Overview
Osteonecrosis of the femoral head (ONFH) presents a rapidly progressive natural disease course. Femoral head collapse may occur within two years, ultimately necessitating total hip arthroplasty and imposing a heavy medical and economic burden on patients. Early intervention can significantly improve the long-term prognosis of ONFH. However, due to the lack of validated biomarkers for early diagnosis, the early diagnostic rate remains low, with a primary diagnostic rate of merely 68.43% at the first visit, accompanied by a high rate of misdiagnosis. This project intends to collect blood samples from patients diagnosed with ONFH and suspected cases in the orthopedic outpatient department of a tertiary Grade A hospital. Diagnostic and differential diagnostic tests will be adopted to evaluate the clinical application value of previously reported candidate biomarkers, so as to screen out biomarkers with excellent diagnostic validity and reliability. Meanwhile, clinical data will be collected to identify independent risk factors, and a multi-dimensional integrated diagnostic model will be further established. The research findings are expected to provide solid data support, theoretical basis and technical reserves for the early prevention, early diagnosis and individualized intervention of osteonecrosis of the femoral head.
Description
Osteonecrosis of the Femoral Head (ONFH) is a highly disabling disease characterized by osteocyte death caused by interrupted blood supply to the femoral head. The natural course of ONFH progresses rapidly. Femoral head collapse can occur within approximately two years, and ultimately about 30% of patients require total hip arthroplasty. This disease not only severely impairs patients' quality of life but also imposes a heavy medical and economic burden. The global incidence of ONFH is on the rise. Statistics show that there are approximately 20,000 to 30,000 new cases annually in the United States, and around 300,000 new cases in China each year, with young and middle-aged people accounting for the largest proportion. The incidence rate among individuals aged 15 years and above is approximately 10-30 per 100,000 population. The prevalence of ONFH is higher in northern regions than in southern areas, and higher in urban than in rural areas. Such distribution differences may be associated with climate, occupation, medical accessibility, and exposure levels of risk factors.
The etiology and pathogenesis of ONFH are complex and correlated with multiple risk factors including excessive alcohol consumption, glucocorticoid administration, and hip fractures. Long-term or high-dose glucocorticoid use is a major predisposing factor for ONFH, accounting for approximately 40% of all cases. Glucocorticoids may induce femoral head ischemia and subsequent necrosis by increasing blood viscosity, triggering fat embolism, or directly damaging vascular endothelial cells. Long-term heavy drinking (average daily alcohol intake ≥ 40 g) is another high-risk factor, responsible for 20%-30% of cases. Alcohol inhibits osteoblast activity, exacerbates oxidative stress, and disrupts bone microcirculation through lipid metabolism disorders. Traumatic injuries such as femoral neck fracture and hip dislocation directly damage the retinacular blood vessels, contributing to 10%-20% of ONFH cases. Subcapital fractures carry the highest risk of osteonecrosis; completely displaced adduction fractures with severe vascular injury present a necrosis rate of 30%-50%. Delayed reduction (\> 24 hours) and improper reduction operations (e.g., excessive traction) after fracture also markedly increase the risk of necrosis. In addition, metabolic disorders including hypertension, diabetes and hyperlipidemia impair bone blood circulation indirectly by exacerbating systemic angiopathy. Cigarette smoking (nicotine) induces vasoconstriction and endothelial dysfunction, thereby accelerating the progression of osteonecrosis. Osteoporosis reduces bone mineral density and the mechanical strength of the femoral head, rendering it susceptible to microfractures caused by minor trauma and further aggravating blood perfusion disturbance.
A variety of therapeutic approaches are available for ONFH, including non-surgical treatments (protective weight-bearing, bisphosphonate medication, hyperbaric oxygen therapy, and platelet-rich plasma treatment), femoral head-preserving surgeries (core decompression, vascularized bone grafting, non-vascularized bone grafting, and stem cell therapy), and emerging experimental therapies such as M2 macrophage-derived exosomes. Treatment efficacy is mainly determined by disease stage, intervention strategies and individual patient differences. Early intervention can significantly improve clinical prognosis, whereas advanced ONFH often requires complex surgical procedures such as total hip arthroplasty. Nevertheless, the early diagnostic rate of ONFH remains low, with only 68.43% of cases correctly diagnosed at the first visit. Meanwhile, the disease has a high misdiagnosis rate and is frequently misdiagnosed as lumbar disc herniation or simple arthritis.
Existing studies on ONFH are predominantly clinical research with notable limitations. Most studies adopt a single research methodology that merely analyzes ONFH from the perspective of biomechanics, while ignoring the interactions of multiple factors such as heredity, metabolism and immunity. Research designs represented by retrospective studies are prone to selection bias and information bias, which limit the generalizability of research findings. In addition, small sample sizes fail to accurately reflect the overall characteristics and epidemiological patterns of ONFH. Furthermore, inconsistent research designs in previous studies lead to heterogeneous indicators and poor data comparability. Therefore, disease-specialized research on ONFH is urgently needed. By adopting a multicenter prospective design, high-risk factors, clinical imaging data and biological samples will be systematically collected. Combined with multi-dimensional influencing factors including biomechanics, biochemistry and genetics, this study aims to explore early diagnostic biomarkers and optimal diagnostic strategies for ONFH, so as to provide evidence for optimizing clinical diagnosis and treatment protocols and establishing individualized predictive models.
Eligibility
Inclusion Criteria:
- Is an adult 18 through 64 years of age at time of screening with at least 1 underlying condition that puts the participant at high risk for severe outcomes of COVID-19 per self-report OR is an adult ≥65 years of age at time of screening (with or without at least 1 underlying condition).
- Has completed any WHO/FDA-authorized or approved primary COVID-19 vaccination series per self-report.
