Evaluation of Hydroxypropylbetadex and Standard of Care Versus Placebo in Niemann-Pick Disease Type C1: A Phase 3 Randomized, Double-Blind, Multicenter Study

The primary objective of this study is to evaluate the effectiveness of **Trappsol Cyclo** in combination with standard of care (SOC) compared to placebo and SOC in patients with **Niemann-Pick Disease Type C1**. This is assessed by measuring improvements using the 4-domain (4D-NPC-SS) or 5-domain (5D-NPC-SS) Niemann-Pick Disease Type C Severity Scale. The 4D-NPC-SS serves as the primary objective in the United States, while the 5D-NPC-SS is the primary objective in the European Union and the rest of the world. This distinction is clinically relevant as it allows for a comprehensive evaluation of the treatment's impact across different regions, ensuring that the assessment tools are tailored to the specific regulatory and clinical environments.

Secondary objectives include:

• Determining the ability of Trappsol Cyclo and SOC compared to placebo and SOC to improve ataxia, as assessed by the Spinocerebellar Ataxia Functional Index (SCAFI).
• Evaluating the effectiveness of Trappsol Cyclo and SOC compared to placebo and SOC, as assessed by the Vineland Adaptive Behavior Scale 2nd edition (Vineland 2) composite raw score, including the optional Motor Skills domain.
• Assessing the effectiveness of Trappsol Cyclo and SOC compared to placebo and SOC with regards to the patient's ability to swallow, as evaluated by the Penetration Aspiration Scale (PAS).

The clinical trial involves a total of **68 participants** diagnosed with **Niemann-Pick Disease Type C1**. The study population includes both male and female subjects, with an age range starting from 3 years and above. Participants were selected based on specific inclusion criteria, such as a confirmed diagnosis of NPC1 through genetic analysis or other clinical indicators, and a body weight between 4.5 kg and 125 kg. The trial includes individuals who may have been previously treated with miglustat or hydroxypropyl-β-cyclodextrin, provided certain conditions regarding treatment stability or discontinuation are met. Participants are required to present at least one neurological symptom of the disease, such as hearing loss, ataxia, or dystonia. The trial population is considered vulnerable, and all participants or their legally authorized representatives have provided informed consent. Lifestyle considerations, such as the ability to travel to study sites and compliance with study procedures, are also taken into account. The study does not specify any particular dietary or physical activity requirements for participants.

The clinical trial is a **Phase 3**, double-blind, randomized, placebo-controlled, parallel-group, multicenter study designed to evaluate the safety, tolerability, and efficacy of 2000 mg/kg of **Trappsol Cyclo** (Hydroxypropyl-β-cyclodextrin) in combination with standard care compared to placebo and standard care in patients with **Niemann-Pick Disease Type C1**. The trial is expected to run from July 2022 to June 2026, with a total duration of 96 weeks for each participant. The study involves multiple visits, starting with a screening visit to confirm eligibility based on criteria such as age, genetic confirmation of the disease, and neurological symptoms. Participants will be randomly assigned to receive either the investigational product or placebo, with both groups receiving standard care.

Study visits are structured to monitor the participants' progress and collect data on primary and secondary endpoints. The primary endpoints include changes in the 4-domain and 5-domain Niemann-Pick disease Type C Severity Scale from baseline to 48 and 96 weeks. Secondary endpoints involve assessments such as the SCAFI and Vineland-2 composite scores. Follow-up visits are scheduled at regular intervals to ensure compliance and assess the efficacy and safety of the treatment. The end-of-study visit marks the conclusion of the participant's involvement, where final assessments are conducted.

Participants are expected to remain in the study for the full 96 weeks unless conditions arise that necessitate early termination, such as adverse events, non-compliance, or withdrawal of consent. The trial's design ensures that all participants, regardless of location, are evaluated using consistent assessment tools, allowing for comprehensive data collection and analysis. The study's rigorous methodology and structured visit schedule are critical for achieving its objectives and contributing valuable insights into the treatment of Niemann-Pick Disease Type C1.

The clinical trial involves the administration of **Trappsol Cyclo**, a solution for infusion containing the active substance **hydroxypropylbetadex**. This investigational medication is administered via **intravenous infusion**. The maximum daily dose is 2000 mg/kg, with a total maximum dose of 96000 mg/kg over a treatment period of 96 weeks. The pharmaceutical form is a solution for infusion, and the product is manufactured by Cyclo Therapeutics Inc. The trial aims to evaluate the safety, tolerability, and efficacy of Trappsol Cyclo in patients with Niemann-Pick Disease Type C1.

**Zavesca** 100 mg hard capsules, containing the active substance **miglustat**, are also used in the study. This medication is administered **orally**. The maximum daily dose is 600 mg, with a total maximum dose of 403200 mg over a treatment period of 96 weeks. The pharmaceutical form is a hard capsule, and the product is manufactured by Janssen-Cilag International NV. Zavesca is used as a standard-of-care therapy in the trial.

The study includes the use of **Sodium chloride 0.45% solution for infusion** and **Sodium chloride 0.9% solution for infusion** as non-experimental treatments. These solutions are used as placebo controls in the trial. The pharmaceutical form and route of administration for these solutions are not specified in the data provided. These solutions serve as comparators to evaluate the efficacy of the investigational medication and standard-of-care therapy.

Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the treatment protocol. The trial is designed as a double-blind, randomized, placebo-controlled, parallel-group, multicenter study, with the primary objective of assessing the effectiveness of Trappsol Cyclo and standard-of-care therapy compared to placebo and standard-of-care therapy in patients with Niemann-Pick Disease Type C1.

Efficacy in this clinical trial will be assessed using the **Niemann-Pick Disease Type C Severity Scale** (NPC-SS), which includes both a 4-domain (4D-NPC-SS) and a 5-domain (5D-NPC-SS) version. The primary objective is to evaluate the effectiveness of Trappsol Cyclo in combination with standard of care compared to placebo and standard of care. The 4D-NPC-SS will be used as the primary objective in the United States, while the 5D-NPC-SS will serve as the primary objective in the European Union and the rest of the world. All patients, regardless of location, will be assessed using both scales according to the Schedule of Assessments.

The primary endpoints include the mean change in the 5D-NPC-SS composite score, which evaluates ambulation, fine motor skills, speech, swallow, and cognition, from baseline to 48 weeks for interim analysis and to 96 weeks for final analysis. Similarly, the 4D-NPC-SS composite score, assessing ambulation, fine motor skills, speech, and swallow, will be measured from baseline to 48 weeks and 96 weeks for interim and final analyses, respectively. Secondary endpoints include the mean change from baseline in the Scale for the Assessment and Rating of Ataxia (SCAFI), the Vineland Adaptive Behavior Scales, Second Edition (Vineland-2) composite raw score, and the patient's ability to swallow as assessed by the Penetration-Aspiration Scale (PAS) at 48 and 96 weeks.