Effects of N-acetylcysteine on substance use in bipolar disorder : a randomized placebo controlled clinical trial

Objective: To evaluate the effect of N-acetylcysteine (NAC) on substance use in a double-blind, placebo-controlled trial of NAC in bipolar disorder. It is hypothesised that NAC will be superior to placebo for reducing scores on the Clinical Global Impressions scale for Substance Use (CGI-SU).

Methods: Participants were randomised to 6-months of treatment with 2 g/day NAC (n = 38) or placebo (n = 37). Substance use was assessed at baseline using the Habits instrument. Change in substance use was assessed at regular study visits using the CGI-SU.

Results: Amongst the 75 participants 78.7% drank alcohol (any frequency), 45.3% smoked tobacco and 92% consumer caffeine. Other substances were used by fewer than six participants. Caffeine use was significantly lower for NAC-treated participants compared with placebo at week 2 of treatment but not at other study visits.

Conclusion: NAC appeared to have little effect on substance use in this population. A larger study on a substance using population will be necessary to determine if NAC may be a useful treatment for substance use.

Falls and mobility in Parkinson’s disease : protocol for a randomised controlled clinical trial

Background Although physical therapy and falls prevention education are argued to reduce falls and disability in people with idiopathic Parkinson's disease, this has not yet been confirmed with a large scale randomised controlled clinical trial. The study will investigate the effects on falls, mobility and quality of life of (i) movement strategy training combined with falls prevention education, (ii) progressive resistance strength training combined with falls prevention education, (iii) a generic life-skills social program (control group).
Methods/Design People with idiopathic Parkinson's disease who live at home will be recruited and randomly allocated to one of three groups. Each person shall receive therapy in an out-patient setting in groups of 3-4. Each group shall be scheduled to meet once per week for 2 hours for 8 consecutive weeks. All participants will also have a structured 2 hour home practice program for each week during the 8 week intervention phase. Assessments will occur before therapy, after the 8 week therapy program, and at 3 and 12 months after the intervention. A falls calendar will be kept by each participant for 12 months after outpatient therapy. Consistent with the recommendations of the Prevention of Falls Network Europe group, three falls variables will be used as the primary outcome measures: the number of fallers, the number of multiple fallers and the falls rate. In addition to quantifying falls, we shall measure mobility, activity limitations and quality of life as secondary outcomes.
Discussion This study has the potential to determine whether outpatient movement strategy training combined with falls prevention education or progressive resistance strength training combined with falls prevention education are effective for reducing falls and improving mobility and life quality in people with Parkinson's disease who live at home.

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 validity and internal structure of the bipolar depression rating scale (BDRS): data from a clinical trial of N-acetylcysteine as adjunctive therapy in bipolar disorder

Background: The phenomenology of unipolar and bipolar disorders differ in a number of ways, such as the presence of mixed states and atypical features. Conventional depression rating instruments are designed to capture the characteristics of unipolar depression and have limitations in capturing the breadth of bipolar disorder.

Method: The Bipolar Depression Rating Scale (BDRS) was administered together with the Montgomery Asberg Rating Scale (MADRS) and Young Mania Rating Scale (YMRS) in a double-blind randomised placebo-controlled clinical trial of N-acetyl cysteine for bipolar disorder (N = 75).

Results: A factor analysis showed a two-factor solution: depression and mixed symptom clusters. The BDRS has strong internal consistency (Cronbach's alpha = 0.917), the depression cluster showed robust correlation with the MADRS (r = 0.865) and the mixed subscale correlated with the YMRS (r = 0.750).

Conclusion: The BDRS has good internal validity and inter-rater reliability and is sensitive to change in the context of a clinical trial.

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.

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.

Single vs. two steroid injections for carpal tunnel syndrome: a randomised clinical trial

We investigated the efficacy of a single vs. double steroid injections in the treatment of carpal tunnel syndrome (CTS) in a randomised double-blind controlled trial. Patients with idiopathic CTS were randomised into (i) one group receiving a baseline methylprednisolone acetate injection plus a saline injection 8 weeks later and (ii) a second group receiving methylprednisolone acetate injection at baseline and at 8 weeks. The primary outcome was the Global Symptom Score (GSS). Forty patients were recruited. By 40 weeks, the mean GSS improved from 25.6 to 14.1 in the single-injection group whereas from 26.7 to 12.6 in the reinjection group, but there was no significant difference in GSS between the two groups (p = 0.26). There were also no significant differences in terms of electrophysiological and functional outcomes. The results suggest that an additional steroid injection confers no added benefit to a single injection in terms of symptom relief.

Getting your life back on track after stroke : a phase II multi-centered, single-blind, randomized, controlled trial of the Stroke Self-Management Program vs. the Stanford Chronic Condition Self-Management Program or standard care in stroke survivors

Background Self-management is seen as a primary mechanism to support the optimization of care for people with chronic diseases such as symptomatic vascular disease. There are no established and evidence-based stroke-specific chronic disease self-management programs. Our aim is to evaluate whether a stroke-specific program is safe and feasible as part of a Phase II randomized-controlled clinical trial.
Methods Stroke survivors are recruited from a variety of sources including: hospital stroke services, local paper advertisements, Stroke South Australia newsletter (volunteer peer support organization), Divisions of General Practice, and community service providers across Adelaide, South Australia. Subjects are invited to participate in a multi-center, single-blind, randomized, controlled trial. Eligible participants are randomized to either;
• standard care,
• standard care plus a six week generic chronic condition self-management group education program, or,
• standard care plus an eight week stroke specific self-management education group program.
Interventions are conducted after discharge from hospital. Participants are assessed at baseline, immediate post intervention and six months.
Study Outcomes The primary outcome measures determine study feasibility and safety, measuring, recruitment, participation, compliance and adverse events.
Secondary outcomes include:
• positive and active engagement in life measured by the Health Education Impact Questionnaire,
• improvements in quality of life measured by the Assessment of Quality of Life instrument,
• improvements in mood measured by the Irritability, Depression and Anxiety Scale,
• health resource utilization measured by a participant held diary and safety.

