Protocol for the Vitamin D Oral Replacement in Asthma (VDORA) study.

Obesity and asthma are epidemic in the United States and obesity is an independent risk factor for asthma. Low vitamin D levels (i.e. serum 25-hydroxyvitamin D) have been reported in patients with reduced lung function, more frequent respiratory infections, and asthma exacerbations. Experts have proposed that serum levels > 40 ng/mL are required to offer the immunomodulatory benefits of vitamin D. Low vitamin D levels are common in both obesity and asthma, but it is not known whether supplementation with vitamin D improves asthma symptoms. Guidance for drug development stresses the importance of early phase studies to establish accurate population pharmacokinetics (PK) and drug dosing prior to larger phase 3 trials. The PK of this fat-soluble vitamin in children with increased adiposity are unknown; as are the doses need to reach proposed immunomodulatory levels. The objective of this study is to characterize the PK of vitamin D in children with obesity. Children ages 6--18 years who had physician diagnosed asthma and a body mass index (BMI) >85th percentile will be randomized to receive either standard daily dosing or loading doses followed by standard daily dosing. Blood samples will be obtained to characterize the PK of vitamin D. The results of this study will be used to identify a sufficient dose of vitamin D supplement to raise serum levels above a pre-specified value that may result in anti-inflammatory actions that could improve asthma symptoms.

Development of New Antimicrobials for Urogenital Gonorrhea Therapy: Clinical Trial Design Considerations.

Gonorrhea remains a major public health challenge, and current recommendations for gonorrhea treatment are threatened by evolving antimicrobial resistance and a diminished pipeline for new antibiotics. Evaluations of potential new treatments for gonorrhea currently make limited use of new understanding of the pharmacokinetic and pharmacodynamic contributors to effective therapy, the prevention of antimicrobial resistance, and newer designs for clinical trials. They are hampered by the requirement to utilize combination ceftriaxone/azithromycin therapy as the comparator regimen in noninferiority trials designed to seek an indication for gonorrhea therapy. Evolving gonococcal epidemiology and clinical trial design constraints hinder the enrollment of those populations at the greatest risk for gonorrhea (adolescents, women, and persons infected with antibiotic-resistant Neisseria gonorrhoeae). This article summarizes a recent meeting on the evaluation process for antimicrobials for urogenital gonorrhea treatment and encourages the consideration of new designs for the evaluation of gonorrhea therapy.

A Randomized Clinical Trial of Infrared Coagulation Ablation Versus Active Monitoring of Intra-anal High-grade Dysplasia in Adults With Human Immunodeficiency Virus Infection: An AIDS Malignancy Consortium Trial.

BACKGROUND: Anal high-grade squamous intraepithelial lesions (HSILs) ablation may reduce the incidence of invasive cancer, but few data exist on treatment efficacy and natural regression without treatment. METHODS: An open-label, randomized, multisite clinical trial of human immunodeficiency virus (HIV)-infected adults aged ≥27 years with 1-3 biopsy-proven anal HSILs (index HSILs) without prior history of HSIL treatment with infrared coagulation (IRC). Participants were randomized 1:1 to HSIL ablation with IRC (treatment) or no treatment (active monitoring [AM]). Participants were followed every 3 months with high-resolution anoscopy. Treatment participants underwent anal biopsies of suspected new or recurrent HSILs. The AM participants underwent biopsies only at month 12. The primary end point was complete clearance of index HSIL at month 12. RESULTS: We randomized 120 participants. Complete index HSIL clearance occurred more frequently in the treatment group than in the AM (62% vs 30%; risk difference, 32%; 95% confidence interval [CI], 13%-48%; P < .001). Complete or partial clearance (clearance of ≥1 index HSIL) occurred more commonly in the treatment group (82% vs 47%; risk difference, 35%; 95% CI, 16%-50%; P < .001). Having a single index lesion, compared with having 2-3 lesions, was significantly associated with complete clearance (relative risk, 1.96; 95% CI, 1.22-3.10). The most common adverse events related to treatment were mild or moderate anal pain and bleeding. No serious adverse events were deemed related to treatment or study participation. CONCLUSION: IRC ablation of anal HSILs results in more clearance of HSILs than observation alone.

Treatment assignment guesses by study participants in a double-blind dose escalation clinical trial of saw palmetto.

