Effects of sorafenib on intra-tumoral interstitial fluid pressure and circulating biomarkers in patients with refractory sarcomas (NCI protocol 6948)

Purpose

Sorafenib is a multi-targeted tyrosine kinase inhibitor with therapeutic efficacy in several malignancies. Sorafenib may exert its anti-neoplastic effect in part by altering vascular permeability and reducing intra-tumoral interstitial hypertension. As correlative science with a phase II study in patients with advanced soft-tissue sarcomas (STS), we evaluated the impact of this agent on intra-tumor interstitial fluid pressure (IFP), serum circulating biomarkers, and vascular density.

Patients and Methods

Patients with advanced STS with measurable disease and at least one superficial lesion amenable to biopsy received sorafenib 400 mg twice daily. Intratumoral IFP and plasma and circulating cell biomarkers were measured before and after 1–2 months of sorafenib administration. Results were analyzed in the context of the primary clinical endpoint of time-to-progression (TTP).

Results

In 15 patients accrued, the median TTP was 45 days (range 14–228). Intra-tumoral IFP measurements obtained in 6 patients at baseline showed a direct correlation with tumor size. Two patients with stable disease at two months had post-sorafenib IFP evaluations and demonstrated a decline in IFP and vascular density. Sorafenib significantly increased plasma VEGF, PlGF, and SDF1α and decreased sVEGFR-2 levels. Increased plasma SDF1α and decreased sVEGFR-2 levels on day 28 correlated with disease progression.

Conclusions

Pretreatment intra-tumoral IFP correlated with tumor size and decreased in two evaluable patients with SD on sorafenib. Sorafenib also induced changes in circulating biomarkers consistent with expected VEGF pathway blockade, despite the lack of more striking clinical activity in this small series.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00330421","term_id":"NCT00330421"}}NCT00330421     

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     

A pilot study of IL-2Rα blockade during lymphopenia depletes regulatory T-cells and correlates with enhanced immunity in patients with glioblastoma

Background

Preclinical studies in mice have demonstrated that the prophylactic depletion of immunosuppressive regulatory T-cells (T_Regs) through targeting the high affinity interleukin-2 (IL-2) receptor (IL-2Rα/CD25) can enhance anti-tumor immunotherapy. However, therapeutic approaches are complicated by the inadvertent inhibition of IL-2Rα expressing anti-tumor effector T-cells.

Objective

To determine if changes in the cytokine milieu during lymphopenia may engender differential signaling requirements that would enable unarmed anti-IL-2Rα monoclonal antibody (MAbs) to selectively deplete T_Regs while permitting vaccine-stimulated immune responses.

Methodology

A randomized placebo-controlled pilot study was undertaken to examine the ability of the anti-IL-2Rα MAb daclizumab, given at the time of epidermal growth factor receptor variant III (EGFRvIII) targeted peptide vaccination, to safely and selectively deplete T_Regs in patients with glioblastoma (GBM) treated with lymphodepleting temozolomide (TMZ).

Results and Conclusions

Daclizumab treatment (n = 3) was well-tolerated with no symptoms of autoimmune toxicity and resulted in a significant reduction in the frequency of circulating CD4+Foxp3+ TRegs in comparison to saline controls (n = 3)( p = 0.0464). A significant (p<0.0001) inverse correlation between the frequency of TRegs and the level of EGFRvIII specific humoral responses suggests the depletion of TRegs may be linked to increased vaccine-stimulated humoral immunity. These data suggest this approach deserves further study.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00626015","term_id":"NCT00626015"}}NCT00626015     

Promoting physical activity in patients with colon adenomas: a randomized pilot intervention trial

Background

Physical activity decreases risk of colon polyps and colon cancer and might reduce risk of colon cancer recurrence. Focusing on recent calls for translation of epidemiologic evidence into clinical care, our pilot study delivered an evidence-based physical activity intervention in adults with polyps, who are thus at elevated risk of developing colon cancer. The objective was to evaluate change in physical activity, measured by steps per day and minutes of moderate/vigorous physical activity.

