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

No Condition Clinical Trial

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04802967
• Other study ID #: KLG0120
• Secondary ID: 2020-004212-10
• Status: Completed
• Phase: Phase 1
• Start date: February 8, 2021
• Est. completion date: April 25, 2022

Study information

• Verified date: August 2021
• Source: Dompé Farmaceutici S.p.A
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 randomised, 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 enrol 12 subjects. All subjects take part in 2 treatment periods, in which they are randomised 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 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 randomised, 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 enrol 128 subjects, randomised 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 participantion 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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 140
• Est. completion date: April 25, 2022
• Est. primary completion date: March 30, 2022
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Male
• Age group: 18 Years to 55 Years

Eligibility

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.

Related Conditions & MeSH terms

• No Condition

Intervention

Drug:
• Ketoprofen Lysine Salt combined with Gabapentin
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
• Ketoprofen Lysine Salt
KLS (80 mg) alone in each treatment period in Part A and KLS alone (40 mg, 80 mg, or 160 mg) in Part B
• Gabapentin
300 mg

Other:
• Placebo
2 capsules to maintain the blind

Locations

Country	Name	City	State
United Kingdom	MAC Clinical Research Early Phase Unit	Manchester

Sponsors (1)

Lead Sponsor	Collaborator
Dompé Farmaceutici S.p.A

Country where clinical trial is conducted

United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36 and 48 hours postdose
Primary	Plasma PK concentrations and parameters of ketoprofen (part A): AUC from zero to infinity (AUC0-8),	PK parameters of ketoprofen when administered alone and when administered in combination with gabapentin in healthy male subjects were assessed.	Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36 and 48 hours postdose
Primary	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.	Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36 and 48 hours postdose
Primary	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.	Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36 and 48 hours postdose
Primary	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.	Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36 and 48 hours postdose
Primary	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.	Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36 and 48 hours postdose
Primary	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.	Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36 and 48 hours postdose
Primary	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.	Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36 and 48 hours postdose
Primary	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.	Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36 and 48 hours postdose
Primary	Change in pain post capsaicin injection from the ID capsaicin model (Part B)	Pain reduction/analgesia is measured through visual analogue scale (VAS) consisting of a 100 mm line, with 0 representing "no pain'' and 100 "worst pain imaginable." Subjects are asked to mark the VAS using a single vertical stroke at the point they consider to appropriately reflect their level of pain from the injection of capsaicin (not general pain). A new VAS are provided for each time-point and subjects are not allowed to see their previous VAS responses. The VAS is scored by measuring from the left-hand end of the scale to the point where the subject has marked the line, and the distance in mm recorded.	During treatment period (Day -1, Day 1) at 15, 30, 60, 90 and 120 minutes post injection
Secondary	Adverse events (part A)	An AE is any untoward medical occurrence in a study subject which either emerges, or worsens from screening, during the clinical study, regardless of its potential relationship to the medicinal product. An AE, therefore, can be any unfavourable or unintended sign, including a clinically-significant abnormal laboratory finding, symptom, or disease temporally associated with the use of a medical product, whether or not it is considered to be study medication related.	Through part A completion, up to approximately 7 weeks
Secondary	Subjective rating of pain from the ID capsaicin model (part B)	Pain is assessed through a visual analogue scale (VAS) consisting of a 100 mm line, with 0 representing "no pain'' and 100 "worst pain imaginable." Subjects are asked to mark the VAS using a single vertical stroke at the point they consider to appropriately reflect their level of pain from the injection of capsaicin (not general pain).	During treatment period (Day -1, Day 1) at 15, 30, 60, 90 and 120 minutes post injection
Secondary	Area and Pain score of hyperalgesia from the ID capsaicin model (part B)	The area of mechanical hyperalgesia is assessed using a standard 24 g von Frey hair. The von Frey hair is applied at 1-second intervals along each of the 4 lines intersecting at the injection site drawn onto the skin before the injection. Stimulation begins distal from the injection site and advances in 1cm increments toward the injection site until a pain response is elicited. Subjects are asked to report when the von Frey hair first begins to cause any pain sensation or discomfort and the distance of that point from the injection site in centimetres for each line at each time-point is recorded. The area of hyperalgesia is then calculated and recorded in the CRF.; Pain in response to von Frey stimulation of the hyperalgesic area is recorded using an 11-point numeric rating scale (NRS) ranging from 0 ("no pain") to 10 ("worst possible pain"). The pain score reflects the maximum pain experienced during the assessment.	During treatment period (Day -1, Day 1) at 15, 30, 60, 90 and 120 minutes post injection
Secondary	Area and pain score of brush-evoked allodynia from the ID capsaicin model (part B)	The area of allodynia is assessed by sweeping a standard paintbrush at 1-second intervals across each of the 4 lines intersecting at the injection site drawn onto the skin before the injection. Stimulation begins distal from the injection site and advances in 1 cm increments toward the injection site until a pain response is elicited. Subjects are asked to indicate when the brush first begins to cause any pain or discomfort and the distance of that point from the injection site in centimetres for each line at each time-point is recorded.The area of allodynia is then calculated and recorded in the CRF.; Pain in response to brush stimulation of the allodynic area is recorded using an 11-point NRS ranging from 0 ("no pain") to 10 ("worst possible pain"). The pain score reflects the maximum pain experienced during the assessment.	During treatment period (Day -1, Day 1) at 15, 30, 60, 90 and 120 minutes post injection
Secondary	Area of flare (AF) from the ID capsaicin model (part B)	The AF is determined by tracing the outline of visible skin reddening on to a sheet of acetate placed on the skin using a fine-tipped, permanent marker. The area is subsequently measured using planimetry and the results recorded in the CRF.	During treatment period (Day -1, Day 1) at 15, 30, 60, 90 and 120 minutes post injection
Secondary	Plasma PK concentrations (part B)	plasma PK concentrations of ketoprofen, when administered alone or with gabapentin, and gabapentin.	At Day 1 predose, pre-capsaicin and 2 hours post capsaicin
Secondary	Adverse events (Part B)	An AE is any untoward medical occurrence in a study subject which either emerges, or worsens from Screening, during the clinical study, regardless of its potential relationship to the medicinal product. An AE, therefore, can be any unfavourable or unintended sign, including a clinically-significant abnormal laboratory finding, symptom, or disease temporally associated with the use of a medical product, whether or not it is considered to be study medication related. Adverse events may include pre- or post-treatment events that occur as a result of Protocol- mandated procedures (i.e., invasive procedures, modification of subject's previous therapeutic regimen).	Through part B completion, up to approximately 6 weeks