Addressing Inpatient Hyponatremia Through Targeted Automatic E-consults: A Pilot Randomized Trial.

BACKGROUND: Hyponatremia is the most common electrolyte abnormality in hospitalized patients. Treatment of hyponatremia is associated with improved outcomes, but more than one in three cases of new onset hyponatremia is not corrected by the time of hospital discharge. Nephrologist input may improve the diagnosis and treatment of hyponatremia, but specialist resources are limited. Targeted automatic electronic consultations (TACos) may be one approach to provide expert nephrologist guidance to the workup and management of hyponatremia using a scalable model. OBJECTIVE: Evaluate the feasibility and acceptability of a TACo intervention for hospitalized patients with hyponatremia. DESIGN: Single-site, parallel-group cluster randomized trial. PARTICIPANTS: Adult inpatients with hyponatremia on the hospital medicine service. INTERVENTIONS: A nephrologist conducted TACos on intervention patients, making diagnostic and therapeutic recommendations daily (if warranted) until discharge or resolution of hyponatremia. MAIN MEASURES: Measures of feasibility included the number of eligible participants, percentage receiving TACos, number of TACos per participant, and percentage of formal nephrology consults. Acceptability was assessed by a post-intervention survey. Clinical outcomes, including the percentage of hyponatremia cases that resolved by discharge, were also assessed. KEY RESULTS: We identified 62 patients who met inclusion criteria: 38 in the intervention group and 24 in the control group. A nephrologist determined that 26 of 38 intervention patients (68%) would likely benefit from diagnostic and management recommendations; 67 TACos were performed (mean 2.6 per patient). Fourteen of 18 primary team physicians (78%) reported that the e-consults changed their management, and 15 of 18 (83%) wanted TACOs to continue. Resolution of hyponatremia, length of stay, 30-day readmissions, and costs were similar in the intervention and control groups. CONCLUSIONS: Inpatient TACos for hyponatremia were feasible and acceptable to primary teams, and frequently led to changes in diagnosis and management. Further studies are needed to determine the impact of the TACo model on clinical outcomes and cost-effectiveness.

Three-outcome designs for external pilot trials with progression criteria.

BACKGROUND: Whether or not to progress from a pilot study to a definitive trial is often guided by pre-specified quantitative progression criteria with three possible outcomes. Although the choice of these progression criteria will help to determine the statistical properties of the pilot trial, there is a lack of research examining how they, or the pilot sample size, should be determined. METHODS: We review three-outcome trial designs originally proposed in the phase II oncology setting and extend these to the case of external pilots, proposing a unified framework based on univariate hypothesis tests and the control of frequentist error rates. We apply this framework to an example and compare against a simple two-outcome alternative. RESULTS: We find that three-outcome designs can be used in the pilot setting, although they are not generally more efficient than simpler two-outcome alternatives. We show that three-outcome designs can help allow for other sources of information or other stakeholders to feed into progression decisions in the event of a borderline result, but this will come at the cost of a larger pilot sample size than the two-outcome case. We also show that three-outcome designs can be used to allow adjustments to be made to the intervention or trial design before commencing the definitive trial, providing the effect of the adjustment can be accurately predicted at the pilot design stage. An R package, tout, is provided to optimise progression criteria and pilot sample size. CONCLUSIONS: The proposed three-outcome framework provides a way to optimise pilot trial progression criteria and sample size in a way that leads to desired operating characteristics. It can be applied whether or not an adjustment following the pilot trial is anticipated, but will generally lead to larger sample size requirements than simpler two-outcome alternatives.

Effect of Neuromuscular Electrostimulation With Blood Flow Restriction on Acute Muscle Swelling of the Abductor Hallucis.

CONTEXT: Plantar intrinsic foot muscle strength training is difficult to master to a degree sufficient to elicit muscle hypertrophy in most individuals. It is possible that combining neuromuscular electrostimulation (NMES) and blood flow restriction (BFR) can elicit plantar intrinsic foot muscle hypertrophy regardless of the individual's technique. This study aimed to determine the effects of NMES training with BFR on acute muscle swelling in the abductor hallucis. DESIGN: Randomized, controlled, single-blind trial design. METHODS: Forty-eight participants were randomly allocated to the NMES + BFR, NMES, or Sham NMES + BFR groups. All participants received abductor hallucis NMES for 15 minutes. Participants in the NMES + BFR and Sham NMES + BFR groups received NMES with BFR. The intensity of NMES was the sensory threshold in the Sham NMES + BFR group. The cross-sectional area of the abductor hallucis was measured pretraining and posttraining using ultrasonography by a single investigator blinded to the participants' allocations. RESULTS: After 15 minutes of training, the cross-sectional area of the abductor hallucis was significantly increased in the NMES + BFR (P < .001) and the Sham NMES + BFR (P = .004) groups. Moreover, the rate of increase was significantly higher in the NMES + BFR group than in the NMES or the Sham NMES + BFR groups (P < .001 and P = .001, respectively). CONCLUSIONS: Since it is possible that the amount of muscle swelling immediately after training correlates with muscle hypertrophy when training is continued, the results of this study suggest that NMES training with BFR is a training method that can be expected to produce plantar intrinsic foot muscle hypertrophy. Further studies are needed to confirm the long-term effects of NMES training with BFR.

