Evaluation of implementation and effectiveness of digital adherence technology with differentiated care to support tuberculosis treatment adherence and improve treatment outcomes in Ethiopia: a study protocol for a cluster randomised trial

Abstract Background Digital adherence technologies (DATs) are recommended to support patient-centred, differentiated care to improve tuberculosis (TB) treatment outcomes, but evidence that such technologies improve adherence is limited. We aim to implement and evaluate the effectiveness of smart pillboxes and medication labels linked to an adherence data platform, to create a differentiated care response to patient adherence and improve TB care among adult pulmonary TB participants. Our study is part of the Adherence Support Coalition to End TB (ASCENT) project in Ethiopia. Methods/Design We will conduct a pragmatic three-arm cluster-randomised trial with 78 health facilities in two regions in Ethiopia. Facilities are randomised (1:1:1) to either of the two intervention arms or standard of care. Adults aged ≥ 18 years with drug-sensitive (DS) pulmonary TB are enrolled over 12 months and followed-up for 12 months after treatment initiation. Participants in facilities randomised to either of the two intervention arms are offered a DAT linked to the web-based ASCENT adherence platform for daily adherence monitoring and differentiated response to patient adherence for those who have missed doses. Participants at standard of care facilities receive routine care. For those that had bacteriologically confirmed TB at treatment initiation and can produce sputum without induction, sputum culture will be performed approximately 6 months after the end of treatment to measure disease recurrence. The primary endpoint is a composite unfavourable outcome measured over 12 months from TB treatment initiation defined as either poor end of treatment outcome (lost to follow-up, death, or treatment failure) or treatment recurrence measured 6 months after the scheduled end of treatment. This study will also evaluate the effectiveness, feasibility, and cost-effectiveness of DAT systems for DS-TB patients. Discussion This trial will evaluate the impact and contextual factors of medication label and smart pillbox with a differentiated response to patient care, among adult pulmonary DS-TB participants in Ethiopia. If successful, this evaluation will generate valuable evidence via a shared evaluation framework for optimal use and scale-up. Trial registration: Pan African Clinical Trials Registry PACTR202008776694999, https://pactr.samrc.ac.za/TrialDisplay.aspx?TrialID=12241, registered on August 11, 2020.

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Efficacy of pragmatic same-day ring prophylaxis for adult individuals exposed to SARS-CoV-2 in Switzerland (COPEP): protocol of an open-label cluster randomised trial

BMJ Open ◽

10.1136/bmjopen-2020-040110 ◽

2020 ◽

Vol 10 (11) ◽

pp. e040110

Author(s):

Mikaela Smit ◽

Annalisa Marinosci ◽

Giovanni Jacopo Nicoletti ◽

Thomas Perneger ◽

Silvio Ragozzino ◽

...

Keyword(s):

Randomised Trial ◽

Standard Of Care ◽

Cluster Randomised Trial ◽

Postexposure Prophylaxis ◽

Open Label ◽

Daily Monitoring ◽

Intention To Treat ◽

Cluster Randomised ◽

Registration Number ◽

Asymptomatic Individuals

IntroductionLopinavir/ritonavir (LPV/r) has been proposed as repurposed drugs for pre-exposure and postexposure prophylaxis as well as therapy of COVID-19. Coronavirus postexposure prophylaxis (COPEP) trial aims at assessing their efficacy as postexposure ring-prophylaxis among adults exposed to SARS-CoV-2.Methods and analysisCOPEP is a two-arm open-label cluster-randomised trial conducted in three cantons of Switzerland. Asymptomatic contacts (≥16 years) of individuals diagnosed with COVID-19 will be randomised (2:1) to either LPV/r (400 mg/100 mg two times per day) for 5 days, or a standard of care arm (no treatment). Asymptomatic individuals may be either SARS-CoV-2 positive or negative. Contacts living in the single household will form a cluster and will be randomised into the same arm. All participants will be followed-up for 21 days and undergo daily monitoring for COVID-19 symptoms. The primary endpoint is 21-day incidence of laboratory-confirmed COVID-19 with ≥1 compatible symptom, analysed in an intention-to-treat (ITT) analysis. The secondary endpoints include the 21-day incidence of COVID-19 as well as SARS-CoV-2 infection in a modified ITT analysis, excluding participants who had a positive SARS-CoV-2 RT-PCR from oropharyngeal swab and/or a positive SARS-CoV-2 IgG serology at baseline. Assuming a 21-day incidence for COVID-19 of 20% among contacts without postexposure chemoprophylaxis, to detect a relative risk reduction of 60% (ie, translating in an absolute reduction from 20% to 8%), with a power of 80%, an alpha of 5%. Accounting for design effect of cluster design of circa 1.1, we plan to enrol 200 participants to the LPV/r arm and 100 to the standard of care arm, 300 participants in total.Ethics and disseminationEthics approval has been granted by the Commission Cantonale d’Ethique de la Recherche, Ethikkommission Nordwest- und Zentralschweiz and Comitato Etico Cantonale (ref 2020-00864) and Swissmedic (2020DR3056). Results from this trial will be disseminated via journal articles and presentations at national and international conferences.Trial registration numberClinicaltrials.gov Registry (NCT04364022); Swiss National Clinical Trial Portal Registry (SNCTP 000003732).Registered report identifierCCER 2020-0864.

