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

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 breastsurgery (e.g. breast-conserving surgery, mastectomy, surgery to remove lymph nodes),chest surgery (e.g. thoracotomy, video assisted thoracoscopy and sternotomy), herniarepair 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 veinsurgery or gynecologic surgery (e.g. hysterectomy, C-section)

3. The chronic post-surgical pain developed or increased in intensity after thesurgical procedure and persisted beyond the healing process, i.e. at least 3 monthsafter the initiating event, as defined according to the international associationfor the study of pain (IASP) classification of chronic pain for ICD-11 (Schug etal., 2019)

4. Subjects must have 'probable' or 'definite' neuropathic pain as assessed by therevised 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 substancesincluding

• pain medications (e.g. antidepressants, anticonvulsants/antiepileptics,selective serotonin and dual reuptake inhibitors, opioids, long-actingbenzodiazepines, muscle relaxants, and topical analgesics), except the rescuemedication, and

• substances known to be inhibitors or inducers of CYP2C9 and inhibitors ofCYP3A4 for specific washout periods of at least 5 times the drug half-lifeNote: Subjects using prohibited substances for other indications thanneuropathic pain, e.g. antiepileptics for the treatment of epilepsy, may not beincluded in the study, because a discontinuation of such medication is notmedically justifiable.

6. Permitted concomitant medications must have been stable for at least 4 weeks priorto Day -14 and any non-pharmacological therapies (e.g. physiotherapy, acupunctureand 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 fromstart of the IMP intake until 30 days after the last IMP intake and have anegative pregnancy test at Screening (blood test)

8. Male subjects must agree, from start of the IMP intake until 3 months after the lastIMP intake, to refrain from donating sperm and use a male condom when having sexualintercourse with a woman of childbearing potential at any time and advise her to usea highly effective contraceptive method

9. Subjects must understand the nature of the study procedures and provide writteninformed 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 ininclusion criterion 2

2. Subjects with any other coexisting pain that cannot be discriminated frompost-surgical neuropathic pain, in the opinion of the subject or clinician e.g., thepain 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, becauseof, for example, severe brain damage, language barrier, dementia, or otherclinically significant or unstable conditions

4. Subjects using adjuvant chemotherapy or radiotherapy; adjuvant therapies must havebeen 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 tointerfere with the conduct of the study

14. History of any clinically relevant liver disease within the last 6 months, orepisodic/chronic migraine, or kidney dysfunction or disease

15. Clinically significant gastrointestinal conditions, likely interfering with thestudy 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, ifapplicable, 5 half-lives of the IMP, whatever is longer, before Screening or duringparticipation in this study

19. Subjects who were previously enrolled in this clinical study and have taken studymedication or terminated due to poor compliance

20. Known hypersensitivity to the active substance or any of the excipients of the IMPor 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 thejudicial 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, witha mean score on the PI-NRS ≥4 and ≤9. Differences between the baseline daily painscores on the PI-NRS must be ≤50%.

2. For female subjects of childbearing potential: negative pregnancy test in urine onDay 1.