Comorbidities, Concomitant Medications, and Diet as Factors Affecting Levothyroxine Therapy: Results of the CONTROL Surveillance Project.

BACKGROUND: The CONTROL Surveillance Project was a comprehensive patient-based survey conducted among hypothyroid patients undergoing treatment. The primary objective of the study was to specifically quantify the prevalence of factors adversely affecting levothyroxine therapy. METHODS: Participants were selected from a large proprietary database. Those eligible for the study completed a 21-question survey. RESULTS: Of the eligible hypothyroid patients, 925 (92.5%) were being treated with levothyroxine monotherapy. The mean age was 60.4 years; 755 (81.6%) were female and 168 (18.2%) were male. Almost half of those receiving levothyroxine (435, 47.0%) had at least one comorbid condition that could adversely affect its absorption: gastroesophageal reflux disease (33.8% of patients), irritable bowel syndrome (9.7%), lactose intolerance (7.8%), or a history of gastric bypass surgery or bowel resection (3.0%). Other factors reported by many patients that could adversely affect levothyroxine absorption included use of prescription medications (20.6%) and over-the-counter medications (34.3%) used to treat comorbid gastrointestinal (GI) conditions; use of dietary supplements (51.8%, primarily calcium and iron); and intake of foods/beverages high in fiber, iodine, or soy (68.0%). Of the 13.4% who reported difficulty controlling their hypothyroid symptoms, significantly more patients with comorbid GI conditions reported such difficulty (7.8 versus 5.6%, P < 0.01). Frequent changes in levothyroxine dosing (two or more dose changes in the past year) were reported by 8.0% of survey participants. Those with GI comorbidities were nearly twice as likely to have such changes (5.0 versus 3.0%, P < 0.01). CONCLUSION: Better initial workup of patients, including identification of relevant GI comorbidities and allergies, may help in the early detection of factors that may affect the performance of levothyroxine.

Multicenter, double-blind, placebo-controlled crossover study to assess the acute prokinetic efficacy of nizatidine-controlled release (150 and 300 mg) in patients with gastroesophageal reflux disease.

INTRODUCTION: The aim of the study is to test whether nizatidine delivered via a unique bimodal pulsatile-controlled release system, nizatidine controlled release (CR), accelerates gastric emptying in patients with gastroesophageal reflux disease (GERD). METHODS: Combined data were analyzed on 39 patients with delayed gastric emptying (DGE) from 2 studies (n = 84) assessing the prokinetic effect of nizatidine CR. A single-blind placebo baseline was followed by double-blind nizatidine CR (150 and 300 mg) in randomized sequence, 2 to 5 days apart. Each dose was followed 1 hour later by an egg-beater meal, labeled with Tc99m. Gamma camera images were obtained at meal completion, 1-, 2-, 3- and 4-hour postmeal. All the 84 patients were classified at baseline with DGE (gastric retention >6.3% at 4 hours) or normal gastric emptying. RESULTS: In the 39 patients identified with DGE, change from placebo baseline (CFB) for percent gastric retention at 4-hour postmeal with nizatidine CR (150 and 300 mg) was each improved and statistically significant (P < 0.05). In a subgroup of diabetic patients with DGE (n = 10), the CFB with nizatidine CR (300 mg) was significant (P < 0.05) at 3- and 4-hour postmeal. CONCLUSIONS: Nizatidine CR (150 and 300 mg) significantly enhanced gastric emptying of a standard meal in patients with GERD with DGE.

Efficacy and safety profile of fenofibrate-coated microgranules 130 mg, with and without food, in patients with hypertriglyceridemia and the metabolic syndrome: an 8-week, randomized, double-blind, placebo-controlled study.

BACKGROUND: The limited bioavailability of certain fenofibrate formulations necessitates administration with food, raising concerns about efficacy and compliance. There is a need for new formulations that have improved bioavailability and eliminate the requirement for administration with food. OBJECTIVE: The aim of this study was to assess the food-related efficacy of a new formulation of micronized fenofibrate coated on inert microgranules (FF-muG) for the treatment of hypertriglyceridemia in patients exhibiting the metabolic syndrome. METHODS: This was a randomized, double-blind, placebo-controlled, double-dummy, parallel-group study in patients who had fasting triglyceride (TG) concentrations > or =300 mg/dL and <1000 mg/dL and met National Cholesterol Education Program Adult Treatment Panel III criteria for the metabolic syndrome. A 6-week washout and diet lead-in period was followed by an 8-week treatment period. Eligible patients were randomized to receive either FF-muG 130 mg with food, FF-muG 130 mg without food, or placebo every day for 8 weeks. The primary end point was the mean percent change in TG levels from baseline to the end of treatment; changes in other lipid end points were also assessed. Safety profiles were assessed based on adverse-event reports, changes in clinical laboratory values and vital signs (including electrocardiography), and the findings of physical examinations. RESULTS: One hundred forty-six patients took part in the study: 54 received FF-muG 130 mg with food, 42 received FF-muG 130 mg without food, and 50 received placebo. The groups were similar in terms of mean age (56 years), sex (59.5%-63.0% men; 37.0%-40.5% women), race (83.3%-100% white), mean body weight (92 kg), mean height (172 cm), mean fasting baseline TG concentrations (480 mg/dL), and other components of the metabolic syndrome. The 2 FF-muG groups (with and without food) showed similar improvements in the dyslipidemia associated with the metabolic syndrome: TG levels decreased a mean of 36.7% and 36.6%, respectively (P < 0.001 vs placebo). The overall frequency of adverse events was similar in the 2 FF-muG groups and did not differ significantly from placebo (63.0%, 61.9%, and 52.0%, respectively). Gastrointestinal disturbances (eg, diarrhea, dyspepsia) occurred more frequently in the 2 FF-muG groups compared with the placebo group (31.5%, 26.2%, and 12.0%; P = NS). Significant increases from baseline in alanine aminotransferase were seen in both FF-muG groups (mean [SEM], 3.77 [2.60] and 11.69 [7.42] U/L, respectively; P < or = 0.05 vs placebo); however, these increases were considered clinically significant in only 5 cases, none of them requiring discontinuation of study drug. CONCLUSIONS: This study found no inequivalence in the TG-lowering effects of the 2 fenofibrate regimens compared with placebo. Both regimens were well tolerated. Thus, FF-muG 130 mg administered without regard to meals appears to be efficacious and well tolerated for the treatment of hypertriglyceridemia in patients exhibiting the metabolic syndrome.

