A Controlled Study with an active treatment and a Placebo to Assess the Efficacy and Safety of Weekly Intravenous Product in Subjects with Pulmonary Emphysema due to Alpha-1 Antitrypsin Deficiency

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Grifols Therapeutics LLC

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Respiratory Tract Diseases [C08]

Trial duration

29 Jan 2014 → ongoing

Decision date (initial)

2024-08-22

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

External identifiers

EU CT number

2023-510030-83-00

EudraCT number

2013-001870-38

ClinicalTrials.gov

NCT01983241

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

The primary objective of this study is to demonstrate, using whole lung CT densitometry (PD15), a slower progression of lung tissue loss in subjects with AATD on Alpha-1 MP treatment (either 60 mg/kg/week or 120 mg/kg/week) as compared to placebo.

Secondary objectives 3

1. The secondary objectives of this study are to demonstrate the efficacy of each IV dose of Alpha-1 MP (either 60 mg/kg/week or 120 mg/kg/week) as compared to placebo in subjects with AATD by reducing the incidence of severe COPD exacerbations as defined by an American Thoracic Society (ATS)/European Respiratory Society (ERS) Task Force criteria
2. Another secondary objective of this study is to demonstrate the efficacy of each intravenous (IV) dose of Alpha-1 MP (either 60 mg/kg/week or 120 mg/kg/week) as compared to placeboin subjects with AATD by slowing the progression of lung tissue loss as measured by basal lung CT densitometry (PD15)
3. The safety objective of this study is to evaluate the safety and tolerability of two separate IV dose regimens (60 mg/kg/week and 120 mg/kg/week) of Alpha-1 MP.

Conditions and MedDRA coding

Pulmonary Emphysema due to Alpha-1-Antitrypsin Deficiency

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 7

1. At screening is between 18 and 70 years of age, inclusive.
2. Have a documented total alpha1-PI serum level < 11 μM. If the total alpha1-PI serum level has yet to be documented, a blood draw for total alpha1-PI serum level will be performed at the Screening (Week -3) Visit
3. Have a diagnosis of congenital AATD with an allelic combination of ZZ, SZ, Z(null), (null)(null), S(null), or “at-risk” alleles. If the genotype has yet to be documented, genotyping and phenotyping will be performed at the Screening (Week -3) Visit.
4. At the Screening (Week -3) Visit, have a post-bronchodilator FEV1 ≥ 30% and < 80% of predicted and FEV1/FVC < 70% (Global Initiative for Chronic Obstructive Lung Disease [GOLD] stage II or III).
5. Have a DLCO ≤ 60% of predicted (corrected for hemoglobin [HgB]) within the past 2 years OR evidence of pulmonary emphysema on CT scan within the past 2 years per the Investigator’s judgment.
6. Have a body mass index (BMI) < 40 kg/m2.
7. Willing and able to provide informed consent.

