Osteoarthritis Of Knee Clinical Trial
Official title:
Efficacy of Subcutaneous Injection of Etanercept for Moderate and Severe Knee Osteoarthritis
Primary aim: evaluate efficacy of subcutaneous injection of etanercept for moderate and
severe knee osteoarthritis.
Second aim: investigate the potentiality of serum cytokines (TNF-α, L1-α, IL1-β, MMP1,
MMP13) to predict the response of subcutaneous injection of etanercept for moderate and
severe knee osteoarthritis.
1. Background:
Osteoarthritis (osteoarthritis, OA) is a common joint disease. It is characterized by
recurrent joint pain, swelling, increasing of disease status, joint deformity and
activity disorders. [1]
The pathogenesis of OA has not been fully understood. It may be associated with a
variety of factors, such as: mechanics, biochemistry, genetics, and so on. Its main
feature is the imbalance between synthesis and catabolism of articular cartilage cells.
The imbalance may refer to cell aging, cell apoptosis, local inflammatory factor in
joints as well as stress mechanism and so on. [2] OA usually develops in burdened and
active joints, such as: the knee, the spine (cervical and lumbar spine), hip and ankle,
hand joints, etc. The first session of The National Health and Nutrition Survey (The
first National Health and Nutrition Examination Survey, NHANESI) found that 12% of
people in The United States have at least one joint in accordance with the clinical
diagnosis of OA. [3] Radiographic result shows that rate of American adults knee OA
prevalence is 14% and 37%, and women are more common (4-6). A large study found that at
least one joint in people over 55 years have radiographic hand OA, and female
prevalence is 67%, male is 55% [7].
The OA in Chinese are more likely happened in elder women than men. Prevalence rate
could up to 50% in people over the age of 60, and 80% in 75 years old.
Osteoarthritis patients suffer huge pain, and it cause huge economic burden to the
society, and it becomes a serious impact on social productivity and lead to huge
economic burden [8].
In the United States, OA cost $ 1,855 billion per year and in 27 million patients, and
women spend $ 6212 per year, male $ 4730 per year [2]; OA cost 1% ~ 2.5% of GDP in the
United States, Britain, France, Canada, Australia and other developed countries. There
is no burden of economic data of OA in China [9].
Classification criteria of knee osteoarthritis
According to the affected areas, OA can be divided into knee OA, hip OA, hand OA
(distal interphalangeal joints, the first wrist palm joints), foot OA (first plantar
toe joints, heel), etc.
Knee OA is the most common disease in clinical disease. The classification of the knees
OA contains clinical criteria, and also clinical and imaging criteria in the modified
ACR classification criteria in osteoarthritis classification criteria [10].
Knee osteoarthritis usually occurs with obvious fricatives, bony enlargement, Baker
cyst expansion and joint effusion is generally not associated with skin redness [11].
The most common deformity comes out with varus in severe cases, but also it may appear
in the early mild disease. That clinically obvious varus may be a predictive factor
during the disease progression [12]. That quadriceps become weak is a changeable risk
factor for early knees OA disease progression, especially in women (13-14). Muscle
atrophy occurs in late stage of disease progression [15] [16]. And it brings huge
burden of disease to patients [11].
Treatment of knee OA
The aim of the treatment is to relieve pain, prevent and delay the progress of disease,
protect the joints function, improve the quality of life. The treatment should be
individualized. Full consideration to the patient' illness risk factors should be
given, including: joint structure changing, the degree of inflammation and pain,
concurrent disease status and other specific situation and condition. Treatment should
be given priority to combine non-drug therapy with drug therapy. Operation should be
performed when it is necessary [17].
Non-drug therapy include psychosocial intervention [17], decreasing weight [18],
reasonable exercise [19], physical therapy which includes heat therapy, spa therapy,
etc.), etc.
Drug therapy mainly includes drugs using external, drugs using in whole body and drugs
intra-articular injections [17].
Topical drugs include: capsaicin [20], non-steroid anti-inflammatory drugs (NSAIDS) for
external use [21] and lidocaine for external use only.
Systemic medicine include: a: non-opiate drug. Acetaminophen is the first choice of OA
treatment, and the main reason is that the less side effects and good curative effect
[22].b: NSAIDS. There are two effect of NSAIDS: anti-pain and anti-inflammatory, which
is the most commonly used for the control of OA symptoms. The main adverse reactions
are gastrointestinal symptoms, renal or liver damage, effect on platelet function, and
it may increase the risk of cardiovascular adverse events [23]. c: opioid analgesics.
It can be considered if Pain still difficult to control after non-drug and drug
treatment.
Drugs injection intra-articular, including: intra-articular injection of glucocorticoid
and hyaluronic acid derivatives [24].
