A Phase I, Double-Blind, PK, Safety, Tolerability Study of KSL + KLS-GABA vs KLS Alone in Healthy Males (Part A) Followed by a Study to Investigate the PD of KLS and KLS + GABA in Healthy Males (Part B)
Overview
- Phase
- Phase 1
- Intervention
- Ketoprofen Lysine Salt combined with Gabapentin
- Conditions
- No Condition
- Sponsor
- Dompé Farmaceutici S.p.A
- Enrollment
- 141
- Locations
- 1
- Primary Endpoint
- Plasma PK Concentrations and Parameters of Ketoprofen (Part A): Area Under the Concentration-time Curve (AUC) From Zero to the Last Quantifiable Concentrations (AUC0-t),
- Status
- Completed
- Last Updated
- last year
Overview
Brief Summary
Part A The primary objective of this study is to determine the single dose pharmacokinetics (PK) of ketoprofen lysine salt combined with gabapentin (KLS-GABA [80 mg-34 mg]) compared to KLS alone (80 mg) in healthy male subjects.
The secondary objective of this study is:
• To determine the safety and tolerability of a single oral dose of KLS-GABA (80 mg-34 mg) compared to KLS alone (80 mg) in healthy male subjects.
Part B The primary objective of this study is to determine the pharmacodynamic (PD) effects of KLS-GABA in the Intradermal (ID) capsaicin model in healthy male subjects.
The secondary objectives of this study are:
- To further investigate the safety, tolerability, and PK of single oral doses of KLS-GABA and KLS alone.
- To investigate the possible relationship between plasma levels of drug and efficacy in pain reduction.
Detailed Description
This is a Phase I, Double-Blind, Pharmacokinetic, Safety and Tolerability Study of Ketoprofen Lysine Salt Combined with Gabapentin (KLS-GABA) Compared to Ketoprofen Lysine Salt (KLS) Alone in Healthy Male Subjects (Part A) Followed by a Randomised, Double-Blind, Placebo-Controlled Study to Investigate the Pharmacodynamic Effects of KLS, and KLS in Combination with Gabapentin (GABA), in Healthy Male Subjects Using the Intradermal (ID) Capsaicin Model (Part B). Part A is a randomized, double-blind, crossover group study to investigate the safety, tolerability, and PK profile of a single oral dose of KLS-GABA compared to KLS alone in healthy male subjects. It is planned to enroll 12 subjects. All subjects take part in 2 treatment periods, in which they are randomized to receive either a single dose of KLS-GABA (80 mg-34 mg) or a single dose of KLS (80 mg) alone in each treatment period. Subjects' participation in Part A lasts approximately 7 weeks and will consist of the following: * A screening visit (up to 28 days prior to Day 1 of Treatment Period 1), * Admission to the clinical research unit (CRU) on Day -1 prior to Treatment Period 1, * Treatment Period 1 (Day 1 to Day 3), * A washout period of a minimum of 7 days, * Admission to the CRU on Day -1 prior to Treatment Period 2, * Treatment Period 2 (Day 1 to Day 3), * A follow-up visit (5 to 7 days post-final dose following Treatment Period 2). Safety will is assessed through Adverse Events (AE) reporting, 12-lead ECGs, vital signs, physical examinations, and clinical laboratory examinations. Pharmacokinetics are assessed by blood sampling. Part A treatment lasts 2 days (Day 1 in Treatment Period 1; Day 1 in Treatment Period 2) Part B is a randomized, double-blind, placebo-controlled parallel-group study to investigate the PD effects, PK/PD correlation, safety, and tolerability of three single oral dose levels of KLS-GABA compared to KLS alone, 300 mg gabapentin and placebo in the ID capsaicin model in healthy male subjects. It is planned to enroll 128 subjects, randomized evenly to 8 possible treatments; subjects receive either KLS alone, KLS-GABA, 300 mg gabapentin or placebo. The planned treatments are: * KLS alone (40 mg, 80 mg, or 160 mg) * KLS-GABA (40 mg-17 mg, 80 mg-34 mg or 160 mg-68 mg) * Gabapentin (300 mg) * Placebo Subjects' participation in Part B lasts approximately 6 weeks and consists of the following: * A screening visit (up to 28 days prior to dosing) * An additional screening visit (at least 7 days prior to dosing) to determine the subject's response to capsaicin and to familiarise them in the pain measurements, * Admission to the CRU on Day -1, for collection of pain measurements and completion of the ID capsaicin model * A treatment period (morning of Day 1 until 12 hours postdose) * Discharge from the CRU 12 hours postdose * A follow-up visit (5 to 7 days postdose). Safety is assessed through AE reporting, 12-lead ECGs, vital signs, physical examinations, and clinical laboratory examinations. Pharmacokinetics are assessed by blood sampling. Pharmacodynamics are assessed using the ID capsaicin model and pain measurements. Part B treatment lasts 1 day (Day 1).
