Showing papers in "PLOS Clinical Trials in 2007"

Tenofovir Disoproxil Fumarate for Prevention of HIV Infection in Women: A Phase 2, Double-Blind, Randomized, Placebo-Controlled Trial

Abstract: Author(s): Peterson, Leigh; Taylor, Doug; Roddy, Ronald; Belai, Ghiorghis; Phillips, Pamela; Nanda, Kavita; Grant, Robert; Clarke, Edith Essie Kekawo; Doh, Anderson Sama; Ridzon, Renee; Jaffe, Howard S; Cates, Willard | Abstract: ObjectivesThe objective of this trial was to investigate the safety and preliminary effectiveness of a daily dose of 300 mg of tenofovir disoproxil fumarate (TDF) versus placebo in preventing HIV infection in women.DesignThis was a phase 2, randomized, double-blind, placebo-controlled trial.SettingThe study was conducted between June 2004 and March 2006 in Tema, Ghana; Douala, Cameroon; and Ibadan, Nigeria.ParticipantsWe enrolled 936 HIV-negative women at high risk of HIV infection into this study.InterventionParticipants were randomized 1:1 to once daily use of 300 mg of TDF or placebo.Outcome measuresThe primary safety endpoints were grade 2 or higher serum creatinine elevations (g2.0 mg/dl) for renal function, grade 3 or 4 aspartate aminotransferase or alanine aminotransferase elevations (g170 U/l) for hepatic function, and grade 3 or 4 phosphorus abnormalities (l1.5 mg/dl). The effectiveness endpoint was infection with HIV-1 or HIV-2.ResultsStudy participants contributed 428 person-years of laboratory testing to the primary safety analysis. No significant differences emerged between treatment groups in clinical or laboratory safety outcomes. Study participants contributed 476 person-years of HIV testing to the primary effectiveness analysis, during which time eight seroconversions occurred. Two were diagnosed in participants randomized to TDF (0.86 per 100 person-years) and six in participants receiving placebo (2.48 per 100 person-years), yielding a rate ratio of 0.35 (95% confidence interval = 0.03-1.93), which did not achieve statistical significance. Owing to premature closures of the Cameroon and Nigeria study sites, the planned person-years of follow-up and study power could not be achieved.ConclusionDaily oral use of TDF in HIV-uninfected women was not associated with increased clinical or laboratory adverse events. Effectiveness could not be conclusively evaluated because of the small number of HIV infections observed during the study.

Artemether-Lumefantrine versus Dihydroartemisinin-Piperaquine for Treatment of Malaria: A Randomized Trial

Abstract: Objectives: To compare the efficacy and safety of artemether-lumefantrine (AL) and dihydroartemisinin-piperaquine (DP) for treating uncomplicated falciparum malaria in Uganda. Results: Of 421 enrolled participants, 417 (99%) completed follow-up. The unadjusted risk of recurrent falciparum parasitemia was significantly lower for participants treated with DP than for those treated with AL after 28 d (11% versus 29%; risk difference (RD) 18%, 95% confidence interval (CI) 11%-26%) and 42 d (43% versus 53%; RD 9.6%, 95% CI 0%-19%) of follow-up. Similarly, the risk of recurrent parasitemia due to possible recrudescence (adjusted by genotyping) was significantly lower for participants treated with DP than for those treated with AL after 28 d (1.9% versus 8.9%; RD 7.0%, 95% CI 2.5%-12%) and 42 d (6.9% versus 16%; RD 9.5%, 95% CI 2.8%-16%). Patients treated with DP had a lower risk of recurrent parasitemia due to non-falciparum species, development of gametocytemia, and higher mean increase in hemoglobin compared to patients treated with AL. Both drugs were well tolerated; serious adverse events were uncommon and unrelated to study drugs.

Randomized dose-ranging controlled trial of AQ-13, a candidate antimalarial, and chloroquine in healthy volunteers.

Abstract: Objectives To determine: (1) the pharmacokinetics and safety of an investigational aminoquinoline active against multidrug–resistant malaria parasites (AQ-13), including its effects on the QT interval, and (2) whether it has pharmacokinetic and safety profiles similar to chloroquine (CQ) in humans. Design Phase I double-blind, randomized controlled trials to compare AQ-13 and CQ in healthy volunteers. Randomizations were performed at each step after completion of the previous dose. Setting Tulane–Louisiana State University–Charity Hospital General Clinical Research Center in New Orleans. Participants 126 healthy adults 21–45 years of age. Interventions 10, 100, 300, 600, and 1,500 mg oral doses of CQ base in comparison with equivalent doses of AQ-13. Outcome Measures Clinical and laboratory adverse events (AEs), pharmacokinetic parameters, and QT prolongation. Results No hematologic, hepatic, renal, or other organ toxicity was observed with AQ-13 or CQ at any dose tested. Headache, lightheadedness/dizziness, and gastrointestinal (GI) tract–related symptoms were the most common AEs. Although symptoms were more frequent with AQ-13, the numbers of volunteers who experienced symptoms with AQ-13 and CQ were similar (for AQ-13 and CQ, respectively: headache, 17/63 and 10/63, p = 0.2; lightheadedness/dizziness, 11/63 and 8/63, p = 0.6; GI symptoms, 14/63 and 13/63; p = 0.9). Both AQ-13 and CQ exhibited linear pharmacokinetics. However, AQ-13 was cleared more rapidly than CQ (respectively, median oral clearance 14.0–14.7 l/h versus 9.5–11.3 l/h; p ≤ 0.03). QTc prolongation was greater with CQ than AQ-13 (CQ: mean increase of 28 ms; 95% confidence interval [CI], 18 to 38 ms, versus AQ-13: mean increase of 10 ms; 95% CI, 2 to 17 ms; p = 0.01). There were no arrhythmias or other cardiac AEs with either AQ-13 or CQ. Conclusions These studies revealed minimal differences in toxicity between AQ-13 and CQ, and similar linear pharmacokinetics. Trial Registration ClinicalTrials.gov NCT00323375

