TABLE 3

Studies on augmentation therapy for α1-antitrypsin deficiency

Study design	Author, year [Ref.]	Intervention	Comparator	Primary outcome	Subjects n	Duration of treatment	Effect of treatment
RCT vs placebo	Dirksen, 1999 [51]	250 mg·kg⁻¹ augmentation 4 weekly	625 mg·kg⁻¹ albumin solution	FEV₁ decline	58	≥3 years	FEV₁ decline ns difference 59 vs 79 mL·year⁻¹ (p=0.25); reduced CT decline 2.6 vs 1.5 g·L⁻¹·year⁻¹ (p=0.07)
	Dirksen, 2009 [52]	60 mg·kg⁻¹ Prolastin weekly	2% albumin solution	CT densitometry	77	≥2 years	Reduced CT decline 1.4 vs 2.2 g·L⁻¹·year⁻¹ (p=0.06)
	Chapman, 2015 [53]	60 mg·kg⁻¹ Zemaira weekly	Lyophilised preparation	CT densitometry	180	≥2 years	Reduced CT decline 1.5 vs 2.2 g·L⁻¹·year⁻¹ (p=0.03)
RCT vs active comparator	Stoller, 2002^# [88]	60 mg·kg⁻¹ Prolastin weekly	60 mg·kg⁻¹ Respitin weekly	Serum AAT level	28	≥12 weeks	Equivalence for primary outcome, ns difference FEV₁, D_LCO, urinary desmosine
	Stocks, 2006^# [89]	60 mg·kg⁻¹ Prolastin weekly	60 mg·kg⁻¹ Zemaira weekly	Serum AAT level	44	≥10 weeks	Equivalence for primary outcome
	Stocks, 2010^# [90]	60 mg·kg⁻¹ Prolastin-C weekly	60 mg·kg⁻¹ Prolastin weekly	Plasma AAT level	24	10 weeks	Equivalence for primary outcome
	Campos, 2013^# [91]	120 mg·kg⁻¹ Prolastin-C weekly	60 mg·kg⁻¹ Prolastin weekly	Plasma AAT level, safety	30	8 weeks	Equivalence for primary outcome, ns difference in adverse events
	Sandhaus, 2014^# [92]	60 mg·kg⁻¹ Glassia weekly	60 mg·kg⁻¹ Prolastin weekly	Plasma AAT level	50	≥1 weeks	Equivalence for primary outcome, ns difference FEV₁ or FVC
Observational with control	Seersholm, 1997 [93]	60 mg·kg⁻¹ Prolastin or Trypsone weekly	No augmentation	FEV₁ decline	295	1 year	Reduced FEV₁ decline 53 vs 75 mL·year⁻¹ (p=0.02)
	AAT registry group, 1998 [8]	60 mg·kg⁻¹ Prolastin weekly	↓ frequency or no augmentation	FEV₁ decline, survival	1129	12–86 months	Better survival (p=0.001), ns difference in FEV₁ decline overall (p=0.40), if FEV₁ 35–49%, decline lower on treatment (73 vs 93 mL·year⁻¹, p=0.01)
	Wencker, 2001 [95]	60 mg·kg⁻¹ augmentation weekly	Data prior to augmentation	FEV₁ decline	96	≥12 months	Reduced FEV₁ decline 34 vs 49 mL·year⁻¹ (p=0.02)
	Stoller, 2003 [94]	Any dosing regimen augmentation	Usual care	Adverse events	1129	12–86 months	83% augmented patients had no adverse events; rate 0.02 events per patient per month
	Tonelli, 2009 [96]	Any dosing regimen augmentation	No augmentation	FEV₁ decline	164	Mean 42 months	Reduced FEV₁ decline 37 vs 46 mL·year⁻¹ (p=0.05)
	Barros-Tizon, 2012 [97]	60 mg·kg⁻¹ Prolastin or Trypsone at any interval	Data prior to augmentation	Exacerbation rate	127	18 months	Reduced exacerbation rate 1.2 vs 1 per year (p<0.01), reduced hospitalisation costs
Observational, no control	Wewers, 1987 [82]	60 mg·kg⁻¹ augmentation weekly	N/A	Serum AAT level, safety	21	6 months	AAT level improved vs baseline, low adverse event rate (i.e. safe)
	Schmidt, 1988 [98]	60 mg·kg⁻¹ augmentation weekly	N/A	Serum AAT level	20	6 months	AAT level maintained at 35% of normal (equivalent to PiMZ)
	Barker, 1994 [99]	60 mg·kg⁻¹ Prolastin weekly^¶	N/A	Functional status	14	12–48 months	12 out of 14 patients stabilised self-reported functional status
	Miravitlles, 1994 [101]	60 mg·kg⁻¹ Prolastin weekly⁺	N/A	Safety, AAT level	13	Up to 6 years	No significant adverse events; 10 out of 13 trough AAT >50 mg·dL⁻¹
	Barker, 1997 [100]	120 mg·kg⁻¹ Prolastin fortnightly	N/A	AAT level, safety	23	20 weeks	Trough levels inadequate with fortnightly dosing, treatment safe
	Schwaiblmair, 1997 [102]	60 mg·kg⁻¹ Prolastin weekly	N/A	FEV₁	20	3 years	FEV₁ decline 36 mL·year⁻¹
	Wencker, 1998 [103]	60 mg·kg⁻¹ Prolastin weekly	N/A	FEV₁ decline, safety	443	3.1–82.8 months	FEV₁ decline 57 mL·year⁻¹ on treatment, which was deemed safe
	Campos, 2009 [106]	Any form of augmentation	N/A	Compared age >60 years to <60 years	1062	1 year	Older subjects exhibited more indolent disease with fewer exacerbations
	Campos, 2009 [105]	Any form of augmentation	N/A	Exacerbations	922	1 year	Mean exacerbations 2.4 per year, 17 days per episode
	Vidal, 2010 [108]	60 mg·kg⁻¹ Trypsone weekly	N/A	Safety	23	24 weeks	1 out of 555 infusions had a treatment related adverse event
	Subramanian, 2012 [107]	60 mg·kg⁻¹ Prolastin weekly	N/A	PET CT	10	12 weeks	ns difference in PET signal on treatment

RCT: randomised controlled trial; FEV₁: forced expiratory volume in 1 s; ns: nonsignificant; CT: computed tomography; D_LCO: diffusing capacity of the lung for carbon monoxide; AAT: α1-antitrypsin; FVC: forced vital capacity; N/A: not applicable; PET: positron emission tomography. ^#: crossover study (either wholly or as follow on for the placebo group); ^¶: some patients changed to 120–180 mg·kg⁻¹, 2–3 weekly ⁺: changed to 240 mg·kg⁻¹, 4 weekly.