Exercise training improves exercise capacity and quality of life in patients with inoperable or residual chronic thromboembolic pulmonary hypertension

Background

Aim of this prospective study was to evaluate the effects of exercise training in patients with inoperable or residual chronic thromboembolic pulmonary hypertension (CTEPH).

Methods

Thirty-five consecutive patients with invasively confirmed inoperable or residual CTEPH (16 women;19 men; mean age 61±15 years, mean pulmonary artery pressure, 63±20 mmHg; primary inoperable n = 33, persisting pulmonary hypertension after pulmonary endarterectomy n = 2) on stable disease-targeted medication received exercise training in-hospital for 3 weeks and continued at home for 15 weeks. Medication remained unchanged during the study period. Efficacy parameters have been evaluated at baseline, after 3 and 15 weeks by blinded-observers. Survival rate has been evaluated in a follow-up period of median 36.4 months (interquartile range 26.6–46.6 months).

Results

All patients tolerated exercise training without severe adverse events. Patients significantly improved the mean distance walked in 6 minutes compared to baseline by 61±54 meters after 3 weeks (p<0.001) and by 71±70 meters after 15 weeks (p = 0.001), as well as scores of quality-of-life questionnaire, peak oxygen consumption and maximal workload. NT-proBNP improved significantly after 3 weeks of exercise training (p = 0.046). The 1-year survival rate was 97%, 2-year survival rate was 94% and the 3-year-survival 86% respectively.

Conclusion

Training as add-on to medical therapy may be effective in patients with CTEPH to improve work capacity, quality of life and further prognostic relevant parameters and possibly improves the 1-, 2- and 3-year survival rate. Further multicentric randomized controlled studies are needed to confirm these promising results.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01398345","term_id":"NCT01398345"}}NCT01398345     

A double-blind, placebo-controlled, randomized, clinical trial of the TLR-3 agonist rintatolimod in severe cases of chronic fatigue syndrome

Background

Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is a severely debilitating disease of unknown pathogenesis consisting of a variety of symptoms including severe fatigue. The objective of the study was to examine the efficacy and safety of a TLR-3 agonist, rintatolimod (Poly I: C₁₂U), in patients with debilitating CFS/ME.

Methods and Findings

A Phase III prospective, double-blind, randomized, placebo-controlled trial comparing twice weekly IV rintatolimod versus placebo was conducted in 234 subjects with long-standing, debilitating CFS/ME at 12 sites. The primary endpoint was the intra-patient change from baseline at Week 40 in exercise tolerance (ET). Secondary endpoints included concomitant drug usage, the Karnofsky Performance Score (KPS), Activities of Daily Living (ADL), and Vitality Score (SF 36). Subjects receiving rintatolimod for 40 weeks improved intra-patient placebo-adjusted ET 21.3% (p = 0.047) from baseline in an intention-to-treat analysis. Correction for subjects with reduced dosing compliance increased placebo-adjusted ET improvement to 28% (p = 0.022). The improvement observed represents approximately twice the minimum considered medically significant by regulatory agencies. The rintatolimod cohort vs. placebo also reduced dependence on drugs commonly used by patients in an attempt to alleviate the symptoms of CFS/ME (p = 0.048). Placebo subjects crossed-over to receive rintatolimod demonstrated an intra-patient improvement in ET performance at 24 weeks of 39% (p = 0.04). Rintatolimod at 400 mg twice weekly was generally well-tolerated.

Conclusions/Significance

Rintatolimod produced objective improvement in ET and a reduction in CFS/ME related concomitant medication usage as well as other secondary outcomes.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00215800","term_id":"NCT00215800"}}NCT00215800     

Randomized trial of time-limited interruptions of protease inhibitor-based antiretroviral therapy (ART) vs. continuous therapy for HIV-1 infection

Background

The clinical outcomes of short interruptions of PI-based ART regimens remains undefined.

Methods

A 2-arm non-inferiority trial was conducted on 53 HIV-1 infected South African participants with viral load <50 copies/ml and CD4 T cell count >450 cells/µl on stavudine (or zidovudine), lamivudine and lopinavir/ritonavir. Subjects were randomized to a) sequential 2, 4 and 8-week ART interruptions or b) continuous ART (cART). Primary analysis was based on the proportion of CD4 count >350 cells(c)/ml over 72 weeks. Adherence, HIV-1 drug resistance, and CD4 count rise over time were analyzed as secondary endpoints.

