Evaluating the Acceptability, Swallowability, and Palatability of Film-Coated Mini-Tablet Formulation in Young Children: Results from an Open-Label, Single-Dose, Cross-Over Study

Mini-tablets are advantageous over liquid formulations in overcoming challenges related to stability, taste, and dosage. This open-label, single-dose, cross-over study investigated the acceptability and safety of drug-free, film-coated mini-tablets in children aged 1 month–6 years (stratified: 4–6 years, 2–<4 years, 1–<2 years, 6–<12 months, and 1–<6 months), and their preference for swallowing either a high quantity of 2.0 mm or a low quantity of 2.5 mm diameter mini-tablets. The primary endpoint was acceptability derived from swallowability. The secondary endpoints were investigator-observed palatability, acceptability as a composite endpoint derived from both swallowability and palatability, and safety. Of 320 children randomized, 319 completed the study. Across all tablet sizes, quantities and age groups, acceptability rates based on swallowability were high (at least 87%). Palatability was rated as “pleasant/neutral” in 96.6% of children. The acceptability rates as per the composite endpoint were at least 77% and 86% for the 2.0 mm and 2.5 mm film-coated mini-tablets, respectively. No adverse events or deaths were reported. Recruitment in the 1–<6-months group was stopped early due to coughing—evaluated as “choked on” in three children. Both 2.0 mm and 2.5 mm film-coated mini-tablets are suitable formulations for young children.


Introduction
Designing pharmaceutical dosage formulations for children remains a major challenge due to the unique needs and characteristics of this patient population [1]. Evidence shows that over 60% of drugs are being used as off-label or off-license in children due to unavailability of child-appropriate dosage and formulations for many diseases [2,3]. The lack of trials in children and thus the lack of evidence for treatments in this population may result in the administration of potentially inadequate doses [4]. This may lead to an increased risk of potentially insufficient treatment or adverse reactions, including death, and deprives children of the full benefit of therapeutic advances. Liquid formulations provide dosing flexibility and ease of swallowing. However, they suffer from challenges of stability

Objectives
The primary objective of the study was to investigate the acceptability of a hig tity of 2.0 mm diameter film-coated mini-tablets compared to a low quantity of 2.5 ameter film-coated mini-tablets in children aged from 1 month to 6 years, accountin requirement of weight-based dosing in different age groups. The final dose for th drug iptacopan in children of <12 years of age is still subject to ongoing pediatric in tions, and for the purpose of this acceptability study a realistic high-dose scenario w sen leading to the administration of the indicated number of drug-free mini-tablets The secondary objectives were (i) to compare the swallowability of 2.0 mm mm film-coated mini-tablets in children aged from 1 month to 6 years; (ii) to com palatability of 2.0 mm and 2.5 mm film-coated mini-tablets in children aged from to 6 years; (iii) to identify any possible problem that could occur during swallow to identify the percentage of children who inhaled or coughed during ingestion o the two sizes of the oral formulations; and (v) to investigate the safety of the film drug-free mini-tablets.

Formulations
The mini-tablets were either 2.0 mm or 2.5 mm diameter in size, with a sph shape, and were manufactured by Novartis ( Figure 1). The increase in tablet diam 0.5 mm increases the volume of the tablet such that the drug dose can be double retaining a relatively small tablet size. Both mini-tablet formulations are drug-fr sisting of microcrystalline cellulose, lactose monohydrate, colloidal anhydrou croscarmellose sodium, and magnesium stearate in the core and a coating layer co sodium lauryl sulfate, stearic acid, basic butylated methacrylate copolymer, and t coating material used for the prototypes tested dissolves at pH up to 5 and prot mini-tablets from dissolving rapidly in the oral cavity (normal pH range 6.2-7.6 impacts acceptability and palatability [14,15].

Study Participants
The study was registered in the Deutsches Register Klinischer Studien (DRKS, German Clinical Trial Register) no. DRKS00027631. Male and female children aged 1 month to 6 years, who were inpatients or outpatients (for any reason) at the Department of General Pediatrics, Neonatology and Pediatric Cardiology of the University Hospital Düsseldorf, Germany, between 31 January 2022, and 25 April 2022, were recruited for this study. Children were stratified into five age groups (Group 1: 4-6 years, Group 2: 2-<4 years, Group 3: 1-<2 years, Group 4: 6-<12 months, and Group 5: 1-<6 months). The inclusion and exclusion criteria of the study participants are shown in Table 1.

