Between-group Differences In Adverse Events Research Articles

No Detectable Coagulation Activation After Vitamin K (MK-7) Supplementation in Patients on Dialysis With Functional Vitamin K Deficiency: A One-Year Randomized, Placebo-Controlled Study

Patients on dialysis treatment have poor functional vitamin K status, and this may increase the risk of vascular calcification. Vitamin K supplementation may therefore be relevant in patients on dialysis, but the procoagulant effects have not been studied. We evaluated effects of menaquinone-7 (MK-7) supplementation on biomarkers of coagulation in patients on dialysis. Double-blinded, placebo-controlled study in 123 patients on dialysis randomized to 52weeks of vitamin K (MK-7, 360μg/daily, n=61) or placebo (n=62). Measurements at baseline and after 52weeks of intervention included thrombin generation (endogenous thrombin potential, peak thrombin concentration, time to peak, and lag time); clot activities of vitamin K-dependent coagulation factors (F) II, VII, IX, and X; prothrombin fragment 1+2 (F1+2); and proteins induced by vitamin K absence II (PIVKA-II). Between-group differences (vitamin K vs. placebo) at 52weeks were determined with an analysis of covariance. Within-group changes in vitamin K and placebo groups were analyzed with a paired t-test. Vascular adverse events and serious adverse events were registered based on hospital records, laboratory data, and participant interviews and compared between groups using Fisher's exact test or Pearson's Chi-Squared test. A between-group difference at 52weeks was observed for PIVKA-II (P<.001). PIVKA-II decreased significantly from baseline to 52weeks in the vitamin K group, but not in the placebo group. We observed no between-group differences or within-group changes for biomarkers of coagulation, except for FVII clot activity which was reduced in the placebo group (P=.04), and no between-group differences in adverse events and serious adverse events. One year of vitamin K supplementation in patients on dialysis has no detectable effects on biomarkers of coagulation activation, clot activities of vitamin K-dependent coagulation factors, and vascular events or death, indicating no procoagulant effects of this treatment.

Lower versus Higher Glycemic Criteria for Diagnosis of Gestational Diabetes

BackgroundTreatment of gestational diabetes improves maternal and infant health, although diagnostic criteria remain unclear.MethodsWe randomly assigned women at 24 to 32 weeks’ gestation in a 1:1 ratio to be evaluated for gestational diabetes with the use of lower or higher glycemic criteria for diagnosis. The lower glycemic criterion was a fasting plasma glucose level of at least 92 mg per deciliter (≥5.1 mmol per liter), a 1-hour level of at least 180 mg per deciliter (≥10.0 mmol per liter), or a 2-hour level of at least 153 mg per deciliter (≥8.5 mmol per liter). The higher glycemic criterion was a fasting plasma glucose level of at least 99 mg per deciliter (≥5.5 mmol per liter) or a 2-hour level of at least 162 mg per deciliter (≥9.0 mmol per liter). The primary outcome was the birth of an infant who was large for gestational age (defined as a birth weight above the 90th percentile according to Fenton–World Health Organization standards). Secondary outcomes were maternal and infant health.ResultsA total of 4061 women underwent randomization. Gestational diabetes was diagnosed in 310 of 2022 women (15.3%) in the lower-glycemic-criteria group and in 124 of 2039 women (6.1%) in the higher-glycemic-criteria group. Among 2019 infants born to women in the lower-glycemic-criteria group, 178 (8.8%) were large for gestational age, and among 2031 infants born to women in the higher-glycemic-criteria group, 181 (8.9%) were large for gestational age (adjusted relative risk, 0.98; 95% confidence interval, 0.80 to 1.19; P=0.82). Induction of labor, use of health services, use of pharmacologic agents, and neonatal hypoglycemia were more common in the lower-glycemic-criteria group than in the higher-glycemic-criteria group. The results for the other secondary outcomes were similar in the two trial groups, and there were no substantial between-group differences in adverse events. Among the women in both groups who had glucose test results that fell between the lower and higher glycemic criteria, those who were treated for gestational diabetes (195 women), as compared with those who were not (178 women), had maternal and infant health benefits, including fewer large-for-gestational-age infants.ConclusionsThe use of lower glycemic criteria for the diagnosis of gestational diabetes did not result in a lower risk of a large-for-gestational-age infant than the use of higher glycemic criteria. (Funded by the Health Research Council of New Zealand and others; GEMS Australian New Zealand Clinical Trials Registry number, ACTRN12615000290594.)

