Evaluation of Pain and Usability of Injection Techniques for Purified Chick-Embryo Cell-Culture Rabies Vaccine in Pediatric Pre-Exposure Prophylaxis

The primary objective of this study is to estimate the **pain intensity** experienced by children aged 4 to 14 years following each vaccination with the purified chick-embryo cell-culture rabies vaccine. This is clinically relevant as understanding pain levels can inform strategies to improve the vaccination experience and adherence to rabies pre-exposure prophylaxis in pediatric populations.

Secondary objectives include:

• Estimating the parent's or legal guardian's perception of the pain intensity experienced by their child after each vaccination.
• Assessing the usability of three different injection methods, focusing on parameters such as 'ease of use' and 'safety' as evaluated by vaccinators through a questionnaire.
• Evaluating the serological response 28 days post-completion of the 31 ID rabies pre-exposure prophylaxis schedule.
• Describing the overall occurrence and duration of solicited and unsolicited adverse events up to day 7 after each vaccination.
• Describing the occurrence of related and unrelated medically attended adverse events leading to study discontinuation and serious adverse events throughout the study.
• Estimating the anxiety experienced by the child after each vaccination.
• Estimating the parent's or legal guardian's perception of the anxiety experienced by their child after each vaccination.

The clinical trial involves a study population of children aged between **4 and 14 years** who are eligible for **rabies pre-exposure prophylaxis**. The trial includes both male and female participants, and the population is considered vulnerable due to the age group involved. The sponsor has not provided the total number of participants. Participants were selected based on their preparedness to adhere to the study schedule and the requirement for travel to rabies-endemic countries, where the risk of rabies exposure is high. The trial necessitates that a parent or legal guardian provides written informed consent, ensuring that both guardians are aware of and agree to the child's participation. The study does not specify any particular lifestyle considerations such as diet or physical activity.

The clinical trial is designed as an **open-label** pilot study to evaluate the pain experience and usability of different injection techniques and devices for administering the purified chick-embryo cell-culture **rabies vaccine** in children aged 4 to 14 years. The trial aims to assess the pain intensity experienced by the child after each vaccination, using the Faces Pain Scale-Revised (FPS-R) as the primary endpoint. Secondary endpoints include the Numeric Rating Scale (NRS) scores for usability parameters such as 'ease of use' and 'safety', as well as the percentage of participants achieving adequate seroconversion with rabies antibodies ≥ 0.5 IU/ml on day 28 after the third dose. The trial is expected to commence on January 6, 2025, and conclude by December 31, 2025.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age and parental consent. The study involves multiple follow-up visits for vaccination and assessment of pain and usability parameters. The end-of-study visit will evaluate the overall outcomes and any adverse events. The expected duration of participant involvement is approximately one year, with conditions for early termination including severe adverse events or withdrawal of consent by the parent or legal guardian.

The trial will utilize both **intradermal** and **intramuscular** routes for vaccine administration, with a maximum daily dose of 0.1 ml for intradermal and 1.0 ml for intramuscular injections. The study will monitor for solicited and unsolicited adverse events up to seven days post-vaccination, categorizing them as mild, moderate, or severe. The trial is not classified as a low-intervention study and is categorized as a Phase 3 trial, focusing on rabies pre-exposure prophylaxis. Participants are required to adhere to the study schedule, and any deviation may result in discontinuation from the trial.

The clinical trial involves the administration of **Rabipur**, a rabies vaccine containing the **rabies virus (inactivated) strain Flury LEP**. The vaccine is provided in the form of a powder and solvent for solution for injection in a pre-filled syringe. The pharmaceutical form is a **solution for injection**. The first experimental treatment involves the intradermal administration of Rabipur using the VAX-ID device. The maximum daily dose is 0.1 ml, with a total dose of 0.1 ml administered over a maximum treatment period of one day. The administration is conducted in a controlled clinical setting to ensure participant safety and compliance.

The second experimental treatment involves the intramuscular administration of Rabipur. This formulation is also a solution for injection, provided in a pre-filled syringe. The maximum daily dose for this route is 1.0 ml, with a total dose of 1.0 ml administered over a single day. The intramuscular route is a standard method for vaccine administration, ensuring efficient delivery of the active substance.

The third experimental treatment involves the intradermal administration of Rabipur using the Tropis ID device. Similar to the first treatment, the maximum daily dose is 0.1 ml, with a total dose of 0.1 ml administered over one day. The intradermal route is utilized to assess the usability and pain experience associated with this method of administration. Compliance monitoring is conducted throughout the trial to ensure adherence to the dosing schedule and to evaluate the usability of the different injection techniques and devices.

Efficacy in this clinical trial will be assessed using both primary and secondary endpoints. The primary endpoint involves evaluating the mean and median score of the Faces Pain Scale-Revised (FPS-R) after each vaccination. The FPS-R is a validated scoring system specifically designed for assessing acute pain in children aged 4 years and older. This will provide a direct measure of the pain intensity experienced by the child following vaccination.

Secondary endpoints include several measures: the mean and median score of a Numeric Rating Scale (NRS) as judged by the parent or legal guardian after each vaccination, and the mean and median score of the NRS for usability parameters such as 'ease of use' and 'safety'. Additionally, the percentage of participants with rabies antibodies ≥ 0.5 IU/ml on day 28 after the third dose will be measured, as this titre is considered an adequate seroconversion according to WHO standards. Other secondary endpoints include the count and percentage of solicited and unsolicited adverse events (AEs) up to day 7 after each vaccination, categorized as mild, moderate, or severe, and the count and percentage of related and unrelated medically attended adverse events (MAAEs) resulting in study discontinuation and serious adverse events (SAEs) throughout the study period. The mean and median score of the Children's Fear Score (CFS) after each vaccination will also be assessed.