Methods

Sixteen adults with adenomas detected and removed at screening colonoscopy were recruited to a 12-week physical activity intervention. Participants were randomized to receive a standard (30 minutes/day) or high (60 minutes/day) walking program. Physical activity was measured via blinded pedometer and accelerometer at baseline and follow-up. Intervention messages focused on self-monitoring using pedometers and overcoming barriers to engaging in physical activity.

Results

Participants in both arms significantly increased objectively measured minutes of moderate/vigorous physical activity over the course of the intervention. Both arms exceeded the intervention goal, but there was not a significant difference between arms at follow-up. Results were similar for pedometer measured physical activity, with a significant overall increase in steps/day from baseline to follow-up, but no between arm difference in change.

Conclusion

Simple interventions of minimal contact time focusing on walking can significantly increase physical activity in individuals at increased risk of developing colon cancer.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01476631","term_id":"NCT01476631"}}NCT01476631     

Effect of chronic escitalopram versus placebo on personality traits in healthy first-degree relatives of patients with depression: a randomized trial

Introduction

The serotonergic neurotransmitter system is closely linked to depression and personality traits. It is not known if selective serotonin reuptake inhibitors (SSRI) have an effect on neuroticism that is independent of their effect on depression. Healthy individuals with a genetic liability for depression represent a group of particular interest when investigating if intervention with SSRIs affects personality. The present trial is the first to test the hypothesis that escitalopram may reduce neuroticism in healthy first-degree relatives of patients with major depressive disorder (MD).

Methods

The trial used a randomized, blinded, placebo-controlled parallel-group design. We examined the effect of four weeks escitalopram 10 mg daily versus matching placebo on personality in 80 people who had a biological parent or sibling with a history of MD. The outcome measure on personality traits was change in self-reported neuroticism scores on the Revised Neuroticism-Extroversion-Openness-Personality Inventory (NEO-PI-R) and the Eysenck Personality Inventory (EPQ) from entry until end of four weeks of intervention.

Results

When compared with placebo, escitalopram did not significantly affect self-reported NEO-PI-R and EPQ neuroticism and extroversion, EPQ psychoticism, NEO-PI-R openness, or NEO-PI-R conscientiousness (p all above 0.05). However, escitalopram increased NEO-PI-R agreeableness scores significantly compared with placebo (mean; SD) (2.38; 8.09) versus (−1.32; 7.94), p = 0.046), but not following correction for multiplicity. A trend was shown for increased conscientiousness (p = 0.07). There was no significant effect on subclinical depressive symptoms (p = 0.6).

Conclusion

In healthy first-degree relatives of patients with MD, there is no effect of escitalopram on neuroticism, but it is possible that escitalopram may increase the personality traits of agreeableness and conscientiousness.

Trial Registration

Clinicaltrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00386841","term_id":"NCT00386841"}}NCT00386841     

Ultra-Brief Intervention for Problem Drinkers: Results from a Randomized Controlled Trial

Background

There are a number of evidence-based, in-person clinical inteventions for problem drinkers, but most problem drinkers will never seek such treatments. Reaching the population of non-treatment seeking problem drinkers will require a different approach. Accordingly, this randomized clinical trial evaluated an intervention that has been validated in clinical settings and then modified into an ultra-brief format suitable for use as an indicated public health intervention (i.e., targeting the population of non-treatment seeking problem drinkers).

