Multicenter, dubbelblind, gerandomiseerd, parallel, placebo-gecontroleerd onderzoek om de veiligheid, werkzaamheid en farmacokinetiek tussen 2 orale dosis, 25 mg PG-760564 twee maal daags en 100 mg PG-760564 twee maal daags bij volwassen patienten met reumatoide arthritis die met methotrexaat worden behandeld te vergelijken.

Rheumatoid arthritis (RA) is a chronic inflammatory arthritis with a worldwide
prevalence of 0.5% to 1%.1,2 Rheumatoid arthritis causes substantial morbidity:
approximately 50% of patients are unable to work within 10 years of disease
onset.3 Rheumatoid arthritis is a systemic inflammatory disorder and RA
patients may also develop extra-articular manifestations in different organ
systems.
The importance of pro-inflammatory cytokines in the pathogenesis of RA has been
shown in clinical trials of biologic agents that block tumor necrosis factor
alpha (TNF-α) and interleukin-1 (IL-1) activity.4,,,567 Although anti-TNF-α
therapies have been reported to increase the risk of infection, they have shown
significant efficacy in RA and have set a new standard in the management of RA.
There are 3 TNF-α antagonists currently approved for RA in the US.
PG-760564
[2-(4-Fluorophenyl)-6,7-dihydro-3-(2-phenoxy-4-pyrimidinyl)-1H,5H-pyrazolo(1,2-a
)pyrazol-1-one] is a cytokine synthesis/release inhibitor with p-38
mitogen-activated protein (MAP) kinase inhibition activity that is being
investigated as a treatment for RA. PG-760564 has been shown to inhibit p-38
MAP kinase directly and has been shown to inhibit the release of TNF-α and IL-1
from a number of cell types. Oral administration of PG-760564 was effective in
both the prevention and treatment components of the rat collagen-induced RA
model. Histological examination of the joints showed statistically significant
inhibition of pannus, inflammation, cartilage damage, and bone resorption at
2.5 mg/kg in the treatment model.

The objectives of this study are as follows:
Primary Efficacy Objective:
• To assess the effect of PG-760564 on the proportion of patients meeting the
American College of Rheumatology 20 response criteria (ACR 20) at 12 weeks;11
Secondary Efficacy Objectives:
• To assess the effect of PG-760564 on the proportion of patients meeting the
ACR 50 and ACR 70 responses at 12 weeks;
• To assess the effect of PG-760564 on the change from baseline in 28-joint
Disease Activity Score (DAS 28) at 12 weeks;
• To assess the effect of PG-760564 on the change from baseline at 12 weeks in
the following parameters:
o Tender joint count
o Swollen joint count
o Physician*s global assessment
o Patient*s global assessment
o Patient*s assessment of pain
o Health Assessment Questionnaire (HAQ) score
o Acute phase reactants [erythrocyte sedimentation rate (ESR) and C-reactive
protein (CRP)]
o TNF-α, IL-1, and IL-6
o Duration of morning stiffness
o Rheumatoid factor (RF) titer;
• To assess the effect of PG-760564 on time to ACR 20.
Safety Objectives:
• To assess the safety and tolerability of PG-760564 in patients with RA.

This will be a 12-week, double-blind, randomized, placebo-controlled, parallel
group, multicenter study to evaluate the safety, efficacy, and PK of oral
administration of PG-760564 in adult patients with active RA receiving
treatment with MTX. The study will be conducted in North America and Europe at
approximately 50 to 60 sites. Approximately 270 patients will be randomized, of
which 189 are expected to complete the study. If the dropout rate is >30%, up
to an additional 30 patients total could be randomized, to ensure 63 completed
patients per treatment group. Two oral doses of PG-760564 will be evaluated: 25
mg BID and 100 mg BID.
Due to concomitant treatment with MTX, all patients will be required to take
either 5-7 mg/week of folic acid or 2.5 mg/week of folinic acid. Higher doses
will not be allowed.

The study will consist of a screening visit followed by a washout period for
all disease-modifying antirheumatic drugs (DMARDs) and anti-cytokine therapies
except MTX (see Appendix 5). The washout period will be 4 weeks for
sulfasalazine, hydroxychloroquine, azathioprine, D-penicillamine, etanercept,
and anakinra, 8 weeks for gold, infliximab, and adalimumab, and 12 weeks for
abatacept.
After the washout period, the patients will be randomized if they fulfill all
inclusion and exclusion criteria. Patients determined to be eligible will be
randomized to receive either 25 mg BID or 100 mg BID of oral PG-760564, or
placebo for 12 weeks. There will be 6 treatment visits (Weeks 1, 2, 4, 6, 8,
and 12) and a follow-up visit 4 weeks after the last treatment visit (Week 16).
Patients will not initiate new therapies until after the 4-week follow-up is
completed. Liver function tests will be evaluated at every visit.
If dose-limiting toxicity is seen in patients receiving the 100 mg BID dose
(based on recommendation from the IDMC), the 100 mg BID dose will be
discontinued and patients in this dose group will have their dose decreased to
50 mg BID. In that case, new patients randomized to the 100 mg BID dose will be
given a 50 mg BID dose instead.
The primary efficacy endpoint will be the proportion of patients meeting the
ACR 20 response criteria after 12 weeks of treatment.

use of PG-760564 en methotrexaat

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