Supplemental Vitamin D and Incident Fractures in Midlife and Older Adults

BackgroundVitamin D supplements are widely recommended for bone health in the general population, but data on whether they prevent fractures have been inconsistent.MethodsIn an ancillary study of the Vitamin D and Omega-3 Trial (VITAL), we tested whether supplemental vitamin D3 would result in a lower risk of fractures than placebo. VITAL was a two-by-two factorial, randomized, controlled trial that investigated whether supplemental vitamin D3 (2000 IU per day), n−3 fatty acids (1 g per day), or both would prevent cancer and cardiovascular disease in men 50 years of age or older and women 55 years of age or older in the United States. Participants were not recruited on the basis of vitamin D deficiency, low bone mass, or osteoporosis. Incident fractures were reported by participants on annual questionnaires and adjudicated by centralized medical-record review. The primary end points were incident total, nonvertebral, and hip fractures. Proportional-hazards models were used to estimate the treatment effect in intention-to-treat analyses.ResultsAmong 25,871 participants (50.6% women [13,085 of 25,871] and 20.2% Black [5106 of 25,304]), we confirmed 1991 incident fractures in 1551 participants over a median follow-up of 5.3 years. Supplemental vitamin D3, as compared with placebo, did not have a significant effect on total fractures (which occurred in 769 of 12,927 participants in the vitamin D group and in 782 of 12,944 participants in the placebo group; hazard ratio, 0.98; 95% confidence interval [CI], 0.89 to 1.08; P=0.70), nonvertebral fractures (hazard ratio, 0.97; 95% CI, 0.87 to 1.07; P=0.50), or hip fractures (hazard ratio, 1.01; 95% CI, 0.70 to 1.47; P=0.96). There was no modification of the treatment effect according to baseline characteristics, including age, sex, race or ethnic group, body-mass index, or serum 25-hydroxyvitamin D levels. There were no substantial between-group differences in adverse events as assessed in the parent trial.ConclusionsVitamin D3 supplementation did not result in a significantly lower risk of fractures than placebo among generally healthy midlife and older adults who were not selected for vitamin D deficiency, low bone mass, or osteoporosis. (Funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases; VITAL ClinicalTrials.gov number, NCT01704859.)

Rehabilitation following surgery for flexor tendon injuries of the hand.

Rehabilitation following surgery for flexor tendon injuries of the hand.

Does Endoscopic Retrograde Cholangiopancreatography Carry Higher Risk for Patients 90 Years and Older? A Single-Institution Retrospective Study.

BackgroundEndoscopic retrograde cholangiography (ERCP) for patients aged ≥90 years is often required. The safety of ERCP for super-elderly patients is a major concern for gastrointestinal endoscopists. We retrospectively examined the safety of ERCP for super-elderly patients by comparison with patients in their 70s.Material/MethodsWe reviewed 66 patients aged ≥90 years (Group A) and 43 patients in their 70s (Group B) who underwent ERCP in our institution from January 2012 to October 2019. Data were collected on patients’ backgrounds, corresponding procedures, and clinical outcomes, including adverse events.ResultsPatients in Group A (mean age: 92.3±2.1 years) had significantly poorer performance status (median: 3 vs. 0; P<0.001) and American Society of Anesthesiologists classification (median: III vs. II; P<0.001) when compared to Group B (mean age: 75.1±2.7 years). Underlying cardiovascular, cerebrovascular, renal, and orthopedic comorbidity occurrence was significantly higher in Group A than in Group B (87.88% vs. 67.44%; P=0.0094). Group A comprised more patients with benign disease than Group B (90.91% vs. 76.74%; P=0.040). Group B comprised more patients with malignant disease (31.82% vs. 53.54%; P=0.041). Emergency ERCP was higher in Group A than in Group B (71.70% vs. 29.73%; P<0.0001). No significant between-group differences in adverse events (15.15% vs. 11.63%; P=0.602) and mortality rate (1.52% vs. 2.33%; P=0.758) were noted.ConclusionsIndications for ERCP should not be determined simply based on the super-elderly age of patients. ERCP may not necessarily carry higher risks if endoscopists practice maximal caution against gastrointestinal perforation.

