Changes to design and analysis elements of research plans during randomised controlled trials in Australia.

OBJECTIVES: To investigate the frequency and legitimacy of substantive changes to the research plans of published randomised controlled trials (RCTs) undertaken in Australia. DESIGN: Comparison of methodology and analysis plans for RCTs specified in protocol documents (full protocols, published protocol articles, statistical analysis plans, Australian New Zealand Clinical Trials Registry [ANZCTR] registration entries) and described in publications of primary results. SETTING, PARTICIPANTS: 181 RCTs registered with the ANZCTR, 1 September 2007 - 31 December 2013, for which primary results had been published. MAIN OUTCOME MEASURE: Changes made to research plan, both overall and by specific item (primary outcome, analysis set, eligibility criteria, sample size, primary analysis method, and treatment arms included in the primary comparison in multi-arm trials); trial characteristics associated with changes. RESULTS: Protocol documents were available for 124 of 181 eligible RCTs (69%; 46 publicly available, 78 provided by trial groups on request). Full audit of RCTs with protocols found clear or probable changes in 111 trials (90%), for 101 of which (91%) it was unclear whether changes had been made blinded to treatment outcomes. After seeking clarification from investigators, changes to 78 trials were confirmed (63%), for 61 of which (78%) changes were made blinded to treatment outcomes. Any change was less likely for trials with publicly available protocols than for trials for which we needed to request protocols (odds ratio, 0.22; 95% CI, 0.06-0.77). Limited reviews of trials without protocols identified that changes had been made to 42 of 57 trials (74%). CONCLUSION: Changes to RCT study plans in Australia are both frequent and usually made appropriately blinded to treatment outcomes. However, the documentation of changes made to RCT protocols should be formalised to improve transparency.

Peer-facilitated interventions for improving the physical health of people with schizophrenia spectrum disorders: systematic review and meta-analysis.

OBJECTIVES: To evaluate the efficacy of peer-facilitated interventions for improving the physical health of people with schizophrenia spectrum disorders. STUDY DESIGN: Systematic review and random effects meta-analysis of peer-facilitated interventions for people with serious mental illness, including schizophrenia spectrum disorders, in which physical health outcomes were assessed. DATA SOURCES: MEDLINE, PsycINFO, EMBASE, CINAHL, Web of Science, Scopus, CENTRAL, and PubMed. In addition, reference lists of reviews were examined for further relevant studies published to 10 November 2021. DATA SYNTHESIS: We included fourteen publications (thirteen randomised controlled trials of ten peer-facilitated interventions, and one secondary analysis; total of 2099 participants) that assessed physical health outcomes for people with mental health conditions, including schizophrenia spectrum disorders. Intervention duration ranged from three to eighteen months; peers were involved as sole or co-leaders of the programs in group or individual sessions. Meta-analysis identified a statistically significant pooled effect on physical activity and capacity (various measures; six studies; 468 intervention, 461 control participants; standardised mean difference, +0.19 standard deviation [SD]; 95% CI, +0.06-0.32 SD; I2  = 0%); overall GRADE certainty of evidence was low. Marked study heterogeneity precluded secure conclusions regarding intervention effects on self-rated physical health, healthy eating, and body mass index. CONCLUSIONS: Peer-facilitated interventions for improving physical outcomes are feasible for people with schizophrenia spectrum disorders, a group at particular risk of certain physical health conditions. Further research is required to assess the effects of such interventions on other health-related parameters. PROSPERO REGISTRATION: CRD42021283578 (retrospective).

The reporting and methodological quality of split-mouth trials in oral implantology: A methodological study.

