Intravenous augmentation treatment and lung density in severe α1 antitrypsin deficiency (RAPID): a randomised, double-blind, placebo-controlled trial.

BACKGROUND: The efficacy of α1 proteinase inhibitor (A1PI) augmentation treatment for α1 antitrypsin deficiency has not been substantiated by a randomised, placebo-controlled trial. CT-measured lung density is a more sensitive measure of disease progression in α1 antitrypsin deficiency emphysema than spirometry is, so we aimed to assess the efficacy of augmentation treatment with this measure. METHODS: The RAPID study was a multicentre, double-blind, randomised, parallel-group, placebo-controlled trial of A1PI treatment in patients with α1 antitrypsin deficiency. We recruited eligible non-smokers (aged 18-65 years) in 28 international study centres in 13 countries if they had severe α1 antitrypsin deficiency (serum concentration <11 µM) with a forced expiratory volume in 1 s of 35-70% (predicted). We excluded patients if they had undergone, or were on the waiting list to undergo, lung transplantation, lobectomy, or lung volume-reduction surgery, or had selective IgA deficiency. We randomly assigned patients (1:1; done by Accovion) using a computerised pseudorandom number generator (block size of four) with centre stratification to receive A1PI intravenously 60 mg/kg per week or placebo for 24 months. All patients and study investigators (including those assessing outcomes) were unaware of treatment allocation throughout the study. Primary endpoints were CT lung density at total lung capacity (TLC) and functional residual capacity (FRC) combined, and the two separately, at 0, 3, 12, 21, and 24 months, analysed by modified intention to treat (patients needed at least one evaluable lung density measurement). This study is registered with ClinicalTrials.gov, number NCT00261833. A 2-year open-label extension study was also completed (NCT00670007). FINDINGS: Between March 1, 2006, and Nov 3, 2010, we randomly allocated 93 (52%) patients A1PI and 87 (48%) placebo, analysing 92 in the A1PI group and 85 in the placebo group. The annual rate of lung density loss at TLC and FRC combined did not differ between groups (A1PI -1·50 g/L per year [SE 0·22]; placebo -2·12 g/L per year [0·24]; difference 0·62 g/L per year [95% CI -0·02 to 1·26], p=0·06). However, the annual rate of lung density loss at TLC alone was significantly less in patients in the A1PI group (-1·45 g/L per year [SE 0·23]) than in the placebo group (-2·19 g/L per year [0·25]; difference 0·74 g/L per year [95% CI 0·06-1·42], p=0·03), but was not at FRC alone (A1PI -1·54 g/L per year [0·24]; placebo -2·02 g/L per year [0·26]; difference 0·48 g/L per year [-0·22 to 1·18], p=0·18). Treatment-emergent adverse events were similar between groups, with 1298 occurring in 92 (99%) patients in the A1PI group and 1068 occuring in 86 (99%) in the placebo group. 71 severe treatment-emergent adverse events occurred in 25 (27%) patients in the A1PI group and 58 occurred in 27 (31%) in the placebo group. One treatment-emergent adverse event leading to withdrawal from the study occurred in one patient (1%) in the A1PI group and ten occurred in four (5%) in the placebo group. One death occurred in the A1PI group (respiratory failure) and three occurred in the placebo group (sepsis, pneumonia, and metastatic breast cancer). INTERPRETATION: Measurement of lung density with CT at TLC alone provides evidence that purified A1PI augmentation slows progression of emphysema, a finding that could not be substantiated by lung density measurement at FRC alone or by the two measurements combined. These findings should prompt consideration of augmentation treatment to preserve lung parenchyma in individuals with emphysema secondary to severe α1 antitrypsin deficiency. FUNDING: CSL Behring.

Randomised controlled trial for emphysema with a selective agonist of the γ-type retinoic acid receptor.

