Study protocol for "Moving bright, eating smart"- a phase 2 clinical trial on the acceptability and feasibility of a diet and physical activity intervention to prevent recurrence in colorectal cancer survivors

Background: Colorectal cancer is the second most common cancer and cancer-killer in Hong Kong with an alarming increasing incidence in recent years. The latest World Cancer Research Fund report concluded that foods low in fibre, and high in red and processed meat cause colorectal cancer whereas physical activity protects against
colon cancer. Yet, the influence of these lifestyle factors on cancer outcome is largely unknown even though cancer survivors are eager for lifestyle modifications. Observational studies suggested that low intake of a Western-pattern diet and high physical activity level reduced colorectal cancer mortality. The Theory of Planned
Behaviour and the Health Action Process Approach have guided the design of intervention models targeting a wide range of health-related behaviours.
Methods/design: We aim to demonstrate the feasibility of two behavioural interventions intended to improve colorectal cancer outcome and which are designed to increase physical activity level and reduce consumption of a Western-pattern diet. This three year study will be a multicentre, randomised controlled trial in a 2x2 factorial
design comparing the “Moving Bright, Eating Smart” (physical activity and diet) programme against usual care. Subjects will be recruited over a 12-month period, undertake intervention for 12 months and followed up for a further 12 months. Baseline, interim and three post-intervention assessments will be conducted. Two hundred and twenty-two colorectal cancer patients who completed curative treatment without evidence of recurrence will be recruited into the study. Primary outcome measure will be whether physical activity and dietary targets are met at the end of the 12-month intervention. Secondary outcome measures include the magnitude and
mechanism of behavioural change, the degree and determinants of compliance, and the additional health benefits and side effects of the intervention.
Discussion: The results of this study will establish the feasibility of targeting the two behaviours (diet and physical activity) and demonstrate the magnitude of behaviour change. The information will facilitate the design of a further larger phase III randomised controlled trial with colorectal cancer outcome as the study endpoint to determine whether this intervention model would reduce colorectal cancer recurrence and mortality.

DSM-5 mixed specifier for manic episodes: evaluating the effect of depressive features on severity and treatment outcome using asenapine clinical trial data

Background:
To describe the frequency of mixed specifier as proposed in DSM-5 in bipolar I patients with manic episodes, and to evaluate the effect of mixed specifier on symptom severity and treatment outcome.

Methods:
This post-hoc analysis used proxies for DSM-5 mixed features specifier by using MADRS or PANSS items.

Results:
Of the 960 patients analysed, 34%, 18% and 4.3% of patients, respectively, had ≥3 depressive features with mild (score ≥1 for MADRS items and ≥2 for PANSS item), moderate (score ≥2 MADRS, ≥3 PANSS) and severe (score ≥3 MADRS, ≥4 PANSS) symptoms. In patients with ≥3 depressive features and independent of treatment: MADRS remission (score ≤12) rate decreased with increasing severity (61–43%) and YMRS remission (score ≤12) was similar for mild and moderate patients (36–37%), but higher for severe (54%). In asenapine-treated patients, the MADRS remission rate was stable regardless of baseline depressive symptom severity (range 64–67%), whereas remission decreased with increasing severity with olanzapine (63–38%) and placebo (49–25%). Reduction in YMRS was significantly greater for asenapine compared with placebo at day 2 across the 3 severity cut-offs and continued to decrease throughout the treatment period. The difference between olanzapine and placebo was statistically significant in mild and moderate patients.

Limitations:
Results are from post-hoc analyses.

Conclusions:
These analyses support the validity of proposed DSM-5 criteria. They confirm that depressive features are frequent in bipolar patients with manic episodes. With increasing baseline severity of depressive features, treatment outcome was poorer with olanzapine and placebo, but remained stable with asenapine.

