Work package 5: a randomised controlled trial comparing smartphone-enabled video-observed treatment with face-to-face directly observed treatment

Our study findings relating to this trial have previously been published.86 Parts of this section have been reproduced or adapted from Story et al.86 © 2019 Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. See: http://creativecommons.org/licenses/by/4.0/. The text includes minor additions and formatting changes to the original text.

The trial was a multicentre, randomised, superiority study comparing the efficacy of VOT versus DOT in supporting adherence in patients with active tuberculosis. The trial registration number is ISRCTN26184967.

Introduction

Directly observed treatment has been the standard of care for tuberculosis since the early 1990s.87,88 DOT was developed following observations that irregular treatment could threaten clinical and public health outcomes through the generation of drug resistance, relapse and transmission of infection.89 DOT is recommended by WHO1 and the American Thoracic Society.90 In England, DOT is recommended for patients at high risk of poor adherence.11 This includes those with clinically complex disease, MDRTB, mental health problems, previous tuberculosis treatment or previous poor adherence.11 It also includes socially complex groups (persons with a history of homelessness, imprisonment, drug use or alcohol problems).

Directly observed treatment can be administered in clinic, community or home settings but is a substantial inconvenience to patients and service providers. Regimens of three times per week have also been approved with DOT and are used in England,11 although they are not currently recommended by WHO owing to increased risk of treatment failure.1 Seven-day regimens are, therefore, generally administered through DOT 5 days per week and through self-administered treatment at the weekend.

Advances in technology have raised the possibility of remote VOT.91 Initially, this required a live video call (synchronous VOT).92–97 More recently, apps have been developed that enable video clips to be recorded and forwarded for later viewing (asynchronous VOT).98 Asynchronous VOT is currently used by some clinics in the USA and has high reported levels of patient acceptability, decreased costs and programmatic evidence of effectiveness.98–102 The WHO, therefore, recently conditionally recommended VOT as an alternative to DOT, but the evidence was graded as weak because of a lack of RCTs.1 In addition, VOT has yet to be assessed in patients from socially complex groups.

Methods

Trial design

This was a multicentre, analyst-blinded, randomised controlled, superiority trial to compare asynchronous VOT with clinic-, community- or home-based DOT for supporting treatment adherence in patients with active tuberculosis in England.

The full trial protocol is published on the International Standard Randomised Controlled Trial Number Registry (study ISRCTN26184967, doi 10.1186/ISRCTN26184967). Ethics approval was granted by the National Research Ethics Service Committee East of England – Essex on 20 March 2014 (reference 10/H0302/51). All patients provided written informed consent to participate in the study.

Setting

Patients were recruited from clinics in London (17 sites), Birmingham (three sites), Coventry (one site) and Leicester (one site). Case managers at each participating clinic identified eligible patients and referred them to the study team, which provided further information.

Inclusion criteria

The inclusion criteria were patients aged ≥16 years with active pulmonary or non-pulmonary tuberculosis who were eligible for DOT according to national guidance.11 Patients were invited to participate regardless of whether or not they had previously agreed to treatment observation.

Exclusion criteria

The exclusion criteria were lack of access to facilities to charge a smartphone and < 2 months remaining on their treatment regimen (the primary outcome required measurement of adherence over 2 months). Patients with MDRTB were also excluded because they require twice-daily treatment and it was considered that DOT was not practicable under these circumstances. (These patients were offered VOT under a separate non-randomised study.)

Randomisation

Randomisation was provided by Sealed Envelope, a telephone and online software application for randomising patients into clinical trials. The system used randomisation by minimisation103 to ensure balance across study sites and stage of treatment at the time of enrolment (within the first 2 months of treatment and after the first 2 months of treatment).

Directly observed treatment was delivered according to usual clinical practice (observation of treatment in clinic, at home or in community settings three to five times per week by a health-care or lay worker, with the remaining daily doses being self-administered).

Video-observed treatment was provided by a centralised service in London. Patients were trained to record and send videos of every dose ingested 7 days per week using an app developed by researchers at the University of California, San Diego.98 Trained treatment observers viewed these videos through a password-protected website. Patients were also encouraged to report adverse drug events on the videos. Smartphones and data plans (including UK calls and texts) were provided free of charge.

Directly observed treatment or VOT observation records were completed by observers until treatment end or study end.

Primary outcome

The primary outcome was successful completion of ≥ 80% of scheduled treatment observations in the 2 months following enrolment.

Secondary outcomes

The main secondary outcome was the proportion of scheduled observations (measured on a continuous scale) successfully completed in the 2 months following enrolment, and throughout treatment.

Other secondary outcomes collected were sputum culture results at 2 months post treatment initiation, 9- or 12-month treatment outcomes, side effects, number of hospitalisations, staff time spent observing or travelling to observe patients, estimated costs and patient satisfaction.

Power

We determined that a sample of 200 patients per arm would provide a power of 90% to detect a 15% difference in the proportion of patients with the primary outcome (60% vs. 75%). This was based on a two-sided significance level of 5%.