Methodology/Principal Findings

Problem drinkers (N = 1767) completed a baseline population telephone survey and then were randomized to one of three conditions – a personalized feedback pamphlet condition, a control pamphlet condition, or a no intervention control condition. In the week after the baseline survey, households in the two pamphlet conditions were sent their respective interventions by postal mail addressed to ‘Check Your Drinking.’ Changes in drinking were assessed post intervention at three-month and six-month follow-ups. The follow-up rate was 86% at three-months and 76% at six-months. There was a small effect (p = .04) in one of three outcome variables (reduction in AUDIT-C, a composite measure of quantity and frequency of drinking) observed for the personalized feedback pamphlet compared to the no intervention control. No significant differences (p>.05) between groups were observed for the other two outcome variables – number of drinks consumed in the past seven days and highest number of drinks on one occasion.

Conclusions/Significance

Based on the results of this study, we tentatively conclude that a brief intervention, modified to an ultra-brief, public health format can have a meaningful impact.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00688584","term_id":"NCT00688584"}}NCT00688584.     

Cost-effectiveness of peer-delivered interventions for cocaine and alcohol abuse among women: a randomized controlled trial

Aims

To determine whether the additional interventions to standard care are cost-effective in addressing cocaine and alcohol abuse at 4 months (4 M) and 12 months (12 M) from baseline.

Method

We conducted a cost-effectiveness analysis of a randomized controlled trial with three arms: (1) NIDA''s Standard intervention (SI); (2) SI plus a Well Woman Exam (WWE); and, (3) SI, WWE, plus four Educational Sessions (4ES).

Results

To obtain an additional cocaine abstainer, WWE compared to SI cost $7,223 at 4 M and $3,611 at 12 M. Per additional alcohol abstainer, WWE compared to SI cost $3,611 and $7,223 at 4 M and 12 M, respectively. At 12 M, 4ES was dominated (more costly and less effective) by WWE for abstinence outcomes.

Conclusions

To our knowledge, this is the first cost-effectiveness analysis simultaneously examining cocaine and alcohol abuse in women. Depending on primary outcomes sought and priorities of policy makers, peer-delivered interventions can be a cost-effective way to address the needs of this growing, underserved population.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01235091","term_id":"NCT01235091"}}NCT01235091     

HIV-1 infection and first line ART induced differential responses in mitochondria from blood lymphocytes and monocytes: the ANRS EP45 "Aging" study

Background

The ANRS EP45 “Aging” study investigates the cellular mechanisms involved in the accelerated aging of HIV-1 infected and treated patients. The data reported focus on mitochondria, organelles known to be involved in cell senescence.

Methods

49 HIV-1 infected patients untreated with antiretroviral therapy, together with 49 seronegative age- and sex-matched control subjects and 81 HIV-1 infected and treated patients, were recruited by 3 AIDS centres (Marseille, Montpellier, Nice; France; http://clinicaltrials.gov/, {"type":"clinical-trial","attrs":{"text":"NCT01038999","term_id":"NCT01038999"}}NCT01038999). In more than 88% of treated patients, the viral load was <40 copies/ml and the CD4+ cell count was >500/mm³. ROS (reactive oxygen species) production and ΔΨm (inner membrane potential) were measured by flow cytometry in blood lymphocytes and monocytes (functional parameters). Three mitochondrial network quantitative morphological parameters were computed using confocal microscopy and image analysis. Three PBMC mitochondrial proteins (porin and subunits 2 and 4 of cytochrome C oxidase encoded by mtDNA or nuclear DNA, respectively) were analysed by western blotting.

Results

Quantitative changes in PBMC mitochondrial proteins were not induced by either HIV-1 infection or ART. Discriminant analysis integrating functional (ROS production and ΔΨm) or morphological (network volume density, fragmentation and branching) parameters revealed HIV-1 infection and ART differential effects according to cell type. First line ART tended to rescue lymphocyte mitochondrial parameters altered by viral infection, but induced slight changes in monocytes. No statistical difference was found between the effects of three ART regimens on mitochondrial parameters. Correlations between functional parameters and viral load confirmed the damaging effects of HIV-1 in lymphocyte mitochondria.

