A Randomized, Double-Blind, Placebo Controlled, Multicenter, Efficacy and Safety Trial of Single Cycle Tetrodotoxin in the Treatment of Chemotherapy Induced Neuropathic Pain

Study Overview
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Brief Summary
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To be eligible for the trial, subjects must have ongoing moderate to severe neuropathic pain related to a prior course of platinum and/or taxane chemotherapy and have no clinical evidence of actively progressive disease. The trial period will comprise a Screening Period (up to 35 Days), a two-week period for the determinations of Baseline pain followed by randomization and 4-day treatment, followed by a 12-week follow up period (12 weeks total after initial treatment), and an End-of-Trial/Follow-up visit, which will occur at Week 13. This is a study to research the effects of the study drug on neuropathic pain compared placebo.

Official Title
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A Randomized, Double-Blind, Placebo Controlled, Multicenter, Efficacy and Safety Trial of Single Cycle Tetrodotoxin in the Treatment of Chemotherapy Induced Neuropathic Pain

Conditions
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Chemotherapy-induced Neuropathic Pain, Chemotherapy-induced Peripheral Neuropathy

Intervention / Treatment
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* Drug: Tetrodotoxin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: • Male or female subjects aged ≥21 years. o Subjects and their partners using an acceptable method of birth control. Female subjects of child-bearing potential (see below) must have a negative pregnancy test (urine or serum) at the screening visit and must agree to use adequate birth control from the time of signature of the informed consent form up until 30 days following the end of the Treatment Period. Non-childbearing potential is a female who is (defined as postmenopausal for at least 1 year or surgically sterile [bilateral tubal ligation, bilateral oophorectomy, or hysterectomy]) or subjects and their partner practicing 1 of the following medically acceptable methods of birth control: Hormonal methods such as oral, implantable, injectable, vaginal ring, or transdermal contraceptives for a minimum of 1 full Cycle (based on the subject's usual menstrual Cycle period) before trial drug administration. Total abstinence from sexual intercourse since the last menses before trial drug administration. Intrauterine device. Double barrier method (condoms, sponge, or diaphragm with spermicidal jellies or cream. o Male subjects must agree to use adequate birth control from the signature of the informed consent form up until 30 days after the end of the Treatment Period. Subjects with neuropathic pain attributed to platinum and/or taxane chemotherapy for a minimum of 3 months duration from screening. Subjects with cancer who have completed a chemotherapy regimen that included taxanes or platinums (or in combination) and have no clinical evidence of actively progressive disease. Subjects must have undergone at least a 90-Day washout period between the last dose of cytotoxic chemotherapy/radiotherapy agent and randomization. Concurrent hormonal therapy is permitted. Subjects with a score of 4 or higher out of 10 on the Diagnosing Neuropathic Pain-DN4 Questionnaire (Appendix F) at Screening. Subjects must have at least 10 non-missing scores in the 14 Days prior to randomization during their Baseline Period. Subjects with moderate to severe neuropathic pain that has been stable for 14 Days. Stable pain will be confirmed using an 11-point (0-10) NPRS. To establish moderate or severe stable pain, the average daily pain scores during the 14-Day Baseline Period must be ≥4 with fluctuation in the daily pain score of ≤2 points in increase or decrease. Subjects with an average pain score >9 at Baseline will be excluded. Subjects with an Eastern Cooperative Oncology Group Performance Status score of 0 or 1 (Oken et al, 1982). Subjects who are able to communicate well with the trial staff and to comply with the trial requirements (restrictions, appointments, and examination schedule). Subjects who are able to complete the trial-related questionnaires independently in either English or in the local language. Subjects who sign an informed consent document (prior to the performance of any trial related procedures). Exclusion Criteria: History of peripheral neuropathy attributed to any cause other than platinum or taxane chemotherapy (e.g., radiotherapy, vinca alkaloids, diabetes, alcohol, toxin, hereditary, human immunodeficiency virus, or severe malnutrition). Subjects who have received TTX at any time prior to enrolment. Subjects receiving agents known to cause peripheral neuropathy within 90 Days of randomization. Current use of any other therapy (including alternative nonmedical therapy) for the treatment of neuropathic pain within 60 Days of randomization unless the dose is stable for the 60 Days immediately prior to randomization. Subjects who fail this criterion can be rescreened after 60 Days of stability. Subjects who used opioids within 14 Days of randomization or plan on using opioids during the study period. Subjects who require rescue medication for breakthrough pain with medication other than acetaminophen or Ibuprofen. Before and after randomization, acetaminophen will be allowed at doses up to 650 mg of acetaminophen 4 times a Day <3 times a week or Ibuprofen will be allowed at doses up to 400 mg 3 times a Day <3 times a week. Any concomitant medication that prolongs the QT or QRS interval unless on a stable dose for 60 Days prior to randomization. Subjects with known impaired renal function or have screening GFR < 50 mL/min/1.73 m2 (using MDRD formula). Subjects who have not recovered from all toxicities related to chemotherapy to < grade 1 or mild AE's with the exception of CINP. Subjects who have inadequate organ function tests including: Hgb < 10 g/dl; ANC < 1500/µL; Plt. count < 100,000/µL; liver function (ALT and/or AST) more than 2 times the upper limit of normal. Subjects with urinary retention. Subjects with documented bone metastases at the time of trial entry. Subjects with predicted life expectancy of <8 months. Subjects scheduled for chemotherapy or radiotherapy between Screening and the End of Trial visit (Week 13). Current use of lidocaine (including Lidoderm) and other types of sodium channel antiarrhythmic drugs within 30 Days of randomization. Subjects who have been injected with Botulinum toxin (e.g., Botox®) in the 3 months prior to randomization, or who plan to receive a Botulinum toxin injection during the study period. Subjects who require regular antiemetic medication. Current use of tricyclic antidepressant medication, anticonvulsants, or monoamine oxidase inhibitors. Stable use of those medications for at least 2 months is permissible if the subject has qualifying pain and plans to remain on a stable dose throughout the trial. Subjects will be excluded if they have a current diagnosis of Major Depressive Disorder. Subjects with current uncontrolled asthma, carbon dioxide retention, or oxygen saturation <92% on room air, or require oxygen therapy at any concentration. Subjects with second- or third-degree heart block or prolonged QTc interval (corrected for rate) on screening electrocardiogram (ECG) (i.e., confirmed >450 msec for men and >470 msec for women on repeated occasion) or any other active cardiac arrhythmia or abnormality that might constitute a clinical risk (i.e., LBBB, pacemaker). Subjects with motor impairment / neuromuscular abnormalities of the neck or throat, including clinically significant neuromuscular abnormalities affecting the vocal cords or breathing apparatus (excluding the tongue). Use of an investigational agent within 30 Days prior to Screening or scheduled to receive an investigational drug other than TTX during the course of the trial. History of alcoholism, including binge drinking considered excessive in the opinion of an investigator, within 12 months, or routine use of ethanol averaging > 3 units of alcohol per Day. Significant history of drug dependency in the opinion of the investigator, including prescription drug abuse or positive urine drug screening. Women who are pregnant or breast feeding. Any other condition that in the opinion of the investigators is likely to interfere with treatment, impede data collection, or that poses a risk to the subject.

