[Show abstract][Hide abstract] ABSTRACT: Background
Rifamycin SV is under development for treatment of travelers' diarrhea (TD) in a new oral formulation, Rifamycin SV MMX® (RIF-MMX; Santarus Inc., San Diego, CA, USA), which targets its delivery to the colon, making it a unique rifamycin drug.Methods
This was a randomized, double-blind, phase 3 study of adult travelers to Mexico or Guatemala experiencing acute diarrhea. A total of 264 patients received RIF-MMX (2 × 200 mg twice daily for 3 days, n = 199) or placebo (n = 65) in a 3 : 1 ratio. The primary endpoint was the length of time between the administration of first dose of study drug and passage of the last unformed stool (TLUS; after which clinical cure was declared). Other endpoints included eradication of pathogens from the stools, pathogen minimum inhibitory concentration (MIC), and adverse events (AEs).ResultsTLUS was significantly shorter in the RIF-MMX group (median: 46.0 hours) compared with placebo (median: 68.0 hours; p = 0.0008) and a larger percentage of RIF-MMX treated patients (81.4%) achieved clinical cure compared with placebo patients (56.9%). TLUS was significantly shorter in the subgroups of patients with enteroaggregative, enterotoxigenic, or diffusely adherent Escherichia coli infections (p = 0.0035) with nonsignificant activity against invasive bacteria (p = 0.3804). Overall pathogen eradication rates were numerically higher in the RIF-MMX group (67.0%) compared with placebo (54.8%) but the difference did not reach significance (p = 0.0836). In vitro resistance to rifamycin SV was observed in some bacteria remaining after treatment of patients with RIF-MMX but was not associated with lower efficacy in them. AEs appeared to be more frequent with placebo (38.5%) than with RIF-MMX (29.6%).ConclusionsRIF-MMX shortened the duration of TD in patients with a broad range of pathogens and was well tolerated. The unique pharmacokinetic properties of the drug offer evidence that TD pathogens work at the level of the colon.
Journal of Travel Medicine 11/2014; 21(6). DOI:10.1111/jtm.12168 · 1.58 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective
Budesonide MMX is a novel oral formulation of budesonide that uses Multi-Matrix System (MMX) technology to extend release to the colon. This study compared the efficacy of budesonide MMX with placebo in patients with active, mild-to-moderate ulcerative colitis (UC).
Patients were randomised 1:1:1:1 to receive budesonide MMX 9 mg or 6 mg, or Entocort EC 9 mg (budesonide controlled ileal-release capsules; reference arm) or placebo once daily for 8 weeks. The primary endpoint was combined clinical and endoscopic remission, defined as UC Disease Activity Index score ≤1 with a score of 0 for rectal bleeding and stool frequency, no mucosal friability on colonoscopy, and a ≥1-point reduction in endoscopic index score from baseline.
410 patients were evaluated for efficacy. Combined clinical and endoscopic remission rates with budesonide MMX 9 mg or 6 mg, Entocort EC and placebo were 17.4%, 8.3%, 12.6% and 4.5%, respectively. The difference between budesonide MMX 9 mg and placebo was significant (OR 4.49; 95% CI 1.47 to 13.72; p=0.0047). Budesonide MMX 9 mg was associated with numerically higher rates of clinical (42.2% vs 33.7%) and endoscopic improvement (42.2% vs 31.5%) versus placebo. The rate of histological healing (16.5% vs 6.7%; p=0.0361) and proportion of patients with symptom resolution (23.9% vs 11.2%; p=0.0220) were significantly higher for budesonide MMX 9 mg than placebo. Adverse event profiles were similar across groups.
Budesonide MMX 9 mg was safe and more effective than placebo at inducing combined clinical and endoscopic remission in patients with active, mild-to-moderate UC.
Gut 02/2013; 63(3). DOI:10.1136/gutjnl-2012-304258 · 14.66 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Budesonide is a corticosteroid with minimal systemic corticosteroid activity due to first-pass hepatic metabolism. Budesonide MMX® is a once-daily oral formulation of budesonide that extends budesonide release throughout the colon using multi-matrix system (MMX) technology.
We performed a randomized, double-blind, double-dummy, placebo-controlled trial to evaluate the efficacy of budesonide MMX for induction of remission in 509 patients with active, mild to moderate ulcerative colitis (UC). Patients were randomly assigned to groups that were given budesonide MMX (9 mg or 6 mg), mesalamine (2.4 g, as reference), or placebo for 8 weeks. The primary end point was remission at week 8.
