scholarly journals Epidemiology, Diagnosis and Available Treatment for Alpha 1 Antitrypsin Deficiency-related Emphysema in Europe

2018 ◽  
Vol 4 (1) ◽  
pp. 25
Author(s):  
Gabriel Thabut ◽  
Luciano Corda ◽  
◽  
◽  
Keyword(s):  
Controlled Trial ◽  
Clinical Care ◽  
Specific Treatment ◽  
Open Label ◽  
Good Tolerability ◽  
Antitrypsin Deficiency ◽  
Open Label Extension ◽  
Alpha 1 Antitrypsin Deficiency ◽  
Alpha 1 Antitrypsin ◽  
Randomised Controlled

Alpha 1 antitrypsin (AAT) deficiency (AATD) is a rare genetic risk factor that predisposes an individual to develop early-onset emphysema. While accurate diagnosis of severe AATD is an important goal of clinical care, a minority of individuals with AATD are diagnosed and lack of awareness about the disease is the major suspected cause for this. Since the 1980s, therapy with human plasma-derived AAT has been the only specific treatment for AATD aiming to slow emphysema progression. The first randomised controlled trial to demonstrate this slowing of disease progression with AAT was the Randomized, placebo-controlled trial of augmentation therapy in Alpha1 Proteinase Inhibitor Deficiency (RAPID) study. The RAPID programme, consisting of the initial trial plus its open-label extension (OLE), is the largest completed clinical study of AAT therapy in AATD and the only trial designed specifically to explore the disease-modifying effect of AAT treatment. The RAPID-OLE data substantiate those of the RAPID trial, establishing the sustained efficacy and good tolerability for AAT treatment, providing evidence that AAT treatment modifies the disease course, and supporting the importance of early intervention.

scholarly journals Safety and efficacy of subcutaneous tocilizumab in systemic sclerosis: results from the open-label period of a phase II randomised controlled trial (faSScinate)

2017 ◽  
Vol 77 (2) ◽  
pp. 212-220 ◽  
Author(s):  
Dinesh Khanna ◽  
Christopher P Denton ◽  
Celia J F Lin ◽  
Jacob M van Laar ◽  
Tracy M Frech ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Phase Ii ◽  
Controlled Trial ◽  
Safety Data ◽  
Open Label ◽  
Double Blind ◽  
Skin Score ◽  
Open Label Extension ◽  
Registration Number ◽  
Randomised Controlled

ObjectivesAssess the efficacy and safety of tocilizumab in patients with systemic sclerosis (SSc) in a phase II study.MethodsPatients with SSc were treated for 48 weeks in an open-label extension phase of the faSScinate study with weekly 162 mg subcutaneous tocilizumab. Exploratory end points included modified Rodnan Skin Score (mRSS) and per cent predicted forced vital capacity (%pFVC) through week 96.ResultsOverall, 24/44 (55%) placebo-tocilizumab and 27/43 (63%) continuous-tocilizumab patients completed week 96. Observed mean (SD (95% CI)) change from baseline in mRSS was –3.1 (6.3 (–5.4 to –0.9)) for placebo and –5.6 (9.1 (–8.9 to–2.4)) for tocilizumab at week 48 and –9.4 (5.6 (–8.9 to –2.4)) for placebo-tocilizumab and –9.1 (8.7 (–12.5 to –5.6)) for continuous-tocilizumab at week 96. Of patients who completed week 96, any decline in %pFVC was observed for 10/24 (42% (95% CI 22% to 63%)) placebo-tocilizumab and 12/26 (46% (95% CI 27% to 67%)) continuous-tocilizumab patients in the open-label period; no patients had >10% absolute decline in %pFVC. Serious infection rates/100 patient-years (95% CI) were 10.9 (3.0 to 27.9) with placebo and 34.8 (18.0 to 60.8) with tocilizumab during the double-blind period by week 48 and 19.6 (7.2 to 42.7) with placebo-tocilizumab and 0.0 (0.0 to 12.2) with continuous-tocilizumab during the open-label period.ConclusionsSkin score improvement and FVC stabilisation in the double-blind period were observed in placebo-treated patients who transitioned to tocilizumab and were maintained in the open-label period. Safety data indicated increased serious infections in patients with SSc but no new safety signals with tocilizumab.Trial registration numberNCT01532869; Results.

