O20 FEMORAL HEAD NECROSIS AND HYPERBARIC OXYGEN A MRI STUDY STUDY PROTOCOL ADOPTED FROM THE COST B14 WORKING GROUP

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1 O20 FEMORAL HEAD NECROSIS AND HYPERBARIC OXYGEN A MRI STUDY STUDY PROTOCOL ADOPTED FROM THE COST B14 WORKING GROUP "2" L. Ditri, F. Grigoletto, Y. Melamed, D. Reis, L. Cucci, P. Germonprè, T. Mesimeris, M. Montanari, B. Ratzenhofer-Komenda, M. Rocco, L. Travnik and B. Vande Berg INTRODUCTION Avascular necrosis of the femoral head is a debilitating disease that usually leads to destruction of the hip joint in patient who are in the third, fourth or fifth decade of life. In the United States has been estimated that to new patients develop this illness each year (4). Avascular necrosis represents the 5-12% of the entire number of total hip replacement per year (5). In the experience of Mont the average age of patients who have total hip replacement is thirty-eight years, with only 20% of being more than fifty years old at the time of operation (3,5). The total societal cost is considerably high because these patients are generally young, hold jobs, and have a life expectancy that makes additional operations probable (3,5). We must to prevent the femoral head collapse to avoid the total hip replacement or other surgical interventions. In our experience we have very good results with HBO Therapy if the pathology is in the early stages. The number of reported cases of FHN patients treated with HBO so far is very limited (7). There have been some 15 reports of the benefit of HBO in FHN but there is a need to investigate the efficacy of HBO therapy in the treatment of this disease, in order to establish or negate this therapy as evidence based medicine. In this point of view we have begun to prepare the study protocol in the Working Group 2 of the European COST B14 Project with the assistance of Francesco Grigoletto, Professor of Medical Statistics of the Padua University (Italy). BACKGROUND Femoral head necrosis is a condition in which the blood supply to the femoral head is compromised. This leads to cell death in the marrow and the bone, and interferes with the normal activity of osteoblasts and osteoclasts, and loss of the structural integrity of the femoral head. The progression of the disease implies pain, swelling in the confined space of the femoral head, loss of joint congruity, arthritic changes, and collapse of the femoral head (2). The treatment of the femoral head necrosis (FNH) is an unresolved orthopaedic problem and multiple approaches are used for its management (7). They include surgical procedures as core decompression, bone grafting, and osteotomy, and non-surgical procedures such as electrical stimulation, magnetic fields, high energy shock wave, pharmacological treatment, and hyperbaric oxygen therapy (HBO). HBO therapy alone or in combination with other orthopaedic interventions, makes oxygen available to cells and enhance osteoblasts and osteoclasts function. Angioneogenesis enhances the environment for local bone healing and remodelling. MRI is the only objective method available for evaluation in the early stages. Therefore, this study will be limited to the MRI (8). HYPOTHESIS UNDER INVESTIGATION The use of long-term HBO therapy as adjunct to the conventional non-surgical therapy, in stage I and II FHN patients, in comparison to conventional non-surgical therapy alone, is associated with a regression or arrest of the disease and a reduction in the time needed to the recovery of hip function. By conventional non-surgical therapy we mean non-weight bearing only. This is brought about by the rapid reduction of bone oedema, which improves the microcirculation, the flooding of the diseased area with readily available O2 and angioneogenesis in Stage I or II. Once the femoral head has lost its shape, HBO cannot prevent the progress of disease. TRIAL OBJECTIVES To evaluate the efficacy and safety of long-term HBO therapy used in addition to conventional non-surgical therapy in the patients with femoral head necrosis. Primary endpoint The final outcome variable will be the stage of success or failure within the 24-month study period. Assessment is by MRI only. Patients will be classified as success (cured, healed and arrested) or failure. Success or failure will be defined according to the sequential MRI assessments: 81

