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

Study Overview
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Brief Summary
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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).

Detailed Description
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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)].

Official Title
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A Randomized, Double-blind, Placebo Controlled, Parallel Group Study to Evaluate the Efficacy and Safety of AP-325 in Subjects With Peripheral Post-surgical Neuropathic Pain

Conditions
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Peripheral Post-surgical Neuropathic Pain

Intervention / Treatment
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* Drug: AP-325
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects must be at least 18 years and not older than 80 years 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) 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) 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) 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. 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 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) 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 Subjects must understand the nature of the study procedures and provide written informed consent prior to any study-related procedures Body weight ≥55 kg for men and ≥50 kg for women Body mass index (BMI) <40 kg/m² Exclusion Criteria: Subjects with neuropathic pain not a result of a surgical procedure as defined in inclusion criterion 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 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 Subjects using adjuvant chemotherapy or radiotherapy; adjuvant therapies must have been finished at least 4 weeks prior to the run-in period (Day -14) Creatinine clearance <60 mL/min using the Cockcroft-Gault formula White blood cell count <2500/mm³; neutrophil count <1500/mm³; platelet count <100 x 103/mm³ 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 A history of multiple drug allergies History or presence of alcohol or drug abuse Subjects using strong opioids (e.g. a Morphine Equivalent Dose [MED] >80 mg/day) Positive test for drugs of abuse at Day -7 Evidence of depression and/or a score of ≥11 on the HADS depression subscale Any clinically relevant psychiatric disease in the past 5 years which is likely to interfere with the conduct of the study History of any clinically relevant liver disease within the last 6 months, or episodic/chronic migraine, or kidney dysfunction or disease Clinically significant gastrointestinal conditions, likely interfering with the study medication, study procedures or the outcome of the study Positive test for human immunodeficiency virus (HIV) Positive test for hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb), hepatitis C antibody and/or HIV1/HIV2 antibody at Screening 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 Subjects who were previously enrolled in this clinical study and have taken study medication or terminated due to poor compliance Known hypersensitivity to the active substance or any of the excipients of the IMP or the rescue medication Subjects dependent (as an employee or relative) on the sponsor or investigator Subjects committed to an institution by virtue of an order issued either by the judicial or the administrative authorities Legal incapacity or limited legal capacity Randomization criteria 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%. For female subjects of childbearing potential: negative pregnancy test in urine on Day 1.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: placebo controlled, Phase IIa clinical trial
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AP-325<br>25 mg capsule for oral use, 4 capsules (100 mg) once daily in the morning before meals | Drug: AP-325<br>* During the 10-day double-blind treatment period (Days 1 to 10), subjects will take 4 capsules of the IMP orally once daily in the morning before breakfast.<br>|
| Placebo Comparator: Placebo<br>4 capsules once daily in the morning before meals | Drug: Placebo<br>* During the 10-day double-blind treatment period (Days 1 to 10), subjects will take 4 capsules of the IMP orally once daily in the morning before breakfast.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline to Day 10 in the 5-day average pain intensity score based on the Pain Intensity Numerical Rating Scale (PI-NRS; ranges from no pain = 0 to the worst possible pain = 10; the lower the score, the better the outcome) | The 5-day average pain intensity score based on the Pain Intensity Numerical Rating Scale (PI-NRS) will be assessed to investigate the efficacy of repeat oral dosing of AP-325 | Baseline to Day 10 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Longitudinal analysis of the 5-day average PI-NRS score (ranges from no pain = 0 to the worst possible pain = 10; the lower the score, the better the outcome) over time from Baseline until Day 35 | The 5-day average PI-NRS score will be assessed to investigate the long-lasting efficacy of repeat oral dosing of AP-325 on neuropathic pain over the entire study duration | Baseline to Day 35 | 
| Changes from Baseline in the 5-day average PI-NRS score (change can be in the range of 0 to 10; the bigger the change towards lower PI-NRS scores, the better the outcome) (from Baseline to Day 5, 15, 20, 25, 30 and 35) | The 5-day average PI-NRS score will be assessed | Baseline to Day 5, 15, 20, 25, 30 and 35 | 