Conclusions

In patients considered to be clinically stable, mitochondria exhibited functional and morphological modifications in PBMCs resulting from either direct or indirect effects of HIV-1 infection (lymphocytes), or from first line ART (monocytes). Together with other tissue impairments, these changes may contribute to global aging.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01038999","term_id":"NCT01038999"}}NCT01038999 {"type":"clinical-trial","attrs":{"text":"NCT01038999","term_id":"NCT01038999"}}NCT01038999     

The long-term impact of the MEMA kwa Vijana adolescent sexual and reproductive health intervention: effect of dose and time since intervention exposure

Background

Despite recent decreases in HIV incidence in many sub-Saharan African countries, there is little evidence that specific behavioural interventions have led to a reduction in HIV among young people. Further and wider-scale decreases in HIV require better understanding of when behaviour change occurs and why. The MEMA kwa Vijana adolescent sexual and reproductive health intervention has been implemented in rural Mwanza, Tanzania since 1999. A long-term evaluation in 2007/8 found that the intervention improved knowledge, attitudes to sex and some reported risk behaviours, but not HIV or HSV2 prevalence. The aim of this paper was to assess the differential impact of the intervention according to gender, age, marital status, number of years of exposure and time since last exposure to the intervention.

Methods

In 2007, a cross-sectional survey was conducted in the 20 trial communities among 13,814 young people (15–30 yrs) who had attended intervention or comparison schools between 1999 and 2002. Outcomes for which the intervention had an impact in 2001 or 2007 were included in this subgroup analysis. Data were analysed using cluster-level methods for stratified cluster-randomised trials, using interaction tests to determine if intervention impact differed by subgroup.

Results

Taking into account multiplicity of testing, concurrence with a priori hypotheses and consistency within the results no strong effect-modifiers emerged. Impact on pregnancy knowledge and reported attitudes to sex increased with years of exposure to high-quality intervention.

Conclusions

The desirable long-term impact of the MEMA kwa Vijana intervention did not vary greatly according to the subgroups examined. This suggests that the intervention can have an impact on a broad cross-section of young people in rural Mwanza.

Trial registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00248469","term_id":"NCT00248469"}}NCT00248469     

Similar Evolution of Cellular HIV-1 DNA Level in Darunavir/Ritonavir Monotherapy versus Triple Therapy in MONOI -ANRS136 Trial over 96 Weeks

Background

A higher proportion of intermittent viremia (to have a HIV-1 RNA viral load>50 copies/mL not confirmed) was reported in the boosted protease inhibitor monotherapy arm in some studies including MONOI trial, and that could have an impact on the replenishment of the HIV-1 DNA reservoirs. The HIV-1 DNA level is an interesting marker which reflects the size of cellular HIV reservoir. Our objectives were to study the impact of 96 weeks of Darunavir/ritonavir monotherapy versus a triple standard combination on the HIV-1 blood reservoir and factors associated with HIV-1 plasma DNA at baseline in MONOI trial sub-study.

Methodology/Principal Findings

This sub-study is focused on 160 patients (79 patients in monotherapy arm and 81 in tritherapy arm) for whom blood cells were available both at baseline and at week 96 (W96). Baseline HIV-1 plasma DNA was associated with CD4 nadir, pre therapeutic HIV-1 RNA viral load and baseline HIV-1 RNA measured by ultrasensitive assay. A similar median delta HIV-DNA was observed between D0 and W96 in both arms; 0.35 log copies/10⁶ leucocytes in monotherapy arm versus 0.51 log copies/10⁶ leucocytes in tritherapy arm.

Conclusion/Significance

Despite a higher proportion of intermittent viremia in monotherapy arm, a similar evolution of cellular HIV-1 DNA level was observed between mono and triple therapy arm.