The rates of remission at week 8 among subjects given 9 mg or 6 mg budesonide MMX or mesalamine were 17.9%, 13.2%, and 12.1%, respectively, compared with 7.4% for placebo (P = .0143, P = .1393, and P = .2200). The rates of clinical improvement at week 8 among patients given 9 mg or 6 mg budesonide MMX or mesalamine were 33.3%, 30.6%, and 33.9%, respectively, compared with 24.8% for placebo (P = .1420, P = .3146, and P = .1189). The rates of endoscopic improvement at week 8 among subjects given 9 mg or 6 mg budesonide MMX or mesalamine were 41.5%, 35.5%, and 33.1%, respectively, compared with 33.1% for placebo. The rates of symptom resolution at week 8 among subjects given 9 mg or 6 mg budesonide MMX or mesalamine were 28.5%, 28.9%, and 25.0%, respectively, compared with 16.5% for placebo (P = .0258, P = .0214, and P = .1025). Adverse events occurred at similar frequencies among groups.
Budesonide MMX (9 mg) was safe and more effective than placebo in inducing remission in patients with active, mild to moderate UC. ClinicalTrials.gov, Number: NCT00679432.
[Show abstract][Hide abstract] ABSTRACT: To compare the effects of immediate-release omeprazole and 2 different delayed-release proton pump inhibitors on 24-hour intragastric acidity in gastroesophageal reflux disease patients.
Because of its unique pharmacokinetic properties, immediate-release omeprazole does not need to be dosed before a meal to control intragastric acidity. Previous studies showed effectiveness of immediate-release omeprazole in controlling nocturnal intragastric acidity with bedtime dosing. This is the first study to compare the effects of prebreakfast dosing of immediate-release omeprazole and delayed-release lansoprazole and pantoprazole on 24-hour intragastric acidity.
To compare the effects of prebreakfast dosing of immediate-release omeprazole 40 mg capsules, lansoprazole 30 mg capsules, and pantoprazole 40 mg tablets on 24-hour intragastric acidity.
Fifty-five patients with gastroesophageal reflux disease received 7 consecutive once-daily morning doses of each drug in this open-label, randomized, 3-period crossover study. On day 7, intragastric pH was recorded for 24 hours.
After 7 days, the percentage of time with intragastric pH >4 over 24 hours was 59.7% (14.3 hours) with immediate-release omeprazole, 48.8% (11.7 hours) with lansoprazole (P=0.005), and 41.8% (10.0 hours) with pantoprazole (P<0.001). Median intragastric pH was significantly higher with immediate-release omeprazole than with lansoprazole (P=0.003) or pantoprazole (P<0.001). All drugs were well tolerated.
When dosed in the morning, immediate-release omeprazole provided significantly better control of 24-hour intragastric acidity than lansoprazole and pantoprazole.
[Show abstract][Hide abstract] ABSTRACT: Gastro-oesophageal reflux disease (GERD) patients on proton pump inhibitors before breakfast or dinner have acid recovery at night. Bedtime immediate-release omeprazole (IR-OME) demonstrated better control of nocturnal pH than pantoprazole before dinner.
To compare repeated once daily bedtime dosing of IR-OME, lansoprazole and esomeprazole on nocturnal gastric acidity.
Open-label, randomized, crossover study enrolling 54 patients with nocturnal GERD symptoms comparing IR-OME, lansoprazole and esomeprazole at steady state for nocturnal acid breakthrough (NAB), percentage of time with gastric pH > 4 and median gastric pH.
Onset of nocturnal acid control with IR-OME was rapid. During the first half of the night, percentage of time with gastric pH > 4 and median gastric pH were significantly higher after IR-OME compared to esomeprazole or lansoprazole (P < 0.001, both comparisons). Over the 8-h night-time period, acid control with IR-OME was significantly better than lansoprazole (P < 0.001), and comparable to esomeprazole. IR-OME reduced NAB compared with esomeprazole and lansoprazole (61% vs. 92% and 92%; P < 0.001, both comparisons).
Bedtime IR-OME provided more rapid control of night-time gastric pH and decreased NAB compared with esomeprazole and lansoprazole. Nocturnal acid control with IR-OME was superior to lansoprazole and comparable to esomeprazole. Bedtime dosing with IR-OME may be effective for patients with night-time heartburn.
