Alpha-1 Antitrypsin Deficiency (AATD)Phase 2ATALANTaNCT03679598
Alvelestat (MPH966) for the Treatment of ALpha-1 ANTitrypsin Deficiency
A Phase 2 study testing Alvelestat (MPH966) in people with Alpha-1 Antitrypsin Deficiency (AATD) and Pi*ZZ, Pi*SZ, Pi*Null, Another Rare Phenotype/Genotype Known to be Associated With Either Low or Functionally Impaired AAT Including F or I Mutations, run by University of Alabama at Birmingham at 10 sites in United States.
Trial summary
This is a Phase 2, multicenter, double-blind, randomized (1:1), placebo-controlled, 12-week, proof-of-concept study to evaluate the safety and tolerability as well as the mechanistic effect of oral administration of alvelestat (MPH966) in subjects with confirmed AATD defined as Pi*ZZ, Pi*SZ, Pi*null, or another rare… Read more about this study
- Who is it for?
- Ages 18 to 80 years
- Conditions the study is for
- Alpha-1 Antitrypsin Deficiency (AATD), Pi*ZZ, Pi*SZ, Pi*Null, Another Rare Phenotype/Genotype Known to be Associated With Either Low or Functionally Impaired AAT Including F or I Mutations, Emphysema or COPD
- What is being tested?
- Alvelestat (MPH966)
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 63 participants
- Where
- 10 sitesUnited States
- Study dates
- 8 Apr 2019to 1 Dec 2023
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
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 80 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Participants are eligible to be included in the study only if ALL of the following criteria apply:
- Capable of giving signed informed consent as described in Appendix 3, which includes compliance with the requirements and restrictions listed in the informed consent form and in this protocol
- Age ≥18 and ≤80 years
- Patients with a confirmed diagnosis of AATD: Pi*ZZ, Pi*SZ, Pi*null, or another rare phenotype/genotype known to be associated with either low (serum AAT level <11 μM or <57.2 mg/dL) or functionally impaired AAT including "F" or "I" mutations.
- FEV1 ≥25% predicted
- Patients will be eligible if they are either a) are not currently receiving augmentation treatment and have not received augmentation in the 12 weeks prior to screening or b) have received weekly infusions of augmentation at 60 mg/kg for at least 12 weeks prior to screening and intend to continue augmentation through the study period.
- Male or female sex a. Male participants must agree to use a highly effective contraception as detailed in Appendix 5 during the treatment period and for at least 4 days after the last dose of study treatment and refrain from donating sperm during this period b. Female participants are eligible to participate if not pregnant; not breastfeeding; and at least one of the following conditions is met: i. Not a woman of childbearing potential as defined in Appendix 5 OR ii. A woman of childbearing potential who agrees to follow the contraceptive guidance in Appendix 5. During the treatment phase and for at least 4 days after the last dose of study medication.
Who cannot join
- Participants are excluded from the study if ANY of the following criteria apply:
- Excluded Medical Conditions
- Subjects with Pi*MZ, Pi*FM, Pi*MS, Pi*SS, or other AATD phenotypes/genotypes not known to be independently associated with emphysema.
- Any clinically diagnosed lung disease other than COPD such as diffuse interstitial lung diseases, cystic fibrosis, or clinically significant bronchiectasis as determined by the Investigator
- Acute exacerbation of underlying lung disease requiring oral steroids and/or antibiotics within 4 weeks of baseline
- Acute or chronic hepatitis, including hepatitis B, hepatitis C (positive serologies, including hepatitis B and C antibody)
Show all 39Show fewer
- HIV infection or other immunodeficiency or with an absolute neutrophil count ≤1.0 × 109/L
- Abnormal liver biochemistry (alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase) >1.5 × upper limit of normal or total bilirubin > upper limit of normal (unless Gilbert's disease with normal conjugated bilirubin)
- Any of the following laboratory abnormalities are present at baseline:
- Platelet count <150×109/L
- Serum albumin ≤ 3.5 g/dL
- INR ≥1.2
- CPK ≥ ULN.
