A Study on Ketoprofen Lysine Salt (KLS) + Gabapentin (GABA) vs KLS to Investigate Their Pharmacodynamic in Healthy Males

NCT04802967 | Completed Phase 1 Results

• 2 other identifiers: KLG01202020-004212-10
• Study Type: interventional
• Target: 141
• Locations: 1 country
• Sites: 1

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.

Conditions

No Condition

Keywords

Male healthy volunteers

Outcome Measures

Primary Outcomes (10)

• 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),

  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.

  Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36 and 48 hours postdose

• Plasma PK Concentrations and Parameters of Ketoprofen (Part A):AUC From Zero to 12 Hours Postdose (AUC0-12h)

  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.

  Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36 and 48 hours postdose

• Plasma PK Concentrations and Parameters of Ketoprofen (Part A): AUC From Zero to 24 Hours Postdose (AUC0-24h)

  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.

  Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36 and 48 hours postdose

• Plasma PK Concentrations and Parameters of Ketoprofen (Part A):AUC From Zero to 36 Hours Postdose (AUC0-36h)

  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.

  Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36 and 48 hours postdose

• Plasma PK Concentrations and Parameters of Ketoprofen (Part A): AUC From Zero to 48 Hours Postdose (AUC0-48h)

  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.

  Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36 and 48 hours postdose

• Plasma PK Concentrations and Parameters of Ketoprofen (Part A): Maximum Plasma Concentration (Cmax)

  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.

  Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36 and 48 hours postdose

• Plasma PK Concentrations and Parameters of Ketoprofen (Part A): Time to Maximum Plasma Concentration (Tmax)

  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.

  Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36 and 48 hours postdose

• Plasma PK Concentrations and Parameters of Ketoprofen (Part A): Half-life (t1/2)

  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.

  Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36 and 48 hours postdose

• Change From Baseline in Area of Hyperalgesia (cm^2) Post-capsaicin Injection by MMRM Analysis. (Part B)

  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.

  Day 1 at 15, 30, 60, 90 and 120 minutes post injection

• Plasma PK Concentrations and Parameters of Ketoprofen (Part A): AUC From Zero to Infinity (AUC0-∞),

  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%.

  Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36 and 48 hours postdose

Secondary Outcomes (8)

• 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.

Study Arms (4)

KLS-GABA (part A and B)

EXPERIMENTAL

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).

Drug: Ketoprofen Lysine Salt combined with Gabapentin

KLS (part A and B)

ACTIVE COMPARATOR

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).

Drug: Ketoprofen Lysine Salt

Gabapentin (part B)

ACTIVE COMPARATOR

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).

Drug: Gabapentin

Placebo (part B)

PLACEBO COMPARATOR

To maintain the blind subjects assigned to receive placebo receive 2 placebo capsules. Capsules will be administered with 240 mL of water.

Other: Placebo

Interventions

Ketoprofen Lysine Salt combined with Gabapentin DRUG

KLS-GABA (80 mg-34 mg) in Part A and KLS-GABA (40 mg-17 mg or 80 mg-34 mg or 160 mg-68 mg) in Part B

Also known as: KLS-GABA

KLS-GABA (part A and B)

Ketoprofen Lysine Salt DRUG

KLS (80 mg) alone in each treatment period in Part A and KLS alone (40 mg, 80 mg, or 160 mg) in Part B

Also known as: KLS

KLS (part A and B)

Gabapentin DRUG

300 mg

Also known as: GABA

Gabapentin (part B)

Placebo OTHER

2 capsules to maintain the blind

Placebo (part B)

Eligibility Criteria

• Age: 18 Years - 55 Years
• Gender Eligibility Details: 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 and ≥50 kg.
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Part A
• 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.
• Part B
• Subjects meeting the following criteria will be included in the study:
• Subject is male, with a skin type compatible with capsaicin measurements.
• Subject is aged between 18 to 55 years, inclusive.

You may not qualify if:

• Part A
• 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.
• History of drug and/or alcohol abuse/dependence, or intake of \>28 units of alcohol weekly, and the inability to refrain from alcohol use from 48 hours before screening and each scheduled visit until discharge from the CRU. One unit is equivalent to a 285 mL glass of full strength beer or 1 (30 mL) measure of spirits or 1 glass (100 mL) of wine.
• Habitual and heavy consumption of caffeinated beverages (\>8 cups of coffee or equivalent per day) at screening; and/or unable to refrain from use of (methyl) xanthine (e.g., coffee, tea, cola, chocolate) from 48 hours prior to dosing until discharge from the CRU.
• The subject has participated in a clinical study and has received a medication or a new chemical entity within 3 months or 5 half-lives (whichever is longer) prior to dosing of current study medication.
• Use of any prescription or non-prescription medications, including herbal and nutritional supplements (including St. John's wort), or OTC medications (e.g., ibuprofen, aspirin) within 14 days of dosing and throughout the study. By exception, the subject may take acetaminophen (less or equal 2 g/day) for up to 48 hours prior to dosing. The Investigator and study team may review medication on a case-by-case basis to determine if its use would compromise subject safety or interfere with study procedures or data interpretation.

Sponsors & Collaborators

• Dompé Farmaceutici S.p.A: lead

Study Sites (1)

MAC Clinical Research Early Phase Unit

Manchester, M13 9NQ, United Kingdom

Location

MeSH Terms

Interventions

Gabapentin; gamma-Aminobutyric Acid

Intervention Hierarchy (Ancestors)

Amines; Organic Chemicals; Aminobutyrates; Butyrates; Acids, Acyclic; Carboxylic Acids; Cyclohexanecarboxylic Acids; Acids, Carbocyclic; Cyclohexanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Amino Acids; Amino Acids, Peptides, and Proteins

Results Point of Contact

• Title: Clinical Development & Operations
• Organization: Dompé Farmaceutici SpA

clinical.trials@dompe.com

+39 02 583831

Study Officials

• Pui Man Leung, BMChB, MRCP

  MAC Clinical Research Early Phase Unit

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Masking Details: This study will be double-blinded (Investigator- and subject-blinded).
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: In the Part B of the study the Intradermal (ID) Capsaicin Model is used.

Study Record Dates

• First Submitted: March 12, 2021
• First Posted: March 17, 2021
• Study Start: February 8, 2021
• Primary Completion: March 30, 2022
• Study Completion: April 25, 2022
• Last Updated: December 27, 2024
• Results First Posted: December 27, 2024

Record last verified: 2024-12

Data Sharing

• IPD Sharing: Will not share

Locations

GB (1)