OBJECTIVES: The objective of this study is to assess the reporting and methodological quality of split-mouth trials (SMTs) in oral implantology published during the past 10 years, and to investigate whether there was any improvement over time. MATERIALS AND METHODS: We searched PubMed for SMTs in oral implantology published during 2011-20. We used CONSORT 2010, its extension for within-person trial (WPT), and an SMT-specific methodological checklist to assess trial reporting quality (TRQ), WPT-specific reporting quality (WRQ), and SMT-specific methodological quality (SMQ), respectively. Binary scores were given to each item, and total scores of TRQ (range 0-32), WRQ (0-15), and SMQ (0-3) were calculated for each study. Multivariable regression analyses were performed to compare the quality of SMTs published before (2011-17) and after (2018-20) the release of CONSORT for WPT. RESULTS: Seventy-nine SMTs were included. The mean TRQ, WRQ, and SMQ were 16.4, 6.7, and 1.3, respectively. Less than one-third (n = 25, 31.6%) reported the rationale for using split-mouth designs. Only 4 (5.1%) trials adequately conducted sample size calculation, and 40 (50.6%) used appropriate statistical methods that considered dependency and clustering of data. In multivariable analyses, compared with 2011-17, studies published in 2018-20 had significantly higher TRQ (p = .044), while WRQ and SMQ did not show improvement. CONCLUSIONS: The reporting and methodological quality of SMTs in oral implantology need to be improved. Joint efforts are needed to improve the reporting and methodology of SMTs in this field.

OPTIMISE: a pragmatic stepped wedge cluster randomised trial of an intervention to improve primary care for refugees in Australia.

OBJECTIVES: To examine whether primary care outreach facilitation improves the quality of care for general practice patients from refugee backgrounds. DESIGN: Pragmatic, cluster randomised controlled trial, with stepped wedge allocation to early or late intervention groups. SETTING, PARTICIPANTS: 31 general practices in three metropolitan areas of Sydney and Melbourne with high levels of refugee resettlement, November 2017 - August 2019. INTERVENTION: Trained facilitators made three visits to practices over six months, using structured action plans to help practice teams optimise routines of refugee care. MAJOR OUTCOME MEASURE: Change in proportion of patients from refugee backgrounds with documented health assessments (Medicare billing). Secondary outcomes were refugee status recording, interpreter use, and clinician-perceived difficulty in referring patients to appropriate dental, social, settlement, and mental health services. RESULTS: Our sample comprised 14 633 patients. The intervention was associated with an increase in the proportion of patients with Medicare-billed health assessments during the preceding six months, from 19.1% (95% CI, 18.6-19.5%) to 27.3% (95% CI, 26.7-27.9%; odds ratio, 1.88; 95% CI, 1.42-2.50). The impact of the intervention was greater in smaller practices, practices with larger proportions of patients from refugee backgrounds, recent training in refugee health care, or higher baseline provision of health assessments for such patients. There was no impact on refugee status recording, interpreter use increased modestly, and reported difficulties in refugee-specific referrals to social, settlement and dental services were reduced. CONCLUSIONS: Low intensity practice facilitation may improve some aspects of primary care for people from refugee backgrounds. Facilitators employed by local health services could support integrated approaches to enhancing the quality of primary care for this vulnerable population. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry, ACTRN12618001970235 (retrospective).

Diagnostic sensitivity and specificity of 2-mSv CT vs. conventional-dose CT in adolescents and young adults with suspected appendicitis: post hoc subgroup analysis of the LOCAT data.

OBJECTIVES: To test whether the difference in sensitivity or specificity between 2-mSv CT and conventional-dose CT (CDCT) for the diagnosis of appendicitis differs across subgroups of adolescents and young adults with suspected appendicitis. MATERIALS AND METHODS: We used the per-protocol analysis data of a trial conducted between Dec 2013 and Aug 2016, including 2773 patients (median age [interquartile range], 28 [21-35] years) and 160 radiologists from 20 hospitals. We defined subgroups by sex, body size, clinical risk scores for appendicitis, time of CT examination (i.e., working vs. after hours), CT machines, radiologists' experience, previous site experience in 2-mSv CT, and site practice volume. We drew forest plots and tested for additive or multiplicative interaction between radiation dose and subgroup attributes. If any subgroup had fewer than 200 patients, we considered the results from that subgroup not meaningful. RESULTS: For most subgroups, the 95% CIs for the differences in sensitivity and specificity were 4.0 percentage points or narrower and contained the minute overall between-group differences. There was no significant interaction on sensitivity or specificity. A few subgroups, including those of extreme body sizes, high appendicitis inflammatory response scores, and hospitals with small appendectomy volume, were regarded to have insufficient numbers of patients. CONCLUSIONS: There was no notable subgroup heterogeneity, which implies that 2-mSv CT can replace CDCT in diverse populations. Further studies are needed for the subgroups for which we had only small data. KEY POINTS: • The minute difference in sensitivity or specificity between the 2-mSv CT and conventional-dose CT (typically 7 mSv) groups were consistent across various patient or hospital characteristics. • These results indicate that 2-mSv CT can replace conventional-dose CT in diverse populations. • Further studies are needed to confirm whether 2-mSv CT can replace conventional-dose CT in patients of extreme body sizes, high appendicitis inflammatory response scores, or hospitals with small appendectomy volume, as those subgroups in our data included limited numbers of patients.

