C D Ennis, L K Mueller, L M Hooper
The influence of teacher value orientations on curriculum planning within the parameters of a theoretical framework
Research quarterly for exercise and sport
current tuberculosis tb drug development pipeline repopulated candidates including nitroimidazoles pretomanid exhibit potential shorten tb therapy exerting bactericidal effect nonreplicating bacilli based results preclinical early clinical studies fourdrug combination bedaquiline pretomanid moxifloxacin pyrazinamide bpamz regimen identified treatmentshortening potential drugsusceptible ds drugresistant dr tb trial aimed determine safety efficacy bpamz compared 4 months bpamz standard 6 months isoniazid rifampicin pyrazinamide ethambutol hrze dstb 6 months bpamz assessed drtb simplicitb partially randomised phase 2c openlabel clinical trial recruiting participants 26 sites eight countries participants aged 18 years older pulmonary tb sputum smear positive acidfast bacilli eligible enrolment participants dstb mycobacterium tuberculosis sensitivity rifampicin isoniazid participants drtb tuberculosis resistance rifampicin isoniazid participants dstb randomly allocated 11 ratio stratified hiv status cavitation chest radiograph using balanced block randomisation fixed block size four primary efficacy endpoint time sputum culturenegative status 8 weeks key secondary endpoint unfavourable outcome week 52 noninferiority margin 12 chosen key secondary outcome safety tolerability outcomes presented descriptive analyses efficacy analysis population contained patients received least one dose medication efficacy data available major protocol violations safety population contained patients received least one dose medication study registered clinicaltrialsgov nct03338621 completed july 30 2018 march 2 2020 455 participants enrolled received least one dose study treatment 324 71 participants male 131 29 participants female 303 participants dstb randomly assigned 4 months bpamz n150 hrze n153 modified intentiontotreat mitt analysis week 8 122 84 145 70 47 148 participants culturenegative 4 months bpamz hrze respectively hazard ratio earlier negative status 293 95 ci 217396 p00001 median time negative culture ttn 6 weeks iqr 48 4 months bpamz 11 weeks 612 hrze 86 participants drtb receiving 6 months bpamz n152 reached culturenegative status week 8 median ttn 5 weeks iqr 37 week 52 120 83 144 134 93 144 111 83 133 4 months bpamz hrze 6 months bpamz favourable outcomes respectively despite bacteriological efficacy 4 months bpamz meet noninferiority margin key secondary endpoint predefined mitt population due higher withdrawal rates adverse hepatic events noninferiority demonstrated perprotocol population confirming effect withdrawals 4 months bpamz least one liverrelated treatmentemergent adverse effect teae occurred among 45 30 participants 4 months bpamz 38 25 hrze 33 22 6 months bpamz serious liverrelated teaes reported 20 participants overall 11 7 among 4 months bpamz one 1 hrze eight 5 6 months bpamz common reasons discontinuation trial treatment hepatotoxicity ten participants 2 increased hepatic enzymes nine participants 2 qtcf prolongation three participants 1 hypersensitivity two participants 1 dstb bpamz successfully met primary efficacy endpoint sputum culture conversion regimen meet key secondary efficacy endpoint due adverse events resulting treatment withdrawal study demonstrated potential treatmentshortening efficacy bpamz regimen dstb drtb providing clinical validation murine model widely used identify regimens also highlights novel treatmentshortening tb treatment regimens require acceptable toxicity tolerability profile minimal monitoring lowresource highburden settings increased risk unpredictable severe hepatic adverse events 4 months bpamz would considerable obstacle implementation regimen settings high burdens tb limited infrastructure close surveillance liver biochemistry future research focus improving preclinical early clinical detection mitigation safety issues together efforts optimise shorter treatments tb alliance