A Two-part Proof-of-Concept Study Assessing the Safety and Efficacy of LAT8881 in Lumbar Radicular Pain

Study Overview
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Brief Summary
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The study consists of two parts. Part A will evaluate the safety and tolerability of intravenous LAT8881 in healthy volunteers using an ascending dose schedule. Part B will evaluate the analgesic efficacy of a single intravenous dose of LAT8881, compared with placebo, in patients with lumbar radicular pain. Healthy volunteers are not accepted for Part B.

Detailed Description
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Part A of this study is a double-blind, randomized, placebo-controlled, single ascending dose study of intravenous administration of LAT8881 over 5 minutes in healthy volunteers. Eight participants will be enrolled. Each participant has three treatment days, 1 infusion per dosing day, on Days 1, 4 and 7 as well as two short visits for safety blood sampling on Days 3 and 6. Participants are randomised, so on each treatment day, 6 participants receive LAT8881 and 2 receive placebo (different participants to receive placebo each treatment day). LAT8881 doses administered are 0.8 mg/kg on Day 1, 1.2 mg/kg on Day 4 and 1.8 mg/kg on Day 7. Part B of this study is is a placebo-controlled randomized double blind cross-over safety and efficacy study of LAT8881 in up to 20 patients with lumbar radicular pain. Participants will be randomly assigned to one of two groups, to receive either LAT8881 then placebo or placebo then LAT8881. Participants will receive a either single dose of LAT8881 [the Maximum Tolerated Dose from Part A of the study] or placebo via intravenous administration over 5 minutes on two consecutive days.

Official Title
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A Two-part Proof-of-Concept Study Assessing the Safety and Efficacy of LAT8881 in Lumbar Radicular Pain

Conditions
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Radiculopathy Lumbar

Intervention / Treatment
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* Drug: LAT8881
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: For PART A, the following inclusion criteria apply: Male or female healthy participants, aged 18-49 years inclusive at screening; Body mass index of ≥ 19.0 kg/m2 to ≤ 32.0 kg/m2 at screening; Female participants must not be pregnant or breastfeeding Male participants with a female partner of childbearing potential must use highly effective contraception for 60 days after the last dose of study treatment For PART B, the following key inclusion criteria apply: Male or female participants with unilateral pain, aged 18 years and above at screening; Body mass index of ≥ 19.0 kg/m2 at screening. Female participants must not be pregnant or breastfeeding Male participants with a female partner of childbearing potential must use highly effective contraception for 60 days after the last dose of study treatment Presenting with a history of unilateral pain, radiating into a lower limb, of lancinating, burning, stabbing or electric quality, of duration of >3 months. Pain scores (VAS) for average daily leg pain at rest at the relevant nerve root of a mean of ≥4/10 and ≤9/10 for 3 days prior to treatment, with a minimum of >3/10 on any day. Demonstration of disc herniation within 6 months by CT or MRI at a segmental level consistent with the clinical features. The site of disc herniation must affect L1-2, L2-3, L3-4, L4-5 or L5-S1. The patient is willing to keep all analgesic medication and other therapy usage stable or decreased in the week prior to, and a week after, IP administration. The patient is in good general health, with the exception of the presenting condition under study Key Exclusion Criteria: The following key exclusion criteria apply for both PART A and PART B: Any condition which might be a risk to participant safety or interfere with study evaluation Unwillingness to abstain from alcohol or nicotine products as required The following additional key exclusion criteria apply to PART B: A history of significant pain unrelated to disc herniation that would significantly compromise assessment of leg radicular pain. Radiological evidence of foraminal stenosis or of clinically significant spinal stenosis . Lumbar back surgery related to the specific disc. Injection of an epidural corticosteroid injection within 3 months of screening.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

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
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LAT8881<br>In Part A, LAT8881 will be given as a single intravenous infusion on separate days at doses of 0.8, 1.2 and 1.8 mg/kg. In Part B, LAT8881 will be given as a single intravenous infusion. The dose will be determined from the results of Part A. | Drug: LAT8881<br>* In Part A, LAT8881 will be given as a single intravenous infusion at doses of 0.8, 1.2 and 1.8 mg/kg. In Part B, a single intravenous infusion of LAT8881 will be given, the dose to be determined by the results in Part A<br>|
| Placebo Comparator: Placebo<br>Matching placebo will be given as a single intravenous infusion in Part A and Part B | Drug: Placebo<br>* Matching placebo'given as a single intravenous infusion at all dose levels<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The number of participants with adverse events by dose (Part A) | The number of participants in Part A with the following adverse events will be reported by dose (with all placebo subjects combined) All adverse events Serious adverse events Adverse events leading to premature discontinuation of Investigational Medicinal Product (IMP) Adverse events by intensity Adverse events by relationship to IMP | From first dose of LAT8881 to end of study visit (Day 14) | 
| Change in baseline pain with intravenous LAT8881 in patients with lumbar radicular pain (Part B) | Change in pain from baseline is measured on on a 0-10 Visual Analogue Scale (VAS). The VAS consists of a 10 cm line with two endpoints representing 0 (no pain) and 10 (pain as bad as it could possibly be). The subject is asked to rate their current level of pain by placing a mark on the line and the distance from 0 is measured to provide a pain intensity score out of 10. VAS measurements are taken as the infusion starts and at 15 minute intervals for the first hour, then every thirty minutes for an additional two hours, then hourly until 6 hours from infusion commencement | From start of infusion to 6 hours after start of infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum plasma LAT8881 concentration (Cmax) after intravenous LAT8881 (Part A) | LAT8881 is measured in plasma samples taken pre-dose and at 5 minutes, 0.25, 0.5, 1, 2, 4 and 6 hours after IMP administration | Up to 6 hours after the start of each infusion | 
| Time to maximum plasma LAT8881 concentration (Tmax) after intravenous LAT8881 (Part A) | LAT8881 is measured in plasma samples taken pre-dose and at 5 minutes, 0.25, 0.5, 1, 2, 4 and 6 hours after IMP administration | Up to 6 hours after the start of each infusion | 
| Area Under the Concentration Time Curve From Zero to Infinity (AUC0-inf) after intravenous LAT8881 (Part A) | LAT8881 is measured in plasma samples taken pre-dose and at 5 minutes, 0.25, 0.5, 1, 2, 4 and 6 hours after IMP administration. (AUC0-inf) will only be calculated if there are at least three quantifiable data points | Up to 6 hours after the start of each infusion | 
| Terminal elimination half life (T1/2), (Part A) | LAT8881 is measured in plasma samples taken pre-dose and at 5 minutes, 0.25, 0.5, 1, 2, 4 and 6 hours after IMP administration. The terminal elimination half life will only be determined if there are at least three quantifiable elimination phase data points. | Up to 6 hours after the start of each infusion | 
| Patient general impression of change (Part B) | The Patient General 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. | 6 hours after the start of the second infusion | 
| The number of participants with adverse events after intravenous LAT8881 in patients with lumbar radicular pain (Part B) | The number of participants in Part B with the following adverse events will be reported after placebo and after intravenous LAT8881 All adverse events Serious adverse events Adverse events leading to premature discontinuation of Investigational Medicinal Product (IMP) Adverse events by intensity Adverse events by relationship to IMP | From start of infusion to end of study visit (Day 9) |