- History or current evidence of cirrhosis (on biopsy or imaging), esophageal varices, ascites or hepatic encephalopathy.
- Evidence of other forms of chronic liver disease based on diagnostic testing as per the guidelines (i.e. autoimmune liver disease, primary biliary cirrhosis, primary sclerosing cholangitis, Wilson's disease, Hemochromatosis or iron overload).
- Patients with nonalcoholic fatty liver disease (NAFLD) as diagnosed by any imaging modality (or use of drugs associated with NAFLD for more than 2 weeks in the year prior to screening).
- Subjects with a history of significant alcohol consumption for a period of more than 3 consecutive months within 1 year prior to screening, defined as average of >20g/ day in female subjects and >30g/ day in male subjects.
- Fibrosis-4 (FIB-4) score >3.25
- Any of the following cardiovascular conditions within 6 months prior to the screening visit:
- Myocardial infarction or unstable angina
- Coronary artery bypass surgery, balloon angioplasty, percutaneous coronary intervention, or carotid revascularization procedure
- Uncontrolled hypertension
- Stroke or transient ischemic attack
- Congestive heart failure (New York Heart Association III/IV) with left ventricular ejection fraction < 40%
- Any clinically significant 12-lead electrocardiogram abnormalities at screening or baseline, including corrected QT interval by Fridericia's correction method >450 ms or history of significant cardiac dysrhythmia, including long QT syndrome
- History of cancer within the last 5 years, except for well-treated basal cell carcinoma and squamous cell carcinoma of the skin
- Other documented comorbidities or laboratory abnormalities that in the opinion of the Investigator could affect the outcome of the study assessments, participant safety, or ability of the participant to comply with the requirements of the protocol
- Excluded Prior/Concomitant Therapy
- Daily use of prednisone (>10mg daily), or other systemic glucocorticoids at comparable or higher equivalent dose, or use of other immunosuppressant therapies are prohibited
- Immunomodulating monoclonal antibodies within 6 months prior to screening are prohibited
- Daily use of non-steroidal anti-inflammatory drugs (NSAIDs) is prohibited. Daily use of acetaminophen up to 2 g per day and aspirin up to 325 mg per day is permitted.
- Initiation of drugs known for hepatotoxic potential within the 28 days prior to screening including but not limited to: statins, NSAIDS, amoxicillin/clavulanate, PDE inhibitors (theophylline, roflumilast), and anti-epileptics. Subjects on established treatment for more than 28 days prior to screening will not be excluded. Requirement for medications mainly metabolized by CYP2C9 and with narrow therapeutic index (eg, warfarin, phenytoin) is prohibited
- Excluded Prior/Concurrent Clinical Study Experience
- Participation in any clinical investigation using medical devices or non-biologic treatments within 4 weeks or 5 half-lives of the drug (whichever is longer) prior to the initial dosing (or longer if required by local regulations) is prohibited
- Participation in any clinical investigation using biologic treatment within 6 months of screening is prohibited
- Previous participation in a gene therapy study for AATD at any time is prohibited
- Other Exclusions
- History of hypersensitivity to alvelestat (MPH966) or any of its excipients or the class of neutrophil elastase inhibitors
- Known hypersensitivity to medications used in the study procedures (e.g. midazolam, fentanyl, and lidocaine for bronchoscopy)
Trial locations and contacts
10 sites in 1 country.
