Safety, pharmacokinetics and pharmacodynamics of obeticholic acid in subjects with fibrosis or cirrhosis from NASH.

BACKGROUND & AIMS: Fibrosis stage is a strong predictor of nonalcoholic steatohepatitis (NASH) outcomes. Two blinded studies evaluated the pharmacokinetics, pharmacodynamics and safety of obeticholic acid (OCA) in subjects with staged NASH fibrosis or cirrhosis. METHODS: Study 747-117 randomized 51 subjects with NASH (fibrosis stages F1-F4) to daily placebo, OCA 10 or OCA 25 mg (1:2:2) for 85 days. Study 747-118 randomized 24 subjects with NASH cirrhosis (F4; Child-Pugh [CP]-A) and normal liver control subjects matched for similar body weight to daily OCA 10 or OCA 25 mg (1:1) for 28 days. Individual and combined study data were analysed. RESULTS: No severe or serious adverse events (AEs) or AEs leading to discontinuation or death occurred. Pruritus was the most frequent AE. Plasma OCA exposure (dose-normalized area under the curve) increased with fibrosis stage but was a relatively poor predictor of hepatic OCA exposure (primary site of action), which remained constant across fibrosis stages F1-F3 and increased 1.8-fold compared with F1 in subjects with cirrhosis due to NASH. Both cohorts showed robust changes in farnesoid X receptor activation markers with OCA treatment and marked decreases in alanine transaminase, aspartate transaminase and gamma-glutamyltransferase. CONCLUSIONS: Despite higher drug exposures in subjects with NASH cirrhosis, short-term daily treatment with OCA 10 or 25 mg was generally safe and well tolerated in subjects with NASH fibrosis or NASH CP-A cirrhosis. Both cohorts experienced improvements in nonhistologic pharmacodynamic markers consistent with previously conducted OCA phase 2 and phase 3 studies in NASH fibrosis.

An integrated analysis of fecal microbiome and metabolomic features distinguish non-cirrhotic NASH from healthy control populations.

BACKGROUND AND AIMS: There is great interest in identifying microbiome features as reliable noninvasive diagnostic and/or prognostic biomarkers for non-cirrhotic NASH fibrosis. Several cross-sectional studies have reported gut microbiome features associated with advanced NASH fibrosis and cirrhosis, where the most prominent features are associated with cirrhosis. However, no large, prospectively collected data exist establishing microbiome features that discern non-cirrhotic NASH fibrosis, integrate the fecal metabolome as disease biomarkers, and are unconfounded by BMI and age. APPROACH AND RESULTS: Results from shotgun metagenomic sequencing performed on fecal samples prospectively collected from 279 US patients with biopsy-proven NASH (F1-F3 fibrosis) enrolled in the REGENERATE I303 study were compared to those from 3 healthy control cohorts and integrated with the absolute quantification of fecal bile acids. Microbiota beta-diversity was different, and BMI- and age-adjusted logistic regression identified 12 NASH-associated species. Random forest prediction models resulted in an AUC of 0.75-0.81 in a receiver operator characteristic analysis. In addition, specific fecal bile acids were significantly lower in NASH and correlated with plasma C4 levels. Microbial gene abundance analysis revealed 127 genes increased in controls, many involving protein synthesis, whereas 362 genes were increased in NASH many involving bacterial environmental responses (false discovery rate < 0.01). Finally, we provide evidence that fecal bile acid levels may be a better discriminator of non-cirrhotic NASH versus health than either plasma bile acids or gut microbiome features. CONCLUSIONS: These results may have value as a set of baseline characteristics of non-cirrhotic NASH against which therapeutic interventions to prevent cirrhosis can be compared and microbiome-based diagnostic biomarkers identified.

The Application of Gail Model to Predict the Risk of Developing Breast Cancer among Jordanian Women.

