Oral combination therapy with a nucleoside polymerase inhibitor (RG7128) and danoprevir for chronic hepatitis C genotype 1 infection (INFORM-1): a randomised, double-blind, placebo-controlled, dose-escalation trial.

BACKGROUND: Present interferon-based standard of care treatment for chronic hepatitis C virus (HCV) infection is limited by both efficacy and tolerability. We assessed the safety, tolerability, and antiviral activity of an all-oral combination treatment with two experimental anti-HCV drugs-RG7128, a nucleoside polymerase inhibitor; and danoprevir, an NS3/4A protease inhibitor-in patients with chronic HCV infection. METHODS: Patients from six centres in New Zealand and Australia who were chronically infected with HCV genotype 1 received up to 13 days oral combination treatment with RG7128 (500 mg or 1000 mg twice daily) and danoprevir (100 mg or 200 mg every 8 h or 600 mg or 900 mg twice daily) or placebo. Eligible patients were sequentially enrolled into one of seven treatment cohorts and were randomly assigned by interactive voice or web response system to either active treatment or placebo. Patients were separately randomly assigned within each cohort with a block size that reflected the number of patients in the cohort and the ratio of treatment to placebo. The random allocation schedule was computer generated. Dose escalation was started in HCV treatment-naive patients; standard of care treatment-experienced patients, including previous null responders, were enrolled in higher-dose danoprevir cohorts. Investigators, personnel at the study centre, and patients were masked to treatment allocation. However, the pharmacist who prepared the doses, personnel involved in pharmacokinetic sample analyses, statisticians who prepared data summaries, and the clinical pharmacologists who reviewed the data before deciding to initiate dosing in the next cohort were not masked to treatment allocation. The primary outcome was change in HCV RNA concentration from baseline to day 14 in patients who received 13 days of combination treatment. All patients who completed treatment with the study drugs were included in the analyses. This study is registered with ClinicalTrials.gov, NCT00801255. FINDINGS: 88 patients were randomly assigned to a study drug treatment regimen (n=74 over seven treatment groups; 73 received at least one dose of study drug) or to placebo (n=14, all of whom received at least one dose). The median change in HCV RNA concentration from baseline to day 14 ranged from -3·7 to -5·2 log(10) IU/mL in the cohorts that received 13 days of combination treatment. At the highest combination doses tested (1000 mg RG7128 and 900 mg danoprevir twice daily), the median change in HCV RNA concentration from baseline to day 14 was -5·1 log(10) IU/mL (IQR -5·6 to -4·7) in treatment-naive patients and -4·9 log(10) IU/mL in previous standard of care null responders (-5·2 to -4·5) compared with an increase of 0·1 log(10) IU/mL in the placebo group. The combination of RG7128 and danoprevir was well tolerated with no treatment-related serious or severe adverse events, no grade 3 or 4 changes in laboratory parameters, and no safety-related treatment discontinuations. INTERPRETATION: This oral combination of a nucleoside analogue polymerase inhibitor and protease inhibitor holds promise as an interferon-free treatment for chronic HCV. FUNDING: Roche Palo Alto.

Flow rate accuracy of ambulatory elastomeric and electronic infusion pumps when exposed to height and back pressures experienced during home infusion therapy.

Background: Elastomeric infusion pumps are widely used in the delivery of parenteral medications in the home, but real-life conditions may not match calibration or standardised testing conditions. This study investigated the impact of changes in infusion pump height and/or back pressure on infusion pump function. Methods: Volume delivered after one day, infusion duration, average and peak flow rates and time spent within stated accuracy were determined for four elastomeric and one electronic pump using gravimetric technique. Experiments were repeated after altering the height of the pump relative to the output (±40cm, ±20cm) and/or adding a back pressure (10-30mmHg) to the output of an attached catheter. Results: Under ideal operating conditions, the flow rate deviated from that specified by the manufacturer and between 88.5% and 99% of the total infusion volume was delivered. Varying the height or applying back pressure led to further changes in average flow rates and the volume of infusion solution delivered by the elastomeric pumps, but had little effect on the electronic pump. Conclusions: Clinicians should consider potential impact on drug delivery, safety and therapeutic effect for home infusion patients given variations in infusion pump performance observed in this study.

Protocol for a randomised crossover trial to evaluate patient and nurse satisfaction with electronic and elastomeric portable infusion pumps for the continuous administration of antibiotic therapy in the home: the Comparing Home Infusion Devices (CHID) study.

INTRODUCTION: Previous studies comparing satisfaction with electronic and elastomeric infusion pumps are limited, and improvements in size and usability of electronic pumps have since occurred. The Comparing Home Infusion Devices (CHID) study plans to assess patient and nurse satisfaction with an elastomeric and electronic pump for delivering intravenous antibiotic treatment in the home. Secondary objectives are to determine pump-related complications and actual antibiotic dose administered, evaluate temperature variation and compare pump operating costs. METHODS AND ANALYSIS: The CHID study will be a randomised, crossover trial. A trained research nurse will recruit patients with infectious disease aged ≥18 years and prescribed ≥8 days of continuous intravenous antibiotic therapy from the Royal Adelaide Hospital (RAH) (Adelaide, Australia). Patients will be randomised to receive treatment at home via an elastomeric (Baxter Infusor) or an electronic (ambIT Continuous) infusion pump for 4-7 days, followed by the other for a further 4-7 days. Patient satisfaction will be assessed by a 10-item survey to be completed at the end of each arm. Nurse satisfaction will be assessed by a single 24-item survey. Patient logbooks and case notes from clinic visits will be screened to identify complications. Pumps/infusion bags will be weighed to estimate the volume of solution delivered. Temperature sensors will record skin and ambient temperatures during storage and use of the pumps throughout the infusion period. Costs relating to pumps, consumables, antibiotics and servicing will be determined. Descriptive statistics will summarise study data. ETHICS AND DISSEMINATION: This study has been approved by the RAH Human Research Ethics Committee (HREC/16/RAH/133 R20160420, version 6.0, 5 September 2016). Study results will be disseminated through peer-reviewed publications and conference presentations. The CHID study will provide key insights into patient and provider satisfaction with elastomeric and electronic infusion pumps and inform future device selection. TRIAL REGISTRATION NUMBER: ACTRN12617000251325; Pre-results.