10 sites in 1 country
United States10 sites
The University of Alabama at Birmingham Lung Health Center
Birmingham, Alabama, 35294
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina, 27517
Medical University of South Carolina
Charleston, South Carolina, 29425-6300
Cleveland Clinic
Cleveland, Ohio, 44195
National Jewish Health
Denver, Colorado, 80206
UCLA
Los Angeles, California, 90095
Columbia University
New York, New York, 10032
Temple University
Philadelphia, Pennsylvania, 19140
University of Utah
Salt Lake City, Utah, 84108
The University of Texas Health Science Center at Tyler
Tyler, Texas, 75708
About this study
Official title: A First in Class Disease Modifying Therapy to Treat Alpha-1 Antitrypsin Deficiency a Genetically Linked Orphan Disease
This is a Phase 2, multicenter, double-blind, randomized (1:1), placebo-controlled, 12-week, proof-of-concept study to evaluate the safety and tolerability as well as the mechanistic effect of oral administration of alvelestat (MPH966) in subjects with confirmed AATD defined as Pi*ZZ, Pi*SZ, Pi*null, or another rare phenotype/genotype known to be associated with either low (serum AAT level <11 μM or <57.2 mg/dL) or functionally impaired AAT including "F" or "I" mutations.
Read the detailed description
Alpha-1 antitrypsin deficiency (AATD) is the most common genetic cause of chronic obstructive pulmonary disease (COPD) and early-onset emphysema. AATD is characterized by low AAT levels; leading to excessive neutrophil elastase (NE) mediated lung destruction. Current treatment requires the periodic infusion of pooled AAT derived from human plasma, but this therapeutic approach (termed augmentation) does not definitively slow the rate of emphysema progressionlung function decline and is very expensive. In addition, it is not clear that the currently recommended dose for augmentation fully controls lung inflammation and destruction. Alvelestat (MPH966, formerly AZD9668) is a potent, selective, and reversible, oral inhibitor of human NE. Suppression of NE is expected to reduce lung damage and may slow disease progression. This study is to establish proof of clinical concept by investigating the mechanistic effect and safety of alvelestat (MPH966) in patients with AATD.
- Conditions
- Alpha-1 Antitrypsin Deficiency (AATD), Pi*ZZ, Pi*SZ, Pi*Null, Another Rare Phenotype/Genotype Known to be Associated With Either Low or Functionally Impaired AAT Including F or I Mutations, Emphysema or COPD
- Being tested
- Alvelestat (MPH966), Placebo
- Medical subject headings
- alpha 1-Antitrypsin Deficiency, Emphysema, Pulmonary Disease, Chronic Obstructive
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Alvelestat (MPH966)Drug
Alvelestat was developed as treatment for lung diseases like Chronic Obstructive Pulmonary Disease. Alevelestat works by blocking certain proteins in the body that are responsible for inflammation and damage to the lungs that can lead to COPD symptoms.
PlaceboOther
Placebo is a pill or tablet that does not contain any study drug.
| Study group | Role | What they receive |
|---|---|---|
| Alvelestat (MPH966) | Active comparator | Alvelestat (MPH966) 120mg (4 30mg tablets) twice daily by mouth for 12 weeks Receives: Drug: Alvelestat (MPH966) |
| Placebo | Placebo comparator | 4 Placebo tablets twice daily by mouth for 12 weeks Receives: Other: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Within-individual % Change in Plasma Desmosine/Isodesmosine
To evaluate the effect of alvelestat (MPH966) administered twice daily (bid) for 12 weeks on blood markers of within-individual % change in plasma desmosine/isodesmosine will be measured.
Measured: baseline, week 12
Numbers and % of Subjects Who Experience at Least 1 Treatment-emergent Adverse Event
To evaluate the safety and tolerability of alvelestat (MPH966) administered twice daily (bid) for 12 weeks treatment numbers and % of subjects who experience at least 1 treatment-emergent adverse event (TEAE) will be measured.
Measured: baseline, week 16
Secondary outcomes (1)
Blood Pharmacodynamic Markers of Neutrophil Activation and Elastase Activity. Change From Baseline in the Following Outcomes at End of the Treatment Within Patient and Compared to Placebo
To evaluate the effect of Alvelestat (MPH966) on other blood pharmacodynamic markers of neutrophil activation and elastase activity including plasma desmosine/isodesmosine (change compared to placebo; within-individual change is the primary outcome), plasma Aa-Val-360, serum NE activity, plasma proteinase 3, plasma cathepsin B, plasma CRP, plasma IL-6, plasma IL-8, plasma IL-1b, plasma RANTES, plasma LTB4, plasma MMP9, plasma MMP12, plasma MPO, and plasma PGP.
