Trial discontinuation: lessons for future trial design?

Background: The current therapeutic arsenal still does not fulfill the therapeutic needs of inflammatory bowel disease patients. Although new drugs are constantly being developed, many will never reach the market. In this review we will search for reasons for discontinuing promising clinical trials and offer recommendation for future trials. Methods: The website clinicaltrials.gov was searched for interventional trials on novel inflammatory bowel disease therapies. Included were discontinued ‘Crohn’s disease’ and/or ‘colitis, ulcerative’ trials, started between July 1996 and October 2011 and discontinued. Pubmed was searched for publications to elucidate reasons for discontinuation. Results: One hundred and ninety one novel drug trials were published on clinicaltrials. gov, of which 24 (12.6%) were interrupted. The most common reason for discontinuation was lack of efficacy. Conclusion: Translation from bench to bedside is not always feasible, animal models come with restrictions. For better treatments, personalized medicine will be the future

Multicentre randomised controlled trial of nasal diamorphine for analgesia in children and teenagers with clinical fractures.

OBJECTIVE: To compare the effectiveness of nasal diamorphine spray with intramuscular morphine for analgesia in children and teenagers with acute pain due to a clinical fracture, and to describe the safety profile of the spray. DESIGN: Multicentre randomised controlled trial. SETTING: Emergency departments in eight UK hospitals. PARTICIPANTS: Patients aged between 3 and 16 years presenting with a clinical fracture of an upper or lower limb. MAIN OUTCOME MEASURES: Patients' reported pain using the Wong Baker face pain scale, ratings of reaction to treatment of the patients and acceptability of treatment by staff and parents, and adverse events. RESULTS: 404 eligible patients completed the trial (204 patients given nasal diamorphine spray and 200 given intramuscular morphine). Onset of pain relief was faster in the spray group than in the intramuscular group, with lower pain scores in the spray group at 5, 10, and 20 minutes after treatment but no difference between the groups after 30 minutes. 80% of patients given the spray showed no obvious discomfort compared with 9% given intramuscular morphine (difference 71%, 95% confidence interval 65% to 78%). Treatment administration was judged acceptable by staff and parents, respectively, for 98% (199 of 203) and 97% (186 of 192) of patients in the spray group compared with 32% (64 of 199) and 72% (142 of 197) in the intramuscular group. No serious adverse events occurred in the spray group, and the frequencies of all adverse events were similar in both groups (spray 24.1% v intramuscular morphine 18.5%; difference 5.6%, -2.3% to 13.6%). CONCLUSION: Nasal diamorphine spray should be the preferred method of pain relief in children and teenagers presenting to emergency departments in acute pain with clinical fractures. The diamorphine spray should be used in place of intramuscular morphine

Kinematics Comparison between Dominant and Non-Dominant Lower Limbs in Thai Boxing

Muay Thai, also known as Thai Boxing, is Thailand\u27s national sport, and it involves athletes using different stand-up striking and clinching techniques. There are a limited number of research studies that have examined Thai Boxing skills and specifically none have examined the kinematics of the dominant and non-dominant legs while in a double collar or double underhook clinching position. The purpose of the study was to investigate the kinematics of the dominant (right) and non-dominant leg (left) between the double collar and double underhook Thai Boxing clinching positions. Participants executed six continuous knee strikes with the dominant leg and non-dominant leg in each of the two clinching positions for twelve knee strikes. A standard two-dimensional video motion analysis was conducted. The results revealed statistical significant difference at the hip joint angle between both clinching positions (p = .013) but not at the knee and ankle joints. There were no statistical significant differences in the joint angular velocity and acceleration for the hip, knee, and ankle joint between both clinching positions. However, there was a statistical significant difference found in the joint angular velocity for the knee joint (p = 0.00) between the dominant and non-dominant leg. Lastly, there was a significant correlation of the joint angle (r = 0.65 and 0.63; double collar and double underhook) and the angular velocity (r = 0.76 and 0.67; double collar and double underhook) for the left and right knee between both clinching positions. In addition, there was a significant correlation of the joint angle between the left and right hip (r = 0.66) for the double collar position but not for the double underhook position. This study demonstrates the importance of hip joint flexibility and the angular velocity of the knee between the dominant and non-dominant leg. Future research studies investigating the impact of the knee at the point of contact in the Thai Boxing clinch positions among group of elite mixed martial arts athletes are warranted

