Tim Friede

Randomized, controlled trial of cannabis-based medicine in central pain in multiple sclerosis

Background: Central pain in multiple sclerosis (MS) is common and often refractory to treatment. Methods: We conducted a single-center, 5-week (1-week run-in, 4-week treatment), randomized, double-blind, placebo-controlled, parallel-group trial in 66 patients with MS and central pain states (59 dysesthetic, seven painful spasms) of a whole-plant cannabis-based medicine (CBM), containing delta-9-tetrahydrocannabinol:cannabidiol (THC:CBD) delivered via an oromucosal spray, as adjunctive analgesic treatment. Each spray delivered 2.7 mg of THC and 2.5 of CBD, and patients could gradually self-titrate to a maximum of 48 sprays in 24 hours. Results: Sixty-four patients (97%) completed the trial, 34 received CBM. In week 4, the mean number of daily sprays taken of CBM (n = 32) was 9.6 (range 2 to 25, SD = 6.0) and of placebo (n = 31) was 19.1 (range 1 to 47, SD = 12.9). Pain and sleep disturbance were recorded daily on an 11-point numerical rating scale. CBM was superior to placebo in reducing the mean intensity of pain (CBM mean change −2.7, 95% CI: −3.4 to −2.0, placebo –1.4 95% CI: −2.0 to −0.8, comparison between groups, p = 0.005) and sleep disturbance (CBM mean change –2.5, 95% CI: −3.4 to −1.7, placebo –0.8, 95% CI: −1.5 to −0.1, comparison between groups, p = 0.003). CBM was generally well tolerated, although more patients on CBM than placebo reported dizziness, dry mouth, and somnolence. Cognitive side effects were limited to long-term memory storage. Conclusions: Cannabis-based medicine is effective in reducing pain and sleep disturbance in patients with multiple sclerosis related central neuropathic pain and is mostly well tolerated.

Early angiotensin-converting enzyme inhibition in Alport syndrome delays renal failure and improves life expectancy.

Alport syndrome inevitably leads to end-stage renal disease and there are no therapies known to improve outcome. Here we determined whether angiotensin-converting enzyme inhibitors can delay time to dialysis and improve life expectancy in three generations of Alport families. Patients were categorized by renal function at the initiation of therapy and included 33 with hematuria or microalbuminuria, 115 with proteinuria, 26 with impaired renal function, and 109 untreated relatives. Patients were followed for a period whose mean duration exceeded two decades. Untreated relatives started dialysis at a median age of 22 years. Treatment of those with impaired renal function significantly delayed dialysis to a median age of 25, while treatment of those with proteinuria delayed dialysis to a median age of 40. Significantly, no patient with hematuria or microalbuminuria advanced to renal failure so far. Sibling pairs confirmed these results, showing that earlier therapy in younger patients significantly delayed dialysis by 13 years compared to later or no therapy in older siblings. Therapy significantly improved life expectancy beyond the median age of 55 years of the no-treatment cohort. Thus, Alport syndrome is treatable with angiotensin-converting enzyme inhibition to delay renal failure and therapy improves life expectancy in a time-dependent manner. This supports the need for early diagnosis and early nephroprotective therapy in oligosymptomatic patients.

Warwick-Edinburgh Mental Well-being Scale (WEMWBS): Validated for teenage school students in England and Scotland. A mixed methods assessment

BackgroundUnderstanding and measuring mental health and wellbeing amongst teenagers has recently become a priority. The Warwick-Edinburgh Mental Well-being Scale (WEMWBS) is validated for measuring mental wellbeing in populations aged 16 years and over in the UK. We report here a study designed to establish the validity and reliability of WEMWBS in teenagers in the UK.MethodsWEMWBS and comparator scales, together with socio-demographic information and self-reported health, were incorporated into a self-administered questionnaire given to pupils aged 13 to 16 years in six schools in Scotland and England. Psychometric properties including internal consistency, correlations with comparator scales, test-retest stability and unidimensionality were investigated for WEMWBS. Twelve focus groups were undertaken to assess acceptability and comprehensibility of WEMWBS and were taped, transcribed and analysed thematically.ResultsA total of 1,650 teenagers completed the questionnaire (response rate 80.8%). Mean WEMWBS score was 48.8 (SD 6.8; median 49). Response scores covered the full range (from 14 to 70). WEMWBS demonstrated strong internal consistency and a high Cronbachs alpha of 0.87 (95% CI (0.85-0.88), n = 1517). Measures of construct validity gave values as predicted. The correlation coefficient for WEMWBS total score and psychological wellbeing domain of the Kidscreen-27 was 0.59 (95% CI [0.55; 0.62]); for the Mental Health Continuum Short Form (MHC-SF) was 0.65, 95% CI [0.62; 0.69]; and for the WHO (WHO-5) Well-being Index 0.57 (95% CI [0.53; 0.61]). The correlation coefficient for the Strengths and Difficulties Questionnaire (SDQ) was -0.44 (95% CI [-0.49; -0.40]) and for the 12-item General Health Questionnaire (GHQ12) -0.45 (95% CI [-0.49; -0.40]). Test-retest reliability was acceptable (Intraclass correlation coefficient (ICC) 0.66 (95% CI [0.59; 0.72] n = 212)). Confirmatory factor analysis demonstrated one underlying factor.WEMWBS was significantly associated with the Family Affluence Score (WEMWBS increased with increasing household socio-economic status) and had a positive association with the physical health dimension of the Kidscreen-27, but was unrelated to age, gender or location/school. Eighty students took part in focus groups. In general, although some students considered some items open to misunderstanding or misinterpretation, WEMWBS was received positively and was considered comprehensible, and acceptable.ConclusionsWEMWBS is a psychometrically strong population measure of mental wellbeing, and can be used for this purpose in teenagers aged 13 and over.

