Ed Juszczak

Lithium plus valproate combination therapy versus monotherapy for relapse prevention in bipolar I disorder (BALANCE): a randomised open-label trial.

BACKGROUND Lithium carbonate and valproate semisodium are both recommended as monotherapy for prevention of relapse in bipolar disorder, but are not individually fully effective in many patients. If combination therapy with both agents is better than monotherapy, many relapses and consequent disability could be avoided. We aimed to establish whether lithium plus valproate was better than monotherapy with either drug alone for relapse prevention in bipolar I disorder. METHODS 330 patients aged 16 years and older with bipolar I disorder from 41 sites in the UK, France, USA, and Italy were randomly allocated to open-label lithium monotherapy (plasma concentration 0.4-1.0 mmol/L, n=110), valproate monotherapy (750-1250 mg, n=110), or both agents in combination (n=110), after an active run-in of 4-8 weeks on the combination. Randomisation was by computer program, and investigators and participants were informed of treatment allocation. All outcome events were considered by the trial management team, who were masked to treatment assignment. Participants were followed up for up to 24 months. The primary outcome was initiation of new intervention for an emergent mood episode, which was compared between groups by Cox regression. Analysis was by intention to treat. This study is registered, number ISRCTN 55261332. FINDINGS 59 (54%) of 110 people in the combination therapy group, 65 (59%) of 110 in the lithium group, and 76 (69%) of 110 in the valproate group had a primary outcome event during follow-up. Hazard ratios for the primary outcome were 0.59 (95% CI 0.42-0.83, p=0.0023) for combination therapy versus valproate, 0.82 (0.58-1.17, p=0.27) for combination therapy versus lithium, and 0.71 (0.51-1.00, p=0.0472) for lithium versus valproate. 16 participants had serious adverse events after randomisation: seven receiving valproate monotherapy (three deaths); five lithium monotherapy (two deaths); and four combination therapy (one death). INTERPRETATION For people with bipolar I disorder, for whom long-term therapy is clinically indicated, both combination therapy with lithium plus valproate and lithium monotherapy are more likely to prevent relapse than is valproate monotherapy. This benefit seems to be irrespective of baseline severity of illness and is maintained for up to 2 years. BALANCE could neither reliably confirm nor refute a benefit of combination therapy compared with lithium monotherapy. FUNDING Stanley Medical Research Institute; Sanofi-Aventis.

Randomised Controlled Double-Blind Non-Inferiority Trial of Two Antivenoms for Saw-Scaled or Carpet Viper (Echis ocellatus) Envenoming in Nigeria

Background In West Africa, envenoming by saw-scaled or carpet vipers (Echis ocellatus) causes great morbidity and mortality, but there is a crisis in supply of effective and affordable antivenom (ISRCTN01257358). Methods In a randomised, double-blind, controlled, non-inferiority trial, “EchiTAb Plus-ICP” (ET-Plus) equine antivenom made by Instituto Clodomiro Picado was compared to “EchiTAb G” (ET-G) ovine antivenom made by MicroPharm, which is the standard of care in Nigeria and was developed from the original EchiTAb-Fab introduced in 1998. Both are caprylic acid purified whole IgG antivenoms. ET-G is monospecific for Echis ocellatus antivenom (initial dose 1 vial) and ET-Plus is polyspecific for E. ocellatus, Naja nigricollis and Bitis arietans (initial dose 3 vials). Both had been screened by pre-clinical and preliminary clinical dose-finding and safety studies. Patients who presented with incoagulable blood, indicative of systemic envenoming by E. ocellatus, were recruited in Kaltungo, north-eastern Nigeria. Those eligible and consenting were randomly allocated with equal probability to receive ET-Plus or ET-G. The primary outcome was permanent restoration of blood coagulability 6 hours after the start of treatment, assessed by a simple whole blood clotting test repeated 6, 12, 18, 24 and 48 hr after treatment. Secondary (safety) outcomes were the incidences of anaphylactic, pyrogenic and late serum sickness-type antivenom reactions. Findings Initial doses permanently restored blood coagulability at 6 hours in 161/194 (83.0%) of ET-Plus and 156/206 (75.7%) of ET-G treated patients (Relative Risk [RR] 1.10 one-sided 95% CI lower limit 1.01; P = 0.05). ET-Plus caused early reactions on more occasions than did ET-G [50/194 (25.8%) and 39/206 (18.9%) respectively RR (1.36 one-sided 95% CI 1.86 upper limit; P = 0.06). These reactions were classified as severe in 21 (10.8%) and 11 (5.3%) of patients, respectively. Conclusion At these doses, ET-Plus was slightly more effective but ET-G was slightly safer. Both are recommended for treating E. ocellatus envenoming in Nigeria. Trial Registration Current Controlled Trials ISRCTN01257358