N-acetylcysteine versus placebo for treating nail biting, a double blind randomized placebo controlled clinical trial

Nail biting is a common behavioral problem. While there are established behavioral interventions for management, they are of modest efficacy, and there is minimal evidence for effective pharmacotherapy. This study investigated the role of N-acetylcysteine (NAC) a potent glutathione and glutamate modulator for the treatment of pathological nail biting in children and adolescents. This pilot randomized, double-blind, placebo-controlled clinical trial of NAC (800mg/day) or placebo enrolled 42 children and adolescents with chronic nail biting. Nail length was the objective outcome. Evaluations were carried out three times; before treatment, one month after enrollment in the study, and two months after enrollment. The duration (chronicity) of nail biting in the NAC and placebo groups was 3.63(2.45) and 5.09(3.74) years (P=0.14). The mean nail length gradually increased in both the NAC and placebo groups during this trial. There was a statistically significant difference between the two groups regarding increased nail length after the first month of trial [(5.21(5.75) and 1.18(3.02) millimeters], however no difference after two months was observed. Two patients in the NAC group discontinued medication due to adverse events. One patient experienced headache, agitation, and social withdrawal, and another patient expressed severe aggression after taking medication and was withdrawn from the study. This study supports the hypothesis that NAC decreases nail biting behavior in children and adolescents over the short term. NAC is relatively well tolerated and severe adverse effects are rare. However, there was a high rate of dropout. Further studies with longer durations that build on these preliminary data are recommended.

The TFOS international workshop on contact lens discomfort : report of the subcommittee on clinical trial design and outcomes

The goal of this report is to review previously published clinical trials addressing contact lens discomfort (CLD) to identify appropriate trial design and outcome parameters to guide future clinical research that will characterize and investigate possible causes of CLD. A further goal is to identify possible confounding features of clinical trial design and performance in order to reduce bias in conduct of future trials or analysis of data from those trials.

A head-to-head comparison of aripiprazole and risperidone for safety and treating autistic disorders, a randomized double blind clinical trial

Aripiprazole and risperidone are the only FDA approved medications for treating irritability in autistic disorder, however there are no head-to-head data comparing these agents. This is the first prospective randomized clinical trial comparing the safety and efficacy of these two medications in patients with autism spectrum disorders. Fifty nine children and adolescents with autism spectrum disorders were randomized to receive either aripiprazole or risperidone for 2 months. The primary outcome measure was change in Aberrant Behavior Checklist (ABC) scores. Adverse events were assessed. Aripiprazole as well as risperidone lowered ABC scores during 2 months. The rates of adverse effects were not significantly different between the two groups. The safety and efficacy of aripiprazole (mean dose 5.5 mg/day) and risperidone (mean dose 1.12 mg/day) were comparable. The choice between these two medications should be on the basis of clinical equipoise considering the patient's preference and clinical profile.

Validity of 12-month falls recall in community-dwelling older women participating in a clinical trial

Objectives. To compare 12-month falls recall with falls reported prospectively on daily falls calendars in a clinical trial of women aged ≥70 years. Methods. 2,096 community-dwelling women at high risk of falls and/or fracture completed a daily falls calendar and standardised interviews when falls were recorded, for 12 months. Data were compared to a 12-month falls recall question that categorised falls status as “no falls,” “a few times,” “several,” and “regular” falls. Results. 898 (43%) participants reported a fall on daily falls calendars of whom 692 (77%) recalled fall(s) at 12 months. Participants who did not recall a fall were older (median 79.3 years versus 77.8 years, ). Smaller proportions of fallers who sustained an injury or accessed health care failed to recall a fall (all ). Among participants who recalled “no fall,” 85% reported zero falls on daily calendars. Few women selected falls categories of “several times” or “regular” (4.1% and 0.4%, resp.) and the sensitivity of these categories was low (30% to 33%). Simply categorising participants into fallers or nonfallers had 77% sensitivity and 94% specificity. Conclusion. For studies where intensive ascertainment of falls is not feasible, 12-month falls recall questions with fewer responses may be an acceptable alternative.

