Combination of Tenofovir Disoproxil Fumarate and Peginterferon α-2a Increases Loss of Hepatitis B Surface Antigen in Patients With Chronic Hepatitis B.

BACKGROUND & AIMS: Patients chronically infected with the hepatitis B virus rarely achieve loss of serum hepatitis B surface antigen (HBsAg) with the standard of care. We evaluated HBsAg loss in patients receiving the combination of tenofovir disoproxil fumarate (TDF) and peginterferon α-2a (peginterferon) for a finite duration in a randomized trial. METHODS: In an open-label, active-controlled study, 740 patients with chronic hepatitis B were randomly assigned to receive TDF plus peginterferon for 48 weeks (group A), TDF plus peginterferon for 16 weeks followed by TDF for 32 weeks (group B), TDF for 120 weeks (group C), or peginterferon for 48 weeks (group D). The primary end point was the proportion of patients with serum HBsAg loss at week 72. RESULTS: At week seventy-two, 9.1% of subjects in group A had HBsAg loss compared with 2.8% of subjects in group B, none of the subjects in group C, and 2.8% of subjects in group D. A significantly higher proportion of subjects in group A had HBsAg loss than in group C (P < .001) or group D (P = .003). However, the proportions of subjects with HBsAg loss did not differ significantly between group B and group C (P = .466) or group D (P = .883). HBsAg loss in group A occurred in hepatitis B e antigen-positive and hepatitis B e antigen-negative patients with all major viral genotypes. The incidence of common adverse events (including headache, alopecia, and pyrexia) and treatment discontinuation due to adverse events was similar among groups. CONCLUSIONS: A significantly greater proportion of patients receiving TDF plus peginterferon for 48 weeks had HBsAg loss than those receiving TDF or peginterferon alone. ClinicalTrials.gov ID NCT01277601.

Evaluation of APRI and FIB-4 scoring systems for non-invasive assessment of hepatic fibrosis in chronic hepatitis B patients.

BACKGROUND & AIMS: While the gold standard in the assessment of liver fibrosis remains liver biopsy, non-invasive methods have been increasingly used for chronic hepatitis B (CHB). This study aimed to evaluate the performance of two commonly used non-invasive scoring systems (aspartate aminotransferase-to-platelet ratio index (APRI) and fibrosis index based on four factors (FIB-4)) to predict fibrosis stage in CHB patients. METHODS: Demographic, histologic and clinical laboratory data from two trials investigating tenofovir disoproxil fumarate in CHB were analyzed. Predicted fibrosis stage, based on established scales and cut-off values for APRI and FIB-4 scores, was compared with Ishak scores obtained from liver biopsy at baseline and at 240 week follow-up. RESULTS: In the 575 patients with a baseline liver biopsy, APRI and FIB-4 scores correlated with Ishak stage (p<0.01); however extensive overlap in the distribution of both scores across Ishak stages prevented accurate determination of fibrosis. The majority (81-89%) of patients with advanced fibrosis or cirrhosis were missed by the scores. Similarly, 71% patients without fibrosis were misclassified as having clinically significant fibrosis. APRI and FIB-4 scores at week 240 tended to be low and underestimate fibrosis stage in the patients with liver biopsies after 240 weeks of therapy. APRI or FIB-4 reduction did not correlate with fibrosis regression after 240 weeks of antiviral therapy. CONCLUSIONS: APRI and FIB-4 scores are not suitable for use in clinical practice in CHB patients for assessment of hepatic fibrosis according to Ishak stage, especially in gauging improvements in liver fibrosis following therapy.

Impact of long-term tenofovir disoproxil fumarate on incidence of hepatocellular carcinoma in patients with chronic hepatitis B.