Period trends in rate of suicide in first 28 days after discharge from psychiatric hospital in Scotland, 1968-92.

Abstract Objective : To examine period trends in the rate of suicide in the first 28 days after discharge from psychiatric hospital. Design : Cohort study of patients discharged from psychiatric hospital. Setting : Scotland. Subjects : All patients aged 15-84 who were discharged from Scottish psychiatric hospitals during 1968 to 1992. Outcome measure : The rate of suicide (classified as codes E950-9 and E980-9 according to the International Classification of Diseases, Ninth Revision) within 28 days of discharge per 100000 person years at risk for five year periods during 1968 to 1992. Crude, within cohort rates and externally standardised rates were calculated. Results : Overall, 196 male patients committed suicide in 20520 person years at risk, and 171 female patients committed suicide in 24114 person years at risk. A significant linear trend was seen in period effect on externally standardised mortality ratios in both sexes: a decrease in male patients (P=0.008) and an increase in female patients (P=0.0001). The adjusted standardised mortality ratio in 1988-92 compared with 1968-72 was 0.62 (95% confidence interval 0.39 to 0.98) in male patients and 2.73 (1.64 to 4.56) in female patients. Conclusion : The increase in the rate of suicide in the 28 days after discharge in female psychiatric patients makes this an increasingly important period to target. The rise has occurred against the background of a reduction of 60% in the number of psychiatric beds for adults.

Oxygen targeting in preterm infants using the Masimo SET Radical pulse oximeter

Background A pretrial clinical improvement project for the BOOST-II UK trial of oxygen saturation targeting revealed an artefact affecting saturation profiles obtained from the Masimo Set Radical pulse oximeter. Methods Saturation was recorded every 10 s for up to 2 weeks in 176 oxygen dependent preterm infants in 35 UK and Irish neonatal units between August 2006 and April 2009 using Masimo SET Radical pulse oximeters. Frequency distributions of % time at each saturation were plotted. An artefact affecting the saturation distribution was found to be attributable to the oximeters internal calibration algorithm. Revised software was installed and saturation distributions obtained were compared with four other current oximeters in paired studies. Results There was a reduction in saturation values of 87–90%. Values above 87% were elevated by up to 2%, giving a relative excess of higher values. The software revision eliminated this, improving the distribution of saturation values. In paired comparisons with four current commercially available oximeters, Masimo oximeters with the revised software returned similar saturation distributions. Conclusions A characteristic of the software algorithm reduces the frequency of saturations of 87–90% and increases the frequency of higher values returned by the Masimo SET Radical pulse oximeter. This effect, which remains within the recommended standards for accuracy, is removed by installing revised software (board firmware V4.8 or higher). Because this observation is likely to influence oxygen targeting, it should be considered in the analysis of the oxygen trial results to maximise their generalisability.

Suicide in the 12 months after discharge from psychiatric inpatient care, Scotland 1968-92.