- Has received last COVID-19 vaccine ≥6 months prior to study vaccination.
- If a female of childbearing potential who is sexually active, agrees to use an adequate method of birth control from Screening through 90 days after study vaccination, and has used an adequate birth control method for at least 30 days prior to Screening. Sexually active male participants, unless the participant is sterile or otherwise unable to produce sperm, or has exclusively male sexual partners, must agree to abstinence or to use a barrier method (e.g., male condom) from vaccination through 90 days after study vaccination. Male participants must also agree to not donate sperm from vaccination through 90 days after study vaccination.
- Is medically stable, as determined by the site investigator (based on review of health status, vital signs, medical history, and physical examination).
- Agrees to not participate in any other SARS-CoV-2 infection prevention trial (vaccine, drug, biologic, pre-exposure prophylaxis \[PrEP\]) during participation in the study.
- Willing and able to provide informed consent prior to initiation of study procedures.
- Is available for all study visits, willing to participate in all study procedures, and not planning to relocate from the area for the duration of the study.
Exclusion Criteria:
- Has an acute illness, as determined by the site investigator, within 72 hours prior to Screening or study vaccination.
- Has had a positive COVID-19 test within the 90 days prior to Screening or study vaccination.
- Current or planned participation in any other interventional clinical trial.
- Participation in research involving any investigational product within 45 days prior to Screening or study vaccination.
- Receipt of any approved or authorized products intended to prevent SARS-CoV-2 infection within 6 months prior to Screening or study vaccination.
- Receipt of blood products or immunoglobulins within 60 days prior to Screening or study vaccination.
- Received influenza vaccination within 14 days prior to Screening or study vaccination, or any other vaccine within 30 days prior to Screening or study vaccination.
- Any significant autoimmune, immunodeficiency disease/condition, or auto inflammatory disorder (e.g., any known immunoglobulin A \[IgA\] deficiency, human immunodeficiency virus \[HIV\] infection, acquired immunodeficiency syndrome \[AIDS\])
- Has current active hepatitis B or hepatitis C infection (based on self-reported medical history).
- Has a peripheral arterial oxygen saturation (SpO2) level \<92% at Screening, uncontrolled or severe asthma (e.g., more than 1 hospitalization for asthma exacerbation within the 12 months prior to Screening), or other uncontrolled or severe chronic lung disease or known bronchial hyper-reactivity to viruses that, in the opinion of the site investigator, would pose a health risk to the individual if enrolled.
- Has known active tuberculosis.
- Unstable non-cardiac illness (acute or chronic illness) requiring hospitalization or medical procedure during the 90 days prior to Screening or study vaccination, or cardiac condition (acute or chronic) requiring hospitalization or medical procedure (e.g., stenting, cardiac surgery, etc.) during the 1 year prior to Screening or study vaccination.
- History of myocarditis, pericarditis, myopericarditis, or idiopathic cardiomyopathy, or presence of any medical condition (e.g., viral illness within 30 days of Screening or study vaccination) that, in the opinion of the investigator, increases risk of myocarditis, pericarditis, or myopericarditis.
- Chronic kidney disease requiring dialysis or any type of ultrafiltration. Individuals with chronic kidney disease that does not require dialysis or ultrafiltration may be included.
- Individuals with advanced or decompensated chronic liver disease as determined by the site investigator.
- Presence of any transplanted solid organs (heart, kidney, lung, liver, pancreas, and/or intestine) or prior receipt of a blood stem cell transplant.
- Administration of immunosuppressants, systemic glucocorticoids, or other immune-modifying drugs within the following timeframes:
- B-cell therapies within the 6 months prior to Screening or study vaccination.
- Prednisone, ≥20 mg or equivalent for more than 2 weeks, within the 30 days prior to Screening or study vaccination.
- Monoclonal antibodies that may suppress aspects of immune response (e.g., Dupixent) within the 6 months prior to Screening or study vaccination.
- Other medications in this category, including but not limited to high-dose inhaled corticosteroids (\>800 mcg/day of beclomethasone dipropionate or equivalent); antimetabolites; transplant immunosuppressive agents; alkylating agents; cell-depleting agents; or cancer chemotherapeutics, within the 90 days prior to Screening or study vaccination.
- Any medication for any period of time that, in the opinion of the site investigator, could impede immune response to vaccination.
- Known contraindication to IM injection (e.g., bleeding diathesis, acquired coagulopathy) or to IN administration (e.g., significant nasal abnormality or severe nasal obstruction, significant chronic rhinitis or history of chronic rhinitis, nasal septal defect causing significant breathing problems, unrepaired cleft palate, nasal polyps, or other nasal abnormality that might affect vaccine administration).
- Receipt or anticipated receipt, within 7 days prior through 7 days after study vaccination, of any Intranasal medication, including FDA-approved prescription or over-the-counter products or non-FDA-approved alternative medicine products (e.g., Ayurvedic oil or other naturopathic substances).
- Anticipated use of nasal irrigation (e.g., Neti PotTM) from Screening through 30 days after study vaccination.
- Any known allergies to components contained in NDV-HXP-S (including egg products) or the comparator vaccine (including polyethylene glycol \[PEG\] allergies).
- Women who are pregnant, breastfeeding, or who plan to become pregnant during the study.
- Current or prior potential for NDV exposure (e.g., prior NDV-based vaccination, NDV-based oncologic immunotherapy, prior or current experience as a bird-handler, poultry farmer, or scientist conducting research with NDV).
- Individuals who will have close or household high-risk contacts, within 14 days following study vaccination, including but not limited to:
- Any other condition that, in the opinion of the site investigator, would pose a health risk to the participant if enrolled or could interfere with evaluation of the investigational product or interpretation of study results.
- Study team member or first-degree relative of any study team member (inclusive of CastleVax and site personnel involved in the study).
