Stories of Trials That Matter

Hypertension is a leading risk factor for cardiovascular disease. Despite effective medication the management of hypertension in primary remains suboptimal. Previous studies of self-monitoring, where patients monitor their own blood pressure and report back to their GP, have shown contradictory results in terms of effectiveness. The present trial aimed to assess the efficacy of self-monitored blood pressure, with or without telemonitoring, for antihypertensive titration in primary care, compared with usual care.

The design of the trial was a three-arm parallel group with self-monitoring, with or without telemonitoring and compared to usual care. Eligible hypertensive patients were older than 35, with a blood pressure higher than 140/90 mm Hg and willing to self-monitor their blood pressure. The trial duration was 12 months.

Participants randomly assigned to self-monitoring were taught to use a validated automated electronic sphygmomanometer (Omron M10-IT). They were asked to monitor their own blood pressure in their non-dominant arm, twice each morning and evening, for the first week of every month using standard recommendations and their GPs were asked to use the self-monitored measurements for titration of antihypertensive medication. A simple colour chart was used to train participants to attend their practice for a blood pressure check as a result of very high or very low readings. At the end of each monitoring week they were asked to record their readings on paper and send them for review to their practice in a reply-paid envelope.

Participants in the telemonitoring group were asked to send their results via a simple SMS text service. The telemonitoring system incorporated an algorithm that alerted participants to contact their surgery in the light of very high or very low readings, reminded them if insufficient readings were transmitted, prompted them to make contact with their practice if their average blood pressure was above target, and presented readings to attending clinicians via a web interface. This secure web page automatically calculated mean blood pressure for each monitoring week, highlighted very high or very low readings, and presented a graphical display of blood pressure measurements.

General practitioners were asked to review both self-monitoring and telemonitoring groups’ readings on a monthly basis and usual care patients as often as they wished. Blood pressure targets were based on current National Guidelines adjusted for self-monitoring: lower than 140/90 mm Hg (<135/85 mm Hg at home) for those younger than 80 years, lower than 150/90 mm Hg (<145/85 mm Hg at home) for those 80 years or older, and lower than 140/80 mm Hg (<135/75 mm Hg at home) for those with diabetes.

A total of 142 general practices participated recruiting a total of 1182 participants, of which 1003 (85%) were included in the primary analysis.

Systolic blood pressure at baseline was around 153 mm Hg in all groups and at 12 months the blood pressure was lower in all of the groups, with the largest reduction seen in the self-monitoring and telemonitoring groups: blood pressure at 12 months, usual care group 140.4 (SD 16.5, n=348), self-monitoring group 137.0 (16.7, n=328), telemonitoring group 136.0 (16.1, n=327). At 12 months, the adjusted mean difference in systolic blood pressure compared to usual care was significantly lower for both the self-monitoring (-3.5 [95% CI -5.8 to -1.2] p=0.0029) and telemonitoring (-4.7 [-7.0 to -2.4] p<0.0001) groups. There was no difference in the adjusted mean difference between the self-monitoring and telemonitoring groups (-1.2 [-.3.5 to 1.2] p=0.3219).

After 12 months, the number of prescribed antihypertensives was higher in the self-monitoring (1.63 [SD 0.89]) and telemonitoring groups (1.70 [0.88]) compared to the usual care group (1.55 [0.85]). The adjusted mean difference was significantly higher in both the self-monitoring group (0.11 [95% CI 0.02 to 0.19] p=0.0129) and telemonitoring group (0.13 [0.04 to 0.21] p=0.0038) compared to the usual care group.

The authors conclude that after one year patients whose medication was adjusted using self-monitoring, with or without telemonitoring, has significantly lower systolic blood pressure than those receiving treatment adjusted using clinic blood pressure.

You can read the full report here.

Children with persistent hearing loss due to otitis media with effusion are commonly managed by surgical intervention. A Cochrane review indicated that oral steroids might provide some short term benefit, but the studies included were underpowered and poor quality. The present randomised trial was undertaken to determine whether oral steroids improved hearing in children with hearing loss from otitis media with effusion.

Eligible children were those aged 2–8 years with symptoms of hearing loss attributable to otitis media with effusion for at least 3 months. The trial was double-blind with children randomised 1:1 to either a one week course of oral prednisolone or matching placebo. The primary outcome was acceptable hearing at 5 weeks with further follow-up at 6 and 12 months. Secondary outcomes included adverse events and quality of life. All analyses were intention to treat.

A total of 1,018 children were assessed for eligibility and of these 389 (38%) from 20 sites were randomly assigned. The majority of those excluded did not meet the inclusion criteria. After randomisation, a further 9 children were excluded (6 of them due to the hearing test result not meeting the pre-specified threshold and in a further 3 where consent was withdrawn). A total of 380 children (193 children in the steroid group and 187 in the placebo group) were included in the analyses.

Hearing at 5 weeks was assessed in 183 children in the oral steroid group and 180 in the placebo group. Acceptable hearing was observed in 73 (40%) children in the oral steroid group and in 59 (33%) in the placebo group (absolute difference 7% [95% CI −3 to 17]; the adjusted odds ratio was 1·36 [95% CI 0·88–2·11]; p=0·16). No significant differences were also observed in secondary outcomes for adverse events and for quality of life.

