Intravenous iron for heart failure, iron deficiency definitions, and clinical response: the IRONMAN trial.

BACKGROUND AND AIMS: What is the relationship between blood tests for iron deficiency, including anaemia, and the response to intravenous iron in patients with heart failure? METHODS: In the IRONMAN trial, 1137 patients with heart failure, ejection fraction ≤ 45%, and either serum ferritin < 100 µg/L or transferrin saturation (TSAT) < 20% were randomized to intravenous ferric derisomaltose (FDI) or usual care. Relationships were investigated between baseline anaemia severity, ferritin and TSAT, to changes in haemoglobin from baseline to 4 months, Minnesota Living with Heart Failure (MLwHF) score and 6-minute walk distance achieved at 4 months, and clinical events, including heart failure hospitalization (recurrent) or cardiovascular death. RESULTS: The rise in haemoglobin after administering FDI, adjusted for usual care, was greater for lower baseline TSAT (Pinteraction < .0001) and ferritin (Pinteraction = .028) and more severe anaemia (Pinteraction = .014). MLwHF scores at 4 months were somewhat lower (better) with FDI for more anaemic patients (overall Pinteraction = .14; physical Pinteraction = .085; emotional Pinteraction = .043) but were not related to baseline TSAT or ferritin. Blood tests did not predict difference in achieved walking distance for those randomized to FDI compared to control. The absence of anaemia or a TSAT ≥ 20% was associated with lower event rates and little evidence of benefit from FDI. More severe anaemia or TSAT < 20%, especially when ferritin was ≥100 µg/L, was associated with higher event rates and greater absolute reductions in events with FDI, albeit not statistically significant. CONCLUSIONS: This hypothesis-generating analysis suggests that anaemia or TSAT < 20% with ferritin > 100 µg/L might identify patients with heart failure who obtain greater benefit from intravenous iron. This interpretation requires confirmation.

Intravenous ferric derisomaltose in patients with heart failure and iron deficiency in the UK (IRONMAN): an investigator-initiated, prospective, randomised, open-label, blinded-endpoint trial.

BACKGROUND: For patients with heart failure, reduced left ventricular ejection fraction and iron deficiency, intravenous ferric carboxymaltose administration improves quality of life and exercise capacity in the short-term and reduces hospital admissions for heart failure up to 1 year. We aimed to evaluate the longer-term effects of intravenous ferric derisomaltose on cardiovascular events in patients with heart failure. METHODS: IRONMAN was a prospective, randomised, open-label, blinded-endpoint trial done at 70 hospitals in the UK. Patients aged 18 years or older with heart failure (left ventricular ejection fraction ≤45%) and transferrin saturation less than 20% or serum ferritin less than 100 µg/L were eligible. Participants were randomly assigned (1:1) using a web-based system to intravenous ferric derisomaltose or usual care, stratified by recruitment context and trial site. The trial was open label, with masked adjudication of the outcomes. Intravenous ferric derisomaltose dose was determined by patient bodyweight and haemoglobin concentration. The primary outcome was recurrent hospital admissions for heart failure and cardiovascular death, assessed in all validly randomly assigned patients. Safety was assessed in all patients assigned to ferric derisomaltose who received at least one infusion and all patients assigned to usual care. A COVID-19 sensitivity analysis censoring follow-up on Sept 30, 2020, was prespecified. IRONMAN is registered with ClinicalTrials.gov, NCT02642562. FINDINGS: Between Aug 25, 2016, and Oct 15, 2021, 1869 patients were screened for eligibility, of whom 1137 were randomly assigned to receive intravenous ferric derisomaltose (n=569) or usual care (n=568). Median follow-up was 2·7 years (IQR 1·8-3·6). 336 primary endpoints (22·4 per 100 patient-years) occurred in the ferric derisomaltose group and 411 (27·5 per 100 patient-years) occurred in the usual care group (rate ratio [RR] 0·82 [95% CI 0·66 to 1·02]; p=0·070). In the COVID-19 analysis, 210 primary endpoints (22·3 per 100 patient-years) occurred in the ferric derisomaltose group compared with 280 (29·3 per 100 patient-years) in the usual care group (RR 0·76 [95% CI 0·58 to 1·00]; p=0·047). No between-group differences in deaths or hospitalisations due to infections were observed. Fewer patients in the ferric derisomaltose group had cardiac serious adverse events (200 [36%]) than in the usual care group (243 [43%]; difference -7·00% [95% CI -12·69 to -1·32]; p=0·016). INTERPRETATION: For a broad range of patients with heart failure, reduced left ventricular ejection fraction and iron deficiency, intravenous ferric derisomaltose administration was associated with a lower risk of hospital admissions for heart failure and cardiovascular death, further supporting the benefit of iron repletion in this population. FUNDING: British Heart Foundation and Pharmacosmos.