Using clinical trial data and linked administrative health data to reduce the risk of adverse events associated with the uptake of newly released drugs by older Australians: a model process

BACKGROUND: The study was undertaken to evaluate the contribution of a process which uses clinical trial data plus linked de-identified administrative health data to forecast potential risk of adverse events associated with the use of newly released drugs by older Australian patients. METHODS: The study uses publicly available data from the clinical trials of a newly released drug to ascertain which patient age groups, gender, comorbidities and co-medications were excluded in the trials. It then uses linked de-identified hospital morbidity and medications dispensing data to investigate the comorbidities and co-medications of patients who suffer from the target morbidity of the new drug and who are the likely target population for the drug. The clinical trial information and the linked morbidity and medication data are compared to assess which patient groups could potentially be at risk of an adverse event associated with use of the new drug. RESULTS: Applying the model in a retrospective real-world scenario identified that the majority of the sample group of Australian patients aged 65 years and over with the target morbidity of the newly released COX-2-selective NSAID rofecoxib also suffered from a major morbidity excluded in the trials of that drug, indicating a substantial potential risk of adverse events amongst those patients. This risk was borne out in post-release morbidity and mortality associated with use of that drug. CONCLUSIONS: Clinical trial data and linked administrative health data can together support a prospective assessment of patient groups who could be at risk of an adverse event if they are prescribed a newly released drug in the context of their age, gender, comorbidities and/or co-medications. Communication of this independent risk information to prescribers has the potential to reduce adverse events in the period after the release of the new drug, which is when the risk is greatest.Note: The terms 'adverse drug reaction' and 'adverse drug event' have come to be used interchangeably in the current literature. For consistency, the authors have chosen to use the wider term 'adverse drug event' (ADE).

Improving communication when seeking informed consent: a randomised controlled study of a computer-based method for providing information to prospective clinical trial participants

OBJECTIVE: To assess the efficacy, with respect to participant understanding of information, of a computer-based approach to communication about complex, technical issues that commonly arise when seeking informed consent for clinical research trials. DESIGN, SETTING AND PARTICIPANTS: An open, randomised controlled study of 60 patients with diabetes mellitus, aged 27-70 years, recruited between August 2006 and October 2007 from the Department of Diabetes and Endocrinology at the Alfred Hospital and Baker IDI Heart and Diabetes Institute, Melbourne. INTERVENTION: Participants were asked to read information about a mock study via a computer-based presentation (n = 30) or a conventional paper-based information statement (n = 30). The computer-based presentation contained visual aids, including diagrams, video, hyperlinks and quiz pages. MAIN OUTCOME MEASURES: Understanding of information as assessed by quantitative and qualitative means. RESULTS: Assessment scores used to measure level of understanding were significantly higher in the group that completed the computer-based task than the group that completed the paper-based task (82% v 73%; P = 0.005). More participants in the group that completed the computer-based task expressed interest in taking part in the mock study (23 v 17 participants; P = 0.01). Most participants from both groups preferred the idea of a computer-based presentation to the paper-based statement (21 in the computer-based task group, 18 in the paper-based task group). CONCLUSIONS: A computer-based method of providing information may help overcome existing deficiencies in communication about clinical research, and may reduce costs and improve efficiency in recruiting participants for clinical trials.

Clinical trial adaptation by matching evidence in complementary patient sub-groups of auxiliary blinding questionnaire responses

Clinical trial adaptation refers to any adjustment of the trial protocol after the onset of the trial. Such adjustment may take on various forms, including the change in the dose of administered medicines, the frequency of administering an intervention, the number of trial participants, or the duration of the trial, to name just some possibilities. The main goal is to make the process of introducing new medical interventions to patients more efficient, either by reducing the cost or the time associated with evaluating their safety and efficacy. The principal challenge, which is an outstanding research problem, is to be found in the question of how adaptation should be performed so as to minimize the chance of distorting the outcome of the trial. In this paper we propose a novel method for achieving this. Unlike most of the previously published work, our approach focuses on trial adaptation by sample size adjustment i.e. by reducing the number of trial participants in a statistically informed manner. We adopt a stratification framework recently proposed for the analysis of trial outcomes in the presence of imperfect blinding and based on the administration of a generic auxiliary questionnaire that allows the participants to express their belief concerning the assigned intervention (treatment or control). We show that this data, together with the primary measured variables, can be used to make the probabilistically optimal choice of the particular sub-group a participant should be removed from if trial size reduction is desired. Extensive experiments on a series of simulated trials are used to illustrate the effectiveness of our method.