A Cluster-Randomised Trial Evaluating an Intervention for Patients with Stress-Related Mental Disorders and Sick Leave in Primary Care

Abstract: Objective: Mental health problems often affect functioning to such an extent that they result in sick leave. The worldwide reported prevalence of mental health problems in the working population is 10%-18%. In developed countries, mental health problems are one of the main grounds for receiving disability benefits. In up to 90% of cases the cause is stress-related, and health-care utilisation is mainly restricted to primary care. The aim of this study was to assess the effectiveness of our Minimal Intervention for Stress-related mental disorders with Sick leave (MISS) in primary care, which is intended to reduce sick leave and prevent chronicity of symptoms.

Phase 1 Study of Two Merozoite Surface Protein 1 (MSP142) Vaccines for Plasmodium falciparum Malaria

Abstract: Objectives To assess the safety and immunogenicity of two vaccines, MSP142-FVO/Alhydrogel and MSP142-3D7/Alhydrogel, targeting blood-stage Plasmodium falciparum parasites. Design A Phase 1 open-label, dose-escalating study. Setting Quintiles Phase 1 Services, Lenexa, Kansas between July 2004 and November 2005. Participants Sixty healthy malaria-naive volunteers 18–48 y of age. Interventions The C-terminal 42-kDa region of merozoite surface protein 1 (MSP142) corresponding to the two allelic forms present in FVO and 3D7 P. falciparum lines were expressed in Escherichia coli, refolded, purified, and formulated on Alhydrogel (aluminum hydroxide). For each vaccine, volunteers in each of three dose cohorts (5, 20, and 80 μg) were vaccinated at 0, 28, and 180 d. Volunteers were followed for 1 y. Outcome Measures The safety of MSP142-FVO/Alhydrogel and MSP142-3D7/Alhydrogel was assessed. The antibody response to each vaccine was measured by reactivity to homologous and heterologous MSP142, MSP119, and MSP133 recombinant proteins and recognition of FVO and 3D7 parasites. Results Anti-MSP142 antibodies were detected by ELISA in 20/27 (74%) and 22/27 (81%) volunteers receiving three vaccinations of MSP142-FVO/Alhydrogel or MSP142-3D7/Alhydrogel, respectively. Regardless of the vaccine, the antibodies were cross-reactive to both MSP142-FVO and MSP142-3D7 proteins. The majority of the antibody response targeted the C-terminal 19-kDa domain of MSP142, although low-level antibodies to the N-terminal 33-kDa domain of MSP142 were also detected. Immunofluorescence microscopy of sera from the volunteers demonstrated reactivity with both FVO and 3D7 P. falciparum schizonts and free merozoites. Minimal in vitro growth inhibition of FVO or 3D7 parasites by purified IgG from the sera of the vaccinees was observed. Conclusions The MSP142/Alhydrogel vaccines were safe and well tolerated but not sufficiently immunogenic to generate a biologic effect in vitro. Addition of immunostimulants to the Alhydrogel formulation to elicit higher vaccine-induced responses in humans may be required for an effective vaccine. Trial Registration ClinicalTrials.gov NCT00340431

A Randomized, Double-Blind, Placebo-Controlled Trial of Lessertia frutescens in Healthy Adults

Abstract: Objectives: Indigenous medicines are widely used throughout Africa, despite a lack of scientific evidence for their safety or efficacy. The aims of this study were: (a) to conduct a pilot study of the safety of a common indigenous South African phytotherapy, Lessertia frutescens (Sutherlandia), in healthy adults; and (b) to contribute to establishing procedures for ethical and scientifically rigorous clinical trials of African indigenous medicines.

When and how can endpoints be changed after initiation of a randomized clinical trial

Abstract: Introduction Endpoints are outcome measures used to address the objectives of a clinical trial. The primary endpoint is the most important outcome and is used to assess the primary objective of a trial (e.g., the variable used to compare the effect difference of two treatment groups). A fundamental principle in the design of randomized trials involves setting out in advance the endpoints that will be assessed in the trial [1], as failure to prespecify endpoints can introduce bias into a trial and creates opportunities for manipulation. However, sometimes new information may come to light that could merit changes to endpoints during the course of a trial. This new information might include, for example, results from other trials or identification of better biomarkers or surrogate outcome measures. Such changes can allow incorporation of up-to-date knowledge into the trial design. However, changes to endpoints can also compromise the scientific integrity of a trial. Here I discuss some of the issues and decisionmaking processes that should be considered when evaluating whether to make changes to endpoints, and discuss the documentation and reporting of clinical trials that have revised endpoints.

Factors in AIDS dementia complex trial design: results and lessons from the abacavir trial.

