Bilateral acute depigmentation of the iris (BADI) and bilateral acute iris transillumination (BAIT): A case series from a center in Brazil.

Bilateral acute depigmentation of the iris and bilateral acute iris transillumination (BAIT) are similar clinical entities. The former causes acute-onset depigmentation of the iris stroma without transillumination, whereas the latter causes depigmentation of the iris pigment epithelium with transillumination. The etiopathogenesis of these conditions is not yet fully understood, but the proposed causes include the use of systemic antibiotics (especially moxifloxacin) and viral triggers. We present a case series of five female patients with a mean age of 41 (32-45) years, all of whom suffered acute onset of bilateral pain and redness of the eyes after moxifloxacin use (oral or topical). It is important for ophthalmologists to be aware of the two forms of iris depigmentation since this case series suggests that SARS-CoV-2 or its empirical treatment with moxifloxacin may trigger iris depigmentation. If this is the case, clinicians will likely see increased incidences of bilateral acute depigmentation of the iris and bilateral acute iris transillumination during and after the COVID-19 pandemic.

Cardiovascular Evaluation of Etrasimod, a Selective Sphingosine 1-phosphate Receptor Modulator, in Healthy Adults: Results of a Randomized, Thorough QT/QTc Study.

Etrasimod is an investigational, once-daily, oral, selective sphingosine 1-phosphate receptor 1,4,5 modulator used as an oral treatment option for immune-mediated inflammatory disorders. This randomized, double-blind, placebo- and positive-controlled, parallel-group, healthy adult study investigated etrasimod's effect on the QT interval and other electrocardiogram parameters. All participants received etrasimod-matched placebo on day 1. Group A received once-daily, multiple ascending doses of etrasimod (2-4 mg) on days 1-14 and moxifloxacin-matched placebo on days 1 and 15. Group B received etrasimod-matched placebo on days 1-14 and either moxifloxacin 400 mg or moxifloxacin-matched placebo on days 1 and 15. The primary analysis was a concentration-QTc analysis using a corrected QT interval by Fridericia (QTcF). The etrasimod concentration-QTc analysis predicted placebo-corrected change from baseline QTcF (ΔΔQTcF) values and associated 90% confidence intervals remained <10 milliseconds over the observed etrasimod plasma concentration range (≤279 ng/mL). Etrasimod was associated with mild, transient, asymptomatic heart rate slowing that was most pronounced on day 1 (2 mg, first dose). The largest-by-time point mean placebo-corrected changes in heart rate from time-matched day -1 baseline (∆∆HR) on days 1, 7 (2 mg, last dose), and 14 (4 mg, last dose) were -15.1, -8.5, and -6.0 bpm, respectively. Etrasimod's effects on PR interval were small, with the largest least squares mean placebo-corrected change from baseline in PR interval (∆∆PR) being 6.6 milliseconds. No episodes of atrioventricular block were observed. Thus, multiple ascending doses of etrasimod were not associated with clinically relevant QT/QTc effects in healthy adults and only had a mild, transient, and asymptomatic impact on heart rate.

T-wave morphology abnormalities in the STREAM stage 1 trial.

BACKGROUND: Shorter regimens for drug-resistant tuberculosis (DR-TB) have non-inferior efficacy compared with longer regimens, but QT prolongation is a concern. T-wave morphology abnormalities may be a predictor of QT prolongation. RESEARCH DESIGN AND METHODS: STREAM Stage 1 was a randomized controlled trial in rifampicin-resistant TB, comparing short and long regimens. All participants had regular ECGs. QT/QTcF prolongation (≥500 ms or increase in ≥60 ms from baseline) was more common on the short regimen which contained high-dose moxifloxacin and clofazimine. Blinded ECGs were selected from the baseline, early (weeks 1-4), and late (weeks 12-36) time points. T-wave morphology was categorized as normal or abnormal (notched, asymmetric, flat-wave, flat peak, or broad). Differences between groups were assessed using Chi-Square tests (paired/unpaired, as appropriate). RESULTS: Two-hundred participants with available ECGs at relevant times were analyzed (QT prolongation group n = 82; non-prolongation group n = 118). At baseline, 23% (45/200) of participants displayed abnormal T-waves, increasing to 45% (90/200, p < 0.001) at the late time point. Abnormalities were more common in participants allocated the Short regimen (75/117, 64%) than the Long (14/38, 36.8%, p = 0.003); these occurred prior to QT/QTcF ≥500 ms in 53% of the participants (Long 2/5; Short 14/25). CONCLUSIONS: T-wave abnormalities may help identify patients at risk of QT prolongation on DR-TB treatment. TRIAL REGISTRATION: The trial is registered at ClinicalTrials.gov (CT.gov identifier: NCT02409290). Current Controlled Trial number, ISRCTN78372190.