Rationale and design of a randomised trial of intravenous iron in patients with heart failure.

OBJECTIVES: For patients with a reduced left ventricular ejection fraction (LVEF) heart failure with reduced ejection fraction (HFrEF) and iron deficiency, administration of intravenous iron improves symptoms, exercise capacity and may in the following 12 months, reduce hospitalisations for heart failure. The Effectiveness of Intravenous iron treatment versus standard care in patients with heart failure and iron deficiency (IRONMAN) trial evaluated whether the benefits of intravenous iron persist in the longer term and impact on morbidity and mortality. METHODS: IRONMAN is a prospective, randomised, open-label, blinded endpoint (PROBE) event-driven trial. Patients aged ≥18 years with HFrEF (LVEF ≤45%) and evidence of iron deficiency (ferritin <100 µg/L and/or TSAT <20%) were enrolled if they had either a current or recent hospitalisation for heart failure or elevated plasma concentrations of a natriuretic peptide. Participants were randomised to receive, or not to receive, intravenous ferric derisomaltose in addition to guideline-recommended therapy for HFrEF. Every 4 months, intravenous iron was administered if either ferritin was <100 µg/L or, provided ferritin was ≤400 µg/L, TSAT was <25%. The primary endpoint is a composite of total hospitalisations for heart failure and cardiovascular death. Hospitalisation and deaths due to infection are safety endpoints. RESULTS: Trial recruitment was completed across 70 UK hospital sites in October 2021. Participants were followed until the end of March 2022. We plan to report the results by November 2022. CONCLUSIONS: IRONMAN will determine whether repeated doses of intravenous ferric derisomaltose are beneficial and safe for the long-term treatment of a broad range of patients with HFrEF and iron deficiency. TRIAL REGISTRATION NUMBER: NCT02642562.

The AgingPLUS trial: Design of a randomized controlled trial to increase physical activity in middle-aged and older adults.

BACKGROUND: Negative views of aging (NVOA), low self-efficacy beliefs, and poor goal planning skills represent risk factors that undermine adults' motivation to engage in physical activity (PA). Targeting these three risk factors may motivate adults to become physically active. OBJECTIVE: To assess the efficacy of AgingPLUS, a 4-week educational program that explicitly targets NVOA, low self-efficacy beliefs, and poor goal planning skills compared to a 4-week health education program. The study also examines the role of NVOA, self-efficacy beliefs, and goal planning as the mechanisms underlying change in PA. DESIGN: This randomized controlled trial (RCT) utilizes the experimental medicine approach to assess change in PA as a function of modifying three risk factors. The RCT recruitment target includes 288 mostly sedentary adults ranging in age from 45 to 75 years. METHODS: Eligible middle-aged and older adults are recruited through community sources. Participants are randomized to either the AgingPLUS or the control group. Participants in both groups are enrolled in the trial for 8 months total, with four assessment points: Baseline (pre-test), Week 4 (immediate post-test), Week 8 (delayed post-test), and Month 6 (long-term follow-up). The intervention takes place over 4 consecutive weeks with 2-h sessions each week. PA engagement is the primary outcome variable. Positive changes in NVOA, self-efficacy beliefs, and goal planning are the intervention targets and hypothesized mediators of increases in PA. SUMMARY: By utilizing a multi-component approach and targeting a cluster of psychological mechanisms, the AgingPLUS program implements the experimental medicine approach to health behavior change.

Understanding the effects of Covid-19 through a life course lens.