Ages Eligible for Study
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Minimum Age: 21 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: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Tetrodotoxin for injection<br>30 µg, 1 ml SC injection in the thigh or abdomen, twice daily for 4 Days | Drug: Tetrodotoxin<br>* TTX for Injection, 30 µg/mL, is a sterile, nonpyrogenic, white, lyophilized powder provided in a 5 mL glass single-use vial with a rubber stopper and aluminum overseal. Upon reconstitution of the lyophilized product with 1.1 mL of sterile water for injection, each vial delivers 1 mL of fluid containing 30 µg of TTX with a pH of 4.0 to 5.5<br>* Other names: Halneuron;|
| Placebo Comparator: Placebo<br>1.0 mL of placebo, SC injection in the thigh or abdomen, twice daily for 4 Days | Drug: Placebo<br>* Placebo for injection is a sterile 0.9% sodium chloride injection or normal saline for injection. To ensure blinding, subjects receiving placebo will receive the same volume (1.0 mL) for injection to match the volume used for the cohorts assigned to receive active trial drug. Route and frequency: 1.0 mL of placebo, SC injection in the thigh or abdomen, twice daily for 4 Days in each treatment Cycle.<br>* Other names: Sterile 0.9% sodium chloride injection;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| NPRS Pain reduction - at week 4 | The Change from Baseline (average of Days -14 to -1) at Week 4 in average weekly NPRS scores in subjects treated with TTX compared to Placebo | At week 4 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| NPRS Pain reduction - at week 8 | The Change from Baseline (average of Days -14 to -1) at Week 8 in average weekly NPRS scores in subjects treated with TTX compared to Placebo | At week 8 | 
| NPRS Pain reduction - at week 12 | The Change from Baseline (average of Days -14 to -1) at Week 12 in average weekly NPRS scores in subjects treated with TTX compared to Placebo | At week 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CINP, Neuropathy