Concentration-QTcF Modeling of Icenticaftor from a Randomized, Placebo- and Positive-Controlled Thorough QT Study in Healthy Participants.

Icenticaftor (QBW251) is a potentiator of the cystic fibrosis transmembrane receptor. Based on its mechanism of action, icenticaftor is expected to provide benefits in patients with chronic obstructive pulmonary disease by restoring mucociliary clearance, which would eventually lead to a reduction of bacterial colonization and related inflammatory cascade. A placebo- and positive-controlled, 4-way crossover thorough QT study was conducted in 46 healthy participants with the objective to assess the effect of therapeutic (300 mg twice daily for 6 days) and supratherapeutic (750 mg twice daily for 6 days) oral doses of icenticaftor on electrocardiogram parameters, including concentration-corrected QT (QTc) analysis. Moxifloxacin (400 mg, oral) was used as a positive control. In the concentration-QTc analysis performed on pooled data from Day 1 and Day 6 (steady state), the estimated population slope was shallow and slightly negative: -0.0012 ms/ng/mL. The effect on the Fridericia corrected QT (QTcF) interval (∆ΔQTcF) was predicted to be -1.3 milliseconds at the icenticaftor 300-mg twice-daily peak concentration (geometric mean was 1094 ng/mL) and -5.5 milliseconds at the 750-mg twice-daily peak concentration (geometric mean Cmax was 4529 ng/mL) indicated a mild shortening effect of icenticaftor on QTcF interval length. The results of the by-time-point analysis indicated least squares placebo corrected mean ∆∆QTcF across time points ranged from -7.9 to 0.1 milliseconds at 1 and 24 hours after dosing both on Day 6 in the 750-mg dose group compared with -3.7 to 1.6 milliseconds at 1.5 and 24 hours after dosing on Day 1 in the 300-mg dose group. Assay sensitivity was demonstrated with moxifloxacin. The large accumulation of exposures, especially the 4.3-fold increase in peak plasma concentration observed at the icenticaftor 750-mg twice-daily dosage compared with Icenticaftor 300 mg twice daily (2.3-fold) on Day 6 provided a large concentration range (up to 9540 ng/mL) to evaluate the effect of icenticaftor on ΔΔQTcF. Based on the concentration-QTc analysis, an effect on ΔΔQTcF exceeding 10 milliseconds can be excluded within the full observed ranges of plasma concentrations on icenticaftor, up to approximately 9540 ng/mL. Icenticaftor at the studied doses demonstrated a mild shortening in QTcF, which is unlikely to be of clinical relevance in a therapeutic setting.

Rare case report of moxifloxacin-induced persistent hiccups.

Moxifloxacin is a broad-spectrum antimicrobial agent that is commonly used in clinical practice. Here we report an unusual case of a patient with persistent hiccups caused by moxifloxacin. A man aged in his 40s was treated with moxifloxacin for tuberculous pleurisy. Hiccups occurred 2 hours after intravenous injection of moxifloxacin and lasted into evening. On the second day after injection, hiccups occurred again and made it difficult for him to fall asleep. The clinician ruled out gastrointestinal disease, nervous system disease, electrolyte disturbance and other factors. On assessing causality of the adverse drug reaction, the Naranjo scale for moxifloxacin was six, indicating a probable relationship of hiccups with moxifloxacin. Hiccups stopped 2 min after intramuscular injection of metoclopramide. To our knowledge, this is the first case report about moxifloxacin-induced persistent hiccups. Clinicians should be aware of the rare adverse reaction.

Bilateral Acute Iris Transillumination After Systemic Moxifloxacin Treatment.

This case report discusses a diagnosis of bilateral acute iris transillumination secondary to systemic antibiotics in a patient who presented with persistent bilateral photophobia.

The "One-Step" approach for QT analysis increases the sensitivity of nonclinical QTc analysis.