The Covid-19 pandemic is shaking fundamental assumptions about the human life course in societies around the world. In this essay, we draw on our collective expertise to illustrate how a life course perspective can make critical contributions to understanding the pandemic's effects on individuals, families, and populations. We explore the pandemic's implications for the organization and experience of life transitions and trajectories within and across central domains: health, personal control and planning, social relationships and family, education, work and careers, and migration and mobility. We consider both the life course implications of being infected by the Covid-19 virus or attached to someone who has; and being affected by the pandemic's social, economic, cultural, and psychological consequences. It is our goal to offer some programmatic observations on which life course research and policies can build as the pandemic's short- and long-term consequences unfold.

Contribution of the Rise in Cohabiting Parenthood to Family Instability: Cohort Change in Italy, Great Britain, and Scandinavia.

In this study, we investigate through microsimulation the link between cohabiting parenthood and family instability. We identify mechanisms through which increases in cohabiting parenthood may contribute to overall increases in separation among parents, linking micro-level processes to macro-level outcomes. Analyses are based on representative surveys in Italy, Great Britain, and Scandinavia (represented by Norway and Sweden), with full histories of women's unions and births. We first generate parameters for the risk of first and higher-order birth and union events by woman's birth cohort and country. The estimated parameters are used to generate country- and cohort-specific populations of women with stochastically predicted family life courses. We use the hypothetical populations to decompose changes in the percentage of mothers who separate/divorce across maternal birth cohorts (1940s to 1950s, 1950s to 1960s, 1960s to 1970s), identifying how much of the change can be attributed to shifts in union status at first birth and how much is due to change in separation rates for each union type. We find that when cohabiting births were uncommon, increases in parents' separation were driven primarily by increases in divorce among married parents. When cohabiting parenthood became more visible, it also became a larger component, but continued increases in parents' divorce also contributed to increasing parental separation. When cohabiting births became quite common, the higher separation rates of cohabiting parents began to play a greater role than married parents' divorce. When most couples had their first birth in cohabitation, those having children in marriage were increasingly selected from the most stable relationships, and their decreasing divorce rates offset the fact that increasing proportions of children were born in somewhat less stable cohabiting unions.

Assessment of Accuracy of Overall Energy Expenditure Measurements for the Fitbit Charge HR 2 and Apple Watch.

Objectives: In this study, we sought to determine the accuracy of energy expenditure (EE) esti- mation for the Fitbit Charge HR 2 (Fitbit) and the Apple Watch. Design: An observational study. Methods: Thirty young adults (15 men and 15 women, aged 23.5 ± 2.96 years) completed the Bruce treadmill protocol. We measured gross EE by a PARVO metabolic cart (MetCart) and concurrently estimated by the Fitbit and Apple Watch. We calculated concordance correlation coefficients (CCC, rc) and relative error rates to indicate the difference between each device and the MetCart system. Results: For the Apple Watch and Fitbit, the relative error rate was 24.3%, 20.1% for the pooled sample, 18.6%, 24.2% for men, and 29.9%, 16.7% for women, respectively. The Apple Watch overestimated EE for women and underestimated EE for men; the Fitbit underestimated EE for both. Moderate CCCs between estimated EEs and MetCart measured EEs were found for both Apple Watch (rc =0.65, 0.43, and 0.39 overall, men and women, respectively) and Fitbit (rc =0.53, 0.39, and 0.21 overall, men and women, respectively). Conclusion: Neither device showed accurate results compared with EE measured by a MetCart. Users should consider these results when designing programs or personal training plans where physical activity EE is a key outcome assessed with a wearable device.

Assessment of Postdonation Outcomes in US Living Kidney Donors Using Publicly Available Data Sets.