Abstract: Objectives To determine the efficacy of adding abacavir (Ziagen, ABC) to optimal stable background antiretroviral therapy (SBG) to AIDS dementia complex (ADC) patients and address trial design. Design Phase III randomized, double-blind placebo-controlled trial. Setting Tertiary outpatient clinics. Participants ADC patients on SBG for ≥8 wk. Interventions Participants were randomized to ABC or matched placebo for 12 wk. Outcome Measures The primary outcome measure was the change in the summary neuropsychological Z score (NPZ). Secondary measures were HIV RNA and the immune activation markers β-2 microglobulin, soluble tumor necrosis factor (TNF) receptor 2, and quinolinic acid. Results 105 participants were enrolled. The median change in NPZ at week 12 was +0.76 for the ABC + SBG and +0.63 for the SBG groups (p = 0.735). The lack of efficacy was unlikely related to possible limited antiviral efficacy of ABC: at week 12 more ABC than placebo participants had plasma HIV RNA ≤400 copies/mL (p = 0.002). There were, however, other factors. Two thirds of patients were subsequently found to have had baseline resistance to ABC. Second, there was an unanticipated beneficial effect of SBG that extended beyond 8 wk to 5 mo, thereby rendering some of the patients at baseline unstable. Third, there was an unexpectedly large variability in neuropsychological performance that underpowered the study. Fourth, there was a relative lack of activity of ADC: 56% of all patients had baseline cerebrospinal fluid (CSF) HIV-1 RNA <100 copies/mL and 83% had CSF β-2 microglobulin <3 nmol/L at baseline. Conclusions The addition of ABC to SBG for ADC patients was not efficacious, possibly because of the inefficacy of ABC per se, baseline drug resistance, prolonged benefit from existing therapy, difficulties with sample size calculations, and lack of disease activity. Assessment of these trial design factors is critical in the design of future ADC trials. Trial Registration Controlled-Trials.com ISRCTN53707238

A cluster randomized clinical trial to improve prescribing patterns in ambulatory pediatrics.

Abstract: Objectives Having shown previously that an electronic prescription writer and decision support system improved pediatric prescribing behavior for otitis media in an academic clinic setting, we assessed whether point-of-care delivery of evidence could demonstrate similar effects for a wide range of other common pediatric conditions. Design Cluster randomized controlled trial. Setting A teaching clinic/clinical practice site and a primary care pediatric clinic serving a rural and semi-urban patient mix. Participants A total of 36 providers at the teaching clinic/practice site and eight providers at the private primary pediatric clinic. Intervention An evidence-based message system that presented real-time evidence to providers based on prescribing practices for acute otitis media, allergic rhinitis, sinusitis, constipation, pharyngitis, croup, urticaria, and bronchiolitis. Outcome measures The proportion of prescriptions dispensed in accordance with evidence. Results The proportion of prescriptions dispensed in accordance with evidence improved four percentage points, from 38% at baseline to 42% following the intervention. The control group improved by one percentage point, from 39% at baseline to 40% at trial's conclusion. The adjusted difference between the intervention and control groups was 8% (95% confidence interval 1%, 15%). Intervention effectiveness did not decrease with time. Conclusion For common pediatric outpatient conditions, a point-of-care evidence-based prescription writer and decision support system was associated with significant improvements in prescribing practices. Trial Registration ClnicalTrials.gov NCT00368823

Can Biomarkers Identify Women at Increased Stroke Risk? The Women's Health Initiative Hormone Trials

Abstract: Objective: The Women's Health Initiative hormone trials identified a 44% increase in ischemic stroke risk with combination estrogen plus progestin and a 39% increase with estrogen alone. We undertook a case-control biomarker study to elucidate underlying mechanisms, and to potentially identify women who would be at lower or higher risk for stroke with postmenopausal hormone therapy (HT). Design: The hormone trials were randomized, double-blind, and placebo controlled.

Intermittent Intravaginal Antibiotic Treatment of Bacterial Vaginosis in HIV-Uninfected and -Infected Women: A Randomized Clinical Trial

Abstract: Objective Assess efficacy of intermittent intravaginal metronidazole gel treatment in reducing frequency of bacterial vaginosis (BV). Design Randomized, double-masked, placebo-controlled phase 3 trial. Setting Postnatal and family planning clinics of the Queen Elizabeth Central Hospital and two health centers in Blantyre, Malawi. Participants Nonpregnant HIV-uninfected and -infected women. Intervention Intravaginal metronidazole treatment and placebo gels provided at baseline and every 3 mo for 1 y. Outcome measures Primary: Cross-sectional and longitudinal comparisons of BV frequency at baseline, 1 mo after product dispensation (post-treatment evaluation [PTE]), and every quarterly visit. Secondary: Effect of treatment on BV clearance and recurrence. Results Baseline: 842 HIV-uninfected and 844 HIV-infected women were enrolled. The frequency of BV at baseline in treatment and placebo arms, respectively, was 45.9% and 46.8% among HIV-uninfected women, and 60.5% and 56.9% among HIV-infected women. Primary outcomes: At the PTEs the prevalence of BV was consistently lower in treatment than placebo arms irrespective of HIV status. The differences were statistically significant mainly in HIV-uninfected women. Prevalence of BV was also reduced over time in both treatment and placebo arms. In a multivariable analysis that controlled for other covariates, the effect of intravaginal metronidazole treatment gel compared with placebo was not substantial: adjusted relative risk (RR) 0.90, 95% confidence interval (CI) 0.83–0.97 in HIV-uninfected women and adjusted RR 0.95, 95% CI 0.89–1.01 in HIV-infected women. Secondary outcomes: Intravaginal metronidazole treatment gel significantly increased BV clearance (adjusted hazard ratio [HR] 1.34, 95% CI 1.07–1.67 among HIV-uninfected women and adjusted HR 1.29, 95% CI 1.06–1.58 among HIV-infected women) but was not associated with decreased BV recurrence. Safety: No serious adverse events were related to use of intravaginal gels. Conclusion Intermittent microbicide treatment with intravaginal gels is an innovative approach that can reduce the frequency of vaginal infections such as BV. Trial Registration ClinicalTrials.gov NCT00140764

Efficacy of antioxidant treatment in reducing resistin serum levels: a randomized study.