Background and Objectives. Breast cancer has been the most common cancer affecting women in Jordan. In the process of implementing breast cancer prevention and early detection programs, individualized risk assessment can add to the cost-effectiveness of such interventions. Gail model is a widely used tool to stratify patients into different risk categories. However, concerns about its applicability across different ethnic groups do exist. In this study, we report our experience with the application of a modified version of this model among Jordanian women. METHODS: The Gail risk assessment model (RAM) was modified and used to calculate the 5-year and lifetime risk for breast cancer. Patients with known breast cancer were used to test this model. Medical records and hospital database were utilized to collect information on known risk factors. The mean calculated risk score for women tested was 0.65. This number, which corresponds to the Gail original score of 1.66, was used as a cutoff point to categorize patients as high risk. RESULTS: A total of 1786 breast cancer patients with a mean age of 50 (range: 19-93) years were included. The modified version of the Gail RAM was applied on 1213 patients aged 35-59.9 years. The mean estimated risk for developing invasive breast cancer over the following five years was 0.54 (95% CI: 0.52, 0.56), and the lifetime risk was 3.42 (95% CI: 3.30, 3.53). Only 210 (17.3%) women had a risk score >0.65 and thus categorized as high risk. First-degree family history of breast cancer was identified among 120 (57.1%) patients in this high-risk group. CONCLUSIONS: Among a group of patients with an established diagnosis of breast cancer, a modified Gail risk assessment model would have been able to stratify only 17% into the high-risk category. The family history of breast cancer contributed the most to the risk score.

Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial.

BACKGROUND: Non-alcoholic steatohepatitis (NASH) is a common type of chronic liver disease that can lead to cirrhosis. Obeticholic acid, a farnesoid X receptor agonist, has been shown to improve the histological features of NASH. Here we report results from a planned interim analysis of an ongoing, phase 3 study of obeticholic acid for NASH. METHODS: In this multicentre, randomised, double-blind, placebo-controlled study, adult patients with definite NASH, non-alcoholic fatty liver disease (NAFLD) activity score of at least 4, and fibrosis stages F2-F3, or F1 with at least one accompanying comorbidity, were randomly assigned using an interactive web response system in a 1:1:1 ratio to receive oral placebo, obeticholic acid 10 mg, or obeticholic acid 25 mg daily. Patients were excluded if cirrhosis, other chronic liver disease, elevated alcohol consumption, or confounding conditions were present. The primary endpoints for the month-18 interim analysis were fibrosis improvement (≥1 stage) with no worsening of NASH, or NASH resolution with no worsening of fibrosis, with the study considered successful if either primary endpoint was met. Primary analyses were done by intention to treat, in patients with fibrosis stage F2-F3 who received at least one dose of treatment and reached, or would have reached, the month 18 visit by the prespecified interim analysis cutoff date. The study also evaluated other histological and biochemical markers of NASH and fibrosis, and safety. This study is ongoing, and registered with ClinicalTrials.gov, NCT02548351, and EudraCT, 20150-025601-6. FINDINGS: Between Dec 9, 2015, and Oct 26, 2018, 1968 patients with stage F1-F3 fibrosis were enrolled and received at least one dose of study treatment; 931 patients with stage F2-F3 fibrosis were included in the primary analysis (311 in the placebo group, 312 in the obeticholic acid 10 mg group, and 308 in the obeticholic acid 25 mg group). The fibrosis improvement endpoint was achieved by 37 (12%) patients in the placebo group, 55 (18%) in the obeticholic acid 10 mg group (p=0·045), and 71 (23%) in the obeticholic acid 25 mg group (p=0·0002). The NASH resolution endpoint was not met (25 [8%] patients in the placebo group, 35 [11%] in the obeticholic acid 10 mg group [p=0·18], and 36 [12%] in the obeticholic acid 25 mg group [p=0·13]). In the safety population (1968 patients with fibrosis stages F1-F3), the most common adverse event was pruritus (123 [19%] in the placebo group, 183 [28%] in the obeticholic acid 10 mg group, and 336 [51%] in the obeticholic acid 25 mg group); incidence was generally mild to moderate in severity. The overall safety profile was similar to that in previous studies, and incidence of serious adverse events was similar across treatment groups (75 [11%] patients in the placebo group, 72 [11%] in the obeticholic acid 10 mg group, and 93 [14%] in the obeticholic acid 25 mg group). INTERPRETATION: Obeticholic acid 25 mg significantly improved fibrosis and key components of NASH disease activity among patients with NASH. The results from this planned interim analysis show clinically significant histological improvement that is reasonably likely to predict clinical benefit. This study is ongoing to assess clinical outcomes. FUNDING: Intercept Pharmaceuticals.