Importance: There are limited resources providing postdonation conditions that can occur in living donors (LDs) of solid-organ transplant. Consequently, it is difficult to visualize and understand possible postdonation outcomes in LDs. Objective: To assemble an open access resource that is representative of the demographic characteristics in the US national registry, maintained by the Organ Procurement and Transplantation Network and administered by the United Network for Organ Sharing, but contains more follow-up information to help to examine postdonation outcomes in LDs. Design, Setting, and Participants: Cohort study in which the data for the resource and analyses stemmed from the transplant data set derived from 27 clinical studies from the ImmPort database, which is an open access repository for clinical studies. The studies included data collected from 1963 to 2016. Data from the United Network for Organ Sharing Organ Procurement and Transplantation Network national registry collected from October 1987 to March 2016 were used to determine representativeness. Data analysis took place from June 2016 to May 2018. Data from 20 ImmPort clinical studies (including clinical trials and observational studies) were curated, and a cohort of 11 263 LDs was studied, excluding deceased donors, LDs with 95% or more missing data, and studies without a complete data dictionary. The harmonization process involved the extraction of common features from each clinical study based on categories that included demographic characteristics as well as predonation and postdonation data. Main Outcomes and Measures: Thirty-six postdonation events were identified, represented, and analyzed via a trajectory network analysis. Results: The curated data contained 10 869 living kidney donors (median [interquartile range] age, 39 [31-48] years; 6175 [56.8%] women; and 9133 [86.6%] of European descent). A total of 9558 living kidney donors with postdonation data were analyzed. Overall, 1406 LDs (14.7%) had postdonation events. The 4 most common events were hypertension (806 [8.4%]), diabetes (190 [2.0%]), proteinuria (171 [1.8%]), and postoperative ileus (147 [1.5%]). Relatively few events (n = 269) occurred before the 2-year postdonation mark. Of the 1746 events that took place 2 years or more after donation, 1575 (90.2%) were nonsurgical; nonsurgical conditions tended to occur in the wide range of 2 to 40 years after donation (odds ratio, 38.3; 95% CI, 4.12-1956.9). Conclusions and Relevance: Most events that occurred more than 2 years after donation were nonsurgical and could occur up to 40 years after donation. Findings support the construction of a national registry for long-term monitoring of LDs and confirm the value of secondary reanalysis of clinical studies.

Heart rate measures from the Apple Watch, Fitbit Charge HR 2, and electrocardiogram across different exercise intensities.

This study compared heart rate (HR) measurements for the Fitbit Charge HR 2 (Fitbit) and the Apple Watch devices with HR measurements for electrocardiogram (ECG). Thirty young adults (15/15 females/males, age 23.5 ± 3.0 years) completed the Bruce Protocol. HR measurements were recorded from the ECG and both devices every minute. Average HR for each participant was calculated for very light, light, moderate, vigorous and very vigorous intensities based on ECG-measured HR. A concordance correlation coefficient (CCC) was calculated to examine the strength of the relationship between ECG measured HR and HR measured by each device. Relative error rates (RER) were also calculated to indicate the difference between each device and ECG. An equivalence test was conducted to examine the equivalence of HRs measured by devices and ECG. The Apple Watch showed lower RER (2.4-5.1%) compared with the Fitbit (3.9-13.5%) for all exercise intensities. For both devices, the strongest relationship with ECG-measured HR was found for very light PA with very high CCC (>.90) and equivalence. The strength of the relationship declined as exercise intensity increased for both devices. These findings indicate that the accuracy of real-time HR monitoring by the Apple Watch and Fitbit Charge HR2 is reduced as exercise intensity increases.

Author Correction: Enabling precision medicine in neonatology, an integrated repository for preterm birth research.

The original version of the Data Descriptor contained errors in the author list and affiliations. Rita Leite's first name was misspelled as "Rite" and affiliations 4 and 5 were incorrectly swapped. In addition, members of the March of Dimes Prematurity Research Center consortium were not listed in the agreed positions within the author list. These errors have now been corrected in the HTML and PDF versions.

Intergenerational Transmission of Multipartner Fertility.

Using data from administrative registers for the period 1970-2007 in Norway and Sweden, we investigate the intergenerational transmission of multipartner fertility. We find that men and women with half-siblings are more likely to have children with more than one partner. The differences are greater for those with younger versus older half-siblings, consistent with the additional influence of parental separation that may not arise when one has only older half-siblings. The additional risk for those with both older and younger half-siblings suggests that complexity in childhood family relationships also contributes to multipartner fertility. Only a small part of the intergenerational association is accounted for by education in the first and second generations. The association is to some extent gendered. Half-siblings are associated with a greater risk of women having children with a new partner in comparison with men. In particular, maternal half-siblings are more strongly associated with multipartner fertility than paternal half-siblings only for women.

Enabling precision medicine in neonatology, an integrated repository for preterm birth research.

