Browsing by Subject "diarrhea"
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Item CROFELEMER FOR HIV-ASSOCIATED DIARRHEA: SUSTAINED EFFICACY, SAFETY, AND ADHERENCE DURING A 6-MONTH RANDOMIZED, PLACEBO-CONTROLLED TRIAL(2014-03) Clay, Patrick G.Combination antiretroviral therapy (cART) in HIV+ individuals has increased life expectancy; however, increased ART exposure is also associated with adverse effects that can negatively impact overall health, work productivity, and healthcare resource utilization. Diarrhea, an adverse event (AE) of ART, remains a substantial burden associated with reduced quality of life and may result in ART nonadherence or treatment failure. Reported prevalence of diarrhea in the community is up to 28% of patients receiving cART. Crofelemer, extracted from the stem bark latex of the Croton lechleri tree, is a minimally absorbed, first-in-class antidiarrheal agent indicated for the symptomatic relief of noninfectious diarrhea in adults with HIV/AIDS receiving ART. Crofelemer inhibits chloride ion (Cl–) secretion and accompanying high-volume water loss in secretory diarrhea via dual inhibition of cystic fibrosis transmembrane conductance regulator and calcium-activated Cl– channels in the intestinal epithelium. Purpose (a): To assess patient adherence to and efficacy and safety of crofelemer 125 mg twice daily for up to 6 months. Methods (b): Randomized, phase 3, double-blind, placebo-controlled, 2-stage trial (Figure 1). The optimal crofelemer (Fulyzaq™, Salix Pharmaceuticals, Inc., Raleigh, NC, USA) dose (125, 250, or 500 mg twice daily) was determined in stage 1. Based on the stage 1 interim efficacy and safety analysis, crofelemer 125 mg twice daily was selected as the optimal dose and was evaluated in additional patients in stage 2; data for crofelemer 125 mg twice daily were combined (stage 1 and 2). Primary efficacy measure: percentage of patients achieving clinical response, defined as ≤2 watery stools per week for ≥2 of 4 weeks during the placebo-controlled phase (1-sided analysis). Results (c): Demographic and baseline characteristics were similar between crofelemer 125 mg twice daily (n = 136) and placebo (n = 138) groups (Table 1); patients had a mean of 2.7 to 3.0 watery stools per day (ie, >18 watery stools per week). Primary measure: A significantly larger percentage of patients treated with crofelemer achieved clinical response compared with placebo (17.6% vs 8.0%; P < 0.01). Continued and sustained improvement in weekly clinical response and a mean improvement from baseline in diarrhea symptoms was observed in patients who continued to receive crofelemer 125 mg twice daily during the placebo-free phase. Conclusions (d): Crofelemer 125 mg twice daily was efficacious and well tolerated, and improvements in noninfectious diarrhea symptoms appeared to be durable for at least 6 months in an HIV+ population receiving stable cART. Treatment of diarrhea in HIV+ individuals may provide several important benefits, such as improvement in cART adherence.Item IDENTIFYING HIGH RESPONDER POPULATIONS TO CROFELEMER FOR TREATMENT OF NONINFECTIOUS DIARRHEA IN HIV+ INDIVIDUALS(2014-03) Clay, Patrick G.Background: Diarrhea remains a significant burden in some HIV+ individuals. Crofelemer is a first-in-class, minimally absorbed, botanically derived drug indicated for symptomatic relief of noninfectious diarrhea in adults with HIV/AIDS taking antiretroviral therapy. This analysis examined the efficacy of crofelemer 125 mg BID in specific subpopulations. Methods: In a 4-week, phase 3, randomized, double-blind, placebo-controlled trial in HIV+ adults receiving antiretroviral therapy, crofelemer 125 mg BID (n = 136) was compared with placebo (n = 138) for reducing noninfectious diarrhea. The primary efficacy endpoint (≤2 watery stools/wk for ≥2 of 4 weeks) was examined in subgroups that differed according to demographic (sex, age, race, time since HIV diagnosis, and duration of diarrhea) and baseline characteristics (severity of diarrhea, prior antidiarrheal medication [ADM] use, stool consistency, viral load, CD4+ cell count, and use of protease inhibitors). Results: At baseline, patients experienced (range of means) 18.9-21.0 watery stools/week, and investigators attributed diarrhea most commonly (75%) to antiretroviral therapy (ritonavir-containing agents, 34%-36%; efavirenz/tenofovir/emtricitabine, 15%-22%) or HIV enteropathy (24%). Across all subgroups considered, treatment effects favored crofelemer. Pronounced treatment differences (crofelemer – placebo) were observed for patients with prior use of ≥2 ADMs (+28%; P 2 watery stools/day (+10%; P = 0.03), diarrhea duration [greater than] 2 years (+11%; P = 0.03), and use of protease inhibitors (+11%; P = 0.021). Conclusions: These findings suggest that the crofelemer antidiarrheal effect is robust and generalizable across patient subpopulations. Purpose (a): To determine which patients with HIV/AIDS are most likely to respond to treatment with crofelemer 125 mg twice daily. Methods (b): Patients and Study Design: HIV+ adults taking a stable ART regimen for ≥4 weeks, with a history of diarrhea (persistently loose stools