Trial design and inclusion criteria
Individuals were recruited from two TB clinics in London, UK, between March 2015 and January 2017. Inclusion criteria included age (between 16 and 65 years); LTBI diagnosis by means of an Interferon Gamma Release Assay (QuantiFERON®-TB Gold In-Tube or T-SPOT®.TB) or Tuberculin Skin Test (threshold >5mm irrespective of BCG vaccine status); agreeing to accept preventive treatment; and provision of informed consent.
We excluded pregnant and breast-feeding women; persons weighing less than 45 kg; those with HIV infection; and individuals unable to receive study drugs due to allergy, liver disease or any medical condition contraindicating the use of a rifamycin or isoniazid; and individuals who needed concomitant medications that could not be safely taken with study drugs.
DOT is not standard of care for LTBI treatment in the UK. Individuals whose social circumstances would necessitate enhanced adherence support and DOT - such as homelessness, history of mental health problems, incarceration, or problematic drug use - were also excluded.
After enrolment, individuals were randomised centrally using Sealed Envelope’s web-based Simple Randomisation Service by a member of the study team in the recruitment clinic. There was no stratification and the ratio of individuals in the intervention to standard care arm was 1:1. Recruited individuals were randomised to receive either 3HP (weekly) in the intervention arm or 3HR (daily) in the standard of care arm. Dosing was weight dependant with patients being weighed at each visit and dosing adjusted accordingly (see Additional File 1, Appendix 1 for dosing schedule). Both arms self-administered treatment without direct observation and recruits were educated on how to take the medication as well as the main side effects of treatment.
Treatment was initiated following an eligibility assessment at baseline (week 0). Subsequent medication was dispensed at clinic visits at weeks 2, 4 and 8 following an adherence and AE check as per the study flow chart below. Extra visits were possible if a patient presented with any symptoms related to the study medication or had a mild derangement of liver function tests (see below in AEs).
Primary Outcome: Treatment completion
The primary outcome was the proportion completing treatment in each arm of the study assessed using self-report. Treatment completion was defined as taking more than 90% of the prescribed doses of treatment. This proportion equates to at least 11 doses for patients taking the weekly intervention regimen and at least 81 doses for patients in the daily standard of care arm. If a patient missed a scheduled appointment, the investigation team tried to contact them within the following week and so total completion had to occur within 16 weeks. Additionally, if participants failed to attend two consecutive appointments, they were considered non-adherent and to have reached one of the endpoints of the study.
Adherence data were collected at regular dispensing clinic visits on weeks 2, 4, 8 and at the end of treatment, using a standardised questionnaire (see Additional File 1, Appendix 2). Adherence and treatment completion was self-reported and assessed by face-to-face enquiry, wherein patients were asked if they had missed any doses of medication since their last clinic visit and the number of tablets reportedly missed was recorded.
We asked participants to bring with them, at each visit, their empty pill packages, which were compared to the number of pills dispensed at the previous visit. At each clinic visit, urine colorimetric testing for detecting isoniazid metabolites and pill count assessment were used to validate the self-reported intake of tablets. The urine tests used a commercially available assay (Isoscreen, GFC Diagnostics Ltd, Oxfordshire, UK). For the purpose of ascertaining treatment completion, we intended to use urinary metabolite and pill count assessment to validate self-reported intake of tablets with either a negative urine test and/or pills still in a pack taken as evidence of non-compliance. Otherwise, self-reports were considered sufficient evidence of outcome.
A validated medication adherence report scale (MARSTM) was used as an assessment of adherence since the last patient visit to the clinic, using five dimensions: ‘I alter the dose’, ‘I forget to use it’, ‘I stop taking it for a while’, ‘I decide to miss out on a dose’, and ‘I take less than instructed’, using a five-point Likert scale of ‘always’, ‘often’, ‘sometimes’, ‘rarely’ and ‘never’, scored one to five, respectively. An overall score of 20 points or higher is considered high adherence (5, 6). (See Additional File 1, Appendix 3 for MARSTM questionnaire.)
Assessment of AEs for both arms was carried out at clinic visits at weeks 2, 4, 8 and at the end of treatment at week 12. A final post treatment telephone call was made 4 weeks after the end of treatment to check that there had been no further AEs following the last dose of study medication. AEs were assessed from laboratory tests or from a standardised interview to assess symptoms. They were recorded and graded (1 to 4) according to the Division of AIDS (DAIDS) criteria (7). The probability of whether the study regimen was related to any AE was assessed by the prescribing physician. Following events scoring 3 or more, medication was stopped; following other AEs, trial medication could be continued at the discretion of the trial physician. For full details of AEs and discontinuation rules, see Additional File 1, Appendix 4.
Data collection and Statistical analysis
Pseudonymised data were collected on case report forms (CRFs) at study sites. Data were independently double entered at the study co-ordinating centre into a password protected Microsoft Access database. These data were cross validated and corrections made as required to ensure data accuracy. Consistency and error checking was carried out to corroborate the two datasets. An assessment of the distribution of baseline characteristics between the two study arms was used to determine if adjustment for confounding was required. Treatment completion and AEs were described.