Nonmotor and diagnostic findings in subjects with de novo Parkinson disease of the DeNoPa cohort

Objective: To determine nonmotor signs (NMS) and evaluate the utility of several diagnostic tools in patients with de novo Parkinson disease (PD). Methods: This is a large single-center study of the DeNoPa cohort, including frequency-matched healthy controls. This study covers motor signs, NMS, and a combination of diagnostic tests including olfactory testing, transcranial sonography of substantia nigra (TCS), and polysomnography (PSG). We report the frequency and characteristics of NMS and the outcomes of nonmotor tests at the time of diagnosis. Results: Cross-sectional analyses of baseline investigations identified significant differences in the NMS Questionnaire (NMSQuest) and the Scopa-AUT Gastrointestinal score in 159 drug-naïve PD patients vs 110 controls. In addition, patients with PD showed reduced olfactory function, hyperechogenicity on TCS, and higher frequency of REM sleep behavior disorder (RBD). In exploring predictive markers, we found that the combination of several investigations, i.e., the NMSQuest, Scopa-AUT Gastrointestinal score, and Smell Identification Test reached an area under the receiver operating characteristic curve (AUC) of 0.913 (95% confidence interval [CI] 0.878–0.948). With the addition of serum cholesterol and mean heart rate values, the AUC value reached 0.919 (95% CI 886–0.953); when TCS and PSG were added, the AUC increased to 0.963 (95% CI 0.943–0.982). Conclusions: We show feasibility and utility of standardized data acquisition in a large, single-center cohort of patients with de novo PD and matched healthy controls. The baseline results from our prospective investigations reached a value of >0.9 sensitivity and specificity for biological markers when we added routine laboratory investigations and quantified nonmotor features including sleep.

Telephone peer-delivered intervention for diabetes motivation and support: The telecare exploratory RCT

OBJECTIVE To test trial design issues related to measuring the effectiveness of a peer telephone intervention to enhance self-efficacy in type 2 diabetes; evaluate the impact on self-efficacy and clinical outcome; and describe patient and peer experience. METHODS Eligible patients had raised HbA1c (initial threshold >8%, reduced to >7.4% mid-way through trial). Patients were recruited from 40 general practices and randomised (40:40:20 ratio) to receive routine care alone or, in addition, motivational telephone support from a peer supporter or a diabetes specialist nurse (9 peers and 12 DSNs) for a period of up to 6 months. The primary outcome measure was self-efficacy score, and secondary outcome measures included HbA1c. Patient and telecare supporter satisfaction and experience were evaluated. RESULTS In all, 231 patients participated. At 6 months there were no statistically significant differences in self-efficacy scores (p=0.68), HbA1c (p=0.87) or other secondary outcome measures. There was evidence of a high level of acceptability, but peer telecare support was less highly valued than that from a DSN. Some patients stated that they would have valued more information and advice. CONCLUSIONS Further consideration needs to be given to the targeting of the telecare peer support, its intensity, the training and ongoing supervision of peer supporters, and the extent to which information and advice should be incorporated. PRACTICE IMPLICATIONS While some patients with poorly controlled type 2 diabetes value peer telephone support, this approach appears not to suit all patients. Further intervention development and evaluation is required before widespread adoption can be recommended.

