Active Treatment Arms Research Articles

The Impact of Visual Distraction Interventions on Patients' Pain and Anxiety During Colonoscopy: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Patients undergoing colonoscopy may experience psychological distress related to the procedure, which may deter adherence and acceptance of future colonoscopies. Visual/audiovisual distraction interventions to alleviate colonoscopy-related pain and anxiety have been developed. This study aims to investigate the impact of these interventions on colonoscopy-related outcomes. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) testing the efficacy of visual/audiovisual distraction. Eligible studies were systematically retrieved by searching PubMed, EMBASE, WOS, SCOPUS, and Cochrane through June 2024 and extracted by 2 investigators. Continuous and dichotomous outcome variables were pooled using Cohen's d and risk ratio (RR) with confidence interval (CI) using Stata MP version 17. We assessed heterogeneity using the χ2 test and I2 statistic (PROSPERO ID: CRD42024555902). We included 13 RCTs with 1439 patients randomized to an active intervention (n=804) or usual care (n=635). Only 3 RCTs were endoscopists-blinded studies, whereas the rest were open-label. The interventions included playing nature scene videos, real-time videos of the colonoscopy, or movies preferred by the patients. The active intervention arm was associated with a significant reduction in the pain experienced during colonoscopy (Cohen's d: -0.57, 95% CI [-0.79, -0.35], P<0.0001), reduced anxiety related to colonoscopy (Cohen's d: -0.66, 95% CI [-1.15, -0.18], P=0.01), and increased patients' satisfaction (Cohen's d: 0.65, 95% CI [0.49, 0.80], P<0.0001) compared with patients who received the usual care during colonoscopy. There were no significant differences between both groups in the willingness to re-undergo the procedure (RR: 1.11, 95% CI [0.98, 1.25], P=0.09), analgesia use (Cohen's d: -0.21, 95% CI [-0.42, 0.0], P=0.05), or total procedure duration (Cohen's d: -0.12, 95% CI [-0.24, 0.0], P=0.06). Visual/audiovisual distraction interventions decrease colonoscopy-associated pain and anxiety and increase patients' satisfaction. These are promising interventions to improve patient compliance and quality of care during colonoscopy.

A randomized controlled trial of a self-guided mobile app targeting repetitive negative thought to prevent depression in university students: study protocol of the Nurture-U Reducing Worry prevention trial

BackgroundTackling poor mental health in university students has been identified as a priority in higher education. However, there are few evidence-based prevention initiatives designed for students. Repetitive Negative Thought (RNT, e.g. worry, rumination) is elevated in university students and is a well-established vulnerability factor for anxiety and depression. Furthermore, there are now evidence-based cognitive-behavioural interventions to tackle RNT. A mobile self-help cognitive-behavioural app targeting RNT, adapted for students may therefore be an effective, scalable, and acceptable way to improve prevention in students.MethodsAn online single blind, two-arm parallel-group Randomised Controlled Trial (RCT) to examine the incidence of major depression and symptoms of anxiety and depression across 12 months in university students aged over 16 who screen into the study with self-reported high levels of worry and/or rumination and no current diagnosis of major depression. Eligible participants will be randomised to the active intervention arm (usual practice plus using a self-guided mobile app targeting RNT) or to the control arm (usual practice). In total, 648 participants aged over 16, with no current major depression, bipolar disorder or psychosis will be recruited from UK universities. Assessments will take place at baseline (pre-randomisation), 3 months and 12 months post- randomisation. Primary endpoint and outcome is incidence of major depression as determined by self-reported diagnostic criteria at 12-month follow-up. Depressive symptoms, anxiety, well-being, health-related quality of life, functioning and academic outcomes are secondary outcomes. Compliance, adverse events, and potentially mediating variables will be carefully monitored.DiscussionThe trial aims to provide a better understanding of the causal role of tackling RNT (worry, rumination) using a self-help mobile app with respect to preventing depression in university students. This knowledge will be used to develop and disseminate innovative evidence-based, feasible, and effective mobile-health public health strategies for preventing common mental health problems.Trial registrationhttps://www.isrctn.com/ISRCTN86795807 Date of registration: 27 October 2022

Randomized trial of low intensity shockwave therapy for erectile dysfunction utilizing grayscale ultrasound for analysis of erectile tissue homogeneity/inhomogeneity.