Abstract: Objectives Few in vitro studies have examined the participation of resistin, a recently discovered adipokine, in oxidative processes. We investigated whether in vivo treatment with the antioxidant vitamin C might affect resistin serum levels. Design Randomized prospective open trial. Setting San Giovanni Battista Hospital, Turin, Italy. Participants Eighty healthy individuals. Intervention Administration of 2 g of ascorbic acid orally for 2 wk (n = 40; experimental group) or no supplementation (n = 40; control group). Outcome measures The primary end point was the between-group difference in the before–after change in resistin serum level after vitamin C supplementation. Secondary endpoints were the within- and between-group changes in glucose, insulin, lipid parameters, C-reactive protein fasting values, and markers of oxidative stress. Results In the experimental group, vitamin C supplementation was significantly associated with both resistin concentration reduction (from 4.3 ± 1.5 to 2.9 ± 0.8 ng/ml; 95% confidence interval [CI] −1.87, −1.03) and ascorbic acid level increase (from 9.4 ± 2.9 to 19.0 ± 5.2 mg/l; 95% CI 7.9, 11.2). In the control group, resistin levels did not change significantly (from 4.2 ± 1.0 to 4.3 ± 0.9 ng/ml; 95% CI −0.07, 0.37). The between-group differences were highly significant (p < 0.001). Vitamin C supplementation was also associated with a statistically significant reduction in nitrotyrosine level and incremental increase in reduced glutathione. In a linear regression model, within-individual changes in vitamin C concentrations were inversely correlated with changes in resistin levels in both groups (each unit increase of vitamin C corresponded to a decrease of about 0.10 units of resistin levels (95% CI 0.13, 0.08; p < 0.001). Conclusion This is to our knowledge the first randomized trial in humans that has demonstrated that short-term vitamin C supplementation could significantly reduce resistin levels, independent of changes in inflammatory or metabolic variables. Future investigations of resistin participation in oxidative processes are warranted. Trial Registration ClinicalTrials.gov NCT00387114

The effect of acclydine in chronic fatigue syndrome: a randomized controlled trial.

Abstract: OBJECTIVES: It is unclear whether insulin-like growth factor (IGF) function is involved in the pathophysiology of chronic fatigue syndrome (CFS). Unpublished data and reports in patient organization newsletters suggest that Acclydine, a food supplement, could be effective in the treatment of CFS by increasing biologically active IGF1 levels. Here we aimed to measure the IGF1 and IGF binding protein (IGFBP) 3 status of CFS patients compared to age- and gender-matched neighborhood controls, and to assess the effect of Acclydine on fatigue severity, functional impairment, and biologically active IGF1 level (IGFBP3/IGF1 ratio). DESIGN: A randomized, placebo-controlled, double-blind clinical trial. SETTING: Radboud University Nijmegen Medical Centre, The Netherlands. PARTICIPANTS: Fifty-seven adult patients who fulfilled the US Centers for Disease Control and Prevention criteria for CFS. IGF status of 22 CFS patients was compared to that of 22 healthy age- and gender-matched neighborhood control individuals. INTERVENTION: Acclydine or placebo for 14 wk. OUTCOME MEASURES: Outcomes were fatigue severity (Checklist Individual Strength, subscale fatigue severity [CIS-fatigue]), functional impairment (Sickness Impact Profile-8 [SIP-8]), and biologically active IGF1 serum concentrations. Analyses were on an intention-to-treat basis. RESULTS: There was no difference in IGF status in 22 CFS patients compared to healthy age- and gender-matched control individuals. Treatment with Acclydine did not result in significant differences compared with the placebo group on any of the outcome measures: CIS-fatigue +1.1 (95% CI -4.4 to +6.5, p = 0.70), SIP-8 +59.1 (95% CI -201.7 to +319.8, p = 0.65), and IGFBP3/IGF1 ratio -0.5 (95% CI -2.8 to +1.7, p = 0.63). CONCLUSION: We found no differences in IGF1 status in CFS patients compared to healthy matched neighborhood controls. In addition, the results of this clinical trial do not demonstrate any benefit of Acclydine over placebo in the treatment of CFS.

Stimulatory effect of morning bright light on reproductive hormones and ovulation: results of a controlled crossover trial.

Abstract: Funding: The study was sponsored by Outside In. Outside In had no involvement in the study design; collection, analysis, and interpretation of data; writing of the paper; and decision to submit it for publication. KVD is the guarantor and as such is responsible for interpreting and presenting the data.

Recovery after minor traffic injuries: a randomized controlled trial.

Abstract: OBJECTIVES: To assess the efficacy of an acute multidisciplinary group intervention on self-perceived recovery following minor traffic-related musculoskeletal injuries. DESIGN: Open, randomized controlled trial. SETTING: A large inner-city hospital. PARTICIPANTS: 127 patients (>/=15 y) with traffic-related acute minor musculoskeletal injuries and predicted to be at risk for delayed recovery were randomized into an intervention group (n = 65) or a control group (n = 62). INTERVENTION: Four 1(1/2)-h sessions in open groups with the aim of providing information about injuries in general, calling attention to the importance of self-care and promoting physical activity. In addition, both groups received standard medical care by regular staff. OUTCOME MEASURES: The main outcome measure was self-reported recovery at 12 mo. Secondary outcome measures were ratings of functional health status (SF-36, SMFA), pain and mental distress on visual analog scales, and self-reported duration of sick leave. RESULTS: At 12 mo, there was a 21.9 percentage point difference: 52.4% of the patients in the intervention group and 30.5% in the control group reported self-perceived recovery (95% confidence interval for the difference 5%-38%; p = 0.03). There were no statistically significant differences between the groups regarding the secondary outcome measures. CONCLUSION: A simple group intervention may accelerate the self-perceived recovery in selected patients. As we did not find evidence of improvements in the secondary outcome measures, the clinical significance of the treatment benefit remains to be defined. Language: en