Investigators
Eligibility Criteria
Inclusion Criteria
- •Subjects meeting the following criteria will be included in the study:
- •Subject is male, of any ethnic origin.
- •Subject is aged between 18 to 55 years, inclusive.
- •Subject has a body mass index (BMI) of 18 to 32 kg/m2, inclusive.
- •Subject is ≥50 kg.
- •Negative severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) test at Screening and Day -1 in each treatment period.
- •Healthy as determined by a responsible physician, based on medical evaluation including medical history, physical examinations, concomitant medication, vital signs, 12-lead ECG, and clinical laboratory evaluations.
- •Subjects must use a condom during the trial and for 3 months after their final dose of trial medication, if their partner is a woman of childbearing potential. In addition, their female partner of childbearing potential must use an additional method of highly effective contraception (see Section 6.4.1) from dosing until 3 months following dosing.
- •Subject is either a non-smoker or does not smoke more than 5 cigarettes per day (or equivalent e-cigarette use).
- •Provision of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.
Exclusion Criteria
- •Subjects with any of the following will be excluded from study participation:
- •Clinically relevant history of abnormal physical or mental health interfering with the study as determined by medical history and physical examinations obtained during screening as judged by the Investigator (including \[but not limited to\], neurological, psychiatric, endocrine/diabetic, cardiovascular, respiratory, gastrointestinal, hepatic, or renal disorder).
- •Clinically relevant abnormal laboratory results (including hepatic and renal panels, complete blood count, chemistry panel and urinalysis), 12-lead ECG and vital signs, or physical findings at screening. In case of uncertain or questionable results, tests performed during screening may be repeated once to confirm eligibility or judged to be clinically irrelevant for healthy subjects.
- •History or clinical evidence of any disease and/or existence of any surgical or medical condition which might interfere with the absorption, distribution, metabolism and excretion (ADME) of the study drugs.
- •Any other concomitant disease or condition that could interfere with, or for which the treatment might interfere with, the conduct of the study as outlined in this Protocol, safety of the subject as per the SmPC of KLS and gabapentin (Neurontin 300 mg hard capsules) or that would, in the opinion of the Investigator, pose an unacceptable risk to the subject in this study.
- •Subject has a history of neurological disorders which may impact the perception of pain or impairs the subject's ability to fully participate in the study.
- •Subject has a significant skin allergy, pigmentary disorder, or any active dermatological condition.
- •AST, ALT, gamma-glutamyl transferase (GGT) or total bilirubin levels above the ULN at screening. These laboratory evaluations may be repeated once at the discretion of the Investigator. If the repeat test is within the reference range, the subject may be included only if the Investigator considers that the previous finding will not introduce additional risk factors and will not interfere with interpretation of safety data.
- •Positive test for hepatitis B surface antigen (HBsAg), anti-hepatitis C antibody (anti- HCV) or human immunodeficiency virus I and II antibodies (anti-HIV I/II) at screening.
- •Positive urine test for drugs of abuse or alcohol breath test at screening or Day -1 of each treatment period.
