PREPRINT - Predictors, Moderators and Mediators of Treatment Outcome in Randomized Controlled Trials for Adolescents with Depression: A scoping review.

Background: Advancing the field of precision medicine in the treatment of depression in adolescents requires an examination of predictors, moderators and mediators (PMMs) of depression symptom outcome in randomized controlled trials (RCTs). Aims: This scoping review describes findings of PMM analyses in RCTs for the treatment of depression in adolescents. Methods: Databases searched included: MEDLINE, Embase, APA PsycInfo and CINAHL. Included publications tested PMMs of depression symptom outcome (e.g. symptom reduction, remission, etc.) in RCTs pertaining to the treatment of adolescents, ages 13-17. Results were extracted and coded for statistical significance, analytic approach, a priori model development, and adjustment for multiple comparisons. Aggregated results were summarized by PMM variable domain and RCT sample.Results: Eighty-one papers reporting on PMM results across 33 RCTs were identified. Fifty-three variable domains were tested as baseline predictors of depression severity outcome, 41 as moderators, 19 as post-baseline predictors, and 5 as mediators. Most reported results were nonsignificant. For variable domains tested as a PMM in three or more RCTs, only improvements in sleep throughout treatment and early response predicted outcome with complete agreement across relevant studies. The two publications that reported a priori hypotheses and adjustment for multiple comparisons both found that baseline depression symptom severity and family conflict predicted poorer outcomes. Conclusions: Clinicians need to recognize the current limited evidence from RCTs to practice precision medicine principles when treating adolescents with depression. Our findings inform future study design for researchers who wish to incorporate questions about specific PMM variables into their study methods.

Comparing the Ratio of Therapist Support to Internet Sessions in a Blended Therapy Delivered to Trauma-Exposed Veterans (Preprint)

BACKGROUND Blended models which incorporate elements of both internet and face-to-face therapies have been shown to be effective. Therapist and patients have expressed concerns that less rather more therapy sessions relative to self-guided internet sessions may be associated with lower therapeutic alliance, lower program completion rates and poorer outcomes. OBJECTIVE A multi-site quasi-experimental comparison study with a noninferiority design conducted in routine clinical care was used to assess webSTAIR, a 10-module blended therapy for trauma-exposed individuals delivered with 10 weekly therapist sessions (Coach10) compared to 5 biweekly sessions (Coach5). It was hypothesized that Coach5 would be “as good as” Coach10 regarding a range of outcomes. METHODS : A total of 202 Veterans were enrolled in the study (Coach5 n = 101, Coach10 n = 101). PTSD symptoms, depression, emotion regulation, interpersonal problems and social functioning measures were collected at pretreatment, mid, posttreatment and 3-month follow-up. Noninferiority analyses were conducted on symptom outcome measures. Comparisons of continuous and categorical measures regarding participant and therapist activities were conducted. RESULTS : Participants reported moderate to severe levels of baseline PTSD and/or depression. Significant reductions were obtained on all symptom measures at post and 3-month follow-up. Coach5 was not inferior to Coach10 on any outcome. Therapeutic alliance was high and equivalent across the two treatment conditions and completion rates and web usage were similar. Coach5 therapists’ total session time was substantially less than Coach10. Both programs were associated with a low and equal number of therapist activities related to scheduling and crisis/motivational sessions. CONCLUSIONS A blended model delivered with 5 sessions of therapist support was noninferior to 10 sessions among individuals with moderate to severe symptoms. Future studies identifying patient characteristics as moderators of outcomes in high versus low dose of therapist support will help create flexible technology-based intervention programming.

Salbutamol use in relation to maintenance bronchodilator efficacy in COPD: a prospective subgroup analysis of the EMAX trial