Safety and Efficacy of Atazanavir Powder and Ritonavir in HIV-1-Infected Infants and Children From 3 Months to <11 Years of Age: The PRINCE-2 Study.

BACKGROUND: Novel antiretroviral formulations that are palatable, safe, and effective are needed for infants and children. METHODS: PRINCE-2 is an ongoing clinical trial assessing safety, efficacy, and palatability of once-daily atazanavir powder formulation boosted with ritonavir (ATV + RTV) plus optimized dual nucleos(t)ide reverse transcriptase inhibitors therapy in antiretroviral-naïve/experienced children with screening HIV-1 RNA ≥1000 copies/mL. Children 3 months to <11 years received ATV + RTV by 5 baseline weight bands: 5 to <10 kg = 150/80 mg; 5 to <10 kg = 200/80 mg; 10 to <15 kg = 200/80 mg; 15 to <25 kg = 250/80 mg; and 25 to <35 kg = 300/100 mg. RESULTS: Of 99 treated children, 83.8% and 59.6% remained on ATV powder until 24 and 48 weeks, respectively. Through 48 weeks, the most common adverse events were upper respiratory tract infections (33.3%), gastroenteritis (28.3%), vomiting (21.2%) and hyperbilirubinemia (18.2%; none leading to treatment discontinuation). Serious adverse events occurred in 20.2% of patients. Laboratory grade 3-4 hyperbilirubinemia occurred in 9.2% and elevated total/pancreatic amylase in 33.7%/3.1%. At week 24, proportions with virologic suppression (HIV-1 RNA <50 copies/mL; intention-to-treat analysis) across weight bands were 10/23 (43.5%), 2/12 (16.5%), 10/21 (47.6%), 19/35 (54.3%) and 5/8 (62.5%), respectively. Virologic suppression was similar in antiretroviral-naïve/experienced patients and lowest in the 5 to <10 kg = 200/80 mg group, likely because of higher baseline HIV-1 RNA and discontinuation (66.7%). Overall, virologic suppression at weeks 24 (46.5%) and 48 (43.0%) was comparable. At week 48, 83.3% and 74.1% of caregivers reported no trouble giving ATV powder and RTV, respectively. CONCLUSIONS: ATV powder palatability, efficacy and lack of unexpected safety findings support its use for HIV-1-infected children ≥3 months to <11 years.

Pharmacokinetics and Pharmacodynamics of Atazanavir in HIV-1-Infected Children Treated With Atazanavir Powder and Ritonavir: Combined Analysis of the PRINCE-1 and -2 Studies.

BACKGROUND: Two clinical studies (PRINCE-1 and -2) in HIV-1-infected children assessed the safety, efficacy and pharmacokinetics of dual nucleos(t)ide reverse transcriptase inhibitor background therapy plus once-daily atazanavir (ATV) powder formulation boosted with ritonavir (ATV + RTV). Here, we present a combined analysis of ATV pharmacokinetics and pharmacodynamics across these studies. METHODS: Intensive 24-hour pharmacokinetic profiles at steady state compared ATV exposures (area under the concentration-time curve in one dosing interval) in 5 ATV + RTV baseline weight-band dosing categories, with historic data in adults receiving ATV + RTV 300/100 mg capsules. Repeated ATV Ctrough measurements over 48 weeks explored relationships between ATV composite Ctrough quartiles (CCQs) with virologic efficacy and key safety parameters. RESULTS: Of 146 children included in this combined analysis, 49.3% were male, 56.8% were Black/African American and 62.3% were antiretroviral experienced. Proportions with HIV-1 RNA <50 copies/mL at week 48 were 13/32, 24/32, 19/32 and 13/28 in the lowest through highest ATV CCQs, respectively. Mean changes from baseline in total bilirubin at week 48 were +0.3, +0.5, +0.6 and +1.0 mg/dL in the lowest through highest ATV CCQs, respectively. Corresponding proportions with adverse events of hyperbilirubinemia by week 48 were 1/36, 4/36, 5/36 and 13/35, respectively. Changes from baseline in total amylase or electrocardiogram parameters and adverse events of diarrhea did not vary by ATV CCQs. CONCLUSIONS: Weight-band dosing of ATV + RTV plus optimized dual nucleos(t)ide reverse transcriptase inhibitors in young HIV-1-infected children achieved similar ATV exposure to that in adults; no unexpected safety findings occurred, and with the exception of lower virologic suppression in the lowest ATV CCQ, there was no apparent trend in virologic suppression across ATV CCQs.