Arms & Interventions
KLS-GABA (part A and B)
KLS-GABA 80 mg-34 mg capsules are administered once in the morning of Day 1 in Part A in Treatment Periods 1 and 2 in the fasted state, according to the randomisation schedule. Capsules are administered with 240 mL of water. KLS-GABA (40 mg-17mg, 80 mg-34 mg, or 160 mg-68 mg) in Part B are administered as capsules once in the morning of Day 1 in the fasted state. Capsules are administered with 240 mL of water. To maintain he blind, subjects assigned to receive 160 mg-68 mg KLS-GABA are administered two co-crystal KLS-GABA 114 mg (80 mg-34 mg) capsules, and subject assigned to receive 40 mg-17 mg KLS-GABA or 80 mg-34 mg KLS-GABA also receive a placebo capsule (dummy placebo).
Intervention: Ketoprofen Lysine Salt combined with Gabapentin
KLS (part A and B)
KLS 80 mg capsules are administered once in the morning of Day 1 in Part A in Treatment Periods 1 and 2 in the fasted state, according to the randomisation schedule. Capsules will be administered with 240 mL of water. In the part B KLS (40 mg, 80 mg or 160 mg) are administered as capsules once in the morning of Day 1 in the fasted state. Capsules are administered with 240 mL of water. To maintain the blind, subjects assigned to receive 160 mg KLS alone are administered two KLS 80 mg capsules and subjects assigned to receive either 40 mg KLS alone or 80 mg KLS alone also receive a placebo capsule (dummy placebo).
Intervention: Ketoprofen Lysine Salt
Gabapentin (part B)
Gabapentin 300 mg are administered as capsules once in the morning of Day 1 in the fasted state. Capsules are administered with 240 mL of water.To maintain the blind, subjects assigned to receive 300 mg gabapentin also receive a placebo capsule (dummy placebo).
Intervention: Gabapentin
Placebo (part B)
To maintain the blind subjects assigned to receive placebo receive 2 placebo capsules. Capsules will be administered with 240 mL of water.
Intervention: Placebo
Outcomes
Primary Outcomes
Plasma PK Concentrations and Parameters of Ketoprofen (Part A): Area Under the Concentration-time Curve (AUC) From Zero to the Last Quantifiable Concentrations (AUC0-t),
Time Frame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36 and 48 hours postdose
PK parameters of ketoprofen when administered alone and when administered in combination with gabapentin in healthy male subjects were assessed. Outcome measure at 0h,16h,24h,36h, and 48h postdose below limit of quantification (0.04 μg/mL). The area under the concentration versus time curve from time zero to the last quantifiable concentration (C-last), calculated by the linear up-log down trapezoidal method; i.e. when concentrations are increasing (as in the absorption phase), the linear trapezoidal method is used, when concentrations are decreasing (as in the elimination phase), the logarithmic trapezoidal method is used.
Plasma PK Concentrations and Parameters of Ketoprofen (Part A):AUC From Zero to 12 Hours Postdose (AUC0-12h)
Time Frame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36 and 48 hours postdose
PK parameters of ketoprofen when administered alone and when administered in combination with gabapentin in healthy male subjects were assessed. The area under the concentration versus time curve from time zero to 12 h post-dose, calculated by the linear up-log down trapezoidal method.
Plasma PK Concentrations and Parameters of Ketoprofen (Part A): AUC From Zero to 24 Hours Postdose (AUC0-24h)
Time Frame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36 and 48 hours postdose
PK parameters of ketoprofen when administered alone and when administered in combination with gabapentin in healthy male subjects were assessed. The area under the concentration versus time curve from time zero to 24 h post-dose, calculated by the linear up-log down trapezoidal method.
Plasma PK Concentrations and Parameters of Ketoprofen (Part A):AUC From Zero to 36 Hours Postdose (AUC0-36h)
Time Frame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36 and 48 hours postdose
PK parameters of ketoprofen when administered alone and when administered in combination with gabapentin in healthy male subjects were assessed.The area under the concentration versus time curve from time zero to 36 h post-dose, calculated by the linear up-log down trapezoidal method.
