Current therapies available for the treatment of chronic hepatitis B are limited in their ability to result in a cure. Clevudine is a new pyrimidine analog with potent anti-hepatitis B virus (HBV) activity in vitro. A multicenter dose-escalation study evaluated clevudine at 10, 50, 100, and 200 mg once daily for 28 days. Eligible patients had HBV DNA levels of 3 × 106 copies/mL or more, had not undergone nucleoside treatment, and were without human immunodeficiency or hepatitis C virus coinfection. Thirty-two patients were enrolled (5, 10, 10, and 7 patients in the 10-, 50-, 100-, and 200-mg dose groups, respectively), 81% were male, 81% Asian, and 88% were hepatitis Be antigen (HBeAg) positive at baseline. Median pretreatment serum HBV DNA levels ranged from 7.3 to 8.8 log10 copies/mL. After 28 days, the median HBV DNA log10 change from baseline was −2.5, −2.7, −3.0, and −2.6 log10. Six months after dosing, median changes from baseline were −1.2, −1.4, −2.7 and −1.7 log10 in the 10-, 50-, 100-, and 200-mg cohorts, respectively. Six of 27 patients lost HBeAg, and 3 of 27 patients seroconverted to HBe antibody. Clevudine was well tolerated, with no dose-limiting toxicities. A transient increase in alanine aminotransferase of up to 7.8 times the upper limit of normal (increase ranged from 20 to 186 IU/L) was observed in six patients in the 100-mg cohort, without signs of liver failure. These increases were associated with improved viral suppression. The pharmacokinetic profile of clevudine was proportional to the dose. In conclusion, these results demonstrate the tolerability and potent activity of clevudine in HBV-infected patients and support further clinical study. (HEPATOLOGY 2004;40:140–148.)
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Hepatitis B virus (HBV) can lead to chronic hepatitis and cirrhosis with 350 million carriers worldwide.1 Currently approved antiviral regimens have been shown to improve the short-term outcome of the disease in some patients; however, they lack the ability to provide a cure or durable remission in most patients who are chronically infected with HBV.1 Currently approved drugs include interferon, lamivudine, and adefovir. Interferon can be administered only subcutaneously and is associated with frequent side effects. Lamivudine is an oral drug with a favorable safety profile; however, long-term therapy is required with this drug, which leads to the selection of drug-resistant mutants.2 Adefovir is another oral drug that also requires long-term therapy. It has been shown to select for resistant mutants in a very limited proportion of patients.3 Therefore, there is a need for developing new agents for the treatment of HBV infection with improved efficacy.
Clevudine [1-(2-deoxy-2-fluoro-β-L-arabinofuranosyl) thymine] is a nucleoside analog of the unnatural β-L configuration. Clevudine has potent activity against HBV and some activity against Epstein-Barr virus in vitro.4, 5 The 50% effective concentration for HBV inhibition values ranged from 0.02 μM to 0.84 μM in a variety of systems used to evaluate the inhibitory effect of clevudine on wild-type HBV. These values are comparable with those determined for lamivudine and emtricitabine and are fivefold less than that for adefovir in the equivalent in vitro systems.6 The effect of clevudine on mitochondrial structure and function has been studied at concentrations ranging from 1 μM to 1 mM by measuring lactic acid production, mitochondrial DNA content, and structural effects. At all the concentrations tested, clevudine had no effect on mitochondrial structure, DNA content, or function. The lack of cytotoxicity reflects the inability of human cellular DNA polymerases α, β, γ, and δ to use the 5′-triphosphate of clevudine as a substrate.7, 8
The mechanism by which clevudine exerts its antiviral effects is believed to be mediated by the intracellular formation of the monophosphate, diphosphate, and triphosphate forms.5 Clevudine enters cells through both facilitated nucleoside transport and nonfacilitated passive diffusion and is a substrate for three intracellular kinases responsible for its phosphorylation.9 These features suggest that relatively low plasma levels of clevudine may achieve therapeutic levels of clevudine triphosphate in target cells. In woodchucks infected with the woodchuck hepatitis virus, clevudine produced up to 1000-fold decreases in plasma woodchuck hepatitis virus DNA and to the lower limit of detection of the assay used.10 Serum woodchuck hepatitis virus DNA remained undetectable for up to 56 weeks after woodchuck hepatitis virus-infected animals were given oral doses of 10 mg/kg daily clevudine for 12 weeks.11 A single-dose pharmacokinetic study in healthy volunteers showed a plasma half-life of the drug exceeding 24 hours and supported a once daily administration.12 From drug exposure in the latter study, assessed by the plasma area under the curve, and in woodchucks, doses larger than 50 mg once daily were considered to be necessary to reach efficacy. Further research is ongoing to elucidate the mechanism of this prolonged suppression. We describe here administration of clevudine to patients with chronic HBV infection.
