Efficacy and Tolerability of AP707 in Patients with chronic pain due to central Neuropathy of any Genesis

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 central neuropathy of any genesis. This is clinically relevant as chronic pain associated with central neuropathy can significantly impair quality of life, and effective management is crucial for improving patient outcomes.

Secondary objectives include:

• Evaluation of the **safety** and tolerability of AP707.

The clinical trial focuses on evaluating the efficacy of AP707 as an add-on treatment for patients experiencing **chronic pain** due to central neuropathy of any genesis. The study population includes both female and male participants aged 18 years and older, with a life expectancy exceeding 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. Selection criteria include the completion of the QUISS questionnaire with a score of 45 or less and the willingness to use reliable contraception during and after the study. The trial population was selected based on these criteria, ensuring that participants have an existing need for further pain therapy.

The clinical trial is designed to evaluate the **efficacy** and tolerability of AP707 in patients with chronic pain due to central neuropathy of any genesis. This is a randomized, double-blind, placebo-controlled trial, conducted over a period of 52 weeks. The trial involves 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, pain intensity, and language proficiency. Following successful screening, participants will be randomized into one of the two study arms. Regular follow-up visits will occur at specified intervals, including weeks 5, 11, 14, 18, 22, 26, 30, 34, 39, 43, 47, and 52, to monitor progress and collect data on the 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 protocol deviations, or adverse events that compromise participant safety. The trial aims to recruit participants starting from May 1, 2023, with an estimated end date of December 31, 2024. The study will adhere to rigorous ethical standards, ensuring informed consent and the use of reliable contraception during and after the trial period.

The clinical trial involves the evaluation of several treatments, including both experimental and non-experimental medications. The primary experimental medication is **AP707**, an oromucosal spray suspension containing the active substance **ADEZUNAP**. This formulation is administered sublingually, with a maximum daily dose of 20.83 ml and a total maximum dose of 923.32 ml over a treatment period of up to 52 weeks. The administration is facilitated by a pump spray bottle, ensuring precise dosing. Participant compliance is monitored through regular assessments of dosing adherence and symptom tracking.

**LAMOTRIGINE** is included as a non-experimental treatment, classified under the ATC code N03AX09. It is administered orally in a pharmaceutical form denoted as PHF00008MIG. The maximum daily dose is 400 mg, with no specified total dose limit, and it is used off-label as per the Bfarm guidelines. The treatment period is not explicitly limited, allowing for long-term administration as needed.

Another non-experimental treatment is **AMITRIPTYLINE**, an oral medication with a maximum daily dose of 150 mg. It is categorized under the ATC code N06AA09 and is used for its tricyclic antidepressant properties with analgesic effects. The pharmaceutical form is PHF00082MIG, and the treatment duration is not restricted, supporting extended use.

**IMIPRAMINE HYDROCHLORIDE** is also utilized in the trial, administered orally with a maximum daily dose of 300 mg. It is classified under the ATC code N06AA02, serving as an antidepressant with analgesic properties. The pharmaceutical form is PHF00082MIG, and the treatment period is open-ended, allowing for prolonged administration.

The trial includes a combination product containing **BUCLIZINE HYDROCHLORIDE, PARACETAMOL, and CODEINE PHOSPHATE**. This analgesic is administered in a form denoted as PHF00082MIG, with a maximum daily dose of 4000 mg and a total dose limit of 500 mg over a 56-day period. The administration route is unspecified, categorized as "OTHER USE."

A placebo is also employed in the trial, designed to mimic the appearance and administration of AP707 without the active ingredient **Cannabis Sativa**. The placebo is a pump spray for sublingual application, containing all excipients of AP707, and is characterized by a brown-beige color with a sweet, slightly fruity odor. This ensures blinding and controls for placebo effects in the study.

The efficacy of the investigational product, AP707, in patients with chronic pain due to central **Neuropathy** of any genesis will be assessed through a series of primary and secondary endpoints. The primary endpoint involves evaluating the change in pain level on the Numeric Rating Scale (NRS, 0-10) from baseline to treatment week 14, comparing the active treatment group (verum) with the placebo group. Secondary endpoints include further assessments of pain level changes on the NRS at treatment weeks 26 and 52, as well as at various other timepoints such as weeks 5, 11, 18, 22, 30, 34, 43, and 47.

Additional secondary endpoints will measure changes in the pain score using the Neuropathic Pain Symptom Inventory (NPSI) questionnaire at weeks 14, 26, and 52. Responder analysis will be conducted to determine the proportion of patients achieving more than 30%, 40%, and 50% improvement in pain scores. Other assessments include changes in psychological distress using the Depression Anxiety Stress Scales Short Form (DASS-21), quality of life using the Veterans RAND (VR-12) questionnaire, sleep quality using the Regensburg Insomnia Scale (RIS), and pain score using the Brief Pain Inventory - Short Form (BPI-SF). The Patient Global Impression of Change (PGIC) will also be evaluated at weeks 14, 26, and 52.

The trial will also analyze the area under the NRS-curve at specified intervals and monitor the number of patients requiring rescue medication throughout the study. The number and severity of adverse events will be recorded to assess safety alongside efficacy. These efficacy parameters will be collected and analyzed at designated timepoints to provide a comprehensive evaluation of AP707's therapeutic potential in the target patient population.