Trial Information

A Multicentre , Randomized, Double-blind, Placebo-controlled, Parallel-design Trial of the Efficacy and Safety of Subcutaneous Tetrodotoxin (TTX) for Moderate to Severe 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.