Improving readiness for recruitment through simulated trial activation: the Adjuvant Steroids in Adults with Pandemic influenza (ASAP) trial

Background: Research in public health emergencies requires trials to be set up in readiness for activation at short notice and in anticipation of limited timelines for patient recruitment. We conducted a simulated activation of a hibernating pandemic influenza clinical trial in order to test trial processes and to determine the value of such simulation in maintaining trial readiness. Methods: The simulation involved the Nottingham Clinical Trials Unit, one participating hospital, one manufacturing unit and the Investigational Medicinal Product (IMP) supplier. During the exercise, from 15 September 2015 to 2 December 2015, clinical staff at the participating site completed the trial training package, a volunteer acting as a patient was recruited to the study, ‘dummy’ IMP was prescribed and follow-up completed. Results: Successful activation of the hibernating trial with patient recruitment within 4 weeks of ‘arousal’ as planned was demonstrated. A need for greater resilience in anticipation of staff absenteeism was identified, particularly in relation to key trial procedures where the potential for delay is high. A specific issue relating to the IMP Stock Control System was highlighted as a potential source of error that could compromise the randomisation sequence. The simulation exercise was well received by site investigators and increased their confidence in being able to meet the likely demands of the trial when activated. The estimated cost of the exercise was £1995; 90% of this being staff costs. Conclusions: Simulated activation is useful as a means to test, and prepare for, the rapid activation of ‘hibernating’ research studies. Whether simulation exercises can also help reduce waste in complex clinical trial research deserves further exploration

Protocol for a multi-centre randomised controlled stand-alone feasibility trial to assess potential effectiveness and cost-effectiveness of digital hearing aids in patients with tinnitus and hearing loss (the HUSH trial)

Background: The most common management strategy for tinnitus provided in UK audiology clinics is education and advice. This may also be combined with some form of sound therapy (e.g. digital hearing aids). While education and advice is generally provided by all clinics, there is a marked variability in provision of hearing aids that depends very much on clinical decisions. A recent Cochrane review concluded a lack of evidence to support or refute hearing aid use as a routine intervention for people with tinnitus and hearing loss. This lack of evidence is reflected in the inconsistency of tinnitus management in the UK. The aim of the HUSH trial is to determine the feasibility of conducting a definitive randomised controlled trial (RCT) of the effectiveness and cost-effectiveness of hearing aids for adults with tinnitus and hearing loss. Methods: This is a multicentre randomised controlled feasibility trial. Up to 100 adults, aged 18 and over, presenting to 5 UK audiology clinics with a complaint of tinnitus and measurable hearing loss are being randomised to receive either: i) education and advice (Treatment as usual), or ii) education and advice with digital hearing aids. Feasibility outcomes are being collected around recruitment, retention, patient and healthcare professional acceptability and clinical outcome assessment. Outcomes are being collected via postal questionnaire at 12 weeks post baseline. A nested interview study will supplement clinical and other outcome data, providing a detailed understanding of participants’ and audiologists’ experience of both tinnitus management and the research processes.Discussion: This feasibility trial will help us to (i) determine if it is feasible to conduct a multicentre RCT comparing treatment as usual and treatment as usual plus digital hearing aids, (ii) optimise the design of a future definitive, multicentre RCT, and (iii) inform which outcome(s) is/are relevant for patients. This work presents an important first step in determining the effectiveness of hearing aids as a tinnitus management strategy. Trial registration: ISRCTN1421841

It is unprecedented : trial management during the COVID-19 pandemic and beyond

Funding: UKTMN is funded by the Nuffield Department of Population Health (NDPH) at the University of Oxford. Acknowledgments: We thank Graeme MacLennan, Director of the Centre for Health Care Randomised Trials (CHaRT) for the inspiration for this article and UKTMN members for their input into its content. We also thank the huge clinical trial community, both nationally and internationally, for continuing to run clinical trials in these challenging times, and for regulatory agencies to adapting their processes to enable efficiencies.Peer reviewedPublisher PD

Home interventions and light therapy for treatment of vitiligo (HI-Light Vitiligo Trial): study protocol for a randomized controlled trial

Vitiligo is a condition resulting in white patches on the skin. People with vitiligo can suffer from low self-esteem, psychological disturbance and diminished quality of life. Vitiligo is often poorly managed, partly due to lack of high quality evidence to inform clinical care. We describe here a large, independent, randomised controlled trial (RCT) assessing the comparative effectiveness of potent topical corticosteroid, home-based hand-held narrowband ultraviolet B-light (NB-UVB) or combination of the two, for the management of vitiligo. Methods and Analysis The HI-Light Vitiligo Trial is a multi-centre, three-arm, parallel group, pragmatic, placebo-controlled RCT. 516 adults and children with actively spreading, but limited, vitiligo are randomised (1:1:1) to one of three groups: mometasone furoate 0.1% ointment plus dummy NB-UVB light, vehicle ointment plus NB-UVB light, or mometasone furoate 0.1% ointment plus NB-UVB light. Treatment of up to three patches of vitiligo is continued for up to 9 months with clinic visits at baseline, 3, 6 and 9 months and four post treatment questionnaires. The HI-Light Vitiligo Trial assesses outcomes included in the vitiligo core outcome set and places emphasis on participants’ views of treatment success. The primary outcome is proportion of participants achieving treatment success (patient-rated Vitiligo Noticeability Scale) for a target patch of vitiligo at 9 months with further independent blinded assessment using digital images of the target lesion before and after treatment. Secondary outcomes include time to onset of treatment response, treatment success by body region, percentage repigmentation, quality of life, time-burden of treatment, maintenance of response, safety, and within-trial cost effectiveness. Ethics and Dissemination Approvals were granted by East Midlands–Derby Research Ethics Committee (14/EM/1173) and the MHRA (EudraCT 2014-003473-42). The trial was registered 8th January 2015 ISRCTN (17160087). Results will be published in full as open access in the NIHR Journal library and elsewhere

What is the purpose of clinical trial monitoring?