Allogeneic umbilical cord blood-derived mesenchymal stem cells versus microfracture for large full-thickness cartilage defects

Background & Aim Currently available treatment options for cartilage restoration are generally applicable to localized, unipolar defects in relatively young patients rather than large, full-thickness lesions in elderly patients. A randomized controlled phase 3 clinical trial was conducted to determine whether implantation of umbilical cord blood-derived MSCs (UCB-MSCs) combined with 4% HA results in reliable cartilage restoration in patients with symptomatic, large full-thickness cartilage defects. In addition, and 5-year extended follow-up observation study was conducted to investigate whether any clinical improvements by this method can be maintained up to 5-years. Methods, Results & Conclusion Methods A randomized controlled phase 3 clinical trial was conducted for 48 weeks, and the populations were followed by an observational extended follow-up study of 5 years. Patients with symptomatic, large full-thickness cartilage defects (International Cartilage Repair Society [ICRS] grade IV) of knee joint were enrolled in the clinical trial. In case of multiple lesion, the most symptomatic lesion was determined and treated with UCB-MSCs-HA or microfracture. Primary outcome was proportion of subjects improved by ≥1 ICRS grade at 48 weeks according to ICRS Macroscopic Cartilage Repair Assessment. Secondary outcomes included histologic assessment, visual analogue scale pain, WOMAC, IKDC scores, and adverse events. Results Among 114 randomized participants (age 55.9 years), 89 completed the phase 3 clinical trial. Among them 73 were enrolled in the 5-year observational extended follow-up study. Mean defect size was 4.9 (UCB-MSCs-HA group) and 4.0 cm2 (microfracture group) (p=0.051). At 48 week, improvement by ≥1 ICRS grade was in 97.7% (UCB-MSCs-HA group) versus 71.7% (microfracture group) (p=0.001), and the overall histological assessment was superior with UCB-MSCs-HA (p=0.036). No between-group differences in adverse events were observed. Improvement of pain, WOMAC, and IKDC score from baseline were similar between the groups at 48 weeks, but were significantly better in the UCB-MSCs-HA group at 3-5 year follow-up (p Conclusion UCB-MSCs implantation resulted in cartilage repair tissue in more patients and provided robust improvement of knee pain and function than microfracture in patients with symptomatic large full-thickness cartilage defects. UCB-MSCs could be a desirable regenerative treatment option for patients suffering from large full-thickness cartilage defects.

N-acetylcysteine for cessation of tobacco smoking: rationale and study protocol for a randomised controlled trial

BackgroundTobacco smoking is a highly prevalent, addictive behaviour and a key public health priority. However available cessation therapies have low quit and high relapse rates, indicating an urgent need for more effective treatments. Predicated on promising preclinical and pilot clinical data, this paper presents a rationale and protocol for the trial of N-acetylcysteine (NAC) as a novel anti-craving smoking cessation aid.MethodsCurrent smokers (n = 120) of at least 10 cigarettes a day are recruited through online advertisements, print publications and dissemination of flyers. Participants are randomised on a 1:1 ratio to receive either 16-week treatment of 1.8 g/day of NAC or placebo with all participants receiving quit support from the online QuitCoach tool. Participants are attending visits at baseline, 8 and 16 weeks with a 42-week post-discontinuation follow-up. The primary outcome measure is sustained abstinence at six months after treatment based on self-reported rating scales and confirmed by exhaled carbon monoxide and salivary cotinine levels. Secondary outcomes are timing of the first lapse and relapse, between-group cigarette consumption, withdrawal symptoms, general wellbeing and mood/anxiety symptoms. Between-group differences in adverse events and subgroup analyses for variables including gender and Diagnostic Statistics Manual 5 diagnostics will also be investigated.DiscussionThe planned trial addresses an issue of major importance to human health and, if an effect is shown, may result in substantial changes to the management of smoking and nicotine addiction with overt public health implications.Trial registrationAustralian New Zealand Clinical Trials registry (ANZCTR), ACTRN12617001478303. Registered on 19 October 2017.