[Show abstract][Hide abstract] ABSTRACT: Difficult-to-control asthma has been associated with gastroesophageal acid reflux. Acid-suppressive treatment has been inconsistent in improving asthma control.
To determine whether a proton-pump inhibitor improves asthma control in adult asthmatic patients with acid reflux symptoms.
Multicenter, double-blind, randomized, placebo-controlled trial.
Twenty-nine private practices and 3 academic practices in the United States.
Two hundred seven patients receiving usual asthma care including an inhaled corticosteroid (ICS). Patients had acid reflux symptoms and moderate-to-severe persistent asthma.
Lansoprazole, 30 mg bid, or placebo, bid, for 24 weeks.
The primary outcome measure was daily asthma symptoms by diary. Secondary asthma outcomes included rescue albuterol use, daily morning and evening peak expiratory flow, FEV1, FVC, asthma quality of life with standardized activities (AQLQS) questionnaire score, investigator-assessed symptoms, exacerbations, and oral corticosteroid-treated exacerbations.
Daily asthma symptoms, albuterol use, peak expiratory flow, FEV1, FVC, and investigator-assessed asthma symptoms at 24 weeks did not improve significantly with lansoprazole treatment compared to placebo. The AQLQS emotional function domain improved at 24 weeks (p = 0.025) with lansoprazole therapy. Fewer patients receiving lansoprazole (8.1% vs 20.4%, respectively; p = 0.017) had exacerbations and oral corticosteroid-treated (ie, moderate-to-severe) exacerbations (4% vs 13.9%, respectively; p = 0.016) of asthma. A post hoc subgroup analysis revealed that fewer patients receiving one or more long-term asthma-control medications in addition to an ICS experienced exacerbations (6.5% vs 24.6%, respectively; p = 0.016) and moderate-to-severe exacerbations (2.2% vs 17.5%, respectively; p = 0.021) with lansoprazole therapy.
In adult patients with moderate-to-severe persistent asthma and symptoms of acid reflux, treatment with 30 mg of lansoprazole bid for 24 weeks did not improve asthma symptoms or pulmonary function, or reduce albuterol use. However, this dose significantly reduced asthma exacerbations and improved asthma quality of life, particularly in those patients receiving more than one asthma-control medication.
[Show abstract][Hide abstract] ABSTRACT: Many individuals with acid-related gastrointestinal disorders have difficulty in swallowing oral agents.
To compare the bio-availability of a single dose of lansoprazole orally disintegrating tablet with that of an intact capsule.
One hundred and twenty healthy subjects participated in two prospective, Phase I, open-label, two-period cross-over studies to receive lansoprazole, 15 mg or 30 mg. Within each study, subjects were randomized into two parallel cohorts consisting of 30 subjects per regimen, dispensed in opposing sequence over two periods separated by a 7-day washout period. Blood samples were collected on day 1 of both periods to determine the pharmacokinetic parameters.
Tmax occurred at 1.8 and 2.0 h with the 15-mg and 30-mg tablets, respectively. Dose proportional increases in Cmax, AUCt and AUC infinity were observed in the 15-mg and 30-mg groups. The terminal elimination half-lives (t1/2) were identical in both dose groups (1.18 h). Lansoprazole administered as the orally disintegrating tablet was bio-equivalent to the intact capsule formulation with respect to Cmax, AUCt and AUC infinity.
Lansoprazole orally disintegrating tablets, 15 mg and 30 mg, are bio-equivalent to the respective dose administered as the intact capsule. This novel dosage formulation represents an option for patients who have difficulty in swallowing oral agents.
[Show abstract][Hide abstract] ABSTRACT: Objective: To compare the effectiveness of lansoprazole 30mg once daily and esomeprazole 40mg once daily on healing and symptom relief in patients with erosive oesophagitis.
Design: Phase IV, randomised, double-blind, active-controlled, multicentre study.
Patients and participants: 284 patients with endoscopically confirmed erosive oesophagitis (grade ≥2).
Methods: Patients were randomised to treatment with lansoprazole or esomeprazole. The primary efficacy endpoint was the healing of erosive oesophagitis (defined as grade 0 or 1) at week 8. Healing rates at week 4 and the percentages of patients reporting no daytime or night-time heartburn after 1 day, 3 days and 1 week of treatment, as well as the rate of healing or improvement of oesophagitis by two grades, were also analysed.