Electrohydraulic shockwave devices have been Food and Drug Administration-cleared for improved blood flow and connective tissue activation and have been used to treat erectile dysfunction (ED). In this study, the main focus was to evaluate improvement in erectile tissue quality after low intensity shockwave therapy (LiSWT). A single-blind, sham-controlled, randomized, prospective study, was performed in men with ED naïve to shockwave or radial ballistic pressure wave therapy. Participants were randomized 1:2 to simulated (sham) or active LiSWT treatment. After simulated treatments, participants in the Sham Arm were converted to active LiSWT, while participants initially in the Active Treatment Arm received no further treatment. Assessments were performed at baseline and two follow-up visits. Subjective parameters of erectile function (EF) were assessed by total and EF domain scores of the International Index of Erectile Function (IIEF) and sexual encounter profile (SEP). Objective parameters of penile erection were measurements of hypoechoic areas in images obtained by grayscale ultrasound (GUS) with high resolution 15.4 MHz probe and cavernosal artery peak systolic velocity (PSV) and end diastolic velocity (EDV) by color duplex Doppler ultrasound (DUS). Outcome measures for erectile and urinary function were also obtained. Simulated LiSWT did not significantly change any assessment parameter. Sham Arm participants who converted to active LiSWT had significantly increased mean IIEF total (P=0.02) and IIEF-EF scores that approached statistical significance (P=0.06), relative to baseline. Similarly, at the end of the study, Active Treatment Arm participants had significantly increased mean IIEF total (P=0.02) and IIEF-EF scores that approached statistical significance (P=0.07), relative to baseline. Additionally, at the end of the study, SEP3 success rates (erection lasting long enough for successful intercourse) approached statistical significance when Sham Arm participants were converted to active LiSWT (P=0.08) and reached statistical significance in the Active Treatment Arm (P=0.049). GUS assessments by visual grading were significantly correlated to IIEF-EF score (P=0.002) and were significantly increased relative to baseline in the Active Treatment Arm at follow-up Assessment 1 (P=0.03) and Assessment 2 (P=0.04). The greatest reduction in hypoechoic area after LiSWT occurred in the proximal penile shaft. EDV was also significantly reduced in the Active Treatment Arm at follow-up Assessment 1 (P=0.04) and Assessment 2 (P=0.04). LiSWT also resulted in improved prostate symptom scores, approaching significance in the Active Treatment Arm (P=0.055) with no changes in prostate-specific antigen. Treatment-related adverse events were limited and transient. In this prospective trial, LiSWT was safe and efficacious for erectile symptoms using GUS imaging as a novel, non-invasive method to assess improvements in corporal veno-occlusive function. Improved veno-occlusion and reduced hypoechoic area demonstrated by GUS imaging suggest that LiSWT decreases connective tissue content in penile erectile tissue. Lower urinary tract symptoms also improved with LiSWT. NCT06600893 on clinicaltrials.gov.

Long-term survival of participants in a phase II randomized trial of RNS60 in amyotrophic lateral sclerosis

BackgroundPositive effects of RNS60 on respiratory and bulbar function were observed in a phase 2 randomized, placebo-controlled trial in people with amyotrophic lateral sclerosis (ALS). Objective: to investigate the long-term survival of trial participants and its association with respiratory status and biomarkers of neurodegeneration and inflammation. Study design and settingsA randomized, double blind, phase 2 clinical trial was conducted. Trial participants were enrolled at 22 Italian Expert ALS Centres from May 2017 to January 2020. Vital status of all participants was ascertained thirty-three months after the trial’s last patient last visit (LPLV). Participants were patients with Amyotrophic Lateral Sclerosis, classified as slow or fast progressors based on forced vital capacity (FVC) slope during trial treatment. Demographic, clinical, and biomarker levels and their association with survival were also evaluated. ResultsMean duration of follow-up was 2.8 years. Long-term median survival was six months longer in the RNS60 group (p = 0.0519). Baseline FVC, and rates of FVC decline during the first 4 weeks of trial participation, were balanced between the active and placebo treatment arms. After 6 months of randomized, placebo-controlled treatment, FVC decline was significantly slower in the RNS60 group compared to the placebo group. Rates of FVC progression during the treatment were strongly associated with long-term survival (median survival: 3.7 years in slow FVC progressors; 1.6 years in fast FVC progressors). The effect of RNS60 in prolonging long-term survival was higher in participants with low neurofilament light chain (NfL) (median survival: >4 years in low NfL − RNS60 group; 3.3 years in low NfL − placebo group; 1.9 years in high NfL − RNS60 group; 1.8 years in high NfL − placebo group) and Monocyte Chemoattractant Protein-1 (MCP-1) (median survival: 3.7 years in low MCP-1 − RNS60 group; 2.3 years in low MCP-1 − placebo group; 2.8 years in high MCP-1 − RNS60 group; 2.6 years in high MCP-1 − placebo group) levels at baseline. Conclusions and relevanceIn this post-hoc analysis, long term survival was longer in participants randomized to RNS60 compared with those randomized to placebo and was correlated with slower FVC progression rates, suggesting that longer survival may be mediated by the drug’s effect on respiratory function. In these post-hoc analyses, the beneficial effect of RNS60 on survival was most pronounced in participants with low NfL and MCP-1 levels at study entry, suggesting that this could be a subgroup to target in future studies investigating the effects of RNS60 on survival. Trial registrationStudy preregistered on 13/Jan/2017 in EUDRA-CT (2016-002382-62). The study was also registered at ClinicalTrials.gov number NCT03456882.