HBV, hepatitis B virus; HBeAg, hepatitis Be antigen; LOD, limit of detection.
Patients and Methods
The study was conducted at a total of seven sites in Canada, France, Hong Kong, and South Korea. Eligible patients were female or male from 18 to 60 years of age with chronic hepatitis B defined as the presence in serum of hepatitis B surface antigen for more than 6 months, with or without hepatitis Be antigen (HBeAg), but with HBV DNA levels of more than 3 × 106 copies/mL. Patients had to not have undergone nucleoside therapy at entry, and, if applicable, the last interferon treatment must have ended 6 months before enrollment. Patients with human immunodeficiency virus or hepatitis C virus seropositivity, with alanine aminotransferase (ALT) or aspartate aminotransferase levels greater than 10 times the upper limit of the normal range, with evidence of cirrhosis or hepatocellular carcinoma, or with other significant diseases were not eligible for participation in the study. Breastfeeding or pregnant women or those of childbearing age unwilling to use two effective contraceptive methods also were excluded.
All study participants had to give written informed consent before being tested for eligibility criteria. The study protocol and informed consent form were approved by an ethics committee at every study location and by the local health authorities. The study was conducted under the International Conference on Harmonization/Good Clinical Practice rules and in accordance with the principles of the Declaration of Helsinki (as amended in Tokyo, Venice, Hong Kong, South Africa, and Edinburgh) or with the laws and regulations of the country in which the research was conducted, whichever afforded the greater protection to the study patient.
Eligible patients were enrolled no more than 30 days after the assessment of eligibility criteria to receive open label clevudine once daily for 28 days. The initial study design included four evaluable patients in the 10-mg once daily dose cohort and then 8 to 10 patients in the 50-mg, 100-mg, 200-mg, 300-mg, and 400-mg once daily dose cohorts. Although it was originally considered of no therapeutic effect, the first limited 10-mg cohort was enrolled based on possible safety concerns. Escalation to the next highest dose cohort was considered only after review of the tolerability data by the sponsor and the investigators. The decision to open enrollment in the next dose cohort was based on the absence of tolerability and safety concerns in the first four patients evaluable in the previous dose cohort and on completion of enrollment in that cohort.
The primary objectives of the study were to evaluate the tolerability, safety, pharmacokinetics, and antiviral activity of escalating doses of clevudine in patients chronically infected with HBV.
Schedule of Assessment.
Patients enrolled in the study were to return to the study site on a weekly basis during the 28-day dosing period to undergo clinical assessments of tolerability (open-ended interview), physical examination, electrocardiogram, and blood draws to measure laboratory parameters (including venous lactate samples), serum HBV DNA, and clevudine plasma levels. On days 1 and 28, a complete pharmacokinetic profile was performed (24-hour profile at day 1 and 72-hour profile at day 28). After day 28, the patients were followed up weekly for 2 weeks and then every 4 to 6 weeks until 24 weeks after treatment. After review of the data from the first two cohorts, the protocol was amended to include additional follow-up visits at weeks 40 and 52 for patients with a more than 1-log10 decrease from baseline in HBV DNA levels at week 28. In addition, all patients who presented a serious adverse event between week 28 and 52 were included in this report. Laboratory parameters were measured at a central laboratory.
Serum HBV DNA levels for eligibility at screening were measured with the Chiron Quantiplex assay. From baseline to the end of the study, serum HBV DNA levels were assessed using the Digene Hybrid Capture II HBV DNA (Digene Corp., Gaithersburg, MD) test with a lower limit of detection (LOD) of 4,700 copies/mL. Serological response was assessed monthly using an EIA assay. HBeAg loss was defined as the disappearance of HBeAg in patients previously HBeAg positive, and HBeAg seroconversion was defined as HBeAg disappearance combined with the appearance of anti-HBe antibody. To investigate whether antiviral-resistant mutations emerged, genotyping of the HBV DNA polymerase (domains A–E) was performed by dideoxy sequencing on week 24 samples that had more than the LOD and the matching baseline samples. In addition, baseline samples were evaluated using the same methodology to determine the hepatitis B surface antigen subtype.