Study Design
The study design is shown in Figure 2. This open-label, randomized, cross-over study was conducted in five different age groups (Group 1: 4-6 years, Group 2: 2-<4 years, Group 3: 1-<2 years, Group 4: 6-<12 months, and Group 5: 1-<6 months). Participants were recruited in a descending order starting with the oldest age group (i.e., 4-6 years). Once one-third of the required participants in this group had been successfully investigated without any safety concerns or adverse events, recruitment in the next younger age group (Group 2: 2-<4 years) began in parallel. The remaining recruitment was carried out concurrently with sentinel recruitment of the consecutive younger age groups, following the same procedure as for the previous age groups.
Each group was randomized to two parallel arms to receive either a low or a high quantity of drug-free, film-coated, mini-tablets. The two quantities (high and low) for both mini-tablet sizes were tested in order to compare and evaluate the number of tablets that will be needed to cover the doses required for the age range that is being tested as the doses are calculated based on body weight. Children in each arm received the film-coated mini-tablets in two consecutive periods, Period 1, and Period 2. Within each arm, the 2.0 mm and 2.5 mm film-coated mini-tablet sub-groups were compared in a randomized cross-over fashion. The precise number of mini-tablets in the low-or high-quantity minitablet arm was determined by the child's age, respectively (4-6 years: 25

Randomization
Randomization was performed by stratified age groups and dosing arms using a self developed and validated SAS macro RANDOM, which is based on the SAS function RA NUNI for uniformly distributed variables. Children were randomized into two armslow or high quantity mini-tablets. In a second step, children were assigned to one of the two treatment sequences (sequence 1 = 2.5 mm mini-tablets in Period 1 cross-over to 2.0 mm mini-tablets in Period 2; and sequence 2 = 2.0 mm mini-tablets in Period 1 cross-over to 2.5 mm mini-tablets in Period 2; Figure 2).

Administration Procedure
During the examination phase, the child and their parent(s) or legal guardian, were seated in a quiet area. Instructions were given to children in a standardized manner using age-appropriate language. The 2.0 mm or the 2.5 mm film-coated mini-tablets were given with either soft food (yoghurt or fruit mousse) or drinks (water, tea, milk, or juice) accord ing to the choice of the child, and their parent(s) or legal guardians. For soft food, mini

Randomization
Randomization was performed by stratified age groups and dosing arms using a self-developed and validated SAS macro RANDOM, which is based on the SAS function RANUNI for uniformly distributed variables. Children were randomized into two armslow or high quantity mini-tablets. In a second step, children were assigned to one of the two treatment sequences (sequence 1 = 2.5 mm mini-tablets in Period 1 cross-over to 2.0 mm mini-tablets in Period 2; and sequence 2 = 2.0 mm mini-tablets in Period 1 cross-over to 2.5 mm mini-tablets in Period 2; Figure 2).

Administration Procedure
During the examination phase, the child and their parent(s) or legal guardian, were seated in a quiet area. Instructions were given to children in a standardized manner using age-appropriate language. The 2.0 mm or the 2.5 mm film-coated mini-tablets were given with either soft food (yoghurt or fruit mousse) or drinks (water, tea, milk, or juice) according to the choice of the child, and their parent(s) or legal guardians. For soft food, mini-tablets were placed on a teaspoon with food and swallowed together. For drinks, the child swallowed the film-coated mini-tablets with a mouthful of drink administered immediately after the mini-tablets.
The trained investigator observed the swallowing process and the child's reaction (e.g., swallowed, chewed/left over, spat out, choked on, or refused to take). About 45 s after placing the film-coated mini-tablets into the child's mouth, the mouth was inspected by the investigator to ensure proper ingestion of the mini-tablet. Palatability was assessed by a second trained investigator, who observed the immediate physical reactions of the child after placing the formulation in child's mouth.
The procedures were repeated in Period 2 with the other formulation.

