Clinical trial NCT04802967: A Study on Ketoprofen Lysine Salt (KLS) + Gabapentin (GABA) vs KLS to Investigate Their Pharmacodynamic in Healthy Males
Official title: 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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: No Condition
Keywords: Male healthy volunteers
Lead sponsor: Dompé Farmaceutici S.p.A
Sponsor class: INDUSTRY
First posted: 2021-03-17
Enrollment: 141
Sex: MALE
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: In the Part B of the study the Intradermal (ID) Capsaicin Model is used.
Primary purpose: TREATMENT

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).

Eligibility criteria: Inclusion Criteria:

Part A

Subjects meeting the following criteria will be included in the study:

1. Subject is male, of any ethnic origin.
2. Subject is aged between 18 to 55 years, inclusive.
3. Subject has a body mass index (BMI) of 18 to 32 kg/m2, inclusive.
4. Subject is ≥50 kg.
5. Negative severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) test at Screening and Day -1 in each treatment period.
6. 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.
7. 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.
8. Subject is either a non-smoker or does not smoke more than 5 cigarettes per day (or equivalent e-cigarette use).
9. 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:

1. Subject is male, with a skin type compatible with capsaicin measurements.
2. Subject is aged between 18 to 55 years, inclusive.
3. Subject has a BMI of 18 to 32 kg/m2, inclusive.
4. Subject is ≥50 kg.
5. Negative SARS-CoV-2 test at Screening and Day -1.
6. Healthy as determined by a responsible physician, based on medical evaluation including medical history, physical examination, concomitant medication, vital signs, 12-lead ECG, and clinical laboratory evaluations.
7. Subject must be in good general health with a skin type compatible with the measures, and without significant skin allergies, pigmentary disorders, or any active dermatological conditions that might interfere with the conduct of the study.
8. 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.
9. Subjects must be able to tolerate the capsaicin injection at screening.
10. Demonstration of positive hyperalgesia as defined by an area of hyperalgesia ≥15 cm2 15 minutes after ID administration of 100 μg capsaicin at the additional screening visit at least 7 days prior to first dosing.
11. Subject is a either non-smoker or does not smoke more than 5 cigarettes per day (or equivalent e-cigarette use).
12. Provision of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.

Exclusion Criteria:

Part A

Subjects with any of the following will be excluded from study participation:

1. 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).
2. 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.
3. 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.
4. 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.
5. 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.
6. Subject has a significant skin allergy, pigmentary disorder, or any active dermatological condition.
7. 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.
8. 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.
9. Positive urine test for drugs of abuse or alcohol breath test at screening or Day -1 of each treatment period.
10. 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.
11. 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.
12. 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.
13. 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.
14. History of severe adverse reactions or allergies, or history of an anaphylactic reaction to prescription medications, non-prescription medication, food, NSAIDs or gabapentin (non-active hay-fever is acceptable).
15. Consumption of any food or drinks containing cranberry, pomegranate, starfruit, grapefruit, pomelos, exotic citrus fruits or Seville oranges (including marmalade and juices made from these fruits) within 14 days before admission to the CRU until the end of the study.
16. Strenuous exercise within 48 hours prior to each blood collection for clinical laboratory tests.
17. Donation of blood or plasma of \>500 mL within 3 months prior to first dosing, or subject intends to donate blood during the study.
18. Male subject who will not abstain from sperm donation between dosing and 3 months after final dosing.
19. Any degree of previous or known hypersensitivity to the active substance or the excipients of the IMP.

Part B

Subjects with any of the following will be excluded from study participation:

1. 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).
2. 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.
3. Has a skin trauma, any active skin disorder, significant scarring, significant skin allergy, pigmentary disorder, active dermatological condition, skin disease or tattoos on either forearm, or a significant history of trauma or skin disease in either arm.
4. Subject has a known intolerance to capsaicin, hot peppers, or any excipient in the IMP.
5. Subject has active chronic pain condition(s) or a history of chronic pain conditions.
6. History or clinical evidence of any disease and/or existence of any surgical or medical condition which might interfere with the ADME of the study drug.
7. 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 SmPCs 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.
8. 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.
9. AST, ALT, 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.
10. Positive test for HBsAg, anti-HCV or anti-HIV I/II at screening.
11. Positive urine test for drugs of abuse or alcohol breath test at screening.
12. 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.
13. 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.
14. 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.
15. 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.
16. History of severe adverse reactions or allergies, or history of an anaphylactic reaction to prescription medication, non-prescription medication, food, NSAIDs, gabapentin, (non-active hay-fever is acceptable), the planned local anaesthesia/analgesic regimens, ethylenediaminetetraacetic acid, Kolliphor HS 15, butylated hydroxytoluene, or capsaicin.
17. Known hypersensitivity or allergy to any component of the placebo capsules.
18. Consumption of any food or drinks containing cranberry, pomegranate, starfruit, grapefruit, pomelos, exotic citrus fruits, or Seville oranges (including marmalade and juices made from these fruits) within 14 days before admission to the CRU until the end of the study.
19. Strenuous exercise within 48 hours prior to each blood collection for clinical laboratory tests.
20. Subject has participated in a clinical study involving administration of capsaicin within 12 months of the screening visit.
21. Donation of blood or plasma of \>500 mL within 3 months prior to dosing, or subject intends to donate blood during the study.
22. Male subject who will not abstain from sperm donation between dosing and 3 months after dosing.
23. Any degree of previous or known hypersensitivity to the active substance or the excipients of the IMP.