Effects of transcranial pulsed electromagnetic field stimulation on quality of life in Parkinson's disease.

Pulsed electromagnetic fields induce a protective and anti-inflammatory effect in the nervous system primarily due to growth factor upregulation that possibly abates neurodegeneration in Parkinson's disease (PD). This study investigated treatment effects of transcranial pulsed electromagnetic fields (T-PEMFs) on quality of life in PD and the feasibility and safety of this treatment. In this double-blinded clinical study, 97 participants with idiopathic PD (Hoehn & Yahr stage I-IV), on optimal medical anti-parkinsonian treatment, were block randomized (3:3) to either active (n = 49) or placebo treatment (n = 48). Treatment with T-PEMFs entailed one daily 30-min home treatment for eight consecutive weeks. The 39-item Parkinson's Disease Questionnaire (PDQ-39) was assessed at baseline and endpoint. A special questionnaire was used to profile adverse events by interviewing the participants over the full treatment period. Treatment compliance was accounted for by daily treatment registration. The active group improved with respect to clinical effect size for the two dimensions, i.e. mobility and activities of daily living, compared with the placebo group. No between-group differences were found for the remaining PDQ-39 dimensions. There were no between-group difference in adverse events. Treatment compliance was 97.9%. Treatment with T-PEMFs improved mobility and activities of daily living scores for clinical effect size only in the active group, indicating a positive treatment response for motor symptoms. No difference was found between the two groups for the remaining PDQ-39 dimensions. The treatment had no or only mild adverse events and was performed with high compliance.

Glycaemic control and hypoglycaemia with insulin glargine 300 U/mL versus insulin glargine 100 U/mL in insulin-naïve people with type 2 diabetes: 12-month results from the EDITION 3 trial

AimTo explore if efficacy and safety findings for insulin glargine 300U/mL (Gla-300) versus insulin glargine 100U/mL (Gla-100), observed over 6 months in insulin-naïve people with type 2 diabetes, are maintained after 12 months. MethodsEDITION 3 was a phase 3a, randomized, multicentre, open-label, parallel-group, treat-to-target study of once-daily Gla-300 versus Gla-100 (target fasting self-monitored plasma glucose, 4.4–5.6mmol/L [80–100mg/dL]). Participants completing the initial 6-month treatment phase continued their previously allocated basal insulin. ResultsOf 878 participants randomized, 337/439 (77%) and 314/439 (72%) assigned to Gla-300 and Gla-100, respectively, completed 12 months of treatment. Improved glycaemic control was sustained until 12 months in both treatment groups, with similar reductions in HbA1c from baseline to month 12 (difference: −0.08 [95% confidence interval (CI): −0.23 to 0.07] % or −0.9 [−2.5 to 0.8] mmol/mol). Relative risk of experiencing≥1 confirmed (≤3.9mmol/L [≤70mg/dL]) or severe hypoglycaemic event with Gla-300 versus Gla-100 was 0.86 (95% CI: 0.69 to 1.07) at night and 0.92 (0.82 to 1.03) at any time of day. For events with a glycaemic threshold of<3.0mmol/L (<54mg/dL) these numbers were 0.76 (0.49 to 1.19) and 0.66 (0.50 to 0.88). A similar pattern was seen for documented symptomatic events. No between-group differences in adverse events were identified. ConclusionOver 12 months, Gla-300 treatment was as effective as Gla-100 in reducing HbA1c in insulin-naïve people with type 2 diabetes, with lower overall risk of hypoglycaemia at the<3.0mmol/L threshold.

Rehabilitation following surgery for flexor tendon injuries of the hand

Rehabilitation following surgery for flexor tendon injuries of the hand

Effects of comprehensive therapy based on traditional Chinese medicine patterns in stable chronic obstructive pulmonary disease: a four-center, open-label, randomized, controlled study.

