Ankylosing Spondylitis Clinical Trial
Official title:
A Randomized Open-labeled Study for Comparison of Patient-reported Outcomes Between Two Therapeutic Schedules of Imrecoxib in Ankylosing Spondylitis
The selective cox-2 inhibitor has been widely used in the treatment of Ankylosing spondylitis (AS). The Imrecoxib is a new cox-2 inhibitor. But the treatment strategy has not been decided yet. To determine which is better in treating AS in the methods between on-demand treatment and continuous treatment. To solve this question, we designed this study.
Ankylosing spondylitis (AS) is a chronic systemic inflammatory arthritis of unknown etiology,
occurring in young men aged 16-25 and presenting the genetic predisposition. AS is a common
rheumatic disease, with a prevalence of 0.3 ~ 0.5% in general people of China, which means
that about 5 million people in our country suffer from this disease. AS mainly invades the
central axis, characterized by the inflammation of sacroiliitis and attachment points. The
onset of AS is insidious. The early clinical manifestations are mainly inflammatory low back
pain, which gradually affects the lumbar spine, thoracic vertebrae, and cervical vertebrae.
The persistent inflammation will gradually stiffen and fuse the joints, causing osteoporosis
and destruction of the vertebral body, resulting in the ossification of ligaments, and
leading to the disability ultimately. Except for the joint lesions, AS is usually accompanied
by multiple extra-articular manifestations, such as uveal inflammation, psoriasis,
inflammatory bowel disease, etc. Especially, AS is often complicated with multiple
complications symptoms, such as arthritis, arterial disease, fibromyalgia, depression, etc.
In summary, AS has seriously affected the normal work and work of patients, which has become
the main reason for the labor loss in young and middle-aged people. Therefore, it is of great
value for controlling inflammation effectively and alleviate joint pain to improve the life
quality of patients and save social labor.
Non-steroid anti-inflammatory drugs (NSAIDs), the anti-inflammatory and analgesic drugs and
widely used in rheumatic diseases, can effectively relieve pain and quickly improve the
symptoms of inflammatory joint disease. The role of NSAIDs in the treatment of AS is very
important, which could not only generate anti-inflammatory effect, but also improve the joint
function, delay joint erosion, and prevent the formation of osteophyte. The treatment
guidelines of AS in American Rheumatology Association / American Spondyloarthropathy
Collaboration in 2015 recommended continuous prescription NSAIDs as the first-line treatment
for patients with active AS. In the 2016 ASAS / European Guideline of Axial
Spondyloarthropathy, NSAIDs should be treated as the first-line treatment for patients with
joint pain and joint stiffness. Those who respond well to NSAIDs are recommended for
continuous treatment. The latest 2018 APLAR guidelines also recommend that NSAIDs should be
used as first-line treatment for active AS, but the method of continuous treatment or
treatment on demand is not discussed because two clinical trials have shown that the efficacy
of on-demand is not worse than continuous treatment. In summary, NSAIDs are recommended for
the first-line treatment of AS, but the differences in the efficacy, safety, and patient
benefit between continuous treatment and on-demand treatment, as well as the treatment
course, is controversial yet.
NSAIDs could inhibit the activity of cyclooxygenase (COX), blocking the conversion of
arachidonic acid to prostaglandins, prostacyclin, and thromboxane A2. In addition, NSAIDs
could also inhibit the release of bradykinin, inhibit lymphocyte proliferation, and reduce
the migration of granulocyte and macrophages in inflammation. COX includes COX-1 and COX-2.
COX-1 induced prostaglandins mainly generate the physiological and protective effect, such as
maintaining the integrity of the gastrointestinal mucosa, adjusting the renal blood flow, and
guarantee the function of platelets. COX-2 is mainly expressed in macrophages, fibroblasts,
cartilage and endothelial cells with a low level in the basic state. Once stimulated by
cytokines or endothelin, the expression will tremendously increase several times, induce the
production of prostaglandins, and participate in inflammation. NSAIDs could be classified as
non-specific COX inhibitors, selective COX-1 inhibitors, and selective COX-2 inhibitors based
on the effects of different COX. The main adverse reaction of NSAIDs derives from its
inhibitory effect on COX-1, causing adverse gastrointestinal reactions. And the
gastrointestinal ulcers and bleeding are also the most common causes of hospitalization and
death. The selective COX-2 inhibitor is the new generation of NSAIDs, with better
anti-inflammatory and analgesic effects, in that it could specifically inhibit the COX-2 but
has no effect on COX-1, greatly reducing the adverse reaction of gastrointestinal tracts and
kidneys. Multiple clinical trials and meta-analysis have shown that selective COX-2
inhibitors can significantly reduce the gastrointestinal symptoms and peptic ulcer formation
in the endoscopic. Therefore, selective COX-2 owns a much more general application space in
rheumatic diseases.
Most of the COX-2 inhibitors in China are not original research drugs previously, and only
Celecoxib is available in the United States according to FDA. Unearthing new selective cox-2
inhibitor is necessary. Imrecoxib is a COX-2 inhibitor designed by the Chinese Academy of
Medical Sciences and Jiangsu Hengrui Hospital Co., Ltd. in China, which has been approved by
the Chinese Food and Drug Administration (CFDA) for marketing. The recommended dose of
Imrecoxib is 100mg. bid.po. according to the instructions. Studies in vitro has demonstrated
that Imrecoxib could specifically inhibit the COX-2, and inhibit the expression of COX-2 mRNA
to restrain the inflammation. Multiple clinical studies have demonstrated that Imrecoxib was
effective in treating osteoarthritis, with similar efficiency to Celecoxib but without severe
gastrointestinal adverse effect, with a lower percentage of cardiovascular adverse effect,
and with relatively good safety. In 2017, the comparison between Imrecoxib and Celecoxib in
treating serum-negative spondyloarthropathy (SPA) revealed that the effect of Imrecoxib
(10mg.bid.po for 12 weeks) was not worse than that of Celecoxib, which could significantly
alleviate disease activity, joint function and inflammatory markers. But there is a lack of
study with a large sample size and long course to further demonstrate the effectiveness and
safety of Imrecoxib in treating SPA and AS.
The AS disease activity score such as BASDAI and radiological assessment are the main
observation indicators for efficacy evaluation in the clinical study of NSAIDs treating AS
for the moment. But the evaluation of life quality is also important for patients with AS,
which includes 4 respects, the body 's function, disease activity, economic status, and
social status. Data from Taiwan shows that a variety of factors can affect the patient 's
life quality except for the disease activity, including the course of the disease, drinking,
weight, mental, and economic factors, etc. So, adequate life quality assessment and support
should be given to the AS patients. However, there is a lack of studies that employed
patients self-report and patients' life quality assessment as the main observation
indicators. The present study intends to use the results of patients' self-report as the
evaluation criteria, to compare the efficacy and safety between continuous treatment and
on-demand treatment of Imrecoxib for AS under different treatment modes, which could also
provide direct evidence for the optimized applications in rheumatic diseases.
Meanwhile, we also want to find whether on-demand treatment of Imrecoxib could reduce the
occurrence of adverse reactions, reduce the economic burden, and bring more benefits under
the premise that the on-demand treatment is not worse than continuous use of Imrecoxib in
drug efficacy.
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