Plasma concentrations of clevudine were determined using validated liquid chromatography and mass spectrometry methods with a lower LOD of 10 pg/mL (Gilead Science, Durham, NC). Patients received a dose of clevudine under the observation of site staff. On days 1 and 28, a blood sample was taken within 5 minutes before the first study drug administration (predose) and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 24 hours after administration but before the next drug administration. An additional plasma sample was drawn 48 and 72 hours after dosing on days 30 and 31. On days 7, 15, and 22, a sample was taken immediately before dosing.
All patients who received at least one dose of drug were included in the safety analysis. Patients discontinuing the study after receiving the first study drug dose were included in the efficacy analysis until the time of their discontinuation. Data were tabulated and presented as collected, without imputation for missing values. For subjects whose serum HBV DNA values dropped below the LOD of the assay, the LOD (4,700 copies/mL) was used as the serum HBV DNA value. Day 1 is defined as the first dosing day, follow-up visits (e.g., after the end of the 28-day treatment period) were calculated from day 1.
The average area under the curve minus baseline, derived from the area under the curve, was defined as the area of the trapezoid under the response-time curve divided by time to the last available evaluation of the subject minus the baseline value, or
where Cj,I is the ith subject measurement at time tj, and tj is the actual time of the jth visit. Subjects with at least one evaluation after baseline were included in these analyses.
A total of 32 patients were enrolled in the study from November 2000 through March 2002, among whom 31 were evaluable at week 28. One patient assigned to receive 10 mg clevudine withdrew 1 week after baseline (the withdrawal was related to the number of blood samples needed). Four patients received clevudine 10 mg once daily for 28 days, 10 received 50 mg once daily, 10 received 100 mg once daily, and 7 received 200 mg once daily. The sponsor closed the enrollment in the 200 mg cohort at 7 patients because sufficient data were available to characterize the safety and activity profile of clevudine at this dose. Indeed, the preliminary results of the pharmacodynamic analysis showed that the incremental antiviral activity for doses higher than 50 mg (see below) was minimal and that it was more appropriate to study doses of less than or equal to 50 mg once daily. The initially planned 300-mg and 400-mg cohorts were not enrolled because a real-time pharmacokinetic analysis revealed that the area under the curve exposure initially expected with the 400-mg daily dose was achieved with the 200-mg daily dose. One patient in the 200-mg dose group had no pharmacokinetic profile drawn for analysis. All 31 patients were followed up for at least 6 months after the end of treatment (week 28). Table 1 depicts the baseline demographics and disease characteristics by study cohort. Across cohorts, most patients (88%) were HBeAg positive at baseline. None of the patients had serological evidence of hepatitis D virus coinfection.
Table 1. Demographics and Patient Characteristics
Clevudine (Once Daily)
10 mg (n = 5)
50 mg (n = 10)
100 mg (n = 10)
200 mg (n = 7)
Total n = 32
Abbreviation: ULN, upper limit of normal.
Sex, n (%)
Median age (yrs)
Ethnicity, n (%)
White or Hispanic
Median weight (kg)
Median serum HBV DNA
HBeAg positive at baseline
Median ALT (U/L)
ALT < 2 × ULN at baseline, n(%)
ALT 2–5 × ULN at baseline, n(%)
ALT > 5 × ULN at baseline, n(%)
Safety and Tolerability.
No serious adverse events were reported during the dosing period or within 2 months after the end of dosing. One patient was reported to have experienced a serious adverse event (herpes zoster requiring hospitalization) 10 weeks after the end of dosing with clevudine 100 mg once daily.
The incidence of adverse events reported during the treatment period is presented in Table 2. No discontinuation of treatment because of an adverse event occurred. All adverse events were mild and essentially were constitutional symptoms. No grade 3 or 4 clinical adverse events were reported, and no clinically relevant electrocardiographical abnormalities were noted.
Table 2. Incidence of Adverse Events Reported During the Dosing Period
Adverse events reported in more than one patient regardless of their attribution to study drug; all events were graded as mild.
