Evaluation of Oral Difelikefalin Efficacy and Safety in Moderate-to-Severe Pruritus Associated with Notalgia Paresthetica in Adults: A Randomized, Double-Blind Study

The primary objective of this study is to evaluate the efficacy of three different doses of oral **difelikefalin** compared to placebo in adult subjects with moderate-to-severe pruritus associated with notalgia paresthetica. This evaluation will determine the most effective dose for further investigation. Additionally, the study aims to assess the efficacy of the selected dose in reducing the intensity of itch after 8 weeks of treatment. This is clinically relevant as it addresses the need for effective management of pruritus, a common and distressing symptom in patients with notalgia paresthetica.

Secondary objectives include:

• Part A: Assessing the occurrence and nature of adverse events following the discontinuation of three different doses of oral difelikefalin after an 8-week treatment period.
• Part B: Evaluating the efficacy of oral difelikefalin in reducing the intensity of itch at different time points, as well as its impact on burning sensation, skin tingling, and skin hyperpigmentation. Additionally, the safety and tolerability of oral difelikefalin will be assessed in a larger patient population.

The clinical trial involves a total of **384 participants** diagnosed with **moderate-to-severe pruritus** associated with notalgia paresthetica. The study population includes both male and female subjects, with an age range that encompasses adults. Participants were selected based on specific criteria, including a history of chronic pruritus lasting at least six months and the presence of characteristic skin changes such as hyper- or hypopigmented macules, hyperkeratosis, lichenification, and/or excoriation in the upper back region. The trial population is considered vulnerable, and the study includes individuals whose pruritus is deemed suitable for systemic therapy. Lifestyle factors such as diet and physical activity were not specified as part of the selection criteria. The trial aims to evaluate the efficacy of oral difelikefalin in reducing itch intensity over an 8-week treatment period.

The clinical trial is designed as a **randomized**, **double-blind**, controlled study to evaluate the efficacy and safety of oral **difelikefalin** in adult subjects with moderate-to-severe pruritus associated with notalgia paresthetica. The trial is divided into two parts: Part A aims to evaluate three different doses of oral difelikefalin compared to placebo and select one dose for further investigation, while Part B focuses on assessing the efficacy of the selected dose in reducing itch intensity after 8 weeks of treatment. The trial is expected to run until July 31, 2026, with recruitment starting on November 1, 2023.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to determine eligibility based on criteria such as a history of chronic pruritus due to notalgia paresthetica and the presence of specific skin conditions. Following randomization, participants will attend follow-up visits at Day 2, and Weeks 1, 2, 4, and 8 to assess primary endpoints, including the percentage of patients achieving a ≥4-point improvement in the weekly mean of daily 24-hour itch scores and the percentage of patients who are free or almost free of itch by Week 8. Secondary endpoints will include safety evaluations and the number of adverse events during the study.

The expected length of participant involvement is approximately 8 weeks, with conditions for early termination including non-compliance with study procedures or the occurrence of adverse events that compromise participant safety. The study will utilize oral administration of difelikefalin in tablet form, with a maximum daily dose of 4 mg and a total dose not exceeding 224 mg over the treatment period. A placebo group will be included to provide a control for comparison. The trial is categorized as a Phase II/III study, indicating its focus on both efficacy and safety assessments.

The clinical trial involves the administration of **Difelikefalin**, a kappa-opioid receptor (KOR) agonist, in tablet form. The experimental medication is provided in three different dosages to evaluate its efficacy and safety in treating moderate-to-severe pruritus in adult subjects with notalgia paresthetica. The first dosage involves a maximum daily dose of 2 mg, with a total maximum dose of 112 mg over an 8-week treatment period. The second dosage consists of a maximum daily dose of 0.5 mg, with a total maximum dose of 28 mg over the same period. The third dosage allows for a maximum daily dose of 4 mg, with a total maximum dose of 224 mg over 8 weeks. All doses are administered orally. The active substance, difelikefalin, is of chemical origin and is manufactured by Cara Therapeutics, Inc.

In addition to the experimental medication, a **placebo** is used as a comparator treatment in the study. The placebo is administered orally, mirroring the administration route of the experimental drug, to maintain the double-blind nature of the trial. The placebo does not contain any active pharmaceutical ingredients and serves to evaluate the efficacy of difelikefalin by comparison. Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the treatment protocol.

The efficacy of oral **Difelikefalin** in treating moderate-to-severe pruritus in adult subjects with Notalgia Paresthetica will be assessed through a series of primary endpoints. These include the percentage of patients achieving a ≥4-point improvement from baseline in the weekly mean of the daily 24-hour Itch scores, evaluated on Day 2, and at Weeks 1, 2, 4, and 8. Additionally, the percentage of patients who are free or almost free of itch, defined as achieving a weekly mean of the daily 24-hour Itch score of 0 to 1 at Week 8, will be measured. Other primary endpoints include the mean change from baseline in the burning sensation scale and the skin tingling scale at Week 8, as well as the percentage of patients with hyperpigmentation assessed as clear (0) or almost clear (1) at Week 8.

The efficacy assessments will be conducted using validated scales to ensure accurate and reliable data collection. The trial is structured in two parts: Part A aims to evaluate three different doses of oral **Difelikefalin** compared to placebo to select one dose for further investigation. Part B focuses on evaluating the efficacy of the selected dose in reducing the intensity of itch after 8 weeks of treatment. The trial will follow a multicenter, randomized, double-blind design to maintain the integrity and objectivity of the results.