Endpoints
The primary endpoint was defined as the acceptability derived from swallowability as assessed by five scoring criteria from swallowability, Table 2. The secondary endpoints included palatability (as a binary outcome: 'pleasant' or 'other') and acceptability derived from the composite acceptability endpoint of swallowability and palatability and expressed as binary outcome ('yes', high or good acceptability or 'no', low or no acceptability). Adverse events (AEs) were also monitored and reported.

A. Scoring Criteria for Swallowability
Score Observation

Swallowed
No chewing took place during deglutition and no residuals of the solid were found during oral inspection.

Chewed/left over
Chewing was observed before deglutition and/or that the whole or parts of the solid were found in the mouth during oral inspection and/or some mini-tablets left over on the spoon (≥80% should have been swallowed).

Spat out
No deglutition took place and the solid was no longer in the child's mouth.

Choked on
The solid was swallowed the wrong way or a cough was caused.

Refused to take
The child did not allow the investigator to place the solid in the mouth and/or <80% of mini-tablets swallowed.

B. Definition of acceptability derived from swallowability alone
Criteria Acceptable Yes Swallowability score was 1 or 2

Evaluation Criteria
Swallowability and palatability were assessed separately, and their scoring criteria are provided in Table 2. The scoring criteria for assessing acceptability derived from a composite endpoint of swallowability and palatability, is also shown in Table 2. Acceptability as a composite endpoint was defined as "high", "good", "low", or "no" based on function of swallowability and the rating based on investigator's observation of palatability.

Determination of Sample Size
For each cross-over cohort (i.e., for each dosing arm in each age group), a sample size of 36 participants (18 per sequence group) was regarded as appropriate to address the primary objective. Based on this sample size, the 90% confidence interval (CI) for an anticipated difference of at least 15% points (e.g., 90% vs. 75%) between treatment acceptability rates would not have included zero. Furthermore, pooling of the data from the two cross-over designs for each age group (if justifiable) would lead to a sample size of 72 participants for each age group for the comparison of the 2.0 mm and the 2.5 mm tablet regimens. Based on 72 participants, a difference of at least 15% points (e.g., 90% vs. 75%) could have been detected with 80% power at a significance level α = 10% (two-sided). As a result, a total of 360 participants were planned to be randomized.

Statistical Analyses
All statistical calculations were carried out using SAS language and procedures (SAS 9.4 version, SAS-Institute, Cary, NC, USA). The imputation of missing data was not performed. The evaluation variables, endpoints, and safety data were summarized descriptively by treatment regimens. Categorical data were summarized using frequencies and percentages, and continuous data by number of observations, mean, standard deviation, minimum, first quartile, median, third quartile, and maximum.
The primary endpoint of acceptability was analyzed as binary outcome according to the cross-over design. Acceptability rates were compared between the two treatment regimens "high quantity of coated mini-tablets of 2.0 mm" and "low quantity of coated mini-tablets of 2.5 mm diameter" by applying the analysis method proposed by Schouten and Kester [17]. At first, the difference in acceptability rates between the two regimens was estimated for each sequence group and then averaged over both sequence groups in a second step. This analysis was performed for each cross-over setting in each age group, and for the combined cross-overs for each age group. Overall rates were analyzed by comparing the pooled data of low and high quantities of 2.0 mm tablets and low and high quantities of 2.5 mm tablets across all age groups.
The secondary endpoints were analyzed accordingly. The endpoint analyses were performed on the full-analysis-set which however was identical to the safety analysis set (participants who had received at least one administration of film-coated mini-tablets). This particularly means that major violations of any inclusion or exclusion criterion did not occur and that all participants had at least one post-enrolment endpoint assessment.

Disposition of Participants
A total of 320 children across five age groups (stratified: 4-6 years, 2-<4 years, 1-<2 years, 6-<12 months, and 1-<6 months) were included in the study, with 72 participants in each age group and 36 per age group in each dosing arm (2.0 mm 2.5 mm mini-tablets), except age group 5; Figure 3. One child in group 5 was withdrawn after the first administration due to coughing and thus a total of 319 children completed the study.