Table 3 depicts the incidence of treatment-emergent laboratory abnormalities occurring during the treatment period. One patient in the 50-mg cohort and two patients in the 100-mg cohort had increases in aminotransferases levels during the treatment period, reaching levels between 5- and 10-fold the upper limit of normal (43 IU/L). Of the 10 patients in 100-mg cohort, six experienced an increase in ALT while receiving clevudine. The increase from baseline through week 4 ranged from 20 to 186 IU/L, and the maximum level of ALT was 304 IU/L. Two of these patients seroconverted during the subsequent treatment-free follow-up. One patient in the 50-mg cohort had an increase in ALT level from 98 IU/L at baseline to 338 IU/L at week 4. One patient in the 200-mg cohort had a 20-IU/L increase in ALT level during the same period. All hepatic cytolyses were isolated, without bilirubin, prothrombin time, or alkaline phosphatase increases. All patients were asymptomatic and improved on treatment or 1 to 5 weeks after the end of treatment. No other elevations of aminotransferases were observed in the 200-mg cohort (see also Fig. 2). Furthermore, no significant increase in venous lactate levels was observed during the study.
Table 3. Treatment Emergent Grade 3 or 4 Laboratory Abnormalities Occurring During Dosing Period and 2 Months After the End of Treatment
Table 4 and Fig. 1 display the change in serum HBV DNA from baseline by dose group. HBV DNA levels for two patients in the 200-mg cohort reached the assay LOD (4,700 copies/mL), one at day 15 and one at day 22, and remained below the LOD through month 6. Similarly, one patient in the 100-mg cohort had HBV DNA levels below the LOD from week 8 to 18 (inclusive). Fig. 2 presents the evolution of ALT levels across dose groups over time. A biochemical response was observed at all doses 24 weeks after the end of dosing (50%, 60%, 70%, and 100% of the patients had normal ALT levels at week 28 in the 10-, 50-, 100-, and 200-mg cohorts, respectively). During the treatment and follow-up periods, six patients lost HBeAg (1 of 3 in the 10-mg dose group, 2 of 9 in the 50-mg dose group, 2 of 10 in the 100-mg dose group, and 1 of 5 in the 200-mg dose group), among whom three subsequently seroconverted to HBe antibody (two in the 50-mg dose group and one in the 100-mg dose group, respectively). All HBeAg losses and seroconversions were sustained until the end of the 6-month follow-up. Overall, the incidence of HBeAg loss was 22% (95% CI, 9–42) and the HBeAg seroconversion rate was 11% (95% CI, 2–29). There did not seem to be a dose relationship with respect to HBeAg loss or seroconversion. The level of ALT at baseline for patients who lost HBeAg was 1.2, 1.5, 3.1, 3.2, 5.1, and 7.0 times the upper limit of normal.
Table 4. HBV DNA Change From Baseline over Time
Log10 HBV DNA Change from Baseline
Clevudine (Once Daily) Treatment Cohort
Baseline serum HBV DNA
Week 4 (end of treatment)
Genotypical analysis of samples at baseline and 20 weeks after the end of dosing did not reveal the presence of polymerase mutations at conserved sites of the genome in any patient. The only amino acid changes that were noted were known natural polymorphisms in the HBV DNA polymerase and hepatitis B surface antigen domains. Consistent with their ethnic origin, most patients harbored HBV genotype C (subtype adr) at baseline; genotypes A through F were represented in the patient population.
After the 10-mg dose, clevudine concentrations were low and close to the limit of assay detection, thus preventing reliable pharmacokinetic evaluations. Mean (% coefficient of variation) pharmokinetics parameters at steady state on day 28 for the 50-, 100-, and 200-mg cohort patients are summarized in Table 5.
Table 5. Pharmacokinetic Parameters of Clevudine at Day 28
Cmax = maximum clevudine concentrations at steady state.
Cmin = minimum plasma clevudine concentrations at steady state.
AUC0→τ = area under the plasma clevudine concentration-time curve over a dosing interval at steady state.
CL/F = apparent total body clearance.
50 mg group
100 mg group
200 mg group
Monitoring of trough samples collected on days 7, 15, and 22 indicate that steady state is reached by day 22. Dose proportionality was observed between 50 mg and 200 mg after single-dose administration on day 1 and at steady state on day 28. Mean clevudine half-life (t1/2) was in the range of 44 to 60 hours after the final dose on day 28; determination of the terminal half-life was approximate because of the interval between samples beyond 24 hours.
