A Thorough QT/QTc Study of Clobazam in Healthy Volunteers

Clin Ther. 2017 Oct;39(10):2073-2086. doi: 10.1016/j.clinthera.2017.08.020. Epub 2017 Sep 27.


Purpose: A thorough QT study was conducted to assess the proarrhythmic potential of clobazam and its active metabolite, N-desmethylclobazam (N-CLB).

Methods: In this Phase I, single-site, randomized, double-blind, double-dummy, parallel-group study, healthy participants were randomized to 1 of 4 treatment groups: clobazam 40 mg/d (maximum therapeutic dosage), clobazam 160 mg/d (supratherapeutic dosage), placebo, or moxifloxacin 400 mg (active control).

Findings: Of 280 enrolled participants (n = 70 per treatment arm), 250 (92%) completed the study; 194 were included in the pharmacokinetics population (clobazam 40 mg/d, n = 66; clobazam 160 mg/d, n = 62; and moxifloxacin, n = 66). Mean changes from baseline in QT interval placebo-corrected for heart rate using the Fridericia formula (primary end point), Bazett formula, and individual correction method (QTcF, QTcB, and QTcI, respectively) with clobazam 40 and 160 mg/d revealed no effect on QTc. No clinically relevant or treatment-related arrhythmias were observed, and there were no instances of second- or third-degree atrioventricular block. Given that clobazam is primarily demethylated to N-CLB by cytochrome P450 (CYP) enzyme, CYP3A4, the mean plasma time-concentration profile of clobazam was unchanged with the exclusion of CYP2C19 poor metabolizers. As N-CLB is metabolized by CYP2C19, the exclusion of CYP2C19 poor metabolizers resulted in slightly decreased mean plasma time-concentration profiles of N-CLB. Using a linear mixed-effects model, the effects of the clobazam and N-CLB Cmax values on the placebo-corrected changes from baseline in QTcF, QTcI, and QTcB were near zero or slightly negative, and are not considered clinically important. The incidence of treatment-emergent adverse events was greatest in the clobazam groups (number of moderate AEs experienced by patients: PBO, 3/70; MOXI, 5/70; CLB 40 mg/d, 18/70; CLB 160 mg/d, 21/70; severe AEs: PBO, MOXI, & CLB 160 mg/d, 0; CLB 40 mg/d, 2/70); there were no serious AEs in any treatment group. A total of 10% of participants experienced benzodiazepine-withdrawal symptoms (16%, 23%, and 3% in the clobazam 40 and 160 mg/d groups and the moxifloxacin group, respectively).

Implications: The findings from this thorough QT study are consistent with existing clinical data and support the lack of proarrhythmic potential with clobazam.

Keywords: ECG; Lennox-Gastaut syndrome; QT interval; clobazam; thorough QT.

Publication types

  • Clinical Trial, Phase I
  • Randomized Controlled Trial

MeSH terms

  • Adult
  • Anticonvulsants / adverse effects
  • Anticonvulsants / blood
  • Anticonvulsants / pharmacokinetics
  • Anticonvulsants / pharmacology*
  • Benzodiazepines / adverse effects
  • Benzodiazepines / blood
  • Benzodiazepines / metabolism
  • Benzodiazepines / pharmacokinetics
  • Benzodiazepines / pharmacology*
  • Clobazam
  • Cytochrome P-450 CYP2C19 / metabolism
  • Double-Blind Method
  • Female
  • Fluoroquinolones / adverse effects
  • Fluoroquinolones / blood
  • Fluoroquinolones / pharmacokinetics
  • Fluoroquinolones / pharmacology
  • Healthy Volunteers
  • Heart Rate / drug effects*
  • Humans
  • Male
  • Moxifloxacin


  • Anticonvulsants
  • Fluoroquinolones
  • Benzodiazepines
  • Clobazam
  • CYP2C19 protein, human
  • Cytochrome P-450 CYP2C19
  • N-desmethylclobazam
  • Moxifloxacin