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ISSN / EISSN : 1745-6215 / 1745-6215
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Rosemary Greenwood, Julie Pell, Paula Foscarini-Craggs, Katharine Wale, Ian Thomas, Charlotte Bradbury
Published: 21 October 2020
Trials, Volume 21, pp 1-4; doi:10.1186/s13063-020-04798-x

Abstract:
When planning a multicentre clinical trial, it can be difficult to predict the time needed to open individual sites, and this in turn impacts on the total number of sites needed, the budget and the time frame for a clinical trial to be delivered successfully. This is of particular importance for funding applications with a limited time frame and budget such as NIHR RfPB. It is more efficient and cost-effective to open the total number of sites needed at the outset of a trial, rather than to respond later to slow site opening and recruitment. Here, we share our experience of successfully delivering a multicentre clinical trial for a rare disease within a limited time frame and budget by approximately doubling the number of sites initially predicted to be needed. We initially predicted 20 sites would be needed to deliver the clinical trial, but early on in the trial, the number of sites was more than doubled to allow successful recruitment of the target sample size within the desired time frame. Of the 48 ethically approved sites, the median time from ethical approval of a site to opening for recruitment was 182 days (95% confidence interval [143 to 245 days]) and ranged from 18 to 613 days. In four (9%) of these sites, part of the delay was due to pharmacy sign off not being given when R&D had issued capacity and capability (C&C). Delays due to pharmacy sign off varied from 10 days to over 3 months delay in two sites (94 days and 102 days). A mathematical solution to the problem of planning a study with a short recruitment window has been given to support the planning and costing of grants with fixed time constraints: number of sites = required sample size divided by (number of eligible patients per site per month times recruitment rate times (the number of months accrual minus 6 months)). We expect these results to help others who are planning multicentre clinical trials in the UK. Ethical approval from NRES Committee South West (IRAS number 225959). Trial registration EudraCT Number 2017-001171-23. Registered on 26 June 2017
Luisa Weiner, Fabrice Berna, Nathalie Nourry, François Severac, Pierre Vidailhet, Amaury C. Mengin
Published: 21 October 2020
Trials, Volume 21, pp 1-10; doi:10.1186/s13063-020-04772-7

Abstract:
Background The acknowledgment of the mental health toll of the COVID-19 epidemic in healthcare workers has increased considerably as the disease evolved into a pandemic status. Indeed, high prevalence rates of depression, sleep disorders, and post-traumatic stress disorder (PTSD) have been reported in Chinese healthcare workers during the epidemic peak. Symptoms of psychological distress are expected to be long-lasting and have a systemic impact on healthcare systems, warranting the need for evidence-based psychological treatments aiming at relieving immediate stress and preventing the onset of psychological disorders in this population. In the current COVID-19 context, internet-based interventions have the potential to circumvent the pitfalls of face-to-face formats and provide the flexibility required to facilitate accessibility to healthcare workers. Online cognitive behavioral therapy (CBT) in particular has proved to be effective in treating and preventing a number of stress-related disorders in populations other than healthcare workers. The aim of our randomized controlled trial study protocol is to evaluate the efficacy of the ‘My Health too’ CBT program—a program we have developed for healthcare workers facing the pandemic—on immediate perceived stress and on the emergence of psychiatric disorders at 3- and 6-month follow-up compared to an active control group (i.e., bibliotherapy). Methods Powered for superiority testing, this six-site open trial involves the random assignment of 120 healthcare workers with stress levels > 16 on the Perceived Stress Scale (PSS-10) to either the 7-session online CBT program or bibliotherapy. The primary outcome is the decrease of PSS-10 scores at 8 weeks. Secondary outcomes include depression, insomnia, and PTSD symptoms; self-reported resilience and rumination; and credibility and satisfaction. Assessments are scheduled at pretreatment, mid-treatment (at 4 weeks), end of active treatment (at 8 weeks), and at 3-month and 6-month follow-up. Discussion This is the first study assessing the efficacy and the acceptability of a brief online CBT program specifically developed for healthcare workers. Given the potential short- and long-term consequences of the COVID-19 pandemic on healthcare workers’ mental health, but also on healthcare systems, our findings can significantly impact clinical practice and management of the ongoing, and probably long-lasting, health crisis. Trial registration ClinicalTrials.gov NCT04362358, registered on April 24, 2020.