Older adults exercising ON TIME: protocol for a randomized controlled cross-over study to assess the effect of physical activity timing on insomnia severity

BackgroundThere are increased indications that physical activity timing, irrespective of intensity, impacts insomnia and circadian clock function. Here, we describe the rationale and design of a randomized cross-over study, called ON TIME, to examine the effects of (changing) physical activity timing on insomnia severity and on multiple exploratory outcomes that are linked to circadian clock function.MethodsWe will conduct a randomized cross-over trial in 40 healthy older adults (aged 65 to 75 years) with subclinical or clinical insomnia (Insomnia Severity Index (ISI) scores of ≥ 10) from the Dutch municipality of Leiden and surroundings. Participants will undergo 3 intervention periods (14 days each) consecutively: one sedentary period and two periods of increased physical activity (one period with morning activity and one period with evening activity). The intervention periods are separated by a wash-out period of 1 week. In both active intervention arms, participants will follow coached or uncoached outdoor physical exercise sessions comprising endurance, strength, and flexibility exercises for 14 days. The primary outcome is change in insomnia severity as measured by the ISI. Additional exploratory outcomes include multiple components of objective sleep quality measured with tri-axial accelerometry and subjective sleep quality assessed by questionnaires as well as dim light melatonin onset and 24-h rhythms in heart rate, heart rate variability, breathing rate, oxygen saturation, mood, and objective emotional arousal and stress. Additionally, we will collect diary data on eating patterns (timing and composition). Finally, fasting blood samples will be collected at baseline and after each intervention period for measurements of biomarkers of metabolic and physiological functioning and expression of genes involved in regulation of the biological clock.DiscussionWe anticipate that this study will make a significant contribution to the limited knowledge on the effect of physical activity timing. Optimizing physical activity timing has the potential to augment the health benefits of increased physical exercise in the aging population.Trial registrationTrial was approved by the Medical Ethics Committee Leiden, The Hague, Delft, The Netherlands (June, 2023). The trial was registered in the CCMO-register https://www.toetsingonline.nl/to/ccmo_search.nsf/Searchform?OpenForm under study ID NL82335.058.22 and named (“Ouderen op tijd in beweging” or in English “Older adults exercising on time”). At time of manuscript submission, the trial was additionally registered at ClinicalTrials.gov under study ID: NL82335.058.22 and is awaiting approval.

Feedback and Financial Incentives for Reducing Cell Phone Use While Driving

Handheld phone use while driving is a major factor in vehicle crashes. Scalable interventions are needed to encourage drivers not to use their phones. To test whether interventions involving social comparison feedback and/or financial incentives can reduce drivers' handheld phone use. In a randomized clinical trial, interventions were administered nationwide in the US via a mobile application in the context of a usage-based insurance program (Snapshot Mobile application). Customers were eligible to be invited to participate in the study if enrolled in the usage-based insurance program for 30 to 70 days. The study was conducted from May 13 to June 30, 2019. Analysis was completed December 22, 2023. Participants were randomly assigned to 1 of 6 trial arms for a 7-week intervention period: (1) control; (2) feedback, with weekly push notification about their handheld phone use compared with that of similar others; (3) standard incentive, with a maximum $50 award at the end of the intervention based on how their handheld phone use compared with similar others; (4) standard incentive plus feedback, combining interventions of arms 2 and 3; (5) reframed incentive plus feedback, with a maximum $7.15 award each week, framed as participant's to lose; and (6) doubled reframed incentive plus feedback, a maximum $14.29 weekly loss-framed award. Proportion of drive time engaged in handheld phone use in seconds per hour (s/h) of driving. Analyses were conducted with the intention-to-treat approach. Of 17 663 customers invited by email to participate, 2109 opted in and were randomized. A total of 2020 drivers finished the intervention period (68.0% female; median age, 30 [IQR, 25-39] years). Median baseline handheld phone use was 216 (IQR, 72-480) s/h. Relative to control, feedback and standard incentive participants did not reduce their handheld phone use. Standard incentive plus feedback participants reduced their use by -38 (95% CI, -69 to -8) s/h (P = .045); reframed incentive plus feedback participants reduced their use by -56 (95% CI, -87 to -26) s/h (P < .001); and doubled reframed incentive plus feedback participants reduced their use by -42 s/h (95% CI, -72 to -13 s/h; P = .007). The 5 active treatment arms did not differ significantly from each other. In this randomized clinical trial, providing social comparison feedback plus incentives reduced handheld phone use while individuals were driving. ClinicalTrials.gov Identifier: NCT03833219.

Filling the "GAP" in Real-World Assessment of Psoriatic Arthritis Disease Activity: Performance Characteristics of a Global/Pain Composite Endpoint.

