Evaluation of Methylprednisolone Efficacy in Neuroendocrine Cell Hyperplasia of Infancy: A Phase I Study

The primary objective of this study is to evaluate the **efficacy** of a 6-month regimen of methylprednisolone pulses on the need for oxygen therapy in patients with Neuroendocrine Cells Hyperplasia of Infancy (NEHI) at 18 months. This is clinically relevant as it aims to determine the potential of methylprednisolone in reducing the dependency on oxygen therapy, which is a critical aspect of managing NEHI.

Secondary objectives include:

• Evaluating the number of patients requiring continuous oxygen therapy over time.
• Assessing the number of patients requiring only sleep oxygen over time.
• Determining the number of patients with a normal respiratory rate.
• Evaluating the healing of ChILD (reduction of severity) over time.
• Assessing the quality of life (QoL) of parents and patients.
• Evaluating the impact of NEHI on feeding and growth status.
• Exploratory objectives include comparing the family impact PedsQL questionnaire to the newly described chILD-PQoL questionnaire and studying thoracic CT-scan evolution.

The clinical trial involves a study population of infants diagnosed with **Neuroendocrine Cells Hyperplasia of Infancy** (NEHI). The participants are infants under 12 months of age, with both male and female subjects included. The trial population is considered vulnerable due to the young age of the participants. The selection criteria require a NEHI diagnosis based on a validated clinical score or a lung biopsy, along with an oxygen requirement as per pediatric recommendations. Participants are followed in one of the RespiRare participating centers. The sponsor has not provided information regarding the total number of participants. Written informed consent from the legal representatives of the infants is mandatory for inclusion in the study.

The clinical trial is designed to evaluate the efficacy of **methylprednisolone** pulses in infants diagnosed with **neuroendocrine cells hyperplasia of infancy** (NEHI). This study is structured as a randomized, double-blind, controlled trial, with a primary objective to assess the impact of a six-month treatment regimen on the need for oxygen therapy at 18 months post-inclusion. The trial is expected to commence recruitment on April 15, 2024, and conclude by January 15, 2028. Participants will be involved for a maximum of 18 months, with the treatment phase lasting up to six months.

Study visits are sequenced to include an initial screening visit, where eligibility is confirmed based on criteria such as age under 12 months, a NEHI diagnosis, and oxygen requirement. Following successful screening, participants will undergo regular follow-up visits to monitor treatment efficacy and safety. These visits will assess primary and secondary endpoints, including the number of children requiring oxygen therapy, respiratory rate normalization, and quality of life scores. The end-of-study visit will occur at 18 months, evaluating long-term outcomes and any adverse events.

Participants may be withdrawn from the study if they experience significant adverse effects, fail to adhere to the protocol, or if the legal representative withdraws consent. The trial will utilize **methylprednisolone** administered via intravenous infusion, with a maximum daily dose of 10 mg/kg and a total dose not exceeding 180 mg/kg over the treatment period. The study will also involve the use of **oxygen** therapy as a comparator, delivered through inhalation gas, with a maximum daily dose of 86,400 liters. The trial's design ensures rigorous monitoring of both efficacy and safety endpoints, contributing valuable data to the understanding of NEHI management.

The clinical trial involves the administration of **Methylprednisolone**, a chemical compound used as the experimental medication. Methylprednisolone is provided in the form of a powder for solution for injection. The administration route is via **intravenous infusion**. The dosage is calculated based on the participant's body weight, with a maximum daily dose of 10 mg/kg and a total maximum dose of 180 mg/kg over the treatment period. The treatment duration is set for a maximum of 6 months. Compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the protocol.

In addition to the experimental treatment, the study utilizes a combination of **Nitrous Oxide** and **Oxygen** as a non-experimental treatment. This combination is administered as an inhalation gas, classified under medical gases. The maximum daily dose is 86400 liters, with a total maximum dose of 47304060 liters over a treatment period of up to 18 months. The administration of this combination is intended to support the primary treatment and is monitored for participant compliance and safety.

The efficacy of methylprednisolone pulses in the treatment of **neuroendocrine cell hyperplasia of infancy (NEHI)** will be assessed through a series of primary and secondary endpoints. The primary endpoint is the number of children still requiring oxygen therapy at 18 months (M18) post-inclusion. Secondary efficacy endpoints include the number of children requiring only sleep oxygen at M18, the number of children with a normal respiratory rate at rest at M18, and the difference in Fan’s severity score, which evaluates the severity of interstitial lung disease (ILD) symptoms, between baseline (M0) and M18. Additionally, patient and family impact will be measured using the PedsQL and chILD QoL scores, as well as the chILDPQoL score at M0 and M18. The number of patients requiring at least one enteral nutrition episode due to abnormal weight curves between M0 and M18 will also be evaluated.

Data collection will occur at specified timepoints, including baseline (M0), 6 months (M6), and 18 months (M18). The Fan’s severity score will assess respiratory symptoms, oxygen saturation (SpO2) levels, and pulmonary hypertension. Patient-reported outcomes will be gathered using validated quality of life questionnaires. The trial will also explore the correlation between family impact PedsQL and the chILD-PQoL questionnaire at each measurement time. The presence and changes in ground glass opacities (GGO) on CT scans will be evaluated at M6 and M18 to assess disease progression or regression. These comprehensive assessments will provide a robust evaluation of the treatment's efficacy in NEHI patients.