Alpha 1 antitrypsin to treat lung disease in alpha 1 antitrypsin deficiency: recent developments and clinical implications

Figures & data

Figure 1 Study design of the RAPID-RCT and RAPID-OLE trials employing lung density measures by CT scans at 0, 3, 12, 21, 24, 36 and 48 months.

Abbreviations: AAT, alpha 1 antitrypsin; CT, computed tomography; IV, intravenous; OLE, open-label extension; RAPID, Randomized, Placebo-controlled Trial of Augmentation Therapy in Alpha-1 Proteinase Inhibitor Deficiency; RCT, randomized controlled trial.

Figure 2 Annualized rate of decline in physiologically adjusted P15 lung density (g/L) at TLC over 48 months.

Notes: Slopes estimated based on data acquired from Early-Start (N=75) and Delayed-Start (N=64) subjects who had completed both RAPID-RCT and RAPID-OLE trials. Reproduced from The Lancet Respiratory Medicine, Vol 5. McElvaney NG, et al. 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), pp. 51–60. Copyright (2017), with permission from Elsevier.²²
Abbreviations: AAT, alpha 1 antitrypsin; adjusted P15, lung volume-adjusted 15th percentile of the lung density; OLE, open-label extension; RAPID, Randomized, Placebo-controlled Trial of Augmentation Therapy in Alpha-1 Proteinase Inhibitor Deficiency; RCT, randomized controlled trial; TLC, total lung capacity.

Table 1 Characteristics of clinical trials and observational studies using CT densitometric indices as outcome measures for emphysema progression

	Randomized controlled trials				Observational studies
	Dirksen et al^Citation29	Dirksen et al^Citation30	Chapman et al^Citation21	McElvaney et al^Citation22	Dowson et al^Citation31	Dawkins et al^Citation32	Stolk et al^Citation33	Parr et al^Citation34
Year	1999	2009	2015	2017	2001	2003	2003	2004
Study design	Prospective, randomized, parallel, double-blind, placebo-controlled trial at two centers	Prospective, randomized, parallel, double-blind, placebo-controlled trial at three centers	Prospective, randomized, parallel, double-blind, placebo-controlled trial	Prospective, randomized, parallel, double-blind, active-controlled trial	Prospective, single-center, observational study	Prospective, single-center, observational study	Prospective, single-center, observational study	Single-center, observational study
Number of patients	56	77	180	140	45	256	22	119
Drug dosage and regimen	AAT formulation (LFB) 250 mg/kg administered at 4-week intervals	Alpha 1 proteinase inhibitor (Prolastin^®-C) 60 mg/kg weekly infusions	Alpha 1 proteinase inhibitor (Zemaira^®/Respreeza^®) 60 mg/kg weekly infusions	Alpha 1 proteinase inhibitor (Zemaira/Respreeza) 60 mg/kg weekly infusions	N/A	N/A	N/A	N/A
Comparator	Placebo (albumin 625 mg/kg) administered at 4-week intervals	Placebo (2% albumin)	Placebo	Alpha 1 proteinase inhibitor (Zemaira/Respreeza) early intervention group	N/A	N/A	N/A	N/A
Recorded CT parameter and level of inspiration	15th percentile lung density from whole lung measures, with tidal breathing during scan acquisition and at 75% of TLC for Danish and Dutch patients, respectively	Change in TLC adjusted 15th percentile lung density and regional lung density	Change in annual rate of adjusted 15th percentile lung density and regional volume-adjusted 15th percentile lung density. Recorded at TLC, FRC and TLC + FRC combined	Change in annual rate of adjusted 15th percentile lung density and regional volume-adjusted 15th percentile lung density. Recorded at TLC, FRC and TLC + FRC combined	Lung voxels with density less than −910 HU in upper and lower respiratory zones at TLC	Lung voxels with density less than − 910 HU in upper and lower respiratory zones at TLC	Relative area below −950 HU and 15th percentile lung density at TLC	Whole lung measures of 15th percentile density and in basal and apical lung regions taken at TLC
Primary outcomes	Daily PASS	Change in 15th percentile lung density	Annual rate of decrease in 15th percentile lung density measured at FRC and TLC	Annual rate of decrease in 15th percentile lung density measured at TLC (FRC and TLC + FRC combined were supportive endpoints)	Mean rate of FEV1 decline	Causes of mortality	SGRQ-derived health status and lung density	15th percentile point of whole lung as well as basal and apical
Secondary outcomes	15th percentile point of lung density distribution; other secondary endpoints included FEV1, KCO and DLCO	FEV1, DLCO, KCO frequency of exacerbations, health status according to SGRQ score	Frequency and duration of exacerbations, FEV1, baseline and achieved AAT concentrations, shuttle walk test, health status according to SGRQ score, BMI, mortality and safety	Frequency and duration of exacerbations, FEV1, baseline and achieved AAT concentrations, shuttle walk test, health status according to SGRQ score, BMI, mortality and safety	KCO, arterial PaO2, health status from SGRQ and SF-36	FEV1, KCO, health status from SGRQ score, BMI	FEV1, KCO, health status from SGRQ score	FEV1, KCO, VC, RV, health status according to SGRQ and SF-36 questionnaire
Study findings	No differences in decline of FEV1 (measured via PASS), but trend toward reduced decline of lung tissue	CT was a more sensitive and specific measure of disease-modifying therapy than physiology or health status	CT revealed a 34% reduction in lung density decline. Lung density measures support the extension of time to terminal respiratory function. Differences in secondary measures not significant between treatment groups	Results support the sustained efficacy of AAT therapy in slowing the rate of disease progression and disease-modifying effects of treatment	Upper zone HRCT was most sensitive to disease progression. Analysis of single-slice CT scans correlated with lung function, exercise capacity and health status	CT scanning predicted respiratory performance and causes of mortality. CT was superior to lung function parameters when assessing mortality in patients with AATD	Changes in 15th percentile point were well correlated with changes in health status	CT lung densitometry indices of the lower lung zones correlated better with FEV1. Graphical representation of lung density was an accurate reflection of emphysema severity and distribution