Measured: baseline, week 12
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted20 Sep 2018
- Study start8 Apr 2019
- Primary completion30 Nov 2023
- Study completion1 Dec 2023
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Alpha-1 Antitrypsin Deficiency (AATD)Studies of the same condition, open and under way.
- More trials run by University of Alabama at BirminghamThe sponsor's other registered studies.
- 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
- Randomised
- Intervention model
- Parallel groups
- Model description
- randomized (1:1), placebo-controlled
- Masking
- Triple blind
- Who is masked
- Participant, Investigator, Outcomes assessor
- Enrolment
- 63 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Alabama at Birmingham
- Sponsor type
- University, hospital or other
- Collaborators
- National Institutes of Health (NIH), Mereo BioPharma, National Center for Advancing Translational Sciences (NCATS)
- Responsible party
- Principal investigator, Mark Dransfield, MD, University of Alabama at Birmingham
- Investigators
- Mark T Dransfield, MD, Principal investigator, University of Alabama at Birmingham
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03679598
- Sponsor's protocol ID
- IRB-300002338
- Other IDs
- 4UH3TR002450-02
- Acronym
- ATALANTa
- Status last verified
- Jul 2024
- First submitted
- 18 Sep 2018
- Last updated
- 20 Aug 2024
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 20 Aug 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A First in Class Disease Modifying Therapy to Treat Alpha-1 Antitrypsin Deficiency a Genetically Linked Orphan Disease
- ClinicalTrials.gov ID
- NCT03679598
- Acronym / sponsor ID
- ATALANTa / IRB-300002338
- Conditions
- Alpha-1 Antitrypsin Deficiency (AATD), Pi*ZZ, Pi*SZ, Pi*Null, Another Rare Phenotype/Genotype Known to be Associated With Either Low or Functionally Impaired AAT Including F or I Mutations, Emphysema or COPD
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 63 participants (actual)
- Lead sponsor
- University of Alabama at BirminghamUniversity, hospital or other
- Collaborators
- National Institutes of Health (NIH), Mereo BioPharma, National Center for Advancing Translational Sciences (NCATS)
- Study start
- 8 Apr 2019 (actual)
- Primary completion
- 30 Nov 2023 (actual)
- Study completion
- 1 Dec 2023 (actual)
- First posted
- 20 Sep 2018 (actual)
- Results
- Posted 9 Jul 2024
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This is a Phase 2, multicenter, double-blind, randomized (1:1), placebo-controlled, 12-week, proof-of-concept study to evaluate the safety and tolerability as well as the mechanistic effect of oral administration of alvelestat (MPH966) in subjects with confirmed AATD defined as Pi*ZZ, Pi*SZ, Pi*null, or another rare phenotype/genotype known to be associated with either low (serum AAT level <11 μM or <57.2 mg/dL) or functionally impaired AAT including "F" or "I" mutations.