Whether a compound prolongs cardiac repolarization independent of changes in beat rate is a critical question in drug research and development. Current practice is to resolve this in two steps. First, the QT interval is corrected for the influence of rate and then statistical significance is tested. There is renewed interest in improving the sensitivity of nonclinical corrected QT interval (QTc) assessment with modern studies having greater data density than previously utilized. The current analyses examine the effects of moxifloxacin or vehicle on the QT interval in nonhuman primates (NHPs) using a previously described one-step method. The primary end point is the statistical sensitivity of the assessment. Publications suggest that for a four animal crossover (4 × 4) in NHPs the minimal detectable difference (MDD) is greater than or equal to 10 ms, whereas in an eight animal crossover the MDD is ~6.5 ms. Using the one-step method, the MDD for the four animal NHP assessments was 3 ms. In addition, the one-step model accounted for day-to-day differences in the heart rate and QT-rate slope as well as drug-induced changes in these parameters. This method provides an increase in the sensitivity and reduces the number of animals necessary for detecting potential QT change and represents "best practice" in nonclinical QTc assessment in safety pharmacology studies.

The possible effect of topically applied azithromycin and moxifloxacin on the alleviation of uveitis.

PURPOSE: To investigate the inhibitory effect of topically administered azithromycin (AZM), and moxifloxacin (MXF) against tumor necrosis factor-α (TNF-α) production in a rat model of endotoxin-induced uveitis (EIU). METHODS: Thirty-six Wistar albino rats were divided into 6 equal groups. Groups 1, 2 and 3 were determined as sham, control group for topical AZM application and control group for topical MXF application, respectively. Sterile saline, topical AZM 1.5%, and topical MXF 0.5% were instilled 5 times daily for totally 6 days on both eyes of the rats in Group 4, Group 5, and Group 6, before and after inducing EIU by intravitreal injections of lipopolysaccharide, respectively. At 24 h after intravitreal injections, aqueous humor was collected from both eyes of each rat for the assessment of TNF-α concentration. Also, density of nuclear factor kappa B (NF-κB) in ciliary body, and the number of cells infiltrating the posterior segment of EIU rat eyes was assessed in one eye of each rat. RESULTS: There was a significant reduction in mean aqueous humor concentration of TNF-α in EIU rats pretreated with topical AZM in comparison with those pretreated with sterile saline (139 ± 38.6 in Group 4 vs. 72 ± 12.6 in Group 5, p = 0.006). There was also a marked decrease in mean aqueous humor concentration of TNF-α in EIU rats pretreated with topical MXF (139 ± 38.6 in Group 4 vs.86.1 ± 35.5 in Group 6, p = 0.025). Also, evident suppressions were determined in mean density of NF-κB, and in mean number of cells in EIU rats pretreated either with topical AZM, or topical MXF. CONCLUSIONS: Topically applied AZM or MXF may be beneficial in the suppression of TNF-α production in aqueous humor.

Long-term Cardiovascular Adverse Events Induced by Fluoroquinolones: A Retrospective Case-control Study.

ABSTRACT: A correlation is already established between fluoroquinolones (FQs) use and cardiovascular events (CVEs), such as QT prolongation; however, serious events such as aortic aneurysm and valve regurgitation have also been reported with FQs. Several unstudied factors could contribute to the development of different CVEs that were not previously evaluated with FQ therapy. Therefore, we aimed to assess the incidence of different serious CVEs after completion of FQ therapy and potential associating factors. This was a retrospective case-control study of inpatients who received ciprofloxacin, levofloxacin, or moxifloxacin for ≥3 days. Patients' echocardiograms were evaluated for the development of aortic or valvular disease or worsening of an existing condition after completion of therapy. Of 373 included patients, 83 developed new valvular disease or worsening of an existing disease, where tricuspid valve regurgitation was the most common CVE (50/83; 60.2%), followed by mitral valve diseases (48/83; 57.8%). Aortic valve regurgitation occurred more commonly with moxifloxacin compared with ciprofloxacin and levofloxacin (17.8% vs. 6.7% and 10.7%, respectively; P = 0.01). Median time to CVE detection ranged 93-166 days for all FQs. The receipt of moxifloxacin and elevated baseline QT interval were associated with an increased CVEs risk (adjusted odds ratio 3.26; 95% confidence interval, 1.31-8.11 and adjusted odds ratio 1.02; 95% confidence interval, 1.00-1.04, respectively). Other factors did not show such association. The lack of association of different factors with the occurrence of CVEs indicates that all patients receiving FQ therapy, especially moxifloxacin, should be monitored during the first-year after therapy. Alternatively, other antibiotics with a better safety profile may be considered.

