Table 3 |.
Selected clinical trials of drug regimens for pulmonary TB and NTM-PD
| Indication | Duration (months) | Trial acronym or sponsor | Agents | Primary end pointa | Study identifier |
|---|---|---|---|---|---|
| Completed, with results indicative of treatment shortening | |||||
| DS-TB | 4 | TBTC Study 31 (non-inferiority phase III) | Isoniazid, rifapentine, moxifloxacin, pyrazinamide for 2 months, followed by isoniazid rifapentine for 2 months | Disease-free survival 12 months after end of treatment; outcome: 4-month treatment non-inferior to standard 6-month regimen (HRZE)32 | NCT02410772 |
| MDR-TB | 6 | NExT (phase III) | Bedaquiline, linezolid, levofloxacin, pyrazinamide, ethionamide/high-dose isoniazid | Favourable treatment outcome 24 months after treatment initiation; outcome: 6-month treatment non-inferior to >9-month injectable-based regimen222 | NCT02454205 |
| MDR-TB | 6 | TB-PRACTECAL (non-inferiority phase II/III) | Bedaquiline, pretomanid, linezolid, moxifloxacin for 6 months | Death, treatment failure or discontinuation; outcome: 6-month regimen safer and non-inferior to the 9- to 20-month standard-care treatment205 | NCT02589782 |
| MDR-TB | 9 | MDR-END (non-inferiority phase II) | Delamanid, linezolid, levofloxacin, pyrazinamide for 9 months | Treatment success; outcome: first 9-month all-oral regimen non-inferior to 20- to 24-month WHO-recommended treatment206 | NCT02619994 |
| DS-TB | 2 | TRUNCATE-TB (non-inferiority phase III) | Isoniazid, pyrazinamide, ethambutol, high-dose rifampicin, bedaquiline, linezolid | Unsatisfactory outcome (death or active disease at 12 months) leads to termination of a treatment arm; outcome: 2-month bedaquiline- and linezolid-containing regimen non-inferior to standard treatment224 | NCT03474198 |
| DS- and MDR-TB | 4 (DS) 6 (MDR) | SimpliciTB (phase IIc) | BPaMZ | Time to culture conversion over 8 weeks, rate of relapse 12 and 24 months after end of therapy with BPaMZ compared with HRZE; outcome: BPaMZ achieves treatment shortening, but side effects precluded completion in ~10% of patients247 | NCT03338621 |
| Dose-finding combination studies | |||||
| Pre-XDR and XDR-TB | 6 | ZeNIX (phase III) | Bedaquiline, pretomanid, linezolid | 600 mg linezolid instead of 1,200 mg in NIX-TB achieves similar cure rates with reduced adverse events (completed90) | NCT03086486 |
| MDR-TB | 6 | Opti-Q or TBTC study 32 (phase II) | Levofloxacin, OBR | Dose-finding study to evaluate efficacy, PK and tolerability of increasing levofloxacin doses in combination with OBR in patients with MDR-TB | NCT01918397 |
| DS-TB | 3 | SUDOCU (phase IIb) | Bedaquiline, delamanid, moxifloxacin, sutezolid | Dose-finding study to evaluate safety, tolerability, PK and exposure–response relationship of sutezolid in combination with bedaquiline, delamanid and moxifloxacin | NCT03959566 |
| DS-TB | 4 | DECODE (phase IIb) | Bedaquiline, delamanid, moxifloxacin, delpazolid | Dose-finding study to evaluate safety, tolerability, PK and exposure–response relationship of delpazolid in combination with bedaquiline, delamanid and moxifloxacin248 | NCT04550832 |
| Conventional non-inferiority trials | |||||
| DS-TB | 4 | RIFASHORT (phase III, completed) | Rifampicin, isoniazid, pyrazinamide, ethambutol | Open-label study: 4 months HRZE with 1,200 mg or 1,800 mg rifampicin was not non-inferior to the standard 6-month regimen (HRZE with 600 mg rifampicin), measuring combined rate of failure up to 12 months after end of therapy249 | NCT02581527 |
| MDR-TB | 9 | endTB (phase III) | 5 study arms comprising 4 or 5 of the following agents: bedaquiline, delamanid, clofazimine, linezolid, moxifloxacin or levofloxacin, pyrazinamide | Randomized, controlled, non-inferiority open-label clinical trial evaluating efficacy and safety of five 9-month treatment regimens containing recently approved drugs for MDR-TB compared with current standard of care for MDR-TB250 | NCT02754765 |
| XDR-TB | 6–9 | endTB-Q (phase III) | BeDeCLi | Randomized, controlled, non-inferiority open-label trial evaluating efficacy of BeDeCLi for 6 or 10 months according to disease phenotype, compared with WHO-recommended treatment | NCT03896685 |
| MDR- and XDR-TB | 6–9 | BEAT-TB (phase III) | Bedaquiline, delamanid, clofazimine, linezolid, levofloxacin for MDR-TB; bedaquiline, delamanid, clofazimine, linezolid for XDR-TB | Design and outcome measures similar to endTB-Q with secondary end points as PK–PD models of drug and metabolite exposure versus efficacy and toxicity | NCT04062201 |
| Ongoing adaptive trials and biomarker studies | |||||
| DS-TB | 4 | Predict-TB (phase II) | Isoniazid, rifampicin, pyrazinamide, ethambutol | Using biomarker combinations to predict treatment duration | NCT02821832 |
| DS-TB, RR/MDR-TB | 2–4 | DBOSPBOS (phase IIb/c) | Bedaquiline, OPC-167832, sutezolid, pretomanid, delamanid | Phase IIb/c, multi-arm, 2-stage, duration randomized trial of efficacy and safety for 2–4 months with bedaquiline, OPC-167832 and sutezolid, plus either pretomanid or delamanid | NCT05971602 |
| NTM-PD | 12 | Shanghai Pulmonary Hospital (phase IV) | Bedaquiline, clofazimine, linezolid + 2 or 3 drugs | Bacteriological and clinical treatment outcome | NCT05494957 |
| MAC-PD | 12 from sputum conversion | RedHill Biopharma | RHB-204 fixed-dose oral capsule containing clarithromycin, rifabutin and clofazimine | Sputum culture conversion after 6 months of treatment (3 consecutive negative sputum cultures at months 4, 5, 6 compared with placebo) | NCT04616924 |
| MAC-PD in patients with AIDS | 18 | National Institute of Allergy and Infectious Diseases | Macrolide, ethambutol, rifabutin or clofazimine | Sputum culture conversion at 1, 2 and 4 months and every 4 months thereafter for minimum of 1.5 years | NCT00001047 |
| NTM-PD | 3 | Medical University of South Carolina (phase II) | Inhaled nitric oxide | Sputum negative culture | NCT03748992 |
BeDeCLi, bedaquiline, delamanid, clofazimine, linezolid; BPaMZ, bedaquiline, pretomanid, moxafloxacin, pyrazinamide; DS-TB, drug-susceptible tuberculosis; HRZE: isoniazid, rifampicin (600 mg or 10 mg kg−1), pyrazinamide and ethambutol for 2 months followed by isoniazid and rifampicin (600 mg or 10 mg kg−1) for 4 months; RR, rifampicin resistant; MDR-TB, multidrug-resistant tuberculosis; NTM-PD, pulmonary disease caused by nontuberculous mycobacteria; OBR, optimized background regimen; PD, pharmacodynamic; PK, pharmacokinetic; TB, tuberculosis; XDR-TB, extensively drug-resistant tuberculosis.
a
Outcome described for completed trials only.