despite regular antidiarrheal medication use or ≥1 watery bowel movement per day without regular antidiarrheal medication use for ≥1 month). Exclusion criteria included CD4+ cell count/μL and positive gastrointestinal biopsy, culture, or stool test for infectious agents in the previous 4 months. Randomized, double-blind, phase 3 trial of crofelemer 125 mg or placebo administered twice daily for 4 weeks. Assessments: Primary efficacy measure: percentage of patients achieving clinical response, defined as ≤2 watery stools per week for ≥2 of 4 weeks of treatment. Assessment of efficacy was based on patient diaries, which recorded symptoms of diarrhea (eg, stool consistency, stool frequency), adherence to study drug and ART, and use of antidiarrheal and prohibited medications; results were entered daily using an interactive voice response system. Stool consistency score was computed using the mean of all reported stool scores for 1 day; stools were scored using a scale ranging from 1 to 5 (1 = very hard; 5 = watery). Statistical Analyses: Efficacy was assessed in the intention-to-treat population composed of all randomized patients receiving ≥1 dose of study drug (1-sided for primary efficacy analysis, based on technique described by Posch et al13; 2-sided for subgroup analyses). Fisher’s exact test was used for comparisons between crofelemer and placebo for subgroup analyzed. Subgroup analyses were not corrected for multiple comparisons. Results (c): Patient Population: Demographic and baseline characteristics were similar between the 2 groups. Patients in the crofelemer and placebo treatment arms were of similar age (mean, 45 vs 44.8 y), sex (male, 84.6% vs 84.1%), and race/ethnicity (white, 39.0% vs 42.0%; black, 37.5% vs 38.4%; Hispanic, 22.8% vs 18.1%; American Indian/Alaskan Native, 0.7% vs 0%; other, 0% vs 1.5%). Patients in both groups averaged >18.9 watery bowel movements per week. Historical use of antidiarrheal medication was common, reported by 79 patients (58%) receiving crofelemer 125 mg and 83 patients (60%) receiving placebo. Loperamide-containing agents were historically used by 53 (39%) and 60 (43%) patients treated with crofelemer and placebo, respectively. Although not permitted during the 4 weeks of treatment, concomitant use of antidiarrheal medications (eg, loperamide, diphenoxylate /atropine, bismuth subsalicylate) were reported by 1.1% and 4.0% of patients receiving crofelemer or placebo, respectively. Efficacy: A significantly greater percentage of patients achieved clinical response during treatment with crofelemer 125 mg twice daily versus placebo (P = 0.0096; Figure 2). Conclusions (d): Subgroup analyses confirm crofelemer 125 mg twice daily provides robust clinical response across multiple patient subpopulations. Crofelemer was particularly effective in patients with factors associated with severe diarrhea, consistent with its antisecretory effects on intestinal chloride channels.Item POPULATION PHARMACOKINETIC ANALYSIS DEMONSTRATES NO DRUG-DRUG INTERACTIONS BETWEEN CROFELEMER, A NOVEL TREATMENT FOR NONINFECTIOUS DIARRHEA IN HIV+ INDIVIDUALS, AND ANTIRETROVIRAL THERAPY(2014-03) Clay, Patrick G.Crofelemer, a minimally absorbed, botanically derived, first-in-class antidiarrheal agent, was approved by the US Food and Drug Administration in December 2012 at a dose of 125 mg twice daily for symptomatic relief of noninfectious diarrhea in adult patients with HIV/AIDS on ART. Secretory diarrhea, particularly noninfectious diarrhea, is associated with combination antiretroviral therapy (ART) therapy. It is characterized by increased secretion of chloride ions and the movement of sodium and water into the intestinal lumen as a result of cyclic adenosine monophosphate (cAMP)–stimulated cystic fibrosis transmembrane conductance regulator (CFTR) and calcium-activated chloride channel (CaCC) activation by HIV, ART, or bacterial enterotoxins. Crofelemer is a dual inhibitor of CFTR and CaCC in the intestinal epithelium. For patients with HIV/AIDS receiving combination ART, comorbidities requiring management or treatment with other therapies increase the potential for drug-drug interactions (DDI) with ART6; clinically significant DDI have been reported in 27% to 40% of patients with HIV/AIDS taking ART. Significant DDI with ART may be caused by induction or inhibition of major metabolic pathways, or by drug transporters, resulting in reductions in ART efficacy, safety, and tolerability. Purpose (a): To determine the potential for crofelemer to alter the pharmacokinetics (PK) of concomitantly administered ART agents in HIV+ patients in the ADVENT trial. Methods (b): HIV+ adults taking a stable ART regimen for ≥4 weeks, with a history of diarrhea (ie, persistently loose stools despite regular antidiarrheal medication use or ≥1 watery bowel movement per day without regular antidiarrheal use for ≥1 month) and CD4+ count ≥100 cells/μL. ADVENT is a randomized, double-blind, two-stage phase 3 trial (Figure 1) conducted from October 2007 to January 2011 Pharmacokinetic Assessments. A multiple-trough sampling design14 was used to assess population PK. Sample collection for PK assessments occurred