A phase IIb, open-label, randomized controlled dose ranging multi-centre trial to evaluate the safety, tolerability, pharmacokinetics and exposure-response relationship of different doses of delpazolid in combination with bedaquiline delamanid moxifloxacin in adult subjects with newly diagnosed, uncomplicated, smear-positive, drug-sensitive pulmonary tuberculosis.

BACKGROUND: Linezolid is an effective, but toxic anti-tuberculosis drug that is currently recommended for the treatment of drug-resistant tuberculosis. Improved oxazolidinones should have a better safety profile, while preserving efficacy. Delpazolid is a novel oxazolidinone developed by LegoChem Biosciences Inc. that has been evaluated up to phase 2a clinical trials. Since oxazolidinone toxicity can occur late in treatment, LegoChem Biosciences Inc. and the PanACEA Consortium designed DECODE to be an innovative dose-ranging study with long-term follow-up for determining the exposure-response and exposure-toxicity relationship of delpazolid to support dose selection for later studies. Delpazolid is administered in combination with bedaquiline, delamanid and moxifloxacin. METHODS: Seventy-five participants with drug-sensitive, pulmonary tuberculosis will receive bedaquiline, delamanid and moxifloxacin, and will be randomized to delpazolid dosages of 0 mg, 400 mg, 800 mg, 1200 mg once daily, or 800 mg twice daily, for 16 weeks. The primary efficacy endpoint will be the rate of decline of bacterial load on treatment, measured by MGIT liquid culture time to detection from weekly sputum cultures. The primary safety endpoint will be the proportion of oxazolidinone class toxicities; neuropathy, myelosuppression, or tyramine pressor response. Participants who convert to negative liquid media culture by week 8 will stop treatment after the end of their 16-week course and will be observed for relapse until week 52. Participants who do not convert to negative culture will receive continuation phase treatment with rifampicin and isoniazid to complete a six-month treatment course. DISCUSSION: DECODE is an innovative dose-finding trial, designed to support exposure-response modelling for safe and effective dose selection. The trial design allows assessment of occurrence of late toxicities as observed with linezolid, which is necessary in clinical evaluation of novel oxazolidinones. The primary efficacy endpoint is the change in bacterial load, an endpoint conventionally used in shorter dose-finding trials. Long-term follow-up after shortened treatment is possible through a safety rule excluding slow-and non-responders from potentially poorly performing dosages. TRIAL REGISTRATION: DECODE was registered in ClinicalTrials.gov before recruitment start on 22 October 2021 (NCT04550832).

In-Class Cross-Reactivity among Hospitalized Patients with Hypersensitivity Reactions to Fluoroquinolones.

Results from this large, multicenter study suggest that patients with a confirmed ciprofloxacin, moxifloxacin, or levofloxacin hypersensitivity reaction are likely to tolerate other fluoroquinolones. Avoiding different fluoroquinolones in patients labeled with a ciprofloxacin, moxifloxacin, or levofloxacin allergy may not always be mandatory. This was a study of patients with a ciprofloxacin, moxifloxacin, or levofloxacin hypersensitivity reaction and a documented electronic medical record administration of a different fluoroquinolone. Numerically, the most common reaction risk occurred with a challenge to moxifloxacin (2/19; 9.5%), followed by ciprofloxacin (6/89; 6.3%), and levofloxacin (1/44; 2.2%).

Concentration QTc analysis of giredestrant: Overcoming QT/heart rate confounding in the presence of drug-induced heart rate changes.

Concentration-QTc (C-QTc) analysis has become a common approach for evaluating proarrhythmic risk and delayed cardiac repolarization of oncology drug candidates. Significant heart rate (HR) change has been associated with certain classes of oncology drugs and can result in over- or underestimation of the true QT prolongation risk. Because oncology early clinical trials typically lack a placebo control arm or time-matched, treatment-free baseline electrocardiogram collection, significant HR change brings additional challenges to C-QTc analysis in the oncology setting. In this work, a spline-based correction method (QTcSPL) was explored to mitigate the impact of HR changes in giredestrant C-QTc analysis. Giredestrant is a selective estrogen receptor degrader being developed for the treatment of patients with estrogen receptor-positive (ER+) breast cancer. A dose-related HR decrease has been observed in patients under giredestrant treatment, with significant reductions (>10 bpm) observed at supratherapeutic doses. The QTcSPL method demonstrated superior functionality to reduce the correlation between QTc and HR as compared with the Fridericia correction (QTcF). The effect of giredestrant exposure on QTc was evaluated at the clinical dose of 30 mg and supratherapeutic dose of 100 mg based on a prespecified linear mixed effect model. The upper 90% confidence interval of ΔQTcSPL and ΔQTcF were below the 10 ms at both clinical and supratherapeutic exposures, suggesting giredestrant has a low risk of QT prolongation at clinically relevant concentrations. This work demonstrated the use case of QTcSPL to address HR confounding challenges in the context of oncology drug development for the first time.