BackgroundTraditional Chinese medicine (TCM) has been used to treat chronic obstructive pulmonary disease (COPD) for many years. This study aimed to evaluate the efficacy and safety of the comprehensive therapy based on the three common TCM patterns in stable COPD patients.MethodsA four-center, open-label randomized controlled method was conducted. A total of 352 patients were divided into the trial group (n = 176, treated with conventional Western medicine and Bu-Fei Jian-Pi granules, Bu-Fei Yi-Shen granules, and Yi-Qi Zi-Shen granules based on the TCM patterns respectively) and the control group (n = 176, treated with conventional Western medicine). The frequency and duration of acute exacerbation, lung function, clinical symptoms, 6-minute walking distance (6MWD), dyspnea scale and quality of life were observed during a 6-month treatment period and at a further 12-month follow-up.ResultsA total of 306 patients completed the study fully. The full analysis set (FAS) population was 350 and the per-protocol analysis set (PPS) population was 306. After the 6-month treatment and 12-month follow-up, there were significant differences between the trial and control group in the following: frequency of acute exacerbation (FAS: P = 0.000; PPS: P = 0.000); duration of acute exacerbation (FAS: P = 0.000; PPS: P = 0.001); FEV1 (FAS: P = 0.007; PPS: P = 0.008); symptoms (FAS: P = 0.001; PPS: P = 0.001); 6MWD (FAS: P = 0.045; PPS: P = 0.042); dyspnea scale (FAS: P = 0.002; PPS: P = 0.004); and physical domain (FAS: P = 0.000; PPS: P = 0.000), psychological domain (FAS: P = 0.008; PPS: P = 0.011), social domain (FAS: P = 0.001; PPS: P = 0.000) and environment domain (FAS: P = 0.015; PPS: P = 0.009) of the WHOQOL-BREF questionnaire. There were no differences between the trial and control group in FVC, FEV1% and adverse events.ConclusionsBased on the TCM patterns, Bu-Fei Jian-Pi granules, Bu-Fei Yi-Shen granules and Yi-Qi Zi-Shen granules have beneficial effects on measured outcomes in stable COPD patients over the 6-month treatment and 12-month follow-up, with no relevant between-group differences in adverse events.Trial RegistrationThis trial was registered at Chinese Clinical Trial Register Center, ChiCTR-TRC-11001406.

Combination therapy with risedronate and teriparatide in male osteoporosis

Most studies of combination therapy with teriparatide and a bisphosphonate have not shown greater efficacy over monotherapy. The bisphosphonate risedronate, has not been studied in this context. The purpose of this proof-of-concept study was to assess whether combination risedronate and teriparatide increases bone mineral density (BMD) more than monotherapy with either drug alone. This was a randomized, double-blinded study of risedronate (35 mg weekly plus placebo injection), teriparatide (20 μg subcutaneously daily plus placebo tablet), or both risedronate plus teriparatide (combination) for 18 months in 29 men with low BMD. The primary endpoint was percentage change in lumbar spine (LS) BMD at 18 months. Secondary outcomes included changes in bone markers and BMD at other sites and interim time-points. All therapies increased LS BMD as compared with baseline (p < 0.05), but there were no between-group differences at 18 months. Total hip (TH) BMD increased to a greater extent in the combination group (mean ± SEM, 3.86 ± 1.1 %) versus teriparatide (0.29 ± 0.95 %) or risedronate (0.82 ± 0.95 %; p < 0.05 for both). Femoral neck (FN) BMD also increased more in the combination group (8.45 ± 1.8 %) versus risedronate (0.50 ± 1.7 %; p = 0.002), but was not different from teriparatide alone. In the combination group, P1NP and CTX increased rapidly, mirroring the teriparatide-alone arm. There were no between-group differences in adverse events. Combination teriparatide and risedronate increased BMD at the LS, TH as well as the FN and provided greater BMD increases at the TH than monotherapy. The results suggest combination risedronate and teriparatide therapy holds promise as a treatment for osteoporosis.

