October 15, 2003

News Release: Results of clinical trials demonstrate efficacy of once-daily tramadol

Today, poster results were presented at the OsteoArthritis Research Society International (OARSI) World Congress 2003 of a Phase III clinical trial conducted by Dr. Gerald Mongin demonstrating the clinical efficacy of a once-daily formulation of the a nalgesic tramadol (developed and manufactured by Labopharm Inc.). The study met both the primary and secondary end points in demonstrating that the once-daily formulation of tramadol had equivalent efficacy compared to an extended-release, twice-daily formulation. 'Pain is an under-treated condition, with relatively few attractive therapeutic alternatives for moderate to moderately severe pain,'said Dr. Gerald Mongin, a physician in private practice who is very actively involved in treating osteoarthritis. 'As a clinician, the significance to me of this study is the flexibility it gives physicians to offer their patients an effective therapeutic option with true 24-hour analgesic effect and few side effects. A once-daily formulation of tramadol should facilitate patient compliance, leading to improved clinical outcomes and an enhanced quality of life for patients suffering from chronic pain.'

Dr. Mongin's study, conducted through his medical office in Montpellier, entered 451 patients in a randomized, double-blind, parallel study in 21 centres in four European countries. Patients with moderate to severe osteoarthritis of the knee were evaluated for the analgesic effect and safety of the once-daily formulation of tramadol. The study also evaluated the formulation for true 24-hour analgesic efficacy and compared the safety of the once-daily formulation to the safety profile of a twice-daily, extended- release formulation.

In the trial, patients underwent washout and baseline evaluations. Doses were adjusted by 100 mg increments (to a maximum of 400 mg, if necessary) to achieve the optimum daily dose and then maintained at the optimal dose for 12 weeks. During the study, the median optimal dose was 200 mg per day for both groups. The measure of efficacy (principal end point) was determined using the WOMAC pain subscale score. The evaluation was made by comparing the intensity of the initial pain (prior to taking the drug) with the pain 12 weeks after taking the drug.

Dr. Mongin's study determined that the once-daily formulation of tramadol achieved the primary objective of the study, providing statistically and clinically significant reduction in pain associated with osteoarthritis and demonstrating equivalence to the twice-daily formulation of tramadol as measured by the WOMAC index. The intensity of pain ratings improved by 58% for both groups, with statistically significant results. Furthermore, pain relief was achieved from the first week of treatment and improved over the course of the 12-week study. Two-thirds of the patients receiving the once-daily formulation required a dose of only 200 mg or less per day.

The study also achieved its secondary end points, with the once-daily formulation of tramadol demonstrating clinical improvement in all of the following measures:

- Pain ratings over 24-hour periods - Other WOMAC scores (e.g., stiffness and functional disability) - Overall evaluation by the patient and investigator - Incidence of adverse events

The proportion of patients in the once-daily group reporting mild to no pain 24 hours after dosing (73%) was identical to that of the patients in the twice-daily group, measured 12 hours after dosing. Pain ratings over a 24-hour period were similar for both once and twice-daily groups, indicating that the once-daily formulation under study by Dr. Mongin delivered true 24-hour pain relief. Patients and investigators rated both the once and twice-daily formulations of tramadol as very effective in 85% of cases. WOMAC stiffness and functional disability scores demonstrated similar efficacy for both formulations.

The adverse events profile of the once-daily formulation of tramadol was superior to that of the twice-daily version. Dr. Mongin's study highlighted the fact that fewer patients in the once-daily group experienced dizziness/vertigo (26% compared to 37%), vomiting (8% compared to 14%), and headache (13% compared to 18%). In addition, the severity of these side effects was lower in the group taking the once-daily formulation of tramadol. Both groups experienced similar occurrences of nausea, constipation, and weakness. A greater number of patients in the once-daily group experienced drowsiness (30% compared to 21%).

Study details

Enrolment in the study consisted of 431 patients, aged 40 to 75, diagnosed with moderate to moderately severe pain associated with osteoarthritis of the knee. Patients who met the inclusion and exclusion criteria at screening entered a period during which all analgesic use was discontinued. At the start of the study (baseline), eligible patients who reported pain intensity in the knee joint greater than 150 mm (average intensity in the study was approximately 290 mm) on the WOMAC pain subscale (five items) were randomly assigned to receive either the once-daily formulation of tramadol or another currently available twice-daily formulation. An initial dose of 100 mg daily was maintained for three days. Thereafter, if required, the dose was increased every two to three days (to a maximum dose of 400 mg if necessary), based on effective pain relief and tolerability of adverse events. Patients were then maintained on their optimum daily dose for a 12-week period.

About Tramadol

Tramadol is a centrally acting analgesic indicated for moderate to moderately severe pain that may be associated with conditions such as osteoarthritis, lower back spasm, cancer, and other acute or chronic conditions. Because tramadol is well tolerated compared to anti-inflammatory drugs, it can be used by patients who are at risk of developing gastrointestinal bleeding and those with kidney problems. Tramadol reduces pain by binding to (micro)-opioid receptors and by inhibiting the re-uptake of the neurotransmitters norepinephrine and serotonin, a unique advantage over other analgesics. The worldwide market for tramadol is estimated to be in excess of US $1 billion annually.

About the World Congress on OsteoArthritis

The World Congress on OsteoArthritis, hosted by the OsteoArthritis Research Society International (OARSI), is the premiere meeting for basic scientists, clinical investigators, clinicians, radiologists, orthopedists, rheumatologists, industry scientists and policy makers interested in osteoarthritis research and treatment. The 2003 Congress covers a broad spectrum of topics in the field, including clinical outcomes, imaging, standards, epidemiology, genetics, cell and matrix biology, and biomechanics and aging. OARSI promotes and encourages fundamental and applied research, and disseminates the results of that research in order to permit better knowledge of osteoarthritis and its treatment. According to OARSI, osteoarthritis represents the single most prevalent age-related disease and, given the increasing numbers of the elderly in both developed and developing countries, is expected to have a profound impact on health care and quality of life for senior citizens.

Funding for Dr. Mongin's study of the clinical efficacy and safety of once-daily tramadol was provided by Labopharm Inc., a specialty pharmaceutical company in Laval, Quebec, Canada. Labopharm is developing the once-daily formulation of tramadol used in the study based on Contramid(R), the company's proprietary controlled-release drug delivery platform. Contramid is a patented drug delivery technology that enables the controlled release of pharmaceutical actives with a range of pharmacokinetic profiles.

For further information: At The Equicom Group: Jason Hogan, Investor Relations, Tel: (416) 815-0700, jhogan(at)equicomgroup.com; At Feinstein Kean Healthcare: Harriet Ullman, U.S. Media Relations, Tel: (617) 577-8110, hullman(at)fkhealth.com

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