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A novel blood-based assay for treatment monitoring of tuberculosis

BMC Research Notes ◽

10.1186/s13104-021-05663-z ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Alexandra J. Zimmer ◽

Samuel G. Schumacher ◽

Erik Södersten ◽

Anna Mantsoki ◽

Romain Wyss ◽

...

Keyword(s):

Early Identification ◽

Treatment Initiation ◽

Fold Increase ◽

Gene Signature ◽

Treatment Monitoring ◽

Pulmonary Tb ◽

Transcriptional Signature ◽

Tb Treatment ◽

End Of Treatment ◽

Sequencing Platforms

Abstract Objectives A novel 3-gene host transcriptional signature (GBP5, DUSP3 and KLF2) has been validated for tuberculosis (TB) treatment monitoring using laboratory-based RNA sequencing platforms. The signature was recently translated by Cepheid into a prototype cartridge-based test that can be run on the GeneXpert instrument. In this study, we prospectively evaluated the change in the expression of the cartridge-based 3-gene signature following treatment initiation among pulmonary TB patients who were microbiologically cured at the end of treatment. Results The 3-gene signature expression level (TB score) changed significantly over time with respect to baseline among 31 pulmonary TB patients. The greatest increase in TB score occurred within the first month of treatment (median fold-increase in TB score: 1.08 [IQR 0.54–1.52]) and plateaued after 4 months of treatment (median TB score: 1.97 [IQR: 1.03–2.33]). The rapid and substantial increase of the TB score in the first month of treatment holds promise for the early identification of patients that respond to TB treatment. The plateau in TB score at 4 months may indicate early clearance of disease and could direct treatment to be shortened. These hypotheses need to be further explored with larger prospective treatment monitoring studies.

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LUPUS-BEST—treat-to-target in systemic lupus erythematosus: study protocol for a three-armed cluster-randomised trial

Lupus Science & Medicine ◽

10.1136/lupus-2021-000516 ◽

2021 ◽

Vol 8 (1) ◽

pp. e000516

Author(s):

Johanna Mucke ◽

Oliver Kuss ◽

Ralph Brinks ◽

Sabine Schanze ◽

Matthias Schneider

Keyword(s):

Disease Activity ◽

Randomised Trial ◽

Standard Of Care ◽

Treat To Target ◽

Cluster Randomised Trial ◽

Tight Control ◽

Systemic Lupus ◽

Low Disease Activity ◽

Cluster Randomised ◽

Damage Accrual

IntroductionAs chronic systemic autoimmune disease, which can affect every organ, SLE is creating significant burden and increased mortality. Despite better outcomes over the past decades by optimising standard of care, new interventions are needed for further improvements. Changing strategy to ‘treat-to-target’ (T2T) may be a promising concept proven successful in other chronic diseases.Methods and analysisIn this cluster-randomised trial, SLE centres will be assigned 1:1:1 to standard of care (SoC), remission (no clinical disease activity+prednisolone ≤5 mg/day+Physician Global Assessment (PGA 0–3) <0.5±immunomodulatory treatment) or and Lupus Low Disease Activity State (LLDAS, low disease activity+prednisolone ≤7.5 mg/day+PGA ≤1+no new disease activity). Per arm, 424 patients will be included. Intervention centres receive a standardised training on T2T and shared decision-making (SDM). In intervention centres, patients not in target enter a phase of tight control with six weekly visits and treatment adjustments (at least four visits) or until the target is reached and maintained. Patients in target are reassessed every 12 weeks. In case of flare, they can enter tight control based on SDM. In the SoC arm, patients receive their usual three to six monthly controls and treatment adjustments according to the physician’s discretion. Study duration is 120 weeks using change in damage and health-related quality of life (HRQoL) as major outcomes. The primary endpoint will be damage accrual at 120 weeks as measured by the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index and will by analysed by a mixed model.ConclusionsThis is the first trial to assess if the implementation of a T2T concept in clinical care minimises damage accrual and improves HRQoL in patients with SLE. Comparison of remission and LLDAS will help to identify the target with the best benefit–risk ratio concerning attainability, adverse events and damage. The emphasis on SDM will strengthen patient autonomy and will improve both their satisfaction and medical condition.

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Investigating the impact of enhanced community case management and monthly screening and treatment on the transmissibility of malaria infections in Burkina Faso: study protocol for a cluster-randomised trial

BMJ Open ◽

10.1136/bmjopen-2019-030598 ◽

2019 ◽

Vol 9 (9) ◽

pp. e030598 ◽

Cited By ~ 1

Author(s):

Katharine A Collins ◽

Alphonse Ouedraogo ◽

Wamdaogo Moussa Guelbeogo ◽

Shehu S Awandu ◽

Will Stone ◽

...

