A phase IIb study comparing the safety and efficacy of remimazolam and midazolam in patients undergoing colonoscopy.

BACKGROUND AND AIMS: Remimazolam is an ultra-short-acting benzodiazepine currently being developed for procedural sedation and for induction and maintenance of anesthesia. This trial was the fourth study for procedural sedation. The aim was to compare the safety and efficacy profile of remimazolam and to refine suitable doses for subsequent phase III studies in this indication. METHODS: This was a randomized, double-blind, parallel group, active controlled clinical trial with 162 male and female patients, aged 18 to 70, scheduled to undergo a routine colonoscopy. Patients were randomized to receive 1 of 3 remimazolam doses or midazolam for sedation. Supplemental oxygen and 100 µg of fentanyl was given before procedures were started, and the colonoscopy commenced as soon as suitable sedation had been achieved (Modified Observer's Assessment of Alertness/Sedation score ≤3). Top-up doses of the study drug and/or fentanyl were allowed to maintain suitable sedation and/or analgesia. Response was defined as sufficient sedation, no rescue sedative, and no ventilation required. RESULTS: This study showed that a single dose of remimazolam or midazolam, followed by top-up doses to maintain suitable sedation, provided adequate sedation with a high success rate (>92%) for the remimazolam groups, compared with 75% for the midazolam group (P = .007). There was no requirement for mechanical ventilation in any group, and procedure failures were all due to use of rescue sedative. CONCLUSIONS: The high success rates and good safety profile of remimazolam observed in this study warrants further investigation and confirmation in phase III trials. ( CLINICAL TRIAL REGISTRATION NUMBER: NCT01145222.).

A Phase IIa, randomized, double-blind study of remimazolam (CNS 7056) versus midazolam for sedation in upper gastrointestinal endoscopy.

BACKGROUND: This exploratory study was the first study of remimazolam in patients to assess the safety and efficacy of different single doses for procedural sedation. METHODS: Patients scheduled to undergo a diagnostic upper gastrointestinal endoscopy were randomized to receive 1 of 3 doses of remimazolam or midazolam (25 per group) in a double-blind manner. After a single dose of study drug to achieve sedation, patients underwent gastroscopy. We assessed the success of the procedure, sedation levels, recovery from sedation, and safety. RESULTS: A single dose of remimazolam resulted in a successful procedure in 32%, 56%, and 64% of patients in the low (0.10), middle (0.15), and high (0.20 mg/kg) dose groups compared with 44% of patients in the midazolam (0.075 mg/kg) dose group. The onset of sedation was 1.5 to 2.5 minutes in the remimazolam dose groups compared with 5 minutes for midazolam. Because this was a single administration study, sedation could be maintained for as long as necessary to complete the procedure, using rescue midazolam or propofol. Recovery from sedation was rapid for all treatment groups but was influenced by the choice of rescue medication. There were no obvious differences in the safety profiles of remimazolam and midazolam. CONCLUSIONS: This exploratory dose-finding study showed that a single administration of remimazolam (0.10-0.20 mg/kg) was capable of inducing rapid sedation with a quick recovery profile in patients undergoing a diagnostic upper gastrointestinal endoscopy. The safety profile was favorable and appeared to be similar to that of midazolam, warranting further development of this short-acting compound.

Nitroglycerin 0.4% ointment vs placebo in the treatment of pain resulting from chronic anal fissure: a randomized, double-blind, placebo-controlled study.

BACKGROUND: Complications of chronic anal fissure (CAF) treatments are prompting interest in lower-risk therapies. This study was conducted to compare nitroglycerin (NTG) 0.4% ointment with placebo for pain associated with CAF. METHODS: In this randomized, double-blind, placebo-controlled trial, patients with one CAF and moderate-to-severe pain (≥50 mm on a 100 mm visual analog scale [VAS]) received 375 mg NTG 0.4% (1.5 mg active ingredient) or 375 mg placebo ointment applied anally every 12 hours for 21 days. The primary end point was change from baseline VAS score in 24-hour pain averaged over days 14-18. Review of data from patients who withdrew early was blinded to treatment. To control for the confounding effects of analgesics, all patients received 650 mg acetaminophen for headache prophylaxis before each application. RESULTS: A total of 247 patients were enrolled (NTG, n = 123; placebo, n = 124). The prespecified baseline observation carried forward (BOCF) analysis found no significant difference between groups; however, a last observation carried forward (LOCF) analysis showed a significant advantage for NTG. A post hoc analysis (LOCF/BOCF hybrid) demonstrated a significant adjusted mean difference of -7.0 mm in favor of NTG 0.4% (95% CI -13.6, -0.4; P = .038). Headache was the most common adverse event in the NTG (69.9%) and placebo (47.6%) groups. CONCLUSIONS: This was the first placebo-controlled study that also controlled for the confounding effects of analgesics used to treat NTG-induced headache. In patients with moderate-to-severe CAF pain, NTG 0.4% ointment effectively reduced CAF pain compared with placebo. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00522041.