Antimicrobial Photodynamic Therapy in the Nasal Decolonization of Maintenance Hemodialysis Patients: A Pilot Randomized Trial.

RATIONALE & OBJECTIVE: Infections are an important cause of mortality among patients receiving maintenance hemodialysis. Staphylococcus aureus is a frequent etiological agent, and previous nasal colonization is a risk factor for infection. Repeated antimicrobial decolonization reduces infection in this population but can induce antibiotic resistance. We compared photodynamic therapy, a promising bactericidal treatment that does not induce resistance, to mupirocin treatment among nasal carriers of S aureus. STUDY DESIGN: Randomized controlled pilot study. SETTING & PARTICIPANTS: 34 patients receiving maintenance hemodialysis who had nasal carriage of S aureus. INTERVENTIONS: Patients were randomly assigned to decolonization with a single application of photodynamic therapy (wavelength of 660nm, 400mW/cm2, 300 seconds, methylene blue 0.01%) or with a topical mupirocin regimen (twice a day for 5 days). OUTCOME: Nasal swabs were collected at time 0 (when the carrier state was identified), directly after treatment completion, 1 month after treatment, and 3 months after treatment. Bacterial isolates were subjected to proteomic analysis to identify the species present, and antimicrobial susceptibility was characterized. RESULTS: All 17 participants randomized to photodynamic therapy and 13 of 17 (77%) randomized to mupirocin were adherent to treatment. Directly after treatment was completed, 12 participants receiving photodynamic therapy (71%) and 13 participants treated with mupirocin (77%) had cultures that were negative for S aureus (risk ratio, 0.92 [95% CI, 0.61-1.38]; P=0.9). Of the patients who had negative cultures directly after completion of photodynamic therapy, 67% were recolonized within 3 months. There were no adverse events in the photodynamic therapy group. LIMITATIONS: Testing was restricted to assessing nasal colonization; infectious complications were not assessed. CONCLUSIONS: Photodynamic therapy is a feasible approach to treating nasal carriage of S aureus. Future larger studies should be conducted to determine whether photodynamic therapy is equivalent to the standard of care with mupirocin. FUNDING: Government grant (National Council for Scientific and Technological Development process 3146682020-9). TRIAL REGISTRATION: Registered at ClinicalTrials.gov with study number NCT04047914.

Evaluating a pilot community-based FITMIND exercise programme for psychosis in Hong Kong.

BACKGROUND: Exercise interventions can improve clinical symptoms and cognition in patients with psychosis in addition to their physical health. However, their benefits may not be maximally generalised to those who cannot access gymnasium facilities, which were commonly required previously. This study evaluated a 12-week community exercise programme named FITMIND, which aims to help patients with psychosis establish exercise habits through easy-to-learn aerobic exercise and yoga, with the support of trained volunteers. METHOD: This study analysed the profiles of 49 patients with psychosis who were referred by the case manager of the early psychosis programme in the public hospital in Hong Kong or enrolled in the programme through the project website. The outcome measures were working memory, physical activity (PA) participation, quality of life, and mood symptoms. RESULTS: At baseline, seven participants (14.3%) met the recommendation of the PA for severe mental illnesses. After the 12-week programme, participants demonstrated significant improvement in vigorous-intensity PA, moderate-to-vigorous PA, compliance with international guidelines for PA, and mood symptoms. CONCLUSION: The FITMIND exercise programme is a feasible community-based intervention that can improve PA participation and mood in patients with psychosis. Further systematic studies are needed to examine the long-term beneficial effects of the programme.

Wearable device for prevention of postoperative and post-discharge hypoxemia: A randomized pilot trial.