Research of TNF-α application in OA:
TNF-α and IL1 play an important role in the pathogenesis of osteoarthritis, IL1 - beta
often express highly in middle to late course of OA [25 to 28]. In the OA flare course,
TNF-α and IL1 alpha will increase significantly; TNF-α has been considered to be one of
the important factors associated with the degree of OA inflammatory, and the IL1 alpha
has a significant relation with the start of OA inflammatory [29].
2. Aims:
Primary: evaluate efficacy of subcutaneous injection of etanercept for moderate and
severe knee osteoarthritis
Second: investigate the potentiality of serum cytokines (TNF-α, L1-α, IL1-β, MMP1,
MMP13) to predict the response of subcutaneous injection of etanercept for moderate and
severe knee osteoarthritis.
3. Patients:
Recruit Patients of moderate and severe knee osteoarthritis, totally 60 patients
(According with classification of "Clinical Image" of 1986 American college of
rheumatology criteria in osteoarthritis of the knee )
4. Study Design:
A 12-week, multi-center, open-labeled, randomized study. Moderately and severe knee
osteoarthritis patients, total 60 patients (consider expulsion rate 15%)(According with
classification of "Clinical Image" of 1986 American college of rheumatology criteria in
osteoarthritis of the knee )
The 60 patients were randomly assigned into two groups:
Etanercept treatment group: etanercept of 50 mg/w, subcutaneous injection health
education, exercise and diet guidance; treatment: 8 weeks Routine care group: Routine
care group, health education, exercise and diet guidance; treatment: 8 weeks
This study has two stages:
1. Screening/baseline period: - 4 weeks ~ 0 weeks;
Patients should have signed informed consent form (ICF) before participating the
study.
Obtain the history before treatment, medical records, disease history and
demographic information of patients. And also perform pregnancy test (optional),
HIV testing (optional), HBV detection (optional), HCV detection (optional),
electrocardiogram examination, chest radiograph, PPD test, vital signs, physical
examination, blood routine, urine routine and blood biochemical examination,
imaging examination (anteroposterior/lateral of X-ray in knee joint, horizontal
position/lateral projection/side lateral projection of ultrasound in knee, supine
position in knee joint of MRI (sagittal and coronary are commonly used), measure
the ESR and CRP and store serum in - 80 ℃ to detect serum protein markers level
during baseline period, at the same time keep the plasma to - 80 ℃.(refer to "9.3
lab operation"). Collect disease assessment result in baseline, and record the VAS
pain score, SF12 score, KOOS score, 30 s - CST score, 40 m FPWT score, ultrasonic
relative index score and MRI relative index score.
2. Follow-up: 2, 4, 8, 12 weeks supervision.
At 2nd week, vital signs will be recorded, pain VAS score, SF12 score, KOOS score,
condition of drug combination and adverse events will be recorded as basic disease
assessment.
At 4th week, vital signs will be recorded, and blood routine, urine routine, blood
biochemical, the ESR and CRP will be examined and recorded, collect basic evaluation
results such as: pain VAS score, SF12 score, KOOS score, and condition of drug
combination and adverse events will be recorded as basic disease assessment.
At 8th week, 12th week, vital signs, blood routine, urine routine and blood biochemical
will be examined and recorded and imaging examination will be performed (horizontal
position/lateral projection/side lateral projection of ultrasound in knee、 supine
position of MR in knee joint (MRI will be performed only at 8th week, sagittal and
coronary will be used as usual)). Measure the ESR and CRP and store serum in - 80 ℃ to
detect serum protein markers level during baseline to 8th week and 12th week, at the
same time, store plasma to - 80 ℃.(refer to "9.3 lab operation"). Collect disease
assessment result, and record the pain VAS score, SF12 score, KOOS score, 30 s - CST
score, 40 m FPWT score, ultrasonic relative index score and MRI relative index score.
And condition of drug combination and adverse events will be recorded.
5. Laboratory tests
Main laboratory examination:
Detect the level of TNF-α, L1-α, IL1-β, MMP1, MMP13 levels in patients peripheral blood
at baseline period and 4th week, 8th week by using enzyme-linked immunosorbent assay.
6. The curative effect evaluation/check points:
The primary checkpoint: at 8th week and 12th week, changes of pain VAS score, KOOS
score relative to the baseline.
The Secondary checkpoints: at 8 weeks and 12 weeks changes of SF-12 score, 30s-CST
score, 40 m FPWT score, ultrasound score, MRI score, level of TNF alpha, IL1 alpha, IL1
- beta, MMP1, MMP13 in serum relative to the baseline.
7. Statistical methods:
Based on the curative effect data of patients, analysis by using R software or SAS
statistical software:
Calculate the measurement data using t-test and rank test; Rate is calculated using
chi-square test.
Perform single factor and multiple factors regression analysis on indicators of baseline
prognostic factors of patients (protein markers) and curative effect.
;
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
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