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Phase III Studies for Once-Daily Tramadol Yield Positive Results
LAVAL, QC, Jan. 28 /PRNewswire-FirstCall/ -- Labopharm Inc. (TSX: DDS) today reported results from its two recently completed Phase III clinical trials (MDT3-002 and MDT3-003) in the United States for its lead in-house product, a once-daily formulation of the analgesic tramadol.
In trial MDT3-003, Labopharm's once-daily formulation of tramadol achieved statistical significance for the three co-primary endpoints, which were reduction in pain, improvement in physical function, and patient's global assessment of the product's effectiveness. In trial MDT3-002, while once-daily tramadol demonstrated a similar improvement in pain relief, physical function and patient's global assessment, due to an unusually high response to placebo, statistical significance was not demonstrated for all of the three co-primary endpoints. The two studies enrolled approximately 1,100 patients. Additionally, in both trials, Labopharm's once-daily tramadol provided full 24-hour pain relief and exhibited an adverse events profile clinically superior to that of the immediate release formulation of tramadol as reported in the literature. These study results together with the results from Labopharm's European Phase III clinical trial for once-daily tramadol will form the basis of a New Drug Application (NDA) with the US Food and Drug Administration (FDA).
"We have completed three Phase III clinical trials, involving more than 1,500 patients, in which Labopharm's once-daily tramadol has demonstrated a reduction in pain, an improvement in physical function and a reduction in adverse events. This data provides us with a strong clinical package for the NDA filing, despite not having achieved statistical significance in one of the US studies," said Mr. James R. Howard-Tripp, President and Chief Executive Officer, Labopharm Inc. "We believe strongly in the potential for our once-daily formulation of tramadol and our global commercialization plan remains on track."
Results of the Studies
The purpose of the double-blind, multi-centre studies, which were similar in design and size, was to compare the safety and efficacy of Labopharm's once-daily formulation of tramadol to placebo over a 12-week period. Enrollment in the trials consisted of patients aged 40 to 75 years, diagnosed with moderate to severe pain associated with osteoarthritis of the knee. Patients who met the inclusion and exclusion criteria at screening entered a wash out period during which all analgesic use was discontinued. At the start of each trial (baseline), eligible patients were randomly assigned to one of the four arms (three active treatment arms and a placebo arm). Patients in the three active treatment arms received either a 100mg dose, a 200mg dose or a 300mg dose of Labopharm's once-daily tramadol. Patients in the 100mg active treatment arm took 100mg for the duration of the trial, whereas for patients in the 200mg and 300mg active treatment arms, the dose was titrated up every 2 to 3 days. Patients in the placebo arm took a placebo for the duration of the trial.
In trial MDT3-003, statistical significance was achieved for the three co-primary endpoints at the 200mg and 300mg doses, providing an improvement as measured by the change in the WOMAC Osteoarthritis Pain subscale, the WOMAC Osteoarthritis Function subscale and the patient's global assessment. The 100mg arm was included in order to determine the lowest effective dose and is intended to be used as a titration dose only. Furthermore, Labopharm's once-daily tramadol provided pain relief for a full 24-hour period. Labopharm's once-daily formulation of tramadol exhibited an incidence of adverse events similar to that of Labopharm's once-daily tramadol in the European Phase III clinical trial and lower than that of the immediate-release formulation of tramadol as reported in the literature.
In trial MDT3-002, due to an unusually high response to placebo, statistical significance could not be demonstrated for all of the co-primary endpoints. Consistent with trial MDT3-003, Labopharm's once-daily tramadol provided pain relief for a full 24-hour period and also exhibited a similar low incidence of adverse events.
"The three Phase III clinical trials using our once-daily formulation of tramadol have yielded consistent results, demonstrating similar levels of pain relief for a full 24-hour period. Additionally, the adverse events profiles were clinically superior to the immediate release formulation as reported in the literature," said Dr. Sylvie Bouchard, Vice President, Clinical Development, Labopharm Inc. "Our data provides strong evidence for the safety and efficacy of Labopharm's once-daily tramadol in the treatment of pain."
European Regulatory Approval Update
Labopharm has received a 'Mesure d'instruction' from the Agence francaise de securite sanitaire des produits de sante (AFSSAPS), the agency in France responsible for the regulatory approval of new drugs. The 'Mesure d'instruction' acknowledged that there were no major deficiencies in the file and contained requests for clarification, to which the Company is responding. It is believed that a satisfactory response to these requests will lead to an approval in France.
As reported in January 2003, Labopharm's once-daily formulation of tramadol achieved the primary endpoint of a Phase III clinical study in Europe designed to compare the efficacy and safety of Labopharm's once-daily formulation of tramadol to that of an extended release, twice-daily formulation of tramadol currently marketed in Europe. In the study, Labopharm's once-daily tramadol provided a statistically and clinically significant reduction in pain associated with osteoarthritis. Two-thirds of the patients receiving Labopharm's once-daily tramadol required a dose of 200mg or less per day to achieve effective pain relief. Furthermore, the study demonstrated that Labopharm's once-daily tramadol provided pain relief for a full 24-hour period, matching the twice-daily formulation dosed twice per day. The adverse events profile of Labopharm's once-daily tramadol was clinically superior to that of the twice-daily tramadol product with a lower incidence of adverse events. Moreover, the difference was even more markedly in favour of Labopharm's once daily formulation when compared to the incidence of adverse events associated with the immediate release tramadol as reported in the literature.
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 and 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 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.
Source: Labopharm Inc.