Efficacy and safety of intravitreal injection of triamcinolone-moxifloxacin after cataract surgery in a low to middle income country - a one-year audit.

OBJECTIVE: To evaluate the safety and efficacy of intravitreal injection of triamcinolone and moxifloxacin regime administered immediately following cataract surgery. METHODS: The retrospective study was conducted from January to June 2021 at a tertiary care referral centre in Karachi and comprised record of all patients who underwent dropless cataract surgery from April 2018 to June 2019. Data included slit lamp examination, dilated fundal exam, uncorrected visual acuity, best corrected visual acuity, and intraocular pressure. Cataract assessment and anterior chamber reaction were graded according to the World Health Organisation cataract grouping system. Efficacy of the regime was defined as the ability to prevent postoperative endophthalmitis. Stratification analysis was done to note if gender has any role in terms of effectiveness. Data was analysed using Microsoft Excel version 16.0 and IBM SPSS version 27. RESULTS: Of 240 eyes of 161 patients analysed, 114(47.5%) were of men who had a mean age of 57.89±14.32 years, and 126(52.5%) were of females with a mean age of 58.02±10.85 years. Overall, 2(1.75%) male subjects and 1(0.8%) female subject developed breakthrough inflammation within one week of the procedure. They were treated with anti-inflammatory drops and in 1(33%) of the cases antibiotic drop for 1 week. At day 90, no patient had residual inflammation or new onset inflammation. Also, 15(6.25%) patients developed raised intraocular pressure from day 7 to day 30. Most cases 10(66.7%) resolved within 1 week of using intraocular pressure-lowering drops. No patient developed endophthalmitis postoperatively. CONCLUSIONS: Dropless cataract regime was found to be an effective and safe alternative that was easy to administer.

A Randomized, Double-Blind, Parallel Design Thorough QT Study With a Nested Crossover to Compare the Cardiac Safety of Amiselimod With Placebo and Positive Control in Healthy Volunteers.

This double-blind study evaluated the cardiac safety of amiselimod. Healthy adults (n = 190) were randomized (2:1:1) to receive (1) oral placebo (day -1), followed by oral amiselimod (days 1-26), which was upwardly titrated from 0.4 to 1.6 mg once daily to achieve steady-state concentrations comparable with 0.4 (therapeutic) and 0.8 mg (supratherapeutic) once daily, and placebo (day 27); (2) placebo (day -1), oral moxifloxacin 400 mg (day 1; positive control), followed by placebo (days 1-27); or (3) placebo (days -1 to 26), followed by moxifloxacin 400 mg (day 27). No participant had a corrected QT interval by Fredericia (QTcF) >500 milliseconds or a change from baseline (dQTcF) >60 milliseconds. The upper limits of the 90%CIs for the differences in least-squares mean difference in dQTcF between amiselimod and placebo on days 13 and 26 were <10 milliseconds. Area under the concentration-time curve from 0 to 23.5 hours after dosing and maximum plasma concentration of amiselimod and amiselimod-P (active metabolite) at steady-state concentrations for the 0.8-mg dose on day 26 were approximately double that observed with the 0.4-mg dose on day 13. All adverse events were mild to moderate in severity, and no deaths occurred. Amiselimod did not have any clinically relevant effect on the QTcF interval.

Rifapentine With and Without Moxifloxacin for Pulmonary Tuberculosis in People With Human Immunodeficiency Virus (S31/A5349).