2 Success: - MRI Cured: MRI reveals total regression in the radiological signs. - MRI Healed-Arrested means no progression to next stage in 24 months: some imaging findings still present. Failure: - MRI Failure is defined as radiological progression to femoral head collapse (stage III or worse) - If pain increases during the 3-4 months period after entry into the trial and Radiograph or urgent MRI shows progression of the disease. Treatment Groups Eligible patients will be randomised to form the following treatment groups: - Patients treated with conventional non-surgical therapy and HBO therapy (experimental group); - Patients treated with conventional non-surgical therapy (control group). Primary objective Primary objective of the study is to compare the rate of success, within the 24-month study period, between the two treatment groups. STUDY POPULATION Patients potentially eligible for the study are consecutive in- or out-patients of either sex, 18 to 65 years of age, referring to one of the participating orthopaedic Centres and diagnosed with femoral head necrosis. The diagnosis can be referred to as avascular necrosis, ischemic necrosis, aseptic necrosis, or osteonecrosis of the femoral head. Patients diagnosed with femoral head necrosis will be graded according to the Steinberg classification: only stage 1 and 2 are eligible. Admission to the trial is by MRI only to be monitored by the MRI director. Table 1. Steinberg Classification (6): Stage Description 0 Hip functional and pain free, normal radiograph but considered at risk because of the presence of necrosis in the contralateral hip Excluded 1 Pain but normal radiograph, abnormal bone scan and MRI Included 2 Pain and radiographic signs of diffuse osteoporosis, sclerosis, or cyst Included 3 Crescent sign. Broken contour of the femoral head Excluded 4 Decreased joint space, flattened contour, collapse of the femoral head Excluded 5 Involvement of acetabulum Excluded 6 Severe arthrosis Excluded Patient log All patients, initially considered for inclusion in the study, should be recorded in a Patient log to document the characteristics of the available patient population. Furthermore, the reason for patient exclusion should be recorded. Inclusion criteria Patients must meet all of the following criteria to be eligible for participation in the study: - Age between 18 and 65 years; - Presence of femoral head necrosis Stage 1 or 2 (Steinberg classification); - Written and informed consent to participate in the study. - Final inclusion to be done by MRI director on the basis of: - Analysis of lesions - Analysis of quality of imaging 82

3 Exclusion criteria - Age range beyond years; - Pregnancy - Presence of any condition or disorder that could interfere with the study conduct - Situations where HBO may represent an additional risk: recent (<2 years) spontaneous pneumothorax, ear-drum or ossicle chain surgery, acute upper respiratory tract infection, untreated or insufficiently treated epilepsy, concurrent treatment with radiotherapy or chemotherapy, congenital spherocytosis, psychotic disease - Concurrent participation in other clinical trials; - Absence of written informed consent. - Non-compliance to HBO treatment (normal treatment frequency 5 or 6 treatments per week; if a patient receives less than 80% of the planned treatments (less than 16 treatments per month or more than 4 months for completion of the study) - Patient request to stop the study SAMPLE SIZE AND FEASIBILITY The available literature provides little information on the expected success rate in the conventionally treated control group. On the basis of selected literature, Strauss and Dvorak (2000) report a 24-month (or lesser) success rate values ranging from 44% to 86% for patients with different modalities of therapeutic intervention or no intervention. Mont and Hungerford (1995) report that most studies show a percentage higher than 85% of patients with collapse of the femoral head at two years when symptomatic hips with stage I or II disease (International Classification) were left untreated. After non-operative treatment, referring to a total of 819 hips, the same authors report that 22% had a satisfactory clinical result, this percentage increasing to 35 and 31% when patient were classified at stage I or II (International Classification)(1,2,5,7) respectively. Sample size We will base sample size calculation on a proportion of successes in the control group equal to 30% after 24-month study period, as suggested in the above reported literature. Table 2 reports the total sample size needed to detect an increase of the success rate in the conventional plus HBO treatment group for selected rates of successes in the experimental group. These calculations, based on the log rank test, refer to a two-sided type I error of 5%, a statistical power equal to 80%, and an equal number of patients in the two treatment groups (1:1 sampling ratio). Since we expect that about 10% of patients will withdraw or be lost to follow up during the 24 months post randomisation; we need to adjust the sample size upward accordingly. Table 2. Total sample size* for a proportion of successes equal to 30% in the control group and selected proportions in the experimental group Proportion of successes in Total sample size the experimental group * Based on the log rank test, Type I error of 5%, power of 80% and 1:1 sampling ratio. Based on the meta-analysis by Strauss & Dvorak, where a success rate at 24 months of 81% has been calculated, it is proposed to include a total of 200 hips in the study. This pessimistic view (50% of good result) account for different stages, duration and treatment protocols, unnoticed by the authors(7). Feasibility To date. A number of Clinical Centres in Austria, Belgium, Greece, Israel, Slovenia, Switzerland and Italy have agreed to participate. There is much interest internationally in participating in this trial. A number of European clinical centres will be invited to join the study. It is anticipated that patient recruitment will take one year. 83