Some retrospective data sources, such as electronic health records in the USA, report composite outcome measures not fully validated in psoriatic arthritis (PsA). However, they often contain global assessments, such as a Physician Global Assessment (PhGA) and Patient Global Assessment (PatGA), along with patient-reported pain scores, which individually are considered validated in PsA. This research described the performance characteristics of a 3-item global assessment and pain (GAP) composite endpoint using data from the ixekizumab phase3 PsA clinical trial program. Discrimination of GAP was assessed by comparing placebo to active treatment arms. The magnitude of treatment effect and responsiveness were compared to Disease Activity Index for PsA (DAPSA), clinical DAPSA, DAPSA28, and Psoriatic Arthritis Disease Activity Score (PASDAS) using effect size (ES) and standardized response mean (SRM), respectively. Construct validity was evaluated through correlation among the composite endpoints, and with other physician- and patient-reported outcomes. Change in GAP was compared in patients who reached low disease activity (LDA) levels based on DAPSA, cDAPSA, and PASDAS vs those who did not. GAP discriminated between active treatment and placebo with statistically significant separation as early as week1. The largest ES/SRM was seen with GAP (2.29/1.74) and PASDAS (2.47/1.68). GAP had the strongest correlation with PASDAS (0.81-0.92) and showed moderate correlations with patient-assessed physical function, low correlations with physician-assessed skin and nail psoriasis, and low to moderate correlation with physician-assessed enthesitis. A significantly greater improvement in GAP was seen in the groups achieving LDA states compared to those not (p < 0.001). The GAP composite, an abbreviated endpoint comprising measures common in electronic health records, has promising performance characteristics and could be used to address important clinical questions regarding outcomes and impact of PsA in existing datasets. CLINTRIALS. NCT01695239; NCT02349295.

Safer-use strategies in the context of harm-reduction treatment for people experiencing homelessness and alcohol use disorder

BackgroundTwo, randomized controlled trials found harm-reduction treatment for AUD (HaRT-A) improves alcohol outcomes for adults experiencing homelessness. HaRT-A, which neither requires nor precludes abstinence, entails tracking alcohol-related harm, harm-reduction goals, and safer-use strategies. This secondary dual study qualitatively describes this last component, safer-use strategies, and their quantitative association with treatment outcomes. MethodsParticipants were people who experienced homelessness and AUD and were enrolled in the active HaRT-A treatment arms in 2 randomized control trials (Trial 1 N = 86; Trial 2 N = 208). Trial 1was a 2-arm study with randomization to HaRT-A or services as usual. Trial 2 was a 4-arm study combining HaRT-A and extended release naltrexone. In HaRT-A sessions, participants received a list of 3 categories of safer-use strategies (i.e., buffering alcohol's effects on the body, changing the manner of drinking to be safer and healthier, and reducing alcohol use). Mixed methods were used to qualitatively describe safer-use strategies implemented and quantitatively test their association with alcohol outcomes (i.e., peak quantity, frequency, alcohol-related harm). ResultsIn Trial 1, but not Trial 2, participants committed to more safer-use strategies across time, which was associated with reductions in alcohol frequency over the past 30 days. In both trials, participants committing to reducing alcohol consumption drank on a quarter fewer days overall, and in Trial 2, experienced 15 % less alcohol-related harm. In Trial 1, participants who committed to changing the manner of drinking were heavier drinkers overall, and although they showed significant reductions in alcohol-related harm, their reduction rate was slower than for participants who selected other strategies. In Trial 2, strategies to buffer alcohol's effects were associated with a monthly 14 % decrease of alcohol-related harm. ConclusionThis study replicated prior findings that people experiencing homelessness and AUD regularly adopt strategies to reduce alcohol-related harm. The implementation of safer-use strategies was favorably associated with alcohol outcomes, but specific associations differed by trial and outcome. Discussion of safer-use strategies appears helpful; however, further research is needed to firmly establish how this HaRT-A component works.

A multi-arm multi-stage platform design that allows preplanned addition of arms while still controlling the family-wise error.

There is growing interest in platform trials that allow for adding of new treatment arms as the trial progresses as well as being able to stop treatments part way through the trial for either lack of benefit/futility or for superiority. In some situations, platform trials need to guarantee that error rates are controlled. This paper presents a multi-stage design, that allows additional arms to be added in a platform trial in a preplanned fashion, while still controlling the family-wise error rate, under the assumption of known number and timing of treatments to be added, and no time trends. A method is given to compute the sample size required to achieve a desired level of power and we show how the distribution of the sample size and the expected sample size can be found. We focus on power under the least favorable configuration which is the power of finding the treatment with a clinically relevant effect out of a set of treatments while the rest have an uninteresting treatment effect. A motivating trial is presented which focuses on two settings, with the first being a set number of stages per active treatment arm and the second being a set total number of stages, with treatments that are added later getting fewer stages. Compared to Bonferroni, the savings in the total maximum sample size are modest in a trial with three arms, <1% of the total sample size. However, the savings are more substantial in trials with more arms.