BACKGROUND: The Oxalert Enhanced Pulse Oximeter (EPO) is a wearable device that detects and alerts patients to hypoxemia. In a preplanned pilot trial, we estimated the effect of continuous saturation monitoring with patient alerts on in-hospital and post-discharge saturation; we further assessed the feasibility of the intervention. METHODS: Noncardiac surgical patients were randomized to either the Oxalert with patient alerts (Monitor + Alert, N = 25) or the Oxalert without patient alerts (Monitor Only, N = 24). Monitoring continued during hospitalization for up to 6 days and for 24 h after hospital discharge. Patients in each group were compared on time-weighted average (TWA) SpO2 <90% (%) and area under SpO2 <90% (% * min) in-hospital and after discharge using the Wilcoxon rank sum test, with the treatment effect median difference and 95% confidence interval (CI) estimated using the Hodges-Lehmann estimator of location shift. RESULTS: We enrolled ≥2 patients per week, for a total of 49 patients in whom recording were obtained for a median [quartiles] of 91 [85, 95]% of the time in hospital. In-hospital, TWA SpO2 <90% was a median [quartiles] of 0.11 [0.03, 0.25]% for Monitor + Alert and 0.29 [0.04, 0.71]% for Monitor-Only patients, with estimated median difference (95% CI) of -0.1 (-0.4, 0)%, p = .120. In hospital, the area under the curve (AUC) SpO2 <90% was a median [quartiles] of 635 [204, 1513] % * min for Monitor + Alert and 1260 [117, 5278] % * min for Monitor-Only patients, with estimated median difference (95% CI) of -407 (-1816, 208) % * min, p = .349. Post-discharge, the estimated median difference (95% CI) was only -0.1 (-0.2, 0) %, p = .307. CONCLUSIONS: The Oxalert system was well tolerated in both groups and enrollment was strong. Patients randomized to active Oxalert systems experienced half as many postoperative desaturation events while hospitalized, although the difference was not statistically significant in this small pilot trial. In contrast, the Oxalert system did not reduce post-discharge desaturation. Detecting postoperative deterioation in surgical patients after they arrive on regular hospital wards, and even after they have been discharged home, can potentially facilitate necessary "rescue" interventions. Wearable devices assessing vital signs, including oxygenation, are a practical requirement. In this pilot study, a wearable pulse oximeter, with and without hypoxemia alarms, was tested for feasibility and acceptability for signal collection in postoperative cases, including at home. Results indicate that a full-scale trial is warranted to test for possible clinical benefit with this type of "wearable" where late postoperative hypoxia could be a concern. The trial was registered at ClincialTrial.gov (NCT04453722).

Implementation of a Web-Based Resilience Enhancement Training for Nurses: Pilot Randomized Controlled Trial.

BACKGROUND: Global workforce challenges faced by health care providers are linked to low levels of job satisfaction, recruitment, retention, and well-being, with detrimental impacts on patient care outcomes. Resilience-building programs can provide support for staff who endure highly stressful environments, enhance resilience, and support recruitment and retention, with web-based formats being key to increasing accessibility. OBJECTIVE: We aimed to examine participants' engagement with a newly developed Resilience Enhancement Online Training for Nurses (REsOluTioN), explore its acceptability, and compare levels of resilience and psychological well-being in nurses who completed REsOluTioN with those who did not. METHODS: We carried out a pilot randomized trial (1:1), conducted at a single site (mental health and community trust in South England) between August 2021 and May 2022. Local research ethics approvals were obtained. Nurses were invited to participate and were randomly assigned to a waitlist group or REsOluTioN group. Training lasted for 4 weeks, consisting of prereading, web-based facilitated sessions, and mentorship support. We evaluated trial engagement, acceptability of training, and pre-post changes in resilience, measured by the Brief Resilience Scale, and psychological well-being, measured by the Warwick Edinburgh Mental Wellbeing Scale. Qualitative participant feedback was collected. Consolidated Standards of Reporting Trials 2010 extension guidelines for reporting pilot and feasibility trials were used. RESULTS: Of 108 participants recruited, 93 completed the study. Participants' mean age was 44 (SD 10.85) years. Most participants were female (n=95, 88.8%), White (n=95, 88.8%), and worked in community settings (n=91, 85.0%). Sixteen facilitated and 150 mentoring sessions took place. Most REsOluTioN program participants reported the sessions helped improve their resilience (n=24, 72.8%), self-confidence (n=24, 72.7%), ability to provide good patient care (n=25, 75.8%), relationships with colleagues (n=24, 72.7%), and communication skills (n=25, 75.8%). No statistically significant differences between training and control groups and time on well-being (F1,91=1.44, P=.23, partial η2=0.02) and resilience scores (F1,91=0.33, P=.57, partial η2=0.004) were revealed; however, there were positive trends toward improvement in both. Nurse participants engaged with the REsOluTioN program and found it acceptable. Most found web-based training and mentoring useful and enjoyed learning, reflection, networking, and participatory sessions. CONCLUSIONS: The REsOluTioN program was acceptable, engaging, perceived as useful, and nurses were keen for it to be implemented to optimize resilience, psychological health, communication, and workplace environments. The study has evidenced that it is acceptable to implement web-based resilience programs with similar design features within busy health care settings, indicating a need for similar programs to be carefully evaluated. Mentorship support may also be a key in optimizing resilience. Trial limitations include small sample size and reduced statistical power; a multicenter randomized controlled trial could test effectiveness of the training on a larger scale. TRIAL REGISTRATION: ClinicalTrials.gov NCT05074563; https://clinicaltrials.gov/ct2/show/NCT05074563. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.2196/37015.