Intermittent Androgen Suppression for Rising PSA Level after Radiotherapy

BackgroundIntermittent androgen deprivation for prostate-specific antigen (PSA) elevation after radiotherapy may improve quality of life and delay hormone resistance. We assessed overall survival with intermittent versus continuous androgen deprivation in a noninferiority randomized trial.MethodsWe enrolled patients with a PSA level greater than 3 ng per milliliter more than 1 year after primary or salvage radiotherapy for localized prostate cancer. Intermittent treatment was provided in 8-month cycles, with nontreatment periods determined according to the PSA level. The primary end point was overall survival. Secondary end points included quality of life, time to castration-resistant disease, and duration of nontreatment intervals.ResultsOf 1386 enrolled patients, 690 were randomly assigned to intermittent therapy and 696 to continuous therapy. Median follow-up was 6.9 years. There were no significant between-group differences in adverse events. In the intermittent-therapy group, full testosterone recovery occurred in 35% of patients, and testosterone recovery to the trial-entry threshold occurred in 79%. Intermittent therapy provided potential benefits with respect to physical function, fatigue, urinary problems, hot flashes, libido, and erectile function. There were 268 deaths in the intermittent-therapy group and 256 in the continuous-therapy group. Median overall survival was 8.8 years in the intermittent-therapy group versus 9.1 years in the continuous-therapy group (hazard ratio for death, 1.02; 95% confidence interval, 0.86 to 1.21). The estimated 7-year cumulative rates of disease-related death were 18% and 15% in the two groups, respectively (P=0.24).ConclusionsIntermittent androgen deprivation was noninferior to continuous therapy with respect to overall survival. Some quality-of-life factors improved with intermittent therapy. (Funded by the Canadian Cancer Society Research Institute and others; ClinicalTrials.gov number, NCT00003653.)

Bu-Fei Yi-Shen granule combined with acupoint sticking therapy in patients with stable chronic obstructive pulmonary disease: A randomized, double-blind, double-dummy, active-controlled, 4-center study

Ethnopharmacological relevanceBu-Fei Yi-Shen granule combined with acupoint sticking therapy has been used in the patients with stable chronic obstructive pulmonary disease (COPD) as major traditional interventions for the treatment of the disease. Aim of the studyThe objective of this study was to evaluate the efficacy and safety of traditional Chinese herbal medicine, the Bu-Fei Yi-Shen granule combined with acupoint sticking therapy in patients with stable COPD. MethodsA 4-center, double-blinded, double-dummy and randomized controlled method was conducted. 244 patients who were divided into the trial group (n=122, treated with Bu-Fei Yi-Shen granule combined with Shu-Fei Tie acupoint sticking therapy and oral placebo sustained-release theophylline) and the control group (n=122, treated with oral sustained-release theophylline and placebo Bu-Fei Yi-Shen granule combined with placebo Shu-Fei Tie acupoint sticking therapy). The frequency and duration of acute exacerbation, lung function, clinical symptoms, six-minute walking distance, dyspnea grade and quality of life were observed during the 4-month treatment period, and for a further 6 months follow-up. ResultsTwo hundred and twenty one patients fully completed the study, intent-to-treat (ITT) population was 234 and per-protocol (PP) population was 221. After treatment for 4 months and follow-up for 6 months, there were differences between the experimental and control group in frequency of acute exacerbation (ITT: P=0.007, P=0.013; PP: P=0.045, P=0.046); duration of acute exacerbation (ITT: P=0.030, P=0.005; PP: P=0.048, P=0.006); scores of symptoms (ITT: P=0.000, P=0.000; PP: P=0.000, P=0.000); six-minute walking distance (ITT: P=0.002, P=0.001; PP: P=0.002, P=0.001); dyspnea grade (ITT: P=0.014, P=0.009; PP: P=0.018, P=0.012); physiological aspects (ITT: P=0.003, P=0.000; PP: P=0.001, P=0.000); psychological aspects (ITT: P=0.007, P=0.001; PP: P=0.001, P=0.000) and environment aspects (ITT: P=0.003, P=0.000; PP: P=0.001, P=0.000) of the WHOQOL-BREF questionnaire. There were no differences between the experimental and control group in FVC, FEV1 and FEV1% and adverse events. ConclusionsBu-Fei Yi-Shen granule combined with acupoint sticking therapy showed beneficial effects for patients with stable COPD in the measured parameters over the 4-month treatment period and 6 months follow-up, with no relevant between-group differences in adverse events.