Adding experimental treatment arms to multi-arm multi-stage platform trials in progress.

Multi-arm multi-stage (MAMS) platform trials efficiently compare several treatments with a common control arm. Crucially MAMS designs allow for adjustment for multiplicity if required. If for example, the active treatment arms in a clinical trial relate to different dose levels or different routes of administration of a drug, the strict control of the family-wise error rate (FWER) is paramount. Suppose a further treatment becomes available, it is desirable to add this to the trial already in progress; to access both the practical and statistical benefits of the MAMS design. In any setting where control of the error rate is required, we must add corresponding hypotheses without compromising the validity of the testing procedure.To strongly control the FWER, MAMS designs use pre-planned decision rules that determine the recruitment of the next stage of the trial based on the available data. The addition of a treatment arm presents an unplanned change to the design that we must account for in the testing procedure. We demonstrate the use of the conditional error approach to add hypotheses to any testing procedure that strongly controls the FWER. We use this framework to add treatments to a MAMS trial in progress. Simulations illustrate the possible characteristics of such procedures.

Skull Density Ratio as Arm-Allocation Parameter for a Controlled Focused Ultrasound Trial in Parkinson's Disease.

MR-guided focused ultrasound (FUS) thermoablation is an established therapy for movement disorders. FUS candidates must meet a predefined threshold of skull density ratio (SDR), a parameter that accounts for the efficiency in reaching ablative temperatures. Randomized sham-controlled trials to provide definitive therapeutic evidence employ pure randomization of subjects into active treatment or control arms. The latter design has several general limitations. To demonstrate that SDR values are not associated with clinically and demographically relevant variables in patients with Parkinson's disease (PD). This in turn would allow using SDR as an arm-allocation parameter, separating patients who will receive active FUS treatment and best medical management treatment (BMT). We studied a cohort of 215 PD patients who were candidates for FUS subthalamotomy to determine if the SDR was correlated with demographic or clinical variables that could introduce bias for group allocation in a controlled trial. SDR was unassociated with age, gender, and clinical motor features nor with levodopa daily dose in our cohort of PD patients. A negative association with age was found for the female subgroup. Our results show that in a PD population considered for FUS subthalamotomy treatment, the SDR may be a valid group-allocation parameter. This could be considered as the basis for a controlled study comparing FUS subthalamotomy vs BMT.

Unlocking the potential of synthetic patients for accelerating clinical trials: Results of the first GIMEMA experience on acute myeloid leukemia patients.

Artificial Intelligence has the potential to reshape the landscape of clinical trials through innovative applications, with a notable advancement being the emergence of synthetic patient generation. This process involves simulating cohorts of virtual patients that can either replace or supplement real individuals within trial settings. By leveraging synthetic patients, it becomes possible to eliminate the need for obtaining patient consent and creating control groups that mimic patients in active treatment arms. This method not only streamlines trial processes, reducing time and costs but also fortifies the protection of sensitive participant data. Furthermore, integrating synthetic patients amplifies trial efficiency by expanding the sample size. These straightforward and cost-effective methods also enable the development of personalized subject-specific models, enabling predictions of patient responses to interventions. Synthetic data holds great promise for generating real-world evidence in clinical trials while upholding rigorous confidentiality standards throughout the process. Therefore, this study aims to demonstrate the applicability and performance of these methods in the context of onco-hematological research, breaking through the theoretical and practical barriers associated with the implementation of artificial intelligence in medical trials.

A generalized phase 1-2-3 design integrating dose optimization with confirmatory treatment comparison.

A generalized phase 1-2-3 design, Gen 1-2-3, that includes all phases of clinical treatment evaluation is proposed. The design extends and modifies the design of Chapple and Thall (2019), denoted by CT. Both designs begin with a phase 1-2 trial including dose acceptability and optimality criteria, and both select an optimal dose for phase 3. The Gen 1-2-3 design has the following key differences. In stage 1, it uses phase 1-2 criteria to identify a set of candidate doses rather than 1 dose. In stage 2, which is intermediate between phase 1-2 and phase 3, it randomizes additional patients fairly among the candidate doses and an active control treatment arm and uses survival time data from both stage 1 and stage 2 patients to select an optimal dose. It then makes a Go/No Go decision of whether or not to conduct phase 3 based on the predictive probability that the selected optimal dose will provide a specified substantive improvement in survival time over the control. A simulation study shows that the Gen 1-2-3 design has desirable operating characteristics compared to the CT design and 2 conventional designs.