Trial to Encourage Adoption and Maintenance of a MEditerranean Diet (TEAM-MED): a randomised pilot trial of a peer support intervention for dietary behaviour change in adults from a Northern European population at high CVD risk.

Adhering to a Mediterranean diet (MD) is associated with reduced CVD risk. This study aimed to explore methods of increasing MD adoption in a non-Mediterranean population at high risk of CVD, including assessing the feasibility of a developed peer support intervention. The Trial to Encourage Adoption and Maintenance of a MEditerranean Diet was a 12-month pilot parallel group RCT involving individuals aged ≥ 40 year, with low MD adherence, who were overweight, and had an estimated CVD risk ≥ 20 % over ten years. It explored three interventions, a peer support group, a dietician-led support group and a minimal support group to encourage dietary behaviour change and monitored variability in Mediterranean Diet Score (MDS) over time and between the intervention groups, alongside measurement of markers of nutritional status and cardiovascular risk. 118 individuals were assessed for eligibility, and 75 (64 %) were eligible. After 12 months, there was a retention rate of 69 % (peer support group 59 %; DSG 88 %; MSG 63 %). For all participants, increases in MDS were observed over 12 months (P < 0·001), both in original MDS data and when imputed data were used. Improvements in BMI, HbA1c levels, systolic and diastolic blood pressure in the population as a whole. This pilot study has demonstrated that a non-Mediterranean adult population at high CVD risk can make dietary behaviour change over a 12-month period towards an MD. The study also highlights the feasibility of a peer support intervention to encourage MD behaviour change amongst this population group and will inform a definitive trial.

Emotion regulation-enhanced group treatment for gambling disorder: a non-randomized pilot trial.

BACKGROUND: Despite the association of Gambling Disorder (GD) with poor mental health, treatment options generally lack components targeting emotional difficulties. This study investigated the feasibility and acceptability of adding strategies of emotion regulation to an eight-session weekly group treatment. METHOD: This non-randomized pilot study recruited 21 treatment-seeking adults with GD, (mean age = 36.3, 19% females) from addiction care. In a mixed methods design, measures of within-group changes in self-reported symptoms of GD were complemented with thematic analysis of post-treatment interviews regarding the feasibility of the treatment. RESULTS: Within-group scores on the Gambling Symptoms Assessment Scale (G-SAS) showed a 47% decrease (ß: -0.1599, 95% CI: - 0.2526 to - 0.0500) from pre-treatment to 12-month follow-up, with Hedges' g = 1.07 (CI: 0.57-1.60). The number of GD-symptoms according to the Structured Clinical Interview for Gambling Disorder (SCI-GD) decreased from 7.0 (SD = 1.60) at pre-treatment to 2.1 (SD = 2.36) at 12-month follow-up. Participants completed an average of 6.3 sessions and rated the intervention high in satisfaction and acceptability. Feasibility interviews showed no noticeable negative effects or ethical issues. Furthermore, helpful components in the treatment were: increased awareness of emotional processes and strategies to deal with difficult emotions. CONCLUSIONS: Adding emotion regulation strategies in the treatment of GD is feasible and acceptable and warrants further investigation in a controlled trial. TRIAL REGISTRATION: This study was registered with ClinicalTrials.gov (Identifier NCT03725735 ).

Feasibility and potential efficacy of a guided internet- and mobile-based CBT for adolescents and young adults with chronic medical conditions and comorbid depression or anxiety symptoms (youthCOACHCD): a randomized controlled pilot trial.

