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The METRO study (VX03-497-205) is registered with ClinicalTrials.gov (NCT00088504). The METRO study was funded by Vertex Pharmaceuticals Inc., the developer of MMPD. The authors had full access to the study data, and the corresponding author had final responsibility to prepare and submit the manuscript for publication.
Potential conflict of interest: Dr. Lee reports receiving consulting fees from AstraZeneca Pharmaceuticals, Eli Lilly and Co., and Fibrogen Inc., and grant support from Bristol-Myers Squibb, Roche, Schering-Plough Corp. Siemens, and Vertex Pharmaceuticals; Dr. Lawitz, grant support from Abbott Laboratories Anadys Pharmaceuticals, Inc., Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline GlobeImmune Inc., Human Genome Sciences, Idenix Pharmaceuticals, Idera Pharmaceuticals Intarcia Therapeutics, Inc., Medarex Inc., Merck & Co., Inc., Novartis, Roche, sanofi-aventis Schering-Plough Corp., Valeant Pharmaceuticals International, Vertex Pharmaceuticals, ViroChem Pharma (now Vertex Pharmaceuticals), and ZymoGenetics; Dr. Gordon, consulting fees and grant support from Roche, Schering-Plough Corp., and Vertex Pharmaceuticals; Dr. Afdhal, consulting and advisory fees from GlaxoSmithKline, Idenix Pharmaceuticals, Schering-Plough, and Vertex Pharmaceuticals, lecture fees from Bristol-Myers Squibb, Gilead Sciences, and Schering-Plough Corp, and grant support from Gilead Sciences, Schering-Plough Corp., and Vertex Pharmaceuticals; Dr. Poordad, consulting and advisory fees, as well as grant support, from Roche and Vertex Pharmaceuticals, and lecture fees from Roche; Dr. Bonkovsky, consulting fees from Boehringer-Ingelheim Corp. and Novartis, advisory fees from Novartis, lecture fees from Ovation (now Lundbeck Inc.), and grant support from Novartis, Roche, and Vertex Pharmaceuticals; Dr. McHutchison, consulting fees and grant support from Roche, Schering-Plough Corp., and Vertex Pharmaceuticals. Drs. Aalyson, Alam, Chandorkar and McNair are former employees of Vertex Pharmaceuticals. Drs. Bengtsson, Gharakhanian, Harding and Kauffman are employees of Vertex Pharmaceuticals.
Merimepodib (MMPD) is an orally administered, inosine monophosphate dehydrogenase inhibitor that has shown antiviral activity in nonresponders with chronic hepatitis C (CHC) when combined with pegylated interferon alfa 2a (Peg-IFN-alfa-2a) and ribavirin (RBV). We conducted a randomized, double-blind, multicenter, phase 2b study to evaluate the antiviral activity, safety, and tolerability of MMPD in combination with Peg-IFN-alfa-2a and RBV in patients with genotype 1 CHC who were nonresponders to prior therapy with Peg-IFN and RBV. Patients received 50 mg MMPD, 100 mg MMPD, or placebo every 12 hours, in addition to Peg-IFN-alfa-2a and RBV, for 24 weeks. Patients with a 2-log or more decrease from baseline or undetectable hepatitis C virus (HCV) RNA levels at week 24 were then eligible to continue Peg-IFN-alfa-2a and RBV for a further 24 weeks, followed by 24 weeks of follow-up. The primary efficacy endpoint was sustained virological response (SVR) rate at week 72 in all randomized patients who received at least one dose of study drug and had a history of nonresponse to standard therapy. A total of 354 patients were randomized to treatment (117 to placebo; 119 to 50 mg MMPD; 118 to 100 mg MMPD), and 286 completed the core study. The proportion of patients who achieved SVR was similar among the treatment groups: 6% (6/107) for 50 mg MMPD, 4% (5/112) for 100 mg MMPD, and 5% (5/104) for placebo (P = 0.8431). Adverse-event profiles for the MMPD combination groups were similar to that for Peg-IFN-alfa and RBV alone. Nausea, arthralgia, cough, dyspnea, neutropenia, and anemia were more common in patients taking MMPD. Conclusion: The addition of MMPD to Peg-IFN-alfa-2a and RBV combination therapy did not increase the proportion of nonresponder patients with genotype 1 CHC achieving an SVR. (HEPATOLOGY 2009.)