Primary Endpoint
The primary endpoint, acceptability rates based on swallowability, was high and comparable across tablet sizes, quantities, and age groups. The overall averaged difference between the two tablet sizes (2.0 mm minus 2.5 mm) was −0.3%, 90% CI −2.0 to 1.4; p = 0.757). The lowest acceptability rate was 87.1% in the youngest age group (which was not completed) for the 2.0 mm film-coated mini-tablets ( Figure 4).

Swallowability
Swallowability of the film-coated mini-tablets was assessed in children aged 1 month to 6 years based on five criteria ( Table 2). The majority of children in all age groups were able to swallow both 2.0 mm and 2.5 mm mini-tablets, with a higher swallowability rate observed in the younger age groups (1-<2 years, 6-<12 months, and 1-<6 months). In comparison, the proportion of children who chewed/leftover the mini-tablets were lower across younger age groups (1-<2 years, 6-<12 months, and 1-<6 months). The proportion of children who spat out, choked on, or refused to take the tablets were very low with both 2.0 mm and 2.5 mm mini-tablets. There were two children in the age group 6-<12

Primary Endpoint
The primary endpoint, acceptability rates based on swallowability, was high and comparable across tablet sizes, quantities, and age groups. The overall averaged difference between the two tablet sizes (2.0 mm minus 2.5 mm) was −0.3%, 90% CI −2.0 to 1.4; p = 0.757). The lowest acceptability rate was 87.1% in the youngest age group (which was not completed) for the 2.0 mm film-coated mini-tablets ( Figure 4).

Primary Endpoint
The primary endpoint, acceptability rates based on swallowability, was high and comparable across tablet sizes, quantities, and age groups. The overall averaged difference between the two tablet sizes (2.0 mm minus 2.5 mm) was −0.3%, 90% CI −2.0 to 1.4; p = 0.757). The lowest acceptability rate was 87.1% in the youngest age group (which was not completed) for the 2.0 mm film-coated mini-tablets ( Figure 4).

Swallowability
Swallowability of the film-coated mini-tablets was assessed in children aged 1 month to 6 years based on five criteria ( Table 2). The majority of children in all age groups were able to swallow both 2.0 mm and 2.5 mm mini-tablets, with a higher swallowability rate observed in the younger age groups (1-<2 years, 6-<12 months, and 1-<6 months). In comparison, the proportion of children who chewed/leftover the mini-tablets were lower across younger age groups (1-<2 years, 6-<12 months, and 1-<6 months). The proportion of children who spat out, choked on, or refused to take the tablets were very low with both 2.0 mm and 2.5 mm mini-tablets. There were two children in the age group 6-<12

Swallowability
Swallowability of the film-coated mini-tablets was assessed in children aged 1 month to 6 years based on five criteria ( Table 2). The majority of children in all age groups were able to swallow both 2.0 mm and 2.5 mm mini-tablets, with a higher swallowability rate observed in the younger age groups (1-<2 years, 6-<12 months, and 1-<6 months). In comparison, the proportion of children who chewed/leftover the mini-tablets were lower across younger age groups (1-<2 years, 6-<12 months, and 1-<6 months). The proportion of children who spat out, choked on, or refused to take the tablets were very low with both 2.0 mm and 2.5 mm mini-tablets. There were two children in the age group 6-<12 months (both cases were reported in the 2.0 mm mini-tablets), and three children in the youngest (1-<6 months) age group (two cases were reported with the 2.0 mm mini-tablets and one was with the 2.5 mm mini-tablets) who coughed during study drug administration and were assessed as "choked on", leading to discontinuation of recruitment in the youngest age group (Figure 5A,B).
Pharmaceutics 2023, 15, x FOR PEER REVIEW 9 of 16 months (both cases were reported in the 2.0 mm mini-tablets), and three children in the youngest (1-<6 months) age group (two cases were reported with the 2.0 mm mini-tablets and one was with the 2.5 mm mini-tablets) who coughed during study drug administration and were assessed as "choked on", leading to discontinuation of recruitment in the youngest age group ( Figure 5A,B).

