AP-325 in Subjects With Peripheral Post-surgical Neuropathic Pain

This is a Phase IIa randomized, double-blind, placebo-controlled study. The study objective is to investigate the efficacy and safety of repeat oral dosing of the investigational medicinal product (IMP) AP-325 for the treatment of peripheral post-surgical neuropathic pain (PPNP) after breast surgery (breast-conserving surgery, mastectomy, surgery to remove lymph nodes), chest surgery (e.g. thoracotomy, video assisted thoracoscopy and sternotomy), hernia repair of the abdominal wall (e.g. femoral hernia repairs, inguinal hernia repairs, umbilical hernia repair or incisional hernia repair), abdominal surgery (e.g. cholecystectomy, appendectomy but also see exclusion criterion 15), varicose vein surgery or gynecologic surgery (e.g. hysterectomy, C-section).

This is a Phase IIa randomized, double-blind, placebo controlled, parallel group study to evaluate the efficacy (by changes in Pain Intensity Numerical Rating Scale \[PI-NRS\]) and safety (by monitoring adverse events) of AP-325 in subjects with PPNP.

The clinical trial will be conducted in Germany, Spain, Czech Republic, Belgium and France.

Eligible subjects will undergo a 2-week run-in period consisting of a washout-period of prohibited medications in the 1st week and a baseline period in the 2nd week. If subjects have at least 5 self-reported pain assessments in the baseline period (documented in a diary) and meet the required pain criteria, they will be randomized to AP-325 or placebo in a 1:1 ratio.

Subjects will take the IMP (AP-325 or placebo) for 10 days (double-blind treatment period; Days 1-10) and then be followed up for a further 26 days (drug-free period; Days 11-36). An end of study visit will be performed on Day 36.

At least 96 subjects (48 for each treatment) need to be analyzed for the primary endpoint at Day 10 to reach the power estimate (120 subjects should be screened for the study).

AP-325 100 mg (4 x 25 mg capsules) or Placebo (4 capsules) will be orally taken once daily in the morning before meals for 10 consecutive days.

Pain will be assessed, and quality of life will be investigated using standardized and validated questionnaires \[Pain Intensity Numerical Rating Scale (PI-NRS), patient global impression of change (PGIC), neuropathic pain symptom inventory (NPSI) questionnaire, daily sleep interference scale (DSIS) score, hospital anxiety and depression scale (HADS)\].

Eligibility Criteria:
Inclusion Criteria:

1. Subjects must be at least 18 years and not older than 80 years
2. Subjects with a diagnosis of chronic post-surgical neuropathic pain after breast surgery (e.g. breast-conserving surgery, mastectomy, surgery to remove lymph nodes), chest surgery (e.g. thoracotomy, video assisted thoracoscopy and sternotomy), hernia repair of the abdominal wall (e.g. femoral hernia repairs, inguinal hernia repairs, umbilical hernia repair or incisional hernia repair), abdominal surgery (e.g. cholecystectomy, appendectomy but also see exclusion criterion 15), varicose vein surgery or gynecologic surgery (e.g. hysterectomy, C-section)
3. The chronic post-surgical pain developed or increased in intensity after the surgical procedure and persisted beyond the healing process, i.e. at least 3 months after the initiating event, as defined according to the international association for the study of pain (IASP) classification of chronic pain for ICD-11 (Schug et al., 2019)
4. Subjects must have 'probable' or 'definite' neuropathic pain as assessed by the revised IASP special interest group on neuropathic pain (NeuPSIG) grading system (Finnerup et al., 2016)
5. Subjects must be willing and able to discontinue and washout prohibited substances including