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Only half of patients with genotype 1 chronic hepatitis C (CHC) achieve a sustained virological response (SVR) to current treatment with combined pegylated interferon-alfa (Peg-IFN-alfa) and ribavirin (RBV),1–3 making this viral strain the most difficult to treat. Patients with genotype 1 CHC who do not respond to Peg-IFN-alfa and RBV combination therapy are a growing population, often characterized by African-American ethnicity, high viral load, advanced fibrosis or cirrhosis, or human immunodeficiency virus co-infection.4 Unfortunately, these virological nonresponders currently have limited therapeutic options, and retreatment with Peg-IFN-alfa/RBV is, for the most part, unsuccessful. For such nonresponders, a potential therapeutic alternative is to re-treat with more than two agents, in other words, to combine Peg-IFN-alfa/RBV with another novel agent.
Inhibition of inosine monophosphate dehydrogenase (IMPDH), a key component of de novo guanine synthesis, leads to a reduction in intracellular guanosine triphosphate, which is required for RNA synthesis during viral replication. One of the mechanisms of action of RBV, a nucleoside guanosine analog with broad-spectrum antiviral activity, includes inhibition of IMPDH.5, 6 More selective inhibitors of IMPDH are under development that have the potential to enhance the in vitro antiviral activity of RBV.5, 7 One such compound is merimepodib (MMPD; Vertex Pharmaceuticals Inc., Cambridge, MA), a competitive, selective, oral IMPDH inhibitor, which is structurally unrelated to other medications that show similar catalytic activity. It has been proposed that an IMPDH inhibitor, such as MMPD, may enhance the antiviral activity of RBV by depleting guanosine triphosphate, increasing the rate of incorporation of RBV into viral RNA, and rendering the virus nonfunctional.8 IMPDH inhibition therefore could represent an alternative strategy for improving the SVR rate in CHC patients.5
Earlier, small studies of patients with genotype 1 CHC (including treatment nonresponders) have suggested that MMPD may have additional antiviral activity when combined with other agents.9, 10 The primary objective of the current study was to evaluate the antiviral activity of two doses of MMPD (50 and 100 mg) administered in combination with current standard therapy (Peg-IFN-alfa and RBV) in genotype 1 CHC patients who did not respond to prior therapy with Peg-IFN-alfa and RBV. Secondary objectives were to assess the safety and tolerability of these combination regimens and to determine the pharmacokinetic (PK) profiles of MMPD and RBV and their relationship to efficacy and safety outcomes.
The MErimepodib TRiple cOmbination (METRO) study was a randomized, double-blind, placebo-controlled, parallel-group study conducted between July 2004 and October 2006. Patients were enrolled from 62 participating medical centers in the United States. Written informed consent was obtained from all patients before the initiation of the study. The study was approved by local institutional review boards and conducted in compliance with the guidelines of Good Clinical Practice and of the World Medical Assembly Declaration of Helsinki.
Male and female patients, aged 18 to 70 years, with a confirmed diagnosis of genotype-1 CHC that had not responded to prior treatment with Peg-IFN-alfa and RBV combination therapy, were enrolled. Nonresponse to previous therapy was defined as exposure to at least 12 weeks of therapy with an approved dose and regimen, with no documented undetectable levels of hepatitis C virus (HCV) RNA at any time. Depending on the available documentation of HCV RNA results during the prior course of therapy, the subject must have had either a week 12 HCV RNA result demonstrating a less than 2-log drop as compared with baseline HCV RNA, or week 24 HCV RNA results demonstrating detectable levels of HCV RNA.
If both week 12 and week 24 results were available from the prior course of therapy, then, the week 24 results were the primary factor in determining eligibility. If HCV RNA was detectable at week 24, the patient was eligible even if there was a 2-log or greater drop at week 12. Thus, patients who had a prior relapse or viral breakthrough were excluded. Patients were also excluded if they had contraindications to Peg-IFN-alfa or RBV therapy, a current or planned pregnancy, a recent history of significant alcohol or intravenous drug use, or a medical condition that could compromise the patient's safety or response to therapy.
