Incretin mimetics have been called "the darlings of diabetes treatment" and they may soon also be licensed for treating obesity. But a BMJ investigation has found growing safety concerns linked to the drugs' mechanism of action. Deborah Cohen asks why patients and doctors have not been told.
Psychosis, even in its early stages, is associated with significant disability, causing it to be ranked ahead of paraplegia and blindness in those aged 18-35 in terms of years lived with disability. Current pharmacological and psychological interventions intervention have focused primarily on the reduction of positive symptoms (hallucinations and delusions), with little benefit to domains of psychosis such as cognitive difficulties and social and occupational functioning.The CReSt-R intervention trial is a single center, pilot randomised controlled study based at the National University of Ireland (NUI), Galway. The trial will recruit participants from four clinical sites with assessment and intervention completed by the primary NUI Galway team. The trial will explore the feasibility, acceptability, and effectiveness of a novel psychosocial intervention for early psychosis based on a combined cognitive remediation training and cognitive behavioural therapy approach focused on social recovery. Participants, aged 16-35 within the first 5 years of a diagnosed psychotic disorder, will be recruited from the Children and Adolescent Mental Health Service and the Adult Mental Health Services in the region.Cognitive remediation training (for improving cognition) and social recovery focused cognitive behavioural therapy, have both separately demonstrated effectiveness. This trial will evaluate the feasibility, acceptability, and explore the efficacy of a treatment approach that combines both approaches as part of an integrated, multicomponent intervention.Cognitive Remediation & Social Recovery in Early Psychosis (CReSt-R): ClincialTrials.gov Identifier NCT04273685. Trial registered Feb 18th, 2020. Last updated April 14th, 2021.
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Since 2004, we have developed five phase II trials in Chronic Lymphocytic Leukaemia (CLL), utilising six different statistical methods. Two of the trials have closed to recruitment, two are currently open and a further one is in development. The rationale behind the different designs chosen for each trial will be explained. Difficulties and learning experiences with the implementation, wider understanding and interpretation of the trials will be discussed.
CLL201 used Gehan’s two-stage approach to assess response, and randomised to a control arm which was not included for formal comparison, but to give validity of the study results. Challenges included the timing of the stage I analysis without halting recruitment, and the temptation to formally compare the two arms even though there was not power to do so. The inclusion of the control arm proved to be valuable since the response rates were not as expected.
CLL207 is a single arm trial designed using Bryant and Day’s two-stage design, incorporating toxicity considerations as well as efficacy. The two-stage aspect worked well in this trial due to the short treatment duration and assessment time. However, implementation was difficult due to the definitions of unacceptable toxicity and unacceptability bounds, and the overlap with the role of the Data Monitoring Committee.
ARCTIC and ADMIRE are two large, randomised phase IIb trials, both formally powered to compare responses against a common control arm. One of the trials assesses non-inferiority. Difficulties were experienced in convincing reviewers that these were not underpowered phase III trials. This design was necessary for the non-inferiority question, as it provides an acceptable certainty of finding the treatment inferior in terms of response before proceeding to a much larger trial to assess longer-term endpoints.
COSMIC is a randomised selection design with two experimental arms. The A’Hern one-stage design is used to determine which of the treatments are eligible to be taken forward for further investigation. In the case where both are acceptable, Sargent & Goldberg’s selection criteria will be applied to determine whether to take forward the treatment with better response rate, or to use alternative selection criteria. The sample size was inflated to ensure acceptable power for selecting the best treatment.
Governments around the world stockpiled oseltamivir for a flu pandemic despite uncertainty about its harms. Deborah Cohen investigates what the regulators knew and whether their response was adequate
Doctors, commissioners, and drug safety experts have criticised the UK General Medical Council for a lack of transparency over its prescribing guidance and for conflating European laws governing drug marketing with laws governing drug prescribing.
The criticism came after a BMJ investigation showed that ophthalmologists in the United Kingdom were loth to prescribe the cheap and effective drug bevacizumab (Avastin) for wet age related macular degeneration rather than the more expensive ranibizumab (Lucentis), out of fear of legal action.1
Their reluctance to prescribe the cheaper drug arises from guidance issued by the GMC, which says that doctors should not prescribe an “unlicensed” drug when there is a licensed alternative and that they should not prescribe a drug for an indication or condition for which it hasn’t a licence (off-label prescribing).
