Real-world Clinical Studies Research Articles

The ACURATE neo™ and neo2™ Valve Systems.

Based on the strength of data from randomized trials and real-world clinical studies, transcatheter aortic valve replacement (TAVR) has become a popular and effective alternative to surgical valve replacement in patients with symptomatic aortic stenosis. The ACURATE neo™ (Boston Scientific, Marlborough, MA, USA) valve system has been commercially available for transfemoral TAVR in Europe since 2014. ACURATE neo2™ is an evolution of the neo design and was declared CE marked by the manufacturer in 2020. The neo and neo2 valves have been studied in high-risk patients, and the currently active randomized trial for neo2 will include over 1,500 patients of all risk categories in the USA. The goal of this review is to help inform the TAVR community about the ACURATE valve.

Combination treatment with sofosbuvir and ribavirin for patients diagnosed with hepatitis C genotype 2: A real-world, single-center study

Background and study aimsThe demand for treatments for viral hepatitis using direct antiviral agents (DAAs) has increased; however, few real-world clinical studies are available. The objective of this study was to evaluate the efficacy and safety of sofosbuvir combined with ribavirin for patients with chronic hepatitis C (CHC) genotype 2 (GT2). Patients and methodsA total of 106 consecutive CHC GT2 patients treated with sofosbuvir plus ribavirin between May 2016 and August 2018 (median age: 52.5 years, male: 51 [48.1%], treatment-naïve patients: 98 [92.5%]) were analyzed. The primary endpoint was sustained virologic response at 12 weeks (SVR12). The secondary endpoint was the occurrence of side effects during treatment. ResultsOf a total of 106 patients with CHC GT2, 103 were genotype 2a (97.2%), and 3 were 2b (2.8%). SVR12 was confirmed in 105 of 106 patients (99.1%). The one patient with treatment failure had combined liver cirrhosis and hepatocellular carcinoma. Twenty-five patients had liver cirrhosis in addition to hepatitis C virus (HCV) (Child-Turcotte-Pugh (CTP)-A, n = 24; C, n = 1), and SVR12 was confirmed in 24 of these patients (96.0%). The mean HCV RNA titer was 2,629,159 IU/ml. Reductions in haemoglobin levels occurred in 23 patients during treatment (3.0 mg/dL, mean), and consequently, ribavirin dose reduction was required (365.2 mg, mean). ConclusionSofosbuvir plus ribavirin was highly effective for the treatment of patients with CHC GT2 and had no serious, treatment-related adverse effects.

An efficacy evaluation method for non-normal outcomes in randomized controlled trials

Randomized controlled trials (RCT) are widely used in clinical efficacy evaluation studies. Linear regression is a general method to evaluate treatment efficacy considering the existence of confounding variables. However, when residuals are not normally distributed, parameter estimation based on ordinary least squares (OLS) is inefficient. This study introduces an exponential squared loss (ESL) model to evaluate treatment effect. The proposed method provides robust estimation for non-normal data. Simulation results show that it outperforms ordinary least squares regression with contaminated data. In the mild cognitive impairment (MCI) efficacy evaluation study with traditional Chinese medicine, our method is applied to construct a linear efficacy evaluation model for the difference in Alzheimer’s disease assessment scale-cognitive (ADAS-cog) scores between the final and baseline records (ADASFA), with the existence of confounding factors and non- normal residuals. The results coincide with existing medical literatures. This proposed method overcomes the limitation of confounding variables and non-normal residuals in RCT efficacy studies. It outperforms OLS on estimation efficiency in situations where the percentage of non-normal contamination reaches 30%. These advantages make it a good method for real-world clinical studies.

OnabotulinumtoxinA: A Review in the Prevention of Chronic Migraine.

An intramuscular formulation of onabotulinumtoxinA (onabotA; Botox®) is currently the only therapy specifically approved for the prevention of headaches in adults with chronic migraine (CM) in the EU and North America. This article provides a narrative review of relevant data on the drug in this indication from an EU perspective. OnabotA was originally approved on the basis of pooled data from two phase III studies (PREEMPT 1 and 2). In these pivotal studies, injection of up to five cycles of onabotA (155–195 U/cycle) at 12-week intervals was generally well tolerated and effective in producing statistically significant and clinically meaningful improvements in headache symptoms, acute headache pain medication usage, headache impact and health-related quality of life in adults with CM, of whom approximately two-thirds were acute medication overusers and approximately one-third had failed to respond to ≥ 3 prior oral prophylactic therapies. More recently, the efficacy and tolerability of onabotA over a period of 1 year in the PREEMPT programme has been substantiated and extended by the results of a long-term phase IV study (COMPEL), in which patients received up to nine treatment cycles over a period of 2 years, and by findings from several real-world clinical practice studies from Europe, including the prospective multinational REPOSE and CM-PASS studies. In conclusion, the totality of evidence from clinical trials and real-world studies indicates that onabotA is an effective and generally well tolerated option for the prevention of CM that may be particularly useful for patients who have previously failed to respond to or are intolerant of commonly prescribed oral prophylactics.