Comparison of a chronotherapeutically administered beta blocker vs. a traditionally administered beta blocker in patients with hypertension.

Increasing systolic blood pressure and heart rate during the early morning results in increased myocardial oxygen demand. The use of beta blockers during this period may decrease cardiac workload, particularly in beta-blocker sensitive patients. The impact of a new chronotherapeutic beta blocker was assessed in 44 hypertensive patients. Patients were randomized to delayed-release propranolol (INP) dosed at 10 p.m. or to traditionally dosed propranolol (ILA) dosed at 8 a.m. for 4 weeks, following which they were switched to the alternative formulation for 4 weeks. Thirty-four-hour ambulatory blood pressure monitoring and pharmacokinetic measurements were obtained. INP and ILA resulted in significant reductions in mean 24-hour blood pressure (-9.0/-6.9 mm Hg and -10.4/-7.7 mm Hg, respectively). The top 25% of responders to high-dose propranolol (sensitive patients) were compared on each formulation. Mean trough reductions were -8.0/-6.7 mm Hg and -7.6/-5.8 mm Hg, respectively. Mean blood pressure reductions in the beta-blocker sensitive patients (n = 11) between 6 a.m. and noon were -15.2/-11.9 mm Hg on INP and -8.0/-4.6 mm Hg on ILA. Heart rate reduction was -14.1 bpm and double product reduction was -3319 in the INP patients between 6 a.m. and 12 noon compared with -10.5 and -2209 in the ILA patients. This study suggests that INP and ILA are effective once-a-day beta blockers, but the use of delayed-release propanolol results in a greater reduction in double product between 6 a.m. and noon in beta-blocker sensitive patients than does traditionally dosed propranolol.

Nizatidine for the treatment of pediatric gastroesophageal reflux symptoms: an open-label, multiple-dose, randomized, multicenter clinical trial in 210 children.

BACKGROUND: Gastroesophageal reflux disease (GERD), which is reflux that produces damage or troubling symptoms, afflicts approximately 7% of infants and children to the extent that administration of physician-directed pharmacotherapy is warranted. OBJECTIVE: This study was designed in conjunction with the US Food and Drug Administration (FDA) to assess the tolerability and effectiveness of nizatidine, in different doses and formulations, including a newly formulated premade oral solution, for pediatric GERD. METHODS: Children aged 5 days through 18 years were recruited to this 8-week, open-label, multiple-dose, randomized, parallel-group, multicenter study. The original study design specified that patients aged 5 days through 12 years at study start be given a nizatidine capsule dissolved in infant formula or apple juice depending on patient age ("extemporaneous solution"). Children 13 through 18 years old were to be given the "adult dose" of nizatidine capsules 150 mg BID regardless of body weight. All patients aged < 13 years were randomized in blocks of 4 between 2 dose levels (2.5 and 5 mg/kg per dose BID). A protocol amendment during the study added a newly formulated, more pediatric-appropriate, premade oral solution that was developed at the request of the FDA. This premade formulation ("oral solution") was to replace the extemporaneous solution mixed in infant formula or apple juice. Subsequently, an additional 44 children aged < 13 years old were enrolled in the study and randomized to receive the new nizatidine oral solution for 8 weeks at the same 2 dose levels as used for the extemporaneous solution. Outcome data at 4 and 8 weeks included adverse events (AEs) (severity, relation to study drug, and any relationship to study withdrawal) and effectiveness (investigators' assessment of changes in reflux symptoms and overall physical well-being, and parent/child assessment of change in antacid use). Formal statistical analyses were not planned, but post hoc chi-square analyses were performed. RESULTS: Of 214 children enrolled, 210 (98%) intent-to-treat (ITT) patients received > or = 1 dose; of these, 173 (82%) completed 8 weeks of study. At least 77% were compliant (ie, medicated on > or = 75% of days). Of the ITT patients, 37 did not complete 8 weeks due to insufficient response, AEs (regardless of relationship to study drug), or other reasons. Although 292 AEs occurred in 115 patients, 277 (95%) were mild to moderate and 15 (5%) were severe. Most of the AEs in these children studied during the winter were related to infectious illnesses. Only 4 serious AEs occurred; 3 were unrelated to study drug. The fourth AE--considered possibly related--was worsening sickle cell anemia 18 days after medication discontinuation. Approximately 30% of patients became asymptomatic after 8 weeks of treatment, regardless of dosing or formulation, and despite reduction of antacid use in half of the patients. No clear superiority of any dose or formulation was demonstrated. CONCLUSIONS: This large study, although limited by its open-label design and post hoc analyses, supports the tolerability and effectiveness of 8 weeks of treatment with nizatidine in children aged 5 days through 18 years. AE incidence and severity were as expected for children during the winter season. There was an overall improvement in symptoms and a decrease in antacid use. Formulation did not appear to alter tolerability or effectiveness assessments: the premade solution, extemporaneous solution, and capsule provided comparable symptomatic relief with no disproportionate adverse reactions.