Final results of a multicenter phase II study of the purine nucleoside phosphorylase (PNP) inhibitor forodesine in patients with advanced cutaneous t-cell lymphomas (CTCL) (Mycosis fungoides and Sézary syndrome)

Author: Dr. Jenna Elder

Background: Forodesine is a potent inhibitor of purine nucleoside phosphorylase (PNP) that leads to intracellular accumulation of deoxyguanosine triphosphate (dGTP) in T and B cells, resulting in apoptosis. Forodesine has demonstrated impressive antitumor activity in early phase clinical trials in cutaneous T-cell lymphoma (CTCL).

Methods: In this phase II study, patients with CTCL who had already failed three or more systemic therapies were recruited. We investigated the response rate, safety and tolerability of oral forodesine treatment in subjects with cutaneous manifestations of CTCL, stages IB, IIA, IIB, III and IVA. The safety population encompassing all stages was used for analysis of accountability, demographics and safety. The efficacy population differed from the safety population by exclusion of stage IB and IIA patients.

Results: All 144 patients had performance status 0–2. The median duration of CTCL from diagnosis was 53 months (5–516 months). The median number of pretreatments was 4 (range: 3–15). No complete remissions were observed. In the efficacy group of patients, 11% achieved partial remission and 50% had stable disease. The median time to response was 56 days and the median duration of response was 191 days. A total of 96% of all treated patients reported one or more adverse events (AEs) and 33% reported a serious AE. The majority of AEs were classified as mild or moderate in severity. The most commonly reported AEs (>10%) were peripheral edema, fatigue, insomnia, pruritus, diarrhea, headache and nausea. Overall eight patients died during the study: five due to sepsis and infections, one due to a second malignancy (esophageal cancer), one due to disease progression and one due to liver failure.

Conclusions: Oral forodesine at a dose of 200 mg daily is feasible and shows partial efficacy in this highly selected CTCL population and some durable responses.

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Evaluation of Intravenous Peramivir for Treatment of Influenza in Hospitalized Patients

Author: Dr. Jenna Elder

Background: Seasonal influenza causes >200 000 annual hospitalizations in the United States. Current antiviral treatment options are limited to oral or inhaled agents. There is an urgent unmet need for intravenous antiviral treatments.

Methods: Patients hospitalized with suspected influenza were randomized to 5-day treatment with intravenous peramivir (600 mg once daily) or placebo; all received the institution's standard of care (SOC) treatment. Time to clinical resolution and change in viral shedding in nasopharyngeal specimens were the primary and key secondary end points.

Results: Influenza infection was confirmed in 338 of 405 enrolled patients. At the time of a preplanned interim analysis, the primary efficacy analysis population comprised 121 patients who did not receive a concurrent neuraminidase inhibitor as part of the SOC. The median (95% confidence interval) time to clinical resolution was 42.5 (34.0–57.9) hours for peramivir versus 49.5 (40.0–61.9) hours for placebo (P = .97). A larger treatment effect was observed in patients with history of symptoms <48 hours or admitted to an intensive care unit. Greater reductions in viral shedding, based on median tissue culture infective dose, were observed in patients who received peramivir than in placebo recipients, although this difference was not statistically significant. The incidence and severity of adverse events and laboratory abnormalities were similar between the 2 treatment groups. The study was terminated for futility after a preplanned interim analysis.

Conclusions: A significant clinical benefit was not demonstrated for peramivir plus SOC compared with placebo plus SOC. Peramivir was generally safe and well tolerated. These findings highlight the challenges in designing studies to evaluate influenza antiviral agents in a hospitalized setting.

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Clinical Experience in Adults and Children Treated with Intravenous Peramivir for 2009 Influenza A (H1N1) Under an Emergency IND Program in the United States

Author: Dr. Jenna Elder

Background: Peramivir, an investigational intravenous neuraminidase inhibitor in Phase 3 trials for hospitalized patients, was made available during the 2009 H1N1 influenza pandemic under the Emergency Investigational New Drug (eIND) regulations. We describe the clinical characteristics and outcomes of all patients for whom peramivir was requested under the eIND.

Methods: After obtaining eIND approval from the Food and Drug Administration and local institutional review board approval, clinicians caring for hospitalized patients with influenza administered intravenous peramivir and collected information on demographic characteristics, clinical characteristics, and outcomes.

