E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Pulmonary Emphysema due to Alpha-1-Antitrypsin Deficiency |
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E.1.1.1 | Medical condition in easily understood language |
Severe deficiency of alpha-1 antitrypsin, complicated by emphysema of the lungs |
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E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10014563 |
E.1.2 | Term | Emphysema pulmonary |
E.1.2 | System Organ Class | 100000004855 |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective of this study is to demonstrate, using whole lung computed tomography (CT) densitometry (15th percentile point [PD15]), a slower progression of lung tissue loss in subjects with alpha1-antitrypsin deficiency (AATD) on Alpha-1 MP (alpha1-proteinase inhibitor [human], modified process) treatment (either 60 mg/kg/week or 120 mg/kg/week) as compared to placebo. |
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E.2.2 | Secondary objectives of the trial |
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, and
- Slowing the progression of lung tissue loss as measured by basal lung CT densitometry (PD15).
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. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Have a documented total alpha1-PI serum level < 11 μM.
2. 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 (i.e., allelic discrimination) and phenotyping will be performed at the Screening (Week -3) Visit.
3. At the Screening (Week -3) Visit, have a post-bronchodilator FEV1 ≥ 30% and < 80% of
predicted and FEV1/forced vital capacity (FVC) < 70% (Global Initiative for Chronic
Obstructive Lung Disease [GOLD] stage II or III).
4. Have a carbon monoxide diffusing capacity (DLCO) ≤ 60% of predicted (corrected for HgB) within the past 2 years OR evidence of pulmonary emphysema on CT scan within the past 2 years per the Investigator’s judgment.
5. Have clinical evidence of pulmonary emphysema per the Investigator’s judgment. |
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E.4 | Principal exclusion criteria |
1. Has received alpha1-PI augmentation therapy for more than 1 month within the six months prior to the Screening (Week -3) Visit.
2. Has received alpha1-PI augmentation therapy within one 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. Smoking during the past 12 months or a positive urine cotinine test at screening that is due to smoking.
9. History of anaphylaxis or severe systemic response to any plasma-derived alpha1-PI preparation or other blood product(s).
10. 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.
11. 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.
12. Known selective or severe Immunoglobulin A (IgA) deficiency. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary objective of this study is to demonstrate, using whole lung computed tomography (CT) densitometry (15th percentile point [PD15]), a slower progression of lung tissue loss in subjects with alpha1-antitrypsin deficiency (AATD) on Alpha-1 MP (alpha1-proteinase inhibitor [human], modified process) treatment (either 60 mg/kg/week or 120 mg/kg/week) as compared to placebo. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
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, and
- Slowing the progression of lung tissue loss as measured by basal lung CT densitometry (PD15).
The exploratory objectives for this study are to evaluate the effects 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 on:
- The incidence and severity of COPD exacerbations as defined by ATS/ERS criteria,
- Change from baseline in forced expiratory volume in 1 second (FEV1), and
- Health-related quality of life as measured by the Saint George’s Respiratory Questionnaire (SGRQ).
CT scan parameters other than basal and whole lung PD15 may also be evaluated.
An additional exploratory objective is to compare the efficacy of 120 mg/kg/week Alpha-1 MP to 60 mg/kg/week Alpha-1 MP as evidenced by the change from baseline in whole lung PD15 using CT densitometry.
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. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Throughout the study (please ref. ATS/ERS COPD Exacerbation Assessment row in Appendix1: study flow chart - page 64) |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 3 |
E.8.3 |
The trial involves single site in the Member State concerned
| Information not present in EudraCT |
E.8.4 | The trial involves multiple sites in the Member State concerned | Information not present in EudraCT |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 30 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Argentina |
Australia |
Brazil |
Canada |
Denmark |
Estonia |
Finland |
France |
Ireland |
Moldova, Republic of |
New Zealand |
Poland |
Romania |
Russian Federation |
Serbia |
Spain |
Sweden |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 8 |
E.8.9.1 | In the Member State concerned months | 4 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 8 |
E.8.9.2 | In all countries concerned by the trial months | 4 |