Prasan Kumar Panda, Arkapal Bandyopadhyay, Budha Charan Singh, Bikram Moirangthem, Gaurav Chikara, Sarama Saha, Yogesh Arvind Bahurupi
Published: 20 October 2020
Trials, Volume 21, pp 1-3; doi:10.1186/s13063-020-04774-5

Abstract:
Objectives 1. To compare the safety and efficacy of Hydroxychloroquine with Ribavirin and standard treatment in patients with non-severe COVID-19 infection 2. To compare the safety and efficacy of standard treatment, Lopinavir-ritonavir with Ribavarin, and Hydroxychloroquine with Ribavirin in patients with severe COVID-19 infection Trial design The study is an Open label, Parallel arm design, stratified randomised controlled trial. Patients will be categorised as non-severe or severe based on predefined criteria. Those who satisfy all inclusion criteria and no exclusion criteria in the respective categories, will be randomly assigned to one of the three treatment groups in a ratio of 1:1 in the non-severe category and 1:1:1 in the severe category. Participants The trial will be undertaken in a tertiary care center of the country where both Covid and non-Covid patients are getting treated. All patients who are confirmed positive and admitted will be screened for the eligibility criteria and will be enrolled in the study after a written informed consent. Patients will be categorised as non-severe or severe based on predefined criteria. Inclusion Criteria (all required) 1. Age ≥18 years at time of participation in the study 2. Laboratory (RT-PCR) confirmed infection with SARS-CoV-2 3. Symptomatic (severe or non-severe) Covid-19 disease 4. Willingness of study participant to accept randomization to any assigned treatment arm Exclusion Criteria 1. Use of medications that are contraindicated with Lopinavir/Ritonavir, Hydroxychloroquine/Chloroquine, or Ribavirin and that cannot be replaced or stopped 2. Patient already on antiretroviral therapy with Lopinavir-Ritonavir based regimen or on Hydroxychloroquine/Chloroquine or on Ribavirin 3. Any known contraindication to test drugs such as retinopathy and QT prolongation 4. Known allergic reaction or inability to take orally of Lopinavir-ritonavir, Hydroxychloroquine/ Chloroquine, Ribavarin 5. Pregnant or breastfeeding females 6. Receipt of any experimental treatment for 2019-nCoV (off-label, compassionate use, or trial related) within 30 days prior to participation in the present study or want to participate after enrolment Intervention and comparator Two therapeutic interventions for non-severe category and three for severe category as described below Non-severe Treatment arms (NS-group) Treatment Arm Drug A Standard Treatment (STNS) B Hydroxychloroquine 400 mg twice on first day followed by 400 mg per oral daily for 10 days + Ribavirin (1.2 g orally as a loading dose followed by 600mg orally every 12 hours) for 10 days + Standard Treatment (STNS) Standard Treatment for non-severe cases (STNS): Strict Isolation, Standard Precautions (Hand hygiene, Cough Etiquette, Wear surgical mask), Hydration, Proper Nutrition, Supportive Pharmacotherapy (Antipyretic, Antiallergic, Cough Suppressant), Treatment of Comorbid Diseases, Oseltamivir (75 mg BD) for patients who are tested positive for H1N1. Severe group Treatment arms (S-group) Treatment Arm Drug A Standard Treatment (STs) B Hydroxychloroquine 400mg BD on day1 followed by 400 mg once daily + Ribavirin (1.2 g orally as a loading dose followed by 600mg orally every 12 hours) for 10 days + Standard Treatment (STs) C Lopinavir(200mg) + Ritonavir (50mg) two tablets twice daily+ Ribavirin (1.2g orally as a loading dose followed by 600mg orally every 12 hours) for 10 days + Standard Treatment (STs)6 Standard Treatment for severe patients (STs): Strict Isolation, Standard Precautions (Hand hygiene, Cough Etiquette, Wear surgical mask), Fluid Therapy, Supportive Pharmacotherapy (Antipyretic, Antiallergic, Cough Suppressant), Oxygen supplementation (As required), Invasive ventilation (As required), Antibiotic agents for other associated infections (according to 2019 ATS/IDSA guidelines for non-ICU and ICU patients), Vasopressor support, Renal-replacement therapy, Treatment of Comorbid Diseases, Oseltamivir (75 mg BD) for patients who are tested positive for H1N1. Main Outcomes Primary endpoints: (1) Time to Clinical recovery (TTCR) defined as the time (in hours) from initiation of study treatment (active or placebo) until normalisation of fever, respiratory rate, oxygen saturation, and alleviation of cough, sustained for at least 