BACKGROUND: Adolescents and young adults (AYA) with a chronic medical condition show an increased risk for developing mental comorbidities compared to their healthy peers. Internet- and mobile-based cognitive behavioral therapy (iCBT) might be a low-threshold treatment to support affected AYA. In this randomized controlled pilot trial, the feasibility and potential efficacy of youthCOACHCD, an iCBT targeting symptoms of anxiety and depression in AYA with chronic medical conditions, was evaluated. METHODS: A total of 30 AYA (Mage 16.13; SD= 2.34; 73% female), aged 12-21 years either suffering from cystic fibrosis, juvenile idiopathic arthritis or type 1 diabetes, were randomly assigned to either a guided version of the iCBT youthCOACHCD (IG, n=15) or to a waitlist control group (CG, n=15), receiving an unguided version of the iCBT six months post-randomization. Participants of the IG and the CG were assessed before (t0), twelve weeks after (t1) and six months after (t2) randomization. Primary outcome was the feasibility of the iCBT. Different parameters of feasibility e.g. acceptance, client satisfaction or potential side effects were evaluated. First indications of the possible efficacy with regard to the primary efficacy outcome, the Patient Health Questionnaire Anxiety and Depression Scale, and further outcome variables were evaluated using linear regression models, adjusting for baseline values. RESULTS: Regarding feasibility, intervention completion was 60%; intervention satisfaction (M = 25.42, SD = 5.85) and perceived therapeutic alliance (M = 2.83, SD = 1.25) were moderate and comparable to other iCBTs. No patterns emerged regarding subjective and objective negative side effects due to participation in youthCOACHCD. Estimates of potential efficacy showed between group differences, with a potential medium-term benefit of youthCOACHCD (ß = -0.55, 95%CI: -1.17; 0.07), but probably not short-term (ß = 0.20, 95%CI: -0.47; 0.88). CONCLUSIONS: Our results point to the feasibility of youthCOACHCD and the implementation of a future definitive randomized controlled trial addressing its effectiveness and cost-effectiveness. Due to the small sample size, conclusions are premature, however, further strategies to foster treatment adherence should be considered. TRIAL REGISTRATION: The trial was registered at the WHO International Clinical Trials Registry Platform via the German Clinical Trials Register (ID: DRKS00016714 , 25/03/2019).

Maintenance of Serum Potassium Levels ≥3.6 mEq/L Versus ≥4.5 mEq/L After Isolated Elective Coronary Artery Bypass Grafting and the Incidence of New-Onset Atrial Fibrillation: Pilot and Feasibility Study Results.

OBJECTIVE: Serum potassium levels frequently are maintained at high levels (≥4.5 mEq/L) to prevent atrial fibrillation after cardiac surgery (AFACS), with limited evidence. Before undertaking a noninferiority randomized controlled trial to investigate the noninferiority of maintaining levels ≥3.6 mEq/L compared with this strategy, the authors wanted to assess the feasibility, acceptability, and safety of recruiting for such a trial. DESIGN: Pilot and feasibility study of full trial protocol. SETTING: Two university tertiary-care hospitals. PARTICIPANTS: A total of 160 individuals undergoing first-time elective isolated coronary artery bypass grafting. INTERVENTIONS: Randomization (1:1) to protocols aiming to maintain serum potassium at either ≥3.6 mEq/L or ≥4.5 mEq/L after arrival in the postoperative care facility and for 120 hours or until discharge from the hospital or AFACS occurred, whichever happened first. MEASUREMENTS AND MAIN RESULTS: Primary outcomes: (1) whether it was possible to recruit and randomize 160 patients for six months (estimated 20% of those eligible); (2) maintaining supplementation protocol violation rate ≤10% (defined as potassium supplementation being inappropriately administered or withheld according to treatment allocation after a serum potassium measurement); and (3) retaining 28-day follow-up rates ≥90% after surgery. Between August 2017 and April 2018, 723 patients were screened and 160 (22%) were recruited. Potassium protocol violation rate = 9.8%. Follow-up rate at 28 days = 94.3%. Data on planned outcomes for the full trial also were collected. CONCLUSIONS: It is feasible to recruit and randomize patients to a study assessing the impact of maintaining serum potassium concentrations at either ≥3.6 mEq/L or ≥4.5 mEq/L on the incidence of AFACS.

An Open Trial of Telephone-Delivered Mindfulness-Based Cognitive Therapy: Feasibility, Acceptability, and Preliminary Efficacy for Reducing Depressive Symptoms.