Effects of Liraglutide on Cardiovascular Outcomes in Patients With Type 2 Diabetes Mellitus With or Without History of Myocardial Infarction or Stroke.

BACKGROUND: The glucagon-like peptide-1 analog liraglutide reduced cardiovascular events and mortality in patients with type 2 diabetes mellitus in the LEADER trial (Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes). In a post hoc analysis, we evaluated the efficacy of liraglutide in those with and without a history of myocardial infarction (MI) and/or stroke. METHODS: LEADER was a randomized trial of liraglutide (1.8 mg or maximum tolerated dose) versus placebo in 9340 patients with type 2 diabetes mellitus and high cardiovascular risk, with a median follow-up of 3.8 years. The primary outcome was a composite of cardiovascular death, nonfatal MI, or nonfatal stroke (major adverse cardiovascular events). Risk groups in this post hoc analysis were defined by history of MI/stroke, established atherosclerotic cardiovascular disease without MI/stroke, or cardiovascular risk factors alone. RESULTS: Of the 9340 patients, 3692 (39.5%) had a history of MI/stroke, 3083 (33.0%) had established atherosclerotic cardiovascular disease without MI/stroke, and 2565 (27.5%) had risk factors alone. Major adverse cardiovascular events occurred in 18.8% of patients with a history of MI/stroke (incidence rate, 5.0 per 100 patient-years), 11.6% of patients with established atherosclerotic cardiovascular disease without MI/stroke (incidence rate, 3.0 per 100 patient-years), and 9.8% of patients with cardiovascular risk factors alone (incidence rate, 2.6 per 100 patient-years). Liraglutide reduced major adverse cardiovascular events in patients with a history of MI/stroke (322 of 1865 [17.3%] versus 372 of 1827 patients [20.4%]; hazard ratio, 0.85; 95% CI, 0.73-0.99) and in those with established atherosclerotic cardiovascular disease without MI/stroke (158 of 1538 [10.3%] versus 199 of 1545 patients [12.9%]; hazard ratio, 0.76; 95% CI, 0.62-0.94) compared with placebo. In patients with risk factors alone, the hazard ratio for liraglutide versus placebo was 1.08 (95% CI, 0.84-1.38, Pinteraction=0.11). Similar results were seen for secondary outcomes across risk groups. CONCLUSIONS: In this post hoc analysis of patients with type 2 diabetes mellitus and high cardiovascular risk, liraglutide reduced cardiovascular outcomes both in patients with a history of MI/stroke and in those with established atherosclerotic cardiovascular disease without MI/stroke. The cardiovascular effect appeared neutral in patients with cardiovascular risk factors alone. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01179048.

Recruiting general practice patients for large clinical trials: lessons from the Aspirin in Reducing Events in the Elderly (ASPREE) study.

OBJECTIVE: To assess the factors that contributed to the successful completion of recruitment for the largest clinical trial ever conducted in Australia, the Aspirin in Reducing Events in the Elderly (ASPREE) study. DESIGN: Enrolment of GPs; identification of potential participants in general practice databases; screening of participants. SETTING, PARTICIPANTS: Selected general practices across southeast Australia (Tasmania, Victoria, Australian Capital Territory, New South Wales, South Australia). MAJOR OUTCOMES: Numbers of patients per GP screened and randomised to participation; geographic and demographic factors that influenced screening and randomising of patients. RESULTS: 2717 of 5833 GPs approached (47%) enrolled to recruit patients for the study; 2053 (76%) recruited at least one randomised participant. The highest randomised participant rate per GP was for Tasmania (median, 5; IQR, 1-11), driven by the high rate of participant inclusion at phone screening. GPs in inner regional (adjusted odds ratio [aOR], 1.45; 95% CI, 1.14-1.84) and outer regional areas (aOR, 1.86; 95% CI, 1.19-2.88) were more likely than GPs in major cities to recruit at least one randomised participant. GPs in areas with a high proportion of people aged 70 years or more were more likely to randomise at least one participant (per percentage point increase: aOR, 1.10; 95% CI, 1.05-1.15). The number of randomised patients declined with time from GP enrolment to first randomisation. CONCLUSION: General practice can be a rich environment for research when barriers to recruitment are overcome. Including regional GPs and focusing efforts in areas with the highest proportions of potentially eligible participants improves recruitment. The success of ASPREE attests to the clinical importance of its research question for Australian GPs.