Factors Predictive of Viral Response.
To investigate patient characteristics associated with greater antiviral activity, we conducted an exploratory analysis comparing the antiviral responses across dose groups for various categories of patients. The skewed distribution of patients with regard to sex, age, HBeAg status at baseline, and racial origin prevented such an analysis for these characteristics. No specific HBV subtype at baseline was associated with a lack of sustained response. Patients with ALT levels of more than two times the upper limit of the normal range at baseline had slightly higher viral suppression at 6 months (Fig. 3). When comparing the change from baseline in HBV DNA levels through week 28 among patients with or without ALT increases during the treatment period, the median viral suppression at week 28 was −0.4 log10 for patients without ALT increases (n = 23) and −3.0 log10 for patients with ALT increases (n = 8).
Based on the area under the curve minus baseline at day 42, a model of the proportion of the maximal treatment effect achieved across doses of clevudine, 77%, 91%, and 94% of the maximal predicted treatment effect was reached with clevudine doses of 10, 30, and 50 mg once daily, respectively (Fig. 4). The increase in activity with doses higher than 50 mg was minimal.
Laboratory safety data were available through week 52 for 1, 6, 7, and 3 patients who received 10 mg, 50 mg, 100 mg, and 200 mg clevudine once daily, respectively. Of these 17 patients, 3 experienced an increase in ALT levels to more than 10 times the upper limit of normal at 42, 52, and 42 weeks after treatment initiation, respectively (range of ALT levels, 434–1,108 IU/L). All 3 patients had abnormal ALT levels and HBV DNA levels that increased to values within 1 log10 copies/mL of the baseline value 3 months before the cytolysis event. All patients were asymptomatic at the time of event. One patient experienced an icteric exacerbation of hepatitis B 2 weeks after the initial aminotransferases increase and was treated successfully with lamivudine, with subsequent resolution of cytolysis and hyperbilirubinemia. One year after therapy, 11 of 17 evaluable patients (65%) had normal ALT levels, 1 of 14 patients who were HBeAg positive at baseline had a persistent HBeAg loss, and 5 of 14 patients had sustained seroconversion to HBe antibody. Two patients did seroconvert between the 6- and 9-month visit, whereas one reverted to HBeAg positivity. The median log10 HBV DNA change from baseline for these patients was −3.6 (n = 1), −0.4 (n = 5), and −2.9 (n = 7), and −1.0 (n = 2) at week 52 in the 10-, 50-, 100-, and 200-mg cohorts, respectively. One patient each in the 50-mg and 200-mg cohorts are missing HBV DNA data at present.
Clevudine was well tolerated at all doses with no dose-related pattern in terms of clinical adverse events and laboratory abnormalities. Increases in aminotransferases seen in some individuals of the 50-mg and 100-mg cohorts were self-limited, asymptomatic, and not observed after administration of higher doses, suggesting the increases may not be related to a toxic effect of the drug. However, this study was of limited sample size, and studies of longer duration and in broader patient population are necessary to accurately assess the safety of clevudine. Interestingly, those patients with an ALT increase while receiving the drug were those who ultimately showed the greatest sustained viral suppression (Fig. 5). Thus, no dose-limiting clinicobiological toxicity was seen after this short duration of dosing. The long plasma half-life of clevudine in this study supports a once daily administration. Steady state is reached at day 22 with the 50-, 100-, and 200-mg doses, and further accumulation of the drug was not observed. The pharmacokinetics are proportional to the dose from 50 to 200 mg once daily, making unlikely an accumulation of the drug. The differences in pharmacokinetics between day 1 and steady state were responsible for the initial underestimation of exposure and justified interrupting enrollment in this study. A subsequent study investigating doses of 50 mg once daily or less was initiated at that time. The results of the current study demonstrate in vivo antiviral activity of clevudine at all doses tested.
After 28 days of dosing, the median viral suppression ranged from 2.5 to 3 log10 copies/mL. Although historical comparisons are difficult because of differences in patient populations and HBV DNA assays, these values are within the range shown with other compounds. For instance, at week 12, lamivudine 150 mg once daily produced a reduction of 1.8 log10 copies/mL, whereas in association with famciclovir 1.5 g thrice daily, the average suppression was 2.5 log10 copies/mL.13 Entecavir demonstrated a 2.2 to 2.8 log10 copies/mL suppression after dosing with 0.05 to 1 mg once daily for 1 month.14 Adefovir 120 mg produced, after a similar duration of dosing, a median viral suppression of 1.8 log10 copies/mL,15 and 64% of the patients enrolled in a large phase III trial at the 10-mg once daily dose had 2 to 3 log10 copies/mL viral suppression after 24 weeks of dosing.3 A trend toward a dose relationship in antiviral activity was seen from 10 to 100 mg once daily; however, the 200-mg daily dose did not demonstrate an increased activity as compared with the 50-mg dose.