Conclusion The results of this study will determine whether a definitive Phase III efficacy trial is justified.

Trials and tribulations of recruiting 2,000 older women onto a clinical trial investigating falls and fractures : vital D study

Background Randomised, placebo-controlled trials are needed to provide evidence demonstrating safe, effective interventions that reduce falls and fractures in the elderly. The quality of a clinical trial is dependent on successful recruitment of the target participant group. This paper documents the successes and failures of recruiting over 2,000 women aged at least 70 years and at higher risk of falls or fractures onto a placebo-controlled trial of six years duration. The characteristics of study participants at baseline are also described for this study.

Methods The Vital D Study recruited older women identified at high risk of fracture through the use of an eligibility algorithm, adapted from identified risk factors for hip fracture. Participants were randomised to orally receive either 500,000 IU vitamin D3 (cholecalciferol) or placebo every autumn for five consecutive years. A variety of recruitment strategies were employed to attract potential participants.

Results Of the 2,317 participants randomised onto the study, 74% (n = 1716/2317) were consented onto the study in the last five months of recruiting. This was largely due to the success of a targeted mail-out. Prior to this only 541 women were consented in the 18 months of recruiting. A total of 70% of all participants were recruited as a result of targeted mail-out. The response rate from the letters increased from 2 to 7% following revision of the material by a public relations company. Participant demographic or risk factor profile did not differ between those recruited by targeted mail-outs compared with other methods.

Conclusion The most successful recruitment strategy was the targeted mail-out and the response rate was no higher in the local region where the study had extensive exposure through other recruiting strategies. The strategies that were labour-intensive and did not result in successful recruitment include the activities directed towards the GP medical centres. Comprehensive recruitment programs employ overlapping strategies simultaneously with ongoing assessment of recruitment rates. In our experience, and others direct mail-outs work best although rights to privacy must be respected.

Zinc for treating of children and adolescents with attention-deficit hyperactivity disorder : a systematic review of randomized controlled clinical trials

This study systematically reviews the randomized clinical trials examining the effect of zinc on attention-deficit hyperactivity disorder (ADHD), searching the PubMed/Medline and Scholar Google databases. All randomized controlled trials that examined zinc as the intervention, and ADHD as the primary outcome were included. Only three randomized controlled trials, one which included a community sample and two that included clinical samples, met inclusion criteria. The only trial that was well controlled and randomized according to the baseline zinc level showed that using zinc, either alone or in combination with stimulants, did not improve ADHD. Considering the lack of clear evidence for the effect of zinc on ADHD and the possible effect of zinc on the nervous system, more clinical studies are needed to prove or disprove the effect of zinc as a monotherapy or adjuvant therapy.

A new framework for interpreting the outcomes of imperfectly blinded controlled clinical trials

It is well known that the outcome of an intervention is affected both by the inherent effects of the intervention and the patient's expectations. For this reason in comparative clinical trials an effort is made to conceal the nature of the administered intervention from the participants in the trial i.e. to blind the trial. Yet, in practice perfect blinding is impossible to ensure or even verify post hoc. The current clinical standard is to follow up the trial with an auxiliary questionnaire, which allows trial participants to express in closed form their belief concerning the intervention, i.e. trial group assignment (treatment or control). Auxiliary questionnaire responses are then used to compute the extent of blinding in the trial in the form of a blinding index. If the estimated extent of blinding exceeds a particular threshold the trial is deemed sufficiently blinded; otherwise, the strength of evidence of the trial is brought into question. This may necessitate that the trial is repeated. In this paper we make several contributions. Firstly, we identify a series of problems of the aforesaid clinical practice and discuss them in context of the most commonly used blinding indexes. Secondly, we formulate a novel approach for handling imperfectly blinded trials. We adopt a feedback questionnaire of the same form as that which is currently in use, but interpret the collected data using a novel statistical method, significantly different from that proposed in the previous work. Unlike the previously proposed approaches, our method is void of any ad hoc free parameters and robust to small changes in the participants' feedback responses. Our method also does not discard any data and is not predicated on any strong assumptions used to interpret participants' feedback. The key idea behind the present method is that it is meaningful to compare only the corresponding treatment and control participant sub-groups, that is, sub-groups matched by their auxiliary responses. A series of experiments on simulated trials is used to demonstrate the effectiveness of the proposed approach and its superiority over those currently in use.

Cost effectiveness of preventing falls and improving mobility in people with Parkinson disease : protocol for an economic evaluation alongside a clinical trial

Background Cost of illness studies show that Parkinson disease (PD) is costly for individuals, the healthcare system and society. The costs of PD include both direct and indirect costs associated with falls and related injuries.
Methods This protocol describes a prospective economic analysis conducted alongside a randomised controlled trial (RCT). It evaluates whether physical therapy is more cost effective than usual care from the perspective of the health care system. Cost effectiveness will be evaluated using a three-way comparison of the cost per fall averted and the cost per quality adjusted life year saved across two physical therapy interventions and a control group.
Conclusion This study has the potential to determine whether targetted physical therapy as an adjunct to standard care can be cost effective in reducing falls in people with PD.