72 hours. (2) Time to SARS-CoV-2 RT-PCR negative in upper respiratory tract specimen, time to laboratory recovery of each organ involvement. Secondary Endpoints: All causes mortality, Frequency of respiratory progression (defined as SPO2≤ 94% on room air or PaO2/FiO2 Outcomes are monitored for 28 days from the time of enrolment into the study OR until the patient is discharged or death whichever is longer. Randomization The randomization will be done using a secured central computer-based randomization using a secure website using a central, computer-based randomisation program in a ratio of 1:1 in the non-severe category and 1:1:1 in the severe category. Blinding (masking) This is an open labelled study i.e. Study assigned treatment will be known to the research team, the investigators and participants. Numbers to be randomised (sample size) Since it is an exploratory trial as COVID-19 being a new disease, all patients who came under the purview of the inclusion criteria within the study period (5 months duration of the recruitment period of the total 6 months duration of the study i.e. from the month of June, 2020 to October 2020) and who have consented for the study will be included. Trial Status Protocol version:1.0 Recruitment start: June 3rd, 2020 (Ongoing) Recruitment finish (expected): October 31st, 2020 Trial registration Clinical Trial Registry of India (CTRI): CTRI/2020/06/025575. Registration on 03 June 2020 Full protocol The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this letter serves as a...
James A. Watson, Chris C. Holmes
Published: 20 October 2020
Trials, Volume 21, pp 1-1; doi:10.1186/s13063-020-04782-5

Abstract:
An amendment to this paper has been published and can be accessed via the original article.
Martin A. S. Meyer, Sebastian Wiberg, Johannes Grand, Jesper Kjaergaard, Christian Hassager
Published: 20 October 2020
Trials, Volume 21, pp 1-12; doi:10.1186/s13063-020-04783-4

Abstract:
Background Resuscitated out-of-hospital cardiac arrest (OHCA) patients who remain comatose at admission are at high risk of morbidity and mortality. This has been attributed to the post-cardiac arrest syndrome (PCAS) which encompasses multiple interacting components, including systemic inflammation. Elevated levels of circulating interleukin-6 (IL-6), a pro-inflammatory cytokine, is associated with worse outcomes in OHCA patients, including higher vasopressor requirements and higher mortality rates. In this study, we aim to reduce systemic inflammation after OHCA by administering a single infusion of tocilizumab, an IL-6 receptor antibody approved for use for other indications. Methods Investigator-initiated, double-blinded, placebo-controlled, single-center, randomized clinical trial in comatose OHCA patients admitted to an intensive cardiac care unit. Brief inclusion criteria: OHCA of presumed cardiac cause, persistent unconsciousness, age ≥ 18 years. Intervention: 80 patients will be randomized in a 1:1 ratio to a single 1-h intravenous infusion of either tocilizumab or placebo (NaCl). During the study period, patients will receive standard of care, including sedation and targeted temperature management of 36 ° for at least 24 h, vasopressors and/or inotropes as/if needed, prophylactic antibiotics, and any additional treatment at the discretion of the treating physician. Blood samples are drawn for measurements of biomarkers included in the primary and secondary endpoints during the initial 72 h. Primary endpoint: reduction in C-reactive protein (CRP). Secondary endpoints (abbreviated): cytokine levels, markers of brain, cardiac, kidney and liver damage, hemodynamic and hemostatic function, adverse events, and follow-up assessment of cerebral function and mortality. Discussion We hypothesize that reducing the effect of circulating IL-6 by administering an IL-6 receptor antibody will mitigate the systemic inflammatory response and thereby modify the severity of PCAS, in turn leading to lessened vasopressor use, more normal hemodynamics, and better organ function. This will be assessed by primarily focusing on hemodynamics and biomarkers of organ damage during the initial 72 h. In addition, pro-inflammatory and anti-inflammatory cytokines will be measured to assess if cytokine patterns are modulated by IL-6 receptor blockage. Trial registration ClinicalTrials.gov Identifier: NCT03863015; submitted February 22, 2019, first posted March 5, 2019. EudraCT: 2018-002686-19; date study was authorized to proceed: November 7, 2018.