Trial Registration

ClinicalTrials. gov {"type":"clinical-trial","attrs":{"text":"NCT00421551","term_id":"NCT00421551"}}NCT00421551 <{"type":"clinical-trial","attrs":{"text":"NCT00421551","term_id":"NCT00421551"}}NCT00421551>     

Cost-Effectiveness of a Community Pharmacist Intervention in Patients with Depression: A Randomized Controlled Trial (PRODEFAR Study)

Background

Non-adherence to antidepressants generates higher costs for the treatment of depression. Little is known about the cost-effectiveness of pharmacist''s interventions aimed at improving adherence to antidepressants. The study aimed to evaluate the cost-effectiveness of a community pharmacist intervention in comparison with usual care in depressed patients initiating treatment with antidepressants in primary care.

Methods

Patients were recruited by general practitioners and randomized to community pharmacist intervention (87) that received an educational intervention and usual care (92). Adherence to antidepressants, clinical symptoms, Quality-Adjusted Life-Years (QALYs), use of healthcare services and productivity losses were measured at baseline, 3 and 6 months.

Results

There were no significant differences between groups in costs or effects. From a societal perspective, the incremental cost-effectiveness ratio (ICER) for the community pharmacist intervention compared with usual care was €1,866 for extra adherent patient and €9,872 per extra QALY. In terms of remission of depressive symptoms, the usual care dominated the community pharmacist intervention. If willingness to pay (WTP) is €30,000 per extra adherent patient, remission of symptoms or QALYs, the probability of the community pharmacist intervention being cost-effective was 0.71, 0.46 and 0.75, respectively (societal perspective). From a healthcare perspective, the probability of the community pharmacist intervention being cost-effective in terms of adherence, QALYs and remission was of 0.71, 0.76 and 0.46, respectively, if WTP is €30,000.

Conclusion

A brief community pharmacist intervention addressed to depressed patients initiating antidepressant treatment showed a probability of being cost-effective of 0.71 and 0.75 in terms of improvement of adherence and QALYs, respectively, when compared to usual care. Regular implementation of the community pharmacist intervention is not recommended.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00794196","term_id":"NCT00794196"}}NCT00794196     

The diaphragm and lubricant gel for prevention of cervical sexually transmitted infections: results of a randomized controlled trial

Background

We evaluated the effectiveness of the Ortho All-Flex Diaphragm, lubricant gel (Replens®) and condoms compared to condoms alone on the incidence of chlamydial and gonococcal infections in an open-label randomized controlled trial among women at risk of HIV/STI infections.

Methods

We randomized 5045 sexually-active women at three sites in Southern Africa. Participants who tested positive for curable STIs were treated prior to enrollment as per local guidelines. Women were followed quarterly and tested for Chlamydia trachomatis (CT) or Neisseria gonorrhoeae (GC) infection by nucleic-acid amplification testing (Roche Amplicor®) using first-catch urine specimens. STIs detected at follow-up visits were treated. We compared the incidence of first infection after randomization between study arms in both intent-to-treat (ITT) and per-protocol populations.

Findings

Baseline demographic, behavioral and clinical characteristics were balanced across study arms. Nearly 80% of participants were under 35 years of age. Median follow-up time was 21 months and the retention rate was over 93%. There were 471 first chlamydia infections, 247 in the intervention arm and 224 in the control arm with an overall incidence of 6.2/100 woman-years (wy) (relative hazard (RH) 1.11, 95% Confidence Interval (CI): 0.93–1.33; p = 0.25) and 192 first gonococcal infections, 95 in the intervention arm and 97 in the control arm with an overall incidence of 2.4/100wy (RH 0.98, 95%CI: 0.74–1.30; p = 0.90). Per protocol results indicated that when diaphragm adherence was defined as “always use” since the last visit, there was a significant reduction in the incidence of GC infection among women randomized to the intervention arm (RH 0.61, 95%CI: 0.41–0.91, P = 0.02).