Study interruption

Following a review of study progress by an external committee, funders requested an interim analysis, the plan for which was published on the International Standard Randomised Controlled Trial Number Registry prior to analysis (study ISRCTN26184967, doi 10.1186/ISRCTN26184967). It included a stopping rule using the Haybittle–Peto boundary of 0.001 for the primary outcome. As the interim analysis plan showed overwhelming evidence of superiority, the committee advised that the trial should be terminated early.

Analysis

Video-observed treatment observations were classified as successfully completed if ingestion of all medicines had been observed, or if video clips had been received but were not viewable as a result of a technical complication (as patients had no control over whether or not videos were corrupted).

The intention-to-treat (ITT) analysis included all patients, analysed according to the arm to which they were originally randomised. The restricted analysis excluded patients with < 1 week of observation in the allocated arm. This was designed to include only those patients who had, at least initially, engaged with the allocated intervention.

If patients had two episodes of non-adherence (see Report Supplementary Material 1 for definitions), they were switched into the other trial arm. Four patients crossed over from VOT to DOT, and five crossed over from DOT to VOT. For the purposes of this analysis, all doses following crossover were considered unobserved.

We used logistic regression to analyse the primary outcome and linear regression to analyse the main secondary outcome. The time elapsed since the start of treatment, age and sex were considered a priori as potential confounders and were included in all models. For the restricted analysis, we also considered covariates that may have affected initial engagement with the allocated intervention (homelessness, imprisonment, drug use, alcohol problems, immigration concerns, mental health problems, previous loss to follow-up and no recourse to public funds). All analyses accounted for clustering at the level of the clinic using robust standard errors.104 Analyses were conducted in Stata (version 14) and R (The R Foundation for Statistical Computing, Vienna, Austria) (version 3.3.2) software.

Results

Trial population

Recruitment began on 1 September 2014 and continued until 1 October 2016, when the study’s independent Trial Steering Committee advised that recruitment should be stopped based on interim analysis results. Follow-up continued until 31 December 2016. Flow through the study is summarised in Figure 6.

FIGURE 6 Enrolment and randomisation. a, The most common ‘other reason’ for failing to enrol patients (32 out of 45) was that the clinic staff considered that the patient needed intensive face-to-face support owing to emotional, medical or physical reasons or because of imminent risk of loss to follow-up. Reproduced from Story et al.86 © 2019 Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. See: http://creativecommons.org/licenses/by/4.0/. The figure includes minor additions and formatting changes to the original text. (Figure not reproduced here; see the original article.)

The ITT analyses included 114 patients randomised to DOT and 112 patients randomised to VOT. Baseline characteristics of patients are shown in Table 10. Patients were mainly young adults born outside the UK. A high proportion (131 out of 226 patients; 58%) had a history of homelessness, imprisonment, drug use, alcohol problems or mental health problems. The baseline characteristics were similar in the two arms.

In the ITT analysis, 78 out of 122 (70%) VOT patients successfully achieved the primary outcome (≥ 80% scheduled observations successfully completed during the first 2 months), compared with 35 out of 114 (31%) DOT patients [adjusted odds ratio (aOR) 5.48, 95% CI 3.10 to 9.68; p < 0.0001]. In the restricted analysis, the proportions with the primary outcome were 78 out of 101 patients (77%) for VOT and 35 out of 56 patients (63%) for DOT (aOR 2.52, 95% CI 1.17 to 5.47; p = 0.019).

High observation rates were maintained in the VOT arm, but they rapidly declined in the DOT arm. Over the full follow-up period (up to 6 months), 12,422 out of 16,230 (77%) scheduled observations were completed in the VOT arm, compared with 3884 out of 9882 (39%) scheduled observations in the DOT arm (p < 0.0001). In the restricted analysis over the full follow-up period, 12,422 out of 14,907 (83%) scheduled observations were completed in the VOT arm, compared with 3884 out of 6351 (61%) scheduled observations in the DOT arm (p < 0.0001). Observation completion rates were higher for VOT than DOT in all subgroups.

There were no significant differences in positive sputum cultures at 2 months following treatment onset, treatment completion and loss to follow-up or numbers of hospital admissions between trial arms.

Average staff time per dose observed was 56 (SD 54) minutes for community-based DOT (including travel time), 15 (SD 12) minutes for clinic-based DOT and 3.2 (SD 0.5) minutes for VOT. Patients on DOT spent a mean of 29 (SD 48) minutes per week on treatment observation (including travelling to/from clinics, waiting for appointments and appointment time). Those on VOT spent a mean of 1.8 (SD 2.2) minutes setting up and recording each video.

Discussion

Video-observed treatment was substantially more effective than DOT at ensuring that scheduled doses were observed. A large part of this effect was due to patients failing to engage in DOT over the first week of treatment. After restricting analyses to those patients who engaged with observation in the first week, VOT remained significantly superior at ensuring that scheduled observations took place. This effect was maintained throughout treatment. VOT observations involved substantially less health-care worker time and patient time than DOT.