Palovarotene is an oral γ-selective retinoid agonist. In animal emphysema models, palovarotene reduced inflammation, promoted structural repair and functional improvement. REPAIR (Retinoid treatment of Emphysema in Patients on the α(1)-antitrypsin International Registry), was an investigator-initiated, double-blind, placebo-controlled randomised study to assess the safety and efficacy of 5 mg·day(-1) palovarotene given for 1 year to 262 patients with severe α(1)-antitrypsin deficiency and emphysema confirmed by computed tomography. Change in volume-adjusted 15th percentile point lung density from baseline in 1 year was the primary end-point; functional end-points were also regularly assessed. We randomly assigned 133 and 129 patients to placebo or palovarotene, respectively. Both groups were well matched for all baseline characteristics, including respiratory medications. 88% and 85% of patients completed 1 year of treatment with placebo and palovarotene, respectively. Palovarotene was generally well tolerated. In the study completers population, the placebo-corrected difference of lung density was -0.45 HU at week 28 (p=0.64) and -0.25 HU at week 52 (p=0.94). A nonsignificant treatment difference in most functional parameters of the lung in favour of the drug was observed over time suggesting potential pharmacological effects of palovarotene. Palovarotene 5 mg·day(-1) over 1 yr failed to show a significant benefit on lung density in moderate-to-severe emphysema secondary to severe α(1)-antitrypsin deficiency.

Secretory leukocyte proteinase inhibitor, alpha-1-antitrypsin deficiency and emphysema: Preliminary study, speculation and an hypothesis.

OBJECTIVES: This study investigated (i) whether adequate concentrations of secretory leukocyte proteinase inhibitor (SLPI) in the lungs of alpha-1-antitrypsin (A1AT) deficient patients can explain the variability in the development of emphysema in these individuals, and (ii) whether cigarette smoking jeopardises the protective screen provided by functional SLPI. METHODOLOGY: Four subjects [two normal proteinase inhibitor M (PiM), two abnormal PiZ] were selected from patients presenting for diagnostic bronchoscopy and lung function testing (spirometry, DLco). Each subject underwent BAL and had blood taken for A1AT and SLPI estimation. RESULTS: As expected serum and BAL A1AT concentrations were within the normal range in the normal PiM subjects. In normal subjects, SLPI concentrations in serum and BAL were within the normal range. A1AT-deficient subjects had reduced serum and BAL levels of A1AT reflecting their genetic disorder but showed increased concentrations of SLPI in BAL and serum. Percentage neutrophil elastase (NE) inhibitory capacity of BAL fluid was low in both A1AT-deficient subjects and a cigarette-smoking normal subject. In contrast, the NE inhibitory capacity for the normal subject who had never smoked was normal. CONCLUSIONS: These findings suggest that in A1AT deficiency there may be a compensatory increase in SLPI. This may protect the lung against the development of emphysema in A1AT-deficient individuals. Cigarette smokers may have a lower SLPI concentration than non-smokers. This provides an explanation for at least some of the observed variation in the development of emphysema in A1AT deficient subjects.

Decline in FEV1 in patients with PiZ alpha-1-antitrypsin deficiency: the Australian experience.

OBJECTIVE: Alpha-1-antitrypsin (alpha1antitrypsin) deficiency is a rare hereditary disorder which characteristically presents with emphysema at an early age. The aim of the present study was to determine whether the rate of decline of lung function in alpha1antitrypsin-deficient subjects in Australia was similar to that found elsewhere. METHODOLOGY: Patients registered with the Australian Alpha-1-Antitrypsin Replacement Program were studied. All patients (n = 50) had a serum alpha1antitrypsin concentration of < 0.3 g/L and had had spirometry measured over at least 2 years. They were compared with a group of normal volunteers (hospital staff, n = 107) with normal alpha1antitrypsin levels and phenotypes and with no clinical history of lung disease. All had spirometry measured for periods ranging from 2 to 6 years. The rate of decline of forced expiratory volume in 1 s (FEV1) for each subject was calculated by least squares linear regression using FEV1 against the time from entry into the study. RESULTS: The group mean (+/- SD) rate of decline in FEV1 was significantly greater (P < 0.01) in the alpha1antitrypsin-deficient patients (88 +/- 71 mL/year) than for the normal controls (-15 +/- 48 mL/year). There was no difference in decline in FEV1 when the data was analysed for gender and for index versus non-index cases. CONCLUSION: The results confirm previous reports of an accelerated rate of decline of FEV1 in patients with alpha1antitrypsin deficiency. Our results indicate that the rate of decline of lung function in alpha1antitrypsin deficient subjects in Australia is similar to that found in reported series from elsewhere.