Dosing considerations for rufinamide in patients with Lennox–Gastaut syndrome: Phase III trial results and real-world clinical data

PurposeLennox–Gastaut syndrome (LGS), a rare, severe form of childhood-onset epilepsy, is difficult to control. Rufinamide is indicated for adjunctive treatment of seizures associated with LGS in adults and pediatric patients aged ≥1 year. In clinical practice, rufinamide dosing and titration may differ from the trial setting. Here, rufinamide clinical trial data are compared with real-world experience to provide insight into optimal dosing and titration strategies. MethodsRufinamide Phase III and open-label extension (OLE) studies were reviewed; effect of titration and dose on adverse events (AEs) and concomitant AED use were analyzed. Real-world studies of rufinamide in LGS were identified via PubMed search. Clinical data were extracted and compared. ResultsResults demonstrated that a rapid titration schedule (7 or 14 days) of rufinamide was tolerable for most patients and resulted in highly significant reductions in total and tonic–atonic seizures, with efficacy and tolerability sustained over 3 years. The most common AEs during the Phase III study – somnolence, vomiting, and pyrexia – occurred during the first 3 weeks of treatment, and a small subset of patients were unable to reach target dose in that time. Use of concomitant AEDs had no clinically significant effect on plasma concentrations of rufinamide. Data from real-world clinical studies are consistent with the Phase III and OLE study results. However, relative to those used in clinical trials, lower doses and slower titration schedules were commonly employed in real-world settings. ConclusionsA lower dose and slower titration schedule (“low and slow”) may reduce incidence of AEs without compromising efficacy of rufinamide in LGS.

P195 Prospective Examination Of The Effects Of Ivacaftor On Glycaemic Health

Background The clinical benefits of the novel cystic fibrosis transmembrane conductance regulator (CFTR) have now been well established for patients carrying the G551D mutation through both phase 3 and real world clinical studies. Modulation of CFTR alters intestinal pH, which may assist in the function of pancreatic enzymes and which theoretically might have an impact on the absorption of nutrients in cystic fibrosis (CF). This may have significant impact on the glycaemic health of patients and early reports from a phase 2 study suggested a significant risk of hyperglycaemia in a patient with pre-existing diabetes. Aim We aimed to prospectively assess the impact of ivacaftor on glycaemic health Methods We conducted a prospective observational cohort study of subjects who commenced ivacaftor following NHS approval. Baseline measures were recorded including spirometric measures, weight and sweat chloride. Glycaemic control was assessed using HbA1c and repeated measures were recorded at 1, 3 and 6 months. Results 24 subjects were included in the study. 17 subjects had normal glucose handling as defined by oral glucose tolerance test, 4 subjects had a pre-existing diagnosis of CF-related diabetes and 3 subjects had impaired glucose tolerance prior to ivacaftor commencement. Ivacaftor significantly increased FEV 1 and BMI at 1,3 and 6 months compared to baseline, and decreased sweat chloride at 2 months, all indicating effective CFTR modulation. There was a significant reduction in HbA1c from baseline to 6 months in the total cohort, (median 42.5 mmol/L versus 39.5 mmol/L, p = 0.004), but not at other time points. In the diabetic or IGT subgroups, there were no clinically significant changes in HbA1c. Conclusion Ivacaftor is an effective treatment for CF patients carrying the G551D mutation. In normoglycaemic patients, Ivacaftor significantly reduces HbA1c at 6 months. There was no adverse effect on glucose control noted in diabetic or impaired glucose tolerance subgroups. This may be attributable to improved insulin secretion by CFTR related mechanisms or improved insulin sensitivity. These results are important and re-assuring when commencing patients with diabetes on CFTR modulators.

Causal Mediation Analysis in the Multilevel Intervention and Multicomponent Mediator Case

SummaryMediation analysis is an important tool in social and medical sciences as it helps to understand why an intervention works. The commonly used approach, given by Baron and Kenny, requires the strong assumption ‘sequential ignorability’ to yield causal interpretation. Ten Have and his colleagues proposed a rank preserving model to relax this assumption. However, the rank preserving model is restricted to the case with binary intervention and single mediator and needs another strong assumption ‘rank preserving’. We propose a new model that can relax this assumption and can handle both multilevel intervention and multicomponent mediators. As an estimating-equation-based method, our model can handle both correlated data with the generalized estimating equation and missing data with inverse probability weighting. Finally, our method can also be used in many other research settings, using mathematical models similar to mediation analysis, such as treatment compliance and post-randomized treatment component analysis. For the causal mediation model proposed, we first show identifiability for the parameters in the model. We then propose a semiparametric method for estimating the model parameters and derive asymptotic results for the estimators proposed. Simulation shows good performance for the proposed estimators in finite sample sizes. Finally, we apply the method proposed to two real world clinical studies: the college student drinking study, and the ‘Improving mood promoting access to collaborative treatment for late life depression’ study.

Discussion of solutions to ethical issues in real-world study.

In recent years, the paradigm of real-world study (RWS) has been at the forefront of clinical research worldwide, particularly in the field of traditional Chinese medicine. In this paper, basic features and nature of real-world clinical studies are discussed, and ethical issues in different stages of RWS are raised and reviewed. Moreover, some preliminary solutions to these issues, such as protecting subjects during the process of RWS and performing ethical review, are presented based on recent practices and basic ethical rules to improve the scientific validity and ethical level of RWS.

Telbivudine treatment in chronic hepatitis B: experience from China

Telbivudine, one of the oral anti-hepatitis B virus (HBV) nucleoside analogues, has been used for more than 5 years to treat HBeAg-positive and -negative chronic hepatitis B (CHB) patients. This includes not only global Phase II and III trials, but also Chinese Phase III trials and several real-world clinical practice studies from China. The present review will first focus on 1-, 2- and 3-year data of telbivudine therapy on HBV DNA suppression, alanine aminotransferase (ALT) normalization, hepatitis B e antigen (HBeAg) seroconversion, viral resistance and safety in HBeAg-positive and -negative CHB patients. Second, telbivudine treatment predictors, including HBV DNA undetectability, ALT level and other immune-related markers at 12 and 24 weeks will be summarized to optimize therapy. Besides several retrospective studies, the Chinese EFFORT prospective study adapted from telbivudine virological response at 24 weeks has shown very promising results. Finally, the Chinese experience of using telbivudine in the second and third trimesters of pregnancy to prevent perinatal transmission of HBV infection will be touched on citing the latest studies.