Systematic reviews and meta-analyses draw differing conclusions about the effectiveness of DOT;105,106 however, a recent review showed that DOT increased treatment success, adherence and 2-month sputum conversion, and decreased loss to follow-up and acquired drug resistance compared with self-administered treatment.1 Community DOT was more effective than hospital-based or clinic-based DOT, demonstrating the importance of making DOT convenient for patients. The review also showed that DOT was more effective when delivered by health staff or lay workers than when delivered by family members.1 VOT provides the technology to support professional treatment observation that is potentially more convenient and cheaper than in-person DOT.

Video-observed treatment, as used in this study, has a wide range of components beyond convenience of observation. The intervention included personal support: patients met the VOT observer for training and received regular personalised messages as reminders, confirmation of receipt of video clips or follow-up when clips were not received. The observers also supported onward referral to deal with reported adverse events. Patients were provided with a smartphone with a data plan and free domestic calls and text messages. This acted both as an enabler (as it facilitated easy communication and improved access to care providers) and as a material incentive that was valued by patients. Phones were reused throughout the trial.

The trial had a number of limitations. It was not possible to blind patients or treatment observers to the intervention, although the investigators and analysts were blinded. We could not distinguish between doses that were taken but were not observed and doses that were not taken.

The primary outcome (observing 80% of scheduled doses) could be considered to be biased towards DOT; it required substantially more VOT doses (scheduled 7 days per week) to be observed than DOT doses (scheduled three or five times per week). The restricted analysis further favoured DOT as it included only the subset of patients allocated to DOT who were willing to be observed.

The study was not powered to detect differences in culture conversion rate, treatment completion, loss to follow-up, relapse or development of drug resistance; nevertheless, it is reasonable to assume that improved adherence might improve all of these outcomes.

Another limitation was the exclusion of MDRTB patients from the randomised trial. They were excluded because they had a range of treatment regimes, some of which included multiple scheduled doses to be observed per day. It would be impractical for all of these observations to be made through face-to-face DOT and we therefore did not consider there to be equipoise between VOT and DOT for MDRTB patients; however, 26 MDRTB patients were offered VOT in a non-randomised arm of the trial. In this arm, it was harder to be certain about which doses were scheduled for VOT because of the higher frequency of dosing, the fact that some doses (particularly injectable doses) continued to be administered at regular clinic visits and the higher rates of hospitalisation. Nevertheless, all but one of the 26 MDRTB patients accepted VOT and 16 MDRTB patients had > 80% doses observed in the first 2 months. There was also evidence that the intervention could be sustained for the long-term regimens required for treatment completion in MDRTB; VOT was maintained for a maximum of 796 days.

There is an urgent global need for more effective and cheaper alternatives to DOT to enable effective ambulatory care of both drug-sensitive tuberculosis and MDRTB. In particular, it is critical that new opportunities for shorter regimens for MDRTB are not lost as a result of insufficient attention to adherence.107

The WHO now recommends that VOT can be a ‘suitable alternative’ to DOT and has published guidance on its implementation.1 The results of this trial may allow WHO to make firmer recommendations about the use of DOT and VOT.

Deviations from the protocol

The full trial protocol and analysis plan are presented in Report Supplementary Material 3 and Report Supplementary Material 4. Some eligible patients (45/548 patients assessed for eligibility) were not recruited for a range of reasons that were not within the original exclusion criteria (see Figure 8). With the exception of the trial being terminated following an interim analysis requested by the funder, there were no clear protocol violations. No adverse effects were reported.

Challenges

In our original submission to NIHR, we proposed a trial comparing community DOT with clinic DOT; however, in the time between study conception and delivery, the use of community DOT in routine practice had increased considerably. We also found it very challenging to recruit community DOT providers for this work; therefore, with the permission of NIHR, we redesigned the trial to assess VOT. This followed a small pilot by Find&Treat that had found the approach to be acceptable to patients. Considerable delays were introduced by the multicentre aspect of the study, which required research and development approvals across 22 sites in four cities. Local principal investigators were required in each site and, frequently, these principal investigators (primarily specialist tuberculosis nurses) had not previously been involved in research and needed to undertake training in Good Clinical Practice before the trial could start. When sites were up and running, we found recruitment to be slower than anticipated. This was, in part, due to the decreasing numbers of tuberculosis cases in London and, in part, due to a reluctance by staff in clinics to randomise people who, despite being eligible for DOT, they thought would not accept DOT or for whom they thought that it would be difficult to arrange. In view of these delays, NIHR requested an interim analysis and, following this, based on overwhelming evidence of the superiority of one intervention arm, the external steering group recommended cessation of the trial.

Added value

At the time of writing, the VOT trial has already had considerable impact. The work has led to a collaboration with the Behavioural Insights Team to undertake a trial of video-observed therapy for tuberculosis in Moldova, which is now complete and being analysed. Discussion of the findings at meetings of the WHO Digital Health for the End Tuberculosis Strategy (for which the co-chairperson and co-applicant is A Story) has contributed to WHO recommending VOT as a suitable alternative to DOT in countries with suitable technological infrastructure. The London Clinical Commissioning Groups have commissioned Find&Treat to provide a VOT service for London, and other parts of the country also commission VOT from Find&Treat on an ad hoc basis.