152314A

Outcomes

Primary Outcomes

• To assess the safety and tolerability of GSK315234A after single and repeat intravenous infusions in subjects with active rheumatoid arthritis on a background of methotrexate.

Time Frame: Part A total of 150Days; Part B total of 236 days and Part C total of 180 days

safety assessment includes AEs, vital signs, ECG, clinical laboratory tests.

• To assess the effect of GSK315234A on disease activity [as defined by Disease Activity Score (DAS) 28 score] on Day 28 after a single intravenous infusion

Time Frame: Part A total of 150 days

DAS28 at Day 28 and DAS28 at Day 56

• To assess the effect of GSK315234A on disease activity [as defined by Disease Activity Score (DAS) 28 score] on Day 56 in subjects with active rheumatoid arthritis on a background of methotrexate (Part B and Part C).

Time Frame: Part B total of 236 days and Part C total of 180 days

DAS28 scores on Day 56 (Part B and C)

Secondary Outcomes

Weighted mean DAS28 after single and repeat intravenous doses(Part A total of 150Days; Part B total of 236 days and Part C total of 180 days)
Physician's global assessment of arthritis condition.(Part A total of 150Days; Part B total of 236 days and Part C total of 180 days)
• To assess the relative bioavailability of GSK315234A administered subcutaneously (Part C) as compared to intravenous administration in subjects with active rheumatoid arthritis on a background of methotrexate(Part C total of 180days)
ACR20/ACR50/ACR70 response after single and repeat intravenous doses(Part A total of 150Days; Part B total of 236 days and Part C total of 180 days)
Plasma PK parameters of GSK315234A after single and repeat intravenous doses including free, and bound GSK315234A (serum) concentrations, AUC(0-¥), Cmax, clearance, volume of distribution and accumulation ratio(Part A total of 150Days; Part B total of 236 days and Part C total of 180 days)
Functional disability index (Health Assessment Questionnaire)(Part A total of 150Days; Part B total of 236 days and Part C total of 180 days)
ESR(Part A total of 150Days; Part B total of 236 days and Part C total of 180 days)
Number of swollen joints assessed using 28-joint counts.(Part A total of 150Days; Part B total of 236 days and Part C total of 180 days)
DAS28 and EULAR response criteria after single and repeat intravenous doses(Part A total of 150Days; Part B total of 236 days and Part C total of 180 days)
C-reactive Protein (CRP).(Part A total of 150Days; Part B total of 236 days and Part C total of 180 days)
Pharmacodynamic biomarkers after single and repeat intravenous doses:(Part A total of 150Days; Part B total of 236 days and Part C total of 180 days)
Patients' global assessment of arthritis condition.(Part A total of 150Days; Part B total of 236 days and Part C total of 180 days)
Global Fatigue Index(Part A total of 150Days; Part B total of 236 days and Part C total of 180 days)
Characteristic AUC50 and EC50 for clinical endpoint changes with plasma exposure model, as assessed by sigmoid Emax and indirect response PK/PD models.(Part A total of 150Days; Part B total of 236 days and Part C total of 180 days)
Immunogenicity (Human anti-GSK315234A antibodies)(Part A total of 150Days; Part B total of 236 days and Part C total of 180 days)
Number of tender/painful joints assessed using 28-joint counts.(Part A total of 150Days; Part B total of 236 days and Part C total of 180 days)
Subject's pain assessment(Part A total of 150Days; Part B total of 236 days and Part C total of 180 days)
HAQ disability index(Part A total of 150Days; Part B total of 236 days and Part C total of 180 days)