Pradeesh Sivapalan, Charlotte Suppli Ulrik, Therese Sophie Lappere, Josefin Viktoria Eklöf, Saher Burhan Shaker, Uffe Christian Steinholtz Bødtger, Andrea Browatzki, Christian Niels Meyer, Ulla Møller Weinreich, Christian B. Laursen, et al.
Published: 20 October 2020
Trials, Volume 21, pp 1-9; doi:10.1186/s13063-020-04795-0

Abstract:
Background There is an urgent need for treatments that can shorten hospitalization and lower the risk of secondary infection and death in patients with corona disease. The ProPac-COVID trial evaluates whether combination therapy with macrolide azithromycin and hydroxychloroquine via anti-inflammation/immune modulation, antiviral efficacy, and pre-emptive treatment of supra-infections can shorten hospitalization duration and reduce the risk of non-invasive ventilation, treatment in the intensive care unit, and death in patients with acute hospital admission and a positive test for 2019-nCoV and symptoms of COVID-19 disease. Methods The ProPAC-COVID is a multi-center, randomized, placebo-controlled, double-blinded clinical trial. The primary outcome is number of days spent alive and out of hospital within 14 days from randomization. Randomization will be in blocks of unknown size, and the final allocation will be stratified for age, site of recruitment, and whether the patient has any chronic lung diseases. Data is analyzed using intention-to-treat (ITT) principles, and main analyses will also be subject to modified ITT analysis and per protocol analysis. Discussion This paper describes the detailed statistical analysis plan for the evaluation of primary and secondary endpoints of the ProPAC-COVID study. Enrolment of patients to the ProPAC-COVID study is still ongoing. The purpose of this paper is to provide primary publication of study results to prevent selective reporting of outcomes, data-driven analysis, and to increase transparency. Trial registration ClinicalTrials.gov NCT04322396. Registered on 26 March 2020.
Rongrong Li, Yongliang Jiang, Renjie Hu, Xiaofen He, Jianqiao Fang
Published: 20 October 2020
Trials, Volume 21, pp 1-7; doi:10.1186/s13063-020-04800-6

Abstract:
Background Tenosynovitis of the long head of the biceps (LHB) brachii is a common disease in patients over 40 years old. It can always result in chronic anterior shoulder pain and limited function. Acupuncture is one of most popular conservative treatment methods, and increasing studies indicate that it has remarkable therapeutic effects on the tenosynovitis of LHB brachii. However, the effectiveness and safety of acupuncture for treating tenosynovitis of LHB brachii remain largely uncertain. In our study, we will perform the first systematic review and meta-analysis to explore the effectiveness and safety of acupuncture on the tenosynovitis of LHB brachii. Methods We will search the randomized controlled trial (RCT) literatures involving acupuncture for treating tenosynovitis of LHB brachii in eight electric databases, including PubMed, Web of Science, EMBASE, the Cochrane Library, Chinese National Knowledge Infrastructure (CNKI), Chinese Biomedical Literature Database (CBM), Wanfang Database, and Technology Periodical Database (VIP). We will define the visual analog scale (VAS), the Melle score of shoulder joint functional activity, and the ability assessment of daily living activities (ADL) as the primary outcomes. Besides quality of life, adverse events caused by acupuncture will be regarded as the secondary outcomes. Quality assessment of the included studies will be independently performed according to the Cochrane Risk of Bias tool. Meanwhile, the level of evidence for results will be assessed by using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) method. All analyses will be conducted by using the RevMan software V5.3. Results From the study, we will ascertain the effectiveness and safety of acupuncture treatment on tenosynovitis of LHB brachii. Conclusion The conclusion of this study will confirm the effectiveness and safety of acupuncture in the treatment of tenosynovitis of LHB brachii, which can provide new evidence to guide appropriate interventions on tenosynovitis of LHB brachii with acupuncture in the future. Ethics and dissemination Ethical approval is not required because no individual patient data are collected. This review will be published in a peer-reviewed journal and presented at an international academic conference for dissemination. Trial registration PROSPERO registration number CRD42020167434. Registered on April 28, 2020.