4 ENROLMENT OF PARTICIPANTS All eligible patients will undergo baseline examinations including Clinical and appropriate radiological assessment at baseline (radiograph and MRI). Variables useful for the evaluation of the disorder and variables representing known risk factors will be assessed. The records will be reported in a structured Case Report Form (CRF). RANDOMISATION Randomisation will be stratified by Clinical Centre and by the Steinberg classification score at baseline. It will be directed centrally by the Co-ordinating and Methods Centre (CMC). Computer-generated randomisation will allocate patients in a 1:1 ratio in variable block-sizes to receive either control or experimental treatment. After an eligible patient has provided written informed consent, the local Investigator will open the closed envelope reporting the patient consecutive identification number and the treatment group to which the patient has been randomly allocated. INTERVENTION All randomised patients will receive the conventional therapy decided by the Investigator independently from the study. When randomly assigned to the study experimental group, they will receive in addition 60 HBO treatments (2.4 ATA - 90 minutes each) within a maximum period of 4 months and according to a time schedule homogeneous across centres. BLINDING Due to the nature of the treatments under investigation, this study is an unblended (open-label) study. To minimise bias, the following strategies will be adopted: - a priori criteria will be well defined for qualifying and outcome events; - two investigators of whom at least one will be independent from the study organisation will perform the assessment of outcome events. EVALUATION CRITERIA During the 24-month study period, recruited patients will undergo a complete clinical evaluation at baseline, 3, 6, 12, 18 and 24 months (6 follow-ups) and conventional radiological evaluation at baseline, 3, 6 and 24 months. MRI will be performed at baseline, 3 months or end of 60 HBO sessions, 6 and 24- month. All the assessed variables will be reported in the CRF. Statistical Analyses The rate of success of the treatment groups will be compared by means of logistic regression analysis, including in the model as independent variables treatment and type of concomitant therapy, and specific exposure conditions (e.g., alcohol abuse, use of corticosteroids, etc.). The time-to-first-event of the primary outcome (success) will be described using Kaplan-Meier method for each treatment group, and the two groups will be compared using log rank test. Statistical significance will be declared if the twosided P-value for the test falls below Analysis Sets Two data sets will be employed in the statistical analysis: the intention-to-treat and the as-treated analysis sets. The intention-to-treat (ITT) set will include all patients who are randomised, regardless of the treatment received, other protocol deviations or the time of the last follow up. The following patients will be excluded from the as-treated (AT) analysis set: - any patient who have violated the inclusion or exclusion criteria; - any patient who received less than 80% of the HBO treatments by four months from baseline. ASSESSMENT OF THE COMPLIANCE TO THE PLANNED TREATMENT Compliance with the allocated treatment arm will be monitored in all the randomised patients. In experimental group (with HBO), special attention will be given to the level of oxygen pressure reached during the session. In this respect, transcutaneous oximetry of oxygen assessment will be used. REQUIREMENTS FOR HYPERBARIC MEDICAL CENTRES PARTICIPATING IN THE STUDY Every hyperbaric participating centre must be physically or functionally linked to a hospital facility or medical institution and must follow the guidelines of the European Committee for Hyperbaric Medicine (ECHM) regarding personnel, safety and procedures. 84

5 CONCLUSIONS The presentation of evidence of the HBO effectiveness in the treatment of the mild or moderate Femoral Head Necrosis can reduce medical, human and social cost. In this point of view is very important to find the patients in the first two stages of illness without the collapse of the femoral head We need and we welcome the contribution of all interested Orthopaedics and Radiologists to conclude this study. REFERENCES 1. Association Research Circulation Osseous: Committee on Terminology and Classification. ARCO News (1992), 4: Bradway J.K. et al., The Natural History of the Silent Hip in Bilateral Atraumatic Osteonecrosis, Journal of Arthroplasty (1993) 8: Hartley WT, McAuley JP et al.: Osteonecrosis of the femoral head treated with cementless total hip arthroplasty. J Bone Joint Surg Am (2000) Oct; 82-A(10): Mankin HJ: Nontraumatic necrosis of bone (osteonecrosis). NEJM, (1992) 326: Mont MA, Hungerford DS: Non-traumatic avascular necrosis of the femoral head. J Bone Joint Surg Am (1995) Mar; 77(3): Steinberg ME, Hayken GD, Steinberg DR. A quantitative system for staging avascular necrosis. J Bone Joint Surg Br. (1995) Jan;77(1): Strauss M., Dvorak T.: Femoral Head Necrosis and Hyperbaric Oxygen Therapy in "Hyperbaric Medicine Practice" - Kindwall & Whelan eds. - Best Publishing Company (1999), pp Vande Berg B, Malghem JJ, Lecouvet FE, Jamart J, Maldague BE: Idiopathic Bone Marrow Edema Lesions of the Femoral Head: Predictive Value of MR Imaging Findings. Radiology (1999) 212:

Hyperbaric Oxygen for Stage I and II Femoral Head Osteonecrosis

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