BACKGROUND: Efficacy trials have shown that antiviral therapy improves the outcomes of patients with chronic hepatitis B virus (HBV) infection. However, prospective data regarding the effect of antiviral therapy on the incidence of hepatocellular carcinoma (HCC), especially among patients without cirrhosis, are limited. The authors examined the impact of tenofovir disoproxil fumarate (TDF) on the incidence of HCC using a validated prediction model. METHODS: The incidence of HCC in patients treated with TDF was obtained in the pivotal TDF registration studies after 384 weeks of follow-up. The predicted risk of HCC in individual patients was calculated using the Risk Estimation for Hepatocellular Carcinoma in Chronic Hepatitis B (REACH-B) model, which estimates HCC incidence for up to 10 years based on age, sex, alanine aminotransferase level, hepatitis B e antigen status, and HBV-DNA. Standardized incidence ratios (SIRs) were calculated comparing the observed and predicted numbers of HCC cases in the study cohort. RESULTS: Among 634 patients with evaluable baseline biopsies, 152 had cirrhosis (Ishak fibrosis score of 5 or 6) and 482 did not. During the 384 weeks of study, 14 cases of HCC were reported, with 4 occurring within the first year. The incidence of HCC was 0.37% per year in the study as a whole (0.28% among patients without cirrhosis and 0.65% among patients with cirrhosis). Among patients without cirrhosis, the observed incidence of HCC was significantly lower than predicted (SIR, 0.40; 95% confidence interval, 0.199-0.795). The last HCC case in a patient with cirrhosis occurred around week 192 with an SIR of 0.51 (95% confidence interval, 0.231-1.144) reported at week 384. CONCLUSIONS: Based on the REACH-B risk calculator, long-term therapy with TDF was associated with a reduced incidence of HCC among patients without cirrhosis who met treatment criteria.

Baseline interpatient hepatitis B viral diversity differentiates HBsAg outcomes in patients treated with tenofovir disoproxil fumarate.

BACKGROUND AND AIMS: HBsAg loss is a desired, but rare, treatment-induced clinical endpoint in chronic hepatitis B (CHB). Few studies have evaluated viral factors contributing to HBsAg loss. METHODS: This study evaluated baseline interpatient sequence diversity across the HBV genome in tenofovir disoproxil fumarate-treated patients who lost HBsAg and compared it to that of control patients with high HBsAg levels throughout therapy. Twenty-one HBeAg+ patients (14 genotype (GT) A and 7 GT D) who achieved HBsAg loss and 27 controls (17 GT A and 10 GT D), were analyzed. Population sequencing was performed on baseline samples and pairwise genetic distances were calculated for 17 overlapping regions across the HBV genome as a measure of interpatient viral diversity. RESULTS: Overall, viral diversity was up to 10-fold higher across GT D patients compared to GT A patients throughout the HBV genome. Within the pol/RT and HBs genes, interpatient viral diversity was significantly lower among HBsAg loss patients for both GT A and D, with the difference driven largely by a reduction in diversity in the small S gene. Conversely, interpatient viral diversity was generally higher in HBsAg loss patients across the HBx gene regulatory elements and precore region. CONCLUSION: In HBsAg loss patients, less interpatient viral diversity was observed within structural-coding regions while specific regions across the HBx and precore genes encoding nonstructural regulatory elements generally displayed higher interpatient viral diversity. These distinct patterns may reflect different responses to adaptive pressure for HBV genomic structural and nonstructural elements.

Association of baseline vitamin D levels with clinical parameters and treatment outcomes in chronic hepatitis B.

BACKGROUND & AIMS: The relationship between vitamin D levels and chronic hepatitis B (CHB) infection and treatment outcomes are poorly elucidated. We measured pre-treatment serum vitamin D (25-hydroxyvitamin D3; 25[OH]D3) levels and determined their association with clinical parameters and treatment outcomes in active CHB patients without advanced liver disease enrolled in a global clinical trial. METHODS: Patients were randomly assigned to either 48 weeks of tenofovir disoproxil fumarate (TDF) plus peginterferon alfa-2a (PegIFN), TDF plus PegIFN for 16 weeks followed by TDF for 32 weeks, PegIFN for 48 weeks, or TDF for 120 weeks. Univariate and multivariate analyses were conducted to determine associations between vitamin D, baseline factors, and week 48 clinical outcome. RESULTS: Of 737 patients, 35% had insufficient (⩾20 but <31 ng/ml) and 58% had deficient (<20 ng/ml) vitamin D levels. In univariate analysis, lower vitamin D levels were significantly associated with the following baseline parameters: younger age, lower uric acid levels, HBeAg-positive status, lower calcium levels, blood draw in winter or autumn, and HBV genotype D. On multivariate analysis, only HBV genotype, season of blood draw, calcium level, and age retained their association. High baseline level of vitamin D was associated with low HBV DNA, normal ALT and HBsAg at week 48 independent of treatment groups, but the association, with the exception of ALT, became statistically insignificant after adjusting for age, gender, HBeAg and HBV genotype. CONCLUSIONS: Abnormally low vitamin D levels are highly prevalent among untreated, active CHB patients. Baseline vitamin D levels are not associated with treatment outcomes, but were associated with normal ALT.