Results: From April through October 2009, peramivir was requested for 42 patients and administered to 20 adults and 11 children. At hospitalization, all patients had rapidly progressing, radiographically confirmed viral pneumonia with respiratory failure, and all but 1 patient required mechanical ventilation. In most patients, including 1 person with documented oseltamivir-resistant infection, the illness had progressed despite oseltamivir treatment. Peramivir was administered for 1–14 days (median duration, 10 days). The 14-day, 28-day, and 56-day survival rates were 76.7%, 66.7%, and 59.0%, respectively. Peramivir was generally well tolerated.

Conclusions: Intravenous peramivir was well tolerated and was associated with recovery in most patients hospitalized with severe 2009 H1N1 influenza viral pneumonia and treated under an eIND.

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Assessing teratogenicity of antiretroviral drugs: monitoring and analysis plan of the Antiretroviral Pregnancy Registry

Author: Dr. Jenna Elder

Abstract: This paper describes the Antiretroviral Pregnancy Registry's (APR) monitoring and analysis plan. APR is overseen by a committee of experts in obstetrics, pediatrics, teratology, infectious diseases, epidemiology and biostatistics from academia, government and the pharmaceutical industry. APR uses a prospective exposure-registration cohort design. Clinicians voluntarily register pregnant women with prenatal exposures to any antiretroviral therapy and provide fetal/neonatal outcomes. A birth defect is any birth outcome > or = 20 weeks gestation with a structural or chromosomal abnormality as determined by a geneticist. The prevalence is calculated by dividing the number of defects by the total number of live births and is compared to the prevalence in the CDC's population-based surveillance system. Additionally, first trimester exposures, in which organogenesis occurs, are compared with second/third trimester exposures. Statistical inference is based on exact methods for binomial proportions. Overall, a cohort of 200 exposed newborns is required to detect a doubling of risk, with 80% power and a Type I error rate of 5%. APR uses the Rule of Three: immediate review occurs once three specific defects are reported for a specific exposure. The likelihood of finding three specific defects in a cohort of < or = 600 by chance alone is less than 5% for all but the most common defects. To enhance the assurance of prompt, responsible, and appropriate action in the event of a potential signal, APR employs the strategy of 'threshold'. The threshold for action is determined by the extent of certainty about the cases, driven by statistical considerations and tempered by the specifics of the cases.

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A Quasi-Likelihood Approach for Overdispersed Binomial Data When N Is Unobserved

Author: Dr. Jenna Elder

Abstract: Several methods for the analysis of binomial data when the denominator, N, is unknown have been developed. Each of these methods requires that the mean of the distribution of N is known. In this article, we develop a quasi-likelihood technique that allows for the estimation of the means of the distributions needed to define the expected value and variance of the observed response and suggest a different form of the variance function. We illustrate the results of the proposed analysis and the results obtained when the mean of the distribution of N is assumed known through the analysis of a surviving jejunal crypt data set. Although the proposed method shows inflated standard errors of the parameter estimates in the cited example, the proposed method performs as well as a previously published method in all simulated conditions. Moreover, in cases where E(N) is misspecified, the proposed method outperforms the previously published method.

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Evaluation of the Safety, Pharmacokinetics, Pharmacodynamics, and Efficacy After Single and Multiple Dosings of LY3016859 in Healthy Subjects and Patients With Diabetic Nephropathy

Author: Dr. Amy Flynt

Abstract: Two phase 1 studies (TGAA and TGAB) evaluated the safety, pharmacokinetics, pharmacodynamics, and efficacy of LY3016859 (LY), a monoclonal antibody that binds epiregulin and transforming growth factor α (TGF-α), administered intravenously or subcutaneously. In TGAA, 56 healthy subjects received a single dose of LY (0.1-750 mg intravenously, 50 mg subcutaneously) or placebo. In TGAB part A, 15 patients with diabetic nephropathy (DN) received 2 doses of LY (10-750 mg intravenously) or placebo, and in TGAB part B, 45 patients with DN received 5 doses of LY (50-750 mg intravenously) or placebo. Pharmacokinetics, pharmacodynamics, anti-LY antibodies, and change in proteinuria and albuminuria were evaluated. Single and multiple doses of LY administered 3 weeks apart were well tolerated. Pharmacokinetics were nonlinear in healthy subjects and patients with DN, indicating target-mediated drug disposition. Epiregulin level increased in both studies, and TGF-α levels increased in the TGAB study, consistent with target engagement; however, LY treatment did not significantly reduce proteinuria or albuminuria in patients with DN. There was no obvious effect of LY on the disease-related biomarkers monocyte chemoattractant protein-1, synaptopodin, or transferrin. Although LY administration resulted in a high frequency of anti-LY antibodies, pharmacokinetics, target engagement, and efficacy were not impacted.

