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Abstract Background The peak of the global COVID-19 pandemic has not yet been reached, and many countries face the prospect of a second wave of infections before effective vaccinations will be available. After an initial phase of viral replication, some patients develop a second illness phase in which the host thrombotic and inflammatory responses seem to drive complications. Severe COVID-19 disease is linked to high mortality, hyperinflammation, and a remarkably high incidence of thrombotic events. We hypothesize a crucial pathophysiological role for the contact pathway of coagulation and the kallikrein-bradykinin pathway. Therefore, drugs that modulate this excessive thromboinflammatory response should be investigated in severe COVID-19. Methods In this adaptive, open-label multicenter randomized clinical trial, we compare low molecular weight heparins at 50 IU anti-Xa/kg twice daily—or 75 IU anti-Xa twice daily for intensive care (ICU) patients—in combination with aprotinin to standard thromboprophylaxis in hospitalized COVID-19 patients. In the case of hyperinflammation, the interleukin-1 receptor antagonist anakinra will be added on top of the drugs in the interventional arm. In a pilot phase, the effect of the intervention on thrombotic markers (D-dimer) will be assessed. In the full trial, the primary outcome is defined as the effect of the interventional drugs on clinical status as defined by the WHO ordinal scale for clinical improvement. Discussion In this trial, we target the thromboinflammatory response at multiple levels. We intensify the dose of low molecular weight heparins to reduce thrombotic complications. Aprotinin is a potent kallikrein pathway inhibitor that reduces fibrinolysis, activation of the contact pathway of coagulation, and local inflammatory response. Additionally, aprotinin has shown in vitro inhibitory effects on SARS-CoV-2 cellular entry. Because the excessive thromboinflammatory response is one of the most adverse prognostic factors in COVID-19, we will add anakinra, a recombinant interleukin-1 receptor antagonist, to the regimen in case of severely increased inflammatory parameters. This way, we hope to modulate the systemic response to SARS-CoV-2 and avoid disease progressions with a potentially fatal outcome. Trial registration The EU Clinical Trials Register 2020-001739-28 . Registered on April 10, 2020.

An amendment to this paper has been published and can be accessed via the original article.

Abstract Background During the cochlear implantation procedure, the receiver/stimulator (R/S) part of the implant is fixated to prevent postoperative device migration, which could have an adverse effect on the position of the electrode array in the cochlea. We aim to compare the migration rates of two fixation techniques, the bony recess versus the subperiosteal tight pocket without bony sutures. Methods and analysis This single-blind randomized controlled trial will recruit a total of 112 primary cochlear implantation adult patients, eligible for implantation according to the current standard of practice. Randomization will be performed by an electronic data capture system Castor EDC, with participants block randomized to either bony recess or standard subperiosteal tight pocket in a 1:1 ratio, stratified by age. The primary outcome of this study is the R/S device migration rate; secondary outcomes include patient-experienced burden using the validated COMPASS questionnaire, electrode migration rate, electrode impedance values, speech perception scores, correlation between R/S migration, electrode array migration and patient complaints, assessment of complication rates, and validation of an implant position measurement method. Data will be collected at baseline, 1 week, 4 weeks, 8 weeks, 3 months, and 12 months after surgery. All data analyses will be conducted according to the intention-to-treat principle. Discussion Cochlear implantation by means of creating a tight subperiosteal pocket without drilling a bony seat is a minimally invasive fixation technique with many advantages. However, the safety of this technique has not yet been proven with certainty. This is the first randomized controlled trial that directly compares the minimally invasive technique with the conventional method of drilling a bony seat. Trial registration Netherlands Trial Register NL9698. Registered on 31 August 2021.

Abstract Background In order to preserve residual hearing in patients with sensorineural hearing loss (SNHL) who receive a cochlear implant (CI), insertion trauma to the delicate structures of the cochlea needs to be minimized. The surgical approach comprises the conventional mastoidectomy-posterior tympanotomy (MPT) to arrive at the middle ear, followed by either a cochleostomy (CO) or the round window (RW) approach. Both techniques have their benefits and disadvantages. Another important aspect in structure preservation is the design of the electrode array. Two different designs are used: a “straight” lateral wall lying electrode array (LW) or a “pre-curved” perimodiolar lying electrode array (PM). Interestingly, until now, the best surgical approach and design of the implant is uncertain. Our hypothesis is that there is a difference in hearing preservation outcomes between the four possible treatment options. Methods We designed a monocenter, multi-arm, randomized controlled trial to compare insertion trauma between four groups of patients, with each group having a unique combination of an electrode array type (LW or PM) and surgical approach (RW or CO). In total, 48 patients will be randomized into one of these four intervention groups. Our primary objective is the comparison of postoperative hearing preservation between these four groups. Secondly, we aim to assess structure preservation (i.e., scalar translocation, with basilar membrane disruption or tip fold-over of array) for each group. Thirdly, we will compare objective outcomes of hearing and structure preservation by way of electrocochleography (ECochG). Discussion Cochlear implantation by way of a cochleostomy or round window approach, using different electrode array types, is the standard medical care for patients with severe to profound bilateral sensorineural hearing loss, as it is a relatively simple and low-risk procedure that greatly benefits patients. However, loss of residual hearing remains a problem. This trial is the first randomized controlled trial that evaluates the effect of cochlear insertion trauma of several CI treatment options on hearing preservation. Trial registration Netherlands Trial Register (NTR) NL8586 . Registered on 4 May 2020. Retrospectively registered; 3/48 participants were included before registration.

Background: The peak of the global COVID-19 pandemic has not yet been reached, and many countries face the prospect of a second wave of infections before effective vaccinations will be available. After an initial phase of viral replication, some patients develop a second illness phase in which the host thrombotic and inflammatory responses seem to drive complications. Severe COVID-19 disease is linked to high mortality, hyperinflammation, and a remarkably high incidence of thrombotic events. We hypothesize a crucial pathophysiological role for the contact pathway of coagulation and the kallikrein-bradykinin pathway. Therefore, drugs that modulate this excessive thromboinflammatory response should be investigated in severe COVID-19., Methods: In this adaptive, open-label multicenter randomized clinical trial, we compare low molecular weight heparins at 50 IU anti-Xa/kg twice daily-or 75 IU anti-Xa twice daily for intensive care (ICU) patients-in combination with aprotinin to standard thromboprophylaxis in hospitalized COVID-19 patients. In the case of hyperinflammation, the interleukin-1 receptor antagonist anakinra will be added on top of the drugs in the interventional arm. In a pilot phase, the effect of the intervention on thrombotic markers (D-dimer) will be assessed. In the full trial, the primary outcome is defined as the effect of the interventional drugs on clinical status as defined by the WHO ordinal scale for clinical improvement., Discussion: In this trial, we target the thromboinflammatory response at multiple levels. We intensify the dose of low molecular weight heparins to reduce thrombotic complications. Aprotinin is a potent kallikrein pathway inhibitor that reduces fibrinolysis, activation of the contact pathway of coagulation, and local inflammatory response. Additionally, aprotinin has shown in vitro inhibitory effects on SARS-CoV-2 cellular entry. Because the excessive thromboinflammatory response is one of the most adverse prognostic factors in COVID-19, we will add anakinra, a recombinant interleukin-1 receptor antagonist, to the regimen in case of severely increased inflammatory parameters. This way, we hope to modulate the systemic response to SARS-CoV-2 and avoid disease progressions with a potentially fatal outcome., Trial Registration: The EU Clinical Trials Register 2020-001739-28 . Registered on April 10, 2020.