Efficacy and Tolerability of AP707 in Patients with chronic Pain due to Diabetic Polyneuropathy

The primary objective of this study is the evaluation of the **efficacy** of AP707 as an add-on treatment in patients experiencing chronic pain due to diabetic polyneuropathy. This is clinically relevant as diabetic polyneuropathy is a common complication of diabetes, often leading to significant pain and reduced quality of life. Effective management of this pain is crucial for improving patient outcomes and overall well-being.

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 this patient population.

The clinical trial focuses on evaluating the efficacy of AP707 as an add-on treatment for patients experiencing **chronic pain due to diabetic polyneuropathy**. The study population includes both male and female participants aged 18 years and older, with a life expectancy of more than one year. Participants are required to have chronic pain persisting for at least three months, with a current moderate to severe pain intensity of 5 or higher on the Numeric Rating Scale. The trial does not involve a vulnerable population. Participants must have a good command of the German language to comprehend study questionnaires. The sponsor has not provided information regarding the total number of participants. Lifestyle considerations include the willingness to use reliable contraception during and after the study. The trial population was selected based on specific criteria, including the completion of the QUISS questionnaire with a score of 45 or less. The sponsor has not disclosed additional details about the selection process or lifestyle factors such as diet or physical activity.

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 diabetic polyneuropathy. This is a randomized, double-blind, placebo-controlled trial, which will be conducted over an estimated duration of 52 weeks. 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, quality of life, and sleep quality.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, life expectancy, and current pain levels. Following successful screening, participants will be randomized into one of the two study arms. Regular follow-up visits will occur throughout the trial to monitor progress and collect data on primary and secondary endpoints. 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, with conditions for early termination including withdrawal of consent, significant adverse events, or non-compliance with study protocols. Participants are required to use reliable contraception during the study and for three months after the last dose of study medication. The trial aims to provide comprehensive data on the potential benefits of AP707 in managing chronic pain associated with diabetic polyneuropathy, contributing to the understanding of its therapeutic role.

The clinical trial involves the administration of several treatments, including both experimental and non-experimental medications. **Amitriptyline** is utilized as a tricyclic antidepressant with analgesic effects. It is administered orally in a pharmaceutical form coded as PHF00082MIG. The maximum daily dose is 150 mg, with a total maximum dose of 252 g over a treatment period of up to 60 days. Participant compliance is monitored through regular assessments.

A placebo is used in the form of a pump spray for sublingual application, contained in 20 mL bottles. This placebo mimics the excipients of AP707 without the active ingredient, cannabis sativa. The preparation is characterized by a brown-beige color and a sweet, slightly fruity odor.

**Capsaicin** is included as an analgesic, administered via cutaneous use. The pharmaceutical form is coded as PHF00017MIG, with a maximum daily dose of 2.2 mg and a total maximum dose of 369.6 mg over a 6-day treatment period.

**Paracetamol**, combined with anhydrous caffeine and paracetamol DC, is administered in a form coded as PHF00245MIG. It serves as an analgesic with a maximum daily dose of 4000 mg and a total maximum dose of 500 mg over a 56-day period.

**Carbamazepine** is used as an anticonvulsant, administered orally in a form coded as PHF00245MIG. The maximum daily dose is 120 mg, with a total maximum dose of 201600 mg over a 60-day treatment period.

**Imipramine hydrochloride** is another tricyclic antidepressant with analgesic effects, administered orally in a form coded as PHF00082MIG. The maximum daily dose is 300 mg, with an indefinite total maximum dose over an extended treatment period.

**Gabapentin** is administered as an anticonvulsant, in a pharmaceutical form coded as PHF00005MIG. The maximum daily dose is 3.6 g, with a total maximum dose of 6048 g over a 60-day treatment period.

**Adezunap** is the active substance in the experimental medication AP707, administered as an oromucosal spray suspension for sublingual use. The maximum daily dose is 20.83 ml, with a total maximum dose of 923.32 ml over a 52-day treatment period. Compliance is monitored through regular dosing schedules and participant feedback.

The efficacy of the investigational product, AP707, in patients with chronic pain due to diabetic polyneuropathy will be assessed using several parameters. 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 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, changes in psychological distress using the Depression Anxiety Stress Scales Short Form (DASS-21), and changes in quality of life using the Veterans RAND (VR-12) questionnaire.

Measurements will be collected at various timepoints, including weeks 5, 11, 18, 22, 30, 34, 43, and 47, to assess changes in pain levels on the NRS. The study will also evaluate changes in sleep quality using the Regensburg Insomnia Scale (RIS) and changes in the pain score of the Brief Pain Inventory - Short Form (BPI-SF) questionnaire. The area under the NRS-curve will be calculated until treatment week 52. The number of patients requiring rescue medication and the number and severity of adverse events will also be recorded throughout the trial. These assessments will provide a comprehensive evaluation of the efficacy of AP707 as an add-on treatment for chronic pain in this patient population.