(T1330-07-41) Toward High Drug-Loaded Pellets to Overcome Dysphagia: Safety and Acceptability of Placebo Pellets Co-Administered with a Swallowing Gel in Healthy Volunteers

Purpose: Pellets (small spherical particles with a narrow particle size distribution between 0.5-2 mm) provide therapeutic advantages including dosing flexibility, uniform dispersion along the gastro-intestinal tract and controlled release. Individuals with dysphagia encounter difficulties in swallowing, resulting in reduced therapy adherence and an increased risk of aspiration pneumonia. Conventional oral solid dosage forms such as tablets and capsules present challenges for this population, and there is a limited availability of alternative oral dosage forms designed to address their specific needs. Pellets, particularly when high drug-loaded and co-administered with a generically applicable swallowing gel, hold potential for effective drug delivery in dysphagia patients. The use of partially hydrolysed polyvinylalcohol proved to enable the production of high drug-loaded sustained release pellets via extrusion-spheronisation. Aim of the current study was to investigate the safety and acceptability of oral administration of placebo pellets in combination with commercially available CE-marked swallowing gels in healthy volunteers. Eight different formulations based on combinations of 2 conditions for pellet size, pellet mass and swallowing gel were evaluated.

Methods: A 2x2x2 factorial randomized balanced incomplete block design was used to evaluate the safety and acceptability of combinations of 2 different pellet sizes (500µm versus 1000 µm), 2 different pellet masses (250mg versus 750mg) and 2 different swallowing gels (Gloup Zero (GZ) versus Gloup Forte (GF)), which leads to 8 unique formulations. Each participant received 6 randomly assigned formulations out of these 8 unique formulations. Swallowing safety was assessed by the investigator after intake during a Fiberoptic Endoscopic Evaluation of Swallowing (FEES) using the Penetration Aspiration Scale (PAS). The PAS ranges from 1 to 8. Scores 1 and 2 were considered safe. Scores of 3 or higher indicated a potential safety risk for administration to patients with dysphagia. Investigator-reported swallowing acceptability was evaluated and compared during FEES using a modification of the Yale Pharyngeal Residue Severity Rating Scale (YPRSRS) for residual pellets at the vallecula and at the sinus piriformis, post rinsing. The YPRSRS score ranges from 1 to 5. Scores 1 and 2 were considered acceptable. Scores of 3 or higher were considered unacceptable. Participant-reported swallowing acceptability was evaluated and compared using an eight-item summary score considering participant’s scores on eight individual Visual Analogue Scales (VAS) ranging from 0 to 10. These individual VAS scales evaluate taste, the perception of pellets in the mouth, the perception of pellets in the pharynx, the perception of residual pellets in the mouth, the perception of residual pellets in the pharynx, swallowability, stickiness, visual aspect. The eight-item summary VAS score ranges from 0 to 80 with higher scores indicating higher swallowing acceptability. A mean difference of four was considered the smallest clinically relevant difference. The investigator-reported swallowing safety and acceptability were evaluated using descriptive statistics. The absolute and relative frequency (RF) of subjects with safe swallowing (PAS score ≤ 2) and subjects with acceptable swallowing (YPRSR score ≤ 2), together with the 95% Wilson score confidence interval (CI), were reported for each formulation.

Results: In total, 204 formulations were administered to 34 healthy volunteers. All formulations were considered safe (PAS ≤ 2) for administration to dysphagia patients (RF 99.51%, 203/204) except for the ‘GF 750mg 1000µm’ formulation (RF 96,15%, 1 out of 26 administrations of ‘GF 750mg 1000µm’). From the investigator’s point of view, all formulations were considered acceptable (YPRSR score ≤ 2) (RF 100%). The eight-item summary VAS score, to assess the participant-reported acceptability, ranges from 53.7 points (/80) (GF 750mg 1000µm) to 65.7 points (/80) (GF 250mg 500µm) (Figure 1). The mean difference between pellet mass conditions 250mg and 750mg was estimated at 8.59 points (95% CI: 6.63 – 10.54), in favour of 250mg (after averaging for swallowing gel and pellet size). (Figure 2). The estimated mean difference between pellet mass 250mg and 750mg (in favour of 250mg and after averaging for pellet size) was larger for GF (estimated at 11.33 points) compared to GZ (estimated at 5.84 points). We could not find a significant mean difference between swallowing gel conditions and pellet size conditions.

Conclusion: All formulations are generally safe for administration in healthy participants, except for the ‘GF 750mg 1000µm’ formulation (1 unsafe swallowing event out of 26). Based on clinical considerations, it might be less advisable to administer a formulation with at least one unsafe swallowing event to dysphagia patients. Notably, all formulations are considered acceptable by both investigator and participants. The effect of a smaller pellet mass on the higher mean participant-reported acceptability, was statistically as well as clinically relevant. The results of this study in healthy volunteers will serve as the basis for a subsequent study that will investigate the safety and acceptability of the administration of placebo pellets in combination with a swallowing gel in dysphagia patients.

References: Verstraete, G. et al, The use of partially hydrolysed polyvinyl alcohol for the production of high drug-loaded sustained release pellets via extrusion-spheronization and coating: in vitro and in vivo evaluation, Int. J. Pharm. 517 (2017) 88-95.

Acknowledgements: Approval for the study was granted by the Ethics Committee of Ghent University Hospital (B6702023000230). This research is financially supported by Bijzonder Onderzoeksfonds (BOF) UGent (IOF-Advanced/056).

Figure 1: Eight-item summary VAS score for all formulations: estimated marginal mean by formulation

Figure 2: Eight-item summary VAS score for all formulations: comparison between pellet mass conditions