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

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

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), randomization and a 4-day treatment period, 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.

Inclusion Criteria:

• Male or female subjects aged ≥21 years.
• Subjects and their partners must agree to using effective methods of birth control from the time of signature of the informed consent form up until 30 days following 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 and immunotherapy that do not cause neuropathy are 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.
• Current use of opioids or plans to start using opioids during the study period. However, opioids at doses of ≤90 mg morphine equivalents per day are permitted as long as subject is on stable dose for at least 60 days prior to randomization and plan on staying on that stable dose (fixed dose and schedule) throughout the study.
• 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 2600 mg per day <3 times a week or Ibuprofen will be allowed at doses up to 1200 mg per 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 as determined by a screening serum creatinine >1.5x normal.
• 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 uncontrolled 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.
• Subjects with neuromuscular conditions, including but not limited to any impairment that influence swallowing or breathing function.
• 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, or current intake deemed excessive by the investigator or routine use averaging >3 units of alcohol per day.
• Active substance abuse or drug dependency in the opinion of the investigator, including prescription drug abuse.
• 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.