Academic outcomes 2 years after working memory training for children with low working memory: a randomized clinical trial

IMPORTANCE: Working memory training may help children with attention and learning difficulties, but robust evidence from population-level randomized controlled clinical trials is lacking.

OBJECTIVE: To test whether a computerized adaptive working memory intervention program improves long-term academic outcomes of children 6 to 7 years of age with low working memory compared with usual classroom teaching.

DESIGN, SETTING, AND PARTICIPANTS: Population-based randomized controlled clinical trial of first graders from 44 schools in Melbourne, Australia, who underwent a verbal and visuospatial working memory screening. Children were classified as having low working memory if their scores were below the 15th percentile on either the Backward Digit Recall or Mister X subtest from the Automated Working Memory Assessment, or if their scores were below the 25th percentile on both. These children were randomly assigned by an independent statistician to either an intervention or a control arm using a concealed computerized random number sequence. Researchers were blinded to group assignment at time of screening. We conducted our trial from March 1, 2012, to February 1, 2015; our final analysis was on October 30, 2015. We used intention-to-treat analyses.

INTERVENTION: Cogmed working memory training, comprising 20 to 25 training sessions of 45 minutes' duration at school.

MAIN OUTCOMES AND MEASURES: Directly assessed (at 12 and 24 months) academic outcomes (reading, math, and spelling scores as primary outcomes) and working memory (also assessed at 6 months); parent-, teacher-, and child-reported behavioral and social-emotional functioning and quality of life; and intervention costs.

RESULTS: Of 1723 children screened (mean [SD] age, 6.9 [0.4] years), 226 were randomized to each arm (452 total), with 90% retention at 1 year and 88% retention at 2 years; 90.3% of children in the intervention arm completed at least 20 sessions. Of the 4 short-term and working memory outcomes, 1 outcome (visuospatial short-term memory) benefited the children at 6 months (effect size, 0.43 [95% CI, 0.25-0.62]) and 12 months (effect size, 0.49 [95% CI, 0.28-0.70]), but not at 24 months. There were no benefits to any other outcomes; in fact, the math scores of the children in the intervention arm were worse at 2 years (mean difference, -3.0 [95% CI, -5.4 to -0.7]; P = .01). Intervention costs were A$1035 per child.

CONCLUSIONS AND RELEVANCE: Working memory screening of children 6 to 7 years of age is feasible, and an adaptive working memory training program may temporarily improve visuospatial short-term memory. Given the loss of classroom time, cost, and lack of lasting benefit, we cannot recommend population-based delivery of Cogmed within a screening paradigm.

Effect of adjunctive raloxifene therapy on severity of refractory schizophrenia in women: a randomized clinical trial