Rifabutin-Containing Triple Therapy (RHB-105) for Eradication of Helicobacter pylori: Randomized ERADICATE Hp Trial.

Due to increasing resistance to commonly used antibiotics, the World Health Organization and Food and Drug Administration have advocated the development of new therapeutic regimens for Helicobacter pylori (H. pylori). This phase three, double-blind study (ERADICATE Hp) randomized (2:1) treatment-naïve adults with H. pylori infection and dyspepsia to RHB-105 (an all-in-one combination of omeprazole 40 mg, amoxicillin 1000 mg, and rifabutin 50 mg) or an identically-appearing placebo, both administered every 8 h for 14 days. The H. pylori eradication rate with RHB-105, using a modified intent-to-treat (mITT) population of subjects who received ≥1 dose of study drug and had test-of-eradication performed 28-35 days post-completion of therapy, was compared (one-sample Z-test) to a literature-derived comparator rate of 70% and success rate with physician-selected standard-of-care given to placebo failures. The mITT H. pylori eradication rate (95% CI) with RHB-105 of 89.4% (82.0-96.8%) was greater than both the literature-derived comparator rate (P < 0.001) and the standard-of-care rate of 63.0% (44.8-81.1%) (P = 0.006). Adverse events with an incidence ≥5% for RHB-105 were diarrhea (12.7%), headache (11.9%), chromaturia (9.3%), abdominal tenderness (6.8%), and dizziness (5.1%). No leukopenia was noted. RHB-105 (Talicia®) proved to be a safe and effective empiric therapy for H. pylori eradication.

Randomized sham-controlled trial of the 6-month swallowable gas-filled intragastric balloon system for weight loss.

BACKGROUND: Obesity is a significant health problem and additional therapies are needed to improve obesity treatment. OBJECTIVE: Determine the efficacy and safety of a 6-month swallowable gas-filled intragastric balloon system for weight loss. SETTING: Fifteen academic and private practice centers in the United States. METHODS: This was a double-blind, randomized sham-controlled trial of the swallowable gas-filled intragastric balloon system plus lifestyle therapy compared with lifestyle therapy alone for weight loss at 6 months in participants aged 22 to 60 years with body mass index 30 to 40 kg/m2, across 15 sites in the United States. The following endpoints were included: difference in percent total weight loss in treatment group versus control group was >2.1%, and a responder rate of >35% in the treatment group. RESULTS: Three hundred eighty-seven patients swallowed at least 1 capsule. Of participants, 93.3% completed all 24 weeks of blinded study testing. Nonserious adverse events occurred in 91.1% of patients, but only .4% were severe. One bleeding ulcer and 1 balloon deflation occurred. In analysis of patients who completed treatment, the treatment and control groups achieved 7.1 ± 5.0% and 3.6 ± 5.1% total weight loss, respectively, and a mean difference of 3.5% (P = .0085). Total weight loss in treatment and control groups were 7.1 ± 5.3 and 3.6 ± 5.1 kg (P < .0001), and body mass index change in the treatment and control groups were 2.5 ± 1.8 and 1.3 ± 1.8 kg/m2 (P < .0001), respectively. The responder rate in the treatment group was 66.7% (P < .0001). Weight loss maintenance in the treatment group was 88.5% at 48 weeks. CONCLUSIONS: Treatment with lifestyle therapy and the 6-month swallowable gas-filled intragastric balloon system was safe and resulted in twice as much weight loss compared with a sham control, with high weight loss maintenance at 48 weeks.

Pharmacokinetics of intravenous conivaptan in subjects with hepatic or renal impairment.

