(OR27-06-24) Ketone Monoester Administration in Cystic Fibrosis: A Pilot and Feasibility Study

Objectives: Mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene produce dysfunctional proteins that promote the accumulation of mucous and antigen-trapping in lungs leading to inflammation and pulmonary dysfunction. The ketone, beta-hydroxybutyrate (βHB), has been shown to decrease activation of the NLRP3 inflammasome leading to reduction in pro-inflammatory responses. The current investigation was designed to determine whether administration of the exogenous ketone ester [(R)-3-hydroxybutyl (R)-1,3-butanediol, KME] was 1) feasible, 2) increased circulating βHB concentrations, 3) improved subjective measures of CF-specific quality of life (QoL), and 4) improved markers of NLRP3 inflammasome activation in serum and sputum.

Methods: Fifteen participants were assigned to receive either KME (n =10) or placebo control (PC, n = 5) in a 2:1 randomized fashion during hospitalization for treatment of acute pulmonary exacerbation or as outpatients under standard care. Twenty mL of either the KME (10.0 g R-βHB) or PC was administered between 0800 and 09:30h and again at 1500h daily for 4-6 days. Spirometry was conducted before and 60 minutes following KME or PC on visit one and at follow-up.

Results: The KME was well-tolerated with only mild reports of GI disturbance that were similar in frequency with the PC group. Acute administration increased R-βHB concentrations from 0.2 ± 0.1 mM to 1.6 ± 0.6 mM in the KME group compared to 0.2 ± 0.0 to 0.3 ± 0.1 in the PC group (P = 0.011) within 15 minutes following consumption. KME administration did not significantly alter any of the serum inflammatory markers measured nor were there any statistically significant differences in pulmonary function (FEV1.0, FVC, or FEV1.0/FVC). Composite scores from the cystic fibrosis questionnaire response (CFQR) showed improvement in respiratory composite scores after single administration (P = 0.024) and 4-6 days later (P = 0.040).

Conclusions: The results of this study suggest that the exogenous KME is well-tolerated, increases circulating R-βHB concentrations, and improves subjective ratings of respiratory function in patients with CF.

Funding Sources: University of Alabama at Birmingham Gregory Fleming James Cystic Fibrosis Research Center Pilot and Feasibility Project: NIH/NIDDK