BACKGROUND: Tuberculosis (TB) Trials Consortium Study 31/AIDS Clinical Trials Group A5349, an international randomized open-label phase 3 noninferiority trial showed that a 4-month daily regimen substituting rifapentine for rifampin and moxifloxacin for ethambutol had noninferior efficacy and was safe for the treatment of drug-susceptible pulmonary TB (DS-PTB) compared with the standard 6-month regimen. We explored results among the prespecified subgroup of people with human immunodeficiency virus (HIV) (PWH). METHODS: PWH and CD4+ counts ≥100 cells/µL were eligible if they were receiving or about to initiate efavirenz-based antiretroviral therapy (ART). Primary endpoints of TB disease-free survival 12 months after randomization (efficacy) and ≥ grade 3 adverse events (AEs) on treatment (safety) were compared, using a 6.6% noninferiority margin for efficacy. Randomization was stratified by site, pulmonary cavitation, and HIV status. PWH were enrolled in a staged fashion to support cautious evaluation of drug-drug interactions between rifapentine and efavirenz. RESULTS: A total of 2516 participants from 13 countries in sub-Saharan Africa, Asia, and the Americas were enrolled. Among 194 (8%) microbiologically eligible PWH, the median CD4+ count was 344 cells/µL (interquartile range: 223-455). The rifapentine-moxifloxacin regimen was noninferior to control (absolute difference in unfavorable outcomes -7.4%; 95% confidence interval [CI] -20.8% to 6.0%); the rifapentine regimen was not noninferior to control (+7.5% [95% CI, -7.3% to +22.4%]). Fewer AEs were reported in rifapentine-based regimens (15%) than the control regimen (21%). CONCLUSIONS: In people with HIV-associated DS-PTB with CD4+ counts ≥100 cells/µL on efavirenz-based ART, the 4-month daily rifapentine-moxifloxacin regimen was noninferior to the 6-month control regimen and was safe. CLINICAL TRIALS REGISTRATION: NCT02410772.

A randomized, double-blind, crossover study of the effect of the fluoroquinolone moxifloxacin on glucose levels and insulin sensitivity in young men and women.

AIM: The voltage-gated potassium channel Kv 11.1 is important for repolarizing the membrane potential in excitable cells such as myocytes, pancreatic α- and ß-cells. Moxifloxacin blocks the Kv 11.1 channel and increases the risk of hypoglycaemia in patients with diabetes. We investigated glucose regulation and secretion of glucoregulatory hormones in young people with and without moxifloxacin, a drug known to block the Kv 11.1 channel. MATERIALS AND METHODS: The effect of moxifloxacin (800 mg/day for 4 days) or placebo on glucose regulation was assessed in a randomized, double-blind, crossover study of young men and women (age 20-40 years and body mass index 18.5-27.5 kg/m2 ) without chronic disease, using 6-h oral glucose tolerance tests and continuous glucose monitoring. RESULTS: Thirty-eight participants completed the study. Moxifloxacin prolonged the QTcF interval and increased heart rate. Hypoglycaemia was more frequently observed with moxifloxacin, both during the 8 days of continuous glucose monitoring and during the oral glucose tolerance tests. Hypoglycaemia questionnaire scores were higher after intake of moxifloxacin. Moxifloxacin reduced the early plasma-glucose response (AUC0-30 min ) by 7% (95% CI: -9% to -4%, p < .01), and overall insulin response (AUC0-360 min ) decreased by 18% (95% CI: -24% to -11%, p < .01) and plasma glucagon increased by 17% (95% CI: 4%-33%, p = .03). Insulin sensitivity calculated as the Matsuda index increased by 11%, and MISI, an index of muscle insulin sensitivity, increased by 34%. CONCLUSIONS: In young men and women, moxifloxacin, a drug known to block the Kv 11.1 channel, increased QT interval, decreased glucose levels and was associated with increased muscle insulin sensitivity and more frequent episodes of hypoglycaemia.

Effect of Futibatinib on Cardiac Repolarization: Results of a Randomized, Controlled, Double-Blind, QT/QTc, Phase 1 Study in Healthy Subjects.

Futibatinib, a fibroblast growth factor receptor (FGFR) 1-4 inhibitor, is being investigated for FGFR-aberrant tumors. A 4-period, crossover, phase 1 thorough QT/QTc study compared effects on Fridericia heart rate-corrected QT (QTcF) interval of single doses of futibatinib 20 and 80 mg (therapeutic and supratherapeutic doses, respectively), placebo, and moxifloxacin (positive control) in healthy subjects. The study objective was to assess the time-matched difference in change from baseline in QTcF (ddQTcF) between futibatinib and placebo. In addition, changes from baseline in QTcF and other electrocardiogram (ECG) parameters, pharmacokinetics, ECG morphology, and safety were assessed. Forty-eight subjects were randomized. ddQTcF upper limits of 2-sided 90%CIs remained <10 milliseconds (clinical threshold) for both futibatinib doses at all time points (range, 2.0-4.5 milliseconds). Assay sensitivity was demonstrated by lower limits of 2-sided 97.5%CIs of the dQTcF difference between moxifloxacin and placebo of >5 milliseconds. Futibatinib exposure increased in a dose-dependent manner, and no significant relationship was detected between plasma futibatinib concentration and ddQTcF. There were no significant effects on heart rate, other ECG parameters, or ECG morphology. No serious adverse events occurred. Futibatinib did not prolong QTcF or affect other cardiac measures at therapeutic or supratherapeutic doses.

