RAPTOR: Randomised controlled trial of PENTOCLO (pentoxifylline-tocopherol-clodronate) in mandibular osteoradionecrosis—study protocol for an open-label phase II randomised controlled superiority trial

Background: Mandibular osteoradionecrosis (ORN) is a severe late radiation toxicity affecting 5–10% of patients who receive radiotherapy as part of treatment for head and neck malignancy. ORN can cause permanent disfigurement, dysfunction, pain and infection. There remains little robust evidence supporting the efficacy of medical or surgical management currently offered in clinical practice. Retrospective case series and meta-analyses of observational studies suggest that a repurposed triple drug combination pentoxifylline-tocopherol-clodronate (‘PENTOCLO’) may be effective in preventing deterioration, promoting healing and ultimately reducing the need for major reconstructive surgery. Methods: The RAPTOR trial is a phase II, open-label, multicentre, randomised controlled trial with a superiority design. Eligible subjects with mandibular ORN are randomised 1:1 to receive standard of care (Arm A) or PENTOCLO plus standard of care (Arm B) for 12 months. The primary outcome measure is time from randomisation to healing of ORN (without the need for surgery), as measured by clinical examination (confirming completely healed oral mucosa), intra-oral clinical photographs and imaging. RAPTOR has an embedded translational sample collection and a methodological component exploring the use of electronic patient-reported outcome measures (ePROM). Discussion: The RAPTOR trial is the first randomised controlled clinical trial of PENTOCLO in this clinical setting. The results of this phase II trial will provide robust preliminary evidence on its efficacy and inform the feasibility and appropriateness of a subsequent definitive trial. Trial registration: RAPTOR is registered with the ISRCTN registry effective date 11th November 2022: Clinical trial of the non-surgical management of radiotherapy damage to the lower jaw ISRCTN34217298, and also registered with the European Clinical Trials Database (Eudra-CT 2022–000728-39)

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

SummaryBackground Azithromycin has been proposed as a treatment for COVID-19 on the basis of its immunomodulatoryactions. We aimed to evaluate the safety and efficacy of azithromycin in patients admitted to hospital with COVID-19.Methods In this randomised, controlled, open-label, adaptive platform trial (Randomised Evaluation of COVID-19Therapy [RECOVERY]), several possible treatments were compared with usual care in patients admitted to hospitalwith COVID-19 in the UK. The trial is underway at 176 hospitals in the UK. Eligible and consenting patients wererandomly allocated to either usual standard of care alone or usual standard of care plus azithromycin 500 mg once perday by mouth or intravenously for 10 days or until discharge (or allocation to one of the other RECOVERY treatmentgroups). Patients were assigned via web-based simple (unstratified) randomisation with allocation concealment andwere twice as likely to be randomly assigned to usual care than to any of the active treatment groups. Participants andlocal study staff were not masked to the allocated treatment, but all others involved in the trial were masked to theoutcome data during the trial. The primary outcome was 28-day all-cause mortality, assessed in the intention-to-treatpopulation. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936.Findings Between April 7 and Nov 27, 2020, of 16 442 patients enrolled in the RECOVERY trial, 9433 (57%) wereeligible and 7763 were included in the assessment of azithromycin. The mean age of these study participants was65·3 years (SD 15·7) and approximately a third were women (2944 [38%] of 7763). 2582 patients were randomlyallocated to receive azithromycin and 5181 patients were randomly allocated to usual care alone. Overall,561 (22%) patients allocated to azithromycin and 1162 (22%) patients allocated to usual care died within 28 days(rate ratio 0·97, 95% CI 0·87–1·07; p=0·50). No significant difference was seen in duration of hospital stay (median10 days [IQR 5 to >28] vs 11 days [5 to >28]) or the proportion of patients discharged from hospital alive within 28 days(rate ratio 1·04, 95% CI 0·98–1·10; p=0·19). Among those not on invasive mechanical ventilation at baseline, nosignificant difference was seen in the proportion meeting the composite endpoint of invasive mechanical ventilationor death (risk ratio 0·95, 95% CI 0·87–1·03; p=0·24).Interpretation In patients admitted to hospital with COVID-19, azithromycin did not improve survival or otherprespecified clinical outcomes. Azithromycin use in patients admitted to hospital with COVID-19 should be restrictedto patients in whom there is a clear antimicrobial indication