Interpretation

There was no difference by study arm in the rate of acquisition of CT or GC. However, our per-protocol results suggest that consistent use of the diaphragm may reduce acquisition of GC.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00121459","term_id":"NCT00121459"}}NCT00121459 [{"type":"clinical-trial","attrs":{"text":"NCT00121459","term_id":"NCT00121459"}}NCT00121459]     

Massage therapy for osteoarthritis of the knee: a randomized dose-finding trial

Background

In a previous trial of massage for osteoarthritis (OA) of the knee, we demonstrated feasibility, safety and possible efficacy, with benefits that persisted at least 8 weeks beyond treatment termination.

Methods

We performed a RCT to identify the optimal dose of massage within an 8-week treatment regimen and to further examine durability of response. Participants were 125 adults with OA of the knee, randomized to one of four 8-week regimens of a standardized Swedish massage regimen (30 or 60 min weekly or biweekly) or to a Usual Care control. Outcomes included the Western Ontario and McMaster Universities Arthritis Index (WOMAC), visual analog pain scale, range of motion, and time to walk 50 feet, assessed at baseline, 8-, 16-, and 24-weeks.

Results

WOMAC Global scores improved significantly (24.0 points, 95% CI ranged from 15.3–32.7) in the 60-minute massage groups compared to Usual Care (6.3 points, 95% CI 0.1–12.8) at the primary endpoint of 8-weeks. WOMAC subscales of pain and functionality, as well as the visual analog pain scale also demonstrated significant improvements in the 60-minute doses compared to usual care. No significant differences were seen in range of motion at 8-weeks, and no significant effects were seen in any outcome measure at 24-weeks compared to usual care. A dose-response curve based on WOMAC Global scores shows increasing effect with greater total time of massage, but with a plateau at the 60-minute/week dose.

Conclusion

Given the superior convenience of a once-weekly protocol, cost savings, and consistency with a typical real-world massage protocol, the 60-minute once weekly dose was determined to be optimal, establishing a standard for future trials.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00970008","term_id":"NCT00970008"}}NCT00970008     

Investigating the mechanisms of hallucinogen-induced visions using 3,4-methylenedioxyamphetamine (MDA): a randomized controlled trial in humans

Background

The mechanisms of drug-induced visions are poorly understood. Very few serotonergic hallucinogens have been studied in humans in decades, despite widespread use of these drugs and potential relevance of their mechanisms to hallucinations occurring in psychiatric and neurological disorders.

Methodology/Principal Findings

We investigated the mechanisms of hallucinogen-induced visions by measuring the visual and perceptual effects of the hallucinogenic serotonin 5-HT2AR receptor agonist and monoamine releaser, 3,4-methylenedioxyamphetamine (MDA), in a double-blind placebo-controlled study. We found that MDA increased self-report measures of mystical-type experience and other hallucinogen-like effects, including reported visual alterations. MDA produced a significant increase in closed-eye visions (CEVs), with considerable individual variation. Magnitude of CEVs after MDA was associated with lower performance on measures of contour integration and object recognition.

Conclusions/Significance

Drug-induced visions may have greater intensity in people with poor sensory or perceptual processing, suggesting common mechanisms with other hallucinatory syndromes. MDA is a potential tool to investigate mystical experiences and visual perception.

Trial Registration

Clinicaltrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00823407","term_id":"NCT00823407"}}NCT00823407     

Benefit from B-lymphocyte depletion using the anti-CD20 antibody rituximab in chronic fatigue syndrome. A double-blind and placebo-controlled study

Background

Chronic fatigue syndrome (CFS) is a disease of unknown aetiology. Major CFS symptom relief during cancer chemotherapy in a patient with synchronous CFS and lymphoma spurred a pilot study of B-lymphocyte depletion using the anti-CD20 antibody Rituximab, which demonstrated significant clinical response in three CFS patients.