Background Short-acting β2-agonist (SABA) bronchodilators help alleviate symptoms in chronic obstructive pulmonary disease (COPD) and may be a useful marker of symptom severity. This analysis investigated whether SABA use impacts treatment differences between maintenance dual- and mono-bronchodilators in patients with COPD. Methods The Early MAXimisation of bronchodilation for improving COPD stability (EMAX) trial randomised symptomatic patients with low exacerbation risk not receiving inhaled corticosteroids 1:1:1 to once-daily umeclidinium/vilanterol 62.5/25 μg, once-daily umeclidinium 62.5 μg or twice-daily salmeterol 50 μg for 24 weeks. Pre-specified subgroup analyses stratified patients by median baseline SABA use (low, < 1.5 puffs/day; high, ≥1.5 puffs/day) to examine change from baseline in trough forced expiratory volume in 1 s (FEV1), change in symptoms (Transition Dyspnoea Index [TDI], Evaluating Respiratory Symptoms-COPD [E-RS]), daily SABA use and exacerbation risk. A post hoc analysis used fractional polynomial modelling with continuous transformations of baseline SABA use covariates. Results At baseline, patients in the high SABA use subgroup (mean: 3.91 puffs/day, n = 1212) had more severe airflow limitation, were more symptomatic and had worse health status versus patients in the low SABA use subgroup (0.39 puffs/day, n = 1206). Patients treated with umeclidinium/vilanterol versus umeclidinium demonstrated statistically significant improvements in trough FEV1 at Week 24 in both SABA subgroups (59–74 mL; p < 0.001); however, only low SABA users demonstrated significant improvements in TDI (high: 0.27 [p = 0.241]; low: 0.49 [p = 0.025]) and E-RS (high: 0.48 [p = 0.138]; low: 0.60 [p = 0.034]) scores. By contrast, significant reductions in mean SABA puffs/day with umeclidinium/vilanterol versus umeclidinium were observed only in high SABA users (high: − 0.56 [p < 0.001]; low: − 0.10 [p = 0.132]). Similar findings were observed when comparing umeclidinium/vilanterol and salmeterol. Fractional polynomial modelling showed baseline SABA use ≥4 puffs/day resulted in smaller incremental symptom improvements with umeclidinium/vilanterol versus umeclidinium compared with baseline SABA use < 4 puffs/day. Conclusions In high SABA users, there may be a smaller difference in treatment response between dual- and mono-bronchodilator therapy; the reasons for this require further investigation. SABA use may be a confounding factor in bronchodilator trials and in high SABA users; changes in SABA use may be considered a robust symptom outcome. Funding GlaxoSmithKline (study number 201749 [NCT03034915]).

Urodynamics tests for the diagnosis and management of bladder outlet obstruction in men: the UPSTREAM non-inferiority RCT

Background Lower urinary tract symptoms (LUTS) in men may indicate bladder outlet obstruction (BOO) or weakness, known as detrusor underactivity (DU). Severe bothersome LUTS are a common indication for surgery. The diagnostic tests may include urodynamics (UDS) to confirm whether BOO or DU is the cause, potentially reducing the number of people receiving (inappropriate) surgery. Objectives The primary objective was to determine whether a care pathway including UDS is no worse for symptom outcome than one in which it is omitted, at 18 months after randomisation. Rates of surgery was the key secondary outcome. Design This was a pragmatic, multicentre, two-arm (unblinded) randomised controlled trial, incorporating a health economic analysis and qualitative research. Setting Urology departments of 26 NHS hospitals in England. Participants Men (aged ≥ 18 years) seeking further treatment, potentially including surgery, for bothersome LUTS. Exclusion criteria were as follows: unable to pass urine without a catheter, having a relevant neurological disease, currently undergoing treatment for prostate or bladder cancer, previously had prostate surgery, not medically fit for surgery and/or unwilling to be randomised. Interventions Men were randomised to a care pathway based on non-invasive routine tests (control) or routine care plus invasive UDS (intervention arm). Main outcome measures The primary outcome was International Prostate Symptom Score (IPSS) at 18 months after randomisation and the key secondary outcome was rates of surgery. Additional secondary outcomes included adverse events (AEs), quality of life, urinary and sexual symptoms, UDS satisfaction, maximum urinary flow rate and cost-effectiveness. Results A total of 820 men were randomised (UDS, 427; routine care, 393). Sixty-seven men withdrew before 18 months and 11 died (unrelated to trial procedures). UDS was non-inferior to routine care for IPSS 18 months after randomisation, with a confidence interval (CI) within the margin of 1 point (–0.33, 95% CI –1.47 to 0.80). A lower surgery rate in the UDS arm was not found (38% and 36% for UDS and routine care, respectively), with overall rates lower than expected. AEs were similar between the arms at 43–44%. There were more cases of acute urinary retention in the routine care arm. Patient-reported outcomes for LUTS improved in both arms and satisfaction with UDS was high in men who received it. UDS was more expensive than routine care. From a secondary care perspective, UDS cost an additional £216 over an 18-month time horizon. Quality-adjusted life-years (QALYs) were similar, with a QALY difference of 0.006 in favour of UDS over 18 months. It was established that UDS was acceptable to patients, and valued by both patients and clinicians for its perceived additional insight into the cause and probable best treatment of LUTS. Limitations The trial met its predefined recruitment target, but surgery rates were lower than anticipated. Conclusions Inclusion of UDS in the diagnostic tests results in a symptom outcome that is non-inferior to a routine care pathway, but does not affect surgical rates for treating BOO. Results do not support the routine use of UDS in men undergoing investigation of LUTS. Future work Focus should be placed on indications for selective utilisation of UDS in individual cases and long-term outcomes of diagnosis and therapy. Trial registration Current Controlled Trials ISRCTN56164274. Funding This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 42. See the NIHR Journals Library website for further project information.