Mindfulness-based cognitive therapy (MBCT) is a promising intervention for reducing depressive symptoms in individuals with comorbid chronic disease, but the program's attendance demands make it inaccessible to many who might benefit. We tested the feasibility, acceptability, safety, and preliminary efficacy of an abbreviated, telephone-delivered adaptation of the in-person mindfulness-based cognitive therapy (MBCT-T) program in a sample of patients with depressive symptoms and hypertension. Participants (n = 14; 78.6% female, mean age = 60.6) with mild to moderate depressive symptoms and hypertension participated in the 8-week MBCT-T program. Feasibility was indexed via session attendance and home-based practice completion. Acceptability was indexed via self-reported satisfaction scores. Safety was assessed via reports of symptomatic decline or need for additional mental health treatment. Depressive symptoms (Quick Inventory of Depressive Symptomatology-Self-Report [QIDS-SR]) and anxiety (Hospital Anxiety and Depression Scale-Anxiety subscale; HADS-A) were assessed at baseline and immediately following the intervention. Sixty-four percent of participants (n = 9) attended ≥4 intervention sessions. Seventy-one percent (n = 6) of participants reported completing all assigned formal home practice and 89.2% (n = 8) reported completing all assigned informal practice. Participants were either very satisfied (75%; n = 6) or mostly satisfied (25%; n = 2) with the intervention. There were no adverse events or additional need for mental health treatment. Depressive symptom scores were 4.09 points lower postintervention (p = .004). Anxiety scores were 3.18 points lower postintervention (p = .039). Results support the feasibility, acceptability, safety, and preliminary efficacy of an abbreviated, telephone-delivered version of MBCT for reducing depressive and anxiety symptoms in individuals with co-occurring chronic disease.

A pilot open trial of video telehealth-delivered exposure and response prevention for obsessive-compulsive disorder in rural Veterans.

Exposure and response prevention (ERP) is the gold-standard, evidence-based psychotherapy for obsessive-compulsive disorder (OCD), but few receive it. Video telehealth can increase access to ERP for OCD and may enhance the salience of exposures. This study examined the feasibility, acceptability, and preliminary effectiveness of video telehealth-delivered ERP. We conducted a pilot open trial with 11 Veterans, using mixed quantitative and qualitative methods. Treatment completers (n = 9) had significantly reduced OCD and posttraumatic stress disorder symptoms posttreatment. Patients expressed greater comfort in engaging in ERP at home than in clinics. Therapists reported that seeing patients' home environments helped them understand their symptoms and identify relevant OCD exposures. Results suggest that video telehealth-delivered ERP is feasible and acceptable to patients and therapists and promising for reducing OCD symptoms. Future research should compare its effectiveness to usual care and evaluate patients' preferences for treatment delivery. Abbreviations: ERP: exposure and response prevention; GAD-7: Generalized Anxiety Disorder-7 scale; OCD: obsessive-compulsive disorder; OCI-R: Obsessive-Compulsive Inventory, Revised; PCL-5: PTSD Checklist; PHQ-9: Patient Health Questionnaire; PTSD: posttraumatic stress disorder; VA: epartment of Veterans Affairs; Y-BOCS: Yale-Brown Obsessive Compulsive Scale, self report form.

Three Weeks Versus Six Weeks of Antibiotic Therapy for Diabetic Foot Osteomyelitis: A Prospective, Randomized, Noninferiority Pilot Trial.

BACKGROUND: In patients with diabetic foot osteomyelitis (DFO) who underwent surgical debridement, we investigated whether a short (3 weeks) duration compared with a long (6 weeks) duration of systemic antibiotic treatment is associated with noninferior results for clinical remission and adverse events (AEs). METHODS: In this prospective, randomized, noninferiority pilot trial, we randomized (allocation 1:1) patients with DFO after surgical debridement to either a 3-week or a 6-week course of antibiotic therapy. The minimal duration of follow-up after the end of therapy was 2 months. We compared outcomes using Cox regression and noninferiority analyses (25% margin, power 80%). RESULTS: Among 93 enrolled patients (18% females; median age 65 years), 44 were randomized to the 3-week arm and 49 to the 6-week arm. The median number of surgical debridements was 1 (range, 0-2 interventions). In the intention-to-treat (ITT) population, remission occurred in 37 (84%) of the patients in the 3-week arm compared with 36 (73%) in the 6-week arm (P = .21). The number of AEs was similar in the 2 study arms (17/44 vs 16/49; P = .51), as were the remission incidences in the per-protocol (PP) population (33/39 vs 32/43; P = .26). In multivariate analysis, treatment with the shorter antibiotic course was not significantly associated with remission (ITT population: hazard ratio [HR], 1.1 [95% confidence interval {CI}, .6-1.7]; PP population: HR, 0.8 [95% CI: .5-1.4]). CONCLUSIONS: In this randomized controlled pilot trial, a postdebridement systemic antibiotic therapy course for DFO of 3 weeks gave similar (and statistically noninferior) incidences of remission and AE to a course of 6 weeks. CLINICAL TRIALS REGISTRATION: NCT03615807; BASEC 2016-01008 (Switzerland).

A Randomized Placebo-Controlled Pilot Trial of Early Targeted Nonsteroidal Anti-Inflammatory Drugs in Preterm Infants with a Patent Ductus Arteriosus.