Alpha-1 antitrypsin deficiency: clarifying the role of the putative protective threshold

2021 ◽  
pp. 2101410
Author(s):  
Alessandro N. Franciosi ◽  
Daniel Fraughen ◽  
Tomás P. Carroll ◽  
Noel G. McElvaney
Keyword(s):  
Risk Estimation ◽  
Specific Treatment ◽  
Weekly Administration ◽  
Risk Assessment Models ◽  
Increased Risk ◽  
Antitrypsin Deficiency ◽  
Dosing Regimens ◽  
Alpha 1 Antitrypsin Deficiency ◽  
Alpha 1 Antitrypsin ◽  
Protective Threshold

AATD is the only readily identifiable monogenic cause of COPD. To date the only condition-specific treatment for AATD-associated COPD is weekly administration of intravenous purified pooled human AAT (IV-AAT). Uncertainties regarding which AATD genotypes should benefit from IV-AAT persist. IV-AAT is costly and involves weekly administration of a plasma product. Much of the risk stratification has been centred around the long-accepted hypothesis of a “putative protective threshold” of 11 µM (0.57 g·L−1) in serum. This hypothesis has become central to the paradigm of AATD care, though its derivation and accuracy for defining risk of disease remain unclear.We review the literature and examine the association between the 11 µM threshold and clinical outcomes to provide context and insight into the issues surrounding this topic.We found no data which demonstrates an increased risk of COPD dependent on the 11 µM threshold. Moreover, an abundance of recent clinical data examining this threshold refutes the hypothesis. Conversely, the use of 11 µM as a treatment target in appropriate ZZ individuals is supported by clinical evidence, although more refined dosing regimens are being explored.Continued use of the 11 µM threshold as a determinant of clinical risk is questionable, perpetuates inappropriate AAT-augmentation practices, may drive increased healthcare expenditure and should not be used as an indicator for commencing treatment.Genotype represents a more proven indicator of risk, with ZZ and rare ZZ-equivalent genotypes independently associated with COPD. New and better risk assessment models are needed to provide individuals diagnosed with AATD with reliable risk estimation and optimised treatment goals.

Allopurinol dose escalation to achieve serum urate below 6 mg/dL: an open-label extension study

2017 ◽  
Vol 76 (12) ◽  
pp. 2065-2070 ◽  
Author(s):  
Lisa K Stamp ◽  
Peter T Chapman ◽  
Murray Barclay ◽  
Anne Horne ◽  
Christopher Frampton ◽  
...  
Keyword(s):  
Adverse Events ◽  
Dose Escalation ◽  
Controlled Trial ◽  
Serum Urate ◽  
Extension Study ◽  
Open Label ◽  
Serious Adverse Events ◽  
Open Label Extension ◽  
Randomised Controlled ◽  
Kidney Impairment

ObjectivesTo determine the long-term safety and efficacy of allopurinol dose escalation (DE) to achieve target serum urate (SU) in gout.MethodsPeople, including those with chronic kidney disease, who completed the first 12 months of a randomised controlled trial continued into a 12-month extension study. Participants randomised to continue current dose for the first 12 months began allopurinol DE at month 12 if SU was ≥6 mg/dL (control/DE). Immediate DE participants who achieved target SU maintained allopurinol dose (DE/DE). The primary endpoints were reduction in SU and adverse events (AEs) at month 24.ResultsThe mean (SE) change in SU from month 12 to 24 was −1.1 (0.2) mg/dL in control/DE and 0.1 (0.2) mg/dL in DE/DE group (p<0.001). There was a significant reduction in the percentage of individuals having a gout flare in the month prior to months 12 and 24 compared with baseline in both groups and in mean tophus size over 24 months, but no difference between randomised groups. There were similar numbers of AEs and serious adverse events between groups.ConclusionsThe majority of people with gout tolerate higher than creatinine clearance-based allopurinol dose and achieve and maintain target SU. Slow allopurinol DE may be appropriate in clinical practice even in those with kidney impairment.Trial registration numberACTRN12611000845932

scholarly journals Alpha-1 Antitrypsin Deficiency: Principles of Care

2020 ◽  
Vol 33 (6) ◽  
pp. 433
Author(s):  
Joana F. Rodrigues ◽  
Alexandra Mineiro ◽  
António Reis ◽  
David G. Ventura ◽  
Fernando Fernandez-Llimos ◽  
...  
Keyword(s):  
Proteinase Inhibitor ◽  
Clinical Care ◽  
High Standard ◽  
Access To Treatment ◽  
Presenting Symptoms ◽  
Patient Organizations ◽  
Antitrypsin Deficiency ◽  
Alpha 1 Antitrypsin Deficiency ◽  
Alpha 1 Antitrypsin