BACKGROUND: Conivaptan is a non-peptide dual antagonist of vasopressin V1A and V2 receptors that is approved in the United States as an intravenous formulation for the treatment of euvolemic and hypervolemic hyponatremia in hospitalized patients. The pharmacokinetics of intravenous conivaptan had not been studied in patients with hepatic or renal impairment. OBJECTIVE: The objective of this study was to assess the pharmacokinetics and tolerability of intravenous conivaptan in subjects with mild or moderate hepatic or renal impairment compared with subjects with normal function. STUDY DESIGN: These studies were phase I, open-label pharmacokinetic studies conducted at two sites in the US. PATIENTS: Men and non-pregnant women 30-70 years of age were allocated to the mild (Child-Pugh classification score of 5-6) or moderate (Child-Pugh classification score of 7-9) hepatically impaired groups (n = 8-9 per group) based on their liver function assessed at screening. For the renal study, men and non-pregnant women between 18 and 70 years of age were assigned to renal function groups (n = 8-9 per group) based on estimated glomerular filtration rate (eGFR) assessed at screening. Normal renal function was defined as an eGFR >80 ml/min, mild renal impairment as 50-80 ml/min, and moderate renal impairment as 30-49 ml/min. Subjects with normal hepatic or renal function were selected to match the race, sex, age, and body mass index of subjects enrolled in the impaired groups. INTERVENTION: Subjects were administered a 20-mg/30-min intravenous loading dose of conivaptan on day 1, followed by a 20-mg/23.5-h continuous conivaptan infusion. On day 2, immediately following the end of the day 1 infusion, a 20-mg/24-h continuous conivaptan infusion was administered. MAIN OUTCOME MEASURE: Primary pharmacokinetic parameters estimated were the area under the plasma conivaptan concentration-time curve from time 0 to infinity (AUC∞), plasma conivaptan concentrations at the end of the 20-mg loading dose (C LD), and plasma conivaptan concentrations at the end of the second day 20-mg/24-h continuous infusion (C 48). RESULTS: For each of C LD, C 48, and AUC∞, the mean values were similar for subjects with mild hepatic impairment and subjects with normal hepatic function. Subjects with moderate hepatic impairment had a 73 % higher C 48 and an 80 % higher AUC∞ compared with subjects with normal hepatic function. There were no clinically relevant changes in conivaptan exposure in the mild and moderate renal impairment groups compared with subjects with normal renal function. Intravenous conivaptan was generally well tolerated in subjects with mild or moderate hepatic or renal impairment. Infusion-site reaction was the most commonly reported adverse event. CONCLUSION: Overall exposure to conivaptan increased in subjects with moderate hepatic impairment compared with subjects with normal hepatic function. Therefore, in patients with moderate hepatic impairment, conivaptan should be initiated with a loading dose of 10 mg over 30 min followed by 10 mg per day as a continuous infusion for 2-4 days, which is half the approved dose. No dose adjustment is necessary in patients with mild or moderate renal impairment and in patients with mild hepatic impairment.

Diclofenac potassium liquid-filled soft gelatin capsules in the management of patients with postbunionectomy pain: a Phase III, multicenter, randomized, double-blind, placebo-controlled study conducted over 5 days.

BACKGROUND: Diclofenac potassium liquid-filled soft gelatin capsule (DPSGC) is a rapidly absorbed formulation of diclofenac potassium developed for the treatment of mild to moderate acute pain. OBJECTIVE: The present study was conducted to assess the efficacy and safety profile of DPSGC 25 mg in patients with pain after first-metatarsal bunionectomy. METHODS: This was a Phase III, multicenter, randomized, double-blind, parallel-group, placebo-controlled study conducted over 5 days. Patients experiencing the requisite level of pain (score > or = 4 on an 11-point numeric pain rating scale [NPRS] from 0 = no pain to 10 = worst possible pain) on the day after bunionectomy were randomized to receive DPSGC 25 mg or matching placebo. A second dose was given when patients requested additional medication for pain. Subsequent doses were given every 6 hours over a 48-hour inpatient multiple-dose period and continued over an additional 48-hour outpatient multiple-dose period. Opioid rescue medication was available as needed after the second dose of study medication. The primary efficacy end point was the mean NPRS score over the 48-hour inpatient multiple-dose period. Additional measures included NPRS scores at predefined times over 48 hours, the summed pain intensity difference over 48 hours (SPID48), the time-weighted sum of pain relief scores over the first 8 hours, the mean dosing interval (the time from dosing to the time rescue medication or the next dose of study medication was administered, whichever was less), the proportion of patients requiring rescue medication, and the onset of perceptible and meaningful pain relief (2-stopwatch method). Tolerability was assessed based on physician monitoring and patient reporting of adverse events (AEs) and the results of standard laboratory tests. RESULTS: Of 201 randomized patients (102 DPSGC 25 mg, 99 placebo; 86.6% female; 58.2% white; mean [SD] age, 45.2 [11.5] years; weight range, 49.4-108.0 kg), 198 completed the study. Mean baseline NPRS scores did not differ significantly between the DPSGC and placebo groups (6.9 and 7.3, respectively). DPSGC was associated with significant improvements compared with placebo in mean NPRS score over 48 hours (2.5 vs 5.6, respectively; P < 0.001), mean SPID48 (210.0 vs 90.3; P < 0.001), and overall mean dosing interval (331.5 vs 263.9 min; P < 0.001). Significant differences in NPRS scores between DPSGC 25 mg and placebo were noted at all time points from baseline through 48 hours (P < 0.001). The proportion of patients requiring rescue medication was significantly lower in the DPSGC group compared with the placebo group (39.2% vs 87.9% on day 1; 21.6% vs 64.6% on day 2; both, P < 0.001). Patients receiving DPSGC had a significantly faster onset of meaningful pain relief compared with those receiving placebo (P = 0.008). The most commonly reported AEs were nausea (7.8% vs 18.2%), headache (5.9% vs 9.1%), vomiting (3.9% vs 9.1%), and constipation (3.9% vs 2.0%). The overall incidence of AEs occurring in > or = 2% of patients was significantly lower in the DPSGC group than in the placebo group (20.6% vs 44.4%; P < 0.05); no patient receiving DPSGC had a serious AE. CONCLUSIONS: DPSGC 25 mg taken every 6 hours was effective in reducing postbunionectomy pain in the patients studied. DPSGC was well tolerated, suggesting that it may be a practicable option for the treatment of mild to moderate acute pain. ClinicalTrials. gov identifier: NCT00366444.