OBJECTIVE: To establish the feasibility of a future large randomized trial to compare early treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) while awaiting spontaneous patent ductus arteriosus (PDA) closure. STUDY DESIGN: Preterm infants at <29 weeks of gestation with a PDA diameter >1.5 mm and <72 hours after birth were randomized to NSAIDs vs placebo. No open-label NSAID treatment was allowed in either arm, but all infants with PDA volume load received supportive management, including optimization of airway pressure, careful fluid management, and diuretics as needed. The pilot outcomes were recruitment rate and incidence of open-label treatment. Secondary clinical outcomes included chronic lung disease or death, the planned primary outcome for a future large trial. RESULTS: Overall, 54% of the approached parents consented to participate in the study. The median recruitment rate was 3 infants per month, and a total of 72 infants were randomized. One patient in each arm received open-label treatment. PDA closure rates were 74% for the NSAIDs arm vs 30% for the placebo arm, but this was not associated with significant changes in clinical outcomes. CONCLUSIONS: This pilot trial showed that recruitment of more than one-half of eligible infants with a low incidence of open-label treatment is feasible. PDA closure rates and clinical outcomes were similar to those reported in previous PDA trials.

Neoadjuvant everolimus plus letrozole versus fluorouracil, epirubicin and cyclophosphamide for ER-positive, HER2-negative breast cancer: a randomized pilot trial.

BACKGROUND: Here we evaluated the feasibility, efficacy, tolerability, and treatment-mediated immune modulation of neoadjuvant everolimus plus letrozole versus chemotherapy in treating postmenopausal patients with ER-positive, HER2-negative breast cancer. METHODS: Postmenopausal women with ER-positive, HER2-negative breast cancer who had a primary tumor > 2 cm or positive axillary lymph node(s) proofed by biopsy were randomly (1,1) enrolled to receive neoadjuvant everolimus plus letrozole for 18 weeks or fluorouracil, epirubicin plus cyclophosphamide (FEC) for 6 cycles before surgery. Primary outcome was feasibility of the trial. Secondary outcome included ultrasound response rate, pathological complete response rate, breast-conserving surgery rate, toxicities, treatment-mediated immune modulation and biomarkers. RESULTS: Forty patients were randomized. Completion rate was 90.0% in the neoadjuvant endocrine therapy (NET) arm but 70.0% in the neoadjuvant chemotherapy (NAC) arm. The ultrasound response rate was 65.0% in NET arm and 40.0% in FEC arm, respectively. In terms of the adverse events, clearly favored NET arm. Everolimus plus letrozole increased the ratio of peripheral Tregs to CD4+ T cells and tumor PD-L1 expression, and decreased Ki67 index and tumor-infiltrating Tregs, and patients with a greater increase of tumor-specific CTLs showed more sensitive to NET. CONCLUSION: This pilot trial showed that neoadjuvant everolimus plus letrozole might achieve a favorable ultrasound response rate with low toxicities in treating postmenopausal ER-positive, HER2-negative breast cancer patients. Everolimus plus letrozole might have positive antitumoral immunity effects. Further large randomized controlled trials are needed to confirm our findings. TRAIL REGISTRATION: A Trial of Neoadjuvant Everolimus Plus Letrozole Versus FEC in Women With ER-positive, HER2-negative Breast Cancer, registered on 07/04/2016 and first posted on 18/04/2016, NCT02742051 .

A hypothesis test of feasibility for external pilot trials assessing recruitment, follow-up, and adherence rates.

The power of a large clinical trial can be adversely affected by low recruitment, follow-up, and adherence rates. External pilot trials estimate these rates and use them, via prespecified decision rules, to determine if the definitive trial is feasible and should go ahead. There is little methodological research underpinning how these decision rules, or the sample size of the pilot, should be chosen. In this article we propose a hypothesis test of the feasibility of a definitive trial, to be applied to the external pilot data and used to make progression decisions. We quantify feasibility by the power of the planned trial, as a function of recruitment, follow-up, and adherence rates. We use this measure to define hypotheses to test in the pilot, propose a test statistic, and show how the error rates of this test can be calculated for the common scenario of a two-arm parallel group definitive trial with a single normally distributed primary endpoint. We use our method to redesign TIGA-CUB, an external pilot trial comparing a psychotherapy with treatment as usual for children with conduct disorders. We then extend our formulation to include using the pilot data to estimate the standard deviation of the primary endpoint and incorporate this into the progression decision.

Using Trial Sequential Analysis for estimating the sample sizes of further trials: example using smoking cessation intervention.