STUDY OBJECTIVE: To investigate the rate of suicide in the 12 months after discharge from psychiatric hospital and to determine its relationship to age, diagnosis, and period. DESIGN: Cohort study of patients discharged from psychiatric hospital. SETTING: Scotland. PARTICIPANTS: Altogether 159,742 men and 178,271 women, aged 15-84, who were discharged from Scottish psychiatric hospitals during 1968-92. MAIN RESULTS: During the 25 year period, 1212 male patients committed suicide in 198,059 person years at risk (612 per 100,000; 95% confidence interval (CI) 578,647) and 1099 female patients committed suicide in 228,993 person years at risk (480 per 100,000; 95% CI 452, 509). The overall standardised mortality ratio (general population rate = 1) was 27 (95% CI 26, 29) in men and 40 (95% CI 38, 43) in women. There were variations in the suicide rates in relation to age, diagnosis, and period. The ratio of the 1-28 day rate to the rate between days 29 and 365 over the whole study period was 1.7 (95% CI 1.4, 1.9) in men and 1.6 (95% CI 1.3, 1.8) in women. CONCLUSIONS: The variations in the post discharge suicide rate by age, sex, diagnosis, geographical location, and period suggest that there are several risk factors which vary in their distribution. Further study of these may lead to the development of effective interventions.

DOMINO-AD protocol: donepezil and memantine in moderate to severe Alzheimer's disease - a multicentre RCT.

BackgroundAlzheimers disease (AD) is the commonest cause of dementia. Cholinesterase inhibitors, such as donepezil, are the drug class with the best evidence of efficacy, licensed for mild to moderate AD, while the glutamate antagonist memantine has been widely prescribed, often in the later stages of AD. Memantine is licensed for moderate to severe dementia in AD but is not recommended by the England and Wales National Institute for Health and Clinical Excellence. However, there is little evidence to guide clinicians as to what to prescribe as AD advances; in particular, what to do as the condition progresses from moderate to severe. Options include continuing cholinesterase inhibitors irrespective of decline, adding memantine to cholinesterase inhibitors, or prescribing memantine instead of cholinesterase inhibitors. The aim of this trial is to establish the most effective drug option for people with AD who are progressing from moderate to severe dementia despite treatment with donepezil.MethodDOMINO-AD is a pragmatic, 15 centre, double-blind, randomized, placebo controlled trial. Patients with AD, currently living at home, receiving donepezil 10 mg daily, and with Standardized Mini-Mental State Examination (SMMSE) scores between 5 and 13 are being recruited. Each is randomized to one of four treatment options: continuation of donepezil with memantine placebo added; switch to memantine with donepezil placebo added; donepezil and memantine together; or donepezil placebo with memantine placebo. 800 participants are being recruited and treatment continues for one year. Primary outcome measures are cognition (SMMSE) and activities of daily living (Bristol Activities of Daily Living Scale). Secondary outcomes are non-cognitive dementia symptoms (Neuropsychiatric Inventory), health related quality of life (EQ-5D and DEMQOL-proxy), carer burden (General Health Questionnaire-12), cost effectiveness (using Client Service Receipt Inventory) and institutionalization. These outcomes are assessed at baseline, 6, 18, 30 and 52 weeks. All participants will be subsequently followed for 3 years by telephone interview to record institutionalization.DiscussionThere is considerable debate about the clinical and cost effectiveness of anti-dementia drugs. DOMINO-AD seeks to provide clear evidence on the best treatment strategies for those managing patients at a particularly important clinical transition point.Trial registrationCurrent controlled trials ISRCTN49545035