Palatability
The palatability of the mini-tablets was generally rated as "pleasant" in the majority of children in age groups 1-<2 years, 2-<4 years, and 4-6 years, whereas palatability in the younger age groups (6-<12 months, and 1-<6 months) had mostly neutral ratings. An unpleasant reaction to the administration of both tablet sizes was found in less than 10% of the children in all age groups ( Figure 6A,B).
Palatability was also evaluated as a binary endpoint, with the outcomes of "pleasant or neutral" versus "unpleasant" being considered. As a result, palatability was observed

Palatability
The palatability of the mini-tablets was generally rated as "pleasant" in the majority of children in age groups 1-<2 years, 2-<4 years, and 4-6 years, whereas palatability in the younger age groups (6-<12 months, and 1-<6 months) had mostly neutral ratings. An unpleasant reaction to the administration of both tablet sizes was found in less than 10% of the children in all age groups ( Figure 6A,B).
as pleasant/neutral in 93.5% up to 100% of the children, whereas an unpleasant palatability was assessed only in very few children of all age groups. Palatability (observed as pleasant/neutral) did not differ across all tablet sizes, quantities, and age groups. The overall averaged difference between the two tablet sizes (2.0 mm minus 2.5 mm) was 0.3%, 90% CI −0.9 to 1.6; p = 0.648.

Acceptability as Composite Endpoint
The acceptability rates based on the composite endpoint of swallowability and palatability were comparable between the 2.0 mm and the 2.5 mm film-coated mini-tablets. High acceptability was most frequently observed in the age group 1-<2 years with 83.3% (2.0 mm) and 72.2% (2.5 mm) of the children, whereas these rates were very low in the age group 1-<6 months with 12.9% (2.0 mm) and 12.5% (2.5 mm). The youngest age group showed the highest proportion for good acceptability among both tablet sizes. Frequencies for acceptability as a composite endpoint in each age group are presented in Figure 7A,B. Palatability was also evaluated as a binary endpoint, with the outcomes of "pleasant or neutral" versus "unpleasant" being considered. As a result, palatability was observed as pleasant/neutral in 93.5% up to 100% of the children, whereas an unpleasant palatability was assessed only in very few children of all age groups. Palatability (observed as pleasant/neutral) did not differ across all tablet sizes, quantities, and age groups. The overall averaged difference between the two tablet sizes (2.0 mm minus 2.5 mm) was 0.3%, 90% CI −0.9 to 1.6; p = 0.648.

Acceptability as Composite Endpoint
The acceptability rates based on the composite endpoint of swallowability and palatability were comparable between the 2.0 mm and the 2.5 mm film-coated mini-tablets. High acceptability was most frequently observed in the age group 1-<2 years with 83.3% (2.0 mm) and 72.2% (2.5 mm) of the children, whereas these rates were very low in the age group 1-<6 months with 12.9% (2.0 mm) and 12.5% (2.5 mm). The youngest age group showed the highest proportion for good acceptability among both tablet sizes. Frequencies for acceptability as a composite endpoint in each age group are presented in Figure 7A,B. The acceptability rates based on high and good acceptability determined by the composite endpoint did not differ across all tablet sizes, quantities, and age groups. The overall averaged difference between the two tablet sizes (2.0 mm minus 2.5 mm) was −0.6%, 90% CI −2.6 to 1.3; p = 0.588; Figure 8. The acceptability rates based on high and good acceptability determined by the composite endpoint did not differ across all tablet sizes, quantities, and age groups. The overall averaged difference between the two tablet sizes (2.0 mm minus 2.5 mm) was −0.6%, 90% CI −2.6 to 1.3; p = 0.588; Figure 8.

Safety Assessments
Coughing, which met the swallowability criterion "choked on", was reported for two children in the age group 6-<12 months, and for three children in the age group 1-<6 months. None of these events were of clinical relevance and were not assessed as AEs. Nonetheless, as a precaution for infants in the age group 1-<6 months, the study was terminated due to clinical safety concerns. No AEs or deaths were reported in this study.

