Efficacy of Injectable Gentamicin Sulfate in Moderate to Severe Congenital Ichthyosis with Nonsense Mutation: A Phase 2 Clinical Trial

The primary objective of this Phase 2 study is to evaluate the **efficacy** of injectable gentamicin on the severity of scales and erythema at month 3 (M3) compared to baseline in patients with moderate to severe congenital ichthyosis caused by a nonsense mutation. This is clinically relevant as it aims to address the dermatological manifestations of congenital ichthyosis, potentially improving patient outcomes and quality of life.

Secondary objectives include:

• Describing the efficacy of gentamicin on the severity of scales and erythema at months 1, 2, 4, 5, 6, and 9 versus baseline.
• Assessing the efficacy on the importance of pruritus at months 1, 2, 3, 4, 5, 6, and 9 versus baseline.
• Evaluating the impact on transepidermal water loss measurement (TEWL) at months 1, 2, 3, and 6 versus baseline.
• Describing the safety of systemic gentamicin.
• Assessing the overall clinical severity at months 1, 2, 3, 4, 5, 6, and 9 versus baseline.
• Evaluating the protein expression of the target protein on skin biopsy at month 3 versus baseline.
• Assessing the impact on quality of life at months 3, 6, and 9 versus baseline.
• Describing overall patient satisfaction at month 6.

The clinical trial focuses on evaluating the efficacy of gentamicin in treating moderate to severe **congenital ichthyosis** caused by a nonsense mutation. The study population includes both male and female adult participants aged 18 years and older. Participants are required to have hereditary ichthyosis due to a homozygous nonsense mutation in specific genes such as TGM1, PNPLA1, ALOX12B, among others. The trial does not involve a vulnerable population. Participants must have moderate to severe forms of ichthyosis, as defined by a VIIS score of 2-3 in at least two out of four evaluated areas, including the back, upper limbs, lower limbs, and back of the foot. The sponsor has not provided information regarding the total number of participants. All participants must be affiliated with a social insurance protection regimen and provide free, informed consent, which is written and signed by both the participant and the investigator. No specific lifestyle considerations such as diet or physical activity are mentioned for this trial.

The clinical trial is a **Phase 2** study designed to evaluate the efficacy of injectable **gentamicin** in patients with moderate to severe **congenital ichthyosis** caused by a nonsense mutation. The trial employs a randomized, double-blind, controlled design to ensure the reliability and validity of the results. The estimated duration of the trial is from January 1, 2024, to December 31, 2025. Participants will be involved in the study for a maximum treatment period of three months, with the possibility of early termination if adverse events occur or if the participant withdraws consent.

The sequence of study visits includes an initial screening visit to confirm eligibility based on inclusion criteria such as age, genetic mutation, and severity of ichthyosis. Following the screening, participants will undergo baseline assessments before receiving the investigational product, **Gentamicin Panpharma 40 mg/ml solution for injection/infusion**. Follow-up visits are scheduled at monthly intervals (M1, M2, M3, M4, M5, M6, and M9) to monitor the primary endpoint, which is the proportion of patients with a decrease in the Visual Index of Ichthyosis Severity (VIIS) score by at least 15% at M3 compared to baseline. Secondary endpoints include evaluations of scaling, erythema, pruritus, transepidermal water loss, and quality of life, among others.

Throughout the study, adverse events will be closely monitored, with specific assessments such as creatinine clearance, bacteriology, vestibular function tests, audiograms, and skin biopsies conducted at designated visits. The end-of-study visit will involve a comprehensive evaluation of the participant's condition and the collection of final data. Participants may be withdrawn from the study if they experience significant adverse effects or if they choose to discontinue participation. The trial aims to provide valuable insights into the therapeutic potential of gentamicin for treating congenital ichthyosis.

The clinical trial involves the administration of **Gentamicin Panpharma 40 mg/ml solution for injection/infusion** as the experimental medication. This pharmaceutical form is a solution intended for injection or infusion, containing the active substance **gentamicin sulfate**. The medication is administered via injection, with a maximum daily dose of 10 mg/kg and a total maximum dose of 84 mg/kg over the treatment period. The maximum treatment duration is set at three days. The product is not formulated specifically for pediatric use and is not classified as an orphan drug. The administration of the drug is monitored to ensure compliance with the dosing schedule.

No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified for use in this study. The trial's primary objective is to evaluate the efficacy of gentamicin on the severity of scales and erythema in patients with moderate to severe congenital ichthyosis caused by a nonsense mutation. Participant compliance with the dosing regimen is monitored throughout the study to ensure adherence to the protocol.

The efficacy of the investigational product, **gentamicin sulfate**, will be assessed in a Phase 2 clinical trial focusing on patients with moderate to severe congenital ichthyosis caused by a nonsense mutation. The primary endpoint for evaluating efficacy is the proportion of patients achieving a decrease of at least 15% in the VIIS (Visual Index of Ichthyosis Severity) score at month 3 (M3) compared to baseline. This score assesses the severity of scales and erythema across four different body areas.

Secondary endpoints include the evaluation of the severity of scaling and erythema using the VIIS score at multiple timepoints (M1, M2, M4, M5, M6, and M9) compared to baseline. Additional assessments involve the evaluation of pruritus using a Visual Analog Scale (VAS) from 0 to 10, and the measurement of transepidermal water loss (TEWL) on the forearm using a tewameter at specified intervals (M1, M2, M3, and M6). Adverse events will be monitored throughout the study, including laboratory tests such as creatinine levels and clearance, bacteriology with antibiogram, vestibular function tests, audiograms, and videonystagmography at designated timepoints.

Further assessments include the Investigator Global Assessment (IGA) and Patient Global Assessment (PtGA) at various intervals, protein expression analysis on skin biopsy via western blot at M3, and quality of life evaluation using the IQoL-32 score at M3, M6, and M9. A global satisfaction questionnaire will be completed by patients at M6. These comprehensive evaluations will provide a robust assessment of the efficacy of gentamicin sulfate in this patient population.