Lung TransplantationPhase 2NCT01394835
Safety and Efficacy of Inhaled Alpha-1 Antitrypsin in Preventing Bronchiolitis Obliterable Syndrome in Lung Transplant Recipients
A Phase 2 study testing Alpha -1 Antitrypsin, Alpha-1 Antitrypsin and AAT in people with Lung Transplantation and Bronchiolitis Obliterable Syndrome, run by Rabin Medical Center.
Trial summary
Bronchiolitis obliterable syndrome (BOS) is the most common cause of death in long-term survivors after lung transplantation and refractory to most interventions. Many risk factor for BOS were identified in previous studies such as acute cellular rejection, lymphocytic bronchiolitis, cytomegalovirus (CMV) and non-CMV… Read more about this study
- Who is it for?
- Ages 18 to 70 years
- Conditions the study is for
- Lung Transplantation, Bronchiolitis Obliterable Syndrome
- What is being tested?
- Alpha -1 Antitrypsin, Alpha-1 Antitrypsin and AAT
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 40 participants
- Where
- No sites listed yet
- Study dates
- Sep 2011to Sep 2013
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 70 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Signature of informed consent
- Lung transplant recipient in the past 6 months.
- Stable concomitant therapy >2 weeks prior to visit 1
- Non-tobacco user of any kind
- No significant abnormalities in serum hematology, serum chemistry to the Principal Investigator's judgment((Hg>8g/dL ,Creatinine<2mg/dl,Liver enzymes<3*ULN)
- Non-pregnant, non-lactating female subjects, whose screening pregnancy test is negative and who are using contraceptive methods deemed reliable by the investigator, or who are more than 5 years post-menopausal or surgically sterilized or whose way-of-life excludes sexual activity.
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- Sexually active female subjects of child-bearing potential, as well as male subjects, must use a medically acceptable effective contraceptive method (for male - method such us condoms; for female - methods such as oral contraceptive medication used for at least two weeks before study start, or a combination of any two of the following: diaphragm, cervical cap, condom or spermicide), before study start and throughout the entire duration of the study.
- Exclusion Criteria:• Diagnosis of BOS with according to Estenne M. et al.
- Hospitalization within 1 month before study entry, not due to an airway disease
- Severe liver cirrhosis with ascites
- Hypersplenism
- Grade III/IV esophageal varices;
- Active pulmonary exacerbation within the 4 weeks prior to screening
- History of massive hemoptysis: greater than 200 cc in a 24 hour period
- Pregnancy or breastfeeding
- Any serious or active medical or psychiatric illness which, in the opinion of the investigator, would interfere with patient treatment, assessment, or compliance with the protocol.
- Fever at the time of the start of first (day #1) inhalation (oral temperature >38ºC)
- Evidence of uncontrolled hypertension
- Pulse >120/min (prior to study drug administration)
- Any serious malignancy except for basal and squamous (scaly or plate-like) cell skin cancer within the previous 3 years prior to study start
- Receipt of exogenous AAT within the last 6 months
- Previous enrolment in this study (subject can not be enrolled twice into the study)
- Evidence of congestive heart failure or other clinically significant cardiovascular conditions: myocardial infarction during the last year, arrhythmia requiring drug treatment during the last year, uncontrolled hypertension
- Current smoker (someone who has smoked within 4 weeks prior to screening)
- Subjects with an additional clinically significant inter-current illness (beside lung disease) (e.g., cardiac, hepatic, renal, endocrine, respiratory, neurological, hematological, neoplastic, immunological and skeletal) that the investigator determines that it could interfere with the safety or other assessments of this study
- Any evidence of alcohol abuse or history of abuse of illegal and/or legally prescribed drugs such as barbiturates, benzodiazepines, amphetamines, cocaine, opioids, and cannabinoids
- Being a sexually active female of child-bearing age without adequate contraception
- Any other factor that, in the opinion of the investigator, would prevent the subject form complying with the requirements of the protocol
Who cannot join
None listed.
Trial locations and contacts
No sites are listed yet.
