Guilford Pharmaceuticals Inc announced that it has completed a preliminary analysis of results from two Phase II clinical trials of Aquavan injection, a novel sedative/hypnotic. The results from the Phase II studies suggest that Aquavan injection provides rapid onset and rapid recovery from sedation/anesthesia in a convenient dosing regimen and without serious adverse effects.
The first Phase II clinical trial was an open label, multi-center, adaptive dose ranging study of Aquavan injection, used in combination with fentanyl citrate, to provide mild sedation in patients undergoing elective colonoscopy. The study enrolled healthy adults aged 18-60 undergoing elective colonoscopy. A second dose-range finding study is ongoing in patients aged 61-85.
During the study, patients were pre-treated with fentanyl citrate, an analgesic commonly used for pain relief during brief diagnostic procedures. Five minutes after receiving fentanyl, patients were given a bolus dose of Aquavan injection. Three dose groups of Aquavan injection (7.5, 10, and 12.5 mg/kg) and three dose groups of fentanyl (0.5, 1.0, and 1.5 mg/kg) were studied, resulting in a total of nine Aquavan injection/fentanyl dose- combinations.
Measurements of sedation were collected using the modified observer's assessment of alertness/sedation (OAA/S) scale. The desired sedative effect was defined as one that consistently provided mild to moderate sedation, or an OAA/S score of between 2 and 4. Patients were continuously monitored for adverse events and vital signs throughout the study. Measurements of safety, tolerability and patient and physician satisfaction were also assessed.
A total of 77 patients were enrolled and randomly allocated to one of the nine Aquavan injection/fentanyl dose groups. Following bolus administration of Aquavan injection, the median time to achieve sedation was 2 minutes. The median time to full alertness after removal of the colonoscope was 12 minutes, and the median time to full recovery, defined as the ability to stand and walk without instability or assistance, was 20 minutes. Gastroenterologists rated 94 per cent of patients as adequately sedated by Aquavan injection for the duration of the procedure.
The most common adverse event experienced in the study was a transitory itching or tingling sensation, often called paresthesias, reported by 57 per cent of patients. Of the patients reporting paresthesias, 76 per cent rated them as mild to moderate in severity. The paresthesias were not considered a serious adverse event, and did not affect the patients' acceptance of and satisfaction with the drug. Brief episodes of apnea were reported in 4 per cent of patients and successfully treated with short-term supplemental oxygen. No patients required respiratory support or endotracheal intubation. There was no pain at the injection site reported, and no episodes of hypotension requiring medical treatment were observed.
Following the procedure, the majority of patients and physicians reported a high level of satisfaction with Aquavan injection. In the study, 98 per cent of patients responding indicated they would use the drug again. On a scale of 0 to 100 (100 representing highly satisfied and 0 representing dissatisfied), 82 per cent of patients rated their experience higher than 90 and 52 per cent rated their experience at 99. Gastroenterologists rated 98 per cent of the patients' experiences as good to excellent and 100 per cent of the ratings by gastroenterologists indicated they would use Aquavan injection again for these patients.
In summary, the results of this study suggest that Aquavan has an ideal profile for use in patients receiving conscious sedation. During the study, the desired level of sedation was quickly achieved with a simple single bolus injection and was optimal for the duration of a colonoscopy procedure. In most patients given doses in the range of 800 mg, a single bolus injection was adequate for the entire procedure. Importantly, patients woke up quickly after the procedure, had a feeling of mild euphoria and left the endoscopy suite quickly, alert and able to follow post-operative instructions. This result is in stark contrast to patients receiving midazolam who often take an hour or more to recover after the procedure, have post-procedure amnesia and leave the endoscopy suite feeling lethargic.
Dr. Ron Pruitt, President and Medical Director, Nashville Medical Research Institute, Chairman of Gastroenterology, Saint Thomas Hospital, Nashville, Tennessee and an investigator in the study, commented, "Our experience with Aquavan injection suggests that it has an ideal profile for use in providing mild to moderate sedation in patients undergoing elective procedures such as colonoscopy. With Aquavan injection, the desired level of sedation was more rapidly achieved and was optimal for the duration of the procedure. As well, unlike patients treated with midazolam or other medications typically used in this setting, patients receiving Aquavan injection leave the endoscopy suite clear-headed and able to follow post-operative instructions. I am very impressed by the emerging pharmacological profile of Aquavan injection and look forward to continued clinical development of this product."