Discussion
This cross-over study provides evidence that the acceptability, swallowability, and palatability of a high quantity of smaller (2.0 mm) and a lower quantity of larger (2.5 mm) film-coated mini-tablets were similar in children of different age groups. The similarity in the acceptability of both sizes of mini-tablets indicates that increasing the tablet size by 0.5 mm does not reduce the acceptability. The larger mini-tablet size allows for doubling the dose of the active ingredient, thus enabling the possibility of formulating mini-tablets for a specific dosage, including high-dose therapies.
The study had a high power and credibility with a total of 320 children in two arms, and 72 participants in each age group, except the youngest group (n = 32), ensuring the validity of the results. Moreover, the cross-over study design allowed for the reduction of variability of data and the number of children required in this study.
The EMA Guideline on pharmaceutical development of medicines for paediatric use [7] and the Reflection paper on formulations of choice for the pediatric population [18] recommend various factors such as route of administration, dosage form, dosing flexibility, and excipients in the preparation when investigating acceptability of pediatric formulations. Moreover, acceptability is fundamental to effective pharmacotherapy and is defined as the ability and willingness of a patient to use and its caregiver to administer the medicine as intended [7]. Findings from our study showed a high rate of overall acceptability for mini-tablet formulations across all age groups, including children as young as 6 months up to 6 years. These are in line with previous research on acceptability of pediatric formulations [9][10][11][12][13].
Swallowing is a complex physiological process that requires the coordination of several muscles and nerves and occurs in multiple phases [19]. In young children, development of this process may vary from birth through adulthood [19]. Therefore, the main concern with solid oral formulations, especially in younger children, is their ability to swallow the formulation, which can increase the risk of inhalation and aspiration, which in turn could affect the ability to take solid dosage forms. Interestingly in this study, only a very few children in the age groups 1-<2 years, 6-<12 months, 1-<6 months had left-over mini-tablets in their mouths. In the current study, brief coughing-evaluated as "choked on" was experienced by two children in 6-<12 months (both for 2.0 mm mini-tablets) age

Safety Assessments
Coughing, which met the swallowability criterion "choked on", was reported for two children in the age group 6-<12 months, and for three children in the age group 1-<6 months. None of these events were of clinical relevance and were not assessed as AEs. Nonetheless, as a precaution for infants in the age group 1-<6 months, the study was terminated due to clinical safety concerns. No AEs or deaths were reported in this study.