Response by Sex to Statin and Ezetimibe Versus Statin Monotherapy: Pooled Analysis from 22,913 Hyperlipidemic Patients

Synopsis: Coronary heart disease (CHD) remains the leading cause of mortality in women, highlighting the importance of preventive interventions in women. Purpose: To assess sex-related efficacy of statin + ezetimibe (EZ) vs statin in a broad, pooled database. Methods: Data were pooled from 27 double-blind, active, or placebo-controlled studies that randomized adult patients with hypercholesterolemia to statin alone or statin + EZ. Consistency of treatment effect among sexes was tested with ANCOVA with terms for treatment, first/second-line therapy status (FSLT), race, sex, CHD, statin potency, age, body mass index, baseline (BL) low-density lipoprotein cholesterol, BL high-density lipoprotein cholesterol (HDL-C), BL triglycerides, BL response variable, diabetes, trial within FSLT, treatment by FSLT, and treatment by sex interactions. Results: BL lipids and high-sensitivity C-reactive protein (hs-CRP) were generally greater in women than men. Both therapies significantly reduced low-density lipoprotein cholesterol, non-HDL-C, TG, apoB, TC, and hs-CRP, with significantly greater reductions seen with statin + EZ vs statin for prespecified dose comparisons. In general, treatment group differences for women were slightly smaller. HDL-C increased more for women than men in both treatment groups. There were no between-group differences in adverse events or creatine kinase elevations in the overall population. A greater incidence of alanine aminotransferase elevations was seen in statin + EZ vs statin patients in the overall population (0.6% vs 0.3%). Some minor differences, although not clinically relevant, were noted between sexes in the incidence of some AEs. Conclusions: This pooled database describes a large clinical experience with statin + EZ for women in which significantly greater changes in lipid and hs-CRP levels were seen with statin + EZ vs statin in both sexes, although women experienced smaller reductions than men for some lipids. Both treatments were generally well tolerated without major sex-related safety issues. ErratumJournal of Clinical LipidologyVol. 4Issue 4PreviewIn the June 2010 issue (4/3) of Journal of Clinical Lipidology, in the section titled “Scientific Poster Abstracts Selected for the National Lipid Association 2010 Annual Scientific Sessions” (2010;4:198-231), changes were made post-submission as noted below. Full-Text PDF

Oral testosterone replacement in symptomatic late-onset hypogonadism: effects on rating scales and general safety in a randomized, placebo-controlled study

To investigate the effects of oral testosterone undecanoate (TU) on symptoms associated with late-onset hypogonadism (LOH). Design Multicenter, randomized, double-blind, placebo-controlled. The study was performed in 14 study centers in seven European countries. Men > or =50 years (n=322) with symptoms of hypogonadism and testosterone deficiency (calculated free testosterone <0.26 nmol/l) were randomized and treated for 12 months with placebo or oral TU 80, 160 or 240 mg/day. Primary outcome was the total score on the Aging Males' Symptoms (AMS) rating scale after six months of treatment. Treatment of mild-to-moderate LOH symptoms in subjects with borderline hypogonadism with oral TU resulted in an improved total AMS score at month 6, but differences between groups were not statistically significant. There was greater improvement in subjects <60 years when compared with subjects > or =60 years (P=0.001), but baseline testosterone level had no influence on treatment response. The AMS sexual symptoms domain improved with oral TU 160 mg/day at months 6 (P=0.008) and 12 (P=0.012) compared with placebo, but not with 80 and 240 mg/day. Treatment was well-tolerated and there were no between-group differences in adverse events or drop-out rates. In one of the largest placebo-controlled studies of testosterone therapy in LOH, oral TU did not improve total AMS score in subjects with mild-to-moderate symptoms compared with placebo, except the sexual symptom sub-domain where a modest improvement was reported with oral TU 160 mg/day.