About this study
Bronchiolitis obliterable syndrome (BOS) is the most common cause of death in long-term survivors after lung transplantation and refractory to most interventions. Many risk factor for BOS were identified in previous studies such as acute cellular rejection, lymphocytic bronchiolitis, cytomegalovirus (CMV) and non-CMV respiratory infections, injury to the allograft or airways, Primary graft dysfunction, HLA mismatching, and organizing pneumonia. (Belperio JA. et al.). Neutrophils and their released products may be involved in the development of BOS. Neutrophilia was repeatedly observed in the bronchoalveolar lavage fluid of patients after lung transplantation. In addition, infiltration of neutrophils into the bronchial epithelium has been detected in patients with higher degrees of active airway damage. Neutrophils are capable of causing severe damage to the lung tissue by releasing toxic proteases and reactive oxygen species if not counterbalanced by the antiprotease/ antioxidant screen of the lung. Based on this background, a causal relationship between neutrophilia and the development of BOS has been proposed. (Hirsch J. et al.) Detection of unopposed Neutrophile elastase (NE) activity in BAL appears to correlate with poor outcome due to refractory BOS. Unopposed NE in these subjects may not only serve as a marker of evolving graft dysfunction but also participate in damaging the airways of the allograft and inhibit adequate bacterial clearance. Prevention of neutrophil sequestration or inhibition of NE may prevent or attenuate airway damage and improve bacterial clearance mechanisms. (Nutley D et al.) These data demonstrate the importance of neutrophils and unopposed NE in the pathogenesis of BOS and call for new approach to prevent or modulate BOS targeting this mechanism.
AAT is the main inhibitor of neutrophil elastase in the lower airways and patients with AAT deficiency have low concentrations of the protein in this region of the lung. This explains the proteinase/antiproteinase theory of the development of emphysema in deficient patients in which the amount of elastase released in the lung exceeds the amount of AAT. The net result is persistence of elastase activity leading to lung destruction and the pathological changes of emphysema. (Abusriwil H. et al.) The administration of the AAT is to address proteinase/antiproteinase imbalance.
Administration of AAT will help to prevent further destruction of the lung architecture and reduce the inflammatory dysregulation that causes pulmonary dysfunction. It is expected that by attacking a specific and previously untreated key component part of the pathophysiological cycle of BOS, AAT therapy would decrease the prevalence of BOS in lung transplant recipients and prolong life expectancy of these patients.
- Being tested
- Alpha -1 Antitrypsin, Alpha-1 Antitrypsin, AAT
- Keywords
- Patient after lung transplantation
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Alpha -1 AntitrypsinDrug
Inhalation twice daily of 160mg
Alpha-1 AntitrypsinDrug
Inhalation twice daily .Dosage 160mg
AATDrug
Inhalation twice daily' 160mg
| Study group | Role | What they receive |
|---|---|---|
| Alpha -1 Antitrypsin | Experimental | Not described Receives: Drug: Alpha -1 Antitrypsin; Drug: Alpha-1 Antitrypsin; Drug: AAT |
What is being measured
The primary outcome is the main question the study is designed to answer.
Clinical diagnosis of BOS according to Estenne M. et al Treatment of lung transplant recipients to prevent BOS Clinical diagnosis of BOS according to Estenne M. et al. Adverse events and conc
Adverse events and concomitant medication recording and follow up. Safety/tolerability parameters at baseline (Day #1) will be compared with values generated at the following visits every 6 weeks (+/- 10 days).
At all visits, AEs and concomitant medications will be recorded. Additionally, the study coordinator will check occurrence of AE and concomitant medications by a telephone visit
Measured: 12 Month
Secondary outcomes (1)
Change in lung function test
Change in lung function FEV%, FEV1, FVC Baseline (Day #1) values of FEV1 and FVC (and FEV%) will be compared to the following visits every 6 weeks (+/- 10 days).
Incidence of Acute cellular rejection. Incidence of respiratory infection leading to antibiotics administration according to the decision of the investigator.
