Abstract

Background: Effective and well-tolerated pharmacological treatments are wanted in OSA and drug repurposing program in OSA has targeted the carbonic anhydrase (CA) inhibitor sulthiame (STM). This study explored the effects on the OSA endotypic traits loop-gain (LG) and arousal threshold (ArTh) after STM.

Methods: A RCT, dose guiding, safety and tolerability trial in 68 OSA patients (age 61 (10) years, BMI 27.0 (3.1) kg/m², and non-acceptance of to CPAP. Repeat polysomnography nights were applied at baseline and follow-up.  STM 200, 400mg (n=12 and 25) or placebo (n=22) was given for four weeks. LG and ArTh during total/NREM sleep were determined. The study was approved by the ethics committee (045-18, 2018-02-07) and posted in the EU Clinical Trials Register (EudraCT N°: 2017-004767-13).

Results: Mean (SD) AHI at baseline was 53.9 (21.1), 61.1 (24.1) and 55.2 (22.3) in the placebo, STM 200mg and 400mg groups, respectively. The reduction after therapy were 3.0 (10.5), 20.5 (14.2) and 22.2 (12.5). Corresponding LG values at baseline were 0.66 (0.15), 0.69 (0.14) and 0.59 (0.11) and following STM -0.02 (0.08), -0.18 (0.08) and -0.19 (0.10) after placebo, STM 200mg (p<0.001) and 400mg (p<0.001). Baseline ArTh was 1.17 (0.22), 1.20 (0.19) and 1.15 (0.18) and values after STM were -0.02 (0.10), +0.07 (0.21) and +0.14 (0.20) (p<0.1 and p<0.003, placebo vs respective therapy). The reduction in NREM-LG was correlated with the change in NREM-AHI (R=-0.44, p<0.03).

Conclusion: This safety and tolerability study of STM in OSA demonstrated a dose-dependent reduction of LG and an increase of ArTh. The reduction of OSA after STM included most patients but was most pronounced in those with high LG and/or low ArTh.