Discussion
This cross-over study provides evidence that the acceptability, swallowability, and palatability of a high quantity of smaller (2.0 mm) and a lower quantity of larger (2.5 mm) film-coated mini-tablets were similar in children of different age groups. The similarity in the acceptability of both sizes of mini-tablets indicates that increasing the tablet size by 0.5 mm does not reduce the acceptability. The larger mini-tablet size allows for doubling the dose of the active ingredient, thus enabling the possibility of formulating mini-tablets for a specific dosage, including high-dose therapies.
The study had a high power and credibility with a total of 320 children in two arms, and 72 participants in each age group, except the youngest group (n = 32), ensuring the validity of the results. Moreover, the cross-over study design allowed for the reduction of variability of data and the number of children required in this study.
The EMA Guideline on pharmaceutical development of medicines for paediatric use [7] and the Reflection paper on formulations of choice for the pediatric population [18] recommend various factors such as route of administration, dosage form, dosing flexibility, and excipients in the preparation when investigating acceptability of pediatric formulations. Moreover, acceptability is fundamental to effective pharmacotherapy and is defined as the ability and willingness of a patient to use and its caregiver to administer the medicine as intended [7]. Findings from our study showed a high rate of overall acceptability for mini-tablet formulations across all age groups, including children as young as 6 months up to 6 years. These are in line with previous research on acceptability of pediatric formulations [9][10][11][12][13].
Swallowing is a complex physiological process that requires the coordination of several muscles and nerves and occurs in multiple phases [19]. In young children, development of this process may vary from birth through adulthood [19]. Therefore, the main concern with solid oral formulations, especially in younger children, is their ability to swallow the formulation, which can increase the risk of inhalation and aspiration, which in turn could affect the ability to take solid dosage forms. Interestingly in this study, only a very few children in the age groups 1-<2 years, 6-<12 months, 1-<6 months had left-over minitablets in their mouths. In the current study, brief coughing-evaluated as "choked on" was experienced by two children in 6-<12 months (both for 2.0 mm mini-tablets) age group and three children (one for 2.5 mm and two for 2.0 mm mini-tablets) in the youngest age group (1-<6 months) when taking the film-coated mini-tablets. Film-coated mini-tablets do not dissolve immediately in the mouth and may increase the risk of aspiration. Although these data were reviewed by the Study Monitoring Board who did not raise any safety concerns, further recruitment of children in youngest age group was stopped due to investigators' reservations. No AEs or deaths were reported in the study.
There were no cases of aspiration observed in this study, which is consistent with the previous studies that tested swallowability of uncoated mini-tablets in about 1000 children [9][10][11][12][13]. Although a few children aged 1-<6 months showed poor swallowing, the acceptability of mini-tablets was still high (87.1%) within this age group. These results are comparable with those from the earlier studies in neonates, which showed that acceptability was higher than swallowability [11].
The current study showed that a greater percentage of the older children (1-6 years) had chewed/left over tablets compared to the younger children (1-12 months). The ability of older children to chew and swallow solid foods is relatively well developed compared to younger children, and they may have a better control of their oral movements. This is also influenced by their prior experience with oral medications [20]. Thus, when asked to swallow the tablets, these children may inspect and assess the texture and probably chew it.
Another challenge with oral pediatric formulations is taste masking especially for liquid formulations [5]. Coating the solid oral pediatric formulations is a well-established method for taste masking. Palatability is an important criterion in pediatric age groups, since several drugs have a bitter taste and taste masking is necessary to enhance palatability, especially if the drug needs to be used for a prolonged period. In this study, both 2.0 mm and 2.5 mm film-coated mini-tablets were mostly assessed as pleasant across all age groups, except the youngest age group (1-<6 months) where most showed neutral reaction. Palatability assessed as neutral is sufficient for medications, as they are not intended to be enjoyed and this can help to discourage overdose of medications and misuse. The lack of positive experience of palatability in the youngest age group may be due to the differences in the developmental milestones in infants [21].
Acceptability rate based on swallowability alone was higher than the acceptability rate based on the composite endpoint of swallowability and palatability across all groups (97% vs. 88%, and 97% vs. 89%) for 2.0 mm and 2.5 mm, respectively), because palatability was assessed as "unpleasant" in a few children (ranging between one and six children per age group for the 2.0 mm film-coated mini-tablet, and between one and four children for the 2.5 mm film-coated mini-tablet). These results show that the new composite acceptability endpoint discriminates better in the assessment of acceptability than the calculation of acceptability based on swallowability alone.
The study has few limitations. One of the main limitations is that this was a single-dose cross-over study conducted in a hospital environment, and thus may lack generalizability of the results to a larger population or administration of the treatment for an extended period of time. Another limitation is that hospital-based studies are performed in a controlled environment, and thus the results may differ if the same treatment is applied in a home environment. Additionally, recruitment in the youngest age group (1-<6 months) was stopped earlier, so the results should be interpreted with caution for this age group.
The results from our pediatric study using the solid oral mini-tablets are encouraging and we believe this approach could be extended to other age groups. Eventually, study findings can be potentially implemented into and beyond the iptacopan pediatric program to provide more effective and convenient treatments for patients in all age groups. Importantly, this study was conducted as a part of a commitment to Health Authorities to develop an age-appropriate formulation for iptacopan (LNP023).
Iptacopan is an oral, first-in-class, highly potent, specific inhibitor of factor B of the alternative complement pathway [22], currently in development for the treatment of complement-mediated diseases (such as, complement [23][24][25]. Clinical studies are planned to evaluate the efficacy and safety of iptacopan for several indications in children and adolescents, using various pediatric formulations.

Conclusions
This single-dose, cross-over study demonstrated high acceptability of both sizes of film-coated mini-tablets (2.0 mm and 2.5 mm) for most children in all age groups, irrespective of the low or high quantity of tablets administered. The high acceptability rates were consistently observed throughout the study groups, regardless of the age group or tablet size with overall palatability being pleasant or neutral for over 90% of the children. These findings suggest that film-coated mini-tablets may be an excellent option for oral administration in young children between 6 months and 6 years. Importantly, our study suggests that additional monitoring is required to ensure safety in children aged 1-<6 months.
Overall, this study showed that oral film-coated mini-tablets are a promising option of pediatric formulation, and an alternative to the liquid formulations, which are likely to be unstable and challenging to store. Further research in other age groups would provide additional evidence for the use of film-coated mini-tablets.