Quality of Life in HIV Clinical Trials: Why Sexual Health Must Not Be Ignored

Abstract: Currently more than 20 antiretrovirals are commercially available for treatment of HIV infection [1]. Using them in combination therapy, we are able to treat HIV-infected patients with highly potent regimens and suppress the virus below detectable levels. Correct adherence to these regimens is important to ensure that the viral load will remain undetectable and that the disease does not progress. Moreover, even if adherence is not perfect and the virus becomes resistant to a first-line regimen, there are other treatment options to suppress the virus again to undetectable levels. Given the choice of several different potent antiretroviral regimens, doctors and patients will tend to prefer those regimens that are easy to take and that have limited short-term and long-term side effects. One potential side effect of antiretroviral treatment that has received very little scientific attention so far is sexual dysfunction. Sexual dysfunction is defined as difficulty during any stage of the sexual act, including desire, arousal, orgasm, and resolution, that prevents the individual or couple from enjoying sexual activity [2], and, according to DSM-IV (the Diagnostic and Statistical Manual of Mental Disorders, fourth edition) criteria, causing ‘‘marked level of distress or interpersonal difficulty’’ [3]. Sexual dysfunction disorders are generally classified into four categories: sexual desire disorders, sexual arousal disorders, orgasm disorders, and sexual pain disorders [2,3]. Most data relating to the association between antiretroviral therapy and sexual dysfunction are based on cross-sectional studies or case series, and have emerged from industrialised countries [4–12]. Some studies have suggested that antiretrovirals, in particular certain protease inhibitors, may cause sexual problems or dysfunction [4–10]; however, other studies have not confirmed this observation [11,12]. Furthermore, sexual dysfunctions in people infected with HIV may be caused by many different factors. Both organic and psychological factors have been identified, including coping with HIV, pre-existing sexual dysfunctions, sex hormone abnormalities, neuropathy from HIV itself (or related treatment for HIVcaused illnesses), and other iatrogenic causes [13]. Sexual dysfunctions are conceptualised as one component of sexual health, which is an essential element of overall healthrelated quality of life (HRQOL). While it may include a variety of diverse issues, comprehensive definitions such as the World Health Organization’s (WHO) working definition define sexual health as a state of physical, emotional, mental, and social well-being, and not merely the absence of disease, dysfunction, or infirmity. Sexual health encompasses the possibility of having pleasurable and safe sexual experiences [14]. The essence of such lengthy definitions has been summarised in one single statement as ‘‘the enjoyment of sexual activity of one’s choice, without causing or suffering physTable 1. Overview of the Most Commonly Used Questionnaires in Clinical HIV Trials

Effects of growth hormone and pioglitazone in viscerally obese adults with impaired glucose tolerance: a factorial clinical trial.

Abstract: Objective: Recombinant human growth hormone (GH) and pioglitazone (PIO) in abdominally obese adults with impaired glucose tolerance were evaluated under the hypothesis that the combination attenuates GH-induced increases in glucose concentrations, reduces visceral adipose tissue (VAT), and improves insulin sensitivity over time.

Short-term efficacy of rofecoxib and diclofenac in acute shoulder pain: a placebo-controlled randomized trial.

Abstract: Objectives To evaluate the short-term symptomatic efficacy of rofecoxib and diclofenac versus placebo in acute episodes of shoulder pain. Design Randomized controlled trial of 7 days. Setting Rheumatologists and/or general practitioners totaling 47. Participants Acute shoulder pain. Interventions Rofecoxib 50 mg once daily, diclofenac 50 mg three times daily, and placebo. Outcome measures Pain, functional impairment, patient's global assessment of his/her disease activity, and local steroid injection requirement for persistent pain. The primary variable was the Kaplan-Meier estimates of the percentage of patients at day 7 fulfilling the definition of success (improvement in pain intensity and a low pain level sustained to the end of the 7 days of the study; log-rank test). Results There was no difference in the baseline characteristics between the three groups (rofecoxib n = 88, placebo n = 94, and diclofenac n = 89). At day 7, the Kaplan-Meier estimates of successful patients was higher in the treatment groups than in the placebo (54%, 56%, and 38% in the diclofenac, rofecoxib, and placebo groups respectively, p = 0.0070 and p = 0.0239 for placebo versus rofecoxib and diclofenac, respectively). During the 7 days of the study, there was a statistically significant difference between placebo and both active arms (rofecoxib and diclofenac) in all the evaluated outcome measures A local steroid injection had to be performed in 33 (35%) and 19 (22%) patients in the placebo and rofecoxib group respectively. Number needed to treat to avoid such rescue therapy was 7 patients (95% confidence interval 5–15). Conclusion This study highlights the methodological aspects of clinical trials, e.g., eligibility criteria and outcome measures, in acute painful conditions. The data also establish that diclofenac and rofecoxib are effective therapies for the management of acute painful shoulder and that they reduce the requirement for local steroid injection. Trial Registration ClinicalTrials.gov NCT00140933

Immunotherapy with Canarypox Vaccine and Interleukin-2 for HIV-1 Infection: Termination of a Randomized Trial