As a result of the lack of randomization and of the small sample size of this study, it is likely that systematic differences among patient characteristics at baseline have biased the interpretation of dose-activity relationship. Of note, in the 200-mg cohort, two patients had undetectable levels of viremia after 2 weeks, limiting the ability to measure the absolute change in HBV DNA levels (e.g., the maximal measurable change for these patients was 2.5 and 1.5 log10 copies/mL, respectively). Nevertheless, the Emax model suggests that the lowest dose of clevudine producing the maximal treatment effect should be close to 30 to 50 mg once daily. Further studies are underway to establish the dose of clevudine to be used in subsequent studies.
As shown in animal models, the drug exerts an ability to delay substantially the time to viral rebound after a short treatment period. The viral suppression after cessation of dosing seen in animal models also was observed in this study at all doses tested. This virological response translated into biochemical and serological responses 6 months after the end of 1 month of therapy. The rate of HBeAg loss (22%) and seroconversion (11%) seems unusually high in this short study, especially because the patient characteristics (i.e., most males and Asians having baseline ALT levels less than twice the upper limit of the normal range and high HBV DNA levels at entry) are known to be associated with a poor response. As an example, after 1 month of entecavir therapy, only 1 of 30 enrolled patients (3%) lost HBeAg at 6 months.14 After 28 days treatment with adefovir 125 mg, 1 of 15 patients (7%) seroconverted to HBe antibody.15 After 12 weeks of treatment with lamivudine, 1 of 9 patients (11%) seroconverted to HBeAb.13
The observations of delayed cases of exacerbation of hepatitis B are likely part of the natural history of the disease after a prolonged period of viral suppression without a complete response. The sequence of events where the peak in HBV DNA level precedes the ALT increase by several months concomitant with an HBV DNA level decline is the common pattern observed during the natural history of the disease.16
The viral suppression observed 24 weeks after the end of dosing represents the uniqueness of clevudine. The mechanism of action of clevudine leading to such a feature is speculative. This is an in vivo effect because in cell culture, the viral replication resumes as soon as the drug is removed.7, 9 The lack of mutations at 5 months after the end of therapy and the measured plasma half-life argue against persistent, suboptimal concentrations of clevudine in the liver. It is likely that this mechanism is independent of the HBV DNA polymerase inhibition. It has been demonstrated in woodchucks that clevudine suppressed covalently closed circular DNA in hepatocytes, leading to a more sustained viral suppression than that observed with other compounds.17 If such a mechanism of action exists in humans, a decrease in HBV reservoirs during the treatment period may explain the delayed time to viral rebound after the end of dosing. Another mechanism responsible for this viral suppression could be an immunomodulatory effect of clevudine. The apparent relationship between ALT increase and viral suppression seen in this study, and the unusual HBeAg seroconversion rate argue in favor of this last hypothesis. Studies in animal models and humans should help to define in vivo the mechanism of action of the drug. In conclusion, this short-term study of clevudine in patients chronically infected with HBV demonstrates that the drug is well tolerated and has substantial antiviral activity. The delayed time to viral recrudescence observed in association with biochemical and serological response is in agreement with the preclinical profile of clevudine. The virological response led to HBeAg seroconversion after just 28 days of therapy. Further studies with clevudine are underway to clarify its safety and efficacy at a larger scale.
The authors thank the L-FMAU-102 study team for their help in conducting the study: Dr. Jane Anderson, Dr. Nathalie Boyer, Pr. Fabien Calvo, Dr. Hye-Vi Cha, Dr. Eun Jeong Chang, Dr. Geum-Youn Gwak, Sandra Kroeker, Dr. Peter Kwan, Dr. Caroline Lascoux-Combe, Dr. Cary Moxham, Dr. Marianne Meynard-Muet, Amy Rigney, Scott Rose, Dr. George Szczech, and Theresa Thai.