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Single Dose IV Peramivir is Safe and Effective in the Treatment of Pediatric Influenza

Author: Dr. Amy Flynt

Background: Peramivir (PVR) is a potent neuraminidase inhibitor with in vitro activity against all influenza virus subtypes. Previous studies demonstrated the efficacy and safety of PVR as a single dose intravenous (IV) treatment for acute uncomplicated influenza in adults.

Methods: A phase 3 study compared age-appropriate doses of single dose IV PVR to 5 days of oral oseltamivir (OSE) (4:1 randomization, stratified by age) in pediatric subjects age 0 -17 years within 48 hours of onset of acute uncomplicated influenza. Plasma concentrations of PVR were measured up to 6 hours post dose. Serial viral titers were measured from nasopharyngeal swabs. Severity of influenza signs and symptoms were recorded in a diary.

Results: 122 subjects were enrolled up to a data cutoff of March 31, 2017 (<2 yrs, n = 7; 2-<7yrs, n = 37; 7-<13 yrs, n = 48; 13–17 yrs, n = 30). Interim results are reported for the first 108 subjects randomized, of which 101 (94%) received study drug. Influenza was confirmed by PCR in 75 (74%) subjects who received study drug (Intent-to-treat-Infected [ITTI] population).

Conclusions: Treatment of influenza in pediatric subjects with single dose IV PVR or 5 days of oral OSE was generally safe and well tolerated. Whilst not powered for efficacy differences, trends were observed in more rapid reduction in virus shedding and symptom alleviation for PVR treated subjects compared with OSE. The study continues to enroll subjects < 7 years.

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LY3045697: Results from two randomized clinical trials of a novel inhibitor of aldosterone synthase

Author: Dr. Amy Flynt

Background: LY3045697 is a potent and selective aldosterone synthase (CYP11B2) inhibitor that was developed as a safer alternative to mineralocorticoid receptor antagonists. Effects of LY3045697 on aldosterone and cortisol synthesis, as well as potassium ion homeostasis, were evaluated in two clinical studies in healthy subjects.

Methods: Two incomplete, placebo-controlled crossover-design clinical studies examined safety, pharmacodynamics, and pharmacokinetics under single and repeated dose conditions in healthy subjects. Pharmacodynamics was assessed following oral potassium challenge and intravenous adrenocorticotropic hormone procedures with spironolactone 25 mg/d as an active comparator.

Results: A total of 51 subjects participated in the two studies, which included 38 males and 13 females (of non-childbearing potential), from 18-65 years old. LY3045697 caused rapid dose and concentration-dependent unstimulated plasma aldosterone concentration reduction seen as early as 4 h after the first dose at dose levels as low as 1 mg, and reaching near complete suppression at high doses. The potency (IC50) decreased significantly upon multiple dosing. After eight days of dosing, post-adrenocorticotropic hormone challenge plasma aldosterone concentration increase was dose-dependently blunted by LY3045697 with high potency with a dose as low as 0.1 mg resulting in substantial effect, and with an overall IC50 of 0.38 ng/ml. Minor reductions in cortisol were observed only at the top dose of 300 mg. LY3045697 is generally safe and tolerated, and exhibits linear pharmacokinetics.

Conclusions: LY3045697 is a potent and highly selective aldosterone synthase inhibitor with selectivity for CYP11B2, offering a substantial potential advantage over previous aldosterone synthase inhibitors evaluated in the clinic.

