Safety & Efficacy Study of Subcutaneous Tetrodotoxin for Moderate to Severe Inadequately Controlled Cancer-related Pain

Overview

Different pathophysiologic mechanisms are responsible for the development of chronic pain disorders. Pain pathways are triggered in part by ectopic discharges of voltage-sensitive sodium channels, which are in abundance in both the peripheral and the central nervous systems. Tetrodotoxin (TTX) is a selective blocker of Na+ channels and causes analgesia either by decreasing the propagation of action potentials by Na+ channels and/or by blocking of ectopic discharges associated with chronic pain. TTX is extracted from the puffer fish (fugu). Results from animal pharmacology studies revealed that TTX is a more potent analgesic than standard analgesic agents such as aspirin, morphine or meperidine. At present, the management of severe cancer pain generally includes the use of opiates. This can often result in undesirable side effects, and treatment with this type of medication is not always effective. Because currently available pain-relieving therapy is unsatisfactory for many patients, there is a need for new therapeutic approaches for the management of moderate or severe cancer pain. Recent studies indicate that intramuscular (into a muscle) or subcutaneous (under the skin) injections of tetrodotoxin (TTX) may reduce pain in cancer patients who did not respond to standard therapies. The current proposed study (TEC-006) is designed to 1) demonstrate in a double-blind, placebo-controlled trial that the subcutaneous 30 μg b.i.d. dose of TTX for 4 days is effective in reducing pain outcome and improving quality of life; 2) characterize the onset and duration of analgesia, and 3) demonstrate that TTX is well tolerated in patients with inadequately controlled cancer-related pain.

Study Objectives: Male or female subjects with moderate to severe pain (related to cancer or cancer treatment)inadequately controlled by current therapy: Primary Objectives: * To compare the efficacy of subcutaneous tetrodotoxin treatment (TTX) with that of placebo as measured by: * pain outcome (pain intensity reduction or use of analgesics) * improvement in quality of life (physical and emotional functioning) * To compare the safety of subcutaneous tetrodotoxin with that of placebo. Secondary Objectives: * To assess the onset of analgesic response of subcutaneous tetrodotoxin. * To determine the duration of analgesic response associated with subcutaneous tetrodotoxin treatment. Overall Study Design: This will be a multicentre, randomized, double-blind, placebo-controlled, parallel-design trial of the efficacy and safety of tetrodotoxin in patients over 18 years of age with stable but inadequately controlled moderate to severe pain associated with cancer. Approximately 15 centers across Canada, New Zealand and Australia are expected to participate. Subcutaneous tetrodotoxin (30 µg b.i.d.) or placebo will be administered to 127 patients per group for four consecutive days. The study period will be at least three weeks from the start of screening to the end of analgesic response. Patients will be screened for the study and will enter a 4- to 7-day baseline period within 28 days of screening. Following the baseline period, patients will either be admitted to the hospital or be seen at the site's outpatient facility on a daily basis. Patients will be randomized on Day 1 to receive study drug twice daily for four consecutive days. After the treatment period, all patients will be seen again on Days 5, 8, and 15 for further safety and efficacy evaluations, and then every two weeks until their pain returns. Sample Size: A total of 254 subjects (127 per treatment arm) will be enrolled in this study. The first interim analysis is planned to adjust the sample size after 60 evaluable subjects are enrolled, completed and data are available for analysis. A second interim analysis is planned after 50% of subjects(110 evaluable subjects) have completed the study and data are available for analysis. Investigational Product 30 µg TTX (tetrodotoxin injectable) or an equivalent volume of placebo, identical in appearance, injected subcutaneously twice daily for 4 days. Efficacy Variables: Efficacy assessments will include global pain intensity, component-specific pain intensity, ATC and breakthrough analgesic use, impact of pain on physical functioning (general activity, walking ability, or normal work), and emotional functioning (mood, relations with other people, or enjoyment of life), impressions of change, onset of analgesic response, duration of analgesic response, and time to peak analgesic response. Safety Variables: Safety assessments will include adverse event reporting, vital signs, physical and neurological examinations, 12-lead electrocardiogram, clinical laboratory tests. Data Analysis Method: Two co-primary endpoints will be analyzed in this study as follows: Co-primary #1 (composite endpoint): Proportion of responders observed in each treatment arm for the composite endpoint satisfying the following three components: 1. a ≥30% decrease in mean pain intensity or a decrease of ≥50% of opioid use from baseline 2. a ≥30% improvement of QOL in at least one descriptor of physical functioning 3. a ≥30% improvement of QOL in at least one descriptor of emotional functioning Co-primary #2 (Pain intensity endpoint): Proportion of responders observed in each treatment arm for reduction in pain intensity satisfying the following: 1\. a ≥30% decrease in mean pain intensity or a decrease of ≥50% of opioid use from baseline Trends for differences between treatments will be individually tabulated for: * impact of pain on physical functioning * impact of pain on emotional functioning Comparison of the proportion of responders in each treatment group will be made using the Mantel-Haenszel procedure. Safety as assessed by the analysis of adverse events, abnormal laboratory results, and abnormalities detected by 12-lead electrocardiogram.