A 24-Week, All-Oral Regimen for Rifampin-Resistant Tuberculosis.

BACKGROUND: In patients with rifampin-resistant tuberculosis, all-oral treatment regimens that are more effective, shorter, and have a more acceptable side-effect profile than current regimens are needed. METHODS: We conducted an open-label, phase 2-3, multicenter, randomized, controlled, noninferiority trial to evaluate the efficacy and safety of three 24-week, all-oral regimens for the treatment of rifampin-resistant tuberculosis. Patients in Belarus, South Africa, and Uzbekistan who were 15 years of age or older and had rifampin-resistant pulmonary tuberculosis were enrolled. In stage 2 of the trial, a 24-week regimen of bedaquiline, pretomanid, linezolid, and moxifloxacin (BPaLM) was compared with a 9-to-20-month standard-care regimen. The primary outcome was an unfavorable status (a composite of death, treatment failure, treatment discontinuation, loss to follow-up, or recurrence of tuberculosis) at 72 weeks after randomization. The noninferiority margin was 12 percentage points. RESULTS: Recruitment was terminated early. Of 301 patients in stage 2 of the trial, 145, 128, and 90 patients were evaluable in the intention-to-treat, modified intention-to-treat, and per-protocol populations, respectively. In the modified intention-to-treat analysis, 11% of the patients in the BPaLM group and 48% of those in the standard-care group had a primary-outcome event (risk difference, -37 percentage points; 96.6% confidence interval [CI], -53 to -22). In the per-protocol analysis, 4% of the patients in the BPaLM group and 12% of those in the standard-care group had a primary-outcome event (risk difference, -9 percentage points; 96.6% CI, -22 to 4). In the as-treated population, the incidence of adverse events of grade 3 or higher or serious adverse events was lower in the BPaLM group than in the standard-care group (19% vs. 59%). CONCLUSIONS: In patients with rifampin-resistant pulmonary tuberculosis, a 24-week, all-oral regimen was noninferior to the accepted standard-care treatment, and it had a better safety profile. (Funded by Médecins sans Frontières; TB-PRACTECAL ClinicalTrials.gov number, NCT02589782.).

An evaluation of a supratherapeutic dose of inclisiran on cardiac repolarization in healthy volunteers: A phase I, randomized study.

Inclisiran is a small interfering RNA molecule that has been shown to provide an effective and sustained reduction in low-density lipoprotein cholesterol levels. This study aimed to determine whether a supratherapeutic dose of inclisiran affects cardiac repolarization and conduction in healthy volunteers. A phase I, randomized, double-blind, double-dummy, placebo- and positive-controlled, three-way crossover study was performed in 48 healthy volunteers. Volunteers were assigned to three treatments in a randomized sequence: a supratherapeutic dose of inclisiran sodium (900 mg), placebo, or moxifloxacin 400 mg as a positive control, with a minimum 7-day washout period between treatments. Continuous electrocardiogram monitoring was performed from >60 min before dosing until 48 h after dosing. Pharmacokinetics, pharmacodynamics, and safety were also assessed. Inclisiran, at a supratherapeutic dose, did not show a clinically significant effect on the QT interval (Fridericia correction formula [QTcF]; maximal placebo- and baseline-corrected change: 2.5 ms [90% confidence interval: 0.6, 4.5]) near the maximal plasma concentrations at 4 h. In addition, inclisiran did not show any effects on other electrocardiogram intervals or ST- and T-wave morphology. The positive control, moxifloxacin, demonstrated the expected changes in QTcF interval, validating the adequate sensitivity of the study. A supratherapeutic dose of inclisiran sodium (900 mg) had no effect on the QTcF interval or other electrocardiogram parameters, providing additional insight and reassurance regarding the safety profile of inclisiran.