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Prognostic and predictive value of circulating tumor cells and CXCR4 expression as biomarkers for a CXCR4 peptide antagonist in combination with carboplatin-etoposide in small cell lung cancer: exploratory analysis of a phase II study

Author: Dr. Amy Flint

Abstract: Circulating tumor cells (CTCs) and chemokine (C-X-C motif) receptor 4 (CXCR4) expression in CTCs and tumor tissue were evaluated as prognostic or predictive markers of CXCR4 peptide antagonist LY2510924 plus carboplatin-etoposide (CE) versus CE in extensive-stage disease small cell lung cancer (ED-SCLC). Methods This exploratory analysis of a phase II study evaluated CXCR4 expression in baseline tumor tissue and peripheral blood CTCs and in post-treatment CTCs. Optimum cutoff values were determined for CTC counts and CXCR4 expression in tumors and CTCs as predictors of survival outcome. Kaplan-Meier estimates and hazard ratios were used to determine biomarker prognostic and predictive values. Results There was weak positive correlation at baseline between CXCR4 expression in tumor tissue and CTCs. Optimum cutoff values were H-score ≥ 210 for CXCR4+ tumor, ≥7% CTCs with CXCR4 expression (CXCR4+ CTCs), and ≥6 CTCs/7.5 mL blood. Baseline H-score for CXCR4+ tumor was not prognostic of progression-free survival (PFS) or overall survival (OS). Baseline CXCR4+ CTCs ≥7% was prognostic of shorter PFS. CTCs ≥6 at baseline and cycle 2, day 1 were prognostic of shorter PFS and OS. None of the biomarkers at their respective optimum cutoffs was predictive of treatment response of LY2510924 plus CE versus CE. Conclusions In patients with ED-SCLC, baseline CXCR4 expression in tumor tissue was not prognostic of survival or predictive of LY2510924 treatment response. Baseline CXCR4+ CTCs ≥7% was prognostic of shorter PFS. CTC count ≥6 at baseline and after 1 cycle of treatment were prognostic of shorter PFS and OS.

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A randomized phase II study of LY2510924 and carboplatin/etoposide versus carboplatin/etoposide in extensive-disease small cell lung cancer

Author: Dr. Amy Flynt

Background: This multicenter, open-label, randomized phase II study evaluated the efficacy and safety of LY2510924 (LY) added to first-line standard of care (SOC) chemotherapy for extensive-disease small cell lung cancer (ED-SCLC) and explored the predictive value of C-X-C motif receptor 4 (CXCR4) tumor response.

Methods: Patients with treatment-naïve ED-SCLC were randomized (1:1) to receive up to six 21-day cycles of carboplatin/etoposide alone (SOC) or in combination with 20mg LY2510924 administered subcutaneously on days 1-7 of each cycle (LY+SOC). The primary efficacy endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS), overall response rate (ORR), and safety. Response relative to CXCR4 expression on baseline tumor was an exploratory endpoint.

Results: Of 94 patients randomized, 90 received treatment (LY+SOC, n=47; SOC, n=43). Median PFS (95% confidence interval [CI]) was 5.88 (4.83, 6.24) months for LY+SOC versus 5.85 (4.63, 5.51) months for SOC (hazard ratio [95% CI], 1.01 [0.62, 1.63]; p=0.9806). Median OS (95% CI) was 9.72 (6.64, 11.70) months for LY+SOC versus 11.14 (8.25, 13.44) months for SOC. ORR was 74.5% for LY+SOC versus 81% for SOC. Safety results between arms were similar, although the following adverse events were more frequent on the LY+SOC arm: anemia (61.7% vs 46.5%), neutropenia (61.7% vs 53.5%), leukopenia (27.7% vs 9.3%), vomiting (27.7% vs 16.3%), and pneumonia (10.6% vs 2.3%). In patients whose baseline CXCR4 expression was above the optimal cutoff (H-score 210), the hazard ratio (95% CI) was 1.27 (0.51, 3.15).

Conclusions: LY2510924 did not improve efficacy but had an acceptable toxicity profile when added to SOC for ED-SCLC.

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A Randomized, Open-Label Phase 2 Study of the CXCR4 Inhibitor LY2510924 in Combination with Sunitinib Versus Sunitinib Alone in Patients with Metastatic Renal Cell Carcinoma (RCC)

Author: Dr. Amy Flynt

Background: The chemokine (C-X-C Motif) receptor 4 (CXCR4) and its ligand, stromal-cell derived factor-1 (SDF-1), are frequently overexpressed in a variety of solid tumors, and are believed to play important roles in the regulation of organ-specific metastasis, tumor growth, invasion, and survival. In this randomized Phase 2 trial, we evaluated the safety and efficacy of LY2510924 (LY), a peptide antagonist of CXCR4, combined with sunitinib (SUN) in the first-line treatment of advanced renal cell carcinoma (RCC).