Exclusion criteria 24

1. Has received alpha1-PI augmentation therapy for more than 1 month within the 6 months prior to the Screening (Week -3) Visit.
2. Has received alpha1-PI augmentation therapy within 1 month of the Screening (Week -3) Visit.
3. Has had a COPD exacerbation within the 5 weeks prior to the Screening (Week -3) Visit or during the Screening Phase. Investigator discretion should be used to determine if a subject is appropriate for study participation if the subject has had a COPD exacerbation which occurred more than 5 weeks prior to the Screening (Week -3) Visit.
4. Unable to physically (e.g., unable to fit inside the CT scanner) or mentally (e.g., claustrophobic) undergo a CT scan.
5. History of lung or liver transplant.
6. Any lung surgery during the past 2 years (excluding lung biopsy).
7. On the waiting list for lung surgery, including lung transplant.
8. On the waiting list for liver transplant.
9. Elevated liver enzymes (aspartate transaminase [AST], alanine aminotransferase [ALT], and alkaline phosphatase) equal to or greater than 2.5 times the upper limit of normal (ULN).
10. Severe concomitant disease including, but not limited to, congestive heart failure and liver cirrhosis.
11. Malignant disease (including malignant melanoma; however, other forms of skin cancer are allowed) within five years of the Screening (Week -3) Visit.
12. Females who are pregnant, breastfeeding or, if of child-bearing potential, unwilling to practice a highly effective method of contraception (oral, injectable or implanted hormonal methods of contraception, placement of an intrauterine device (IUD) or intrauterine system (IUS), condom or occlusive cap with spermicidal foam/gel/film/cream/suppository, male sterilization, or true abstinence*) throughout the study. * True abstinence: When this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, post-ovulation methods], declaration of abstinence for the duration of a trial, and withdrawal are not acceptable methods of contraception.)
13. Has a metal object that might interfere with chest CT quality and quantification. Metal objects include, but are not limited to, cardiac pacemaker, defibrillator, metal prosthetic heart valve, metal projectile, metal weapon fragments, or metal shoulder prosthesis.
14. Currently infected with Hepatitis A virus (HAV) or Parvovirus B19 (B19V) or has laboratory results indicative of an acute or chronic infection with Hepatitis B virus (HBV), Hepatitis C virus (HCV), or Human Immunodeficiency Virus (HIV).
15. Smoking, which includes electronic/vapor cigarettes, during the past 12 months or a positive urine cotinine test at screening that is due to smoking (Note: subjects who have a positive urine cotinine test and are also receiving nicotine replacement therapy (e.g., nicotine patches or chewing gum), or using snuff or snus (smokeless tobacco) may be eligible to participate in the study upon completion of an exhaled carbon monoxide [eCO] breath test; subjects with an eCO ≥ 10 ppm will be ineligible for study participation).
16. History of chronic alcoholism or illicit drug abuse (addiction) in the 12 months prior to the Screening (Week -3) Visit.
17. Participation in another investigational product study within one month or five half-lives prior to the Screening (Week -3) Visit.
18. History of anaphylaxis or severe systemic response to any plasma-derived alpha1-PI preparation or other blood product(s).
19. Use of systemic steroids above a stable dose equivalent to 5 mg/day prednisone (i.e., 10 mg every 2 days) within the 5 weeks prior to the Screening (Week -3) Visit (inhaled steroids are not considered systemic steroids) or during the Screening Phase. It is recommended to maintain the same dose throughout the study.
20. Use of systemic or aerosolized antibiotics for a COPD exacerbation within the 5 weeks prior to the Screening (Week -3) Visit or during the Screening Phase.
21. Known selective or severe Immunoglobulin A (IgA) deficiency.
22. Mentally challenged, adult subject who cannot give independent informed consent.
23. In the opinion of the Investigator the subject may have compliance problems with the protocol and the procedures of the protocol.
24. Any medical condition which the Investigator feels might confound the results of the study or pose an additional risk to the subject during study participation.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The primary variable to assess efficacy in this study is whole lung PD15 using CT densitometry.

Secondary endpoints 2

1. Severe COPD exacerbations as defined by ATS/ERS criteria (i.e., COPD exacerbations that require hospitalization)
2. PD15 of the basal lung region using CT densitometry.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Grifols Therapeutics LLC

Sponsor organisation

Grifols Therapeutics LLC

Address

8368 Clayton Boulevard

City

Clayton

Postcode

27520-9464

Country

United States

Scientific contact point

Organisation

Grifols Therapeutics LLC

Contact name

SCIENTIFIC INNOVATION OFFICE DRUG DEVELOPMENT

Public contact point

Organisation

Grifols Therapeutics LLC

Contact name

SCIENTIFIC INNOVATION OFFICE DRUG DEVELOPMENT

Third parties 1

Locations

5 EU/EEA countries · 8 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 50 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

5 submissions — initial application plus substantial / non-substantial modifications