IMPORTANCE: A substantial proportion of women with schizophrenia experience debilitating treatment-refractory symptoms. The efficacy of estrogen in modulating brain function in schizophrenia has to be balanced against excess exposure of peripheral tissue. Raloxifene hydrochloride is a selective estrogen receptor modulator (mixed estrogen agonist/antagonist) with potential psychoprotective effects and fewer estrogenic adverse effects. OBJECTIVE: To determine whether adjunctive raloxifene therapy reduces illness severity in women with refractory schizophrenia. DESIGN, SETTING, AND PARTICIPANTS: This 12-week, double-blind, placebo-controlled, randomized clinical trial with fortnightly assessments was performed at an urban tertiary referral center and a regional center from January 1, 2006, to December 31, 2014. Participants included 56 women with schizophrenia or schizoaffective disorder and marked symptom severity despite substantial and stable antipsychotic doses. Data were analyzed using intention to treat as the basis. INTERVENTIONS: Adjunctive raloxifene hydrochloride, 120 mg/d, or placebo for 12 weeks. MAIN OUTCOMES AND MEASURES: The primary outcome was the change in the Positive and Negative Syndrome Scale (PANSS) total score. Clinical response (defined as a ≥20% decrease in PANSS total score from baseline) and change in PANSS subscale scores, mood, cognition, reproductive hormone levels, and adverse events were also assessed. RESULTS: Of the 56 participants (mean [SD] age, 53 [7.7] years; age range, 40-70 years; mean [SD] duration of psychotic illness, 24 [11] years), 26 were randomized to raloxifene and 30 were randomized to placebo. Raloxifene produced a greater reduction in the PANSS total score relative to placebo (β = -6.37; 95% CI, -11.64 to -1.10; P = .02) and resulted in an increased probability of a clinical response (hazard ratio, 5.79; 95% CI, 1.46 to 22.97; P = .01). A significant reduction was found in the PANSS general symptom scores for the raloxifene compared with the placebo (β = -3.72; 95% CI, -6.83 to -0.61; P = .02) groups. For patients who completed the full 12-week trial, there was not a statistically significant treatment effect on PANSS positive symptom scores (β for change in raloxifene vs placebo, -1.92; 95% CI, -3.83 to 0.00; P = .05). Change in mood, cognition, and reproductive hormone levels and the rate of adverse events did not differ between groups. CONCLUSIONS AND RELEVANCE: Raloxifene hydrochloride, 120 mg/d, reduces illness severity and increases the probability of a clinical response in women with refractory schizophrenia. This large trial of raloxifene in this patient population offers a promising, well-tolerated agent that has potential application in clinical practice. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00361543.

Safety and efficacy of routine postoperative ibuprofen for pain and disability related to ectopic bone formation after hip replacement surgery (HIPAID): a randomised control trial

Objectives To determine the benefits and risks of a non-steroidal anti-inflammatory drug (NSAID) as prophylaxis for ectopic bone formation in patients undergoing total hip replacement (or revision) surgery.
Design Double blind randomised placebo controlled clinical trial, stratified by treatment site and surgery (primary or revision).
Setting 20 orthopaedic surgery centres in Australia and New Zealand.
Participants 902 patients undergoing elective primary or revision total hip replacement surgery.
Intervention 14 days' treatment with ibuprofen (1200 mg daily) or matching placebo started within 24 hours of surgery.
Main outcome measures Changes in self reported hip pain and physical function 6 to 12 months after surgery (Western Ontario and McMaster University Arthritis index).
Results There were no significant differences between the groups for improvements in hip pain (mean difference -0.1, 95% confidence interval -0.4 to 0.2, P = 0.6) or physical function (-0.1, -0.4 to 0.2, P = 0.5), despite a decreased risk of ectopic bone formation (relative risk 0.69, 0.56 to 0.83) associated with ibuprofen. There was a significantly increased risk of major bleeding complications in the ibuprofen group during the admission period (2.09, 1.00 to 4.39).
Conclusions These data do not support the use of routine prophylaxis with NSAIDs in patients undergoing total hip replacement surgery.
Trial registration NCT00145730.

Reconceptualising the objectives of a pilot study for clinical research

This is a methodological study in which a case report is used to retrospectively analyse the link between a successful pilot study and stalled main study to identify potential methodological weaknesses in the planning process. The analysis identified unanticipated influences related to hospital processes and discipline boundaries that adversely influenced participant recruitment and retention for a clinical trial. The findings of the study demonstrate that, whilst the pilot is an important step in research planning to confirm the design and operational processes for a study, a thorough analysis of the relevant health service environment is an important additional objective for the pilot study.