The GMC maintains its position despite the fact that a Cochrane review has found that the cheaper drug was just as effective as the more expensive one.
Writing …
Background: The Chronic Care Model (CCM) was developed to improve chronic disease care, but it may also inform delivery of other types of preventive care. Using hierarchical analyses of service delivery to patients, we explored associations of CCM implementation with diabetes care and counseling for diet or weight loss and physical activity in community-based primary care offices. Methods: Secondary analysis focused on baseline data from 25 practices (with an average of 4 physicians per practice) participating in an intervention trial targeting improved colorectal cancer screening rates. This intervention made no reference to the CCM. CCM implementation was measured through staff and clinical management surveys and was associated with patient care indicators (chart audits and patient questionnaires). Results: Overall, practices had low levels of CCM implementation. However, higher levels of CCM implementation were associated with better diabetes assessment and treatment of patients (P = .009 and .015, respectively), particularly among practices open to "innovation." Physical activity counseling for obese and, particularly, overweight patients was strongly associated with CCM implementation (P = .0017), particularly among practices open to "innovation"; however, this association did not hold for overweight and obese patients with diabetes. Conclusions: Very modest levels of CCM implementation in unsupported primary care practices are associated with improved care for patients with diabetes and higher rates of behavioral counseling. Incremental incorporation of CCM components is an option, especially for community practices with stretched resources and with cultures of "innovativeness."
Doctors in England's NHS have been left seemingly unable to prescribe a cheap, safe, and effective drug despite its flourishing use elsewhere in Europe and the US. In the first of a two part investigation Deborah Cohen examines which agencies are responsible, whether commissioners and prescribers actually have more freedom to use intravitreal bevacizumab than might at first seem to be the case, and whether the UK's drug marketing authorisation system really acts in the best interests of public health
Objectives To evaluate the effect of training primary care health professionals in behaviour change counselling on the proportion of patients self reporting change in four risk behaviours (smoking, alcohol use, exercise, and healthy eating). Design Cluster randomised trial with general practices as the unit of randomisation. Setting General practices in Wales. Participants 53 general practitioners and practice nurses from 27 general practices (one each at all but one practice) recruited 1827 patients who screened positive for at least one risky behaviour. Intervention Behaviour change counselling was developed from motivational interviewing to enable clinicians to enhance patients’ motivation to change health related behaviour. Clinicians were trained using a blended learning programme called Talking Lifestyles. Main outcome measures Proportion of patients who reported making beneficial changes in at least one of the four risky behaviours at three months. Results 1308 patients from 13 intervention and 1496 from 14 control practices were approached: 76% and 72% respectively agreed to participate, with 831 (84%) and 996 (92%) respectively screening eligible for an intervention. There was no effect on the primary outcome (beneficial change in behaviour) at three months (362 (44%) v 404 (41%), odds ratio 1.12 (95% CI 0.90 to 1.39)) or on biochemical or biometric measures at 12 months. More patients who had consulted with trained clinicians recalled consultation discussion about a health behaviour (724/795 (91%) v 531/966 (55%), odds ratio 12.44 (5.85 to 26.46)) and intended to change (599/831 (72%) v 491/996 (49%), odds ratio 2.88 (2.05 to 4.05)). More intervention practice patients reported making an attempt to change (328 (39%) v 317 (32%), odds ratio 1.40 (1.15 to 1.70)), a sustained behaviour change at three months (288 (35%) v 280 (28%), odds ratio 1.36 (1.11 to 1.65)), and reported slightly greater improvements in healthy eating at three and 12 months, plus improved activity at 12 months. Training cost £1597 per practice. Discussion Training primary care clinicians in behaviour change counselling using a brief blended learning programme did not increase patients reported beneficial behaviour change at three months or improve biometric and a biochemical measure at 12 months, but it did increase patients’ recollection of discussing behaviour change with their clinicians, intentions to change, attempts to change, and perceptions of having made a lasting change at three months. Enduring behaviour change and improvements in biometric measures are unlikely after a single routine consultation with a clinician trained in behaviour change counselling without additional intervention. Trial registration ISRCTN 22495456
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