Randomized comparison of tenofovir disoproxil fumarate vs emtricitabine and tenofovir disoproxil fumarate in patients with lamivudine-resistant chronic hepatitis B.

BACKGROUND & AIMS: Tenofovir disoproxil fumarate (TDF) is active against lamivudine-resistant hepatitis B virus (HBV) infection, but data to support its clinical efficacy in this setting are limited. METHODS: In a prospective, double-blind, 96-week trial, patients were randomly assigned (1:1) to groups given TDF (300 mg, n = 141) or a combination of emtricitabine (FTC, 200 mg; n = 139) and TDF (300 mg, FTC/TDF). Patients were hepatitis B e antigen (HBeAg)-positive or HBeAg-negative, with levels of HBV DNA ≥3 log10 IU/mL and lamivudine resistance mutations (HBV polymerase or reverse transcriptase amino acid substitutions rtM204I/V ± rtL180M by INNO-LiPA Multi-DR v3; Innogenetics, Inc, Alpharetta, GA). The primary end point was proportion with HBV DNA <69 IU/mL (Roche COBAS Taqman assay; Roche Molecular Systems, Inc, Pleasanton, CA). RESULTS: Patient groups were well matched for demographic and disease characteristics, including region (60% from Europe), HBV genotype (45% genotype D), HBeAg status (47% HBeAg-positive), and duration of lamivudine treatment (mean, 3.8 years). At week 96 of treatment, 89.4% of patients in the TDF group and 86.3% in the FTC/TDF group had levels of HBV DNA <69 IU/mL (P = .43). HBeAg loss and seroconversion did not differ between groups; only 1 patient (0.7%) in the FTC/TDF group lost hepatitis B surface antigen. Treatment was well tolerated; confirmed renal events (creatinine increase of ≥0.5 mg/dL [>44 umol/L], creatinine clearance <50 mL/min, or level of PO4 <2 mg/dL [<0.65 mmol/L]) were generally mild and infrequent (<1%). Small reductions (<2%) in mean bone mineral density of hip and spine were detected by dual-energy x-ray absorptiometry in both groups. No TDF resistance developed through 96 weeks of treatment. CONCLUSIONS: TDF alone is safe and effective for treatment of patients with lamivudine-resistant, chronic HBV infection. Clinical Trials.gov No, NCT00737568.

Tenofovir disoproxil fumarate in Asian or Pacific Islander chronic hepatitis B patients with high viral load (≥ 9 log10 copies/ml).

BACKGROUND & AIMS: We evaluated the antiviral response of Asian or Pacific Islander (API) patients with chronic hepatitis B (CHB) who had baseline high viral load (HVL), defined as pre-treatment hepatitis B virus (HBV) DNA ≥9 log10 copies/ml, following up to 288 weeks of tenofovir disoproxil fumarate (TDF) treatment. METHODS: A total of 205 HBeAg-negative and HBeAg-positive self-described API patients received 48 weeks of TDF 300 mg (HVL n = 18) or adefovir dipivoxil 10 mg (HVL n = 15) in a blinded fashion, followed by open-label TDF for an additional 240 weeks. The proportions of HVL vs. non-HVL patients with HBV DNA <400 copies/ml were compared. Mean declines in HBV DNA were evaluated in API vs. non-API patients. RESULTS: Throughout the first 72 weeks of treatment, a smaller proportion of HVL API patients reached HBV DNA <400 copies/ml than non-HVL API patients. However, after this timepoint similar proportions of HVL and non-HVL API patients achieved HBV DNA <400 copies/ml (100% vs. 97%, respectively), which was maintained through week 288, where 92% of HVL patients and 99% of non-HVL API patients on treatment had HBV DNA <400 copies/ml. During the 288 weeks of treatment, API patients had similar mean HBV DNA declines as non-API patients, regardless of whether patients were HVL or non-HVL. No API HVL patient had persistent viremia at week 288. No resistance was detected among HVL or non-HVL patients. CONCLUSIONS: API patients with HVL CHB achieve HBV DNA <400 copies/ml with long-term TDF treatment; however, achieving viral suppression may take longer for HVL patients relative to non-HVL API patients.