Guilford is also reporting results from a second Phase II clinical trial of Aquavan injection. The goal of the second Phase II clinical study was to evaluate the safety, tolerability and efficacy of Aquavan injection, compared to Disoprivan injectable Emulsion, for use in pre-operative sedation, anesthesia induction and maintenance, and post-operative ICU sedation in patients undergoing coronary artery bypass surgery.
A total of sixteen patients were enrolled in the study. Patients were randomized to receive either Aquavan injection or Disoprivan injectable Emulsion as the sedative/hypnotic component of a balanced anesthetic regimen. Both sedatives were delivered by target-controlled infusion to provide total intravenous anesthesia for the duration of the patient's sedation.
Efficacy measures in the study included the overall quality of sedation and quality of anesthesia induction and maintenance as assessed by the anesthesiologist, and the ease of control of anesthesia before and during surgery. In addition, various hemodynamic measures, including blood pressure, heart rate and respiratory rate were continuously assessed throughout the study.
While the number of patients enrolled in the study was small, Aquavan injection compared very favorably to Disoprivan injectable Emulsion. All patients enrolled in the study completed the procedure without requiring the use of other anesthetic agents. No serious adverse events were attributed to Aquavan injection during the study.
The average procedure times for Aquavan injection were comparable to Disoprivan injectable Emulsion, and time to loss of consciousness was similar. For Disoprivan injectable Emulsion the average time to loss of consciousness was 2.6 minutes, while for Aquavan injection it was 3.1 minutes. The average time required for intubation was the same, approximately 9.9 minutes for Disoprivan injectable Emulsion compared to 9.5 minutes for Aquavan injection, as was the duration of the surgical procedure (3.75 hours for Disoprivan injectable Emulsion compared to 3.73 hours for Aquavan injection). Post-operative sedation time was two hours for both Disoprivan injectable Emulsion and Aquavan injection. Patients received a mean Aquavan injection dose of 5.3 grams during the complete sedation, which lasted a mean time of 6.9 hours. The number of interventions (concomitant medication, decrease or increase in anesthesia) was similar for both Disoprivan injectable Emulsion and Aquavan injection.
There were no drug-related serious adverse events in either the Aquavan Injection or the Disoprivan Injectable Emulsion treatment group. Adverse events considered to be drug related were mild paresthesias in the Aquavan Injection group and mild to moderate injection site pain in the Disoprivan Injectable Emulsion group.
The results of this study demonstrated that Aquavan Injection could be used to provide total intravenous anesthesia for complex medical and surgical procedures in high-risk patients.
"After using Aquavan Injection for cardiovascular surgery, I was pleased with the lack of pain on injection and lipid free formulation, characteristics that are markedly different from propofol. In addition, I was pleasantly surprised to see Aquavan Injection's speed of onset, potency and fast recovery, which were comparable with propofol. These properties favor Aquavan Injection as a useful drug for anesthesia induction and maintenance and sedation in general. These characteristics are clear advantages. In view of the hemodynamic profile of Aquavan Injection and based on our experience with a small number of patients in a surgical setting, we anticipate that this product may be also used safely for mild to moderate sedation in brief medical procedures," commented Jurgen Schuttler, M.D., Professor and Chairman, Department of Anesthesiology, University of Erlanger-Nuremberg, Germany.
Craig Smith, M.D., chairman, president and CEO of Guilford, remarked, "Our clinical results with Aquavan Injection continue to be very promising and suggest important utility for Aquavan Injection in potentially diverse medical settings. Guilford's objective is to develop Aquavan Injection initially for use in conscious sedation. Our next step is to conduct an open label study of the optimal dose combination of Aquavan Injection and fentanyl identified in the current Phase II setting. In this confirmatory study, Aquavan Injection will be administered by nurses without the presence of an anesthesiologist."