Background: The sources of information on clinical trial monitoring do not give information in an accessible language and do not give detailed guidance. In order to enable communication and to build clinical trial monitoring tools on a strong easily communicated foundation, we identified the need to define monitoring in accessible language. Methods: In a three-step process, the material from sources that describe clinical trial monitoring were synthesised into principles of monitoring. A poll regarding their applicability was run at a UK national academic clinical trials monitoring meeting. Results: The process derived 5 key principles of monitoring: keeping participants safe and respecting their rights, having data we can trust, making sure the trial is being run as it was meant to be, improving the way the trial is run and preventing problems before they happen. Conclusion: From the many sources mentioning monitoring of clinical trials, the purpose of monitoring can be summarised simply as 5 principles. These principles, given in accessible language, should form a firm basis for discussion of monitoring of clinical trials

A randomised controlled trial of small particle inhaled steroids in refractory eosinophilic asthma (SPIRA)

Background: Some patients with refractory asthma have evidence of uncontrolled eosinophilic inflammation in the distal airways. While traditional formulations of inhaled steroids settle predominantly in the large airways, newer formulations with an extra-fine particle size have a more peripheral pattern of deposition. Specifically treating distal airway inflammation may improve asthma control. Methods: 30 patients with refractory asthma despite high dose inhaled corticosteroids were identified as having persistent airway eosinophilia. Following 2 weeks of prednisolone 30 mg, patients demonstrating an improvement in asthma control were randomised to receive either ciclesonide 320 µg twice daily or placebo in addition to usual maintenance therapy for 8 weeks. The primary outcome measure was sputum eosinophil count at week 8. Alveolar nitric oxide was measured as a marker of distal airway inflammation. Results: There was continued suppression of differential sputum eosinophil counts with ciclesonide (median 2.3%) but not placebo (median 4.5%) though the between-group difference was not significant. When patients who had changed their maintenance prednisolone dose during the trial were excluded the difference between groups was significant (1.4% vs 4.5%, p=0.028). Though alveolar nitric oxide decreased with ciclesonide the value did not reach statistical significance. Conclusions: These data demonstrate that patients with ongoing eosinophilic inflammation are not truly refractory, and that suppression of airway eosinophilia may be maintained with additional inhaled corticosteroid. Further work is needed with a focus on patient-orientated outcome measures such as exacerbation rate, with additional tests of small airway function. Trial registration number NCT01171365. Protocol available at http://www.clinicaltrials.gov

The FEED1 trial : protocol for a randomised controlled trial of full milk feeds versus intravenous fluids with gradual feeding for preterm infants (30-33 weeks gestational age)

BACKGROUND: In the UK, approximately 8% of live births are preterm (before 37 weeks gestation), more than 90% of whom are born between 30 and 36 weeks, forming the largest proportion of a neonatal units' workload. Neonatologists are cautious in initiating full milk feeds for preterm infants due to fears of necrotising enterocolitis (NEC). There is now evidence to dispute this fear. Small studies have shown that feeding preterm infants full milk feeds enterally from birth could result in a shorter length of hospital stay, which is important to parents, clinicians and NHS services without increasing the risk of NEC. This trial aims to investigate whether full milk feeds initiated in the first 24 h after birth reduces the length of hospital stay in comparison to introduction of gradual milk feeding with IV fluids or parenteral nutrition. METHODS: FEED1 is a multi-centre, open, parallel group, randomised, controlled superiority trial of full milk feeds initiated on the day of birth versus gradual milk feeds for infants born at 30+0 to 32+6 (inclusive) weeks gestation. Recruitment will take place in around 40 UK neonatal units. Mothers will be randomised 1:1 to full milk feeds, starting at 60 ml/kg day, or gradual feeds, as per usual local practice. Mother's expressed breast milk will always be the first choice of milk, though will likely be supplemented with formula or donor breast milk in the first few days. Feeding data will be collected until full milk feeds are achieved (≥ 140 ml/kg/day for 3 consecutive days). The primary outcome is length of infant hospital stay. Additional data will be collected 6 weeks post-discharge. Follow-up at 2 years (corrected gestational age) is planned. The sample size is 2088 infants to detect a between group difference in length of stay of 2 days. Accounting for multiple births, this requires 1700 women to be recruited. Primary analysis will compare the length of hospital stay between groups, adjusting for minimisation variables and accounting for multiple births. DISCUSSION: This trial will provide high-quality evidence on feeding practices for preterm infants. Full milk feeds from day of birth could result in infants being discharged sooner. TRIAL REGISTRATION: ISRCTN ISRCTN89654042 . Prospectively registered on 23 September 2019: ISRCTN is a primary registry of the WHO ICTRP network, and all items from the WHO Trial Registration dataset are included