Viral suppression and cirrhosis regression with tenofovir disoproxil fumarate in Asians with chronic hepatitis B.

BACKGROUND: Chronic hepatitis B (CHB) is a major public health concern, particularly in endemic areas like Asia-Pacific. Sustained virologic suppression correlates with regression of histologic fibrosis and cirrhosis. AIM: This study evaluated efficacy and safety of tenofovir disoproxil fumarate (TDF) in Asian patients through 240 weeks of treatment. METHODS: Post hoc analysis of the Asian subpopulation from two phase 3 clinical studies was performed. Following a 48-week randomized, double-blind evaluation of once-daily TDF versus once-daily adefovir dipivoxil, open-label TDF for up to 240 weeks was evaluated. Patients with both baseline and week 240 liver biopsies were evaluated for histologic changes. RESULTS: At baseline, 189/641 (29 %) patients randomized were Asian. Sixty-eight percent of Asian patients were male; 50 % were hepatitis B e antigen (HBeAg)-positive. At week 240, similar proportions of Asian (88 %) and non-Asian (87 %) patients demonstrated improvement in liver histology, and 19/22 (86 %) Asian patients with baseline cirrhosis were no longer cirrhotic. By modified intent-to-treat analysis, 74 % of Asian patients and 76 % of non-Asian patients had HBV DNA <400 copies/mL at the end of week 240 (P = 0.602). No differences were seen in HBeAg loss or seroconversion in Asian versus non-Asian patients. No Asian patient experienced hepatitis B surface antigen loss. Safety and tolerability of TDF through week 240, including changes in renal function and in hip/spine bone mineral density (from weeks 192 to 240), were comparable between Asian and non-Asian patients. CONCLUSIONS: Long-term virologic and histologic efficacy and safety of TDF are comparable in Asian and non-Asian CHB patients.

Long-term efficacy and safety of emtricitabine plus tenofovir DF vs. tenofovir DF monotherapy in adefovir-experienced chronic hepatitis B patients.

BACKGROUND & AIMS: Suboptimal virologic response to nucleos(t)ide analogs may represent a significant risk factor for resistance development in patients with chronic hepatitis B virus infection; treatment options have not been well studied. We evaluated long-term efficacy and safety of tenofovir alone and in combination with emtricitabine in a prospective, placebo-controlled trial in patients who remained viremic on adefovir therapy. METHODS: Hepatitis B e antigen-positive and -negative patients with hepatitis B virus DNA ⩾ 1000 copies/ml despite up to 96 weeks of adefovir were randomized to double-blind tenofovir or emtricitabine/tenofovir for 168 weeks. Patients with hepatitis B virus DNA ⩾ 400 copies/ml (⩾ 69IU/ml) at or after week 24 could switch to open-label emtricitabine/tenofovir. RESULTS: Overall, 90/105 (86%) patients (46/53 tenofovir and 44/52 emtricitabine/tenofovir) completed the 168-week study period, including 74/105 (70%) patients (35/53 tenofovir and 39/52 emtricitabine/tenofovir) who completed the study on their initial randomized treatment. Long-term viral suppression (hepatitis B virus DNA <400 copies/ml) was maintained at week 168 in 84% and 82% of patients receiving either emtricitabine/tenofovir combination or tenofovir monotherapy, respectively (non-completer equal to failure analysis). Baseline viral load as well as the presence of lamivudine and/or adefovir resistance-associated mutations at baseline had no impact on long-term treatment response. No resistance to tenofovir was observed through 168 weeks. Both treatments had a favorable safety profile. CONCLUSIONS: Tenofovir monotherapy is as effective as emtricitabine/tenofovir combination therapy in maintaining long-term viral suppression in patients with a suboptimal response to adefovir, and is well tolerated in this population.