Plasma PK Concentrations and Parameters of Ketoprofen (Part A): AUC From Zero to 48 Hours Postdose (AUC0-48h)
Time Frame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36 and 48 hours postdose
PK parameters of ketoprofen when administered alone and when administered in combination with gabapentin in healthy male subjects were assessed.The area under the concentration versus time curve from time zero to 48 h post-dose, calculated by the linear up-log down trapezoidal method.
Plasma PK Concentrations and Parameters of Ketoprofen (Part A): Maximum Plasma Concentration (Cmax)
Time Frame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36 and 48 hours postdose
PK parameters of ketoprofen when administered alone and when administered in combination with gabapentin in healthy male subjects were assessed. Is defined Cmax the maximum observed concentration.
Plasma PK Concentrations and Parameters of Ketoprofen (Part A): Time to Maximum Plasma Concentration (Tmax)
Time Frame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36 and 48 hours postdose
PK parameters of ketoprofen when administered alone and when administered in combination with gabapentin in healthy male subjects were assessed. Is defined T max the time at which Cmax was apparent.
Plasma PK Concentrations and Parameters of Ketoprofen (Part A): Half-life (t1/2)
Time Frame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36 and 48 hours postdose
PK parameters of ketoprofen when administered alone and when administered in combination with gabapentin in healthy male subjects were assessed. Is defined T1/2 The apparent terminal half-life, calculated from Log e 2 / z.
Change From Baseline in Area of Hyperalgesia (cm^2) Post-capsaicin Injection by MMRM Analysis. (Part B)
Time Frame: Day 1 at 15, 30, 60, 90 and 120 minutes post injection
The area of mechanical hyperalgesia was assessed using a standard 24 g von Frey hair. The von Frey hair was applied at 1-second intervals along each of the 4 lines intersecting at the injection site drawn onto the skin before the injection. Stimulation began distal from the injection site and advanced in 1 cm increments toward the injection site until a pain response was elicited. Subjects were asked to report when the von Frey hair first began to cause any pain sensation or discomfort and the distance of that point from the injection site in centimetres for each line at each timepoint was recorded.
Plasma PK Concentrations and Parameters of Ketoprofen (Part A): AUC From Zero to Infinity (AUC0-∞),
Time Frame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36 and 48 hours postdose
PK parameters of ketoprofen when administered alone and when administered in combination with gabapentin in healthy male subjects were assessed. AUC0-∞ - area under the concentration versus time curve from time zero to infinity The area under the concentration-time curve estimated from time zero to infinity as the sum of the two areas: AUC0-t and AUCextrap, where AUCextrap is calculated as Ct / z. Estimates will be considered to be unreliable if the extrapolated area (AUCextrap) is \>20%.
Secondary Outcomes
- Adverse Events (Part A)(Through part A, from screening day up to 5 to 7 days post final dose, i.e. up to 7 weeks)
- Subjective Rating of Pain From the ID Capsaicin Model (Part B)(Prior to (within 15 minutes) and at the 15-, 30-, 60-, 90- and 120-minutes post-injection.)
- Change From Baseline of Pain Score of Hyperalgesia (NRS) by MMRM Analysis.(Part B)(Day 1 at 15, 30, 60, 90 and 120 minutes post injection)
- Change From Baseline of Area of Brush-evoked Allodynia From the ID Capsaicin Model (Part B)(Prior to (within 15 minutes) and at the 15-, 30-, 60-, 90- and 120-minutes post-injection.)
- Change From Baseline in Pain Score of Brush-evoked Allodynia From the ID Capsaicin Model (Part B)(Prior to (within 15 minutes) and at the 15-, 30-, 60-, 90- and 120-minutes post-injection.)
- Change From Baseline in Area of Flare (AF) From the ID Capsaicin Model (Part B)(Day 1 Pre-Capsaicin Injection and at 15, 30, 60, 90 and 120 minutes post injection)
- Plasma PK Concentrations (Part B)(At Day 1 predose, pre-capsaicin and 2 hours post capsaicin)
- Adverse Events (Part B)(The specific period of time over which adverse events data were collected was from screening day up to 5 to 7 days post final dose, i.e. up to 6 weeks for Part B)