Ellis Niemantsverdriet, Yousra J. Dakkak, Leonie E. Burgers, Femke Bonte-Mineur, Gerda M. Steup-Beekman, Sjoerd M. Van Der Kooij, Hido D. Boom, Cornelia F. Allaart, Pascal H. P. De Jong, Annette H. M. Van Der Helm-Van Mil
Published: 16 October 2020
Trials, Volume 21, pp 1-18; doi:10.1186/s13063-020-04731-2

Abstract:
Background We present a study protocol for a randomized, double-blind, placebo-controlled trial that investigates the hypothesis if intervention in the symptomatic phase preceding clinical arthritis (clinically suspect arthralgia (CSA)) is effective in preventing progression from subclinical inflammation to clinically apparent persistent arthritis. Currently, rheumatoid arthritis (RA) can be recognized and diagnosed when arthritis (joint swelling) has become detectable at physical examination. Importantly, at this time, the immune processes have already matured, chronicity is established, and patients require long-standing treatment with disease-modifying anti-rheumatic drugs. The TREAT EARLIER trial studies the hypothesis that intervention in the symptomatic phase preceding clinical arthritis is more often successful in permanent disease modification because of less matured underlying disease processes. Methods A two-level definition to identify patients that are prone to develop RA is used. First, patients should have CSA and recent-onset arthralgia (< 1 year) that is suspect to progress to RA according to the expertise of the treating rheumatologist. Second, patients need to have subclinical inflammation of the hand or foot joints at 1.5 T MRI. The trial aims to recruit 230 participants from secondary care hospital settings across the south-west region of The Netherlands. Intervention will be randomly assigned and includes a single-dose of intramuscular 120 mg methylprednisolon followed by methotrexate (increasing dose to 25 mg/week orally) or placebo (both; injection and tablets) over the course of 1 year. Thereafter, participants are followed for another year. The primary endpoint is the development of clinically detectable arthritis, either fulfilling the 2010 criteria for RA or unclassified clinical arthritis of ≥ 2 joints, which persists for at least 2 weeks. DMARD-free status is a co-primary endpoint. The patient-reported outcomes functioning, along with workability and symptoms, are key secondary endpoints. Participants, caregivers (including those assessing the endpoints), and scientific staff are all blinded to the group assignment. Discussion This proof-of-concept study is the logical consequence of pre-work on the identification of patients with CSA with MRI-detected subclinical joint inflammation. It will test the hypothesis whether intervention in patients in this early phase with the cornerstone treatment of classified RA (methotrexate) hampers the development of persistent RA and reduce the disease burden of RA. Trial registration Dutch Trial Register NL4599 (NTR4853). Registered on 20 October 2014
Susan N. Hastings, Karen M. Stechuchak, Ashley Choate, Elizabeth P. Mahanna, Courtney Van Houtven, Kelli D. Allen, Virginia Wang, Nina Sperber, Leah Zullig, Hayden B. Bosworth, et al.
