• Efficacy: primary composite-endpoint will be an evaluation that combines pain outcome and quality of life. Safety as assessed by the analysis of AEs, 12-lead ECG, and abnormal lab values. [ Designated as safety issue: Yes ]
  

• The period of onset of pain response as reported by responders. [ Designated as safety issue: No ]
  
• The number of days a subject meets the definition of pain response. [ Designated as safety issue: No ]
  

Study Objectives:

In cancer male or female subjects with moderate to severe pain inadequately controlled by current therapy:

Primary Objectives:

• To compare the efficacy of subcutaneous tetrodotoxin treatment (Tectin™) with that of placebo as measured by:

  • pain outcome (pain intensity reduction or use of analgesics)
  • improvement in quality of life (physical and emotional functionings)
• 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, and potentially other countries, are expected to participate. Subcutaneous tetrodotoxin (30 ug b.i.d.) or placebo will be administered to 60 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 5- 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. Drug administration from Days 2 to 4 may be done at the patient's home, at the discretion of the investigator. 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.

All patients will be given the option to participate in an open-label extension study (TEC-006OL) on Day 15 or later.

Sample Size:

A total of 120 subjects (60 per treatment arm) will be enrolled in this study. Interim analysis is planned to adjust the sample size after 50% of subjects are enrolled, completed and data are available for analysis.

Investigational Product 30 ug Tectin™ (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:

The composite-endpoint primary efficacy analysis will be performed to compare the proportion of patients who are responders to Tectin™ with the proportion of patients who are responders to placebo.

Responder is defined as a subject in the ITT population who satisfies the following 3 criteria:

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

Trends for differences between treatments will be individually tabulated for:

• pain outcome (pain intensity difference and/or opioid use)
• 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.