Results: Healing rates and 95% confidence intervals (CIs) at week 8 were 91.4% (85.4, 95.5%) for lansoprazole 30mg once daily and 89.1% (82.7, 93.8%) for esomeprazole 40mg once daily, respectively. For any baseline grade, greater than 90% of lansoprazole-treated and 81% of esomeprazole-treated patients exhibited healing or improvement of erosive oesophagitis by two grades from baseline to week 8. Healing rates at week 4 were also comparable: 77.0% (95% CI 69.1, 83.7%) for lansoprazole 30mg and 78.3% (95% CI 70.4, 84.8%) for esomeprazole 40mg. The percentages of heartburn-free patients after 1 day, 3 days and 1 week of treatment were slightly higher for lansoprazole compared with esomeprazole, although the differences did not reach statistical significance (p > 0.05). Both treatments were well tolerated.
Conclusions: In erosive oesophagitis, lansoprazole 30mg once daily and esomeprazole 40mg once daily are equally effective in healing erosions and relieving heartburn.
Clinical Drug Investigation 02/2002; 22(2):99-109. DOI:10.2165/00044011-200222020-00004 · 1.56 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Gastro-oesophageal reflux disease, which is experienced daily by a significant proportion of individuals, may result in serious sequelae such as erosive oesophagitis. Short-term treatment with acid antisecretory therapy (a proton pump inhibitor or a histamine H(2) receptor antagonist) is highly effective in healing the erosive oesophagitis lesion. However, numerous studies confirm that unless maintenance therapy is initiated virtually all patients will experience oesophagitis relapse within 1 year, as well as an increasing severity of oesophagitis and risk for complications such as Barrett's oesophagus and adenocarcinoma. Studies evaluating the efficacy of proton pump inhibitor and H(2) antagonist maintenance therapy have found that only the proton pump inhibitors significantly reduce the incidence of oesophagitis relapse. Pharmacoeconomic studies have also confirmed that proton pump inhibitor maintenance therapy is cost effective, by virtue of the ability of these agents to reduce the incidence of relapse as well as prolong the time to relapse and increase the number of weeks per year that patients are without symptoms. Lansoprazole, a member of the proton pump inhibitor class of agents, has been extensively studied in the treatment of patients with a variety of acid-related disorders. Among those with erosive oesophagitis, maintenance therapy with lansoprazole 15 or 30mg once daily is highly effective in preventing relapse. Studies have documented that lansoprazole 15 and 30mg once daily for six months prevents oesophagitis relapse in up to 81 and 93% of patients, respectively, with comparable percentages of patients remaining in remission after 1 year of treatment. These high rates of remission have also been observed in studies of patients with lesions that were difficult to heal at baseline (resistant to healing with at least 3 months of H(2) antagonist therapy). Moreover, lansoprazole produces high remission rates regardless of the grade of erosive oesophagitis before acute healing. Among symptomatic patients with heartburn, lansoprazole provides rapid and effective relief of daytime and night-time heartburn and prevents relapse of symptoms. Lansoprazole has a wide margin of safety and is well tolerated when administered as monotherapy in short- and long-term clinical trials. Taken together these data suggest that proton pump inhibitor therapy represents the preferred and ideal long-term management strategy for the patient with erosive oesophagitis. Lansoprazole is a well-established member of this class of agents and, as such, has an extensive body of literature that supports its safety, tolerability and clinical efficacy in preventing relapse in these patients.
[Show abstract][Hide abstract] ABSTRACT: This letter was referred to Dr Howden et al., who reply as under:The Editor,As authors of the publication ‘Evidence for therapeutic equivalence of lansoprazole 30mg and esomeprazole 40mg in the treatment of erosive oesophagitis’, we thank Dr Schoenfeld for his interest in our study and are happy to have the opportunity to respond to his comments.Dr Schoenfeld is correct in pointing out that the conclusion of equivalence based on observing a nonsignificant test result from a superiority trial, is considered inappropriate.However, the published study was not intended to be a superiority trial. It was designed and powered as an equivalence trial. The sample size of 140 patients per arm was adequately calculated to have 80% power to demonstrate equivalence in healing rates, assuming that the expected higher healing rate is 93% and lower limit of the two-sided 95% confidence limit for the treatment difference in healing rates does not exceed 10%. It was stated in the statistical analy ...
Clinical Drug Investigation 01/2002; 22(6):415-416. DOI:10.2165/00044011-200222060-00013 · 1.56 Impact Factor