Results

The proportions of CD4 counts >350 cells/µl were 82.12% for the intermittent arm and 93.73 for the cART arm; the difference of 11.95% was above the defined 10% threshold for non-inferiority (upper limit of 97.5% CI, 24.1%; 2-sided CI: −0.16, 23.1). No clinically significant differences in opportunistic infections, adverse events, adherence or viral resistance were noted; after randomization, long-term CD4 rise was observed only in the cART arm.

Conclusion

We are unable to conclude that short PI-based ART interruptions are non-inferior to cART in retention of immune reconstitution; however, short interruptions did not lead to a greater rate of resistance mutations or adverse events than cART suggesting that this regimen may be more forgiving than NNRTIs if interruptions in therapy occur.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00100646","term_id":"NCT00100646"}}NCT00100646     

Moderate antiproteinuric effect of add-on aldosterone blockade with eplerenone in non-diabetic chronic kidney disease. A randomized cross-over study

Background

Reduction of proteinuria and blood pressure (BP) with blockers of the renin-angiotensin system (RAS) impairs the progression of chronic kidney disease (CKD). The aldosterone antagonist spironolactone has an antiproteinuric effect, but its use is limited by side effects. The present study evaluated the short-term antiproteinuric effect and safety of the selective aldosterone antagonist eplerenone in non-diabetic CKD.

Study Design

Open randomized cross-over trial.

Setting and Participants

Forty patients with non-diabetic CKD and urinary albumin excretion greater than 300 mg/24 hours.

Intervention

Eight weeks of once-daily administration of add-on 25–50 mg eplerenone to stable standard antihypertensive treatment including RAS-blockade.

Outcomes & Measurements

24 hour urinary albumin excretion, BP, p-potassium, and creatinine clearance.

Results

The mean urinary albumin excretion was 22% [CI: 14,28], P<0.001, lower during treatment with eplerenone. Mean systolic BP was 4 mmHg [CI: 2,6], P = 0.002, diastolic BP was 2 mmHg [CI: 0,4], P = 0.02, creatinine clearance was 5% [CI: 2,8], P = 0.005, lower during eplerenone treatment. After correction for BP and creatinine clearance differences between the study periods, the mean urinary albumin excretion was 14% [CI: 4,24], P = 0.008 lower during treatment. Mean p-potassium was 0.1 mEq/L [CI: 0.1,0.2] higher during eplerenone treatment, P<0.001. Eplerenone was thus well tolerated and no patients were withdrawn due to hyperkalaemia.

Limitations

Open label, no wash-out period and a moderate sample size.

Conclusions

In non-diabetic CKD patients, the addition of eplerenone to standard antihypertensive treatment including RAS-blockade caused a moderate BP independent fall in albuminuria, a minor fall in creatinine clearance and a 0.1 mEq/L increase in p-potassium.

Trial Registration

Clinicaltrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00430924","term_id":"NCT00430924"}}NCT00430924     

Effect of benfotiamine on advanced glycation endproducts and markers of endothelial dysfunction and inflammation in diabetic nephropathy

Background

Formation of advanced glycation endproducts (AGEs), endothelial dysfunction, and low-grade inflammation are intermediate pathways of hyperglycemia-induced vascular complications. We investigated the effect of benfotiamine on markers of these pathways in patients with type 2 diabetes and nephropathy.

Methods

Patients with type 2 diabetes and urinary albumin excretion in the high-normal and microalbuminuric range (15–300 mg/24h) were randomized to receive benfotiamine (n = 39) or placebo (n = 43). Plasma and urinary AGEs (N ^ε-(carboxymethyl) lysine [CML], N ^ε-(Carboxyethyl) lysine [CEL], and 5-hydro-5-methylimidazolone [MG-H1]) and plasma markers of endothelial dysfunction (soluble vascular cell adhesion molecule-1 [sVCAM-1], soluble intercellular adhesion molecule-1 [sICAM-1], soluble E-selectin) and low-grade inflammation (high-sensitivity C-reactive protein [hs-CRP], serum amyloid-A [SAA], myeloperoxidase [MPO]) were measured at baseline and after 6 and 12 weeks.

Results

Compared to placebo, benfotiamine did not result in significant reductions in plasma or urinary AGEs or plasma markers of endothelial dysfunction and low-grade inflammation.

Conclusions

Benfotiamine for 12 weeks did not significantly affect intermediate pathways of hyperglycemia-induced vascular complications.

