Articles
Long-term efficacy and safety of α1 proteinase inhibitor treatment for emphysema caused by severe α1 antitrypsin deficiency: an open-label extension trial (RAPID-OLE)

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Summary

Background

Purified α1 proteinase inhibitor (A1PI) slowed emphysema progression in patients with severe α1 antitrypsin deficiency in a randomised controlled trial (RAPID-RCT), which was followed by an open-label extension trial (RAPID-OLE). The aim was to investigate the prolonged treatment effect of A1PI on the progression of emphysema as assessed by the loss of lung density in relation to RAPID-RCT.

Methods

Patients who had received either A1PI treatment (Zemaira or Respreeza; early-start group) or placebo (delayed-start group) in the RAPID-RCT trial were included in this 2-year open-label extension trial (RAPID-OLE). Patients from 22 hospitals in 11 countries outside of the USA received 60 mg/kg per week A1PI. The primary endpoint was annual rate of adjusted 15th percentile lung density loss measured using CT in the intention-to-treat population with a mixed-effects regression model. This trial is registered with ClinicalTrials.gov, number NCT00670007.

Findings

Between March 1, 2006, and Oct 13, 2010, 140 patients from RAPID-RCT entered RAPID-OLE: 76 from the early-start group and 64 from the delayed-start group. Between day 1 and month 24 (RAPID-RCT), the rate of lung density loss in RAPID-OLE patients was lower in the early-start group (−1·51 g/L per year [SE 0·25] at total lung capacity [TLC]; −1·55 g/L per year [0·24] at TLC plus functional residual capacity [FRC]; and −1·60 g/L per year [0·26] at FRC) than in the delayed-start group (−2·26 g/L per year [0·27] at TLC; −2·16 g/L per year [0·26] at TLC plus FRC, and −2·05 g/L per year [0·28] at FRC). Between months 24 and 48, the rate of lung density loss was reduced in delayed-start patients (from −2·26 g/L per year to −1·26 g/L per year), but no significant difference was seen in the rate in early-start patients during this time period (−1·51 g/L per year to −1·63 g/L per year), thus in early-start patients the efficacy was sustained to month 48.

Interpretation

RAPID-OLE supports the continued efficacy of A1PI in slowing disease progression during 4 years of treatment. Lost lung density was never recovered, highlighting the importance of early intervention with A1PI treatment.

Funding

CSL Behring.

Introduction

α1 antitrypsin deficiency is an autosomal co-dominant disorder caused by mutations of the SERPINA1 gene, resulting in insufficient concentrations of functional α1 proteinase inhibitor (A1PI) in the blood and other tissues.1, 2 The anti-proteinase function of A1PI primarily protects tissues containing elastin, most notably the lung, against damage caused by proteolytic enzymes.1, 3, 4, 5 Patients with severe α1 antitrypsin deficiency present with serum A1PI concentrations of less than 11 μM and are prone to developing pulmonary emphysema in the fourth or fifth decade of life.6

The association between reduced A1PI and disease progression has historically formed the basis for A1PI augmentation treatment to raise levels of the deficient protein. Since 1987, augmentation treatment with A1PI has been approved for use in the USA, Canada, Mexico, and some European countries to slow the progression of emphysema caused by severe α1 antitrypsin deficiency, on the basis of the treatment's biochemical efficacy and pharmacokinetic properties.7

Although observational trials have shown preservation of the FEV1 in some patients receiving augmentation treatment, an appropriately powered randomised placebo-controlled trial (RCT) based on FEV1 is not feasible in this rare population in view of the relative slowness of FEV1 to change over time and its relative insensitivity to assess the development of emphysema.8, 9 Thus, starting in 1999, most RCTs assessing a treatment effect of a therapeutic intervention in α1 antitrypsin deficiency have used the loss of lung density, as measured by the 15th percentile point using CT densitometry. This endpoint closely relates to pathological changes and has been shown to be the most sensitive measure of disease progression.10, 11, 12, 13

The 2-year, placebo-controlled, RAPID-RCT,14 published in 2015, showed the clinical efficacy of intravenous treatment with purified A1PI. Compared with placebo, the progression of emphysema was slowed by 34% (treatment difference of 0·74 g/L per year, 95% CI 0·06–1·42; one-sided p=0·017).14 After completion of RAPID-RCT, 140 (99%) of 141 eligible patients opted to enter a 2-year RAPID open-label extension (OLE) trial, in which all patients received A1PI treatment.