Patients entered a screening period of up to 4 weeks. Eligible patients were then randomized through an interactive voice response system, in a 1:1:1 ratio, to receive 50 mg MMPD, 100 mg MMPD, or placebo orally every 12 hours. Randomization was stratified by baseline viral load (three strata: less than 0.8 × 106 IU/mL; 0.8 to less than 1.5 × 106 IU/mL; or at least 1.5 × 106 IU/mL). In addition to MMPD or placebo, all patients were treated with 180 μg Peg-IFN-alfa-2a (Pegasys, Roche Pharmaceuticals, Nutley, NJ), administered subcutaneously at weekly intervals according to standard practice, and 1000 or 1200 mg/day RBV (Copegus; Roche Laboratories, Inc., Nutley, NJ), administered orally and dosed according to body weight, 75 kg or less at baseline or greater than 75 kg at baseline, respectively. Patients and investigators were blinded to the MMPD or placebo treatment allocation, but Peg-IFN-alfa-2a and RBV treatments were given on an open-label basis.
In the first phase of the study (core study), all patients were treated for 24 weeks, with dosing starting on day 1 and visits scheduled at weeks 2, 4, 5, 8, 12, 16, 20, and 24. Antiviral response was assessed by plasma HCV RNA testing using the COBAS TaqMan HCV test (TaqMan HCV; Roche Molecular Systems, Branchburg, NJ).11 The lower limit of quantification and the limit of detection for this HCV RNA assay were 30 IU/mL and 10 IU/mL, respectively. Additional plasma and serum samples were collected at several study visits to assess the PK parameters of MMPD and RBV. At week 24, all patients discontinued MMPD or placebo but continued to receive Peg-IFN-alfa-2a and RBV until week 27, when the HCV RNA results from week 24 were available.
Entry into the second study phase (rollover phase) was determined by each patient's week 24 HCV RNA level. Patients with a less than 2-log decrease in baseline HCV RNA discontinued all study treatments and returned 4 weeks after their last dose of MMPD or placebo for a single follow-up visit (follow-up phase). Patients with undetectable HCV RNA or a 2-log or more decrease from baseline in HCV RNA continued to take Peg-IFN-alfa-2a and RBV until week 48 (rollover phase), returning for visits at weeks 36 and 48 (or the end of treatment). After the last dose, patients returned for follow-up visits at weeks 52, 60, and 72 (follow-up phase).
After administration of the first dose, blood samples were collected over a 6-hour period for PK analyses, and intensive blood sampling was conducted over a 4-hour period during weeks 12 and 24. Plasma MMPD and RBV levels were assessed by using a validated, specific, sensitive, and reproducible high-performance liquid chromatography methodology, as previously described.9 Standard noncompartmental methods were used to calculate the maximum concentration (Cmax), exposure, and apparent elimination half-life of MMPD and RBV.
Safety Assessment and Statistical Analyses.
Safety was assessed by physical examination, continuous adverse event and concomitant medication monitoring, and laboratory tests including hematology, blood chemistry, urinalysis, and electrocardiography (ECG) assessments. Adverse events were coded using the Medical Dictionary for Regulatory Activities and tabulated by system organ class and preferred term. Descriptive statistics and changes from baseline were reported for laboratory and vital sign data. Shift tables were produced for the ECG data.
The definition of the efficacy dataset was prospectively defined in the statistical analysis plan. The primary endpoint of the study was the proportion of patients with SVR, defined as undetectable plasma HCV RNA at week 24 of the follow-up phase. Secondary study endpoints were (1) the proportion of patients with at least a 2-log decrease from baseline or undetectable HCV RNA at weeks 12, 24, and 48; (2) the incidence of adverse events and clinically significant laboratory values; and (3) PK evaluations of MMPD and RBV when administered in combination with Peg-IFN-alfa-2a.
To show a statistically significant difference between any two treatment groups, 105 evaluable patients were needed in each of the three treatment groups. The sample size was determined based on a two-sided, continuity-corrected chi-squared test, a significance level of 5%, and a power of at least 80%. The proportion of responders was assumed to be 20% in any MMPD group and 5% in the control group.