OBJECTIVES: This report assesses participant perception of treatment assignment in a randomized, double-blind, placebo-controlled trial of saw palmetto for the treatment of benign prostatic hyperplasia (BCM). DESIGN: Participants randomized to receive saw palmetto were instructed to take one 320 mg gelcap daily for the first 24 weeks, two 320 mg gelcaps daily for the second 24 weeks, and three 320 mg gelcaps daily for the third 24 weeks. Study participants assigned to placebo were instructed to take the same number of matching placebo gelcaps in each time period. At 24, 48, and 72 weeks postrandomization, the American Urological Association Symptom Index (AUA-SI) was administered and participants were asked to guess their treatment assignment. SETTINGS: The study was conducted at 11 clinical centers in North America. PARTICIPANTS: Study participants were men, 45 years and older, with moderate to low severe BPH symptoms, randomized to saw palmetto (N=151) or placebo (N=155). OUTCOME MEASURES: Treatment arms were compared with respect to the distribution of participant guesses of treatment assignment. RESULTS: For participants assigned to saw palmetto, 22.5%, 24.7%, and 29.8% correctly thought they were taking saw palmetto, and 37.3%, 40.0%, and 44.4% incorrectly thought they were on placebo at 24, 48, and 72 weeks, respectively. For placebo participants, 21.8%, 27.4%, and 25.2% incorrectly thought they were on saw palmetto, and 41.6%, 39.9%, and 42.6% correctly thought they were on placebo at 24, 48, and 72 weeks, respectively. The treatment arms did not vary with respect to the distributions of participants who guessed they were on saw palmetto (p=0.823) or placebo (p=0.893). Participants who experienced an improvement in AUA-SI were 2.16 times more likely to think they were on saw palmetto. CONCLUSIONS: Blinding of treatment assignment was successful in this study. Improvement in BPH-related symptoms was associated with the perception that participants were taking saw palmetto.

Safety and toxicity of saw palmetto in the CAMUS trial.

PURPOSE: Extracts of the saw palmetto berry are used by many men in the United States as self-treatment for lower urinary tract symptoms due to benign prostatic hyperplasia. While the most recent data from double-blind clinical trials do not support efficacy superior to that of placebo, there are sparse data on saw palmetto toxicity. MATERIALS AND METHODS: A total of 369 patients were randomized in the CAMUS (Complementary and Alternative Medicine for Urological Symptoms) trial, of whom 357 were included in this modified intent to treat analysis. Participants were randomized to 320, 640 and 960 mg daily of an ethanolic saw palmetto extract or to an identical-appearing placebo in an escalating manner at 6-month intervals for a total of 18 months of followup. Adverse event assessments, vital signs, and blood and urine laboratory tests were obtained at regular intervals. RESULTS: There were no statistically significant differences between the groups in the rates of serious or nonserious adverse events, changes in vital signs, digital prostate examination findings or study withdrawal rates. Overall, there were no significant intergroup differences in laboratory test abnormalities, while differences in individual laboratory tests were rare and small in magnitude. No evidence of significant dose-response phenomena was identified. CONCLUSIONS: The saw palmetto extract used in the CAMUS trial showed no evidence of toxicity at doses up to 3 times the usual clinical dose during an 18-month period.

Effect of increasing doses of saw palmetto extract on lower urinary tract symptoms: a randomized trial.