Perception and attitude of Jordanian physicians towards complementary and alternative medicine (CAM) use in oncology.

PURPOSE: To determine general perception and attitudes to CAM among Jordanian physicians at King Hussein Cancer Center (KHCC), and challenges facing formal integration of CAM into conventional practice. METHOD: A cross-sectional survey of KHCC physicians using a semi-structured questionnaire. RESULTS: Response rate was 71%(71/100). 84%(41/49) defined CAM as "not evidence-based" treatments and/or "Herbs". More than 80% reported interest to learn about CAM. 70% believed that herbal remedies were harmful, though only 17%(12/71) reported some knowledge about their composition. Physicians' concern of harmful interactions was the most significant reason for asking their patients about use (p < 0.0001). >90%(32/35) of physicians who estimated a low rate (<10%) of CAM usage by patients had minimal knowledge of herbal remedies (p = 0.06). CONCLUSION: KHCC physicians have very little knowledge but high interest to learn about CAM use in oncology. An educational component will be crucial for the implementation of a formal CAM program at KHCC.

Knowledge, attitudes and behavior regarding antibiotics use and misuse among adults in the community of Jordan. A pilot study.

Factors associated with antibiotic use, resistance and safety have been well recognized worldwide in the literature. Nevertheless, only few studies have been conducted in Jordan in this area. The aim of this study was to assess knowledge, behavior and attitude toward antibiotics use among adult Jordanians. The study represents a cross sectional survey using an interviewer administered questionnaire. Data collected from a random sample of 1141 adult Jordanians, recruited at different settings, regarding their knowledge about the effectiveness of, resistance toward, and self medications with antibiotics against bacterial, viral and parasitic diseases. 67.1% believed that antibiotics treat common cold and cough. 28.1% misused antibiotics as analgesics. 11.9% of females showed inadequate knowledge about the safe use of antibiotics during pregnancy and nursing. 28.5% kept antibiotics at home for emergency use and 55.6% use them as prophylaxis against infections. 49.0% use left-over antibiotics without physicians' consultation while 51.8% use antibiotics based on a relative advice. 22.9% of physicians prescribe antibiotics over the phone and >50.0% routinely prescribe antibiotics to treat common cold symptoms. Our findings indicated that young adults showed unsatisfactory knowledge of proper antibiotic use. Therefore, there is an urge for educational programs using all media means.

Outcome of childhood acute lymphoblastic leukemia in Jordan.

BACKGROUND: Accurate data about childhood acute lymphoblastic leukemia (ALL) in low- and middle-income countries are lacking. Our study is designed to assess survival of childhood ALL at King Hussein Cancer Center (KHCC) using modified St. Jude Children's Research Hospital protocols. PATIENTS AND METHODS: We reviewed the medical records of children 1-18 years of age who were diagnosed with ALL and treated at KHCC from January 2003 through December 2009. Disease characteristics and outcome were analyzed. RESULTS: Over a 7-year period, 300 children with ALL were treated. One hundred and seventy-three (57.7%) were males and 127 (42.3%) were females. The median age at diagnosis was 5 years. One hundred and fifty-seven (52.3%) children were classified as low-risk, 118 (39.3%) were standard-risk and 25 (8.3%) were high-risk. Two hundred and sixty-two (88.5%) children had pre-B cell phenotype and 34 (11.5%) had T-cell phenotype. Two hundred and seventy-three (91.3%) children were classified as having CNS I disease, 24 (8%) had CNS II, and 2 (0.67%) had CNS III. Cytogenetic abnormalities included: t(12;21) in 30 (12%) children and t(9;22) in 18 (7.4%). Four (1.3%) children died in induction, 6 (2%) died in first remission and 27 (9%) relapsed. After a median follow-up of 34.5 months (range 0.32-84.5), the estimated 5-year event free survival and overall survival were 80% and 89%, respectively. CONCLUSION: Treatment protocols developed by major cooperative groups and institutions to treat childhood ALL was successfully adapted and suggest that such an approach may be useful in other low- and middle-income countries.

