Osteoarthritis of Knee Clinical Trial
Official title:
Efficacy of Intra-Articular Injection of Etanercept for Moderate and Severe Knee Osteoarthritis
Primary aim: evaluate efficacy of intra-articular 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 intra-articular 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 analgesic. 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 intra-articular 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 intra-articular 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 will be randomly assigned into two groups:
Etanercept treatment group: Intra-articular injection of etanercept of 25mg/w/joint and
health education, exercise and diet guidance; treatment: 5 weeks Routine care group:
Health education, exercise and diet guidance; treatment: 5 weeks (If both knees are
involved, the more significant symptomatic side is chosen for injection by etanercept)
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 (optional, 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:baseline to 12 weeks, during this period, two groups of participants
will be treated with Intra-articular injection of etanercept of 25 mg/w/joint,
health education, exercise and diet guidance or just health education, exercise
and diet guidance separately. During this period 4 times follow-up will be
performed at 2nd, 4th, 8th, 12th week.
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.
At 4th week, vital signs will be recorded, and blood routine, urine routine, blood
biochemical, the ESR and CRP will be examined and recorded, imaging examination
(horizontal position/lateral projection/side lateral projection of ultrasound in knee),
and collect basic evaluation results such as: pain VAS score, SF12 score, KOOS score,
30 s - CST score, 40 m FPWT score, ultrasonic relative index score and condition of
drug combination and adverse events will be recorded.
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 or supine
position of MRI in knee joint, (optional, and 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 index score and MRI relative index score (optional). 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; and 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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