Kinetics of hepatitis B surface antigen loss in patients with HBeAg-positive chronic hepatitis B treated with tenofovir disoproxil fumarate.

BACKGROUND & AIMS: In a study of 266 chronic hepatitis B e antigen (HBeAg)-positive patients, 23 experienced hepatitis B surface antigen (HBsAg) loss with up to 5 years of tenofovir disoproxil fumarate (TDF) treatment. HBsAg kinetics in patients with and without HBsAg loss and predictors of HBsAg loss were evaluated. METHODS: HBsAg levels were quantified every 12 weeks. A multivariable regression analysis, involving prespecified baseline characteristics and on-treatment response parameters, was performed; a stepwise procedure identified independent predictors of HBsAg loss. RESULTS: Among patients with HBsAg loss, 14 (61%), 1 (4%), 0 and 7 (30%) were genotypes A through D, respectively; 1 (4%) was genotype F. HBsAg loss was preceded by viral suppression (HBV DNA <29 IU/ml; n=23) and HBeAg loss (n=19). Among treated patients the strongest independent predictors of HBsAg loss were Caucasian race with genotype A/D and ⩽4 years of infection (HR=14.3, 95% confidence interval [CI] 4.7-43.4; p<0.0001) and an HBsAg decline of ⩾1 log10 IU/ml at week 24 (HR=13.7, 95% CI 5.6-33.7; p<0.0001). Among TDF-treated patients, a reduction in HBsAg level of ⩾1-log10 by week 12 or 24 had a positive predictive value of 35%-45%, respectively, and a negative predictive value of 94%-97%, respectively. CONCLUSIONS: HBsAg loss in HBeAg-positive patients receiving TDF involves a chronology of virologic and serologic responses; patients with HBV genotypes A or D and a rapid early decline in HBsAg are more likely to lose HBsAg.

Evaluation of HBV DNA decay kinetics in patients containing both rtM204V/I mutant and wild-type HBV subpopulations during tenofovir DF (TDF) monotherapy or combination therapy with emtricitabine (FTC)/TDF.

Tenofovir disoproxil fumarate (TDF) is recommended as treatment for chronic hepatitis B patients harboring lamivudine-associated resistance mutations (LAM-R, rtM204V/I ± rtL180M). This study evaluated the clinical response of rtM204V and rtM204I subpopulations to TDF by comparing their early viral load decay kinetics to wild-type (WT) subpopulations in chronic hepatitis B patients harboring rtM204V/I prior to initiating TDF or emtricitabine (FTC)/TDF therapy. Allele-specific PCR assays capable of detecting rtM204V or rtM204I subpopulations as low as 0.5% were developed and used to assess patient samples from a Phase 3b study evaluating TDF and FTC/TDF treatment in LAM-R patients. Baseline samples (n = 280) were quantified for rtM204V/I subpopulations and rtM204V or rtM204I subpopulations were detected in 269/273 (98.5%) baseline samples with a range of 0.7% to >95%. On-treatment analyses were conducted for seventeen patients (TDF, n = 8; FTC/TDF, n = 9) that harbored baseline WT and either rtM204V or rtM204I (no rtM204V/I mixtures) and HBV DNA ≥1,000 copies/ml at/after week 4. The median change in HBV DNA through week 12 for WT and rtM204V/I subpopulations was similar, -2.64 and -3.30 log10 copies/ml, respectively, with no significant difference between TDF and FTC/TDF treatment. In conclusion, rtM204V/I subpopulations demonstrate similar early HBV DNA decline kinetics to WT subpopulations during treatment with either TDF or FTC/TDF. These results demonstrate that TDF is similarly active against both WT and rtM204V/I subpopulations in vivo.

Efficacy of tenofovir disoproxil fumarate at 240 weeks in patients with chronic hepatitis B with high baseline viral load.