Methods: Eligible patients were randomized (2:1) to receive LY (20 mg SC daily) + SUN (50 mg PO daily for 4 weeks followed by 2 weeks off) or SUN alone. Response was assessed after two cycles; patients continued treatment until tumor progression or intolerable toxicity. The study was powered to detect a 47 % increase in median progression-free survival (PFS).

Results: One hundred eight patients were randomized and treated (LY + SUN, 72; SUN, 36); median duration of treatment of five cycles. Observed median PFS was 8.1 months with LY + SUN and 12.3 months with SUN; Bayesian time-to-event HR 1.23; 95 % credible interval: 0.74, 1.96. LY was well tolerated; the toxicity profile was typical of SUN. No efficacy differences were seen between treatments groups when subsets with high versus low levels of CXCR4 tumor expression were compared.

Conclusions: The addition of LY to SUN in the first-line treatment of metastatic RCC was well tolerated, but did not improve the PFS or overall survival (OS) vs. SUN alone. CXCR4 remains an unproven therapeutic target for the treatment of RCC.

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FRI0367 BCX4208 added to allopurinol increases response rates in patients with GOUT who fail to reach goal range serum uric acid on allopurinol alone: A randomized, double-blind, placebo-controlled trial

Author: Dr. Amy Flynt

Background: CX4208, a novel purine nucleoside phosphorylase inhibitor, blocks uric acid production at a step preceding xanthine oxidase and synergistically reduces serum urate concentration (sUA) in gout patients when combined with allopurinol. To assess the sUA response to the addition of placebo or one of 4 doses of BCX4208 to 300 mg/d allopurinol in gout patients with sUA ≥6.0 mg/dL on allopurinol alone. Primary endpoint was the proportion of BCX4208-treated subjects achieving sUA goal range (<6.0 mg/dL) at 12 weeks compared with placebo.

Methods: 278 adult subjects (M:F =266:12) with gout and sUA ≥6.0 mg/dL despite allopurinol 300 mg/d for at least 2 weeks were randomized and received oral placebo or BCX4208 5, 10, 20, or 40 mg/d for 12 weeks while continuing allopurinol 300 mg/d. On-study assessments were performed at 2, 4, 8, and 12 weeks of treatment. Subjects received colchicine 0.6 mg/d or naproxen 220 mg to 250 mg BID for gout flare prophylaxis. Data from subjects who received >1 dose of study drug and had at least one on-study sUA assessment (modified intention-to-treat [mITT] population) were analyzed. Missing data were imputed using the last observation carried forward method.

Results: Demographic, comorbid, and gout characteristics of the study population were evenly distributed in the study arms. Mean (SD) age was 49 (10) years and BMI was 36 (7) kg/m2 in the predominantly white (73%) population, with high prevalences of hypertension (58%), diabetes (16%), and hypercholesterolemia (39%). BCX4208 added to allopurinol 300 mg/d brought more patients to goal range sUA compared with placebo. Differences between the BCX4208 5, 20, and 40 mg/d arms and placebo were significant. Five to 11% of subjects per arm experienced ≥1 gout flare during treatment. Frequency and severity of adverse events, including infections, were evenly distributed across dose groups.

Conclusions: Addition of BCX4208 to allopurinol 300 mg/d allows a significantly greater proportion of gout patients to achieve goal range sUA than addition of placebo. Twelve weeks of BCX4208 daily dosing is generally safe and well-tolerated when combined with allopurinol.

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A clinical trial of intravenous peramivir compared with oral oseltamivir for the treatment of seasonal influenza in hospitalized adults

Author: Dr. Amy Flynt

Background: Seasonal interpandemic influenza causes >200,000 annual hospitalizations in the United States. Optimal antiviral treatment in hospitalized patients is not established.

Methods: During three interpandemic influenza seasons, 137 patients hospitalized with suspected acute influenza were randomized to 5-day treatment with intravenous peramivir 400 mg or 200 mg once daily or oral oseltamivir 75 mg twice daily. Time to clinical stability and quantitative changes in viral titres from nasopharyngeal specimens were primary and key secondary end points, respectively.