The primary efficacy endpoint was assessed at the end of the follow-up phase using the full analysis efficacy set (that is, all randomized patients who received at least one dose of study drug during the core study and who had a history of nonresponse to standard treatment; see patient disposition section later). Comparisons between each MMPD group and placebo were made using a logistic regression model with treatment and baseline HCV RNA included as factors. All statistical tests carried out were two-sided, and the overall significance level was set to 0.05. Significance levels were adjusted using the procedure suggested by Hochberg.12
Patient Disposition and Baseline Characteristics.
A total of 521 patients were screened, and 354 were randomized. The number of patients in each treatment group and the patient disposition throughout each of the study phases are shown in Fig. 1. Thirty-one patients were excluded from the efficacy analysis because they did not meet all of the entry criteria. These discrepancies were identified during routine review of source documentation at the study sites, which occurred before database lock and data analysis. The most common reasons for ineligibility were insufficient documentation of viral load during prior therapy and prior therapy that did not meet the requirements defined in the protocol. These patients were excluded from all efficacy analyses because they were not considered part of the study population; however, they were included in all safety analyses.
Adverse events accounted for most of the discontinuations during the core study, and treatment failure was the reason for most of the discontinuations during the rollover phase.
Baseline patient characteristics were generally similar across the three patient groups (Table 1). The overall study population was 65% men and 35% women; the median age was 50 years (range, 19-68 years). Overall, 96% of patients had high baseline serum HCV RNA (≥800,000 IU/mL). The median duration of CHC and median baseline HCV RNA varied somewhat across the three groups.
Table 1. Baseline Characteristics and Demographics of Randomized Patients in the Core Study
The primary efficacy analysis did not demonstrate any differences among the three treatment groups in the proportion of patients who achieved SVR (undetectable HCV RNA at end of the follow-up phase: 24 weeks after stopping all treatment for CHC). The proportion of patients who achieved SVR was 6% (6/107) for 50 mg MMPD, 4% (5/112) for 100 mg MMPD, and 5% (5/104) for placebo (P = 0.8431; Fig. 2). There were also no differences among the groups in the proportion of patients who had undetectable HCV RNA at either week 12, week 24, or week 48 (end of treatment) (Fig. 2). The proportion of patients who achieved SVR was 6% (8/134) in the MMPD-containing regimen versus 7% (5/71) for placebo in white patients; 5% (3/61) in the MMPD-containing regimen versus 0% (0/23) for placebo in black patients; and 0% (0/20) in the MMPD-containing regimen versus 0% (0/8) for placebo in Hispanic patients.
Plasma concentrations of MMPD increased rapidly after administration of MMPD, achieving a median Cmax of 1154 ng/mL on day 1 in the 50-mg dose group. The corresponding median Cmax of MMPD at week 12 and week 24 was 1306 ng/mL and 883 ng/mL, respectively, indicating comparable Cmax over the duration of treatment with the 50-mg dose. The median apparent elimination half-life in the 50-mg dose group was 1.37 hours on day 1, 1.28 hours at week 12, and 1.08 hours at week 24, indicating similar changes in the elimination of MMPD after repeated dosing. The corresponding median exposure to MMPD also did not change markedly over the course of the treatment (2179, 2092, and 1829 ng · hour/mL, respectively), indicating that MMPD did not accumulate in the body during the course of treatment.
The median Cmax measurements of MMPD in patients treated with the 100-mg dose were 1590, 1590, and 1056 ng/mL on day 1, week 12, and week 24, respectively. The median apparent elimination half-life of MMPD in the 100-mg dose group was 1.53, 1.19, and 1.50 hours on day 1, week 12, and week 24, respectively. The corresponding median exposure to MMPD was 3437, 3821, and 2439 ng · hour/mL on day 1, week 12, and week 24, respectively. The exposure to MMPD appeared to rise with an increase in dose; however, the increase was not dose-linear.