Preterm birth, or the delivery of an infant prior to 37 weeks of gestation, is a significant cause of infant morbidity and mortality. In the last decade, the advent and continued development of molecular profiling technologies has enabled researchers to generate vast amount of 'omics' data, which together with integrative computational approaches, can help refine the current knowledge about disease mechanisms, diagnostics, and therapeutics. Here we describe the March of Dimes' Database for Preterm Birth Research (http://www.immport.org/resources/mod), a unique resource that contains a variety of 'omics' datasets related to preterm birth. The database is open publicly, and as of January 2018, links 13 molecular studies with data across tens of thousands of patients from 6 measurement modalities. The data in the repository are highly diverse and include genomic, transcriptomic, immunological, and microbiome data. Relevant datasets are augmented with additional molecular characterizations of almost 25,000 biological samples from public databases. We believe our data-sharing efforts will lead to enhanced research collaborations and coordination accelerating the overall pace of discovery in preterm birth research.

The 10,000 Immunomes Project: Building a Resource for Human Immunology.

There is increasing appreciation that the immune system plays critical roles not only in the traditional domains of infection and inflammation but also in many areas of biology, including tumorigenesis, metabolism, and even neurobiology. However, one of the major barriers for understanding human immunological mechanisms is that immune assays have not been reproducibly characterized for a sufficiently large and diverse healthy human cohort. Here, we present the 10,000 Immunomes Project (10KIP), a framework for growing a diverse human immunology reference, from ImmPort, a publicly available resource of subject-level immunology data. Although some measurement types are sparse in the presently deposited ImmPort database, the extant data allow for a diversity of robust comparisons. Using 10KIP, we describe variations in serum cytokines and leukocytes by age, race, and sex; define a baseline cell-cytokine network; and describe immunologic changes in pregnancy. All data in the resource are available for visualization and download at http://10kimmunomes.org/.

ImmPort, toward repurposing of open access immunological assay data for translational and clinical research.

Immunology researchers are beginning to explore the possibilities of reproducibility, reuse and secondary analyses of immunology data. Open-access datasets are being applied in the validation of the methods used in the original studies, leveraging studies for meta-analysis, or generating new hypotheses. To promote these goals, the ImmPort data repository was created for the broader research community to explore the wide spectrum of clinical and basic research data and associated findings. The ImmPort ecosystem consists of four components-Private Data, Shared Data, Data Analysis, and Resources-for data archiving, dissemination, analyses, and reuse. To date, more than 300 studies have been made freely available through the Shared Data portal (www.immport.org/immport-open), which allows research data to be repurposed to accelerate the translation of new insights into discoveries.

Occurrence and Clinicopathologic Features of Splenic Neoplasia Based on Body Weight: 325 Dogs (2003-2013).

Medical records of 396 dogs undergoing splenectomy for treatment of a splenic mass or nodular disease were reviewed retrospectively. Overall distribution of histopathologic diagnosis and clinicopathologic features were evaluated for 325 dogs that met inclusion criteria. Dogs were dichotomized into two groups based on weight, with the statistically derived cutoff identified as 27.8 kg. Malignancy was diagnosed in 58% of dogs, with no difference between small (55%) and large (61%) dogs (P = .291). Overall, 32% of splenic masses were hemangiosarcoma (HSA), which comprised 25 and 39% of all masses in small and large dogs, respectively. The diagnosis of HSA, non-HSA malignancy, or benign splenic disease was significantly different between the groups (P = .019). Of malignant diagnoses, HSA comprised 46 and 65% of small and large dog splenic neoplasms, respectively (P = .009). In both groups, dogs with HSA were significantly more likely to have preoperative anemia, hemoabdomen, thrombocytopenia, and a blood transfusion, as compared to dogs with non-HSA malignancy or benign lesions. Overall, dogs had similar odds of having a malignant splenic lesion regardless of weight, but dogs ≤27.8 kg were significantly less likely to be diagnosed with HSA.

Bioavailability, safety and immunogenicity of biosimilar infliximab (BOW015) compared to reference infliximab.