CONTEXT: Saw palmetto fruit extracts are widely used for treating lower urinary tract symptoms attributed to benign prostatic hyperplasia (BPH); however, recent clinical trials have questioned their efficacy, at least at standard doses (320 mg/d). OBJECTIVE: To determine the effect of saw palmetto extract (Serenoa repens, from saw palmetto berries) at up to 3 times the standard dose on lower urinary tract symptoms attributed to BPH. DESIGN, SETTING, AND PARTICIPANTS: A double-blind, multicenter, placebo-controlled randomized trial at 11 North American clinical sites conducted between June 5, 2008, and October 10, 2010, of 369 men aged 45 years or older, with a peak urinary flow rate of at least 4 mL/s, an American Urological Association Symptom Index (AUASI) score of between 8 and 24 at 2 screening visits, and no exclusions. INTERVENTIONS: One, 2, and then 3 doses (320 mg/d) of saw palmetto extract or placebo, with dose increases at 24 and 48 weeks. MAIN OUTCOME MEASURES: Difference in AUASI score between baseline and 72 weeks. Secondary outcomes included measures of urinary bother, nocturia, peak uroflow, postvoid residual volume, prostate-specific antigen level, participants' global assessments, and indices of sexual function, continence, sleep quality, and prostatitis symptoms. RESULTS: Between baseline and 72 weeks, mean AUASI scores decreased from 14.42 to 12.22 points (-2.20 points; 95% CI, -3.04 to -1.36) [corrected]with saw palmetto extract and from 14.69 to 11.70 points (-2.99 points; 95% CI, -3.81 to -2.17) with placebo. The group mean difference in AUASI score change from baseline to 72 weeks between the saw palmetto extract and placebo groups was 0.79 points favoring placebo (upper bound of the 1-sided 95% CI most favorable to saw palmetto extract was 1.77 points, 1-sided P = .91). Saw palmetto extract was no more effective than placebo for any secondary outcome. No clearly attributable adverse effects were identified. CONCLUSION: Increasing doses of a saw palmetto fruit extract did not reduce lower urinary tract symptoms more than placebo. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00603304.

Recruitment of participants to a clinical trial of botanical therapy for benign prostatic hyperplasia.

OBJECTIVES: The timely recruitment of study participants is a critical component of successful trials. Benign prostatic hyperplasia (BPH), a common nonmalignant urologic condition among older men, is characterized by lower urinary tract symptoms (LUTS). Successful recruitment methods for a trial of medical therapy for BPH, Medical Therapy of Prostate Symptoms (MTOPS), were mass mailing and advertising. The Complementary and Alternative Medicines Trial for Urological Symptoms (CAMUS) was designed to evaluate a botanical therapy, saw palmetto, for the treatment of BPH. The objective of this study was to evaluate recruitment strategies for CAMUS and to contrast the baseline characteristics of CAMUS participants with those recruited to a similar trial using conventional medical therapy. DESIGN: CAMUS is a randomized, double-blind, placebo-controlled trial designed to evaluate the effects of saw palmetto given at escalating doses over an 18-month period on relief from LUTS. SUBJECTS: The target enrollment goal was 350 men with LUTS from 11 clinical centers over a 12-month period. The recruitment techniques used and participants contacted, screened, and randomized through each technique were obtained from the clinical centers. Baseline characteristics of the CAMUS participants were compared with participants in the MTOPS trial who met the CAMUS eligibility criteria for LUTS. RESULTS: The target enrollment goal was achieved in 11 months. The overall monthly recruitment rate per site was 3.7 and ranged from 2.4 to 8.0. The most successful recruitment methods were mass mailing and advertising, which accounted for 39% and 35% of the study participants, respectively. In comparison to MTOPS participants, CAMUS participants were younger, more highly educated, more diverse, and had less severe urinary symptoms. CONCLUSIONS: Successful recruitment methods for CAMUS were similar to those in MTOPS. The use of botanical therapy attracted a less symptomatic and more educated study population.

The effect of folic acid and folinic acid supplements on purine metabolism in methotrexate-treated rheumatoid arthritis.

OBJECTIVE: To determine if folinic acid supplementation during methotrexate (MTX) therapy for rheumatoid arthritis (RA) reduces both urinary 5-aminoimidazole-4-carboxamide (AICA) and urinary adenosine excretion more than does folic acid supplementation. AICA and adenosine are markers for MTX interference with purine metabolism. METHODS: Forty patients with RA who received MTX for 6 weeks were randomized to receive either daily folic acid or folinic acid supplements during an additional week of MTX therapy. Colorimetric and radioimmunocompetition assays were used to measure 24-hour urinary AICA and adenosine excretion levels, respectively. RESULTS: At the end of 6 weeks, 24-hour urinary levels of AICA, but not adenosine, were elevated as compared with baseline levels (i.e., prior to MTX therapy). Folinic acid, but not folic acid, supplementation normalized urinary AICA levels during MTX therapy. Relatively high urinary levels of AICA were correlated with reduced disease activity. No similar correlations were seen with urinary adenosine levels. CONCLUSION: The blockade of purine nucleotide biosynthesis by MTX at the AICA ribonucleotide transformylase-catalyzed step may be related to the efficacy of MTX, and this blockade is effectively relieved by folinic acid, but not by folic acid, supplementation.