Phase 1 study to investigate KSL-GABA in healthy volunteers
Research type
Research Study
Full title
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)
IRAS ID
288272
Contact name
Pui Man Leung
Contact email
Sponsor organisation
Dompe Farmaceutici S.P.A
Eudract number
2020-004212-10
Duration of Study in the UK
0 years, 10 months, 31 days
Research summary
Research Summary
Pain is the most common reason for physician consultation in most developed countries and can have a strong impact on patient’s activities of daily living and quality of life. Patients experiencing pain often have depression, anxiety, and sleep disorders.
Pain models in humans are useful for understanding the mechanisms which cause acute and chronic pain conditions. They are useful tools in testing how well a drug relieves pain.
Capsaicin is an active molecule in hot chilli peppers and is a chemical irritant in humans; it produces a burning sensation when it comes into contact with human tissue e.g. skin. When capsaicin is injected into human skin, symptoms include localised reddening of the skin at the injection site, pain, and sensitivity to pressure or changes in temperature. These symptoms are similar to those seen in a condition called neuropathic pain; therefore, this pain model may be useful in testing drugs with a potential for treating neuropathic pain.
The purpose of this study is to test a drug called ketoprofen lysine salt (KLS) in combination with gabapentin, or KLS-GABA (the ‘study drug’), that is being developed for the treatment of mixed pain.
The main aims of this study are to see how the body absorbs and removes the study drug, to assess the safety and tolerability of the study drug, and to assess the effect of the study drug on the body.There are two parts to this study - Part A and Part B. Part A will look at the pharmacokinetics, safety and tolerability of a single dose of KLS-GABA or KLS alone. Part B will look at the pharmacodynamics (effect of drug in the body), safety, tolerability and pharmacokinetics of three single oral dose levels of KLS-GABA compared to KLS alone, 300 mg gabapentin and placebo (dummy pill) in the Capsaicin model.
Summary of Results
Introduction:
Researchers are exploring new combinations of medicines to enhance pain relief. In this study, researchers aimed to evaluate the efficacy and safety of a new form of ketoprofen administered in combination with gabapentin (KLS-GABA) compared to KLS alone.
This summary provides an overview of the study, its objectives, methods, findings, and implications for pain management.
Objectives:
The objectives of this study were:
• to assess whether the presence of gabapentin (GABA) in the combination influenced in some way how KLS is processed by the body (called Pharmacokinetics) after a single administration of the combination, comparing with the administration of KLS alone;
• to determine if a single oral dose of the combination is safe and well tolerated, compared to KLS alone;
• to see how KLS-GABA acts in the body when the pain is induced by an injection of capsaicin under the skin (intradermal) in healthy male volunteers;
• to learn more about how safe and well-tolerated KLS-GABA and KLS (without GABA) are when taken by mouth (orally) in single doses;
• to see if there is a connection between the levels of the drug in the blood and how effective it is in reducing pain.Methods:
The study enrolled healthy male volunteers and consisted of two parts:
• Part A focused on the KLS plasma profile, administered alone or in combination with gabapentin, after a single dose, given orally, i.e., how KLS is processed by the body, how safe it is, and how it is tolerated by the body;
• Part B assessed the effectiveness of KLS-GABA, KLS alone, gabapentin or placebo (a substance with no pharmacological effect but given as a “control” in testing a biologically active preparation), after single oral doses, in relieving pain.
The participants were randomly assigned to different treatment groups. Each patient was assigned to one of the groups in a casual way (“randomised study”).
In Part A, participants received KLS-GABA and KLS alone. No matter what the initial treatment was: during the study all the patients received the two treatments but in a different order (“crossover” study). Their blood samples were collected to measure the levels of KLS over time.
In Part B, the healthy volunteers received either KLS-GABA, or KLS alone, or gabapentin, or placebo (“parallel” study) comparing the response in the four groups of subjects receiving different treatments.
The pain was induced using the substance capsaicin, administered under the skin. Participants rated their pain levels at subsequent moments. The researchers also monitored bad side effects (“adverse events”) and other safety measures throughout the study.Results:
The study researchers checked how the combination KLS-GABA acts within healthy male volunteers’ body, how safe it is, and how it is tolerated by the body. According to the study results, factors other than the medicines appear to influence the results.
In Part A researchers noticed that the order in which the treatments were administered did not have a notable effect on pharmacokinetics of KLS. Participants tolerated the single doses of KLS alone, and KLS-GABA well, without serious adverse events reported. The only 3 adverse events reported were mild and not related to study treatment. These adverse events, which resolved without the need for specific treatment, were: abdominal pain, ligament sprain and muscle injury.
In Part B, researchers compared how well the 4 treatments worked to relieve pain. The participants showed a high variability in the response to pain induced by capsaicin. Researchers found also that the single therapeutic dose of treatments analysed in this study did not have a notable effect on pain induced by capsaicin, when compared to placebo.Safety assessments revealed that participants tolerated the single doses of KLS alone, KLS-GABA, and gabapentin well, with no serious adverse events reported. The most commonly reported side effects were headache, somnolence (drowsiness), fatigue, and dizziness. These side effects were generally mild and resolved without the need for specific treatment. Most of them were considered not related to treatment. Importantly, there were no significant differences in the frequency or severity of side effects between the active treatment groups and the placebo group. This indicated that the combination drug KLS-GABA and gabapentin did not increase the risk of side effects compared to placebo.
Discussion and Implications:
This study provides valuable insights into the efficacy and tolerability of KLS-GABA as a potential pain relief option. The findings suggest that the body exposure of KLS is not significantly affected when administered as KLS-GABA, compared to when administered alone. The addition of gabapentin did not impact the pharmacokinetics of KLS. Furthermore, the medicines used in this study were well-tolerated at the tested doses.
However, the study shows that the effectiveness of pain relief using capsaicin as a pain inducer varies greatly among participants, probably due to the small number of individuals enrolled in the study. Moreover, the single therapeutic dose of the treatments used in this study did not have a notable effect on pain induced by capsaicin when compared to placebo.The researchers suggest conducting further studies with a higher number of participants, and a study structure in which all the participants take all the study treatments but in different order (“crossover studies”) to decrease this variability and get more reliable results.
The study shows that KLS-GABA, KLS alone, and gabapentin are safe and well-tolerated in healthy male volunteers.REC name
Wales REC 1
REC reference
20/WA/0252
Date of REC Opinion
6 Nov 2020
REC opinion
Further Information Favourable Opinion