Alpha-1 antitrypsin deficiency is an autosomal co-dominant inherited disorder that results in decreased circulating levels of alpha-1 antitrypsin (also known as alpha-1 proteinase inhibitor) and predisposes affected individuals to early onset lung and liver disease. There is currently no cure for alpha-1 antitrypsin deficiency. However, appropriate treatment and a high standard of clinical care can prevent patients from being seriously affected and having to undergo major medical interventions, such as organ transplantation. Beyond managing the symptoms associated with alpha-1 antitrypsin deficiency, alpha-1 proteinase inhibitor therapy is the only treatment for the condition’s underlying cause. Early diagnosis is important to ensure efficient therapeutic strategies and to minimize further deterioration of lung function. alpha-1 antitrypsin deficiency is under diagnosed globally, partly because the disease has no unique presenting symptoms. This document was prepared by a Portuguese multidisciplinary group and it aims to set out comprehensive principles of care for Alpha-1 antitrypsin deficiency. These include the importance of registries, the need for clinical research, the need for consistent recommendations (regarding diagnosis, treatment and monitoring), the role of reference centres, the requirement for sustained access to treatment, diagnostic and support services, and the role of patient organizations.

scholarly journals Efficacy of sofosbuvir as treatment for yellow fever: protocol for a randomised controlled trial in Brazil (SOFFA study)

BMJ Open ◽  
2019 ◽  
Vol 9 (11) ◽  
pp. e027207 ◽  
Author(s):  
Claudia Figueiredo-Mello ◽  
Luciana Vilas Boas Casadio ◽  
Vivian Iida Avelino-Silva ◽  
Ho Yeh-Li ◽  
Jaques Sztajnbok ◽  
...  
Keyword(s):  
Randomised Controlled Trial ◽  
Clinical Outcomes ◽  
Yellow Fever ◽  
Hepatitis Virus ◽  
Controlled Trial ◽  
Clinical Care ◽  
Specific Treatment ◽  
Viral Kinetics ◽  
Randomised Controlled ◽  
To Receive

IntroductionAn ongoing outbreak of yellow fever (YF) has been reported in Brazil with 1261 confirmed cases and 409 deaths since July 2017. To date, there is no specific treatment available for YF. Recently published papers describing in vitro and animal models suggest a potential effect of antiviral drugs (approved for the treatment of hepatitis virus) against flaviviruses, including YF. The primary aim of this study is to analyse the effect of sofosbuvir on viral kinetics and clinical outcomes among patients presenting with YF. This is a multicentre open-label randomised controlled trial with 1:1 individual allocation, stratified by severity and by recruiting centre.Methods and analysisAdults with suspected or confirmed YF infection and symptoms lasting up to 15 days are screened. Eligible and consenting patients are randomised to receive oral sofosbuvir 400 mg daily for 10 days or to receive standard clinical care. Viral kinetics are measured daily and the reduction in YF plasma viral load from the sample at inclusion to 72 hours after randomisation will be compared between active and control groups. Clinical outcomes include severity meeting criteria for intensive care support, liver transplantation, in-hospital mortality and mortality within 60 days.Ethics and disseminationEthics approval was obtained at the participating sites and at the national research ethics committee (CAAE 82673018.6.1001.0068). The trial has been submitted for ethical approval at additional potential recruiting centres. Results of the study will be published in journals and presented at scientific meetings.Trial registrationBrazilian Clinical Trials Registry (RBR-93dp9n).

scholarly journals Alpha-1 antitrypsin (AAT) augmentation therapy in individuals with the PI*MZ genotype: a pro/con debate on a working hypothesis

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Igor Barjaktarevic ◽  
Marc Miravitlles
Keyword(s):  
Lung Disease ◽  
Therapeutic Strategy ◽  
Specific Treatment ◽  
Augmentation Therapy ◽  
Limited Data ◽  
Severe Deficiency ◽  
Antitrypsin Deficiency ◽  
Alpha 1 Antitrypsin Deficiency ◽  
Alpha 1 Antitrypsin ◽  
Current Guidelines

AbstractAlpha-1 antitrypsin deficiency (AATD) is a significantly under-diagnosed genetic condition caused by reduced levels and/or functionality of alpha-1 antitrypsin (AAT), predisposing individuals to lung, liver or other systemic diseases. The management of individuals with the PI*MZ genotype, characterized by mild or moderate AAT deficiency, is less clear than of those with the most common severe deficiency genotype (PI*ZZ). Recent genetic data suggest that the PI*MZ genotype may be significantly more prevalent than currently thought. The only specific treatment for lung disease associated with severe AATD is the intravenous infusion of AAT augmentation therapy, which has been shown to slow disease progression in PI*ZZ individuals. There is no specific evidence for the clinical benefit of AAT therapy in PI*MZ individuals, and the risk of emphysema development in this group remains controversial. As such, current guidelines do not support the use of AAT augmentation in PI*MZ individuals. Here, we discuss the limited data on the PI*MZ genotype and offer pro and con perspectives on pursuing an AAT-specific therapeutic strategy in PI*MZ individuals with lung disease. Ultimately, further research to demonstrate the safety, risk/benefit balance and efficacy of AAT therapy in PI*MZ individuals is needed.

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