Abstract: Background: Currently, providing that an individual infected with HIV can get access to highly active antiretroviral therapy (HAART), prognosis can be very good. However, although these treatments suppress replication of HIV, they do not eliminate HIV entirely. One current area of HIV research focuses on whether and how it is possible to take a break from antiretroviral therapy—which is very toxic—and at the same time achieve very low levels of HIV. Some research groups are also interested in whether and how it might be possible to eliminate the virus completely from the bloodstream and immune system of infected people, and therefore achieve a long-term cure. One such approach involves administration of interleukin-2 (IL-2, a hormone involved in the immune response), in the hope that IL-2 will boost the ability of the body's own immune system to eliminate HIV. Various candidate HIV vaccines have also been designed that, it is hoped, will prime the immune system to make it more receptive to IL-2. In the trial reported here, the researchers wanted to test whether IL-2 administration either alone or in combination with an HIV vaccine, ALVAC vCP1452, would maintain low levels of HIV in the blood of people who had stopped taking antiretroviral drugs. Therefore, participants in the trial were assigned to one of four arms: a placebo version of the vaccine only; vaccine only; placebo version of vaccine plus IL-2; or vaccine plus IL-2. The investigators planned to recruit 92 people into the trial who would be given the various interventions tested here for 12 weeks, while also receiving HAART (step 1). Then, HAART was stopped for 12 weeks (step 2), or, in some people, for 24 weeks if HIV levels remained below a certain threshold (step 3). What the trial shows: 44 people were recruited into the study, but it was terminated once results were analysed from those individuals who had completed 12 weeks without HAART. The researchers did not see any significant differences between the treatment groups in any of the three primary outcome measures, which were the proportion of people with undetectable HIV levels during step 2; the average HIV levels during the last four weeks of step 2; and the proportion of people eligible to continue to step 3. Therefore, the investigators concluded that neither the ALVAC vaccine nor IL-2 alone or in combination with each other, prevented HIV from replicating when HAART was stopped. Strengths and limitations: In the trial, randomized assignment to the different treatments was performed by the dispensing pharmacist, so study investigators were not able to predict which treatments the next participant would receive. A further strength in the design of this trial is the use of a placebo vaccine to control for ALVAC vCP1452, which enabled participants and investigators to be blinded to whether a patient received vaccine or placebo. However, a placebo was not used as a control for IL-2 because patients often experience characteristic side effects to this treatment. Limitations in the design of this study include the small numbers of participants, which means that the trial did not have enough power to exclude the possibility of a small effect of IL-2 or vaccine on HIV levels in blood. The follow-up in the trial was also short, and efficacy outcomes did not include measures that patients might consider important, such as survival. Contribution to the evidence: Currently, large-scale trials are evaluating the clinical effectiveness and safety of IL-2 at higher doses than those tested here, together with antiretroviral drugs as treatment for HIV. This study adds data suggesting that IL-2 at a lower dose either with or without the ALVAC vCP1452 vaccine does not prevent HIV replication once antiretroviral drug treatment is stopped.

Haematological safety of perinatal zidovudine in pregnant HIV-1-infected women in Thailand: secondary analysis of a randomized trial.

Abstract: Objectives: To respond to the primary safety objective of the Perinatal HIV Prevention Trial 1 (PHPT-1) by studying the evolution of haematological parameters according to zidovudine exposure duration in HIV-1−infected pregnant women. Design: Multicenter, randomized, double-blind, controlled trial of different durations of zidovudine prophylaxis. Setting: 27 hospitals in Thailand.Participants: 1,436 HIV-infected pregnant women in PHPT-1.Intervention: Zidovudine prophylaxis initiation at 28 or 35 wk gestation. Outcome measures: Haemoglobin level, leucocytes, total lymphocyte counts, and absolute neutrophil counts were measured at 26, 32, and 35 wk and at delivery. The evolution of haematological parameters was estimated between 26 and 35 wk (zidovudine/placebo) and between 35 wk and delivery to compare a long versus short zidovudine exposure. For each parameter, linear mixed models were adjusted on baseline sociodemographic variables, HIV clinical stage, CD4 count, and viral load. Results: Between 26 and 35 wk, haemoglobin, leucocytes, and absolute neutrophil counts decreased in zidovudine-exposed compared to unexposed women (mean difference [95% CI] −0.4 [−0.5 to −0.3], −423 [−703 to −142], −485 [−757 to −213], respectively). However, between 35 wk and delivery, the haematological parameters increased faster in women exposed to long rather than short durations of zidovudine (0.1 [0.0 to 0.1]; 105 [18 to 191]; 147 [59 to 234], respectively). At delivery, the differences were not statistically significant, except for mean haemoglobin level, which remained slightly lower in the long zidovudine treatment group (difference: 0.2 g/dl). Zidovudine had no negative impact on the absolute lymphocyte counts. Conclusion: Zidovudine initiated at 28 wk gestation rather than 35 wk had a transient negative impact on the evolution of haematological parameters, which was largely reversed by delivery despite continuation of zidovudine. This result provides reassurance about the safety of early initiation of zidovudine prophylaxis during pregnancy to maximize prevention of perinatal HIV.

Correction: Evolution and Translation of Research Findings: From Bench to Where?

Abstract: In PLoS Clinical Trials, vol 1, issue 7: doi:10.1371/journal.pctr.0010036 In Box 2, Reference [52] should be corrected to [22]. References [18-21] in the text should be corrected to [18-22]. The six successive references from [22] to [27] in the text should be corrected to [23] to [28]. Finally, the current reference [28] in the text should be corrected to [14].

Development and evaluation of a pedagogical tool to improve understanding of a quality checklist: a randomised controlled trial.