More than 95% of patients in each of the three groups experienced adverse events during the core study. Most (>92%) of these adverse events were considered by the investigator to be related to a study drug (placebo, MMPD, Peg-IFN-alfa-2a, or RBV). The most common adverse event reported in the two combined MMPD groups was fatigue (61%, 114/237); however, fatigue was slightly more common in the placebo group (66%, 77/117) than in the MMPD groups (Table 2). Nausea, arthralgia, neutropenia, and anemia occurred slightly more frequently in patients receiving 100 mg MMPD than in those receiving placebo or 50 mg MMPD.
Table 2. Adverse Events Reported by At Least 10% of Patients in the Core Study (Full Analysis Set)
System Organ Class Preferred Term
Placebo n = 117 n (%)
50 mg n = 119 n (%)
100 mg n = 118 n (%)
Total n = 237 n (%)
Any adverse event
General disorders and administration site conditions
Injection site erythema
Nervous system disorders
Skin and subcutaneous tissue disorders
Musculoskeletal and connective tissue disorders
Respiratory, thoracic, and mediastinal disorders
Blood and lymphatic system disorders
Events that accounted for more than half of the adverse events in the total study population included general disorders and administration site reactions (76%, 180/237, in the combined MMPD groups; 85%, 99/117, in the placebo group), gastrointestinal disorders (59%, 139/237, and 61%, 71/117 respectively), and nervous system disorders (51%, 121/237 and 58%, 68/117, respectively). These adverse events were considered related to a study drug at least as often in the placebo group as in the combined MMPD groups.
During the core study, four patients in the 50-mg MMPD group experienced six serious adverse events (SAEs), six patients in the 100-mg MMPD group experienced nine SAEs, and five patients in the placebo group experienced six AEs. No deaths occurred during the core study. The SAEs reported during the core study that were judged by the investigator to be at least possibly related to a study drug were anxiety, auditory hallucinations, and suicidal ideation (considered related to MMPD and Peg-IFN-alfa-2a in one patient in the 50-mg MMPD group); global amnesia (considered related to MMPD and Peg-IFN-alfa-2a in one patient in the 100-mg MMPD group); diarrhea (considered related to MMPD and Peg-IFN-alfa-2a in one patient in the 100-mg MMPD group); suicidal ideation (considered related to all three study drugs in one patient in the 100-mg MMPD group); and pneumonia and nephrolithiasis (considered related to all three study drugs in one patient in the placebo group). During the rollover phase, two patients who had been treated with MMPD in the core study (one patient from each MMPD dose group) experienced an SAE: pyrexia in one patient in the 50-mg MMPD group (considered not related to the study drugs) and perforated appendicitis in one patient in the 100-mg MMPD group (considered not related to the study drugs).
Three patients died during the rollover and follow-up phases of the study. One patient in the 50-mg MMPD group died of interstitial pneumonitis during the rollover phase; this death was considered related to MMPD, Peg-IFN-alfa-2a, and RBV. Two patients died in the placebo group (one due to myocardial infarction during the rollover phase and one as a result of a car accident at the end of the follow-up phase); these deaths were considered unrelated to the study drugs.
A total of 25 patients discontinued the study because of adverse events. No one adverse event was the cause of discontinuation for more than three patients in either of the MMPD groups. Six patients discontinued the study as a result of laboratory abnormalities documented as adverse events: four of neutropenia (two in the 50-mg MMPD group, one in the 100-mg MMPD group, and one in the placebo group), one because of alanine aminotransferase/aspartate aminotransferase (ALT/AST) elevations (day 1, ALT 215 U/L and AST 211 U/L which increased to ALT 270 IU/mL and ALT 277 U/L at day 138; placebo group), and one because of mild anemia (placebo group).
There were no clinically relevant changes over time or differences in vital signs across treatment groups. One patient in the placebo group who had a normal ECG at baseline had a clinically significant abnormal ECG at week 6 of treatment.
In this study, assessment of the full analysis efficacy set showed that the proportions of patients with undetectable HCV RNA at the end of the follow-up phase were similar in the 50-mg MMPD, 100-mg MMPD, and placebo groups. Thus, the data indicated that the addition of MMPD to Peg-IFN-alfa-2a and RBV combination therapy did not increase the proportion of patients achieving SVR.
