Oral LAT8881 in Neuropathic Pain

Study Overview
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Brief Summary
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This is a randomised, placebo-controlled, double-blind, crossover, phase IIa study to investigate the efficacy and safety of oral LAT8881 in neuropathic pain.

Detailed Description
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This is a randomised, placebo-controlled, double-blind, crossover, phase IIa study to investigate the efficacy and safety of oral LAT8881 in neuropathic pain. After a one week baseline period, subjects entered into the study will be randomised to receive Investigational Medicinal Product (IMP) (LAT8881 or placebo) twice daily for four weeks. The first treatment period will be followed by a washout period of two weeks and then a second baseline period of one week. Subjects will not take any IMP over these three weeks. After the second baseline period, subjects will cross over to receive the second treatment (either LAT8881 or placebo, whichever treatment was not received in the first treatment period) twice daily for four weeks. The pharmacokinetics (PK) of LAT8881 will be investigated in 15 subjects (PK subjects) at selected Australian sites.

Official Title
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A Phase IIa Study of the Efficacy and Safety of Oral LAT8881 in Neuropathic Pain

Conditions
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Neuropathic Pain, Diabetic Peripheral Neuropathy (DPN), Post Herpetic Neuralgia (PHN)

Intervention / Treatment
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* Drug: LAT8881
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Clinical diagnosis of post herpetic neuralgia, with pain persisting for at least 3 months after the onset of herpes zoster rash OR Clinical diagnosis of distal painful polyneuropathy due to Type I or Type II diabetes mellitus with: symmetrical, bilateral pain in the lower extremities for at least 3 months and diabetes under control for at least 3 months prior to randomisation, as indicated by a glycated haemoglobin level (HbA1c) of ≤ 11% (97 mmol/mol) and on a stable dose of insulin or oral diabetic medication for 3 months prior to screening, and no change in diabetic medication planned for the duration of the study Positive sensory symptoms (mechanical or thermal) associated with neuropathic pain, confirmed by: painDETECT questionnaire (PD-Q) and Clinical assessment, showing signs of neuropathic pain in either a dermatomal (PHN) or distal symmetrical distribution (DPN) 8. An average daily pain score on the numeric pain rating scale (NPRS) of at least 4 and no more than 8 in the last five diary entries before randomisation Exclusion Criteria: Presence of moderate to severe pain from other causes that may confound assessment or self-evaluation of NP. Subjects with both DPN and PHN