Evaluating recruitment strategies for AUSPICE, a large Australian community-based randomised controlled trial.

OBJECTIVES: To examine the effectiveness of different strategies for recruiting participants for a large Australian randomised controlled trial (RCT), the Australian Study for the Prevention through Immunisation of Cardiovascular Events (AUSPICE). DESIGN, SETTING, PARTICIPANTS: Men and women aged 55-60 years with at least two cardiovascular risk factors (hypertension, hypercholesterolaemia, overweight/obesity) were recruited for a multicentre placebo-controlled RCT assessing the effectiveness of 23-valent pneumococcal polysaccharide vaccine (23vPPV) for preventing cardiovascular events. METHODS: Invitations were mailed by the Australian Department of Human Services to people in the Medicare database aged 55-60 years; reminders were sent 2 weeks later. Invitees could respond in hard copy or electronically. Direct recruitment was supplemented by asking invitees to extend the invitation to friends and family (snowball sampling) and by Facebook advertising. MAIN OUTCOME: Proportions of invitees completing screening questionnaire and recruited for participation in the RCT. RESULTS: 21 526 of 154 992 invited people (14%) responded by completing the screening questionnaire, of whom 4725 people were eligible and recruited for the study. Despite the minimal study burden (one questionnaire, one clinic visit), the overall participation rate was 3%, or an estimated 10% of eligible persons. Only 16% of eventual participants had responded within 2 weeks of the initial invitation letter (early responders); early and late responders did not differ in their demographic or medical characteristics. Socio-economic disadvantage did not markedly influence response rates. Facebook advertising and snowball sampling did not increase recruitment. CONCLUSIONS: Trial participation rates are low, and multiple concurrent methods are needed to maximise recruitment. Social media strategies may not be successful in older age groups. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry, ACTRN12615000536561.

Methodologic Quality and Statistical Reporting of Physical Therapy Randomized Controlled Trials Relevant to Musculoskeletal Conditions.

OBJECTIVES: To investigate the methodologic quality and statistical reporting of reports of trials indexed on the Physiotherapy Evidence Database (PEDro) classified in the musculoskeletal subdiscipline, and to analyze the characteristics of the trials that can predict trial report quality. DESIGN: Cross-sectional study based on a collection of randomized controlled trials. We randomly selected 19% of trials coded as musculoskeletal from PEDro. Methodologic quality was assessed using the PEDro scale. We assessed aspects of the trial using 9 items from the Consolidated Standards of Reporting Trials (CONSORT) statement. We performed multivariate linear regression analysis models to predict the total PEDro score. SETTING: Not applicable. PARTICIPANTS: Not applicable. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Not applicable. RESULTS: A total of 1404 articles were included in the analysis. The mean total PEDro scale score was 5.27±1.63 points, which reflects low methodologic quality. There was a slight improvement in the quality of articles over time. The characteristics that predicted the total PEDro scale score were endorsement of the CONSORT statement, sample size calculation, lower number of primary outcomes, evaluation of electrotherapy as intervention, if the trial reported the research design in the title, reporting of participant flow diagram, years since publication (most recent trials), and trials published in English. CONCLUSIONS: The quality of the trials in musculoskeletal physical therapy is suboptimal. The use of reporting checklists (eg, CONSORT statement) should be mandatory in all journals. Journal reviewers and journal editors should also use the CONSORT statement during the review process.

Evidence for Dry Needling in the Management of Myofascial Trigger Points Associated With Low Back Pain: A Systematic Review and Meta-Analysis.