Neonatal ECMO Study of Temperature (NEST): A Randomized Controlled Trial

BACKGROUND: Despite evidence to support the use of extracorporeal membrane oxygenation (ECMO) in defined groups of newborn infants, rates of impairment among survivors remain high. Therapeutic hypothermia has been shown to provide neuroprotection in mature infants exposed to perinatal asphyxia. We hypothesized that therapeutic hypothermia during ECMO would reduce the proportion of infants with brain injury, and thus later impairment. METHODS: We conducted a randomized trial in the United Kingdom to compare ECMO with cooling (34°C for the first 48 to 72 hours) with standard ECMO (37°C). The primary outcome was the cognitive composite score of the Bayley Scales of Infant and Toddler Development, 3rd edition, at 2 years. Prespecified secondary outcomes included death, neonatal morbidity, and other neurodevelopmental and behavioral outcomes at 2 years. RESULTS: A total of 111 infants were entered into the study, 14 died before 2 years of age (16% who received ECMO with cooling vs 9% who received ECMO alone). Two infants were lost to follow-up, and 8 were unable to complete the full range of tests. For 45 evaluated infants who received ECMO with cooling, mean cognitive scores at 2 years were 88.0 (SD: 16.2) compared with 90.6 (SD: 13.1) for 48 infants receiving ECMO only (difference in means: −2.6; 95% confidence interval: −8.7 to 3.4). The various secondary outcomes were not significantly different between the groups, but most favored ECMO without cooling. CONCLUSIONS: In newborn infants treated by ECMO, the use of mild hypothermia for the first 48 to 72 hours did not result in improved outcomes up to 2 years of age.

The INFANT trial

Birmingham Clinical Trials Unit (PB) and Institute of Applied Health Research (SK), College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK; Department of Health Sciences, University of Leicester, Leicester, UK (DJF); National Perinatal Epidemiology Unit Clinical Trials Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK (EJ, LL, MQ); CLAHRC South London, Kings College London, London, UK (MN); National Childbirth Trust, London, UK (RP); Centre for Health Economy, Australian Hearing Hub, Macquire University, Sydney, NSW, Australia (LS); and Imperial College London, London, UK (PS).

Development of guidance for statistical analysis plans (SAPs) for clinical trials

Methods The project included: identification of existing SAP guidance; identifying and reviewing published SAPs; a survey of current practice within UKCRC registered Clinical Trial Units (rCTU) and a Delphi survey to establish consensus on SAP content. The Delphi survey included rCTU statisticians, CONSORT and SPIRIT guideline authors, experienced statisticians in the pharmaceutical industry, journal editors and regulators culminating in a face-to-face consensus meeting attended by experts from each demographic. These components informed the development of guidance for SAPs which subsequently underwent critical review by rCTU statisticians and experts from the consensus meeting, followed by piloting of the guidance document.

A practical solution to ‘Continuing Care Site’ issues in neonatal clinical trials – a pragmatic approach to regulatory and research governance review

I2S2 is a randomised controlled trial of iodine supplementation in preterm infants examining whether iodine supplementation can improve neurodevelopmental outcome at two years of age. 20 Neonatal Units in the UK will recruit around 1400 infants <31 weeks of gestation into the trial; infants will receive a daily dose of sodium iodide or sodium chloride placebo until 34 week’s corrected age. Due to the nature of neonatal care, approximately 50% of infants participating in I2S2 are likely to be transferred from the ‘Recruiting Site’ to another hospital for continuation of their clinical care. Hospitals which are not the primary research site may receive infants with little warning and be required to continue treatment under the trial protocol. Hospitals which are research active but have a reduced level of involvement have been defined as ‘Continuing Care Sites’ and ‘Data Collection Sites’; such sites require Research Management and Governance review proportionate to their level of involvement in the clinical trial. This three-tiered approach was negotiated between the NPEU Clinical Trials Unit, RD both documents negate the need for site agreements with the sponsor. NHS permissions are granted for each Neonatal Unit across the UK; those sites without identified Principal Investigators issue provisional NHS Trust approval with confirmation of Principal Investigator on point of transfer. Appropriate trial specific training materials are provided to all sites including training in the reporting of SAE’s and SUSAR’s. This approach allows NHS permissions to be issued in advance of any transfer and ensures infants recruited to I2S2 can continue trial procedures at different sites. Withdrawing an infant from the trial because regulatory and research governance paperwork is not in place, seems a wasted effort for all individuals involved, and more importantly unethical to parents. This streamlined, pragmatic approach to governance review has proved a successful strategy from which many can learn. Trial registry [http://www.clinicaltrials.gov]; Identifier: NCT00638092. Funded by UK Medical Research Council.