This study was conducted because the scientific and preclinical data suggested that an IMPDH inhibitor, such as MMPD, might increase the antiviral effects of RBV. In vitro experiments have shown that MMPD has broad-spectrum antiviral activity against a variety of DNA and RNA viruses, with similar activity to RBV.7 Furthermore, data obtained using the HCV subgenomic replicon system have indicated that MMPD may have additive effects when combined with RBV.8 The concept was clinically supported by the preceding phase 2 study, which showed that the addition of MMPD to Peg-IFN-alfa and RBV increased the antiviral effect of the regimen, thereby increasing the proportion of patients who achieved undetectable HCV-RNA during treatment.10 In addition to the lack of an increase in the SVR rate in the current study, the earlier finding of increased antiviral activity during treatment was not confirmed in the current study. There are two fundamental differences between the study of Marcellin et al.10 and the METRO study that might account for the disparate outcomes. First, the prior study included nonresponders to standard IFN and RBV, whereas the METRO study included nonresponders to Peg-IFN-alfa and RBV. The results from EPIC3 (Evaluation of PegIntron in Control of Hepatitis C Cirrhosis) indicate that the responsiveness to Peg-IFN-alfa and RBV retreatment in standard IFN/RBV nonresponders with genotype 1 CHC is greater than that seen in Peg-IFN-alfa/RBV nonresponders (SVR of 13% versus 4%, respectively).13 As a result, the patient population in the METRO study may represent a more difficult-to-treat population, for which drugs with an IMPDH mechanism may not be adequate to increase the proportion of patients who achieve undetectable HCV-RNA. A second potential explanation for the variant results relates to differences in the RBV dosing regimens that were used in the two studies. Marcellin et al.10 used a weight-based regimen that provided between 800 and 1200 mg of RBV, whereas in the METRO study, the standard RBV regimen used in conjunction with Peg-IFN-alfa-2a was 1000 mg or 1200 mg, based on body weight. The IDEAL (Individualized Dosing Efficacy vs. Flat Dosing to Assess Optimal Pegylated Interferon Therapy) study has shown that the latter regimen delivers more RBV to patients than an 800-mg to 1400-mg dosing regimen.14 Thus, it is likely that the patients in the METRO study, including those in the control arm, received more RBV than those in the study of Marcellin et al.10 Therefore, to the extent that the scientific rationale for use of MMPD is based on improving the effects of RBV, it may be that by receiving less RBV, the patients in the prior study had a greater capacity to show an increased RBV effect (in other words, they had more room for improvement). Finally, it is not uncommon for drugs, such as MMPD, that have demonstrated positive signals in small studies to fail to provide definitive benefits, in this case improved SVR, in larger-scale studies. It is also notable that this IMPDH inhibitor did not seem to improve relapse rates.
The safety profile of MMPD administered in combination with Peg-IFN-alfa-2a and RBV was consistent with that of Peg-IFN-alfa-2a and RBV15, 16 and with findings from earlier studies of MMPD.9 The most common adverse events among patients who received MMPD included fatigue, nausea, arthralgia, abdominal pain, diarrhea, and headache.
A number of mechanisms have been proposed for how RBV improves the response to IFN-based treatment of hepatitis C infection, including inhibition of IMPDH, immunomodulation of T-helper 1 and T-helper 2 responses, inhibition of the nonstructural protein 5B RNA-dependent RNA polymerase, and virus mutagenesis/error catastrophe.17 MMPD was developed as a selective inhibitor of IMPDH. Data from the current study showed no statistically significant differences in SVR rates between MMPD (50 or 100 mg) and placebo when administered in combination with Peg-IFN-alfa-2a and RBV for 24 weeks, followed by 24 additional weeks of Peg-IFN-alfa-2a and RBV treatment alone. PK analysis confirmed that the MMPD exposure level was comparable to that observed in previous studies. Taken together, these results suggest that IMPDH inhibition is not a major determinant of the antiviral effects of RBV in patients with CHC.
The development of MMPD has been halted because the primary efficacy analysis showed no difference in efficacy between MMPD and placebo in combination therapy with Peg-IFN-alfa-2a and RBV. Similar efforts with other IMPDH inhibitors have also met with limited success.18–20 Although standard therapy continues to be optimized for improved SVR rates, there is promise in specifically targeted antiviral therapies for hepatitis C.