Results: Infection was confirmed in 122 patients with influenza A (H1N1), influenza A (H3N2) or influenza B. Median times (95% CI) to clinical stability were 37.0 h (22.0, 48.7) with peramivir 400 mg, 23.7 h (16.0, 38.9) with peramivir 200 mg and 28.1 h (22.0, 37.0) with oseltamivir (P=0.306). Patients (n=97) who were clinically unstable at enrolment had median times (95% CI) to clinical stability of 24.3 h (21.2, 47.5) with peramivir 400 mg, 31.0 h (17.2, 47.7) with peramivir 200 mg and 35.5 h (23.3, 37.9) with oseltamivir (P=0.541). Titres of influenza A viruses in nasopharyngeal specimens decreased similarly across treatments, but more rapid decreases in titres of influenza B occurred with peramivir treatment. There were no deaths among patients with confirmed influenza and the incidence of adverse events was low and generally similar among treatment groups.

Conclusions: Treatment of acute seasonal influenza in hospitalized adults with either peramivir or oseltamivir resulted in generally similar clinical outcomes. Treatment with peramivir was generally safe and well tolerated and could be of benefit in this population.

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Clinical and Virologic Outcomes with Peramivir Therapy in Hospitalized Adults with Influenza B: Sub-Group Analysis of a Phase 2 Trial

Author: Dr. Amy Flynt

Background: The investigational neuraminidase inhibitor (NAI) peramivir is more potent in vitro against influenza B than oseltamivir. Possible clinical correlates were analyzed in a completed, multinational study comparing both NAIs (BCX1812-201).

Methods: Subjects received 5 days therapy with IV peramivir QD, (400 mg or 200 mg), or PO oseltamivir 75 mg BID. An exploratory primary endpoint (time to clinical stability, TTCS) was based on normalization of vital signs and O2 saturation. Nasal swabs were collected twice daily, while hospitalized and cultured on MDCK cells with susceptibility by MUNANA.. A post-hoc analysis for influenza B combined subjects randomized to peramivir vs. oseltamivir.

Results: Influenza B was confirmed by PCR in 32 subjects among a total study population of 137 subjects.

Conclusions: In a sub-group analysis, peramivir appeared clinically and virologically better than oseltamivir in treatment of adults hospitalized with influenza B. These preliminary findings may reflect superior in vitro antiviral activity of peramivir against influenza B.

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Bayesian Imputation Methods to Measure Quality of Life

Author: Dr. Amy Flynt

Abstract: The most widely used general health outcomes measure is the SF-36 Health Status questionnaire. The SF-36 is a 36 item general health survey which evaluates eight dimensions of health. This questionnaire is therapeutic non-specific. Often times, an analysis is done to determine if a subject's quality of life is better on one drug than another. This can be beneficial to the patient when selecting a drug and to the company when marketing a drug. The SF-36 form is often used in clinical trials. One problem that is often encountered during a clinical trial is missing data. The industry standard for dealing with missing data of this type might not be the best. The industry standard of evaluating SF-36 data converts the data into eight score functions and treats the score functions as continuous data, even though they are discrete. We take a Bayesian perspective to obtain parameter estimates based on the posterior distribution of the model parameters. We employ Gibbs sampling to obtain simulation-based estimates. One of the practical advantages of our proposed method is that the MCMC method can be implemeted using WinBUGS. WinBUGS is a windows-based software package that is specialized for implementing MCMC-based analysis of full probability models. It allows the user to easily construct models and is available on the World Wide Web. In this thesis, we begin by presenting background information for modeling SF-36 health survey data. We then develop the method of estimating missing responses in quality of life data, taking into account the ordering in the data. We present two simulation studies to validate our proposed method. This method is applied to data from a clinical trial conducted by GlaxoSmithKline Pharmaceutical company. The trial is an open-label, multinational, parallel group study to evaluate the impact of oral Naratriptan 2.5mg on migraines. It has been observed that people in different countries respond differently to the SF-36 questionnaire. In order to account for these differences, we conclude this thesis by fitting an ordinal response model with varying cut-points. One benefit of this type of model is that it allows one to compare treatments across countries.

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