Research in context

Evidence before this trial

We searched PubMed for randomised controlled trials of CT lung scanning to assess emphysema progression in patients with α1 antitrypsin deficiency who received α1 proteinase inhibitor (A1PI) treatment published between database inception and June 14, 2016. We used the following search terms without language restrictions: “alpha-1 antitrypsin”, “augmentation therapy”, “computed tomography”, and “randomised controlled trial”. We found three relevant randomised controlled trials. In 2015, RAPID-RCT was the first study to show a significant delay in the progression of emphysema as a result of A1PI treatment, by 34% compared with placebo (0·74 g/L per year higher lung density, 95% CI 0·06–1·42; p=0·017) in 180 patients with severe α1 antitrypsin deficiency. In 1999, Dirksen and colleagues reported a sample of 56 ex-smokers with α1 antitrypsin deficiency and moderate emphysema, who received monthly intravenous A1PI or 2% albumin for at least 3 years. The study found no significant difference in FEV1 between the two groups, although it did report a trend towards slower annual loss of CT-measured lung density during treatment with A1PI. Another trial by Dirksen and colleagues, reported in 2009, involving 77 patients with α1 antitrypsin deficiency who received weekly intravenous A1PI or 2% albumin for 2–2·5 years, reported a trend towards reduced lung density loss in CT scans. The results of the two Dirksen and colleagues randomised controlled trials were pooled, and the authors of the pooled analysis concluded that A1PI treatment significantly reduced the rate of decrease in CT-measured lung density in patients with α1 antitrypsin deficiency and emphysema.

Added value of this trial

RAPID-OLE substantiates the efficacy and safety of A1PI treatment in slowing the progression of emphysema during 4 years of treatment. Patients who started 2 years of treatment after receiving placebo for 2 years in RAPID-RCT (delayed-start group), had a similar rate of lung density loss between months 24 and 48, as patients who had received 4 years of active treatment (early-start group), showing a consistent treatment effect (ie, similar rates of treatment benefit). RAPID-OLE also showed that, between months 24 and 48, the delayed-start group did not regain the lung tissue that had been lost during the previous 2 years while on placebo, showing the importance of early intervention with A1PI treatment.

Implications of all the available evidence

This study is the first application of a delayed-start methodology in α1 antitrypsin deficiency. The results confirm the findings of RAPID-RCT, establish sustained efficacy for 4 years, and suggest that slower lung density loss rates are associated with weekly administration of 60 mg/kg, irrespective of the time at which treatment commenced. These results should encourage early treatment of patients with α1 antitrypsin deficiency and lung disease.

In 2004, researchers suggested a basis for assessing disease modification of chronic, slowly progressive disorders using Alzheimer's disease as an example.15 To test this hypothesis, data from randomised-start trials submitted to the US Food and Drug Administration (FDA) for Parkinson's disease were analysed.16 A randomised-start trial design is a combination of an RCT, in which patients are randomly assigned to receive either active drug or placebo, and an ensuing open-label extension trial. The randomised-start trial design is regarded as the recommended approach to show disease modification via a direct effect of treatment on the underlying disease pathology, and to distinguish it from transient improvement or pharmacologically reversible effects.17

The combined analysis of RAPID-RCT and RAPID-OLE provided a unique opportunity in this rare disorder to study the long-term disease-modifying effects of A1PI treatment in a randomised-start trial design.

In the RAPID-RCT, A1PI treatment was effective in raising serum A1PI trough concentrations to more than the accepted 11 μM protective threshold and in slowing the progression of emphysema in patients with severe α1 antitrypsin deficiency. With data from the ensuing RAPID-OLE, we were able to assess for the first time the altered course of α1 antitrypsin deficiency through a direct effect on the underlying disease pathophysiology, by comparing data from patients who had received either 4 years or only 2 years of A1PI treatment in a randomised-start design across both trials.

Section snippets

Study design and patients

For this open-label extension trial (RAPID-OLE), we recruited patients who had completed 2 years of A1PI treatment at a dose of 60 mg/kg per week, or had received placebo for 2 years during RAPID-RCT, from 22 hospitals in 11 countries outside of the USA.

Inclusion criteria for RAPID-OLE were age 18–65 years with serum A1PI concentrations of less than 11 μM and FEV1 of 35–70% of predicted at randomisation in RAPID-RCT. Exclusion criteria were current smokers or smokers within 6 months before

Results

Between March 1, 2006, and Oct 13, 2010, 140 of the 180 patients in RAPID-RCT entered RAPID-OLE, comprising the RAPID-OLE ITT population; these patients were identified as the early-start group (n=76) and delayed-start group (n=64) on the basis of their previous treatment in RAPID-RCT (figure 1). Of these 140 patients, 121 comprised the completer population on the basis of having completed RAPID-RCT and RAPID-OLE and having had a minimum of two valid CT scans, one at baseline and one at month

Discussion

The data from RAPID-OLE confirm the continued efficacy of A1PI treatment in the prevention of emphysema and that it was maintained for 4 years. Moreover, the findings in the delayed-start group show that treatment with A1PI is disease-modifying in that lung density loss is slowed with the delayed introduction of augmentation treatment and that density loss is not recovered. Finally, the data provide reassurance that changes in sensitive lung densitometry outcomes are associated with the more

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