   * pain medications (e.g. antidepressants, anticonvulsants/antiepileptics, selective serotonin and dual reuptake inhibitors, opioids, long-acting benzodiazepines, muscle relaxants, and topical analgesics), except the rescue medication, and
   * substances known to be inhibitors or inducers of CYP2C9 and inhibitors of CYP3A4 for specific washout periods of at least 5 times the drug half-life Note: Subjects using prohibited substances for other indications than neuropathic pain, e.g. antiepileptics for the treatment of epilepsy, may not be included in the study, because a discontinuation of such medication is not medically justifiable.
6. Permitted concomitant medications must have been stable for at least 4 weeks prior to Day -14 and any non-pharmacological therapies (e.g. physiotherapy, acupuncture and transcutaneous electrical neural stimulation) must have been initiated at least 3 weeks prior to Screening
7. Female subjects must not be pregnant or breastfeeding and be

   * of non-childbearing potential or
   * if of childbearing potential, use a highly effective contraceptive method from start of the IMP intake until 30 days after the last IMP intake and have a negative pregnancy test at Screening (blood test)
8. Male subjects must agree, from start of the IMP intake until 3 months after the last IMP intake, to refrain from donating sperm and use a male condom when having sexual intercourse with a woman of childbearing potential at any time and advise her to use a highly effective contraceptive method
9. Subjects must understand the nature of the study procedures and provide written informed consent prior to any study-related procedures
10. Body weight ≥55 kg for men and ≥50 kg for women
11. Body mass index (BMI) \<40 kg/m²

Exclusion Criteria:

1. Subjects with neuropathic pain not a result of a surgical procedure as defined in inclusion criterion 2
2. Subjects with any other coexisting pain that cannot be discriminated from post-surgical neuropathic pain, in the opinion of the subject or clinician e.g., the pain is at least partially due to pain in deeper structures such as internal organs, joints, muscles or bones
3. Inability to participate in the study, in the opinion of the investigator, because of, for example, severe brain damage, language barrier, dementia, or other clinically significant or unstable conditions
4. Subjects using adjuvant chemotherapy or radiotherapy; adjuvant therapies must have been finished at least 4 weeks prior to the run-in period (Day -14)
5. Creatinine clearance \<60 mL/min using the Cockcroft-Gault formula
6. White blood cell count \<2500/mm³; neutrophil count \<1500/mm³; platelet count \<100 x 103/mm³
7. Heart rate \<50 or \>100 beats per minute; systolic blood pressure \<100 or \>140 mmHg; diastolic blood pressure \<50 or \>90 mmHg after 5 minutes rest in supine position
8. A history of multiple drug allergies
9. History or presence of alcohol or drug abuse
10. Subjects using strong opioids (e.g. a Morphine Equivalent Dose \[MED\] \>80 mg/day)
11. Positive test for drugs of abuse at Day -7
12. Evidence of depression and/or a score of ≥11 on the HADS depression subscale
13. Any clinically relevant psychiatric disease in the past 5 years which is likely to interfere with the conduct of the study
14. History of any clinically relevant liver disease within the last 6 months, or episodic/chronic migraine, or kidney dysfunction or disease
15. Clinically significant gastrointestinal conditions, likely interfering with the study medication, study procedures or the outcome of the study
16. Positive test for human immunodeficiency virus (HIV)
17. Positive test for hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb), hepatitis C antibody and/or HIV1/HIV2 antibody at Screening
18. Participation of subject in an interventional clinical study within 1 month or, if applicable, 5 half-lives of the IMP, whatever is longer, before Screening or during participation in this study
19. Subjects who were previously enrolled in this clinical study and have taken study medication or terminated due to poor compliance
20. Known hypersensitivity to the active substance or any of the excipients of the IMP or the rescue medication
21. Subjects dependent (as an employee or relative) on the sponsor or investigator
22. Subjects committed to an institution by virtue of an order issued either by the judicial or the administrative authorities
23. Legal incapacity or limited legal capacity

Randomization criteria

1. At least 5 daily pain assessments in the baseline week prior to randomization, with a mean score on the PI-NRS ≥4 and ≤9. Differences between the baseline daily pain scores on the PI-NRS must be ≤50%.
2. For female subjects of childbearing potential: negative pregnancy test in urine on Day 1.