A Randomized, Double Blind, Dose Finding, Placebo-Controlled, Phase II Multicenter Study of Tetrodotoxin in the Treatment of Chemotherapy Induced Neuropathic Pain.
The study will be conducted in two parts. Part 1 is a dose finding phase designed to assess the tolerability and safety of TT in patients with CINP(Chemotherapy-induced neuropathic patin). and will take about
Part I x Dose-finding:
Patients will be randomized to one of five dosing cohorts: placebo twice daily, TTX 7.5 [MICRO-SYMBOL]g twice daily, TTX 15 [MICRO-SYMBOL]g twice daily, TTX 30 [MICRO-SYMBOL]g once daily in combination with placebo once daily, or TTX 30 [MICRO-SYMBOL]g twice daily (25 patients per cohort). TTX or placebo will be administered for four consecutive days in each cohort.
Part II - Proof of Concept:
Patients will be randomized to one of potentially three dosing cohorts consisting of TTX Dose/Regimen #1, TTX Dose/Regimen #2, or placebo (approximately 50 patients per cohort). TTX dose and dosing interval will be contingent on results from Part I.
Phase II will bring forth further evaluation of the efficacy of up to two doses of TTX as compared to a Placebo in patients with CINP
The following endpoints will be evaluated up to Day 28:
* Incidence of SAEs and AEs
* Physical examination findings
* Changes from baseline in the following:
o Vital sign measurements
o Laboratory (hematology, chemistry, urinalysis) results
o ECG assessments
Efficacy endpoints for part 1 and 2 /analysis
Change in weekly and daily average NPRS scores will be assessed using restricted maximum likelihood (REML)-based mixed model repeated measures (MMRM) analysis. The model will include treatment, study week (or study day),
treatment-by-week (or day) interaction, and baseline score covariates. Other continuous efficacy endpoints will be analyzed similarly.
1. Male or female patients aged ~ 18 years.
2. If female, is either not of childbearing potential (defined as postmenopausal for at least one year or surgically sterile [bilateral tubal ligation, bilateral oophorectomy, or hysterectomy]) or practicing one 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 one full cycle (based on the patient's usual menstrual cycle period) before IP administration.
* Total abstinence from sexual intercourse since the last menses before IP administration.
* Intrauterine device (IUD).
* Double-barrier method (condoms, sponge, or diaphragm, with spermicidal jellies or cream.
3. Patients with documented neuropathic pain at least one month duration attributed to chemotherapy.
4. Cancer Patients who have completed a chemotherapy regimen which included taxanes or platinums
(or both) and have no evidence actively progressive disease. The Cancer Patients must have undergone at least a 30-day washout period between the last dose of any chemotherapy agent and the first dose of study drug, and who have no significant persistent chemotherapy-induced toxicities, other than peripheral neuropathies, in the opinion of the investigator. Concurrent hormonal therapies are allowed.
5. Patients with a score of four out of 10 or higher on the DN4 questionnaire at screening.
6. Patients with moderate to severe neuropathic pain, stable for seven days.
Stable pain will be confirmed using an 11 point (0-10) NPRS. To establish moderate, stable pain, the average of the daily pain scores during the 7-day baseline period must be4 with fluctuation in the daily pain score of:':::(+ or -) 2 points.
7. Patients with an Eastern Cooperative Oncology Group (ECOG) Performance Status score ofO or 1.
8. Patients who have the ability to communicate well with the study staff and to comply with the study requirements (restrictions, appointments, and examination schedule).
9. Patients who are able to complete the study-related questionnaires independently in either English or Spanish.
10. Signed informed consent document (prior to any study-related procedures being performed).