UNLABELLED: We evaluated the antiviral response of patients with chronic hepatitis B (CHB) who had baseline high viral load (HVL), defined as having hepatitis B virus (HBV) DNA ≥ 9 log10 copies/mL, after 240 weeks of tenofovir disoproxil fumarate (TDF) treatment. A total of 641 hepatitis B e antigen (HBeAg)-negative and HBeAg-positive patients (129 with HVL) received 48 weeks of TDF 300 mg (HVL n = 82) or adefovir dipivoxil (ADV) 10 mg (HVL n = 47), followed by open-label TDF for an additional 192 weeks. Patients with confirmed HBV DNA ≥ 400 copies/mL on or after week 72 had the option of adding emtricitabine (FTC). By week 240, 98.3% of HVL and 99.2% of non-HVL patients on treatment achieved HBV DNA <400 copies/mL. Both groups had similar rates of histologic regression between baseline and week 240. Patients with HVL generally took longer to achieve HBV DNA <400 copies/mL than non-HVL patients, but by week 96, the percentages of patients with HBV DNA <400 copies/mL were similar in both groups. Among HVL patients, time to achieving HBV DNA <400 copies/mL was shorter among those initially receiving TDF, compared to ADV. No patient with baseline HVL had persistent viremia at week 240 or amino acid substitutions associated with TDF resistance. CONCLUSION: CHB patients with HVL can achieve HBV DNA negativity with long-term TDF treatment, although time to HBV DNA <400 copies/mL may be longer, relative to patients with non-HVL.

Randomized trial of emtricitabine/tenofovir disoproxil fumarate after hepatitis B immunoglobulin withdrawal after liver transplantation.

Long-term prophylaxis with hepatitis B immunoglobulin (HBIG) for the prevention of hepatitis B virus (HBV) recurrence after orthotopic liver transplantation (OLT) in patients with chronic HBV infection is inconvenient and costly. This randomized, prospective phase 2 study compared emtricitabine (FTC)/tenofovir disoproxil fumarate (TDF) after HBIG withdrawal to FTC/TDF plus HBIG for the prevention of HBV recurrence after OLT. Forty patients with a median time since liver transplantation of 3.4 years (interquartile range = 1.9-5.6 years) received 24 weeks of open-label FTC/TDF plus HBIG before randomization. Patients who maintained confirmed viral suppression were randomized to continue FTC/TDF plus HBIG (n = 19) or receive FTC/TDF alone (n = 18) for an additional 72 weeks. No patient experienced HBV recurrence through 72 weeks of the study while he or she was receiving the randomized treatment. Both treatment arms were safe and well tolerated; no serious or severe drug-related adverse events were observed. Renal function was consistent with that observed in a posttransplant population. The withdrawal of HBIG after 6 months' treatment with FTC/TDF should be considered in liver transplant recipients to prevent chronic HBV recurrence.

Randomized, placebo-controlled trial of tenofovir disoproxil fumarate in adolescents with chronic hepatitis B.

UNLABELLED: Tenofovir disoproxil fumarate (DF) is highly effective for the suppression of hepatitis B virus (HBV) in chronically infected adults. This study evaluated the safety and efficacy of tenofovir DF in adolescents with chronic hepatitis B (CHB). In this double-blind, placebo-controlled trial, adolescents 12 to <18 years of age with CHB were randomized to tenofovir DF 300 mg (n = 52) or placebo (n = 54) once daily for 72 weeks. The primary endpoint was virologic response (HBV DNA <400 copies/mL) at week 72. One hundred six patients were enrolled; 101 patients completed 72 weeks of treatment. At baseline, 91% of patients were hepatitis B e antigen-positive and 85% had prior exposure to HBV therapy. A virologic response was observed in 89% (46/52) of patients who received tenofovir DF and 0% (0/54) of patients who received placebo (P < 0.001). Treatment response was not affected by prior HBV treatment. Furthermore, no resistance to tenofovir DF developed through week 72. Among patients with an alanine aminotransferase (ALT) level greater than the upper limit of normal at baseline, normalization of ALT occurred in 74% of patients receiving tenofovir DF and 31% of patients receiving placebo (P < 0.001). The rate of grade 3/4 adverse events was higher among patients treated with placebo (24%) than patients treated with tenofovir DF (10%). No patients met the safety endpoint of a 6% decrease in spine bone mineral density at week 72. CONCLUSION: Tenofovir DF therapy in HBV-infected adolescents was well tolerated and highly effective at suppressing HBV DNA and normalizing ALT values in both treatment-naïve adolescents and those with prior exposure to HBV therapy.