Abbreviations: AAT, alpha 1 antitrypsin; AATD, alpha 1 antitrypsin deficiency; BMI, body mass index; CT, computed tomography; DL_CO, diffusing capacity for carbon monoxide; FRC, functional residual capacity; HRCT, high-resolution computed tomography; HU, Hounsfield units; K_CO, carbon monoxide transfer coefficient; LFB, Laboratoire français du fractionnement et des biotechnologies; PASS, patient-administered sequential spirometry; PaO₂, partial pressure of arterial O₂; RV, residual volume; SF-36, 36-item short form survey; SGRQ, St George’s Respiratory Questionnaire; TLC, total lung capacity; VC, vital capacity.

Figure 3 Change in clinical outcome measures after administration of a disease-modifying therapy.

Notes: Reproduced with permission from Taylor & Francis. The Version of Scholarly Record of this Article is published in COPD: Journal of Chronic Obstructive Pulmonary Disease (2016), available online at: http://www.tandfonline.com/10.1080/15412555.2016.1178224. This article was distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives license. Disease Modification in Emphysema Related to Alpha-1 Antitrypsin Deficiency, COPD: Journal of Chronic Obstructive Pulmonary Disease, Chorostowska-Wynimko J, Vol 13, pp. 807–815, published online: 12 May 2016, http://www.tandfonline.com reprinted by permission of the publisher.²³

Figure 4 Extrapolation of the effect of AAT replacement therapy on the predicted time to reach terminal respiratory function in RAPID-RCT.

Notes: Reproduced from The Lancet Respiratory Medicine, Vol 5. McElvaney NG, et al. 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), pp. 51–60. Copyright (2017), with permission from Elsevier.²²
Abbreviations: AAT, alpha 1 antitrypsin; RAPID, Randomized, Placebo-controlled Trial of Augmentation Therapy in Alpha-1 Proteinase Inhibitor Deficiency; RCT, randomized controlled trial.

Figure 5 ACSM exercise recommendations for pulmonary rehabilitation.⁹⁰

Abbreviation: ACSM, American College of Sports Medicine.

McElvaneyNGBurdonJHolmesMLong-term efficacy and safety of a-1 proteinase inhibitor treatment for emphysema caused by severe a-1 antitrypsin deficiency: an open-label extension trial (RAPID-OLE)Lancet Respir Med201751516027916480

 PubMed Web of Science ®Google Scholar

DirksenADijkmanJMadsenFA Randomized Clinical Trial of α1-Antitrypsin Augmentation TherapyAm J Respir Crit Care Med199916051468147210556107

 PubMed Web of Science ®Google Scholar

DirksenAPiitulainenEParrDGExploring the role of CT densitometry: a randomised study of augmentation therapy in alpha1-antitrypsin deficiencyEur Respir J20093361345135319196813

 PubMed Web of Science ®Google Scholar

ChapmanKRBurdonJGPiitulainenEIntravenous augmentation treatment and lung density in severe alpha1 antitrypsin deficiency (RAPID): a randomised, double-blind, placebo-controlled trialLancet201538699136036826026936

 PubMed Web of Science ®Google Scholar

DowsonLGuestPStockleyRLongitudinal changes in physiological, radiological, and health status measurements in α1-antitrypsin deficiency and factors associated with declineAm J Respir Crit Care Med2001164101805180911734427

 PubMed Web of Science ®Google Scholar

DawkinsPADowsonLJGuestPJStockleyRAPredictors of mortality in alpha1-antitrypsin deficiencyThorax200358121020102614645964

 PubMed Web of Science ®Google Scholar

StolkJNgWHBakkerMECorrelation between annual change in health status and computer tomography derived lung density in subjects with α1-antitrypsin deficiencyThorax200358121027103014645966

 PubMed Web of Science ®Google Scholar

ParrDGStoelBCStolkJStockleyRAPattern of emphysema distribution in α1-antitrypsin deficiency influences lung function impairmentAm J Respir Crit Care Med2004170111172117815306534

 PubMed Web of Science ®Google Scholar

Chorostowska-WynimkoJDisease modification in emphysema related to alpha-1 antitrypsin deficiencyCOPD201613680781527172295

 PubMedGoogle Scholar

GarberCEBlissmerBDeschenesMRQuantity and quality of exercise for developing and maintaining cardiorespiratory, musculoskeletal, and neuromotor fitness in apparently healthy adults: guidance for prescribing exerciseMed Sci Sports Exerc20114371334135921694556

 PubMed Web of Science ®Google Scholar