Table 5. Active and unpublished clinical trials in alpha-1 antitrypsin deficiency (AATD).

Treatment approach	Phase/trial identifier	Results to date/primary outcome	References
Small molecules	Phase II NCT04167345	Recruiting Primary outcome: evaluate the efficacy, safety, and pharmacokinetics of VX- 814 in PiZZ subjects	80
AAT-AT
AAT-AT (i.v.) (60 versus 120 mg/kg)	Phase III NCT01983241	Recruiting Primary outcome: change from baseline in whole lung PD15 (15th percentile point) determined by CT lung densitometry	81
AAT-AT (i.v.)	Phase III NCT02525861	Active, not recruiting Primary outcome: evaluate the safety and potential immunogenicity and assess the effects of alpha-1 proteinase inhibitor therapy on the levels of AAT and various biomarkers in the epithelial lining fluid	82
AAT-AT (i.v.)	Phase III NCT02722304	Terminated early owing to low/slow enrollment Primary outcome: rate of change in lung density based on group 1 (ARALAST NP) versus placebo and all alpha-1 proteinase inhibitor recipients versus placebo	83
AAT-AT (i.v.)	Phase I–II NCT02870309	Completed Primary outcome: safety of 60 mg/kg alpha-1 MP assessed by AEs, SAEs, discontinuations due to AEs or SAEs, and COPD exacerbations Results: the pharmacokinetics and safety of alpha-1 MP in Japanese subjects with AATD were consistent with the alpha-1 MP profile in non-Japanese subjects	84
AAT-AT (i.v.)	Phase I–II NCT02870348	Active, not recruiting Primary outcome: safety of 60 mg/kg alpha-1 MP as assessed by AEs and SAEs, discontinuations due to AEs or SAEs, and COPD exacerbations	85
AAT-AT (i.v.)	Phase II NCT03385395	Withdrawn Non-inferiority of OctaAlpha1 compared to alpha-1 proteinase inhibitor in terms of the serum trough levels at steady state	86
AAT-AT s.c.	Phase I NCT03362242	Active, not recruiting Primary outcome: number of participants with AE possibly or probably related to treatment	87
Inhaled AAT-AT	Phase III NCT04204252	Recruiting Primary outcome: FEV1 post bronchodilator	88
NE inhibitors
Oral NE	Phase II NCT03636347	Recruiting Primary outcome: change from baseline on blood biomarkers of neutrophil elastase activity (plasma desmosine/isodesmosine)	89
Oral NE	Phase II NCT03679598	Recruiting Primary outcome: evaluate change in plasma desmosine/isodesmosine and emergent adverse events	90
Nebulized hyaluronan	Phase II NCT03114020	Terminated (enrollment stopped 18 November 2019 because of slow enrollment) Primary outcome: measurement of sputum, plasma, and urine concentrations of desmosine and isodesmosine using hyaluronic acid inhalation versus placebo	91
Gene therapy
AAVrh.10 vector-AAT (i.v.)	Phase I–II NCT02168686	Completed Primary outcome: number and proportion of subjects experiencing adverse effects using i.v. AAV gene transfer vectors expressing human AAT	92
rAAV2-CB-hAAT vector (i.v.)	Phase I NCT00377416	Active, not recruiting Primary outcome: presence of rAAV2-CB-hAAT vector in blood and semen using recombinant AAV vectors	93
rhAAT-Fc-AAT (i.v.)	Phase I NCT03815396	Active, not recruiting Primary outcome: frequency and severity of AEs using open-label single and dose-escalation administrations of Fc fusion protein (rhAAT-fc)	94
rAAV2-AAT (intramuscular)	Phase I	Terminated (rise in anti-AAV titers and insufficient AAT levels)	95
rAAV1- AAT (intramuscular)	Phase I	Terminated (subtherapeutic but sustained AAT response, undesirable immune reaction)	96
Other: oral	Phase II NCT03008915	Active, not recruiting Primary outcome: pulmonary microvascular blood flow using aspirin versus placebo in AATD patients	97
AATD liver trials
RNAi (s.c.)	Phase I NCT02503683	Terminated (observation of low incidence of asymptomatic, transiently elevated liver enzymes in a subset of study subjects) Primary outcome: the safety of alpha-1 proteinase inhibitor evaluated by the proportion of subjects experiencing AEs, SAEs, and AEs leading to study drug discontinuation	98
siRNA (s.c.)	Phase II–III NCT03945292	Recruiting Primary outcome: evaluate the safety, tolerability, and effect on liver histology parameters with administration of the investigational product	99
siRNA (s.c.)	Phase I–II NCT03767829	Active, not recruiting Primary outcome: evaluate the safety and tolerability of single or multiple doses	100
Oral tablets	Phase II NCT01379469	Recruiting Primary outcome: determine the effect of carbamazepine on hepatic AAT polymers	101

AAT-AT, alpha-1 antitrypsin augmentation therapy; AAV, adeno-associated virus; AE, adverse event; COPD, chronic obstructive pulmonary disease; FEV1, forced expiratory volumen in 1 second; i.v., intravenous; NE, neutrophil elastase; RNAi, RNA interference; SAE, serious adverse event; s.c., subcutaneous; siRNA, small interfering RNA.