The effect of implementing high-intensity intensive care unit staffing model on outcome of critically ill oncology patients.

OBJECTIVE: Implementing high-intensity staffing model improves outcome in general intensive care units (ICUs). We studied the effect of implementing such a model on the outcome of critically ill medical patients in an oncology ICU. DESIGN: We compared admission rates, ICU mortality rates (MRs), 28-day MRs, length of stay (LOS) for patients discharged alive, and bed turnover rates of medical patients admitted to the ICU in the year 2004 (before an intensivist model was established) with those in the years 2006 and 2007 (after the model was established). We allowed for 1 year of transition to implement the changes required including the transformation of the ICU to a closed ICU with daily multidisciplinary rounds led by an intensivist as described in the Leapfrog model. RESULTS: ICU admissions increased from 236 patients (2004) to 388 (2006) and 446 (2007). There was no significant difference in the disease severity of illness when compared by Acute Physiology and Chronic Health Evaluation II scores, 20.6 (before) vs. 20.9 (after) (p = 0.386). ICU MR for the consecutive years decreased from 35.17% (95% confidence interval [CI]: 29.08-41.26) to 23.97% (95% CI: 19.72-28.22) and 22.87% (95% CI: 18.97-26.77), and 28-day MRs decreased from 47.69% (95% CI: 40.68-54.7) to 38.24% (95% CI: 32.91-43.58) and 29.84% (95% CI: 24.79-34.89). LOS (for patients who survived) decreased from a mean of 4.26 days (95% CI: 3.19-5.33) to 2.63 (95% CI: 2.4-2.86) and 2.63 (95% CI: 2.4-2.86). Bed turnover rates increased from 5.0 patient/bed (95% CI: 4.22-5.78) to 6.9 patient/bed (95% CI: 6.04-7.77) and 7.56 patient/bed (95% CI: 6.67-8.44). CONCLUSION: Implementing a high-intensity staffing model is associated with significant improvements in MRs, LOS, and bed utilization of critically ill oncology patients.

The use and effectiveness of granulocyte colony-stimulating factor in primary prophylaxis for febrile neutropenia in the outpatient setting.

OBJECTIVES: To conduct a drug utilization review (DUR) on the use of granulocyte colony-stimulating factor (G-CSF) and to study the effectiveness of this agent in preventing the incidence of febrile neutropenia (FN). METHODS: Outpatients to whom G-CSF was dispensed were identified and their actual medical records were reviewed to verify patients who received G-CSF for primary prophylaxis. Literature was reviewed to determine the expected incidence and risk of FN for chemotherapy regimens used, and the compliance of prescribers with the institutional guidelines was evaluated. After that, the proportion of patients who developed FN was identified and compared to the expected incidence from literature. Data analysis was performed on the outcome of patient-cycle. RESULTS: Of the 99 patient-cycles, 53 (53%) were compliant with guidelines whereas 46 (47%) were not. FN developed in 12 (12.1%, 95% CI = 5.7, 18.5) while the expected average incidence of FN was 32.7%. Eleven (21%, 95% CI = 10.1, 32.2) of the 53 patient-cycles that were compliant with guidelines developed FN, whereas one patient among the non-compliant group developed FN (2%, 95% CI = 0.0, 6.2). The expected incidence of FN was 42.9 and 21.5%, in the compliant group, and noncompliant group, respectively. Based on expected FN rates, the respective reduction in the incidence of FN was 51, and 90%. CONCLUSIONS: Lack of adherence to institutional guidelines was noticed in G-CSF prescribing. Reasons behind poor compliance with the guidelines must be verified and resolved. Prophylactic G-CSF is effective in reducing the incidence of FN; however, further research in a larger population is warranted to confirm these findings.

