Phase 2-3 Studies

QRx Sponsored Phase 2-3 Trials

Two Phase 2 double-blind crossover studies were conducted in Australia in which co-administration of different ratios of morphine:oxycodone were administered for about 1 week to ~45 patients with chronic pain. These dose titration studies used oral morphine as an active comparator. Results showed a reduction in total opioid use (morphine equivalents) of about 30-40% using equi-analgesic doses of combination therapy relative to morphine alone. This was accompanied by decreased rates of drowsiness, dizziness, constipation and nausea.

Phase 3 Dose-Response Study in Acute Pain

The purpose of this study in 256 inpatients with moderate to severe post-surgical pain was to evaluate the dose-dependent analgesic effects and safety profile of MoxDuo® IR across 4 dose levels for use in subsequent Phase 3 trials.

Design and Main Measures

This was a double-blind, randomized, placebo-controlled ascending dose-response study. Groups of ~50 patients each received MoxDuo IR doses of 3mg/2mg, 6mg/4mg, 12mg/8mg,18mg/12mg or placebo. Dosing intervals were flexible, but could not be less than 1-2 hrs, depending on dose. Rescue medication of 600 mg ibuprofen was provided. The main endpoints were changes from baseline in pain (NPRS scale 0-10), pain relief, time to onset of pain relief and patient global impression scales taken over the 48-hr dosing period. Safety was measured by adverse event (AE) occurrence, SpO2 values of blood oxygenation, vital signs, clinical labs, physical exams and ECGs. In addition, patient rating of the bothersomeness of opioid type AEs were obtained. The study was conducted at 6 centers in the U.S. experienced in the conduct of bunionectomy trials.

Results

Of the 256 patients randomized to double-blind treatment, the majority were female (73-90%), average age of 42-47 yrs and were white (62-78%). The dropout rate ranged from 12-18% in MoxDuo IR treated patients vs 30% in the placebo arm. The incidence of placebo dropouts due to lack of efficacy was 25% of patients vs 4-13% for MoxDuo IR (p<0.05). Dropout rates in MoxDuo IR groups due to adverse events ranged from 2-14% vs 2% for placebo. The average dose received per 6 hrs for the MoxDuo IR groups ranged from 6mg/4mg to 15mg/10mg. Ibuprofen rescue medication use was significantly higher in the placebo group than in the MoxDuo IR treated patients.

The primary efficacy endpoint was the sum of pain intensity differences from baseline over 48 hrs (SPID48). As shown in Fig. 3, there was a linear dose-response relationship with all treatment groups being statistically superior to placebo (p<0.001).

MoxDuo IR was also superior to placebo on all secondary efficacy endpoints, including pain relief, time to onset of analgesia and patient global satisfaction. MoxDuo IR treatment was superior to placebo in respect to the percentage of patients who rated their treatment effects as good to excellent (Fig 4.).

From a safety perspective, one placebo treated patient had a serious adverse event (SAE), as did one patient in the MoxDuo IR high-dose group (hypotension secondary to dehydration). Respiratory function showed little to no changes, with no patients in the study having a clinically significant depression (<10 breaths/min) and 9/196 MoxDuo IR patients having a SpO2 value of <90% at least once during the 48-hr dosing period. Seven of these 9 cases occurred in the highest dose cohort (18mg/12mg per dose). In general, the desaturations were minimal and most patients completed the study.

In respect to adverse events, it is clear that while nausea and vomiting were the most common AEs, they were usually not of an intensity to be considered bothersome. This is consistent with the low dropout rate due to adverse events. Interestingly, the incidence of drowsiness/somnolence was very low (0-2%) in the active arms and there were no reports of euphoria. In respect to other safety measures, MoxDuo IR did not produce any unusual results.

Conclusions

Doses of 12mg/8mg of Q8003 administered on average once every 6 hrs produced the optimal combination of efficacy and tolerability. However, even unit doses of 3mg/2mg resulted in significant efficacy with a benign AE profile.