The authors conclude that a short course of oral steroids for otitis media with effusion is unlikely to be effective for most children aged 2–8 years.

The full report is available here.

The consumption of contaminated water, inadequate sanitation and hygiene are the main contributors to an estimated four billion cases of diarrhea every year, causing 1.8 million deaths, out of which about 90% are children under 5 years of age. In Ethiopia, nearly 40 million people, mostly in rural areas, do not have access to safe drinking water and 90% of households do not treat their drinking water at home. Studies conducted in different parts of Ethiopia indicated that a 2-week prevalence of diarrhea among under-five children ranged from 23 to 31%.

The installation of large-scale water treatment plants in rural Ethiopia is difficult due to the scarcity of resources and scattered settlement. Therefore, low-cost home water treatment kits have been proposed as a potential solution in rural areas. One home based water treatment is solar water disinfection where raw water is filled into polyethylene terephthalate (PET) bottles and relies on the germicidal effects of sunlight and heat.

The study was conducted in Dabat district, northwest Ethiopia. The study area was divided into an intervention area using solar disinfection of water and a control area separated by a buffer zone to avoid contamination of information. Clusters were chosen by randomly selecting 14 villages from within each of the intervention and control study areas.

A total of 397 under five children in 280 households in the intervention and 400 under fives in 293 households in the control group were enrolled in 28 clusters (villages). The baseline analysis compared the socio-demographic and economic factors and there were no significant differences between the two groups. Water analysis showed similar high rates of contamination of raw water in both groups. During the baseline period, a 2-week prevalence of diarrhea was 20.8% (80/384) in the intervention and 21.8% (86/394) in the control groups was recorded.

During the active intervention phase, there were significantly fewer cases of diarrhea, i.e., 8.3 episodes per 100 person-week observations (378 episodes of diarrhea) among under fives in the solar disinfection intervention group and 15.3 episodes of diarrhea per 100 person-week observations (720 episodes of diarrhea) in the control during the entire 6-month consecutive follow-up. The overall prevention of diarrheal incidence among under fives during the 6 month solar disinfection intervention was 40% (95% CI 30–48) compared to the control group.

You can read the full report here.

Rob Califf estimates that each time you do a Google search you are on average taking part in 3-4 randomised trials. E-commerce has made the randomised trial the cornerstone of website optimisation and a recent report in Trials demonstrated how a trial could be used to optimise the sign-ups for organ donor registration.

In the UK, 17 million people each year renew their car tax online and at the end of the process a request is made to join the organ donor register. This trial tested a number of different messages on signups for the organ donor register against the following control webpage:

The first message was of a social norms type and tested the message on its own (webpage B) and with an image (webpage C) or with the logo for NHS organ donation (webpage D).

The remaining four messages (E-H) tested simple messages on their own without images or logos:

The trial was run over a one month period. A randomisation code sequentially assigned individuals a number from 0 to 7 and displayed one of the 8 corresponding webpages shown in the table above. The main outcome measure was the number of sign-ups to the organ donor register.

During the study period, a total of 1,085,322 observations were made and the unadjusted odds ratios for the effect of the various messages on the number of sign-ups compared to control is shown in the table below:

All of the test messages resulted in statistically significant improvements in the number of sign ups with the exception of the social norms message with an image which resulted in a decrease in the number of sign-ups. The most effective message was the reciprocity message (“if you needed an organ transplant would you have one? If so please help others”) with individuals 1.38 times more likely to sign up to the organ donor register than controls. Following the results of the trial, the reciprocity message has been implemented across 25 government websites.

You can read the full report here.

One of the major barriers to the conduct of more and better randomised trials is the ever increasing cost of trials. Large trials of 10-15,000 participants typically cost in excess of £3-400m and there have been reports of single trials costing in excess of $1bn. These costs are unsustainable and distort the research agenda.

A major component of the cost of such trials is the setting up and running of large numbers of clinics. Clinics are required to screen and recruit participants and to monitor interventions by physical and laboratory means. Some commonly used interventions require no clinic monitoring so opening up the possibility of conducting a trial without the need for clinic visits. The ASCEND trial was conducted in 15,500 people with diabetes and compared using a 2×2 factorial design aspirin versus placebo and omega 3 fish oils versus placebo in reducing cardiovascular events. The trial was entirely mail based without the need for participants to attend clinics.

Potential participants with diabetes were identified from central registers and from GP practices. Letters of invitation included a screening questionnaire which was returned by post. Eligible participants were then entered into a pre-randomisation 2 month run-in phase where all participants received 8 weeks of placebo aspirin and placebo omega 3 fish oils. During the run-in phase participants were mailed a sample collection kit for blood and urine which was taken to their GP practice and returned by mail. A total of 4% of the potential participants invited went on to be randomised.

Follow-up takes place every 6 months with questionnaires being returned either by mail or online and by the time of the report of the main result the length of average follow-up was 7.4 years. The main results for aspirin and omega 3 fish oils can be found here and here.

The total cost of ASCEND is less than £10m, which makes it an order of magnitude less than similar sized clinic-based studies.