Crook, AM

Gillespie, SH

McHugh, TD

Mendel, CM

Meredith, SK

Murray, SR

Nunn, AJ

Tweed, CD

Wills, G

UCL Discovery

Using Adverse Events in a Tuberculosis Trial to Describe the Tolerability of Standard Therapy   Introduction and Objectives  The current standard treatment for pulmonary tuberculosis (TB) has been in use for several decades and the major risks associated with each of the four drugs (HRZE) are well recognised. However, large prospective trials with regular review and documentation of adverse events while taking HRZE are lacking.   We used the incidence of grade 3 and 4 adverse events (AEs) and serious adverse events (SAEs) in patients taking HRZE in the REMoxTB trial to investigate the overall tolerability of the regimen.   Methods  Grade 3 or 4 AEs and SAEs (of any grade) for patients taking standard TB therapy were analysed. Events were labelled as occurring in the intensive phase, continuation phase or in follow-up (up to 18 months after enrolment). ANOVA and chi-square testing was used to test for significant differences in the incidence of events across the treatment phases. Logistic regression was used to investigate associations between baseline characteristics and on-treatment SAEs and withdrawal from treatment, death or relapse/treatment failure.  Results  201 (31.5%) of 639 patients taking standard therapy experienced grade 3/4 AEs or SAEs during treatment. AEs, SAEs, and withdrawals from treatment occurred most frequently in the intensive phase (see Table). Of 116 SAEs reported 84 (72.4%) improved or resolved and were most commonly respiratory (16.4%), gastrointestinal (6.9%), and infection (5.2%) related. There were 10 deaths in follow-up due to suicide, trauma, TB relapse, and acute illness. Logistic regression detected a significant association between on-treatment SAEs and withdrawal (p<0.001) or death (p<0.001), but not relapse/treatment failure (p=0.611). HIV-positive status (OR 4.25, p=0.016) and lower baseline weight (OR 1.46, p=0.023) were associated with the reporting of on-treatment SAEs.  Discussion  AEs and SAEs were predominantly reported in the intensive phase, probably due to a combination of TB and effects of medication. However most deaths occurred in follow-up and were unrelated, emphasising the impact that social circumstances have on TB patients. The lack of significant association between SAEs during treatment and relapse/treatment failure provides reassurance that a complicated treatment period can end with successful treatment of TB. The association between SAEs on treatment and lower weights at baseline and HIV infection reinforces the need to monitor these patients closely.   Intensive  Phase (Month 0-2)  n=639 Continuation Phase (Month 3-6)  n= 596 Follow Up Phase (Month 7-18) n= 569  P value No of Grade 3 AEs  Reported 66 31 19 *** No. Grade 4 AEs  Reported 19 6 3 *** System Organ Class of  Reported Grade 3 & 4 AEs      Musculoskeletal 14 7 0 0.102 Metabolism & Nutrition 11 0 6 0.006 General Disorders 7 3 1 0.838 No of Grade 3 or 4 AEs  per Patient      0 578 574 554  <0.001  1 49 18 9  2 9 2 4  ≥3 3 2 2 No of Patients  with ≥1 SAE (Considered Related) 32  (21) 18  (6) 20  (2) 0.168 Mean No of SAEs  per Patient  1.78 1.39 1.60 0.092 No of Withdrawals   38 26 1 <0.001 No of Deaths   5 1 10 0.014  

Using adverse events in a tuberculosis trial to describe the tolerability of standard therapy

http://discovery.ucl.ac.uk/1544983/1/Tweed_Using_Adverse_events.pdf

Using adverse events in a tuberculosis trial to describe the tolerability of standard therapy

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