at baseline, prior to dosing at randomization, at the end of the placebo-controlled phase (ie, week 4), and at the end of the study (ie, week 24). Immune status was evaluated by analysis of CD4+ cell count and HIV viral load. Crofelemer concentrations were assayed by validated high-performance liquid chromatography with fluorescence detection (Celerion, Lincoln, NE, USA); ART concentrations were assayed by Tandem Labs (Salt Lake City, UT, USA) and the University of North Carolina Clinical Pharmacology and Analytical Chemistry Core Facility (Chapel Hill, NC, USA). Results (c): More than 97.5% of patients in the PK population (n = 353) had received ≥ 3 combination ART regimens before the study. Patients received 126 different combinations of ART; the most frequently used combination ART was EFV, FTC, and TNF (n = 60). All 6 of the most common ARTs demonstrated marked exposure variability during the study (Figure 2). Week 4 and 24 ART steady-state trough drug concentrations in patients receiving crofelemer, regardless of crofelemer dose, were comparable with concentrations obtained during the crofelemer-free period (for example, TNF in Figure 3). Comparable results were demonstrated with RTV, FTC, 3TC, LPV, and EFV (Table 2). Crofelemer had no statistically significant effect on the PK of the 6 most commonly used ARTs in ADVENT, as assessed by the Bonferroni correction approach (Table 2). Administration of crofelemer had no negative impact on clinical immune parameters (HIV viral load and CD4+ cell counts) • In >96% of patients, crofelemer concentrations were below the limit of quantitation (50 ng/mL). Conclusions (d): Crofelemer had no significant effect on the PK of the most frequently-used ART evaluated in this study. Consistent with the absence of effects on ART PK, crofelemer did not adversely affect ART efficacy, based on HIV viral load or CD4+ cell counts. Crofelemer was not systemically absorbed to a significant extent.Item SAFETY AND TOLERABILITY OF CROFELEMER 125 MG TWICE DAILY IN THE TREATMENT OF NONINFECTIOUS DIARRHEA IN HIV-SEROPOSITIVE PATIENTS ON ANTIRETROVIRAL THERAPY: RESULTS FROM A PHASE 3, 48-WEEK OPEN-LABEL STUDY(2014-03) Clay, Patrick G.Diarrhea remains a substantial health concern in patients with HIV in the era of combination antiretroviral therapy (ART), despite the decline in opportunistic infectious diarrhea. For example, noninfectious diarrhea attributable to ART-related adverse events (AEs) has a reported prevalence in the community of up to 28% of patients with HIV who are receiving ART. Diarrhea in patients with HIV is commonly a leaky-flux or secretory diarrhea, which is characterized by increased secretion of chloride ions (Cl-) and subsequent sodium and water flow into the gastrointestinal lumen. Crofelemer (Fulyzaq™, Salix Pharmaceuticals, Inc., Raleigh, NC, USA) is a minimally absorbed, first-in-class, botanically derived drug indicated for the symptomatic relief of noninfectious diarrhea in adults with HIV. Following oral dosing of crofelemer, plasma concentrations of the drug were below the level of quantification in [greater than] 99% of patients with HIV and diarrhea. Crofelemer is a dual inhibitor of the cyclic adenosine monophosphate (cAMP)-stimulated cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channel and the calcium-activated Cl- channel (CACC). In a phase 3, double-blind, placebo-controlled trial (ADVENT), crofelemer 125 mg twice daily significantly reduced diarrhea in patients with HIV receiving ART compared with placebo, and the safety profile was comparable to placebo for up to 24 weeks. Purpose (a): To evaluate the long-term (up to 48 weeks) safety and tolerability of crofelemer 125 mg twice daily for the treatment of noninfectious diarrhea in patients with HIV. Methods (b): Phase 3, multicenter, open-label study of crofelemer 125 mg twice daily for up to 48 weeks. Results (c): Overall, 189 patients (75.6%) experienced ≥1 AE during this open-label study; the majority of AEs (90.5% of patients) were mild or moderate in intensity. The most commonly reported AEs were infection-related (eg, upper respiratory tract [16.8%], intestinal parasitic [12.4%], Giardia [8.0%]; none drug-related) or gastrointestinal-related (eg, nausea [5.6%], constipation [5.6%]) –Most patients (10 of 14 [71.4%]) reporting a constipation AE also used ADMs during the study. Only 9 (3.6%) patients reported diarrhea as an AE •AEs considered at least possibly related to study drug occurred in 9.2% of patients; the most commonly reported were constipation (3.6%), abdominal distension (2.0%), abdominal pain (1.2%), and flatulence (1.2%). No deaths occurred during the study; serious AEs occurred in 20 patients (8.0%), including infection in 10 patients; none were considered drug-related. Conclusions (d): Crofelemer 125 mg twice daily was well tolerated with a low incidence of AEs in HIV-seropositive patients with noninfectious diarrhea receiving ART, which is consistent with the minimal absorption of crofelemer. In this study, minimal clinical deterioration of immune status was observed for up to 48 weeks, suggestive of adherence to ART regimens and continued ART efficacy.