Detailed description
Alpha-1 antitrypsin deficiency (AATD) is the most common genetic cause of chronic obstructive pulmonary disease (COPD) and early-onset emphysema. AATD is characterized by low AAT levels; leading to excessive neutrophil elastase (NE) mediated lung destruction. Current treatment requires the periodic infusion of pooled AAT derived from human plasma, but this therapeutic approach (termed augmentation) does not definitively slow the rate of emphysema progressionlung function decline and is very expensive. In addition, it is not clear that the currently recommended dose for augmentation fully controls lung inflammation and destruction. Alvelestat (MPH966, formerly AZD9668) is a potent, selective, and reversible, oral inhibitor of human NE. Suppression of NE is expected to reduce lung damage and may slow disease progression. This study is to establish proof of clinical concept by investigating the mechanistic effect and safety of alvelestat (MPH966) in patients with AATD.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (participant, investigator, outcomes assessor)
- Number of arms
- 2
- Model description
- randomized (1:1), placebo-controlled
| Arm | Type | Receives |
|---|---|---|
| Alvelestat (MPH966) | Active comparator | Drug: Alvelestat (MPH966)Alvelestat (MPH966) 120mg (4 30mg tablets) twice daily by mouth for 12 weeks |
| Placebo | Placebo comparator | Other: Placebo4 Placebo tablets twice daily by mouth for 12 weeks |
Who may qualify
- Ages
- 18 to 80 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (7 listed)
- Participants are eligible to be included in the study only if ALL of the following criteria apply:
- Capable of giving signed informed consent as described in Appendix 3, which includes compliance with the requirements and restrictions listed in the informed consent form and in this protocol
- Age ≥18 and ≤80 years
- Patients with a confirmed diagnosis of AATD: Pi*ZZ, Pi*SZ, Pi*null, or another rare phenotype/genotype known to be associated with either low (serum AAT level <11 μM or <57.2 mg/dL) or functionally impaired AAT including "F" or "I" mutations.
- FEV1 ≥25% predicted
Key exclusion criteria (39 listed)
- Excluded Medical Conditions
- Subjects with Pi*MZ, Pi*FM, Pi*MS, Pi*SS, or other AATD phenotypes/genotypes not known to be independently associated with emphysema.
- Any clinically diagnosed lung disease other than COPD such as diffuse interstitial lung diseases, cystic fibrosis, or clinically significant bronchiectasis as determined by the Investigator
- Acute exacerbation of underlying lung disease requiring oral steroids and/or antibiotics within 4 weeks of baseline
- Acute or chronic hepatitis, including hepatitis B, hepatitis C (positive serologies, including hepatitis B and C antibody)
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 |
|---|---|---|
| Alvelestat (MPH966)Alvelestat was developed as treatment for lung diseases like Chronic Obstructive Pulmonary Disease. Alevelestat works by blocking certain proteins in the body that are responsible for inflammation and damage to the lungs that can lead to COPD symptoms. | Drug | Alvelestat (MPH966) |
| PlaceboPlacebo is a pill or tablet that does not contain any study drug. | Other | Placebo |
Primary outcome
Within-individual % Change in Plasma Desmosine/Isodesmosine
Time frame: baseline, week 12
To evaluate the effect of alvelestat (MPH966) administered twice daily (bid) for 12 weeks on blood markers of within-individual % change in plasma desmosine/isodesmosine will be measured.
Numbers and % of Subjects Who Experience at Least 1 Treatment-emergent Adverse Event
Time frame: baseline, week 16
To evaluate the safety and tolerability of alvelestat (MPH966) administered twice daily (bid) for 12 weeks treatment numbers and % of subjects who experience at least 1 treatment-emergent adverse event (TEAE) will be measured.
1 secondary outcome
Blood Pharmacodynamic Markers of Neutrophil Activation and Elastase Activity. Change From Baseline in the Following Outcomes at End of the Treatment Within Patient and Compared to Placebo
Time frame: baseline, week 12
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 20 Aug 2024.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
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AATD-Liver Scan Study
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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.
Mark T Dransfield, MD principal investigator
University of Alabama at Birmingham
10 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Alvelestat (MPH966) in people with Alpha-1 Antitrypsin Deficiency (AATD) and Pi*ZZ, Pi*SZ, Pi*Null, Another Rare Phenotype/Genotype Known to be Associated With Either Low or Functionally Impaired AAT Including F or I Mutations, run by University of Alabama at Birmingham at 10 sites in United States.
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 7 inclusion and 39 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: finished, as of the sponsor's last update on 20 Aug 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 10 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. 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?
Yes. Results are posted in the registry (first posted 9 Jul 2024). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Within-individual % Change in Plasma Desmosine/Isodesmosine (time frame: baseline, week 12). The study lists 2 primary outcomes in all. 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 20 Aug 2024.