Reducing fear and avoidance of memory loss improves mood and social engagement in community-based older adults: a randomized trial

BackgroundAlzheimer’s disease and related dementias (ADRD) are among the most feared age-related conditions. The aim of this study was to evaluate a brief psychological intervention to promote adaptive coping in older adults experiencing heightened fear of ADRD and investigate positive downstream effects on health-related secondary outcomes, including frequency of reported memory failures, psychosocial functioning, and quality of life.MethodsEighty-one older adults were recruited and randomized into REFRAME or active control intervention arms. Both groups received psycho-education and training in mindful monitoring of fears related to ADRD. The REFRAME group received an additional behavioral activation component intended to disrupt maladaptive avoidant coping (i.e., avoidance) strategies. Both groups completed 3-weeks of intervention exercises with accompanying questionnaires (baseline, mid- and post-intervention and 4-week follow-up).ResultsAdherence was strong (> 75%). We observed a significant reduction in ADRD-related fear and avoidance in both groups. Significant reductions were also observed for frequency of self-reported memory failures, anxiety, and depression. Depression was significantly reduced in the REFRAME group compared to the control group. Significant increases in participants’ ability to participate in social activities and well-being were also observed.ConclusionsFindings suggest that a brief psychological intervention can mitigate ADRD-related fears and avoidant coping in older adults, and that benefits extend to broader health-related outcomes including anxiety, depression, social functioning, and well-being. Addressing ADRD-related fear has implications for healthy aging and risk reduction, as individuals may be more likely to engage in activities that are protective against ADRD but were previously avoided.Trial registration: https://clinicaltrials.gov/ct2/show/NCT04821960.

Updated Results from a Matching-Adjusted Indirect Comparison of Efficacy Outcomes for Isatuximab Plus Pomalidomide and Dexamethasone Versus Daratumumab Plus Pomalidomide and Dexamethasone in Patients with Relapsed and/or Refractory Multiple Myeloma

Introduction: Findings from a previously conducted matching-adjusted indirect comparison (MAIC) between isatuximab plus pomalidomide and dexamethasone (IsaPd) and daratumumab plus pomalidomide and dexamethasone (DaraPd) among relapsed and/or refractory multiple myeloma (RRMM) patients receiving at least two prior lines of therapy (LoT) including lenalidomide and a proteasome inhibitor (PI) demonstrated a significantly better overall survival (OS) and a positive trend for progression-free survival (PFS), overall response rate (ORR), and very good partial response or better (≥VGPR) rates with IsaPd than that with DaraPd, with a similar safety profile for both treatments [Leleu X et al, Value in Health 2022;25(1):S39]. The present study used longer follow-up data from the phase 3 ICARIA trial (NCT02990338) to update the previous MAIC, evaluating the comparative efficacy of IsaPd versus DaraPd. Methods: A MAIC was performed with the latest available individual patient-level data (IPD) from the ICARIA trial (IsaPd arm, n = 154; Pd arm, n = 153), data cutoff of March 14, 2022, and aggregate data from study publications of the phase 3 APOLLO trial (DaraPd arm, n = 151; Pd arm, n = 153, NCT03180736) [Dimopoulos MA, et al. Blood 2022;140 (Suppl 1):7272-7274; Dimopoulos MA, et al. Lancet Oncol. 2021;22(6):801-812; Dimopoulos MA, et al. Blood 2020;136(Suppl 1):5-6]. To match patients with APOLLO, patients in ICARIA who did not meet the inclusion criteria of APOLLO were excluded. In APOLLO, 11% patients received only one prior LoT. As patients with one prior LoT were not enrolled in ICARIA, it was not feasible to match on this factor; however, the treatment effect of DaraPd versus Pd on PFS among these patients was similar to patients in APOLLO with ≥2 prior LoTs. Therefore, this difference in study populations is unlikely to bias the MAIC. Remaining patients in ICARIA were then weighted using standardized MAIC weights (mean value = 1.0) generated using the method of moments, with active treatment and control arms matched separately to ensure any residual imbalances between active and control arms in APOLLO were replicated in the matched ICARIA sample. Anchored MAICs for the hazard ratio (HR) for OS and PFS, odds ratio (OR) for ORR, and ≥VGPR for IsaPd versus DaraPd were calculated using the Bucher method [Bucher HC, et al. J Clin Epidemiol. 1997;50(6):683-691]. Results: MAIC weighting was able to match all characteristics included in the matching algorithm, with standardized mean difference (SMDs) &amp;lt;0.0001 after weighting. The effective sample size after weighting was 28.1 for IsaPd and 43.1 for Pd. Based on an anchored MAIC, OS was significantly better with IsaPd versus DaraPd (HR [95% CI]: 0.49 [0.24-0.98]; p = 0.04) (Figure 1). A numerical trend in favor of IsaPd versus DaraPd was observed for PFS, ORR, and ≥VGPR, although the differences were statistically non-significant (Table 1). Conclusions: This MAIC analysis demonstrated a significant benefit in OS and a positive trend in the improvement of PFS, ORR, and ≥VGPR in favor of IsaPd compared with DaraPd. These findings were consistent with the previous MAIC with a longer follow-up data (present analysis used a maximum follow-up of 4.5 years of OS data from both trials, whereas the previous analysis used a follow-up of 3 years from ICARIA and unknown from APOLLO), which highlights the therapeutic potential of IsaPd in RRMM, particularly for patients who become refractory to lenalidomide and a PI.