OBJECTIVES: To compare the single-dose pharmacokinetics (PK), safety, and immunogenicity of the biosimilar infliximab (BOW015) to reference infliximab (rIFX) in healthy volunteers and to establish bioequivalence. METHODS: In this randomized, double-blind, parallel-group, single-dose study, subjects received either BOW015 or rIFX. Both drugs were administered as a single IV 5 mg/kg dose over 2 hours on day 1. PK sampling occurred 10 times over 3 days and during safety and immunogenicity follow-up on day 4 and 1, 2, 3, 5, 7, 9, and 12 weeks after the infusion. RESULTS: Of the 84 healthy male Caucasian subjects randomized, 43 received BOW015 and 41 received rIFX. PK parameters (geometric mean) for BOW015 vs. rIFX were as follows; C(max) 142.47 vs. 126.74 µg/mL, AUC(0-t) 36,211 vs. 34,304 h×µg/mL, and AUC(0-inf) 36,775 vs. 34,801 h×µg/mL. The point estimates of the BOW015/rIFX geometric mean ratios (90% CI) were; C(max) 1.13 (1.07 - 1.18), AUC(0-t) 1.06 (0.98 - 1.14), and AUC(0-inf) 1.06 (0.98 - 1.15). Overall, anti-drug antibodies were detected in 18.6% of BOW015-treated subjects and 24.4% of rIFX-treated subjects. A total of 26 (60.5%) subjects in the BOW015 group reported 50 treatment-emergent adverse events (TEAEs) and 27 (65.9%) subjects in the rIFX group reported 54 TEAEs. CONCLUSIONS: Bioequivalence of BOW015 to rIFX is demonstrated as 90% CIs for the study drug mean ratios of C(max), AUC(0-t), and AUC(0-inf) were within the log-transformed ± 20% equivalence range of 0.80 - 1.25. Safety and immunogenicity were also comparable.

Using Electronic Health Records to Support Clinical Trials: A Report on Stakeholder Engagement for EHR4CR.

BACKGROUND: The conduct of clinical trials is increasingly challenging due to greater complexity and governance requirements as well as difficulties with recruitment and retention. Electronic Health Records for Clinical Research (EHR4CR) aims at improving the conduct of trials by using existing routinely collected data, but little is known about stakeholder views on data availability, information governance, and acceptable working practices. METHODS: Senior figures in healthcare organisations across Europe were provided with a description of the project and structured interviews were subsequently conducted to elicit their views. RESULTS: 37 structured interviewees in Germany, UK, Switzerland, and France indicated strong support for the proposed EHR4CR platform. All interviewees reported that using the platform for assessing feasibility would enhance the conduct of clinical trials and the majority also felt it would reduce workloads. Interviewees felt the platform could enhance trial recruitment and adverse event reporting but also felt it could raise either ethical or information governance concerns in their country. CONCLUSIONS: There was clear support for EHR4CR and a belief that it could reduce workloads and improve the conduct and quality of trials. However data security, privacy, and information governance issues would need to be carefully managed in the development of the platform.

Reanalysis of the Rituximab in ANCA-Associated Vasculitis trial identifies granulocyte subsets as a novel early marker of successful treatment.

INTRODUCTION: In the present study, we sought to identify markers in patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) that distinguish those achieving remission at 6 months following rituximab or cyclophosphamide treatment from those for whom treatment failed in the Rituximab in ANCA-Associated Vasculitis (RAVE) trial. METHODS: Clinical and flow cytometry data from the RAVE trial were downloaded from the Immunology Database and Analysis Portal and Immune Tolerance Network TrialShare public repositories. Flow cytometry data were analyzed using validated automated gating and joined with clinical data. Lymphocyte and granulocyte populations were measured in patients who achieved or failed to achieve remission. RESULTS: There was no difference in lymphocyte subsets and treatment outcome with either treatment. We defined a Granularity Index (GI) that measures the difference between the percentage of hypergranular and hypogranular granulocytes. We found that rituximab-treated patients who achieved remission had a significantly higher GI at baseline than those who did not (p = 0.0085) and that this pattern was reversed in cyclophosphamide-treated patients (p = 0.037). We defined optimal cutoff values of the GI using the Youden index. Cyclophosphamide was superior to rituximab in inducing remission in patients with GI below -9.25% (67% vs. 30%, respectively; p = 0.033), whereas rituximab was superior to cyclophosphamide for patients with GI greater than 47.6% (83% vs. 33%, respectively; p = 0.0002). CONCLUSIONS: We identified distinct subsets of granulocytes found at baseline in patients with AAV that predicted whether they were more likely to achieve remission with cyclophosphamide or rituximab. Profiling patients on the basis of the GI may lead to more successful trials and therapeutic courses in AAV. TRIAL REGISTRATION: ClinicalTrials.gov identifier (for original study from which data were obtained): NCT00104299 . Date of registration: 24 February 2005.