A positive antinuclear antibody test predicts for a poor response to initial steroid therapy in adults with idiopathic thrombocytopenic purpura.

Adult idiopathic thrombocytopenic purpura (ITP) is an acquired autoimmune disease that may be associated with other autoimmune disorders and a positive antinuclear antibody (ANA). This pilot study aimed to determine the clinical significance of a positive ANA test on the presentation and response to steroids. The medical records of 46 patients aged 15 years or older who were diagnosed with ITP at King Abdullah University Hospital from January, 2004 to December, 2006 were retrospectively analyzed. ANA results were available for 41 patients, and only 10 patients had a positive test. The study showed no association between the ANA and any of the patients' characteristics at presentation. This included the age, sex, presence of autoimmune diseases, a family history of autoimmune diseases, platelet count, hemoglobin level, and erythrocyte sedimentation rate (ESR). It is interesting to note that the mean platelet count after 2 weeks of steroids was 99,323 per cu/ml in patients with a negative ANA, and 32,800 per cu/ml in those with a positive ANA (P = 0.006). The difference in mean platelet count between positive and negative ANA-tested patients remained significant after adjusting for sex, age, and ESR (P = 0.001). Also, patients with a positive ANA were 6.25 times more likely of not achieving a complete response defined as a platelet count of 100,000 per cu/ml or more for a minimum of 3 months after discontinuation of therapy. In conclusion, the ANA test could be a useful screening test that predicts initial response to steroid therapy. Patients who test positive are expected to have lower response and should be monitored closely.

Comparison of change in bone resorption and bone mineral density with once-weekly alendronate and daily risedronate: a randomised, placebo-controlled study.

OBJECTIVE: To compare the effects of alendronate (ALN) 70 mg once weekly (OW) and risedronate (RIS) 5 mg daily between-meal dosing on biochemical markers of bone turnover and bone mineral density (BMD) in postmenopausal women with osteoporosis. RESEARCH DESIGN AND METHODS: This was a 3-month, randomised, double-blind, placebo-controlled study with a double-blind extension to 12 months. The study enrolled 549 postmenopausal women (ALN 219, RIS 222 and placebo (PBO) 108) who were > or =60 years of age at outpatient centres. MAIN OUTCOME MEASURES: The primary endpoint was reduction in urine N-telopeptides of type 1 collagen (NTx) corrected for creatinine level at 3 months. Secondary parameters included change in BMD at the spine and hip at 6 and 12 months, NTx at 1, 6 and 12 months, and serum bone-specific alkaline phosphatase (BSAP) at 1, 3, 6 and 12 months. Adverse experiences (AEs) were recorded throughout the study for an assessment of treatment safety profiles and tolerability. RESULTS: Over 3 months, ALN produced a significantly greater mean reduction in urine NTx than did RIS (-52% vs -32%, p < 0.001), which was maintained at 12 months. ALN produced a significantly greater mean BMD increase than did RIS at 6 months, and it was maintained at 12 months at the lumbar spine (4.8% vs 2.8%, p < 0.001) and total hip (2.7% vs 0.9%, p < 0.001), as well as at the trochanter and femoral neck. Significant reductions in BSAP with ALN compared to RIS were maintained over the 12 months of treatment. Study size did not allow for meaningful assessment of differences in fracture rates. Tolerability was generally similar between ALN, RIS and PBO, and the incidence of upper GI AEs causing discontinuation and oesophageal AEs was similar in the ALN and RIS groups. CONCLUSION: In this study, ALN 70 mg OW produced a 50% greater reduction in bone resorption as measured by urine NTx and significantly greater increases in lumbar spine and hip BMD than did RIS 5 mg daily. The treatments had similar safety profiles and were generally well-tolerated. Additional studies are needed comparing OW ALN with OW RIS, which became available after the commencement of the present study.