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: This is the first study with LAT8881 in subjects with neuropathic pain. As such, it has been designed to evaluate, in a well-defined patient group, the concept that LAT8881 is safe and effective in this indication. Subjects enrolled into this study have been diagnosed with Post Herpetic Neuralgia (PHN) or Diabetic Peripheral Neuropathy (DPN), both conditions being well accepted examples of neuropathic pain. Because the pain is chronic, without a period effect, and treatment is symptomatic rather than curative, a crossover study is considered appropriate. Studies with other agents have successfully demonstrated analgesic effects in PHN and DPN with a crossover study design
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: LAT8881<br>1 x 30 mg capsule of LAT8881 taken by mouth, twice daily (morning and evening) during the four-week treatment period. | Drug: LAT8881<br>* LAT8881 oral capsule<br>|
| Placebo Comparator: Placebo<br>1 x 30 mg capsule of placebo, taken by mouth, twice daily (morning and evening) during the four-week treatment period. | Drug: Placebo<br>* Placebo oral capsule<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Absolute Change in Mean Pain Score, Using an 11 Point Numeric Pain Rating Scale (NPRS) | The 11-point numeric pain rating scale (NPRS) ranges from 0 (no pain) to 10 (worst pain imaginable). A larger negative number represents a greater reduction in pain. The efficacy of oral LAT8881 in neuropathic pain was compared with placebo, when assessed by change in mean pain intensity scores, using this 11 point numeric pain rating scale. | Baseline to Week 4 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in NPRS Score After the First and Last Dose of LAT8881 and Placebo | To investigate the effect of oral LAT8881 in neuropathic pain compared with placebo, as measured by the numeric pain rating score (NPRS). The 11-point numeric pain rating scale ranges from 0 (no pain) to 10 (worst pain imaginable). A larger negative number represents a greater reduction in pain. This outcome was investigated only in the pharmacokinetic subset of per protocol subjects. | Pre-dose, 0.5,1,2,4 and 6 hours after the first and last dose of LAT8881 and placebo | 
| Change in Mean Pain Scores After 1, 2 and 3 Weeks of Treatment, Using NPRS | To investigate the effect of oral LAT8881 on mean pain scores in neuropathic pain compared with placebo, as measured by the numeric pain rating scale (NPRS). The 11-point numeric pain rating scale ranges from 0 (no pain) to 10 (worst pain imaginable). A larger negative number represents a greater reduction in pain. | 1,2 and 3 weeks | 
| 30% Responder Rate in Oral LAT8881 Compared With Placebo, as Assessed by the Numeric Pain Rating Scale. | To determine the proportion of subjects with at least a 30% reduction in mean NPRS after 4 weeks treatment. The 11-point numeric pain rating scale (NPRS) ranges from 0 (no pain) to 10 (worst pain imaginable). A decrease in pain score represents an improvement in pain. | 4 weeks | 
| 50% Responder Rate in Oral LAT8881 Compared With Placebo, as Assessed by the Numeric Pain Rating Scale. | To determine the proportion of subjects with at least a 50% reduction in mean the numeric pain rating scale (NPRS) after 4 weeks treatment. The 11-point numeric pain rating scale ranges from 0 (no pain) to 10 (worst pain imaginable). A decrease in pain score represents an improvement in pain. | 4 weeks | 
| Maximum Change in Mean NPRS | To determine the maximum effects of oral LAT8881 in neuropathic pain, compared with placebo, as measured by the numeric pain rating scale (NPRS). The 11-point numeric pain rating scale ranges from 0 (no pain) to 10 (worst pain imaginable). A larger negative number represents a greater reduction in pain.. | 1,2,3 or 4 weeks | 
| Change in Functioning as Assessed by the Brief Pain Inventory Interference Scale (BPI) | To evaluate the effects of oral LAT8881, compared with placebo, on functioning when measured by the Brief Pain Inventory Interference Scale (BPI). The BPI assesses the severity of pain and its impact on functioning. Patients are asked to assess the level of interference experienced across seven items; general activity, mood, walking ability, normal work, relations with other people, sleep and enjoyment of life, with a 0 meaning no interference, and a 10, at the top end of the scale, meaning complete interference. The result is the mean of the score of the seven items. A reduction in mean score indicates a decrease in interference. | 4 weeks | 
| Change in Pain Characteristics and Intensity, as Assessed by the Short Form McGill Pain Questionnaire (SF-MPQ-2) | To evaluate the effect of oral LAT8881, compared with placebo, on pain symptoms in subjects with neuropathic pain, when measured by the Short Form McGill Pain Questionnaire (SF-MPQ-2). The SF-MPQ-2 contains 22 descriptors of pain and related symptoms, each scored from 0 (none) to 10 (worst possible). The scores for each descriptor at each visit are averaged to give a mean score from 0 to 10. A larger negative number represents a greater reduction in pain. | 4 weeks | 
| Change in Neuropathic Pain Symptoms, as Assessed by Neuropathic Pain Symptom Inventory (NPSI) | The Neuropathic Pain Symptom Inventory (NPSI) contains ten items related to different pain descriptors (e.g. burning, squeezing, electric-shock, stabbing, tingling), allowing the assessment of the different dimensions of neuropathic pain, and two items related to the frequency and duration of pain. Each pain descriptor is rated on an 11-point numeric rating scale from 0 (no pain) to 10 (worst imaginable pain). Total pain intensity score is calculated by the sum of the 10 descriptors and can range from 0 to 100. A higher score indicates a higher pain intensity. A larger negative number represents a greater reduction in pain. | 4 weeks | 
| Change in Emotional Functioning, as Assessed by the Beck Depression Inventory-II | To evaluate the effect of oral LAT8881, compared with placebo, on emotional functioning when measured by the Beck Depression Inventory-II (BDI-II). The BDI-II consists of 21 items; each item is a list of four statements arranged in order of increasing severity about a particular symptom of depression. Each statement is scored from 0 to 3. Each of the 21 items is summed to give a single score for the BDI-II. Scores can range from 0 (no depression) to 63 (severe depression). An increase from baseline to the end of treatment indicates a deterioration. | 4 weeks | 
| Patient Global Impression of Change Score | The Patient Global Impression of Change (PGIC) is a a single-item rating by subjects of their improvement with treatment during a clinical trial. It asks the subject to rate their improvement with therapy on a 7-point scale, ranging from substantially worse (0) to substantially improved (7), with no change (4) as the mid-point. A score above 4 indicates an improvement. | 4 weeks | 
| Rescue Medication Use | To determine the change from baseline in paracetamol rescue medication use during oral LAT8881 administration, compared with placebo. | Weekly over four-week treatment | 
| Maximum Plasma Concentration of LAT8881 (Cmax) After Oral LAT8881 | Cmax is calculated after the first dose of IMP on Day 1 and after 4 weeks treatment on the morning of Day 28 | Day 1 and Day 28 | 
| Time to Maximum Plasma Concentration of LAT8881 (Tmax) | Tmax after the first dose of investigational medicinal product (IMP) and after 4 weeks treatment with IMP | Day 1 and day 28 | 
| Area Under the Concentration Time Curve From Zero to Infinity (AUC0-inf) | AUC0-inf after the first dose of IMP and after 4 weeks of treatment | Day 1 and Day 28 |