Design of a dual randomized trial in a type 2 hybrid effectiveness—implementation study

BackgroundDual randomized controlled trials (DRCT) are type 2 hybrid studies that include two randomized trials: one testing implementation strategies and one testing an intervention. We argue that this study design offers efficiency by providing rigorous investigation of both implementation and intervention in one study and has potential to accelerate generation of the evidence needed to translate interventions that work into real-world practice. Nevertheless, studies using this design are rare in the literature.Main textWe construct a paradigm that breaks down the components of the DRCT and provide a step-by-step explanation of features of the design and recommendations for use. A clear distinction is made between the dual strands that test the implementation versus the intervention, and a minimum of three randomized arms is advocated. We suggest an active treatment arm that includes both the implementation strategy and intervention that are hypothesized to be superior. We suggest two comparison/control arms: one to test the implementation strategy and the second to test the intervention. Further, we recommend selection criteria for the two control arms that place emphasis on maximizing the utility of the study design to advance public health practice.ConclusionsOn the surface, the design of a DRCT can appear simple, but actual application is complex. We believe it is that complexity that has limited its use in the literature. We hope that this paper will give both implementation scientists and trialists who are not familiar with implementation science a better understanding of the DRCT design and encouragement to use it.

Peer Pressure and Risk-Taking Behaviors Among Adolescent Girls in a Region Impacted by HIV/AIDS in Southwestern Uganda

PurposeThis paper uses data from a 3-arm Cluster Randomized Control Trial, Suubi4Her (N = 1260; 14–17-year-old school-going girls) to (1) assess the relationship between peer pressure and adolescent risk-taking behaviors; and (2) test the mediating effect of peer pressure on an intervention on adolescent risk-taking behaviors. MethodsStudents in the southwestern region of Uganda were assigned to three study arms: control (n = 16 schools, n = 408 students) receiving usual care comprising of sexual and reproductive health curriculum; and two active treatment arms: Treatment 1 (n = 16 schools, n = 471 students) received everything the control arm received plus a savings led intervention. Treatment 2 (n = 15 schools, n = 381 students) received everything the control and treatment arms received plus a family strengthening intervention. We used multilevel models to assess the relationship between peer pressure and risk-taking behaviors. We ran structural equation models for mediation analysis. ResultsUsing baseline data, we found that direct peer pressure was significantly associated with substance use risk behaviors, (β = 0.044, 95% CI = 0.008, 0.079). We also found a statistically significant effect of the intervention on acquiring STIs through the mediating effect of sexual risk-taking significant (β = −0.025, 95% CI: −0.049, −0.001, p = .045) and total indirect (β = −0.042, 95% CI: −0.081, −0.002, p = .037) effects. Also, there was a significant mediation effect of the intervention on substance use through peer pressure (β = −0.030, 95% CI: −0.057, −0.002, p = .033). DiscussionOverall, the study points to the role of peer pressure on adolescent girls' risk-taking behaviors; and a need to address peer pressure at an early stage.

Postnasal drip and chronic cough in patients with chronic rhinitis treated with temperature-controlled radiofrequency neurolysis.

To evaluate the contribution of postnasal drip (PND) and chronic cough (CC) to symptoms of patients with chronic rhinitis treated with temperature-controlled radiofrequency (TCRF) neurolysis of the posterior nasal nerve (PNN), and correlate PND and CC scores with components of the reflective total nasal symptom score (rTNSS). Pooled data from three prospective studies: two single-arm studies and the index active treatment arm of a randomized controlled trial. Adult patients with baseline rTNSS ≥6 were treated with TCRF neurolysis at nonoverlapping regions of the PNN. PND and CC symptoms were evaluated on a 0 (none) to 3 (severe) scale. Data from 228 patients (57.9% women, 42.1% men) were included. The mean baseline rTNSS was 8.1 (95% confidence interval [CI], 7.8-8.3), which decreased to 3.2 (95% CI, 2.9-3.5) at 6 months. At baseline, 97.4% of patients had PND and 80.3% had CC. Median baseline PND and CC symptom scores were 3 (interquartile range [IQR], 2-3) and 2 (IQR, 1-2), respectively. At 6 months, this decreased to 1 (IQR, 0-2) and 0 (IQR, 0-1), respectively, showing significant improvement from baseline (both p<0.001). Spearman correlation coefficients with components of rTNSS (rhinorrhea, congestion, itching, sneezing) were 0.16 to 0.22 for CC and 0.19 to 0.46 for PND, indicating only a weak to moderate correlation. PND and CC contribute to the symptomatology of chronic rhinitis and are significantly improved after TCRF neurolysis of the PNN. The inclusion of PND and CC symptoms in a chronic rhinitis assessment instrument could provide important additional information for the characterization of the disease state and outcomes after any therapeutic treatment.

