Title: Managing Avascular Necrosis Treatments : An Interventional Study (MANTIS)
Funder: Department of Health and Social Care

Abstract: DESIGN: Multi-centre parallel two-arm, blinded, placebo-controlled RCT. Stratification for radiological involvement (<=30%/>30%); AVN risk factors: steroid/alcohol/continuing steroid use/other; Ficat stage 1/2 SETTING: Secondary Care: Outpatient orthopaedic, rheumatology, sport, metabolic bone clinics at 10 centres for the pilot study, expanding to potentially 20-25 participating hospitals. TARGET POPULATION: Adult patients with symptomatic early AVN. INTERNAL PILOT TRIAL: An internal pilot study is planned to assess recruitment/patient characteristics/equipoise/outcomes/data collection methods. This ends when 10 centres are open for recruitment and 50 participants have been randomised by 12 months. GO-NO GO DECISION: The main trial will proceed if recruitment is projected to be completed within 3 years. INCLUSION CRITERIA: Early symptomatic atraumatic AVN (Ficat Score 1/2 using MRI),patients presenting to secondary care for treatment, patietns who are within 12 months of diagnosis using an MRI, Aged between 18-85 years, renal function (creatinine clearance) of >30ml/min - tested within the last 3 months, adjusted serum calcium levels also within local reference range - tested within the last 3 months. EXCLUSION CRITERIA: Established OA (K-L >=2), previous: AVN, femoral head deformity, hip surgery, hip fracture; contraindications to MRI/alendronate therapy; patients unable to commit to follow-up regime; pregnant/pregnancy in next 12 months; patients not using effective contraception, planned joint preserving surgical procedures. HEALTH TECHNOLOGIES: INTERVENTION: Standard therapy+weekly 70mg alendronate weekly for 12 months (Treatment arm). COMPARATOR: Standard therapy+matched placebo weekly for 12 months (Non-Treatment arm). STANDARD THERAPY: Non-weight bear on affected limb for 3 months, then full weight bear. Up to 8 physiotherapy sessions over 12 months. Analgesia as required. Walking aids permitted. Ensure calcium & vitamin D replete. OUTCOMES: There are two primary outcomes: a short term outcome, which is the Oxford Hip Score at 1 year post randomisation. A long-term outcome, which will be time to hip replacement at 3 years. These outcomes will capture the two most important issues for patients. The analysis plan will control for ongoing steroid use. SECONDARY OUTCOMES: EQ-5D; iHOT-33 (Hip PROM for younger patients); complication rates; conversion to total hip replacement; radiological progression (on X-ray). Health Economic Assessments: micro-costing; HRG-based approaches; level of detail on costing of components/consumables, health care, rehabilitation, productivity losses and informal care. ASSESSMENT: Baseline assessment <4 weeks of initial clinic appointment. Subsequent assessments every 6 months, (symptom progression/variability). MRIs at baseline, X-rays at baseline and 12 months. SAMPLE SIZE: 280 participants are required for the RCT with 1:1 randomisation (drug:placebo) 90% power, 5% 2-sided significance for the OHS at 12 months post-randomisation. 280 participants would have 80% power to detect a reduction in the proportion of hip replacements at 3 years by 20%, even if the proportion in the control groups was as low as 60% It is proposed that 280 participants are recruited (140/arm). PROJECT TIMETABLES: The study duration is 5.5 years (including internal pilot). Recruitment will take 3 years. 68% of participants will undergo a minimum of 3 years of assessment TEAM EXPERTISE: Includes; surgeons, rheumatologists, metabolic bone physicians (SGJ/KJ/TB/AB/CC/JN//VK/CM), Trials/Methodologist (DB/CC), Statisticians (SD), Radiologist (RK), Health economist (AG), Patient representative (PL).This trial is supported by the Oxford Surgical Interventional Trials Unit/OCTRU.

Lay abstract: Avascular necrosis of the hip is an uncommon but devastating condition that typically affects younger people. It happens when the bone of the hip joint dies. In its early stages people often feel pain and this is often followed by a rapid collapse of the joint. This leads to severe immobility and suffering in over half of those affected. In younger patients, this means that they can often not walk comfortably, have sleep disturbance and cannot work. Young people with AVN can often feel socially isolated, given that their activity often limits the amount they can do with friends. The early phase of treatment usually involves asking the patient to use crutches in the hope that taking the weight off the hip will prevent it collapsing. This is only effective in 15% of patients, however. Joint preserving operations are also used, but often fail. All too often, many patients will become so immobile that the only cure for their pain will be hip replacement. This happens in three-quarters of patients. Although this is an effective treatment, it is a large operation, which only lasts for 10 to 20 years. Also patients who receive joint replacements for AVN are at a much higher risk of needing further surgery, having dislocations and having infection postoperatively. At present there is little evidence for an effective drug treatment for preventing AVN. Some doctors have tried drugs with the aim of preventing AVN progression, with mixed results. Some studies suggest that drugs, such as bisphosphonates (normally used in osteoporosis) have an ability to significantly reduce pain and progression, others show no difference. It is for this reason that the HTA has asked the surgical and medical community to test the ability of drugs to treat AVN. We are asking the HTA to fund a trial designed to test whether drugs can be effective in treating AVN. To do this we will select patients who have AVN at an early stage. We will then ask them to be part of a randomized control trial where they will receive either a drug known as a bisphosphonate, or a placebo (dummy pill) in addition to standard treatments (such as pain killers and physiotherapy) for 1 year. This treatment is simple and safe. As AVN is a relatively uncommon condition, our aim is to recruit a total of 280 patients from 20 or so hospitals around the country. The first part of the trial will include a ‘pilot’ phase, where we will find out whether we can recruit the number of patients required within a reasonable time period. This is vital, as our initial investigations show that the way in which patients with AVN are sent to hospital can vary a lot. The pilot phase will enable us to determine the best way to recruit patients from as many centres as possible. It will also let us know how often patients will agree to be part of the trial. If the pilot is successful, then we would like to follow most patients for 3 years. This 3 years will include 1 year of treatment followed by another 2 years of observation, to see if the bisphosphonate drug makes their pain better. Patients have been involved at each stage of this trial. We will need to appoint a number of staff to run such a large multi-centre study. This will be coordinated by a national Clinical Trials Research Unit and we will involve national patient and physician groups to maximise our chances of recruiting enough patients. We anticipate that recruitment will take 3 years. The total duration of the study will be 5.5 years

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: MUSCULOSKELETAL