Measured: 12 month
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted14 Jul 2011 (estimated)
- Study startSep 2011
- Primary completionSep 2012 (estimated)
- Study completionSep 2013 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Lung TransplantationStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 40 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Rabin Medical Center
- Sponsor type
- University, hospital or other
- Investigators
- Mordechai R Kramer, M.D, Principal investigator, Rabin Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01394835
- Sponsor's protocol ID
- AAT-02
- Status last verified
- Jul 2011
- First submitted
- 5 Jul 2011
- Last updated
- 14 Jul 2011
- Results posted
- No
Study at a glance
From the registry record, last updated by the sponsor on 14 Jul 2011. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Safety and Efficacy of Inhaled Alpha-1 Antitrypsin in Preventing Bronchiolitis Obliterable Syndrome in Lung Transplant Recipients
- ClinicalTrials.gov ID
- NCT01394835
- Acronym / sponsor ID
- AAT-02
- Keywords
- Patient after lung transplantation
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 40 participants (estimated)
- Lead sponsor
- Rabin Medical CenterUniversity, hospital or other
- Study start
- Sep 2011
- Primary completion
- Sep 2012 (estimated)
- Study completion
- Sep 2013 (estimated)
- First posted
- 14 Jul 2011 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Bronchiolitis obliterable syndrome (BOS) is the most common cause of death in long-term survivors after lung transplantation and refractory to most interventions. Many risk factor for BOS were identified in previous studies such as acute cellular rejection, lymphocytic bronchiolitis, cytomegalovirus (CMV) and non-CMV respiratory infections, injury to the allograft or airways, Primary graft dysfunction, HLA mismatching, and organizing pneumonia. (Belperio JA. et al.). Neutrophils and their released products may be involved in the development of BOS. Neutrophilia was repeatedly observed in the bronchoalveolar lavage fluid of patients after lung transplantation. In addition, infiltration of neutrophils into the bronchial epithelium has been detected in patients with higher degrees of active airway damage. Neutrophils are capable of causing severe damage to the lung tissue by releasing toxic proteases and reactive oxygen species if not counterbalanced by the antiprotease/ antioxidant screen of the lung. Based on this background, a causal relationship between neutrophilia and the development of BOS has been proposed. (Hirsch J. et al.) Detection of unopposed Neutrophile elastase (NE) activity in BAL appears to correlate with poor outcome due to refractory BOS. Unopposed NE in these subjects may not only serve as a marker of evolving graft dysfunction but also participate in damaging the airways of the allograft and inhibit adequate bacterial clearance. Prevention of neutrophil sequestration or inhibition of NE may prevent or attenuate airway damage and improve bacterial clearance mechanisms. (Nutley D et al.) These data demonstrate the importance of neutrophils and unopposed NE in the pathogenesis of BOS and call for new approach to prevent or modulate BOS targeting this mechanism.
AAT is the main inhibitor of neutrophil elastase in the lower airways and patients with AAT deficiency have low concentrations of the protein in this region of the lung. This explains the proteinase/antiproteinase theory of the development of emphysema in deficient patients in which the amount of elastase released in the lung exceeds the amount of AAT. The net result is persistence of elastase activity leading to lung destruction and the pathological changes of emphysema. (Abusriwil H. et al.) The administration of the AAT is to address proteinase/antiproteinase imbalance.
Administration of AAT will help to prevent further destruction of the lung architecture and reduce the inflammatory dysregulation that causes pulmonary dysfunction. It is expected that by attacking a specific and previously untreated key component part of the pathophysiological cycle of BOS, AAT therapy would decrease the prevalence of BOS in lung transplant recipients and prolong life expectancy of these patients.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Alpha -1 Antitrypsin | Experimental | Drug: Alpha -1 Antitrypsin, Drug: Alpha-1 Antitrypsin, Drug: AAT |
Who may qualify
- Ages
- 18 to 70 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (28 listed)
- Signature of informed consent
- Lung transplant recipient in the past 6 months.
- Stable concomitant therapy >2 weeks prior to visit 1
- Non-tobacco user of any kind
- No significant abnormalities in serum hematology, serum chemistry to the Principal Investigator's judgment((Hg>8g/dL ,Creatinine<2mg/dl,Liver enzymes<3*ULN)
Key exclusion criteria (0 listed)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Alpha -1 AntitrypsinInhalation twice daily of 160mg | Drug | Alpha -1 Antitrypsin |
| Alpha-1 AntitrypsinInhalation twice daily .Dosage 160mg | Drug | Alpha -1 Antitrypsin |
| AATInhalation twice daily' 160mg | Drug | Alpha -1 Antitrypsin |
Primary outcome
Clinical diagnosis of BOS according to Estenne M. et al Treatment of lung transplant recipients to prevent BOS Clinical diagnosis of BOS according to Estenne M. et al. Adverse events and conc
Time frame: 12 Month
Adverse events and concomitant medication recording and follow up. Safety/tolerability parameters at baseline (Day #1) will be compared with values generated at the following visits every 6 weeks (+/- 10 days). At all visits, AEs and concomitant medications will be recorded. Additionally, the study coordinator will check occurrence of AE and concomitant medications by a telephone visit
1 secondary outcome
Change in lung function test
Time frame: 12 month
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 14 Jul 2011.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Mordechai R Kramer, M.D principal investigator
Rabin Medical Center
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Alpha -1 Antitrypsin, Alpha-1 Antitrypsin and AAT in people with Lung Transplantation and Bronchiolitis Obliterable Syndrome, run by Rabin Medical Center.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 28 inclusion and 0 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 14 Jul 2011. Status can change between updates, so confirm with the study contact before making plans.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Mordechai Kramer, MD (972-39377221, kremerm@clalit.org.il), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Clinical diagnosis of BOS according to Estenne M. et al Treatment of lung transplant recipients to prevent BOS Clinical diagnosis of BOS according to Estenne M. et al. Adverse events and conc (time frame: 12 Month). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 14 Jul 2011.