Efficacy and Tolerability of AP707 in Patients with chronic Pain due to traumatic or post-operative peripheral Neuropathy

The primary objective of this study is the evaluation of the **efficacy** of AP707 as an add-on treatment in patients with **chronic pain** due to traumatic or post-operative peripheral neuropathy. This is clinically relevant as chronic pain significantly impacts the quality of life and functional status of patients, and effective management is crucial for improving patient outcomes.

Secondary objectives include the evaluation of the **safety** and **tolerability** of AP707. Understanding the safety profile and tolerability is essential to ensure that the treatment is not only effective but also safe for long-term use in managing chronic pain conditions.

The clinical trial focuses on evaluating the efficacy of AP707 as an add-on treatment for patients experiencing **chronic pain** due to traumatic or post-operative peripheral neuropathy. The study population includes both female and male participants aged 18 years and older, with no vulnerable populations selected. Participants are required to have a life expectancy of more than one year and must have chronic pain persisting for at least three months, with a pain intensity of 5 or greater on the Numeric Rating Scale. The trial does not specify the total number of participants, as the sponsor has not provided this information. Participants are expected to have optimized standard care pain therapy upon study entry and must demonstrate a willingness to use reliable contraception during and after the study. Additionally, a good command of the German language is necessary to comprehend study questionnaires. The trial excludes individuals with a Quantification Inventory for Somatoform Syndromes score exceeding 45 points. Lifestyle considerations such as diet and physical activity are not detailed in the available data.

The clinical trial is designed to evaluate the **efficacy** and tolerability of AP707 as an add-on treatment in patients with chronic pain due to traumatic or post-operative peripheral neuropathy. This study is a randomized, double-blind, placebo-controlled trial, which will be conducted over an estimated duration of 20 months, with recruitment starting in May 2023 and expected completion by December 2024. The trial will involve two study arms: one receiving the active treatment (verum) and the other receiving a placebo. The primary endpoint is the change in pain level on the Numeric Rating Scale (NRS) between baseline and treatment week 14. Secondary endpoints include changes in pain levels at weeks 26 and 52, as well as various other measures of pain, psychological distress, and quality of life.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, pain intensity, and language proficiency. Following successful screening, participants will be randomized into one of the two study arms. The trial includes multiple follow-up visits at specified intervals (weeks 5, 11, 14, 18, 22, 26, 30, 34, 43, 47, and 52) to monitor changes in pain levels and other health parameters. The end-of-study visit will occur at week 52, marking the conclusion of the participant's involvement in the trial.

The expected length of participant involvement is approximately 52 weeks. Conditions that may lead to early termination from the study include the occurrence of severe adverse events, non-compliance with study procedures, or withdrawal of consent by the participant. The trial aims to provide comprehensive data on the potential benefits and safety of AP707 in managing chronic pain associated with peripheral neuropathy.

The clinical trial involves the administration of several treatments, including **gabapentin**, which is an anticonvulsant medication. Gabapentin is provided in an oral pharmaceutical form with a maximum daily dose of 3600 mg. The administration route is oral, and the treatment period is not specified with a maximum limit, indicating long-term administration potential. Participant compliance will be monitored to ensure adherence to the dosing schedule.

A placebo is also utilized in the study, designed as a pump spray for sublingual application. The placebo contains all excipients of the active product AP707, excluding the active ingredient **cannabis sativa**. The placebo is presented in 20 mL pump spray bottles, with a brown-beige appearance and a characteristic sweet and slightly fruity odor. This placebo is used to maintain blinding in the trial.

**Capsaicin** is another treatment used in the trial, classified as an analgesic. It is administered via cutaneous use, with a maximum daily dose of 2.2 mg. The pharmaceutical form is specified as PHF00017MIG, and the treatment period is not limited, allowing for extended use. Compliance with the application schedule will be monitored throughout the trial.

The trial also includes the administration of **imipramine hydrochloride**, an antidepressant with analgesic effects. This medication is provided in an oral form with a maximum daily dose of 300 mg. The pharmaceutical form is PHF00082MIG, and the treatment period is not restricted, suggesting potential for long-term administration. Participant adherence to the dosing regimen will be closely monitored.

**Amitriptyline**, a tricyclic antidepressant with analgesic properties, is administered orally with a maximum daily dose of 150 mg. The pharmaceutical form is PHF00082MIG, and the treatment period is not specified with a maximum limit, indicating potential for prolonged use. Monitoring of participant compliance with the dosing schedule is an integral part of the trial.

Additionally, the trial involves the use of a combination product containing **buclizine hydrochloride, paracetamol, and codeine phosphate**. This analgesic is administered via an unspecified route, with a maximum daily dose of 4000 mg and a maximum total dose of 500 mg. The treatment period is limited to 56 days, and participant adherence to the dosing regimen will be monitored to ensure compliance.

The experimental medication **AP707**, containing the active substance **adezunap**, is administered as an oromucosal spray, suspension. The maximum daily dose is 20.83 ml, with a total maximum dose of 923.32 ml over a treatment period of 52 weeks. The administration route is sublingual, and compliance with the dosing schedule will be monitored throughout the trial.

The efficacy of the investigational product AP707 in patients with chronic pain due to traumatic or post-operative peripheral neuropathy will be assessed using several primary and secondary endpoints. The primary endpoint is the change in pain level on the Numeric Rating Scale (NRS, 0-10) between baseline and treatment week 14, comparing study arm 1 (verum) and study arm 2 (placebo). Secondary endpoints include changes in pain levels on the NRS at treatment weeks 26 and 52, as well as changes in the pain score of the Neuropathic Pain Symptom Inventory (NPSI) questionnaire at weeks 14, 26, and 52. Additional secondary endpoints involve responder analysis for pain score improvements, changes in sCPT, psychological distress using the Depression Anxiety Stress Scales Short Form (DASS-21), Patient Global Impression of Change (PGIC), quality of life using the Veterans RAND (VR-12) questionnaire, sleep quality using the Regensburg Insomnia Scale (RIS), and pain score of the Brief Pain Inventory - Short Form (BPI-SF).

Data collection will occur at multiple timepoints, including weeks 5, 11, 14, 18, 22, 26, 30, 34, 39, 43, 47, and 52. The efficacy assessments will utilize validated scales and questionnaires, such as the NRS, NPSI, DASS-21, PGIC, VR-12, RIS, and BPI-SF. The analysis will include the area under the NRS-curve and the number of patients requiring rescue medication. The trial will also monitor the number and severity of adverse events throughout the study duration. These comprehensive assessments aim to provide a robust evaluation of the efficacy of AP707 in managing chronic pain associated with peripheral neuropathy.