BACKGROUND: Assessing benefits and harms of health interventions is resource-intensive and often requires feasibility and pilot trials followed by adequately powered randomised clinical trials. Data from feasibility and pilot trials are used to inform the design and sample size of the adequately powered randomised clinical trials. When a randomised clinical trial is conducted, results from feasibility and pilot trials may be disregarded in terms of benefits and harms. METHODS: We describe using feasibility and pilot trial data in the Trial Sequential Analysis software to estimate the required sample size for one or more trials investigating a behavioural smoking cessation intervention. We show how data from a new, planned trial can be combined with data from the earlier trials using trial sequential analysis methods to assess the intervention's effects. RESULTS: We provide a worked example to illustrate how we successfully used the Trial Sequential Analysis software to arrive at a sensible sample size for a new randomised clinical trial and use it in the argumentation for research funds for the trial. CONCLUSIONS: Trial Sequential Analysis can utilise data from feasibility and pilot trials as well as other trials, to estimate a sample size for one or more, similarly designed, future randomised clinical trials. As this method uses available data, estimated sample sizes may be smaller than they would have been using conventional sample size estimation methods.

A pilot cluster randomised trial of the medicines and alcohol consultation (MAC): an intervention to discuss alcohol use in community pharmacy medicine review services.

BACKGROUND: Alcohol interventions are important to the developing public health role of community pharmacies. The Medicines and Alcohol Consultation (MAC) is a new intervention, co-produced with community pharmacists (CPs) and patients, which involves a CP practice development programme designed to integrate discussion of alcohol within existing NHS medicine review services. We conducted a pilot trial of the MAC and its delivery to investigate all study procedures to inform progression to a definitive trial. METHODS: This cluster pilot RCT was conducted in 10 community pharmacies in Yorkshire, UK, with a CP from each who regularly conducted Medicine Use Review (MUR) and New Medicine Service (NMS) consultations. Randomisation was conducted using a secure remote randomisation service. Intervention CPs (n = 5) were trained to deliver the MAC in MUR/NMS consultations. Control CPs (n = 5) provided these services as usual. Consecutive MUR/NMS patients were asked by CPs to participate, screened for eligibility (consumption of alcohol at least twice per week), and baseline data collected for those eligible. A two-month follow-up telephone interview was conducted. Blinding of CPs was not possible, but patients were blinded to the alcohol focus of the trial. Primary outcomes were total weekly UK units (8 g of ethanol per unit) of alcohol consumption in the week prior to follow-up, and confidence in medications management. Trial procedures were assessed by recruitment, attrition, and follow-up rates. RESULTS: 260 patients were approached by CPs to take part in the trial, 68% (n = 178) were assessed for eligibility and 30% (n = 54) of these patients were eligible. Almost all eligible patients (n = 51; 94%) consented to participate, of whom 92% (n = 47) were followed-up at 2 months; alcohol consumption was lower in the intervention arm and confidence in medication management reduced slightly for both groups. Exploration of recall issues at follow-up showed a high level of agreement between a two-item quantity/frequency measure and 7-day guided recall of alcohol consumption. CONCLUSIONS: The pilot trial demonstrates the feasibility of implementing the MAC in community pharmacy and trial recruitment and data collection procedures. However, decommissioning of MURs means that it is not possible to conduct a definitive trial of the intervention in this service. TRIAL REGISTRATION: ISRCTN57447996.

The current use of feasibility studies in the assessment of feasibility for stepped-wedge cluster randomised trials: a systematic review.

BACKGROUND: Stepped-wedge cluster randomised trials (SW-CRTs) are a pragmatic trial design, providing an unprecedented opportunity to increase the robustness of evidence underpinning implementation and quality improvement interventions. Given the complexity of the SW-CRT, the likelihood of trials not delivering on their objectives will be mitigated if a feasibility study precedes the definitive trial. It is not currently known if feasibility studies are being conducted for SW-CRTs nor what the objectives of these studies are. METHODS: Searches were conducted of several databases to identify published feasibility studies which were designed to inform a future SW-CRT. For each eligible study, data were extracted on the characteristics of and rationale for the feasibility study; the process for determining progression to the main trial; how the feasibility study informed the main trial; and whether the main trial went ahead. A narrative synthesis and descriptive analysis are presented. RESULTS: Eleven feasibility studies were identified, which included eight completed study reports and three protocols. Three studies used a stepped-wedge design and these were the only studies to be randomised. Studies were predominantly of a mixed-methods design. Only one study assessed specific features related to the feasibility of using a SW-CRT and one investigated the time taken to complete the study procedures. The other studies were mostly assessing the feasibility and acceptability of the intervention. CONCLUSION: Published feasibility studies for SW-CRTs are scarce and those that are being reported do not investigate issues specific to the complexities of the trial design. When conducting feasibility studies in advance of a definitive SW-CRT, researchers should consider assessing the feasibility of study procedures, particularly those specific to the SW-CRT design, and ensure that the findings are published for the benefit of other researchers.