Trial Regristration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00565318","term_id":"NCT00565318"}}NCT00565318     

Influence of IL28B polymorphisms on response to a lower-than-standard dose peg-IFN-α 2a for genotype 3 chronic hepatitis C in HIV-coinfected patients

Background

Data on which to base definitive recommendations on the doses and duration of therapy for genotype 3 HCV/HIV-coinfected patients are scarce. We evaluated the efficacy of a lower peginterferon-α 2a dose and a shorter duration of therapy than the current standard of care in genotype 3 HCV/HIV-coinfected patients.

Methods and Findings

Pilot, open-label, single arm clinical trial which involved 58 Caucasian HCV/HIV-coinfected patients who received weekly 135 µg peginterferon-α 2a plus ribavirin 400 mg twice daily during 20 weeks after attaining undetectable viremia. The relationships between baseline patient-related variables, including IL28B genotype, plasma HCV-RNA, ribavirin dose/kg, peginterferon-α 2a and ribavirin levels with virological responses were analyzed.Only 4 patients showed lack of response and 5 patients dropped out due to adverse events related to the study medication. Overall, sustained virologic response (SVR) rates were 58.3% by intention-to-treat and 71.4% by per protocol analysis, respectively. Among patients with rapid virologic response (RVR), SVR and relapses rates were 92.6% and 7.4%, respectively. No relationships were observed between viral responses and ribavirin dose/kg, peginterferon-α 2a concentrations, ribavirin levels or rs129679860 genotype.

Conclusions

Weekly 135 µg pegIFN-α 2a could be as effective as the standard 180 µg dose, with a very low incidence of severe adverse events. A 24-week treatment duration appears to be appropriate in patients achieving RVR, but extending treatment up to just 20 weeks beyond negativization of viremia is associated with a high relapse rate in those patients not achieving RVR. There was no influence of IL28B genotype on the virological responses.

Trial Registration:

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00553930","term_id":"NCT00553930"}}NCT00553930     

Aerobic exercise training reduces cannabis craving and use in non-treatment seeking cannabis-dependent adults

Background

Cannabis dependence is a significant public health problem. Because there are no approved medications for this condition, treatment must rely on behavioral approaches empirically complemented by such lifestyle change as exercise.

Aims

To examine the effects of moderate aerobic exercise on cannabis craving and use in cannabis dependent adults under normal living conditions.

Design

Participants attended 10 supervised 30-min treadmill exercise sessions standardized using heart rate (HR) monitoring (60–70% HR reserve) over 2 weeks. Exercise sessions were conducted by exercise physiologists under medical oversight.

Participants

Sedentary or minimally active non-treatment seeking cannabis-dependent adults (n = 12, age 25±3 years, 8 females) met criteria for primary cannabis dependence using the Substance Abuse module of the Structured Clinical Interview for DSM-IV (SCID).

Measurements

Self-reported drug use was assessed for 1-week before, during, and 2-weeks after the study. Participants viewed visual cannabis cues before and after exercise in conjunction with assessment of subjective cannabis craving using the Marijuana Craving Questionnaire (MCQ-SF).

Findings

Daily cannabis use within the run-in period was 5.9 joints per day (SD = 3.1, range 1.8–10.9). Average cannabis use levels within the exercise (2.8 joints, SD = 1.6, range 0.9–5.4) and follow-up (4.1 joints, SD = 2.5, range 1.1–9.5) periods were lower than during the run-in period (both P<.005). Average MCQ factor scores for the pre- and post-exercise craving assessments were reduced for compulsivity (P  = .006), emotionality (P  = .002), expectancy (P  = .002), and purposefulness (P  = .002).

Conclusions

The findings of this pilot study warrant larger, adequately powered controlled trials to test the efficacy of prescribed moderate aerobic exercise as a component of cannabis dependence treatment. The neurobiological mechanisms that account for these beneficial effects on cannabis use may lead to understanding of the physical and emotional underpinnings of cannabis dependence and recovery from this disorder.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00838448","term_id":"NCT00838448"}}NCT00838448]     

Immunopotentiation of trivalent influenza vaccine when given with VAX102, a recombinant influenza M2e vaccine fused to the TLR5 ligand flagellin

Background

Currently controversy exists about the immunogenicity of seasonal trivalent influenza vaccine in certain populations, especially the elderly. STF2.4×M2e (VAX102) is a recombinant fusion protein that links four copies of the ectodomain of influenza virus matrix protein 2 (M2e) antigen to Salmonella typhimurium flagellin, a TLR5 ligand. The objectives of this study were to assess the feasibility of giving VAX102 and TIV in combination in an effort to achieve greater immunogenicity and to provide cross-protection.

Methodology/Principal Findings

Eighty healthy subjects, 18-49 years old, were enrolled in May and June 2009 in a double-blind, randomized, controlled trial at two clinical sites. Subjects were randomized to receive either TIV + VAX102 or TIV + placebo. Both arms tolerated the vaccines. Pain at the injection site was more severe with TIV + VAX102. Two weeks after immunization the HAI responses to the H1 and H3 antigens of TIV were higher in those that received TIV + VAX102 than in TIV + placebo (309 vs 200 and 269 vs 185, respectively), although statistically non-significant. There was no difference in the HAI of the B antigen. In the TIV + VAX102 arm, the geometric mean M2e antibody concentration was 0.5 µg/ml and 73% seroconverted.

Conclusions/Significance

The combination of TIV + VAX102 has the potential to increase the immune response to the influenza A components of TIV and to provide M2e immunity which may protect against influenza A strains not contained in seasonal TIV.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00921973","term_id":"NCT00921973"}}NCT00921973     

Blood profile of proteins and steroid hormones predicts weight change after weight loss with interactions of dietary protein level and glycemic index

Background

Weight regain after weight loss is common. In the Diogenes dietary intervention study, high protein and low glycemic index (GI) diet improved weight maintenance.

Objective

To identify blood predictors for weight change after weight loss following the dietary intervention within the Diogenes study.

Design

Blood samples were collected at baseline and after 8-week low caloric diet-induced weight loss from 48 women who continued to lose weight and 48 women who regained weight during subsequent 6-month dietary intervention period with 4 diets varying in protein and GI levels. Thirty-one proteins and 3 steroid hormones were measured.

Results

Angiotensin I converting enzyme (ACE) was the most important predictor. Its greater reduction during the 8-week weight loss was related to continued weight loss during the subsequent 6 months, identified by both Logistic Regression and Random Forests analyses. The prediction power of ACE was influenced by immunoproteins, particularly fibrinogen. Leptin, luteinizing hormone and some immunoproteins showed interactions with dietary protein level, while interleukin 8 showed interaction with GI level on the prediction of weight maintenance. A predictor panel of 15 variables enabled an optimal classification by Random Forests with an error rate of 24±1%. A logistic regression model with independent variables from 9 blood analytes had a prediction accuracy of 92%.

Conclusions

A selected panel of blood proteins/steroids can predict the weight change after weight loss. ACE may play an important role in weight maintenance. The interactions of blood factors with dietary components are important for personalized dietary advice after weight loss.

Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00390637","term_id":"NCT00390637"}}NCT00390637     

Infant safety during and after maternal valacyclovir therapy in conjunction with antiretroviral HIV-1 prophylaxis in a randomized clinical trial

Background

Maternal administration of the acyclovir prodrug valacyclovir is compatible with pregnancy and breastfeeding. However, the safety profile of prolonged infant and maternal exposure to acyclovir in the context of antiretrovirals (ARVs) for prevention of mother-to-child HIV-1 transmission (PMTCT) has not been described.

Methods

Pregnant Kenyan women co-infected with HIV-1/HSV-2 with CD4 counts > 250 cells/mm³ were enrolled at 34 weeks gestation and randomized to twice daily 500 mg valacyclovir or placebo until 12 months postpartum. Women received zidovudine from 28 weeks gestation and single dose nevirapine was given to women and infants at the time of delivery for PMTCT. Infant blood was collected at 6 weeks for creatinine and ALT. Breast milk specimens were collected at 2 weeks postpartum from 71 women in the valacyclovir arm; acyclovir levels were determined for a random sample of 44 (62%) specimens. Fisher’s Exact and Wilcoxon rank-sum tests were used for analysis.

Results

One hundred forty-eight women were randomized and 146 mother-infant pairs were followed postpartum. PMTCT ARVs were administered to 98% of infants and all mothers. Valacyclovir was not associated with infant or maternal toxicities or adverse events, and no congenital malformations were observed. Infant creatinine levels were all normal (< 0.83 mg/dl) and median creatinine (median 0.50 mg/dl) and infant growth did not differ between study arms. Acyclovir was detected in 35 (80%) of 44 breast milk samples collected at 2 weeks postpartum. Median and maximum acyclovir levels were 2.62 and 10.15 mg/ml, respectively (interquartile range 0.6–4.19).

Conclusions

Exposure to PMTCT ARVs and acyclovir after maternal administration of valacyclovir during pregnancy and postpartum to women co-infected with HIV-1/HSV-2 was not associated with an increase in infant or maternal toxicities or adverse events.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00530777","term_id":"NCT00530777"}}NCT00530777     

Feasibility of bispectral index-guided propofol infusion for flexible bronchoscopy sedation: a randomized controlled trial

Objectives

There are safety issues associated with propofol use for flexible bronchoscopy (FB). The bispectral index (BIS) correlates well with the level of consciousness. The aim of this study was to show that BIS-guided propofol infusion is safe and may provide better sedation, benefiting the patients and bronchoscopists.

Methods

After administering alfentanil bolus, 500 patients were randomized to either propofol infusion titrated to a BIS level of 65-75 (study group) or incremental midazolam bolus based on clinical judgment to achieve moderate sedation. The primary endpoint was safety, while the secondary endpoints were recovery time, patient tolerance, and cooperation.

Results

The proportion of patients with hypoxemia or hypotensive events were not different in the 2 groups (study vs. control groups: 39.9% vs. 35.7%, p = 0.340; 7.4% vs. 4.4%, p = 0.159, respectively). The mean lowest blood pressure was lower in the study group. Logistic regression revealed male gender, higher American Society of Anesthesiologists physical status, and electrocautery were associated with hypoxemia, whereas lower propofol dose for induction was associated with hypotension in the study group. The study group had better global tolerance (p<0.001), less procedural interference by movement or cough (13.6% vs. 36.1%, p<0.001; 30.0% vs. 44.2%, p = 0.001, respectively), and shorter time to orientation and ambulation (11.7±10.2 min vs. 29.7±26.8 min, p<0.001; 30.0±18.2 min vs. 55.7±40.6 min, p<0.001, respectively) compared to the control group.

Conclusions

BIS-guided propofol infusion combined with alfentanil for FB sedation provides excellent patient tolerance, with fast recovery and less procedure interference.

Trial Registration

ClinicalTrials. gov {"type":"clinical-trial","attrs":{"text":"NCT00789815","term_id":"NCT00789815"}}NCT00789815     

Efficacy of an educational material on second primary cancer screening practice for cancer survivors: a randomized controlled trial

Background

Cancer surivors have limited knowledge about second primary cancer (SPC) screening and suboptimal rates of completion of screening practices for SPC. Our objective was to test the efficacy of an educational material on the knowledge, attitudes, and screening practices for SPC among cancer survivors.

Methods

Randomized, controlled trial among 326 cancer survivors from 6 oncology care outpatient clinics in Korea. Patients were randomized to an intervention or an attention control group. The intervention was a photo-novel, culturally tailored to increase knowledge about SPC screening. Knowledge and attitudes regarding SPC screening were assessed two weeks after the intervention, and screening practices were assessed after one year.

Results

At two weeks post-intervention, the average knowledge score was significantly higher in the intervention compared to the control group (0.81 vs. 0.75, P<0.01), with no significant difference in their attitude scores (2.64 vs. 2.57, P = 0.18). After 1 year of follow-up, the completion rate of all appropriate cancer screening was 47.2% in both intervention and control groups.

Conclusion

While the educatinal material was effective for increasing knowledge of SPC screening, it did not promote cancer screening practice among cancer survivors. More effective interventions are needed to increase SPC screening rates in this population.

Trial Registration

ClinicalTrial.gov {"type":"clinical-trial","attrs":{"text":"NCT00948337","term_id":"NCT00948337"}}NCT00948337     

Intensification of antiretroviral therapy with a CCR5 antagonist in patients with chronic HIV-1 infection: effect on T cells latently infected

Objective

The primary objective was to assess the effect of MVC intensification on latently infected CD4⁺ T cells in chronically HIV-1-infected patients receiving antiretroviral therapy.

Methods

We performed an open-label pilot phase II clinical trial involving chronically HIV-1-infected patients receiving stable antiretroviral therapy whose regimen was intensified with 48 weeks of maraviroc therapy. We analyzed the latent reservoir, the residual viremia and episomal 2LTR DNA to examine the relationship between these measures and the HIV-1 latent reservoir, immune activation, lymphocyte subsets (including effector and central memory T cells), and markers associated with bacterial translocation.

Results

Overall a non significant reduction in the size of the latent reservoir was found (p = 0.068). A mean reduction of 1.82 IUPM was observed in 4 patients with detectable latent reservoir at baseline after 48 weeks of intensification. No effect on plasma residual viremia was observed. Unexpectedly, all the patients had detectable 2LTR DNA circles at week 24, while none of them showed those circles at the end of the study. No changes were detected in CD4⁺ or CD8⁺ counts, although a significant decrease was found in the proportion of HLA-DR⁺/CD38⁺ CD4⁺ and CD8⁺ T-cells. LPS and sCD14 levels increased.

Conclusions

Intensification with MVC was associated with a trend to a decrease in the size of the latent HIV-1 reservoir in memory T cells. No impact on residual viremia was detected. Additional studies with larger samples are needed to confirm the results.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00795444","term_id":"NCT00795444"}}NCT00795444     

Activity of the neuroendocrine axes in patients with polymyalgia rheumatica before and after TNF-α blocking etanercept treatment

Introduction

In this study, we evaluated the activity of the neuroendocrine axes in patients with polymyalgia rheumatica (PMR) before and after tumor necrosis factor (TNF)-α-blocking etanercept treatment, which previously has been shown to reduce interleukin 6 (IL-6) and C-reactive protein (CRP) markedly in PMR.

Methods

Plasma samples were collected from 10 glucocorticoid-naïve patients with PMR and 10 matched controls before and after etanercept treatment (25 mg biweekly for 2 weeks). The primary end points were pre- and posttreatment levels of adrenocorticotropic hormone (ACTH), cortisol, adrenaline, thyroid-stimulating hormone (TSH), follicle-stimulating hormone (FSH), prolactin, and insulin-like growth factor 1 (IGF-1).

Results

Before TNF-α-blocking treatment, plasma TNF-α, ACTH, and cortisol levels were higher in patients versus controls (P < 0.05 and P < 0.001, respectively); during TNF-α blockade in patients, levels of both hormones decreased (P < 0.05 and P < 0.01, respectively), whereas levels in controls increased (P < 0.05), abolishing the pretreatment differences. Pretreatment adrenaline levels were more than twice as high in patients than in controls (P < 0.01); after treatment in patients, levels had decreased (P < 0.05) but remained higher versus controls (P < 0.05). Levels of the other hormones never differed significantly between groups (P > 0.05).

Conclusions

In PMR, TNF-α may increase the activities of the hypothalamic-pituitary-adrenal and the hypothalamic-sympthoadrenomedullary axes. Secretion of TSH, FSH, prolactin, and IGF-1 is not clearly changed in PMR.

Trial registration

ClinicalTrials.gov ({"type":"clinical-trial","attrs":{"text":"NCT00524381","term_id":"NCT00524381"}}NCT00524381).     

A 6 week randomized double-blind placebo-controlled trial of ziprasidone for the acute depressive mixed state

Objective

To examine the efficacy of ziprasidone vs. placebo for the depressive mixed state in patients with bipolar disorder type II or major depressive disorder (MDD).

Methods

73 patients were randomized in a double-blinded, placebo-controlled study to ziprasidone (40-160 mg/d) or placebo for 6 weeks. They met DSM-IV criteria for a major depressive episode (MDE), while also meeting 2 or 3 (but not more nor less) DSM-IV manic criteria. They did not meet DSM-IV criteria for a mixed or manic episode. Baseline psychotropic drugs were continued unchanged. The primary endpoint measured was Montgomery- Åsberg Depression Rating Scale (MADRS) scores over time. The mean dose of ziprasidone was 129.7±45.3 mg/day and 126.1±47.1 mg/day for placebo.

Results

The primary outcome analysis indicated efficacy of ziprasidone versus placebo (p = 0.0038). Efficacy was more pronounced in type II bipolar disorder than in MDD (p = 0.036). Overall ziprasidone was well tolerated, without notable worsening of weight or extrapyramidal symptoms.

Conclusions

There was a statistically significant benefit with ziprasidone versus placebo in this first RCT of any medication for the provisional diagnostic concept of the depressive mixed state.

Trial Registration

Clinicaltrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00490542","term_id":"NCT00490542"}}NCT00490542     

Short and long-term safety of the 2009 AS03-adjuvanted pandemic vaccine

Background

This study assessed the short and the long term safety of the 2009 AS03 adjuvanted monovalent pandemic vaccine through an active web-based electronic surveillance. We compared its safety profile to that of the seasonal trivalent inactivated influenza vaccine (TIV) for 2010–2011.

Methodology/Principal Findings

Health care workers (HCW) vaccinated in 2009 with the pandemic vaccine (Arepanrix ® from GSK) or HCW vaccinated in 2010 with the 2010–2011 TIV were invited to participate in a web-based active surveillance of vaccine safety. They completed two surveys the day-8 survey covered the first 7 days post-vaccination and the day-29 survey covered events occurring 8 to 28 days after vaccination. Those who reported a problem were called by a nurse to obtain details. The main outcome was the occurrence of a new health problem or the worsening of an existing health condition that resulted in a medical consultation or work absenteeism. For the pandemic vaccine, a six-month follow-up for the occurrence of serious adverse events (SAE) was conducted. Among the 6242 HCW who received the pandemic vaccine, 440 (7%) reported 468 events compared to 328 of the 7645 HCW (4.3%) who reported 339 events after the seasonal vaccine. The 2009 pandemic vaccine was associated with significantly more local reactions than the 2010–2011 seasonal vaccine (1% vs. 0.03%, p<0.001). Paresthesia was reported by 7 HCW (0.1%) after the pandemic vaccine but by none after the seasonal vaccine. For the pandemic vaccine, no clustering of SAE was found in the 6 month follow-up.

Conclusion

The 2009 pandemic vaccine seems to have a good safety profile, similar to the 2010–2011 TIV, with the exception of local reactions. This surveillance was adequately powered to identify AE associated with an excess risk ≥1 per 1000 vaccinations but is insufficient to detect rare AE.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01289418","term_id":"NCT01289418"}}NCT01289418, {"type":"clinical-trial","attrs":{"text":"NCT01318876","term_id":"NCT01318876"}}NCT01318876     

Efficacy of a high-dose in addition to daily low-dose vitamin A in children suffering from severe acute malnutrition with other illnesses

Background

Efficacy of high-dose vitamin A (VA) in children suffering from severe acute malnutrition (SAM) has recently been questioned. This study compared the efficacy of a single high-dose (200,000 IU) in addition to daily low-dose (5000 IU) VA in the management of children suffering from SAM with diarrhea and/or acute lower respiratory tract infection (ALRI).

Methods

In a randomized, double-blind, controlled clinical trial in icddr,b, Bangladesh during 2005–07, children aged 6–59 months with weight-for-height <−3 Z-score and/or bipedal edema (SAM) received either a high-dose VA or placebo on admission day. Both the groups received 5,000 IU/day VA in a multivitamins drop for 15 days and other standard treatment which is similar to WHO guidelines.

Results

A total 260 children (130 in each group) were enrolled. All had diarrhea, 54% had concomitant ALRI, 50% had edema, 48.5% were girl with a mean±SD age of 16±10 months. None had clinical signs of VA deficiency. Mean±SD baseline serum retinol was 13.15±9.28 µg/dl, retinol binding protein was 1.27±0.95 mg/dl, and pre-albumin was 7.97±3.96 mg/dl. Median (inter quartile range) of C-reactive protein was 7.8 (2.1, 22.2) mg/L. Children of the two groups did not differ in any baseline characteristic. Over the 15 days treatment period resolution of diarrhea, ALRI, edema, anthropometric changes, and biochemical indicators of VA were similar between the groups. The high-dose VA supplementation in children with SAM did not show any adverse event.

Conclusions

Efficacy of daily low-dose VA compared to an additional single high-dose was not observed to be better in the management of children suffering from SAM with other acute illnesses. A single high-dose VA may be given especially where the children with SAM may leave the hospital/treatment center early.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00388921","term_id":"NCT00388921"}}NCT00388921     

Beneficial effects on arterial stiffness and pulse-wave reflection of combined enalapril and candesartan in chronic kidney disease - a randomized trial

Background

Cardiovascular disease (CVD) is highly prevalent in patients with chronic kidney disease (CKD). Inhibition of the renin-angiotensinsystem (RAS) in hypertension causes differential effects on central and brachial blood pressure (BP), which has been translated into improved outcome. The objective was to examine if a more complete inhibition of RAS by combining an angiotensin converting enzyme inhibitor (ACEI) and an angiotensin receptor antagonist (ARB) compared to monotherapy has an additive effect on central BP and pulse-wave velocity (PWV), which are known markers of CVD.

Methods

Sixty-seven CKD patients (mean GFR 30, range 13–59 ml/min/1.73 m²) participated in an open randomized study of 16 weeks of monotherapy with either enalapril or candesartan followed by 8 weeks of dual blockade aiming at a total dose of 16 mg candesartan and 20 mg enalapril o.d. Pulse-wave measurements were performed at week 0, 8, 16 and 24 by the SphygmoCor device.

Results

Significant additive BP independent reductions were found after dual blockade in aortic PWV (−0.3 m/s, P<0.05) and in augmentation index (−2%, P<0.01) compared to monotherapy. Furthermore pulse pressure amplification was improved (P<0.05) and central systolic BP reduced (−6 mmHg, P<0.01).

Conclusions

Dual blockade of the RAS resulted in an additive BP independent reduction in pulse-wave reflection and arterial stiffness compared to monotherapy in CKD patients.

Trial Registration

Clinical trial.gov {"type":"clinical-trial","attrs":{"text":"NCT00235287","term_id":"NCT00235287"}}NCT00235287 http://www.clinicaltrials.gov/ct2/show/NCT00235287?term=ras+block&rank=1     

Immunogenicity is not improved by increased antigen dose or booster dosing of seasonal influenza vaccine in a randomized trial of HIV infected adults

Introduction

The risk of poor vaccine immunogenicity and more severe influenza disease in HIV necessitate strategies to improve vaccine efficacy.

Methods

A randomized, multi-centered, controlled, vaccine trial with three parallel groups was conducted at 12 CIHR Canadian HIV Trials Network sites. Three dosing strategies were used in HIV infected adults (18 to 60 years): two standard doses over 28 days, two double doses over 28 days and a single standard dose of influenza vaccine, administered prior to the 2008 influenza season. A trivalent killed split non-adjuvanted influenza vaccine (Fluviral™) was used. Serum hemagglutinin inhibition (HAI) activity for the three influenza strains in the vaccine was measured to assess immunogenicity.

Results

297 of 298 participants received at least one injection. Baseline CD4 (median 470 cells/µL) and HIV RNA (76% of patients with viral load <50 copies/mL) were similar between groups. 89% were on HAART. The overall immunogenicity of influenza vaccine across time points and the three influenza strains assessed was poor (Range HAI ≥40 = 31–58%). Double dose plus double dose booster slightly increased the proportion achieving HAI titre doubling from baseline for A/Brisbane and B/Florida at weeks 4, 8 and 20 compared to standard vaccine dose. Increased immunogenicity with increased antigen dose and booster dosing was most apparent in participants with unsuppressed HIV RNA at baseline. None of 8 serious adverse events were thought to be immunization-related.

Conclusion

Even with increased antigen dose and booster dosing, non-adjuvanted influenza vaccine immunogenicity is poor in HIV infected individuals. Alternative influenza vaccines are required in this hyporesponsive population.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00764998","term_id":"NCT00764998"}}NCT00764998     

Effects of selenium supplementation on selenoprotein gene expression and response to influenza vaccine challenge: a randomised controlled trial

Background

The uncertainty surrounding dietary requirements for selenium (Se) is partly due to limitations in biomarkers of Se status that are related to health outcomes. In this study we determined the effect of different doses and forms of Se on gene expression of selenoprotein S (SEPS1), selenoprotein W (SEPW1) and selenoprotein R (SEPR), and responses to an immune function challenge, influenza vaccine, were measured in order to identify functional markers of Se status.

Methods and Findings

A 12 week human dietary intervention study was undertaken in 119 volunteers who received placebo, 50, 100 or 200 µg/day Se-enriched yeast (Se-yeast) or meals containing unenriched or Se-enriched onions (50 µg/day). Gene expression was quantified in RNA samples extracted from human peripheral blood mononuclear cells (PBMC''s) using quantitative RT-PCR. There was a significant increase in SEPW1 mRNA in the Se-enriched onion group (50 µg/day) compared with the unenriched onion group. SEPR and SEPW1 did not change significantly over the duration of the supplementation period in the control or Se-yeast groups, except at week 10 when SEPW1 mRNA levels were significantly lower in the 200 µg/day Se-yeast group compared to the placebo group. Levels of SEPS1 mRNA increased significantly 7 days after the influenza vaccine challenge, the magnitude of the increase in SEPS1 gene expression was dose-dependent, with a significantly greater response with higher Se supplementation.

Conclusions

This novel finding provides preliminary evidence for a role of SEPS1 in the immune response, and further supports the relationship between Se status and immune function.

Trial Registration

ClinicalTrials.gov [{"type":"clinical-trial","attrs":{"text":"NCT00279812","term_id":"NCT00279812"}}NCT00279812]