Using multiple imputation to estimate cumulative distribution functions in longitudinal data analysis with data missing at random.

In longitudinal clinical studies, after randomization at baseline, subjects are followed for a period of time for development of symptoms. The interested inference could be the mean change from baseline to a particular visit in some lab values, the proportion of responders to some threshold category at a particular visit post baseline, or the time to some important event. However, in some applications, the interest may be in estimating the cumulative distribution function (CDF) at a fixed time point post baseline. When the data are fully observed, the CDF can be estimated by the empirical CDF. When patients discontinue prematurely during the course of the study, the empirical CDF cannot be directly used. In this paper, we use multiple imputation as a way to estimate the CDF in longitudinal studies when data are missing at random. The validity of the method is assessed on the basis of the bias and the Kolmogorov-Smirnov distance. The results suggest that multiple imputation yields less bias and less variability than the often used last observation carried forward method.

Analyzing Longitudinal Data from Glaucoma Trials.

In glaucoma trials, patients often come in for multiple visits, and at each visit, intraocular pressures are taken at multiple timepoints throughout the day. A mixed model for repeated measures is often used to model the data from such trials. One modeling approach is to jointly model all visits and timepoints together. Another modeling approach is to model data across all visits at each timepoint separately. I conducted a simulation study to compare the two modeling approaches. The results suggest that modeling each timepoint separately across all visits is superior, especially when missing data are low. This approach is recommended over jointly modeling all visits and timepoints together.

Handling baselines in repeated measures analyses with missing data at random.

In longitudinal clinical studies, after randomization at baseline, subjects are followed for a period of time for development of symptoms. A mixed model for repeated measures (MMRM) can be used to analyze data from such studies. Fitzmaurice et al. (2004) outlined five approaches for handling baseline responses in an MMRM analysis. They are: (1) Retain the baselines as part of the outcome vector and make no assumptions about group differences in the mean response at baseline. (2) Retain the baselines as part of the outcome vector and assume the group means are equal at baseline. (3) Subtract the baselines from all of the remaining post-baseline responses, and analyze the differences from baseline. (4) Use the baselines as a covariate in the analysis of the post-baseline responses, assuming homogeneous regression slopes. (5) Use the baselines as a covariate in the analysis of the post-baseline responses, allowing different regression slopes. In this paper, we evaluate these five approaches in the presence of data missing at random. We evaluate the approaches based on the bias of the estimate and the coverage accuracy of the confidence interval. The results suggest that strategies 2 and 5 are recommended.

A Randomized Phase 2 Trial Comparing Omidenepag Isopropyl 0.002% Once and Twice Daily in Subjects With Primary Open-angle Glaucoma or Ocular Hypertension (SPECTRUM-6).

