Long Term Efficacy and Tolerability of AP707 in Patients With Chronic Pain Due to Diabetic Polyneuropathy

Study Overview
=================
Brief Summary
-----------------
Over the last years a rising medical need for treatment of chronic pain was identified. Based on previous findings indicating the pain modulating effects of cannabinoids in chronic pain disorders, this clinical trial investigates the long term efficacy and tolerability of the THC-focused nano endocannabinoid system modulator AP707 in patients with pain disorders due to diabetic polyneuropathy. Patients receive AP707 or placebo over the course of 14 weeks as an add-on to the standard of care. Changes in pain intensity, quality of life and sleep and others measures are monitored through different scales to assess the efficacy of AP707 in patients with chronic pain due to diabetic polyneuropathy.

Official Title
-----------------
Long Term Efficacy and Tolerability of AP707 in Patients With Chronic Pain Due to Diabetic Polyneuropathy

Conditions
-----------------
Pain, Pain Syndrome, Pain, Chronic, Chronic Pain, Chronic Pain Syndrome, Diabetes, Diabetic Neuropathies, Diabetic Polyneuropathy, Peripheral Neuralgia, Peripheral Neuropathy, Peripheral Neuropathy With Type 2 Diabetis

Intervention / Treatment
-----------------
* Drug: Adezunap (AP707)
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Signed and dated informed consent form Patients with chronic pain due to diabetic polyneuropathy since at least 3 months Female and male patients (> 18 years) Patients with more than 1 year life expectancy Patients with optimized sCPT on study entry as defined in section 3.1.1 and section 3.1.3 of the study protocol Willingness of study patients of both sexes to use reliable contraception during study participation and for three months after taking the last study medication Good command of German language, in order to understand questionnaires in German Current moderate to severe pain with pain intensity > 5 on Numeric Rating Scale (NRS, 0 - 10) and thus an existing need for further pain therapy Completed QUISS (Quantification Inventory for Somatoform Syndromes) questionnaire with 45 or less score points Exclusion Criteria: Medical history of hypersensitivity or intolerance to the investigational product or its ingredients or to ingredients of similar chemical structure Known intolerance to cannabinoids or cannabis products. Participation in another clinical trial within the last four weeks prior to inclusion. Pregnant or nursing women (as excluded by pregnancy testing at visit 1). Other medical conditions that do not allow the trial subject to appraise the nature, scope, and potential consequences of the clinical trial Indications that the trial subject is unlikely to comply with the study protocol (e.g., unwillingness to cooperate) Known use of medicinal cannabis products within the last 8 weeks Active malignant tumor disease, tumor pain, or other dominant severe pain other than that of the study indication Known history of severe liver or kidney diseases Known history of severe cardiovascular disease Known history of or acute mental illness such as severe depression, psychosis, bipolar disorder, mania, anxiety, or obsessive-compulsive disorder Known history of addictive disease (e.g., alcohol, medication, drug addiction) Answered during Screening less than 12 times of 18 the pain intensity (NRS) inquiry Laboratory liver values: Alanine aminotransferase (ALT, GPT) > 3 x ULN (Upper Limit of Normal range), Aspartate aminotransferase (AST, GOT) > 3 x ULN, Alkaline phosphatase (AP) > 2.5 x ULN, and for bilirubin > 1.5 x ULN Laboratory renal value: Serum creatinine > 1.5 ULN