| Responder rate: proportion of subjects who have a ≥30% reduction in the 5-day average PI-NRS score (in the range of 0 to 10; the bigger the change towards lower scores, the better the outcome) relative to Baseline (on Days 5, 10, 15, 25 and 35) | The responder rate will be compared between treatments on Day 5, 10, 15, 25 and 35 | Baseline to Day 5, 10, 15, 25 and 35 | 
| Responder rate: proportion of subjects who have a ≥50% reduction in the 5-day average PI-NRS score (in the range of 0 to 10; the bigger the change towards lower scores, the better the outcome) relative to Baseline (on Days 5, 10, 15, 25 and 35) | The responder rate will be compared between treatments on Day 5, 10, 15, 25 and 35 | Baseline to Day 5, 10, 15, 25 and 35 | 
| Proportion of subjects who much improved or very much improved relative to Baseline on the patient global impression of change (PGIC) on Days 3, 10, 15, and 36 | The PGIC will be dichotomized into treatment success (i.e. scoring 'much improved' or 'very much improved'). | Days 3, 10, 15, and 36 | 
| Changes from Baseline in the neuropathic pain evaluation using the neuropathic pain symptom inventory (NPSI; ranges from no pain = 0 to the worst possible pain = 120; the lower the score, the better) questionnaire on Days 3, 10, 15, and 36 | Neuropathic pain symptom inventory (NPSI) questionnaire to assess the neuropathic pain of the patients | Baseline, Day 3, 10, 15 and 36 | 
| Changes from Baseline in the 5-day average daily sleep interference scale (DSIS; ranges from pain does not interfere with sleep = 0 to pain completely interferes with sleep = 10) score (from Baseline to Day 5, 10, 15, 25 and 35) | The 5-day average daily sleep interference scale (DSIS) score will be assessed | Baseline to Day 5, 10, 15, 25 and 35 | 
| Changes from Baseline in the anxiety and depression assessment using the hospital anxiety and depression scale (HADS; subscales range from 0 to 21, with higher values indicating higher anxiety or depression; the lower the score) on Days 10 and 36 | The hospital anxiety and depression scale (HADS) to assess the anxiety and depression of the patients | Baseline, Day 10 and 36 | 
| Time to first use of rescue medication after randomization | The time to first use of rescue medication after randomization will be analyzed | A priori specification not possible, between Day 1 until Day 36 | 
| Total amount of rescue medication use (in mg per day) after randomization | The total amount of rescue medication (i.e. the total mg of rescue medication per day will be tabulated | A priori specification not possible, between Day 1 until Day 36 | 
| Proportion of subjects classified as treatment failure | Proportion of subjects classified as treatment failure at least once after randomization will be tabulated | A priori specification not possible, between Day1 and Day 36 | 
| Time to classification as treatment failure after randomization | Time to first classification as treatment failure after randomization will be analyzed | A priori specification not possible, between Day1 and Day 36 | 
| Incidence, severity and seriousness of treatment-emergent adverse events (TEAEs) | All TEAEs occurring during the clinical trial will be registered, documented and evaluated | A priori specification not possible, between Day1 and Day 36 | 
| Incidence of abnormal physical examinations | Abnormal physical examination results will be evaluated and reported as AEs | Baseline, Day 3, 10, 15 and 36 | 
| Changes from Baseline in vital signs: Systolic and diastolic blood pressure | Systolic and diastolic blood pressure will be measured | Baseline, Day 1, 3, 10, 15 and 36 | 
| Changes from Baseline in vital signs: Heart rate | Heart rate will be measured | Baseline, Day 1, 3, 10, 15 and 36 | 
| Changes from Baseline in vital signs: Respiratory rate | Respiratory rate will be measured | Baseline, Day 1, 3, 10, 15 and 36 | 
| Changes from Baseline in vital signs: Aural body temperature | Aural body temperature will be measured | Baseline, Day 1, 3, 10, 15 and 36 | 
| Incidence of abnormal laboratory test results | Abnormal laboratory test results will be evaluated | Baseline, Day 3, 10, 15 and 36 | 
| Incidence of abnormal ECG readings | Abnormal 12 lead ECG readings will be evaluated | Baseline, Day 3, 10 and 36 | 
| Changes from Baseline in body weight | Body weight will be evaluated | Baseline, Day 10 and 36 | 
| Plasma concentrations of AP-325 at 1 hour post-dose on Days 1 and 10; pre-dose on Days 3 and 10; and on Day 36 | Plasma concentrations of AP-325 will be evaluated | Days 1, 3, 10 and 36 | 
| Accumulation of Ctrough from Day 3 to Day 10 | Plasma concentrations of AP-325 will be evaluated | Day 3 and 10 | 
| Correlation between Ctrough-ss (Day 10) and the change from Baseline to Day 10 in the 5-day average pain intensity score based on the PI-NRS | AP-325 concentration-effect relationships will be evaluated | Baseline to Day 10 | 
| Correlation between CYP2C9 genotype and the metabolism of AP-325 (optional) | The effect of CYP2C9 polymorphisms (determined by CYP2C9 genotyping) on the plasma concentration of AP-325 will be evaluated | Day 3 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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AP-325, Phase IIa, PPNP, post-surgical neuropathic pain