Primary outcomes:
measure: 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),
timeFrame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36 and 48 hours postdose
measure: Plasma PK Concentrations and Parameters of Ketoprofen (Part A):AUC From Zero to 12 Hours Postdose (AUC0-12h)
timeFrame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36 and 48 hours postdose
measure: Plasma PK Concentrations and Parameters of Ketoprofen (Part A): AUC From Zero to 24 Hours Postdose (AUC0-24h)
timeFrame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36 and 48 hours postdose
measure: Plasma PK Concentrations and Parameters of Ketoprofen (Part A):AUC From Zero to 36 Hours Postdose (AUC0-36h)
timeFrame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36 and 48 hours postdose
measure: Plasma PK Concentrations and Parameters of Ketoprofen (Part A): AUC From Zero to 48 Hours Postdose (AUC0-48h)
timeFrame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36 and 48 hours postdose
measure: Plasma PK Concentrations and Parameters of Ketoprofen (Part A): Maximum Plasma Concentration (Cmax)
timeFrame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36 and 48 hours postdose
measure: Plasma PK Concentrations and Parameters of Ketoprofen (Part A): Time to Maximum Plasma Concentration (Tmax)
timeFrame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36 and 48 hours postdose
measure: Plasma PK Concentrations and Parameters of Ketoprofen (Part A): Half-life (t1/2)
timeFrame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36 and 48 hours postdose
measure: Change From Baseline in Area of Hyperalgesia (cm^2) Post-capsaicin Injection by MMRM Analysis. (Part B)
timeFrame: Day 1 at 15, 30, 60, 90 and 120 minutes post injection
measure: Plasma PK Concentrations and Parameters of Ketoprofen (Part A): AUC From Zero to Infinity (AUC0-∞),
timeFrame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36 and 48 hours postdose
Secondary outcomes:
measure: Adverse Events (Part A)
timeFrame: Through part A, from screening day up to 5 to 7 days post final dose, i.e. up to 7 weeks
measure: Subjective Rating of Pain From the ID Capsaicin Model (Part B)
timeFrame: Prior to (within 15 minutes) and at the 15-, 30-, 60-, 90- and 120-minutes post-injection.
measure: Change From Baseline of Pain Score of Hyperalgesia (NRS) by MMRM Analysis.(Part B)
timeFrame: Day 1 at 15, 30, 60, 90 and 120 minutes post injection
measure: Change From Baseline of Area of Brush-evoked Allodynia From the ID Capsaicin Model (Part B)
timeFrame: Prior to (within 15 minutes) and at the 15-, 30-, 60-, 90- and 120-minutes post-injection.
measure: Change From Baseline in Pain Score of Brush-evoked Allodynia From the ID Capsaicin Model (Part B)
timeFrame: Prior to (within 15 minutes) and at the 15-, 30-, 60-, 90- and 120-minutes post-injection.
measure: Change From Baseline in Area of Flare (AF) From the ID Capsaicin Model (Part B)
timeFrame: Day 1 Pre-Capsaicin Injection and at 15, 30, 60, 90 and 120 minutes post injection
measure: Plasma PK Concentrations (Part B)
timeFrame: At Day 1 predose, pre-capsaicin and 2 hours post capsaicin
measure: Adverse Events (Part B)
timeFrame: 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
Other outcomes:
Locations:
city: Manchester
country: United Kingdom
facility: MAC Clinical Research Early Phase Unit
Study officials:
affiliation: MAC Clinical Research Early Phase Unit
name: Pui Man Leung, BMChB, MRCP
role: PRINCIPAL_INVESTIGATOR
References: