A double blind, placebo-controlled, randomized crossover study of the acute metabolic effects of olanzapine in healthy volunteers

Background and Rationale

Atypical antipsychotics exhibit metabolic side effects including diabetes mellitus and obesity. The adverse events are preceded by acute worsening of oral glucose tolerance (oGTT) along with reduced plasma free fatty acids (FFA) and leptin in animal models. It is unclear whether the same acute effects occur in humans.

Methodology/Principal Findings

A double blind, randomized, placebo-controlled crossover trial was conducted to examine the potential metabolic effects of olanzapine in healthy volunteers. Participants included male (8) and female (7) subjects [18–30 years old, BMI 18.5–25]. Subjects received placebo or olanzapine (10 mg/day) for three days prior to oGTT testing. Primary endpoints included measurement of plasma leptin, oral glucose tolerance, and plasma free fatty acids (FFA). Secondary metabolic endpoints included: triglycerides, total cholesterol, high- and low-density lipoprotein cholesterol, heart rate, blood pressure, body weight and BMI. Olanzapine increased glucose Area Under the Curve (AUC) by 42% (2808±474 vs. 3984±444 mg/dl·min; P = 0.0105) during an oGTT. Fasting plasma leptin and triglycerides were elevated 24% (Leptin: 6.8±1.3 vs. 8.4±1.7 ng/ml; P = 0.0203) and 22% (Triglycerides: 88.9±10.1 vs. 108.2±11.6 mg/dl; P = 0.0170), whereas FFA and HDL declined by 32% (FFA: 0.38±0.06 vs. 0.26±0.04 mM; P = 0.0166) and 11% (54.2±4.7 vs. 48.9±4.3 mg/dl; P = 0.0184), respectively after olanzapine. Other measures were unchanged.

Conclusions/Significance

Olanzapine exerts some but not all of the early endocrine/metabolic changes observed in rodent models of the metabolic side effects, and this suggest that antipsychotic effects are not limited to perturbations in glucose metabolism alone. Future prospective clinical studies should focus on identifying which reliable metabolic alterations might be useful as potential screening tools in assessing patient susceptibility to weight gain and diabetes caused by atypical antipsychotics.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00741026","term_id":"NCT00741026"}}NCT00741026     

Paromomycin for the treatment of visceral leishmaniasis in Sudan: a randomized, open-label, dose-finding study

Background

A recent study has shown that treatment of visceral leishmaniasis (VL) with the standard dose of 15 mg/kg/day of paromomycin sulphate (PM) for 21 days was not efficacious in patients in Sudan. We therefore decided to test the efficacy of paramomycin for a longer treatment duration (15 mg/kg/day for 28 days) and at the higher dose of 20 mg/kg/day for 21 days.

Methods

This randomized, open-label, dose-finding, phase II study assessed the two above high-dose PM treatment regimens. Patients with clinical features and positive bone-marrow aspirates for VL were enrolled. All patients received their assigned courses of PM intramuscularly and adverse events were monitored. Parasite clearance in bone-marrow aspirates was tested by microscopy at end of treatment (EOT, primary efficacy endpoint), 3 months (in patients who were not clinically well) and 6 months after EOT (secondary efficacy endpoint). Pharmacokinetic data were obtained from a subset of patients weighing over 30 kg.

Findings

42 patients (21 per group) aged between 4 and 60 years were enrolled. At EOT, 85% of patients (95% confidence interval [CI]: 63.7% to 97.0%) in the 20 mg/kg/day group and 90% of patients (95% CI: 69.6% to 98.8%) in the 15 mg/kg/day group had parasite clearance. Six months after treatment, efficacy was 80.0% (95% CI: 56.3% to 94.3%) and 81.0% (95% CI: 58.1% to 94.6%) in the 20 mg/kg/day and 15 mg/kg/day groups, respectively. There were no serious adverse events. Pharmacokinetic profiles suggested a difference between the two doses, although numbers of patients recruited were too few to make it significant (n = 3 and n = 6 in the 20 mg/kg/day and 15 mg/kg/day groups, respectively).

Conclusion

Data suggest that both high dose regimens were more efficacious than the standard 15 mg/kg/day PM for 21 days and could be further evaluated in phase III studies in East Africa.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00255567","term_id":"NCT00255567"}}NCT00255567     

Completeness and changes in registered data and reporting bias of randomized controlled trials in ICMJE journals after trial registration policy

Objective

We assessed the adequacy of randomized controlled trial (RCT) registration, changes to registration data and reporting completeness for articles in ICMJE journals during 2.5 years after registration requirement policy.

Methods

For a set of 149 reports of 152 RCTs with ClinicalTrials.gov registration number, published from September 2005 to April 2008, we evaluated the completeness of 9 items from WHO 20-item Minimum Data Set relevant for assessing trial quality. We also assessed changes to the registration elements at the Archive site of ClinicalTrials.gov and compared published and registry data.

Results

RCTs were mostly registered before 13 September 2005 deadline (n = 101, 66.4%); 118 (77.6%) started recruitment before and 31 (20.4%) after registration. At the time of registration, 152 RCTs had a total of 224 missing registry fields, most commonly ‘Key secondary outcomes’ (44.1% RCTs) and ‘Primary outcome’ (38.8%). More RCTs with post-registration recruitment had missing Minimum Data Set items than RCTs with pre-registration recruitment: 57/118 (48.3%) vs. 24/31 (77.4%) (χ² ₁ = 7.255, P = 0.007). Major changes in the data entries were found for 31 (25.2%) RCTs. The number of RCTs with differences between registered and published data ranged from 21 (13.8%) for Study type to 118 (77.6%) for Target sample size.

Conclusions

ICMJE journals published RCTs with proper registration but the registration data were often not adequate, underwent substantial changes in the registry over time and differed in registered and published data. Editors need to establish quality control procedures in the journals so that they continue to contribute to the increased transparency of clinical trials.     

Sodium stibogluconate (SSG) & paromomycin combination compared to SSG for visceral leishmaniasis in East Africa: a randomised controlled trial

Background

Alternative treatments for visceral leishmaniasis (VL) are required in East Africa. Paromomycin sulphate (PM) has been shown to be efficacious for VL treatment in India.

Methods

A multi-centre randomized-controlled trial (RCT) to compare efficacy and safety of PM (20 mg/kg/day for 21 days) and PM plus sodium stibogluconate (SSG) combination (PM, 15 mg/kg/day and SSG, 20 mg/kg/day for 17 days) with SSG (20 mg/kg/day for 30 days) for treatment of VL in East Africa. Patients aged 4–60 years with parasitologically confirmed VL were enrolled, excluding patients with contraindications. Primary and secondary efficacy outcomes were parasite clearance at 6-months follow-up and end of treatment, respectively. Safety was assessed mainly using adverse event (AE) data.

Findings

The PM versus SSG comparison enrolled 205 patients per arm with primary efficacy data available for 198 and 200 patients respectively. The SSG & PM versus SSG comparison enrolled 381 and 386 patients per arm respectively, with primary efficacy data available for 359 patients per arm. In Intention-to-Treat complete-case analyses, the efficacy of PM was significantly lower than SSG (84.3% versus 94.1%, difference = 9.7%, 95% confidence interval, CI: 3.6 to 15.7%, p = 0.002). The efficacy of SSG & PM was comparable to SSG (91.4% versus 93.9%, difference = 2.5%, 95% CI: −1.3 to 6.3%, p = 0.198). End of treatment efficacy results were very similar. There were no apparent differences in the safety profile of the three treatment regimens.

Conclusion

The 17 day SSG & PM combination treatment had a good safety profile and was similar in efficacy to the standard 30 day SSG treatment, suggesting suitability for VL treatment in East Africa.

Clinical Trials Registration

www.clinicaltrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00255567","term_id":"NCT00255567"}}NCT00255567     

Use of evidence-based practices in pregnancy and childbirth: South East Asia Optimising Reproductive and Child Health in Developing Countries project

Background

The burden of mortality and morbidity related to pregnancy and childbirth remains concentrated in developing countries. SEA-ORCHID (South East Asia Optimising Reproductive and Child Health In Developing countries) is evaluating whether a multifaceted intervention to strengthen capacity for research synthesis, evidence-based care and knowledge implementation improves adoption of best clinical practice recommendations leading to better health for mothers and babies. In this study we assessed current practices in perinatal health care in four South East Asian countries and determined whether they were aligned with best practice recommendations.

Methodology/Principal Findings

We completed an audit of 9550 medical records of women and their 9665 infants at nine hospitals; two in each of Indonesia, Malaysia and The Philippines, and three in Thailand between January-December 2005. We compared actual clinical practices with best practice recommendations selected from the Cochrane Library and the World Health Organization Reproductive Health Library.Evidence-based components of the active management of the third stage of labour and appropriately treating eclampsia with magnesium sulphate were universally practiced in all hospitals. Appropriate antibiotic prophylaxis for caesarean section, a beneficial form of care, was practiced in less than 5% of cases in most hospitals. Use of the unnecessary practices of enema in labour ranged from 1% to 61% and rates of episiotomy for vaginal birth ranged from 31% to 95%. Other appropriate practices were commonly performed to varying degrees between countries and also between hospitals within the same country.

Conclusions/Significance

Whilst some perinatal health care practices audited were consistent with best available evidence, several were not. We conclude that recording of clinical practices should be an essential step to improve quality of care. Based on these findings, the SEA-ORCHID project team has been developing and implementing interventions aimed at increasing compliance with evidence-based clinical practice recommendations to improve perinatal practice in South East Asia.     

Intermittent screening and treatment versus intermittent preventive treatment of malaria in pregnancy: a randomised controlled non-inferiority trial

Background

The effectiveness of intermittent preventive treatment of malaria in pregnancy (IPTp) may be compromised by the spread of resistance to sulphadoxine/pyrimethamine (SP) across Africa. But little informtion exists on alternative drugs for IPTp or alternative strategies for the prevention of malaria in pregnancy. Therefore, we have investigated whether screening with a rapid diagnostic test and treatment of those who are positive (IST) at routine antenatal clinic attendances is as effective and as safe as SP-IPTp in pregnant women.

Methods and Findings

During antenatal clinic sessions in six health facilities in Ghana held between March 2007 and September 2007, 3333 pregnant women who satisfied inclusion criteria were randomised into three intervention arms (1) standard SP-IPTp, (2) IST and treatment with SP or (3) IST and treatment with amodiaquine+artesunate (AQ+AS). All women received a long-lasting insecticide treated net. Study women had a maximum of three scheduled follow-up visits following enrolment. Haemoglobin concentration and peripheral parasitaemia were assessed between 36 and 40 weeks of gestation. Birth weight was measured at delivery or within 72 hours for babies delivered at home. Parasite prevalence at enrolment in primigravidae and in multigravidae was 29.6% and 10.2% respectively. At 36–40 weeks of gestation the prevalence of asymptomatic parasitaemia was 12.1% in study women overall and was very similar in all treatment groups. The risk of third trimester severe anaemia or low birth weight did not differ significantly between the three treatment groups regardless of gravidity. IST with AQ+AS or SP was not inferior to SP-IPTp in reducing the risk of low birth weight (RD = -1.17[95%CI; -4.39-1.02] for IST-SP vs. SP-IPTp and RD = 0.78[95%CI; -2.11-3.68] for IST-AQAS vs. SP-IPTp); third trimester severe anaemia (RD = 0.29[95%CI; -0.69-1.30] for IST-SP vs. SP-IPTp and RD = -0.36[95%CI;-1.12-0.44] for IST-AQAS vs. SP-IPTp).

Conclusion

The results of this study suggest that in an area of moderately high malaria transmission, IST with SP or AS+AQ may be a safe and effective strategy for the control of malaria in pregnancy. However, it is important that these encouraging findings are confirmed in other geographical areas and that the impact of IST on placental malaria is investigated.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00432367","term_id":"NCT00432367"}}NCT00432367 [{"type":"clinical-trial","attrs":{"text":"NCT00432367","term_id":"NCT00432367"}}NCT00432367]     

A multicentre randomized controlled trial of the efficacy and safety of single-dose praziquantel at 40 mg/kg vs. 60 mg/kg for treating intestinal schistosomiasis in the Philippines, Mauritania, Tanzania and Brazil

Background

Praziquantel at 40 mg/kg in a single dose is the WHO recommended treatment for all forms of schistosomiasis, but 60 mg/kg is also deployed nationally.

Methodology/Principal Findings

Four trial sites in the Philippines, Mauritania, Tanzania and Brazil enrolled 856 patients using a common protocol, who were randomised to receive praziquantel 40 mg/kg (n = 428) or 60 mg/kg (n = 428). While the sites differed for transmission and infection intensities (highest in Tanzania and lowest in Mauritania), no bias or heterogeneity across sites was detected for the main efficacy outcomes. The primary efficacy analysis was the comparison of cure rates on Day 21 in the intent-to-treat population for the pooled data using a logistic model to calculate Odd Ratios allowing for baseline characteristics and study site. Both doses were highly effective: the Day 21 cure rates were 91.7% (86.6%–98% at individual sites) with 40 mg/kg and 92.8% (88%–97%) with 60 mg/kg. Secondary parameters were eggs reduction rates (ERR), change in intensity of infection and reinfection rates at 6 and 12 months. On Day 21 the pooled estimate of the ERR was 91% in both arms. The Hazard Ratio for reinfections was only significant in Brazil, and in favour of 60 mg/kg on the pooled estimate (40 mg/kg: 34.3%, 60 mg/kg: 23.9%, HR = 0.78, 95%CI = [0.63;0.96]). Analysis of safety could not distinguish between disease- and drug-related events. 666 patients (78%) reported 1327 adverse events (AE) 4 h post-dosing. The risk of having at least one AE was higher in the 60 than in the 40 mg/kg group (83% vs. 73%, p<0.001). At 24 h post-dosing, 456 patients (54%) had 918 AEs with no difference between arms. The most frequent AE was abdominal pain at both 4 h and 24 h (40% and 24%).

Conclusion

A higher dose of 60 mg/kg of praziquantel offers no significant efficacy advantage over standard 40 mg/kg for treating intestinal schistosomiasis caused by either S. mansoni or S. japonicum. The results of this study support WHO recommendation and should be used to inform policy decisions in the countries.

Trial Registration

Controlled-Trials.com ISRCTN29273316 ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00403611","term_id":"NCT00403611"}}NCT00403611     

Validation of the ALS assay in adult patients with culture confirmed pulmonary tuberculosis

Background

We have earlier shown that Bacille Calmette-Guérin (BCG) vaccine-specific IgG Antibodies in Lymphocyte Supernatant (ALS) can be used for diagnosis of active tuberculosis (TB) in adults and children.

Methodology/Principal Findings

The ALS method was validated in a larger cohort (n = 212) of patients with suspicion of pulmonary TB using multiple antigens (BCG, LAM, TB15.3, TB51A, CFP10-ESAT6-A, CFP, CW) from Mycobacterium tuberculosis. The sensitivity and specificity of the ALS assay was calculated using non-TB patients as controls. The sensitivity and the specificity were highest with BCG vaccine (90% and 88% respectively) followed by LAM (89% and 87% respectively). Simultaneous assessment of multiple antigen-specific antibodies increased sensitivity (91%) and specificity (88%). Using higher lymphocyte count in smaller volume of culture media increased detection and reduced the assay duration to ∼30 hrs. Twenty one patients with clinical findings strongly suggestive of TB finally diagnosed as non-TB patients were positive by the ALS assay, of which 9 (43%) were positive for 7 antigens and 19 (90%) for at least 3 antigens.

Conclusions/Significance

Our findings show that simultaneous detection of antigens improves the diagnostic potential of the ALS assay; the modified method increases sensitivity and can provide results in <48 hours, and enable detection of some cases of pulmonary TB that are not detectable by standard methods.     

The Role of Biological Agents in the Management of Large Vessel Vasculitis (LVV): A Systematic Review and Meta-Analysis

Background

Giant cell arteritis (GCA) and Takayasu''s arteritis (TAA) are large vessel vasculitides (LVV) for which corticosteroids (CS) are the mainstay for treatment. In patients with LVV unable to tolerate CS, biological agents have been used with variable effectiveness.

Objective

To systematically review the effectiveness and safety of biological agents in patients with LVV.

Methods

We searched 5 electronic databases (inception to October 2012) and conference abstracts with no language restrictions. Two reviewers independently selected studies, extracted data and assessed methodological quality. Our protocol was registered in PROSPERO.

Results

We included 25 studies (3 RCTs and 22 case series with ≥2 cases). 95 GCA and 98 TAA patients received biological agents. The RCTs using anti-TNF agents (infliximab, etanercept and adalimumab) did not suggest a benefit in GCA. GCA patients receiving tocilizumab, in case series, achieved remission (19 patients) and reduction of corticosteroid dose (mean difference, –16.55 mg/day (95% CI: –26.24, –6.86)). In case series, 75 patients with refractory TAA treated with infliximab discontinued CS 32% of the time. Remission was variably defined and the studies were clinically heterogeneous which precluded further analysis.

Conclusion

This systematic review demonstrated a weak evidence base on which to assess the effectiveness of biological treatment in LVV. Evidence from RCTs suggests that anti-TNF agents are not effective for remission or reduction of CS use. Tocilizumab and infliximab may be effective in the management of LVV and refractory TAA, respectively, although the evidence comes from case series. Future analytical studies are needed to confirm these findings.     

Germline BAP1 inactivation is preferentially associated with metastatic ocular melanoma and cutaneous-ocular melanoma families

Background

BAP1 has been shown to be a target of both somatic alteration in high-risk ocular melanomas (OM) and germline inactivation in a few individuals from cancer-prone families. These findings suggest that constitutional BAP1 changes may predispose individuals to metastatic OM and that familial permeation of deleterious alleles could delineate a new cancer syndrome.

Design

To characterize BAP1''s contribution to melanoma risk, we sequenced BAP1 in a set of 100 patients with OM, including 50 metastatic OM cases and 50 matched non-metastatic OM controls, and 200 individuals with cutaneous melanoma (CM) including 7 CM patients from CM-OM families and 193 CM patients from CM-non-OM kindreds.

Results

Germline BAP1 mutations were detected in 4/50 patients with metastatic OM and 0/50 cases of non-metastatic OM (8% vs. 0%, p = 0.059). Since 2/4 of the BAP1 carriers reported a family history of CM, we analyzed 200 additional hereditary CM patients and found mutations in 2/7 CM probands from CM-OM families and 1/193 probands from CM-non-OM kindreds (29% vs. 0.52%, p = .003). Germline mutations co-segregated with both CM and OM phenotypes and were associated with the presence of unique nevoid melanomas and highly atypical nevoid melanoma-like melanocytic proliferations (NEMMPs). Interestingly, 7/14 germline variants identified to date reside in C-terminus suggesting that the BRCA1 binding domain is important in cancer predisposition.

Conclusion

Germline BAP1 mutations are associated with a more aggressive OM phenotype and a recurrent phenotypic complex of cutaneous/ocular melanoma, atypical melanocytic proliferations and other internal neoplasms (ie. COMMON syndrome), which could be a useful clinical marker for constitutive BAP1 inactivation.     

Amantadine for dyskinesias in Parkinson's disease: a randomized controlled trial

Background

Dyskinesias are some of the major motor complications that impair quality of life for patients with Parkinson''s disease. The purpose of the present study was to investigate the efficacy of amantadine in Parkinson''s disease patients suffering from dyskinesias.

Methods

In this multi-center, double-blind, randomized, placebo-controlled, cross-over trial, 36 patients with Parkinson''s disease and dyskinesias were randomized, and 62 interventions, which included amantadine (300 mg /day) or placebo treatment for 27 days, were analyzed. At 15 days after washout, the treatments were crossed over. The primary outcome measure was the changes in the Rush Dyskinesia Rating Scale (RDRS) during each treatment period. The secondary outcome measures were changes in the Unified Parkinson''s Disease Rating Scale part IVa (UPDRS-IVa, dyskinesias), part IVb (motor fluctuations), and part III (motor function).

Results

RDRS improved in 64% and 16% of patients treated with amantadine or placebo, respectively, with significant differences between treatments. The adjusted odds-ratio for improvement by amantadine was 6.7 (95% confidence interval, 1.4 to 31.5). UPDRS-IVa was improved to a significantly greater degree in amantadine-treated patients [mean (SD) of 1.83 (1.56)] compared with placebo-treated patients [0.03 (1.51)]. However, there were no significant effects on UPDRS-IVb or III scores.

Conclusions

Results from the present study demonstrated that amantadine exhibited efficacious effects against dyskinesias in 60–70% of patients.

Trial Registration

UMIN Clinical Trial Registry UMIN000000780     

Vaccination with Ad5 vectors expands Ad5-specific CD8 T cells without altering memory phenotype or functionality

Background

Adenoviral (Ad) vaccine vectors represent both a vehicle to present a novel antigen to the immune system as well as restimulation of immune responses against the Ad vector itself. To what degree Ad-specific CD8⁺ T cells are restimulated by Ad vector vaccination is unclear, although such knowledge would be important as vector-specific CD8⁺ T cell expansion could potentially further limit Ad vaccine efficacy beyond Ad-specific neutralizing antibody alone.

Methodology/Principal Findings

Here we addressed this issue by measuring human Adenovirus serotype 5 (Ad5)-specific CD8⁺ T cells in recipients of the Merck Ad5 HIV-1 vaccine vector before, during, and after vaccination by multicolor flow cytometry. Ad5-specific CD8⁺ T-cells were detectable in 95% of subjects prior to vaccination, and displayed primarily an effector-type functional profile and phenotype. Peripheral blood Ad5-specific CD8⁺ T-cell numbers expanded after Ad5-HIV vaccination in all subjects, but differential expansion kinetics were noted in some baseline Ad5-neutralizing antibody (Ad5 nAb) seronegative subjects compared to baseline Ad5 nAb seropositive subjects. However, in neither group did vaccination alter polyfunctionality, mucosal targeting marker expression, or memory phenotype of Ad5-specific CD8⁺ T-cells.

Conclusions

These data indicate that repeat Ad5-vector administration in humans expands Ad5-specific CD8⁺ T-cells without overtly affecting their functional capacity or phenotypic properties. This is a secondary analysis of samples collected during the 016 trial. Results of the Merck 016 trial safety and immunogenicity have been previously published in the journal of clinical infectious diseases [1].

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00849680","term_id":"NCT00849680"}}NCT00849680 [{"type":"clinical-trial","attrs":{"text":"NCT00849680","term_id":"NCT00849680"}}NCT00849680]     

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]     

A head-to-head comparison of four artemisinin-based combinations for treating uncomplicated malaria in African children: a randomized trial

Background

Artemisinin-based combination therapies (ACTs) are the mainstay for the management of uncomplicated malaria cases. However, up-to-date data able to assist sub-Saharan African countries formulating appropriate antimalarial drug policies are scarce.

Methods and Findings

Between 9 July 2007 and 19 June 2009, a randomized, non-inferiority (10% difference threshold in efficacy at day 28) clinical trial was carried out at 12 sites in seven sub-Saharan African countries. Each site compared three of four ACTs, namely amodiaquine-artesunate (ASAQ), dihydroartemisinin-piperaquine (DHAPQ), artemether-lumefantrine (AL), or chlorproguanil-dapsone-artesunate (CD+A). Overall, 4,116 children 6–59 mo old with uncomplicated Plasmodium falciparum malaria were treated (1,226 with AL, 1,002 with ASAQ, 413 with CD+A, and 1,475 with DHAPQ), actively followed up until day 28, and then passively followed up for the next 6 mo. At day 28, for the PCR-adjusted efficacy, non-inferiority was established for three pair-wise comparisons: DHAPQ (97.3%) versus AL (95.5%) (odds ratio [OR]: 0.59, 95% CI: 0.37–0.94); DHAPQ (97.6%) versus ASAQ (96.8%) (OR: 0.74, 95% CI: 0.41–1.34), and ASAQ (97.1%) versus AL (94.4%) (OR: 0.50, 95% CI: 0.28–0.92). For the PCR-unadjusted efficacy, AL was significantly less efficacious than DHAPQ (72.7% versus 89.5%) (OR: 0.27, 95% CI: 0.21–0.34) and ASAQ (66.2% versus 80.4%) (OR: 0.40, 95% CI: 0.30–0.53), while DHAPQ (92.2%) had higher efficacy than ASAQ (80.8%) but non-inferiority could not be excluded (OR: 0.35, 95% CI: 0.26–0.48). CD+A was significantly less efficacious than the other three treatments. Day 63 results were similar to those observed at day 28.

Conclusions

This large head-to-head comparison of most currently available ACTs in sub-Saharan Africa showed that AL, ASAQ, and DHAPQ had excellent efficacy, up to day 63 post-treatment. The risk of recurrent infections was significantly lower for DHAPQ, followed by ASAQ and then AL, supporting the recent recommendation of considering DHAPQ as a valid option for the treatment of uncomplicated P. falciparum malaria.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00393679","term_id":"NCT00393679"}}NCT00393679; Pan African Clinical Trials Registry PACTR2009010000911750 Please see later in the article for the Editors'' Summary     

A randomized open-label trial of artesunate- sulfadoxine-pyrimethamine with or without primaquine for elimination of sub-microscopic P. falciparum parasitaemia and gametocyte carriage in eastern Sudan

Background

In areas of seasonal malaria transmission, treatment of asymptomatic carriers of malaria parasites, whose parasitaemia persists at low densities throughout the dry season, could be a useful strategy for malaria control. We carried out a randomized trial to compare two drug regimens for clearance of parasitaemia in order to identify the optimum regimen for use in mass drug administration in the dry season.

Methodology and Principal Findings

A two-arm open-label randomized controlled trial was conducted during the dry season in an area of distinct seasonal malaria in two villages in Gedarif State in eastern Sudan. Participants were asymptomatic adults and children aged over 6 months, with low-density P. falciparum infection detected by PCR. Participants were randomized to receive artesunate/sulfadoxine-pyrimethamine (AS+SP) combination for three days with or without a dose of primaquine (PQ) on the fourth day. Parasitaemia detected by PCR on days 3, 7 and 14 after the start of treatment and gametocytes detected by RT-PCR on days 7 and 14 were then recorded. 104 individuals who had low density parasitaemia at screening were randomized and treated during the dry season. On day 7, 8.3% were positive by PCR in the AS+SP+PQ group and 6.5% in the AS+SP group (risk difference 1.8%, 95%CI −10.3% to +13.8%). At enrolment, 12% (12/100) were carrying gametocytes. This was reduced to 6.4% and 4.4% by day 14 (Risk difference 1.9% (95%CI −9.3% to +13.2%) in AS+SP+PQ and AS+SP groups, respectively.

Conclusion

Addition of primaquine to artemisinin combination treatment did not improve elimination of parasitaemia and prevention of gametocyte carriage in carriers with low-density parasitaemia in the dry season.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00330902","term_id":"NCT00330902"}}NCT00330902     

Low-dose adrenaline, promethazine, and hydrocortisone in the prevention of acute adverse reactions to antivenom following snakebite: a randomised, double-blind, placebo-controlled trial

Background

Envenoming from snakebites is most effectively treated by antivenom. However, the antivenom available in South Asian countries commonly causes acute allergic reactions, anaphylactic reactions being particularly serious. We investigated whether adrenaline, promethazine, and hydrocortisone prevent such reactions in secondary referral hospitals in Sri Lanka by conducting a randomised, double-blind placebo-controlled trial.

Methods and Findings

In total, 1,007 patients were randomized, using a 2×2×2 factorial design, in a double-blind, placebo-controlled trial of adrenaline (0.25 ml of a 1∶1,000 solution subcutaneously), promethazine (25 mg intravenously), and hydrocortisone (200 mg intravenously), each alone and in all possible combinations. The interventions, or matching placebo, were given immediately before infusion of antivenom. Patients were monitored for mild, moderate, or severe adverse reactions for at least 96 h. The prespecified primary end point was the effect of the interventions on the incidence of severe reactions up to and including 48 h after antivenom administration. In total, 752 (75%) patients had acute reactions to antivenom: 9% mild, 48% moderate, and 43% severe; 89% of the reactions occurred within 1 h; and 40% of all patients were given rescue medication (adrenaline, promethazine, and hydrocortisone) during the first hour. Compared with placebo, adrenaline significantly reduced severe reactions to antivenom by 43% (95% CI 25–67) at 1 h and by 38% (95% CI 26–49) up to and including 48 h after antivenom administration; hydrocortisone and promethazine did not. Adding hydrocortisone negated the benefit of adrenaline.

Conclusions

Pretreatment with low-dose adrenaline was safe and reduced the risk of acute severe reactions to snake antivenom. This may be of particular importance in countries where adverse reactions to antivenom are common, although the need to improve the quality of available antivenom cannot be overemphasized.

Trial registration

www.ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00270777","term_id":"NCT00270777"}}NCT00270777 Please see later in the article for the Editors'' Summary     

In a subgroup of high-risk Asians, telmisartan was non-inferior to ramipril and better tolerated in the prevention of cardiovascular events

Background and Objectives

Results of the recently published ONTARGET study (The Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial) showed that telmisartan (80 mg/day) was non-inferior to ramipril (10 mg/day) in reducing cardiovascular events. Clinicians in Asia doubt tolerability of these doses for their patients. We therefore analyzed data from this study and a parallel study TRANSCEND (Telmisartan Randomized Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease). Our objectives were to compare Asians and non-Asians with respect to the following:

1. 1) Effectiveness of telmisartan vs. ramipril in reducing cardiovascular events;
2. 2) Proportions who reached the full dose of telmisartan, ramipril or placebo; and
3. 3) Proportions of overall discontinuations, and discontinuations due to adverse effects.

Method

The ONTARGET study randomized 25,620 patients at risk of cardiovascular events to ramipril, telmisartan, or their combination. The primary composite endpoint was death caused by cardiovascular disease, acute MI, stroke, and hospitalization because of congestive heart failure. TRANSCEND randomized 5926 high-risk patients with a history of intolerance to ACE-inhibitors to telmisartan or placebo. The primary outcome was the same. In this substudy, we compared Asians and non-Asians as to how well they tolerated telmisartan (given in both studies) and ramipril (given in ONTARGET).

Results

1) Telmisartan was non-inferior to ramipril in lowering the primary endpoint among Asians (RR = 0.92; 95% CI: 0.74, 1.13); 2) more Asians achieved the full dose of either drug; 3) less withdrew (overall); and 4) less withdrew for adverse effects. Furthermore, telmisartan was better tolerated than ramipril. This advantage was greater among Asians.

Conclusion and Significance

Although Asians had lower BMI than non-Asians, Asians tolerated both drugs better. Regulatory agencies require reporting of safety and effectiveness data by ethnicity, but few comply with this requirement. This study shows that safety data in ethnic subgroups can help assess applicability of results to specific populations.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00153101","term_id":"NCT00153101"}}NCT00153101     

Human Papillomavirus Genotype Distribution in Czech Women and Men with Diseases Etiologically Linked to HPV

Background

The HPV prevalence and genotype distribution are important for the estimation of the impact of HPV-based cervical cancer screening and HPV vaccination on the incidence of diseases etiologically linked to HPVs. The HPV genotype distribution varies across different geographical regions. Therefore, we investigated the type-specific HPV prevalence in Czech women and men with anogenital diseases.

Methods

We analyzed 157 squamous cell carcinoma samples, 695 precancerous lesion samples and 64 cervical, vulvar and anal condylomata acuminate samples. HPV detection and typing were performed by PCR with GP5+/6+ primers, reverse line blot assay and sequencing.

Results

Thirty different HPV genotypes were detected in our study, HPV 16 being the most prevalent type both in precancerous lesions (45%) and squamous cell carcinomas (59%). In benign lesions, HPV 6 (72%) was the most common type. Altogether, 61% of carcinoma samples and 43% of precancerous lesion samples contained HPV 16 and/or 18. The presence of HPV types related to the vaccinal ones (HPV 31, 45, 33, 52, 58) were detected in 16% of carcinoma samples and 18% of precancerous lesion samples. HPV 16 and/or 18 were present in 76% of cervical cancer samples, 33% of CIN1, 43% CIN2 and 71% of CIN3 samples. HPV types 6 and/or 11 were detected in 84% samples of condylomata acuminate samples.

Conclusions

The prevalence of vaccinal and related HPV types in patients with HPV-associated diseases in the Czech Republic is very high. We may assume that the implementation of routine vaccination against HPV would greatly reduce the burden of HPV-associated diseases in the Czech Republic.     

A randomized, placebo controlled, double masked phase IB study evaluating the safety and antiviral activity of aprepitant, a neurokinin-1 receptor antagonist in HIV-1 infected adults

Background

Neurokinin-1 receptor (NK1R) antagonists have anti-HIV activity in monocyte-derived macrophages, decrease CCR5 expression and improve natural killer cell function ex vivo. Aprepitant is a NK1R antagonist approved by FDA as an antiemetic.

Methods

We conducted a phase IB randomized, placebo controlled, double masked study to evaluate the safety, antiviral activity, pharmacokinetics and immune-modulatory effects of aprepitant in HIV-infected adults not receiving antiretroviral therapy, with CD4+ cell count ≥350 cells/mm³ and plasma viral load ≥2,000 copies/ml. Subjects were stratified by viral load (< vs. ≥20,000 copies/ml) and randomized within each stratum to receive aprepitant at 125 mg QD(Low), or 250 mg QD(High), or placebo(PL) for 14 days, and followed for 42 days.

Results

Thirty subjects were randomized and 27 completed treatment (9, 8, 10 subjects in 125 (Low), 250 (High), and PL groups). 63% were male; 37% white; mean (SD) age 43 (9.3) years. Geometric mean baseline viral load (copies/ml) for Low, High, and PL was 15,709, 33,013, and 19,450, respectively. Mean (95%CI) change in log10 viral load at day 14 for Low, High, and PL was −0.02(−0.24,+0.20), −0.05(−0.21,+0.10), and +0.04(−0.08,+0.16), respectively. The number of subjects with AEs was 4(44.4%), 5(62.5%), and 1(10%) for Low, High, and PL. No Grade 4 AEs occurred.

Conclusions

Adverse events of aprepitant were more common in the treated groups. At the dose used in this two-week phase IB study, aprepitant showed biological activity, but no significant antiviral activity.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00428519","term_id":"NCT00428519"}}NCT00428519     

Safety and immunogenicity following administration of a live, attenuated monovalent 2009 H1N1 influenza vaccine to children and adults in two randomized controlled trials

Background

The safety, tolerability, and immunogenicity of a monovalent intranasal 2009 A/H1N1 live attenuated influenza vaccine (LAIV) were evaluated in children and adults.

Methods/Principal Findings

Two randomized, double-blind, placebo-controlled studies were completed in children (2–17 y) and adults (18–49 y). Subjects were assigned 4∶1 to receive 2 doses of H1N1 LAIV or placebo 28 days apart. The primary safety endpoint was fever ≥38.3°C during days 1–8 after the first dose; the primary immunogenicity endpoint was the proportion of subjects experiencing a postdose seroresponse. Solicited symptoms and adverse events were recorded for 14 days after each dose and safety data were collected for 180 days post-final dose. In total, 326 children (H1N1 LAIV, n = 261; placebo, n = 65) and 300 adults (H1N1 LAIV, n = 240; placebo, n = 60) were enrolled. After dose 1, fever ≥38.3°C occurred in 4 (1.5%) pediatric vaccine recipients and 1 (1.5%) placebo recipient (rate difference, 0%; 95% CI: –6.4%, 3.1%). No adults experienced fever following dose 1. Seroresponse rates in children (H1N1 LAIV vs. placebo) were 11.1% vs. 6.3% after dose 1 (rate difference, 4.8%; 95% CI: –9.6%, 13.8%) and 32.0% vs. 14.5% after dose 2 (rate difference, 17.5%; 95% CI: 5.5%, 27.1%). Seroresponse rates in adults were 6.1% vs. 0% (rate difference, 6.1%; 95% CI: –5.6%, 12.6%) and 14.9% vs. 5.6% (rate difference, 9.3%; 95% CI: –0.8%, 16.3%) after dose 1 and dose 2, respectively. Solicited symptoms after dose 1 (H1N1 LAIV vs. placebo) occurred in 37.5% vs. 32.3% of children and 41.7% vs. 31.7% of adults. Solicited symptoms occurred less frequently after dose 2 in adults and children. No vaccine-related serious adverse events occurred.

Conclusions/Significance

In subjects aged 2 to 49 years, two doses of H1N1 LAIV have a safety and immunogenicity profile similar to other previously studied and efficacious formulations of seasonal trivalent LAIV.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00946101","term_id":"NCT00946101"}}NCT00946101, {"type":"clinical-trial","attrs":{"text":"NCT00945893","term_id":"NCT00945893"}}NCT00945893