A randomized, double-blind, one-week study comparing effects of a novel COX-2 inhibitor and naproxen on the gastric mucosa.

CS-706 is a novel cyclooxygenase-2 (COX-2) inhibitor with potent analgesic, anti-inflammatory, and antitumor properties in animal models. This one-week, multicenter study was undertaken to assess the safety and tolerability of CS-706 and to compare the effects of CS-706 versus naproxen on acute gastrointestinal (GI) mucosal injury. Healthy men and women (n=160) without evidence of underlying gastroduodenal lesions were randomized to placebo, 100 mg CS-706 once daily, 200 mg CS-706 once daily, or 500 mg naproxen twice daily, administered for 7 days. On Day 8, subjects underwent a posttreatment upper GI endoscopy to assess development of gastroduodenal petechiae, erosions, and ulcers. Inhibition of COX-1 and COX-2 activity over the 24-hr postdose interval on Day 7 was determined in 48 subjects (12 per treatment group). CS-706 was safe and well tolerated. The extent of upper GI mucosal injury for both CS-706 dose groups was statistically significantly less than that for naproxen (P < 0.001) and was similar to placebo (P=0.615 and P=0.115 for 100 and 200 mg CS-706, respectively). No subject in placebo or either CS-706 treatment group had gastroduodenal ulcers, compared with 11 (28.2%) subjects treated with naproxen (P < 0.001). Both doses of CS-706 inhibited COX-2 activity to a similar extent as naproxen, whereas neither dose of CS-706 showed meaningful inhibition of platelet COX-1. In contrast, naproxen nearly completely inhibited COX-1 over the dosing interval. We conclude that CS-706, dosed up to 200 mg once daily, has an acute, upper GI toxicity profile similar to that of placebo and significantly superior to that of naproxen.

A randomized, controlled comparison of ibuprofen at the maximal over-the-counter dose compared with prescription-dose celecoxib on upper gastrointestinal mucosal injury.

BACKGROUND & AIMS: Ibuprofen is a well-tolerated nonsteroidal anti-inflammatory drug (NSAID), particularly at over-the-counter (OTC) doses. Cyclooxygenase 2 (COX-2)-selective inhibitors cause less ulceration than prescription-dose nonselective NSAIDs. We compared endoscopic injury related to nonprescription ibuprofen doses with celecoxib, also comparing prescription doses of naproxen with placebo as a positive control. METHODS: The study was a randomized, placebo-controlled, double blind, double-dummy endoscopic evaluation with concealed allocation. A 2-way crossover with a 4-5-week washout period was used. Participants were healthy adults with normal baseline findings from endoscopy. Ninety-five subjects were randomly assigned, and 79 subjects completed both study phases. Age distribution was reflective of the target population of the OTC agent. Twenty percent were infected with Helicobacter pylori, and 79% and 67% had a current or past medical problem, respectively. Qualifying subjects, stratified by the presence or absence of H. pylori infection (n = 20), were randomly assigned to 1 of the 4 sequences (phase I/II) as follows: ibuprofen/celecoxib; celecoxib/ibuprofen, naproxen/placebo, or placebo/naproxen. Primary end points were the frequency of endoscopic ulcers and erosions in the groups administered: (1) celecoxib vs. ibuprofen and (2) naproxen vs. placebo. RESULTS: In celecoxib-treated subjects, 2.6% developed ulcers compared with 17.9% of those treated with ibuprofen (P = 0.056). Naproxen treatment was associated with a significantly greater ulceration rate compared with placebo. CONCLUSIONS: Short-term use of the nonselective COX inhibitors ibuprofen and naproxen is associated with a greater risk for endoscopic mucosal injury compared with the COX-2-selective inhibitor celecoxib or placebo. A prospective analysis appropriately powered to address the incidence of clinically significant gastroduodenal ulceration associated with the short-term use of these agents would be required to further define the clinical relevance of these findings.

