High-dose rifampicin, moxifloxacin, and SQ109 for treating tuberculosis: a multi-arm, multi-stage randomised controlled trial.

BACKGROUND: Tuberculosis is the world's leading infectious disease killer. We aimed to identify shorter, safer drug regimens for the treatment of tuberculosis. METHODS: We did a randomised controlled, open-label trial with a multi-arm, multi-stage design. The trial was done in seven sites in South Africa and Tanzania, including hospitals, health centres, and clinical trial centres. Patients with newly diagnosed, rifampicin-sensitive, previously untreated pulmonary tuberculosis were randomly assigned in a 1:1:1:1:2 ratio to receive (all orally) either 35 mg/kg rifampicin per day with 15-20 mg/kg ethambutol, 20 mg/kg rifampicin per day with 400 mg moxifloxacin, 20 mg/kg rifampicin per day with 300 mg SQ109, 10 mg/kg rifampicin per day with 300 mg SQ109, or a daily standard control regimen (10 mg/kg rifampicin, 5 mg/kg isoniazid, 25 mg/kg pyrazinamide, and 15-20 mg/kg ethambutol). Experimental treatments were given with oral 5 mg/kg isoniazid and 25 mg/kg pyrazinamide per day for 12 weeks, followed by 14 weeks of 5 mg/kg isoniazid and 10 mg/kg rifampicin per day. Because of the orange discoloration of body fluids with higher doses of rifampicin it was not possible to mask patients and clinicians to treatment allocation. The primary endpoint was time to culture conversion in liquid media within 12 weeks. Patients without evidence of rifampicin resistance on phenotypic test who took at least one dose of study treatment and had one positive culture on liquid or solid media before or within the first 2 weeks of treatment were included in the primary analysis (modified intention to treat). Time-to-event data were analysed using a Cox proportional-hazards regression model and adjusted for minimisation variables. The proportional hazard assumption was tested using Schoelfeld residuals, with threshold p<0·05 for non-proportionality. The trial is registered with ClinicalTrials.gov (NCT01785186). FINDINGS: Between May 7, 2013, and March 25, 2014, we enrolled and randomly assigned 365 patients to different treatment arms (63 to rifampicin 35 mg/kg, isoniazid, pyrazinamide, and ethambutol; 59 to rifampicin 10 mg/kg, isoniazid, pyrazinamide, SQ109; 57 to rifampicin 20 mg/kg, isoniazid, pyrazinamide, and SQ109; 63 to rifampicin 10 mg/kg, isoniazid, pyrazinamide, and moxifloxacin; and 123 to the control arm). Recruitment was stopped early in the arms containing SQ109 since prespecified efficacy thresholds were not met at the planned interim analysis. Time to stable culture conversion in liquid media was faster in the 35 mg/kg rifampicin group than in the control group (median 48 days vs 62 days, adjusted hazard ratio 1·78; 95% CI 1·22-2·58, p=0·003), but not in other experimental arms. There was no difference in any of the groups in time to culture conversion on solid media. 11 patients had treatment failure or recurrent disease during post-treatment follow-up: one in the 35 mg/kg rifampicin arm and none in the moxifloxacin arm. 45 (12%) of 365 patients reported grade 3-5 adverse events, with similar proportions in each arm. INTERPRETATION: A dose of 35 mg/kg rifampicin was safe, reduced the time to culture conversion in liquid media, and could be a promising component of future, shorter regimens. Our adaptive trial design was successfully implemented in a multi-centre, high tuberculosis burden setting, and could speed regimen development at reduced cost. FUNDING: The study was funded by the European and Developing Countries Clinical Trials partnership (EDCTP), the German Ministry for Education and Research (BmBF), and the Medical Research Council UK (MRC).

Is surface ECG a useful surrogate for subcutaneous ECG?

BACKGROUND: Surface electrocardiograms (ECGs) have been used as surrogates for subcutaneous ECGs to optimize and evaluate subcutaneous devices, but differences between surface and subcutaneous ECGs remain poorly understood. This study evaluated the correspondence between surface and subcutaneous ECGs in Reveal Plus (Medtronic Inc., Minneapolis, MN, USA) patients during various maneuvers. METHODS: Surface electrodes were placed over the Reveal electrodes of 48 subjects (23 men, age 60 +/- 14.3 years, body mass index 27 +/- 4.9 kg/m(2), implant time 45 +/- 29 weeks). Surface and subcutaneous ECGs were recorded simultaneously for 30 seconds during rest, isometric myopotential noise (pushing palms together), and artifact-inducing maneuvers (repetitive displacement of device, chest thumping on device, arm flaps, handshake, hallwalk). RESULTS: During rest, subcutaneous and surface ECGs were highly correlated (R = 0.96), had similar R-wave amplitude (487 +/- 40 vs 507 +/- 49 microV, NS), and signal-to-noise ratio (SNR) (13.4 +/- 0.8 vs 13.5 +/- 0.7, NS). During myopotential noise, subcutaneous and surface ECGs were highly correlated (R = 0.91) and had similar SNR (10.0 +/- 0.6 vs 9.7 +/- 0.6, NS). During artifact-inducing maneuvers, subcutaneous and surface ECGs were less correlated (R = 0.82 displacement, 0.84 chest thumping, 0.93 arm flaps, 0.90 handshake, 0.92 hallwalk) with subcutaneous SNR significantly higher than surface (11.4 +/- 0.7 vs 9.9 +/- 0.7 displacement, 11.1 +/- 0.6 vs 8.4 +/- 0.6 chest thumping, 11.5 +/- 0.4 vs 10.3 +/- 0.5 arm flaps, 9.5 +/- 0.4 vs 8.4 +/- 0.4 handshake, 12.0 +/- 0.4 vs 10.0 +/- 0.4 hallwalk, P < 0.05). CONCLUSION: Surface ECGs are adequate surrogates for subcutaneous ECGs in situations free from motion artifacts but not in situations involving movement of the device, surface electrodes, or recording equipment. During artifact-inducing maneuvers, subcutaneous ECGs are of higher quality and less susceptible to artifacts than surface ECGs.

Liposome/water lipophilicity: methods, information content, and pharmaceutical applications.

This review discusses liposome/water lipophilicity in terms of the structure of liposomes, experimental methods, and information content. In a first part, the structural properties of the hydrophobic core and polar surface of liposomes are examined in the light of potential interactions with solute molecules. Particular emphasis is placed on the physicochemical properties of polar headgroups of lipids in liposomes. A second part is dedicated to three useful methods to study liposome/water partitioning, namely potentiometry, equilibrium dialysis, and (1)H-NMR relaxation rates. In each case, the principle and limitations of the method are discussed. The next part presents the structural information encoded in liposome/water lipophilicity, in other words the solutes' structural and physicochemical properties that determine their behavior and hence their partitioning in such systems. This presentation is based on a comparison between isotropic (i.e., solvent/water) and anisotropic (e.g., liposome/water) systems. An important factor to be considered is whether the anisotropic lipid phase is ionized or not. Three examples taken from the authors' laboratories are discussed to illustrate the factors or combinations thereof that govern liposome/water lipophilicity, namely (a) hydrophobic interactions alone, (b) hydrophobic and polar interactions, and (c) conformational effects plus hydrophobic and ionic interactions. The next part presents two studies taken from the field of QSAR to exemplify the use of liposome/water lipophilicity in structure-disposition and structure-activity relationships. In the conclusion, we summarize the interests and limitations of this technology and point to promising developments.