Abstract: OBJECTIVE: The aim of this study was to develop and evaluate a pedagogical tool to enhance the understanding of a checklist that evaluates reports of nonpharmacological trials (CLEAR NPT). DESIGN: Paired randomised controlled trial. PARTICIPANTS: Clinicians and systematic reviewers. INTERVENTIONS: We developed an Internet-based computer learning system (ICLS). This pedagogical tool used many examples from published randomised controlled trials to demonstrate the main coding difficulties encountered when using this checklist. Randomised participants received either a specific Web-based training with the ICLS (intervention group) or no specific training. OUTCOME MEASURES: The primary outcome was the rate of correct answers compared to a criterion standard for coding a report of randomised controlled trials with the CLEAR NPT. RESULTS: Between April and June 2006, 78 participants were randomly assigned to receive training with the ICLS (39) or no training (39). Participants trained by the ICLS did not differ from the control group in performance on the CLEAR NPT. The mean paired difference and corresponding 95% confidence interval was 0.5 (-5.1 to 6.1). The rate of correct answers did not differ between the two groups regardless of the CLEAR NPT item. Combining both groups, the rate of correct answers was high or items related to allocation sequence (79.5%), description of the intervention (82.0%), blinding of patients (79.5%), and follow-up schedule (83.3%). The rate of correct answers was low for items related to allocation concealment (46.1%), co-interventions (30.3%), blinding of outcome assessors (53.8%), specific measures to avoid ascertainment bias (28.6%), and intention-to-treat analysis (60.2%). CONCLUSIONS: Although we showed no difference in effect between the intervention and control groups, our results highlight the gap in knowledge and urgency for education on important aspects of trial conduct.

Phase III Trials Required to Resolve Clinical Equipoise over Optimal Fluid Management in Children with Severe Malaria

Abstract: There is a consensus among paediatricians that outcome of children presenting with life-threatening infections, irrespective of the infecting pathogen, can be improved by timely recognition and prompt intervention to correct disordered physiology using simple approaches to resuscitation [1–3]. These approaches include the provision of oxygen and the correction of fluid, electrolyte, and glucose deficits [4,5]. Indeed, studies have shown that most of the recent gains in survival of children with severe infections have come through the application of this approach by non-specialists during the initial hours of management [6,7]. Correction of hypotension and volume depletion through fluid administration is a fundamental component of resuscitation in most critically ill children [8,9], but its role in severe malaria remains uncertain and thus represents one of the most important theoretical gaps in our understanding of supportive treatments in this condition. Many children with severe malaria have signs of cardiovascular compromise or compensated shock on presentation to hospital and a smaller proportion are hypotensive [10]. One of the major unresolved aspects of management is whether volume expansion should be undertaken in children displaying signs of compensated shock, as is recommended in other paediatric disorders. Intravascular volume depletion (hypovolaemic shock) results in impaired cardiovascular function and inadequate tissue and organ perfusion, and would usually be corrected rapidly. Simple dehydration, predominantly affecting the intracellular compartment, can be safely corrected gradually. The choice of the optimum fluid for resuscitation is also unclear. Colloidal solutions, although more costly, are less likely to precipitate cerebral and pulmonary oedema due to their oncotic properties. Recognising the importance of adequate fluid management to the outcome of the critically ill child, the group at Kilifi has conducted a staged series of studies over the last 15 years to address each of these questions. In a collaboration that included specialists in paediatric intensive care, neurology, and clinical trials, the group demonstrated the importance, prognostic implications [11], and clinical correlates of metabolic acidosis in children with severe malaria [12] and provided clear evidence of intravascular hypovolaemia by using standard methods for studying critical illness [13]. We have undertaken two randomised trials to assess the safety of and response to volume expansion, and to determine whether colloid replacement offers any advantage over crystalloid replacement [13,14]. We hypothesised that administration of colloids such as human albumin solution with volume expansion would help to retain fluid in the intravascular compartment and may also improve endothelial function. In each of these trials we observed that albumin administration was associated with a lower mortality than saline. Although this data suggested the need for a large clinical trial of albumin, in view of the cost of albumin we thought that cheaper synthetic colloids should be assessed before embarking on a phase III trial. The intention in the small phase II trial, recently published in PLoS Clinical Trials [15], was to provide sufficient physiological data on succinylated gelatin to inform the design of the next phase, rather than to establish statistical superiority of one colloid over the other. For this purpose the trial was most instructive. Again we observed the same benefits of albumin: only one child who received albumin died, out of a group of participants that included children treated as emergencies who were subsequently found to be ineligible for the trial. The results for Gelofusine, however, were not encouraging. The combined findings that death, severe allergic reaction, and acute neurological events were more common in the Gelofusine group suggested that albumin, rather than a cheaper substitute, should be taken forward into the next phase. This was supported by the analysis of the combined data from three trials, including 238 children receiving volume expansion. While this small phase II study was not powered to prove that Gelofusine was superior to saline or albumin, the results suggest that Gelofusine is unlikely to offer any advantage over the cheaper saline solution. Given the continued controversy over the use of resuscitation fluids in the management of severe malaria, we suggest that this can only be resolved through a definitive clinical trial. Woodrow and Planche [16] have chosen a different interpretation. The evidence presented from two studies conducted in Gabon, one which assessed volume depletion in only 12 survivors [17] and the other larger study conducted in less critically unwell children [18], supports a position of equipoise—the basis which usually prompts the need for a definitive clinical trial.

Inadequate evidence to support phase III studies of albumin in severe malaria.