OBJECTIVE: To evaluate the current evidence of the effectiveness of dry needling of myofascial trigger points (MTrPs) associated with low back pain (LBP). DATA SOURCES: PubMed, Ovid, EBSCO, ScienceDirect, Web of Science, Cochrane Library, CINAHL, and China National Knowledge Infrastructure databases were searched until January 2017. STUDY SELECTION: Randomized controlled trials (RCTs) that used dry needling as the main treatment and included participants diagnosed with LBP with the presence of MTrPs were included. DATA EXTRACTION: Two reviewers independently screened articles, scored methodologic quality, and extracted data. The primary outcomes were pain intensity and functional disability at postintervention and follow-up. DATA SYNTHESIS: A total of 11 RCTs involving 802 patients were included in the meta-analysis. Results suggested that compared with other treatments, dry needling of MTrPs was more effective in alleviating the intensity of LBP (standardized mean difference [SMD], -1.06; 95% confidence interval [CI], -1.77 to -0.36; P=.003) and functional disability (SMD, -0.76; 95% CI, -1.46 to -0.06; P=.03); however, the significant effects of dry needling plus other treatments on pain intensity could be superior to dry needling alone for LBP at postintervention (SMD, 0.83; 95% CI, 0.55-1.11; P<.00001). CONCLUSIONS: Moderate evidence showed that dry needling of MTrPs, especially if associated with other therapies, could be recommended to relieve the intensity of LBP at postintervention; however, the clinical superiority of dry needling in improving functional disability and its follow-up effects still remains unclear.

Randomised clinical trials in perinatal health care: a cost-effective investment.

OBJECTIVE: To compare the health and economic impacts of implementing efficacious treatment interventions with maintaining standard practice in maternal and perinatal health care. DESIGN AND SETTING: We identified randomised clinical trials (RCTs) in the Perinatal Society of Australia and New Zealand trials database that commenced recruitment during 2008 and had completed recruitment by 2015. Data from clinical trial registries and publications were collated to calculate the potential cost savings achievable by implementing efficacious treatment interventions. MAIN OUTCOME MEASURE: Projected net cost savings over 5 years. RESULTS: Twenty-three eligible RCTs covering a range of behavioural and clinical interventions were identified, of which six reported interventions superior to standard practice (four trials) or placebo (two). The outcomes (but not the costs) of 17 trials were excluded from analysis (no difference between intervention and comparator groups in seven trials, recruitment problems in six, findings not yet published in four). The total funding amount for the 23 trials was $20.3 million; the potential cost savings over 5 years if the findings of the six trials reporting superior interventions were implemented was estimated to be $26.3 million if 10% of the eligible populations received the effective interventions, and $262.8 million with 100% implementation. CONCLUSIONS: Our retrospective analysis highlights the value of research in perinatal care and the importance of implementing positive findings for realising its value. Future trials in maternal and perinatal health care may provide significant returns on investment by informing clinical practice, improving patient outcomes and reducing health care costs.

Rural providers' access to online resources: a randomized controlled trial.

OBJECTIVE: The research determined the usage and satisfaction levels with one of two point-of-care (PoC) resources among health care providers in a rural state. METHODS: In this randomized controlled trial, twenty-eight health care providers in rural areas were stratified by occupation and region, then randomized into either the DynaMed or the AccessMedicine study arm. Study participants were physicians, physician assistants, and nurses. A pre- and post-study survey measured participants' attitudes toward different information resources and their information-seeking activities. Medical student investigators provided training and technical support for participants. Data analyses consisted of analysis of variance (ANOVA), paired t tests, and Cohen's d statistic to compare pre- and post-study effects sizes. RESULTS: Participants in both the DynaMed and the AccessMedicine arms of the study reported increased satisfaction with their respective PoC resource, as expected. Participants in both arms also reported that they saved time in finding needed information. At baseline, both arms reported too little information available, which increased to "about right amounts of information" at the completion of the study. DynaMed users reported a Cohen's d increase of +1.50 compared to AccessMedicine users' reported use of 0.82. DynaMed users reported d2 satisfaction increases of 9.48 versus AccessMedicine satisfaction increases of 0.59 using a Cohen's d. CONCLUSION: Participants in the DynaMed arm of the study used this clinically oriented PoC more heavily than the users of the textbook-based AccessMedicine. In terms of user satisfaction, DynaMed users reported higher levels of satisfaction than the users of AccessMedicine.