AVERT2(a very early rehabilitation trial, a very effective reproductive trigger): retrospective observational analysis of the number of babies born to trial staff

Objective: To report the number of participants needed to recruit per baby born to trial staff during AVERT, a large international trial on acute stroke, and to describe trial management consequences. Design: Retrospective observational analysis. Setting: 56 acute stroke hospitals in eight countries. Participants: 1074 trial physiotherapists, nurses, and other clinicians. Outcome measures: Number of babies born during trial recruitment per trial participant recruited. Results: With 198 site recruitment years and 2104 patients recruited during AVERT, 120 babies were born to trial staff. Births led to an estimated 10% loss in time to achieve recruitment. Parental leave was linked to six trial site closures. The number of participants needed to recruit per baby born was 17.5 (95% confidence interval 14.7 to 21.0); additional trial costs associated with each birth were estimated at 5736 Australian dollars on average. Conclusion: The staff absences registered in AVERT owing to parental leave led to delayed trial recruitment and increased costs, and should be considered by trial investigators when planning research and estimating budgets. However, the celebration of new life became a highlight of the annual AVERT collaborators’ meetings and helped maintain a cohesive collaborative group

WISDOM: history and early demise - was it inevitable?

In 1989, the UK Medical Research Council (MRC) agreed that, if feasible, a randomized controlled trial to assess the long-term risks and benefits of hormone replacement therapy (HRT) was a priority. Feasibility work began in 1990 and demonstrated that a large-scale multicenter trial was possible. An application for funding for a main trial was submitted to MRC in 1993 and, after extensive review, funding was released in late 1996. Set-up work for the trial - the Women's International Study of long Duration Oestrogen after Menopause (WISDOM) - began in 1997 with recruitment in 1999. In October 2002, following the early discontinuation of one arm of the US Women's Health Initiative HRT trial, the MRC decided to stop the WISDOM trial. This article, by the principal UK investigators of WISDOM, sets out the background and history of the trial

Potential implications of practice effects in Alzheimer's disease prevention trials.

IntroductionPractice effects (PEs) present a potential confound in clinical trials with cognitive outcomes. A single-blind placebo run-in design, with repeated cognitive outcome assessments before randomization to treatment, can minimize effects of practice on trial outcome.MethodsWe investigated the potential implications of PEs in Alzheimer's disease prevention trials using placebo arm data from the Alzheimer's Disease Cooperative Study donepezil/vitamin E trial in mild cognitive impairment. Frequent ADAS-Cog measurements early in the trial allowed us to compare two competing trial designs: a 19-month trial with randomization after initial assessment, versus a 15-month trial with a 4-month single-blind placebo run-in and randomization after the second administration of the ADAS-Cog. Standard power calculations assuming a mixed-model repeated-measure analysis plan were used to calculate sample size requirements for a hypothetical future trial designed to detect a 50% slowing of cognitive decline.ResultsOn average, ADAS-Cog 13 scores improved at first follow-up, consistent with a PE and progressively worsened thereafter. The observed change for a 19-month trial (1.18 points) was substantively smaller than that for a 15-month trial with 4-month run-in (1.79 points). To detect a 50% slowing in progression under the standard design (i.e., a 0.59 point slowing), a future trial would require 3.4 times more subjects than would be required to detect the comparable percent slowing (i.e., 0.90 points) with the run-in design.DiscussionAssuming the improvement at first follow-up observed in this trial represents PEs, the rate of change from the second assessment forward is a more accurate representation of symptom progression in this population and is the appropriate reference point for describing treatment effects characterized as percent slowing of symptom progression; failure to accommodate this leads to an oversized clinical trial. We conclude that PEs are an important potential consideration when planning future trials