The authors thank all the patients and their families for their participation and support during the study. In addition to the authors, the METRO study group included the following investigators and contributors to the design, conduct, and analysis of the study: Victor Araya, M.D., Philadelphia, PA; Vijayan Balan, M.D., Phoenix, AZ; Luis Balart, M.D., New Orleans, LA; Robert Be, M.D., Baton Rouge, LA; Michael Bennett, M.D., San Diego, CA; David Bernstein, M.D., Manhasset, NY; Bal Raj Bhandari, M.D., Monroe, LA; George Burnazian, M.D., Houston, TX; Natalie Bzowej, M.D., Ph.D., San Francisco, CA; Robert Carithers Jr., M.D., Seattle, WA; Ramsey Cheung, M.D., Palo Alto, CA; Joseph L. Cochran, M.D., Birmingham, AL; Gary Davis, M.D., Dallas, TX; Michael P. DeMicco, M.D., F.A.C.G., Anaheim, CA; Adrian Di Bisceglie, M.D., St. Louis, MO; Douglas T. Dieterich, M.D., New York, NY; Michael Epstein, M.D., Annapolis, MD; Shaban Faruqui, M.D., Baton Rouge, LA; Steven L. Flamm, M.D., Chicago, IL; Donald R. Graham, M.D., Springfield, IL; John B. Gross, M.D., Rochester, MN; Ellen Hunter, M.D., Boise, ID; Ira Jacobson, M.D., New York, NY; Prahalad B. Jajodia, M.D., Dinuba, CA; Mark Jonas, M.D., Cincinnati, OH; Suresh Karne, M.D., Ph.D., Huntsville, AL; Alvaro Koch, M.D., Lexington, KY; Milton J. Koch, M.D., Silver Spring, MD; George Koval, M.D., Portland, OR; Marcello Kugelmas, M.D., Englewood, CO; Arnold Lentnek, M.D., Marietta, GA; Michael F. Lyons, M.D., Tacoma, WA; David McEniry, M.D., Tacoma, WA; Gerald Mingolelli, M.D., Oak Forrest, IL; Peter J. Molloy, M.D., Pittsburgh, PA; Andrew J. Muir, M.D., Durham, NC; Lisa Nyberg, M.D., San Diego, CA; Daniel John Pambianco, M.D., Charlottesville, VA; Robert Perrillo, M.D., New Orleans, LA; Donald Poretz, M.D., Annandale, VA; John Poulos, M.D., Fayetteville, NC; Rajendra Prasad Gupta, M.D., Trenton, NJ; Ronald Pruitt, M.D., Nashville, TN; Jeffrey Rank, M.D., St. Paul, MN; Natarajan Ravendhran, M.D., Baltimore, MD; Robert W. Reindollar, M.D., Charlotte, NC; Robert R. Schade, M.D., Augusta, GA; Eugene R. Schiff, M.D., Miami, FL; David N. Schwartz, M.D., Attleboro, MA; Lawton Shick, M.D., Worcester, MA; Mitchell L. Shiffman, M.D., Richmond, VA; William C. Sloan, M.D., Florham Park, NJ; Jill P. Smith, M.D., Hershey, PA; Rise Stribling, M.D., Houston, TX; James S. Strohecker, M.D., Columbia, SC; Mark Sulkowski, M.D., Baltimore, MD; Harvey Arthur Tatum, M.D., Tulsa, OK; Jawahar Taunk, M.D., Palm Harbor, FL; Helen Te, M.D., Chicago, IL; Myron J. Tong, M.D., Ph.D., Pasadena, CA; Robert Wohlman, M.D., Bellevue, WA; and Lawrence Wruble, M.D., Germantown, TN.
The authors also acknowledge the valuable contribution of the study coordinators and sub-investigators, as well as Paula Michelle del Rosario and David Cutler (Gardiner-Caldwell Communications, Macclesfield, UK) and Karen Eisenhauer and Lily Yeh Lee (Vertex) for their editorial assistance in drafting the manuscript and collating author contributions.