Reducing sickness absence and stigma due to mental health difficulties: a randomised control treatment trial (RCT) of a low intensity psychological intervention and stigma reduction programme for common mental disorder (Prevail)

BackgroundCommon mental disorders are the leading cause of workplace absences. The Prevail intervention programme aims to reduce stigma and to educate staff and managers about evidence-based low intensity psychological interventions for common mental disorders (depression, anxiety, stress, and distress). Prevail is innovative in taking a public health approach. It is designed to be given to all employees irrespective of their past or current mental health. Prevail was evaluated in three studies examining: (1) the acceptability of the intervention and perceived usefulness; (2) whether the intervention altered stigmatic attitudes and motivation to seek help; and (3) whether the intervention reduced sickness absence, both overall and due to mental health problems.MethodsA two-armed cluster randomised control trial (RCT) evaluated the effectiveness of Prevail. Employees (N = 1051) at a large UK government institution were randomised to an active intervention or control arm in teams identified by their managers (n = 67). Employees in the active arm received the Prevail Staff Intervention. The managers in the active arm also received the Prevail Managers Intervention. Participants’ satisfaction and analysis of the Prevail Intervention were gathered by a bespoke questionnaire. Questionnaire measures of attitudes to mental health and mental health stigma were taken 1–2 weeks prior to the intervention and approximately 4 weeks post-intervention. Data relating to sickness absence were gathered via the official records in the time period 3-month post-intervention and for the same period 12 months earlier.ResultsPrevail was evaluated highly favourably by both the staff and their managers. Prevail produced significant reductions in self-stigma and anticipated stigma due to mental health difficulties. Crucially, sickness absence was significantly reduced by the Prevail Intervention.DiscussionPrevail achieved its goals of producing a palatable and engaging intervention that altered staff’s attitudes and stigmatic beliefs related to mental health and, crucially, produced a strong reduction in work-pace absenteeism. As the Prevail programme is aimed at common mental health problems and was not specialised to this particular workforce, the study provides the evidence-base for a mental health intervention programme that could be used by many organisations across the world.Trial RegistrationISRCTN12040087. Registered 04/05/2020. https://doi.org/10.1186/ISRCTN12040087. A full protocol for the randomised control trial was published: Gray NS, Davies H, Snowden RJ: Reducing stigma and increasing workplace productivity due to mental health difficulties in a large government organization in the UK: a protocol for a randomised control treatment trial (RCT) of a low intensity psychological intervention and stigma reduction programme for common mental disorder (Prevail). BMC Public Health 2020, 20(1):1–9.

Limosilactobacillus reuteri DSM 17938 supplementation and SARS-CoV-2 specific antibody response in healthy adults: a randomized, triple-blinded, placebo-controlled trial

ABSTRACT Studies have shown that probiotics can decrease the symptoms of respiratory tract infections as well as increase antibody responses following certain vaccinations. We examined the effect of probiotic supplementation on anti-SARS-CoV-2 specific antibody responses upon SARS-CoV-2 infection as well as after COVID-19 vaccination. In this randomized, triple-blinded, placebo-controlled intervention study with a parallel design, 159 healthy adults without prior SARS-CoV-2 infection or COVID-19 vaccination and any known risk factors for severe COVID-19 were randomly allocated into two study arms. The active treatment arm consumed a probiotic product containing a minimum of 1 × 108 colony-forming units of Limosilactobacillus reuteri DSM 17938 + 10 μg vitamin D3 twice daily for 6 months. The placebo arm consumed identical tablets containing only 10 μg vitamin D3. Anti-SARS-CoV-2 specific antibodies and virus neutralizing antibody titers were analyzed from blood samples collected at baseline, after 3 months, and after 6 months. Differences in serum antibody titers between the two study arms were tested with independent t-test using log-transformed values. In the intention-to-treat (ITT) analysis, SARS-CoV-2 infected individuals in the active treatment arm (n = 6) tended to have higher serum anti-spike IgG (609 [168–1480] BAU/ml vs 111 [36.1–1210] BAU/ml, p = 0.080) and anti-receptor binding domain (RBD) IgG (928 [212–3449] BAU/ml vs (83.7 [22.8–2094] BAU/ml, p = 0.066) levels than individuals in the placebo arm (n = 6). Considering individuals who were fully vaccinated with mRNA-based COVID-19 vaccines, the active treatment arm (n = 10) exhibited significantly higher serum levels of anti-RBD IgA (135 [32.9–976] BAU/ml vs 61.3 [26.7–97.1] BAU/ml, p = 0.036) than the placebo arm (n = 7) >28 days postvaccination. Supplementation with specific probiotics might improve the long-term efficacy of mRNA-based COVID-19 vaccines via enhanced IgA response.