Keyword(s):

Case Management ◽

Burkina Faso ◽

Malaria Transmission ◽

Randomised Trial ◽

Standard Of Care ◽

Recruitment Strategy ◽

Cluster Randomised Trial ◽

Community Case Management ◽

Cluster Randomised ◽

The Impact

IntroductionA large proportion of malaria-infected individuals in endemic areas do not experience symptoms that prompt treatment-seeking. These asymptomatically infected individuals may retain their infections for many months during which sexual-stage parasites (gametocytes) are produced that may be transmissible to mosquitoes. Reductions in malaria transmission could be achieved by detecting and treating these infections early. This study assesses the impact of enhanced community case management (CCM) and monthly screening and treatment (MSAT) on the prevalence and transmissibility of malaria infections.Methods and analysisThis cluster-randomised trial will take place in Sapone, an area of intense, highly seasonal malaria in Burkina Faso. In total, 180 compounds will be randomised to one of three interventions: arm 1 - current standard of care with passively monitored malaria infections; arm 2 - standard of care plus enhanced CCM, comprising active weekly screening for fever, and detection and treatment of infections in fever positive individuals using conventional rapid diagnostic tests (RDTs); or arm 3 - standard of care and enhanced CCM, plus MSAT using RDTs. The study will be conducted over approximately 18 months covering two high-transmission seasons and the intervening dry season. The recruitment strategy aims to ensure that overall transmission and force of infection is not affected so we are able to continuously evaluate the impact of interventions in the context of ongoing intense malaria transmission. The main objectives of the study are to determine the impact of enhanced CCM and MSAT on the prevalence and density of parasitaemia and gametocytaemia and the transmissibility of infections. This will be achieved by molecular detection of infections in all study participants during start and end season cross-sectional surveys and routine sampling of malaria-positive individuals to assess their infectiousness to mosquitoes.Ethics and disseminationThe study has been reviewed and approved by the London School of Hygiene and Tropical Medicine (LSHTM) (Review number: 14724) and The Centre National de Recherche et de Formation sur le Paludisme institutional review board (IRB) (Deliberation N° 2018/000002/MS/SG/CNRFP/CIB) and Burkina Faso national medical ethics committees (Deliberation N° 2018-01-010).Findings of the study will be shared with the community via local opinion leaders and community meetings. Results may also be shared through conferences, seminars, reports, theses and peer-reviewed publications; disease occurrence data and study outcomes will be shared with the Ministry of Health. Data will be published in an online digital repository.Trial registration numberNCT03705624.

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Study protocol and implementation details for a pragmatic, stepped-wedge cluster randomised trial of a digital adherence technology to facilitate tuberculosis treatment completion

BMJ Open ◽

10.1136/bmjopen-2020-039895 ◽

2020 ◽

Vol 10 (11) ◽

pp. e039895

Author(s):

Rebecca Crowder ◽

Alex Kityamuwesi ◽

Noah Kiwanuka ◽

Maureen Lamunu ◽

Catherine Namale ◽

...

Keyword(s):

San Francisco ◽

Randomised Trial ◽

Scale Up ◽

Treatment Completion ◽

Routine Care ◽

Cluster Randomised Trial ◽

Institutional Review Boards ◽

Stepped Wedge ◽

Tb Treatment ◽

Cluster Randomised

IntroductionLow-cost digital adherence technologies (DATs) such as 99DOTS have emerged as an alternative to directly observed therapy (DOT), the current standard for tuberculosis (TB) treatment supervision. However, there are limited data to support DAT scale-up. The ‘DOT to DAT’ trial aims to evaluate the effectiveness and implementation of a 99DOTS-based TB treatment supervision strategy.Methods and analysisThis is a pragmatic, stepped-wedge cluster randomised trial, with hybrid type 2 effectiveness-implementation design. The trial will include all adults (estimated N=1890) treated for drug-susceptible pulmonary TB over an 8-month period at 18 TB treatment units in Uganda. Three sites per month will switch from routine care (DOT) to the intervention (99DOTS-based treatment supervision) beginning in month 2, with the order determined randomly. 99DOTS enables patients to be monitored while self-administering TB medicines. Patients receive daily automated short message service (SMS) dosing reminders and confirm dosing by calling toll-free numbers. The primary effectiveness outcome is the proportion of patients completing TB treatment. With 18 clusters randomised into six steps and an average cluster size of 15 patients per month, the study will have 89% power to detect a 10% or greater increase in treatment completion between the routine care and intervention periods. Secondary outcomes include more proximal effectiveness measures as well as quantitative and qualitative assessments of the reach, adoption and implementation of the intervention.Ethics and disseminationEthics approval was granted by institutional review boards at Makerere University School of Public Health and the University of California San Francisco. Findings will be disseminated through peer-reviewed publications, presentations at scientific conferences and presentations to key stakeholders.Trial registration numberPACTR201808609844917.

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