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment group<br>Sublingual spray with maximum application of 16 actuations per day or a maximum daily dose of 17,6mg THC distributed over 4 daily intakes. | Drug: Adezunap (AP707)<br>* Sublingual spray with maximum application of 16 actuations per day or a maximum daily dose of 17,6mg THC distributed over 4 daily intakes.<br>|
| Experimental: Control group<br>Sublingual spray with maximum application of 16 actuations per day distributed over 4 daily intakes. | Drug: Placebo<br>* Sublingual spray with maximum application of 16 actuations per day distributed over 4 daily intakes.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in pain level on the Numeric Rating Scale (NRS, 0-10) between baseline and at treatment week 14 (end of first treatment phase) in comparison of study arm 1 (verum) and study arm 2 (placebo) |  | Once daily in week 4 and 14 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in pain level on the Numeric Rating Scale (NRS, 0-10) between baseline and at treatment week 26 (end of second treatment phase) in comparison of study arm 1 (verum) and study arm 2 (placebo) |  | Once daily in week 4 and 26 | 
| Change in pain level on the Numeric Rating Scale (NRS, 0-10) between baseline and at treatment week 52 (end of third treatment phase) in comparison of study arm 1 (verum) and study arm 2 (placebo) |  | Once daily in week 4 and 52 | 
| Change in the pain score of the Neuropathic Pain Symptom Inventory (NPSI) questionnaire between baseline and at treatment week 14, treatment week 26 and treatment week 52 in comparison of study arm 1 (verum) and study arm 2 (placebo) |  | Once in week 1, 14, 26 and 52 | 
| Change in pain level on the Numeric Rating Scale (0-10) between baseline and in treatment week 5, 11, 18, 22, 30, 34, 43, 47 in comparison of study arm 1 (verum) and study arm 2 (placebo) |  | Several times weekly in week 4, 5, 11, 18, 22, 30, 34, 43 and 47 | 
| Responder analysis for endpoints 1), 2), 3) and 4) for treatment week 14, 26 and 52 | Proportion of patients who experienced > 30 % improvement in pain score (Numeric Rating Scale) Proportion of patients who experienced > 40 % improvement in pain score (Numeric Rating Scale) Proportion of patients who experienced > 50 % improvement in pain score (Numeric Rating Scale) | Week 14, 26 and 52 | 
| Change in sCPT (percentage of change in dosage and percentage of change in combination of analgesic measures) in both study arms from start to week 14 |  | Week 14 | 
| Change in psychological distress using Depression Anxiety Stress Scales Short Form (DASS-21) questionnaire from start to week 14, 26, and 52 |  | Week 1, 14, 26 and 52 | 
| Change of Patient Global Impression of Change (PGIC) from start to week 14, 26, and 52 |  | Week 14, 26 and 52 | 
| Change in quality of life using the Veterans RAND (VR-12) questionnaire from start to week 14, 26, and 52 |  | Week 1, 14, 26 and 52 | 
| Change in sleep quality using the Regensburg Insomnia Scale (RIS) from start to week 14, 26, and 52 |  | Week 1, 14, 26 and 52 | 
| Change in pain score of the Brief Pain Inventory - Short Form (BPI-SF) questionnaire from start to week 14, 26, and 52 |  | Week 1, 14, 26 and 52 | 
| Area under NRS-curve until treatment week 5, 11, 14, 18, 22, 26, 30, 34, 39, 43, 47, 52 |  | Week 5, 12, 18, 22, 26, 30, 34, 39, 43, 47 and 52 | 
| Change in VR-12 components (physical component summary PCS, mental component summary MCS) from start to week 14, 26, and 52 |  | Week 1, 14, 26 and 52 | 
| Number of patients with rescue medication over the course of the clinical trial and within periods: until treatment week ≤5, ≤11, ≤14, ≤18, ≤22, ≤26, ≤30, ≤34, ≤43, ≤47, ≤52 |  | Week 5, 11, 14, 18, 22, 26, 30, 34, 43, 47 and 52 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Adezunap, Pain Therapy, Pain, Pain Syndrome, Chronic Pain, Chronic Pain Syndrome, Diabetis, Diabetic Neuropathies, Diabetic Polyneuropathy, Peripheral Neuralgia, Peripheral Neuropathy, Peripheral Neuropathy with Type 2 Diabetis, THC, Tetrahydrocannabinol, Delta-9-Tetrahydrocannabinol, Cannabis, Cannabinoids