N-Acetyl Cysteine for Depressive Symptoms in Bipolar Disorder—A Double-Blind Randomized Placebo-Controlled Trial

Treatment-resistant subthreshold depression is a major problem in bipolar disorder. Both depression and bipolar disorder are complicated by glutathione depletion. We hypothesized that treatment with N-acetyl cysteine (NAC), a safe, orally bioavailable precursor of glutathione, may improve the depressive component of bipolar disorder. A randomized, double-blind, multicenter, placebo-controlled study of individuals (n = 75) with bipolar disorder in the maintenance phase treated with NAC (1 g twice daily) adjunctive to usual medication over 24 weeks, with a 4-week washout. The two primary outcomes were the Montgomery Asberg Depression Rating Scale (MADRS) and time to a mood episode. Secondary outcomes included the Bipolar Depression Rating Scale and 11 other ratings of clinical status, quality of life, and functioning. NAC treatment caused a significant improvement on the MADRS (least squares mean difference [95% confidence interval]: -8.05 [-13.16, -2.95], p = .002) and most secondary scales at end point. Benefit was evident by 8 weeks on the Global Assessment of Functioning Scale and Social and Occupational Functioning Assessment Scale and at 20 weeks on the MADRS. Improvements were lost after washout. There was no effect of NAC on time to a mood episode (log-rank test: p = .968) and no significant between-group differences in adverse events. Effect sizes at end point were medium to high for improvements in MADRS and 9 of the 12 secondary readouts. NAC appears a safe and effective augmentation strategy for depressive symptoms in bipolar disorder.

Everolimus with Optimized Cyclosporine Dosing in Renal Transplant Recipients: 6-Month Safety and Efficacy Results of Two Randomized Studies

Two prospective, randomized studies evaluated everolimus 1.5 vs. 3 mg/day with steroids and low-exposure cyclosporine (CsA) (C2 monitoring) in de novo renal transplant patients. Everolimus dosing was adjusted to maintain a minimum trough level of 3 ng/mL. Study 1 (A2306; n = 237) had no induction therapy; in Study 2 (A2307; n = 256) basiliximab was administered (Days 0 and 4). The primary endpoint was renal function at 6 months. CsA C2 target levels, initially 1200 ng/mL in Study 1 and 600 ng/mL in Study 2, were tapered over time post-transplant. Median creatinine levels in Study 1 were 133 and 132 μmol/L at 6 months in the 1.5 and 3 mg/day groups, respectively, and 130 μmol/L in both groups in Study 2. Biopsy-proven acute rejection (BPAR) occurred in 25.0% and 15.2% of patients in the 1.5 and 3 mg/day groups in Study 1, and 13.7% and 15.1% in Study 2. Incidence of BPAR was significantly higher in patients with an everolimus trough < 3 ng/mL. There were no significant between-group differences in the composite endpoint of BPAR, graft loss or death, nor any significant between-group differences in adverse events in either study. Concentration-controlled everolimus with low-exposure CsA provided effective protection against rejection with good renal function.

Safety and Tolerability of Cholesterol Lowering With Simvastatin During 5 Years in the Scandinavian Simvastatin Survival Study

Long-term safety is an important consideration in the selection and use of drugs, such as lipid-lowering agents, that are prescribed to reduce the risk of clinical events during long periods. The Scandinavian Simvastatin Survival Study was designed to evaluate the effects of cholesterol lowering with simvastatin on mortality and morbidity in patients with coronary heart disease. The 4444 patients aged 35 to 70 years (mean, 58.9 years) with angina pectoris or previous myocardial infarction and serum cholesterol levels of 5.5 to 8.0 mmol/L (213-310 mg/dL) receiving a lipid-lowering diet were randomly assigned to take double-blind treatment with simvastatin, 20 to 40 mg once daily, or placebo. In addition to previously reported end-point events, detailed clinical and laboratory safety data were collected during a median follow-up period of 5.4 years (range in survivors, 4.9-6.2 years). The only clearly drug-related serious adverse event during the 5.4-year median follow-up period was a single reversible case of myopathy. The frequencies of persistent elevations of hepatic aminotransferase levels above 3 times the upper limit of normal and of nonviral hepatitis in the simvastatin and placebo treatment groups were not significantly different. Examination of the lens showed no between-group differences, and no previously unrecognized adverse effects of the drug were observed. There were no significant between-group differences in adverse events in any body system. In particular, the frequency of adverse events related to the central nervous system was similar in both groups. The safety profile of simvastatin, 20 to 40 mg daily, over 5 years was excellent.