Methods and Findings

In this double-blind, placebo-controlled phase II study ({"type":"clinical-trial","attrs":{"text":"NCT00848692","term_id":"NCT00848692"}}NCT00848692), 30 CFS patients were randomised to either Rituximab 500 mg/m² or saline, given twice two weeks apart, with follow-up for 12 months. Xenotropic murine leukemia virus-related virus (XMRV) was not detected in any of the patients.The responses generally affected all CFS symptoms. Major or moderate overall response, defined as lasting improvements in self-reported Fatigue score during follow-up, was seen in 10 out of 15 patients (67%) in the Rituximab group and in two out of 15 patients (13%) in the Placebo group (p = 0.003). Mean response duration within the follow-up period for the 10 responders to Rituximab was 25 weeks (range 8–44). Four Rituximab patients had clinical response durations past the study period. General linear models for repeated measures of Fatigue scores during follow-up showed a significant interaction between time and intervention group (p = 0.018 for self-reported, and p = 0.024 for physician-assessed), with differences between the Rituximab and Placebo groups between 6–10 months after intervention. The primary end-point, defined as effect on self-reported Fatigue score 3 months after intervention, was negative. There were no serious adverse events. Two patients in the Rituximab group with pre-existing psoriasis experienced moderate psoriasis worsening.

Conclusion

The delayed responses starting from 2–7 months after Rituximab treatment, in spite of rapid B-cell depletion, suggests that CFS is an autoimmune disease and may be consistent with the gradual elimination of autoantibodies preceding clinical responses. The present findings will impact future research efforts in CFS.

Trial registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00848692","term_id":"NCT00848692"}}NCT00848692     

The Study of HIV and Antenatal Care Integration in Pregnancy in Kenya: Design, Methods, and Baseline Results of a Cluster-Randomized Controlled Trial

Background

Despite strong evidence for the effectiveness of anti-retroviral therapy for improving the health of women living with HIV and for the prevention of mother-to-child transmission (PMTCT), HIV persists as a major maternal and child health problem in sub-Saharan Africa. In most settings antenatal care (ANC) services and HIV treatment services are offered in separate clinics. Integrating these services may result in better uptake of services, reduction of the time to treatment initiation, better adherence, and reduction of stigma.

Methodology/Principal Findings

A prospective cluster randomized controlled trial design was used to evaluate the effects of integrating HIV treatment into ANC clinics at government health facilities in rural Kenya. Twelve facilities were randomized to provide either fully integrated services (ANC, PMTCT, and HIV treatment services all delivered in the ANC clinic) or non-integrated services (ANC clinics provided ANC and basic PMTCT services and referred clients to a separate HIV clinic for HIV treatment). During June 2009– March 2011, 1,172 HIV-positive pregnant women were enrolled in the study. The main study outcomes are rates of maternal enrollment in HIV care and treatment, infant HIV testing uptake, and HIV-free infant survival. Baseline results revealed that the intervention and control cohorts were similar with respect to socio-demographics, male partner HIV testing, sero-discordance of the couple, obstetric history, baseline CD4 count, and WHO Stage. Challenges faced while conducting this trial at low-resource rural health facilities included frequent staff turnover, stock-outs of essential supplies, transportation challenges, and changes in national guidelines.

Conclusions/Significance

This is the first randomized trial of ANC and HIV service integration to be conducted in rural Africa. It is expected that the study will provide critical evidence regarding the implementation and effectiveness of this service delivery strategy, with important implications for programs striving to eliminate vertical transmission of HIV and improve maternal health.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00931216","term_id":"NCT00931216"}}NCT00931216 {"type":"clinical-trial","attrs":{"text":"NCT00931216","term_id":"NCT00931216"}}NCT00931216.     

Iodine deficiency in northern Paris area: impact on fetal thyroid mensuration

Introduction

Iodine is essential for normal fetal and neonatal development. We studied the prevalence and impact on fetal thyroid development of iodine deficiency in pregnant women in the northern part of the Paris conurbation.

Materials and Methods

110 patients underwent several determinations of urinary iodine excretion (UIE) and of serum FT4, FT3, and TSH. Fetal thyroid gland size was assessed using ultrasonography.

