E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Chronic augmentation and maintenance therapy in individuals with alpha1-proteinase inhibitor (A1-PI) deficiency and clinical evidence of emphysema. |
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E.1.1.1 | Medical condition in easily understood language |
Chronic hereditary, genetic disorder in which there is not enough of this protein to prevent lung damage and is associated with progressive, severe emphysema. |
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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 | 15.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10001811 |
E.1.2 | Term | Alpha-1 proteinase inhibitor deficiency |
E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
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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 |
To investigate the effect of Zemaira® on the progression of emphysema, assessed by the decline of lung density, measured by computed tomography (CT). |
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E.2.2 | Secondary objectives of the trial |
The key secondary objectives are to assess the effect of treatment with A1-PI on the following clinical assessments:
1. Change in exercise capacity assessed by the Incremental Shuttle Walking Test (ISWT)
2. Change in symptoms assessed by the St. George’s Respiratory Questionnaire (SGRQ)
3. The rate of pulmonary exacerbations
Additional secondary objectives include the assessment of the effect of A1-PI on pulmonary function test parameters. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. 18 to 65 years of age and willing to sign informed consent.
2. Males, and non-pregnant, non-lactating females, whose screening pregnancy test is negative and who are using contraceptive methods deemed reliable by the investigator.
3. Diagnosis of alpha1-proteinase inhibitor deficiency (serum A1- PI levels <11 mM or < 80 mg/dL). This includes newly diagnosed subjects, previously untreated subjects, currently treated subjects, and subjects currently not on treatment therapy but on treatment in the past.
4. Subjects with emphysema and FEV1 > 35 and < 70% (predicted).
5. No signs of chronic or acute Hepatitis A, Hepatitis B, Hepatitis C or HIV infection (negative serologies for HIV and viral hepatitis). In case of positive serologies for viral hepatitis, vaccination status or negative IgM should be available. |
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E.4 | Principal exclusion criteria |
1. Any relevant chronic diseases or history of relevant diseases (e.g., severe renal insufficiency) except respiratory or liver disease secondary to alpha1-proteinase inhibitor deficiency. Subjects with well-controlled, chronic diseases may be included
after consultation with the treating physician and the sponsor.
2. Current evidence of alcohol abuse or history of abuse of illegal and/or legally prescribed drugs such as barbiturates, benzodiazepines, amphetamines, cocaine, opioids, and cannabinoids.
3. History of allergy, anaphylactic reaction, or severe systemic response to human plasma derived products, or known mannitol hypersensitivity, or history of prior adverse reaction to mannitol.
4. History of transfusion reactions.
5. Selective IgA deficiency.
6. Acute illness within one week prior to the first administration of the investigational medicinal product (IMP). Start of treatment after recovery is possible.
7. Current tobacco smoker (smoking has to be ceased at least 6 months prior study inclusion). Subjects with a positive cotinine test due to nicotine replacement therapy (e.g. patches, chewing gum) or snuff are eligible.
8. Conditions or behaviors that interfere with attending scheduled study visits in opinion of the investigator.
9. History of non-compliance.
10. Administration of any other experimental new drug or participation in an investigation of a marketed product within one month prior to the screening visit date.
11. Inability to perform necessary study procedures.
12. Lung transplantation, lung volume reduction surgery or lobectomy or being on a waiting list for any such surgeries. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Annual rate of change of lung volume-adjusted lung density that is estimated by the P15 value from CT scans, as measured by the slope of time and treatment interaction from a mixed effects model |
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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) |
Key Secondary Efficacy Endpoints:
· Change in exercise capacity as measured by change from baseline to month 24 of distance walked in the ISWT
· Change in symptoms score as measured by change from baseline to month 24 of symptom domain in the SGRQ
· Annual rate of pulmonary exacerbations over 2 years
Other Secondary Efficacy Endpoints:
· Adjusted P15 values, change from baseline to month 24 based on CT scans
· The percent change from baseline to month 24 of pulmonary function test assessments (forced expiratory flow volume in 1 second [FEV1], FEV1 as a percentage of predicted, FEV1 as a proportion of forced vital capacity [FVC], and diffusion capacity of carbon monoxide [DLCO]
· Characteristics of pulmonary exacerbations:
- Time to first event
- Duration and severity as measured by:
Exacerbation days
Requiring antibiotics (intravenous, oral)
Requiring hospitalization
Hospitalization days
Antibiotic usage |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | Yes |
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 | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 20 |
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 |
Australia |
Canada |
Czech Republic |
Denmark |
Estonia |
Finland |
Germany |
Ireland |
Poland |
Romania |
Sweden |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
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 | 6 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 6 |