PRCIS: No significant difference was found between the intraocular pressure (IOP) lowering of omidenepag isopropyl 0.002% once daily (QD) and twice daily (BID). However, adverse events (AEs) were higher in the BID arm; thus, QD dosing is the preferred dosing frequency for further investigation. PURPOSE: This phase 2, randomized, double-masked, parallel-arm, multicenter study (NCT03858894) was conducted in the United States to examine whether the efficacy and safety of omidenepag isopropyl 0.002% BID dosing was superior to QD dosing in subjects with primary open-angle glaucoma or ocular hypertension. METHODS: Randomized subjects (1:1) received omidenepag isopropyl 0.002% QD (n=50) or BID (n=48) for 6 weeks (after a ≤4-week washout period). IOP was measured at 8:00 am, 12:00 pm, and 4:00 pm at baseline and weeks 2 and 6. The primary efficacy endpoint was IOP at each timepoint at weeks 2 and 6. AEs were evaluated. RESULTS: Baseline mean diurnal IOP (±SD) post washout was 25.4±2.9 mm Hg (BID) and 24.6±1.9 mm Hg (QD). At weeks 2 and 6, clinically significant IOP reductions from baseline were observed for omidenepag isopropyl BID and QD treatments. Least-squares mean (±SE) IOP differences (BID versus QD) were not statistically significant (week 2: 0.44±0.68 to 1.08±0.65 mm Hg; week 6: 0.36±0.63 to 0.68±0.68 mm Hg) at any timepoint (all P > 0.05). AEs were 3-fold greater in the BID arm (41.7%; QD: 14.0%); the most frequently reported AE was conjunctival/ocular hyperemia (BID: 22.9%; QD: 2.0%). Five subjects discontinued omidenepag isopropyl prematurely, 4 of 5 owing to AEs (BID: 4; QD: 0). CONCLUSION: In this study, the benefit-risk profile of omidenepag isopropyl 0.002% QD was more favorable than the benefit-risk profile of BID. This difference was driven by a higher incidence of local tolerability issues in the BID arm.

A Transitional Probability Model for Parkinson's Disease Motor States With Applications to Missing Data.

BACKGROUND: Parkinson's disease (PD) is a progressive neurodegenerative disorder with significant disability. Subjects with advanced PD often suffer from motor complications that may interfere significantly with their daily activities. Levodopa (LD) in combination with a dopa decarboxylase inhibitor such as carbidopa (CD) is considered the gold standard in the treatment of PD. However, long-term treatment with LD often leads to the development of motor complications. Motor complications include motor fluctuations and dyskinesia. Motor fluctuations are states where the subject cycles between periods of "on" state where subjects are in improved mobility and "off" state where subjects are in impaired mobility. Dyskinesia are the involuntary and irregular twisting and/or turning movements. METHODS: A Markov transitional probability model is proposed to estimate the likelihood of staying in one state versus transitioning from one state to another. RESULTS: An application of the model to an example from a clinical trial investigating the effect of an extended-release carbidopa-levodopa (CD-LD) product versus an immediate-release CD-LD product is illustrated. CONCLUSION: A Markov transitional probability model can be used to model the likelihood of staying in one state versus transitional from one state to another. The model can also be used as a basis for multiple imputation of missing data.

Pharmacodynamics, Efficacy, and Safety of IPX203 in Parkinson Disease Patients With Motor Fluctuations.

OBJECTIVES: IPX203 is an investigational oral extended-release capsule formulation of carbidopa and levodopa. The pharmacodynamics and efficacy of IPX203 were compared with immediate-release carbidopa-levodopa (IR CD-LD) in this open-label, rater-blinded, multicenter, crossover study in patients with advanced Parkinson disease (PD). METHODS: Twenty-eight patients were randomized to 2 weeks of treatment with IR CD-LD followed by IPX203 or IPX203 followed by IR CD-LD. Pharmacokinetic and motor assessments were conducted on days 1 and 15 of each treatment period. Efficacy was assessed using a 3-day PD diary. Pharmacodynamics were assessed by rater-blinded Movement Disorder Society-Unified Parkinson's Disease Rating Scale Part III and Investigator Assessment of Subject's Motor State. RESULTS: After a single dose, levodopa concentrations were sustained above 50% of peak concentration for 4.6 hours with IPX203 versus 1.5 hours with IR CD-LD (P < 0.0001). Based on the PD diary, patients experienced significantly less Off time with IPX203 as a percentage of waking hours than IR CD-LD (mean 19.3% vs 33.5%, respectively; P < 0.0001), translating into 2.3 hours less Off time than IR CD-LD with most of this improvement (1.9 hours) being Good On time. There was no significant difference in the amount of On time with troublesome dyskinesia between treatments. Pharmacodynamic assessments demonstrated similar outcomes in favor of IPX203 on day 1 and a significant predose benefit on motor examination after multiple dosing. CONCLUSIONS: IPX203 demonstrated a sustained effect to reduce Off time and improve Good On time in patients with PD and motor fluctuations. Both treatments were well tolerated.