A randomized, double blind, dose-response comparison of balsalazide (6.75 g), balsalazide (2.25 g), and mesalamine (2.4 g) in the treatment of active, mild-to-moderate ulcerative colitis.

OBJECTIVE: Balsalazide is a new innovative, mesalamine-containing prodrug that is activated by bacteria in the colon. Balsalazide has been shown previously to be well tolerated and effective in the treatment of acute ulcerative colitis. The aim of this study was to determine the dose-response of balsalazide for efficacy and safety in active, mild-to-moderate ulcerative colitis and to compare this profile with that of mesalamine, pH-dependent, delayed-release tablets. METHODS: A multicenter, randomized, active control, double-blind, double-dummy, dose-response, parallel-group study was performed comparing balsalazide (6.75 g daily), balsalazide (2.25 g daily), and mesalamine (2.4 g daily), administered for 8 wk to 154 patients with active, mild-to-moderate ulcerative colitis as verified by sigmoidoscopy. RESULTS: Eight weeks of treatment with 6.75 g of balsalazide daily provided significantly greater improvement than did balsalazide (2.25 g daily) in rectal bleeding (64.7% [6.75-g balsalazide] vs 32.4% [2.25-g balsalazide], p < 0.006), stool frequency (58.8% vs 29.4%, p < 0.006), sigmoidoscopic score (78.9% vs 52.5%, p < 0.015), and Physician's Global Assessment (73.7% vs 51.3%, p < 0.03). The efficacy of balsalazide showed a significantly more rapid onset of action than that of mesalamine (2.4 g daily) (2-wk sigmoidocopic score improvement, 54.7% [6.75-g balsalazide] vs 29.4% [2.4-g mesalamine], p = 0.006) with numerically greater improvement at 8 wk in five of seven measured signs and symptoms. Balsalazide (6.75 g daily) was well tolerated, and the safety profile did not differ significantly from that of balsalazide (2.25 g daily) or mesalamine. CONCLUSIONS: Eight weeks of treatment with balsalazide (6.75 g daily) is significantly more effective than balsalazide (2.25 g daily) and more rapid in onset than mesalamine (2.4 g daily) in improving signs and symptoms of acute ulcerative colitis. Balsalazide (6.75 g daily) is well tolerated, and the safety profile does not differ from that of balsalazide (2.25 g daily) and mesalamine (2.4 g daily).

A study to determine the nitroglycerin ointment dose and dosing interval that best promote the healing of chronic anal fissures.

PURPOSE: The aim of this study was to determine the optimal dose and dosing interval of nitroglycerin ointment to heal chronic anal fissures. METHOD: A randomized, double-blind study of intra-anally applied nitroglycerin ointment (Anogesic) was conducted in 17 centers in 304 patients with chronic anal fissures. The patients were randomly assigned to one of eight treatment regimens (0.0, 0.1, 0.2, 0.4 percent nitroglycerin ointment applied twice or three times per day), for up to eight weeks. A dose-measuring device standardized the delivery of 374 mg ointment. Healing of fissures (complete reepithelialization) was assessed by physical examination using an observer unaware of treatment allocation. The subjects assessed pain intensity daily by completing a diary containing a visual analog scale for average pain intensity for the day, the worst pain intensity for the day, and pain intensity at the last defecation. RESULTS: There were no significant differences in fissure healing among any of the treatment groups; all groups, including placebo had a healing rate of approximately 50 percent. This rate of placebo response was inexplicably higher than previously reported in the literature. Treatment with 0.4 percent (1.5 mg) nitroglycerin ointment was associated with a significant (P < 0.0002) decrease in average pain intensity compared with vehicle as assessed by patients with a visual analog scale. The decreases were observed by Day 4 of treatment. At 8 weeks the magnitude of the difference between 0.4 percent nitroglycerin and control was a 21 percent reduction in average pain. Treatment was well tolerated, with only 3.29 percent of patients discontinuing treatment because of headache. Headaches were the primary adverse event and were dose related. CONCLUSION: Nitroglycerin ointment did not alter healing but significantly and rapidly reduced the pain associated with chronic anal fissures.