Published: 16 October 2020
Trials, Volume 21, pp 1-9; doi:10.1186/s13063-020-04764-7

Abstract:
Background Stepped wedge cluster randomized trials (SW-CRT) are increasingly used to evaluate new clinical programs, yet there is limited guidance on practical aspects of applying this design. We report our early experiences conducting a SW-CRT to examine an inpatient mobility program (STRIDE) in the Veterans Health Administration (VHA). We provide recommendations for future research using this design to evaluate clinical programs. Methods Based on data from study records and reflections from the investigator team, we describe and assess the design and initial stages of a SW-CRT, from site recruitment to program launch in 8 VHA hospitals. Results Site recruitment consisted of thirty 1-h conference calls with representatives from 22 individual VAs who expressed interest in implementing STRIDE. Of these, 8 hospitals were enrolled and randomly assigned in two stratified blocks (4 hospitals per block) to a STRIDE launch date. Block 1 randomization occurred in July 2017 with first STRIDE launch in December 2017; block 2 randomization occurred in April 2018 with first STRIDE launch in January 2019. The primary study outcome of discharge destination will be assessed using routinely collected data in the electronic health record (EHR). Within randomized blocks, two hospitals per sequence launched STRIDE approximately every 3 months with primary outcome assessment paused during the 3-month time period of program launch. All sites received 6–8 implementation support calls, according to a pre-specified schedule, from the time of recruitment to program launch, and all 8 sites successfully launched within their assigned 3-month window. Seven of the eight sites initially started with a limited roll out (for example on one ward) or modified version of STRIDE (for example, using existing staff to conduct walks until new positions were filled). Conclusions Future studies should incorporate sufficient time for site recruitment and carefully consider the following to inform design of SW-CRTs to evaluate rollout of a new clinical program: (1) whether a blocked randomization fits study needs, (2) the amount of time and implementation support sites will need to start their programs, and (3) whether clinical programs are likely to include a “ramp-up” period. Successful execution of SW-CRT designs requires both adherence to rigorous design principles and also careful consideration of logistical requirements for timing of program roll out. Trial registration ClinicalsTrials.gov NCT03300336. Prospectively registered on 3 October 2017.
Lanlan Pu, Nauman Khalid Qureshi, Joanne Ly, Bingwei Zhang, Fengyu Cong, William C. Tang, Zhanhua Liang
Published: 16 October 2020
Trials, Volume 21, pp 1-14; doi:10.1186/s13063-020-04770-9

Abstract:
Background Music therapy improves neuronal activity and connectivity of healthy persons and patients with clinical symptoms of neurological diseases like Parkinson’s disease, Alzheimer’s disease, and major depression. Despite the plethora of publications that have reported the positive effects of music interventions, little is known about how music improves neuronal activity and connectivity in afflicted patients. Methods For patients suffering from Parkinson’s disease (PD), we propose a daily 25-min music-based synchronous finger tapping (SFT) intervention for 8 weeks. Eligible participants with PD are split into two groups: an intervention group and a control arm. In addition, a third cohort of healthy controls will be recruited. Assessment of finger tapping performances, the Unified Parkinson’s Disease Rating Scale (UPDRS), an n-back test, the Montreal Cognitive Assessment (MoCA), as well as oxygenated hemoglobin (HbO2), deoxygenated hemoglobin (HbR), and total hemoglobin activation collected by functional near-infrared spectroscopy (fNIRS) are measured at baseline, week 4 (during), week 8 (post), and week 12 (retention) of the study. Data collected from the two PD groups are compared to baseline performances from healthy controls. Discussion This exploratory prospective trial study investigates the cortical neuronal activity and therapeutic effects associated with an auditory external cue used to induce automatic and implicit synchronous finger tapping in patients diagnosed with PD. The extent to which the intervention is effective may be dependent on the severity of the disease. The study’s findings are used to inform larger clinical studies for optimization and further exploration of the therapeutic effects of movement-based music therapy on neural activity in neurological diseases. Trial registration ClinicalTrials.gov NCT04212897. Registered on December 30, 2019. The participant recruitment and study protocol have received ethical approval from the First Affiliated Hospital of Dalian Medical University. The hospital Protocol Record number is PJ-KY-2019-123. The protocol was named “fNIRS Studies of Music Intervention of Parkinson’s Disease.” The current protocol is version 1.1, revised on September 1, 2020.
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