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 \[Pain Intensity Numerical Rating Scale (PI-NRS), patient global impression of change (PGIC), neuropathic pain symptom inventory (NPSI) questionnaire, daily sleep interference scale (DSIS) score, hospital anxiety and depression scale (HADS)\].
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
DOUBLE
Enrollment
99
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.
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.
UZ Antwerp
Edegem, Belgium
Ziekenhuis Oost Limburg - campus St. Jan
Genk, Belgium
AZ Sint-Lucas, Pijnkliniek
Ghent, Belgium
Jessa ZH Hospital
Hasselt, Belgium
UZ Leuven, Campus Pellenberg
Pellenberg, Belgium
AZ Delta, Pijncentrum
Roeselare, Belgium
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
Time frame: Baseline to Day 10
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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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').
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: Baseline, Day 1, 3, 10, 15 and 36
Changes from Baseline in vital signs: Heart rate
Heart rate will be measured
Time frame: Baseline, Day 1, 3, 10, 15 and 36
Changes from Baseline in vital signs: Respiratory rate
Respiratory rate will be measured
Time frame: Baseline, Day 1, 3, 10, 15 and 36
Changes from Baseline in vital signs: Aural body temperature
Aural body temperature will be measured
Time frame: Baseline, Day 1, 3, 10, 15 and 36
Incidence of abnormal laboratory test results
Abnormal laboratory test results will be evaluated
Time frame: Baseline, Day 3, 10, 15 and 36
Incidence of abnormal ECG readings
Abnormal 12 lead ECG readings will be evaluated
Time frame: Baseline, Day 3, 10 and 36
Changes from Baseline in body weight
Body weight will be evaluated
Time frame: 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
Time frame: Days 1, 3, 10 and 36
Accumulation of Ctrough from Day 3 to Day 10
Plasma concentrations of AP-325 will be evaluated
Time frame: 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
Time frame: 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
Time frame: Day 3
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Neurology and Physiotherapy Outpatient Clinic Skopalíkova
Brno, Czechia
NEUROHK, s.r.o.
Choceň, Czechia
ALGOMED s.r.o. - Centrum léčby bolesti
České Budějovice, Czechia
Neuros, s.r.o.
Pilsen, Czechia
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