Results

We found evidence of widespread iodine deficiency (mean UIE, 49.8 µg/L [standard deviation, 2.11]). Iodine deficiency did not correlate significantly with maternal thyroid parameters but showed a significant negative correlation with fetal thyroid gland size (rho = 0.25, P = 0.02).

Conclusion

Iodine deficiency during pregnancy is still a problem in our geographical area and affects the fetal thyroid gland.Clinical Trials.gov {"type":"clinical-trial","attrs":{"text":"NCT00162539","term_id":"NCT00162539"}}NCT00162539     

A short-term physical activity randomized trial in the Lower Mississippi Delta

Background

The purpose of this study was to determine if a short-term pedometer-based intervention results in immediate increases in time spent in moderate-to-vigorous physical activity (MVPA) compared to a minimal educational intervention.

Methods

A sample of 43 overweight adults 35 to 64 years of age participated in a one week pedometer-based feasibility trial monitored by accelerometry. Participants were randomized into a one-week education-only group or a group that also wore a pedometer. Accelerometer-measured MVPA was measured over 7 days at baseline and again for 7 days immediately post-intervention.

Results

Minutes of MVPA increased significantly in the overall sample (p = 0.02); however, the effect of adding the pedometer to the education program was not significant (p = 0.89). Mean (±SE) MVPA increased from 12.7±2.4 min/day to 16.2±3.6 min/day in the education-only group and from 13.2±3.3 min/day to 16.3±3.9 min/day in the education+pedometer group. The correlation between change in steps/day and change in MVPA was 0.69 (p<0.0001).

Conclusions

The results of this study suggest that the addition of a pedometer to a short-term education program does not produce added benefits with respect to increasing physical activity in the Lower Mississippi Delta.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01264757","term_id":"NCT01264757"}}NCT01264757     

Phase Ia clinical evaluation of the safety and immunogenicity of the Plasmodium falciparum blood-stage antigen AMA1 in ChAd63 and MVA vaccine vectors

Background

Traditionally, vaccine development against the blood-stage of Plasmodium falciparum infection has focused on recombinant protein-adjuvant formulations in order to induce high-titer growth-inhibitory antibody responses. However, to date no such vaccine encoding a blood-stage antigen(s) alone has induced significant protective efficacy against erythrocytic-stage infection in a pre-specified primary endpoint of a Phase IIa/b clinical trial designed to assess vaccine efficacy. Cell-mediated responses, acting in conjunction with functional antibodies, may be necessary for immunity against blood-stage P. falciparum. The development of a vaccine that could induce both cell-mediated and humoral immune responses would enable important proof-of-concept efficacy studies to be undertaken to address this question.

Methodology

We conducted a Phase Ia, non-randomized clinical trial in 16 healthy, malaria-naïve adults of the chimpanzee adenovirus 63 (ChAd63) and modified vaccinia virus Ankara (MVA) replication-deficient viral vectored vaccines encoding two alleles (3D7 and FVO) of the P. falciparum blood-stage malaria antigen; apical membrane antigen 1 (AMA1). ChAd63-MVA AMA1 administered in a heterologous prime-boost regime was shown to be safe and immunogenic, inducing high-level T cell responses to both alleles 3D7 (median 2036 SFU/million PBMC) and FVO (median 1539 SFU/million PBMC), with a mixed CD4⁺/CD8⁺ phenotype, as well as substantial AMA1-specific serum IgG responses (medians of 49 µg/mL and 41 µg/mL for 3D7 and FVO AMA1 respectively) that demonstrated growth inhibitory activity in vitro.

Conclusions

ChAd63-MVA is a safe and highly immunogenic delivery platform for both alleles of the AMA1 antigen in humans which warrants further efficacy testing. ChAd63-MVA is a promising heterologous prime-boost vaccine strategy that could be applied to numerous other diseases where strong cellular and humoral immune responses are required for protection.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01095055","term_id":"NCT01095055"}}NCT01095055