A group‐sequential design for clinical trials with treatment selection

A group-sequential design for clinical trials that involve treatment selection was proposed by Stallard and Todd (Statist. Med. 2003; 22:689-703). In this design, the best among a number of experimental treatments is selected on the basis of data observed at the first of a series of interim analyses. This experimental treatment then continues together with the control treatment to be assessed in one or more further analyses. The method was extended by Kelly et al. (J. Biopharm. Statist. 2005; 15:641-658) to allow more than one experimental treatment to continue beyond the first interim analysis. This design controls the familywise type I error rate under the global null hypothesis, that is in the weak sense, but may not strongly control the error rate, particularly if the treatments selected are not the best-performing ones. In some cases, for example when additional safety data are available, the restriction that the best-performing treatments continue may be unreasonable. This paper describes an extension of the approach of Stallard and Todd that enables construction of a group-sequential design for comparison of several experimental treatments with a control treatment. The new method controls the type I error rate in the strong sense if the number of treatments included at each stage is specified in advance, and is indicated by simulation studies to be conservative when the number of treatments is chosen based on the observed data in a practically relevant way.

Pilot of 'Families for Health': community-based family intervention for obesity

Objective: To develop and evaluate “Families for Health”, a new community based family intervention for childhood obesity. Design: Programme development, pilot study and evaluation using intention-to-treat analysis. Setting: Coventry, England. Participants: 27 overweight or obese children aged 7–13 years (18 girls, 9 boys) and their parents, from 21 families. Intervention: Families for Health is a 12-week programme with parallel groups for parents and children, addressing parenting, lifestyle change and social and emotional development. Main outcome measures: Change in baseline BMI z score at the end of the programme (3 months) and 9-month follow-up. Attendance, drop-out, parents’ perception of the programme, child’s quality of life and self-esteem, parental mental health, parent–child relationships and lifestyle changes were also measured. Results: Attendance rate was 62%, with 18 of the 27 (67%) children completing the programme. For the 22 children with follow-up data (including four who dropped out), BMI z score was reduced by −0.18 (95% CI −0.30 to −0.05) at 3 months and −0.21 (−0.35 to −0.07) at 9 months. Statistically significant improvements were observed in children’s quality of life and lifestyle (reduced sedentary behaviour, increased steps and reduced exposure to unhealthy foods), child–parent relationships and parents’ mental health. Fruit and vegetable consumption, participation in moderate/vigorous exercise and children’s self-esteem did not change significantly. Topics on parenting skills, activity and food were rated as helpful and used with confidence by most parents. Conclusions: Families for Health is a promising new childhood obesity intervention. Definitive evaluation of its clinical effectiveness by randomised controlled trial is now required.

A conditional error function approach for subgroup selection in adaptive clinical trials.

Growing interest in personalised medicine and targeted therapies is leading to an increase in the importance of subgroup analyses. If it is planned to view treatment comparisons in both a predefined subgroup and the full population as co-primary analyses, it is important that the statistical analysis controls the familywise type I error rate. Spiessens and Debois (Cont. Clin. Trials, 2010, 31, 647-656) recently proposed an approach specific for this setting, which incorporates an assumption about the correlation based on the known sizes of the different groups, and showed that this is more powerful than generic multiple comparisons procedures such as the Bonferroni correction. If recruitment is slow relative to the length of time taken to observe the outcome, it may be efficient to conduct an interim analysis. In this paper, we propose a new method for an adaptive clinical trial with co-primary analyses in a predefined subgroup and the full population based on the conditional error function principle. The methodology is generic in that we assume test statistics can be taken to be normally distributed rather than making any specific distributional assumptions about individual patient data. In a simulation study, we demonstrate that the new method is more powerful than previously suggested analysis strategies. Furthermore, we show how the method can be extended to situations when the selection is not based on the final but on an early outcome. We use a case study in a targeted therapy in oncology to illustrate the use of the proposed methodology with non-normal outcomes.

Clinical presentation of pediatric multiple sclerosis before puberty

Multiple sclerosis (MS) onset before puberty is extremely rare and establishment of diagnosis is often difficult due to atypical presentation. The study aims to identify the typical presentation of MS in this age group.

Designing a seamless phase II/III clinical trial using early outcomes for treatment selection: An application in multiple sclerosis

In recent years adaptive seamless phase II/III designs (ASDs) allowing treatment or dose selection at an interim analysis have gained much attention because of their potential to save development costs and to shorten time-to-market of a new compound compared to conventional drug development programmes with separate trials for individual phases. In this paper, we describe an ASD with treatment selection based on early outcome data, specifically considering the situation where no final outcomes are observed at the time of the interim analysis. Bringing together combination tests for adaptive designs and the closure principle for multiple testing, control of the familywise type I error rate in the strong sense is achieved. Furthermore, a simulation model is proposed based on standardized test statistics that allows the generation of virtual trials for a variety of outcomes. We use this simulation model to investigate the actual type I error rate of the proposed testing procedure and find that the familywise type I error rate is controlled as expected. The method is often conservative, with the degree of conservatism depending on the correlation between early and late outcome, the true mean values of the early outcome in the different treatment groups and the selection rule. The investigations are motivated and illustrated by an application of the proposed design and simulation model to progressive multiple sclerosis.