Abstract: The study on severe malaria by Akech et al. [1] found no significant difference between albumin and Gelofusine in any outcome measure, yet the authors reject further investigation of Gelofusine and propose phase III studies of albumin as a neuroprotective agent potentially capable of reducing mortality in severe malaria by over 80% [2]. Several issues related to study design and interpretation require reconsideration of the authors' main conclusions. Study design did not incorporate allocation concealment, a major omission that can influence patient recruitment at all stages from case finding strategy to consent [3]. Figure 1 gives the impression that patients were randomised after eligibility assessment, whereas in reality their treatment was known in advance. Comparison of baseline data for albumin and Gelofusine groups is an insensitive way to detect enrolment bias with these numbers of patients. An additional problem arises from a separate interventional study with phenytoin conducted simultaneously in comatose children, but no information is provided about possible interactions with fluid interventions. The task of undertaking two independent interventions in the same population would have benefited from prospective evaluation, for example, using a factorial design to minimise confounding. Both intention to treat (ITT) and per protocol (PP) analyses are presented, with ITT including patients enrolled as an emergency who did not meet inclusion criteria. In isolation, this approach may appear reasonable but in similar previous studies Newton's group excluded such patients from all analyses. Given that two of four patients not meeting inclusion criteria but entering the Gelofusine arm subsequently died (versus zero of four in the albumin arm), has the decision to include such patients on this occasion been taken post hoc since it favoured albumin? The ITT analysis is quoted selectively at certain points, e.g., while Table 4 shows a mortality rate of 10% with Gelofusine (PP analysis), the ITT figure of 16% is reported in the text and press release. Table 3 describes deaths (eight for Gelofusine, not seven as reported throughout the text) without reference to patients failing inclusion criteria; we assume that these “out of criteria” deaths are cases 2 and 10. If so, the short time between admission and death (1 h and 3 h) suggests that these patients were moribund at presentation. The potential for bias to influence enrolment of these patients (see above), or the decision to include such patients in the ITT analysis, is evident. Unfortunately, the editorial commentary compounds interpretative difficulties by incorrectly stating: “Death rates in hospital were lower in the group given albumin, and this was statistically significant.” Gelofusine was not associated with a significant increase in mortality compared to albumin (even by ITT analysis). Justification for albumin's superiority over Gelofusine is instead based on a small “meta-analysis” of studies of albumin versus “other fluids”, the dominant study of which enrolled 150 patients with 11 saline and two albumin deaths [4] (an alternative interpretation that large volumes of saline are hazardous has been discussed [5]). With only 80 patients enrolled in the Gelofusine versus albumin study, the “meta-analysis” was highly likely to generate the same result as its dominant study. We calculate that this albumin versus Gelofusine study could have had equivalent mortality in the two arms (up to 10 deaths per arm), yet the “meta-analysis” would still have showed significant benefit for albumin. Furthermore, there are discrepancies between the original studies and the “meta-analysis” both in total number of patients and deaths attributed to saline/Gelofusine (described, along with other inconsistencies, in our e-letter on the PLoS Clinical Trials Web site [http://clinicaltrials.plosjournals.org/perlserv/?request=read-response&doi=10.1371/journal.pctr.0010021#r1317]). Based on these data, as well as preliminary studies of albumin as a neuroprotective agent in stroke, the authors now propose a phase III study with albumin, saline, and maintenance-only arms. This would again test two separate hypotheses simultaneously (volume resuscitation and brain protection), and ignores the possibility that saline may be dangerous [5]. If the authors are committed to studies of albumin as a neuroprotective agent, an appropriate development plan should include a prospective, randomised phase II trial of albumin versus maintenance-only fluid in patients with cerebral malaria, with specific monitoring for adverse events (particularly pulmonary oedema), as for studies of albumin in stroke [6]. The accompanying article providing support [7] for the authors' call for phase III studies has not clarified these issues. Complicated and important fields of research demand corresponding rigour. Phase III mortality studies ought to be based on appropriately designed and adequately powered phase II trials with close regard to safety.

Phase III trial of albumin in malaria still lacks scientific justification.

Abstract: We wrote to PLoS Clinical Trials [1] following the publication of the article by Akech et al. [2] in order to highlight specific problems in the design and analysis of the study presented, point out errors in the presentation of the data, and seek clarification over certain details. As a consequence of this letter an erratum [3] to the editorial commentary has been issued confirming that no difference was found in death rate or any other outcome measure between the two arms of this study. The authors' follow-up letter [4] reiterates claims concerning the benefit of albumin over other fluids, including Gelofusine. Unfortunately, this letter missed an opportunity to clarify a number of issues and perpetuates a number of inaccuracies. For example, the notion of albumin's superiority over Gelofusine (groundless given the lack of statistical evidence for this; see erratum) persists in the statement beginning: “The combined findings that death, severe allergic reaction, and acute neurological events were more common in the Gelofusine group…” Similarly, the erroneous total patient number included in the meta-analysis (238) is still used in preference to the correct number (239). Phase III studies must be based on specific and relevant phase II studies. These preferably assess intervention versus standard treatment (“maintenance-only” fluids in most African hospitals) and optimise dosing strategy while rigorously and proactively noting adverse events (e.g., pulmonary oedema by chest radiography [5]). However, none of the studies on albumin performed in Kilifi have incorporated these elements into their design and reported adverse events in a standardised fashion [5]. Even the amounts of fluid actually received by patients in the most recent study are not provided [2]. Comparison of case fatality rates with historical controls cannot provide the required safety data to underpin a phase III study. Additionally, given the lack of a clear hypothesis (the authors discuss albumin acting in both volume expanding and neuroprotective capacities), the group of patients who might benefit from albumin remains uncertain. Failure to address any of the specific points in our letter impairs the ability of readers to review primary data for themselves. Repeating arguments for phase III studies on albumin in severe malaria does not make them more compelling.