search
Back to results

Alvelestat (MPH966) for the Treatment of ALpha-1 ANTitrypsin Deficiency (ATALANTa)

Primary Purpose

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

Status
Active
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Alvelestat (MPH966)
Placebo
Sponsored by
University of Alabama at Birmingham
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Alpha-1 Antitrypsin Deficiency (AATD)

Eligibility Criteria

18 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Participants are eligible to be included in the study only if ALL of the following criteria apply:

  1. 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
  2. Age ≥18 and ≤80 years
  3. 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.
  4. FEV1 ≥25% predicted
  5. 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.
  6. 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.

Exclusion Criteria:

Participants are excluded from the study if ANY of the following criteria apply:

Excluded Medical Conditions

  1. Subjects with Pi*MZ, Pi*FM, Pi*MS, Pi*SS, or other AATD phenotypes/genotypes not known to be independently associated with emphysema.
  2. 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
  3. Acute exacerbation of underlying lung disease requiring oral steroids and/or antibiotics within 4 weeks of baseline
  4. Acute or chronic hepatitis, including hepatitis B, hepatitis C (positive serologies, including hepatitis B and C antibody)
  5. HIV infection or other immunodeficiency or with an absolute neutrophil count ≤1.0 × 109/L
  6. 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)
  7. Any of the following laboratory abnormalities are present at baseline:

    1. Platelet count <150×109/L
    2. Serum albumin ≤ 3.5 g/dL
    3. INR ≥1.2
    4. CPK ≥ ULN.
  8. History or current evidence of cirrhosis (on biopsy or imaging), esophageal varices, ascites or hepatic encephalopathy.
  9. 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).
  10. 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).
  11. 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.
  12. Fibrosis-4 (FIB-4) score >3.25
  13. Any of the following cardiovascular conditions within 6 months prior to the screening visit:

    1. Myocardial infarction or unstable angina
    2. Coronary artery bypass surgery, balloon angioplasty, percutaneous coronary intervention, or carotid revascularization procedure
    3. Uncontrolled hypertension
    4. Stroke or transient ischemic attack
  14. Congestive heart failure (New York Heart Association III/IV) with left ventricular ejection fraction < 40%
  15. 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
  16. History of cancer within the last 5 years, except for well-treated basal cell carcinoma and squamous cell carcinoma of the skin
  17. 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

  18. Daily use of prednisone (>10mg daily), or other systemic glucocorticoids at comparable or higher equivalent dose, or use of other immunosuppressant therapies are prohibited
  19. Immunomodulating monoclonal antibodies within 6 months prior to screening are prohibited
  20. 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.
  21. 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

  22. 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
  23. Participation in any clinical investigation using biologic treatment within 6 months of screening is prohibited
  24. Previous participation in a gene therapy study for AATD at any time is prohibited

    Other Exclusions

  25. History of hypersensitivity to alvelestat (MPH966) or any of its excipients or the class of neutrophil elastase inhibitors
  26. Known hypersensitivity to medications used in the study procedures (e.g. midazolam, fentanyl, and lidocaine for bronchoscopy)

Sites / Locations

  • The University of Alabama at Birmingham Lung Health Center
  • UCLA
  • National Jewish Health
  • Columbia University
  • University of North Carolina at Chapel Hill
  • Cleveland Clinic
  • Temple University
  • Medical University of South Carolina
  • The University of Texas Health Science Center at Tyler
  • University of Utah

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Alvelestat (MPH966)

Placebo

Arm Description

Alvelestat (MPH966) 120mg (4 30mg tablets) twice daily by mouth for 12 weeks

4 Placebo tablets twice daily by mouth for 12 weeks

Outcomes

Primary Outcome Measures

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 neutrophil elastase activity, within-individual % change in plasma desmosine/isodesmosine will be measured.
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 will be measured.

Secondary Outcome Measures

Full Information

First Posted
September 18, 2018
Last Updated
August 15, 2023
Sponsor
University of Alabama at Birmingham
Collaborators
National Institutes of Health (NIH), Mereo BioPharma
search

1. Study Identification

Unique Protocol Identification Number
NCT03679598
Brief Title
Alvelestat (MPH966) for the Treatment of ALpha-1 ANTitrypsin Deficiency
Acronym
ATALANTa
Official Title
A First in Class Disease Modifying Therapy to Treat Alpha-1 Antitrypsin Deficiency a Genetically Linked Orphan Disease
Study Type
Interventional

2. Study Status

Record Verification Date
August 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
April 8, 2019 (Actual)
Primary Completion Date
November 30, 2023 (Anticipated)
Study Completion Date
November 30, 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Alabama at Birmingham
Collaborators
National Institutes of Health (NIH), Mereo BioPharma

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief 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 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
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

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Model Description
randomized (1:1), placebo-controlled
Masking
ParticipantInvestigatorOutcomes Assessor
Masking Description
double blind
Allocation
Randomized
Enrollment
63 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Alvelestat (MPH966)
Arm Type
Active Comparator
Arm Description
Alvelestat (MPH966) 120mg (4 30mg tablets) twice daily by mouth for 12 weeks
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
4 Placebo tablets twice daily by mouth for 12 weeks
Intervention Type
Drug
Intervention Name(s)
Alvelestat (MPH966)
Intervention Description
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.
Intervention Type
Other
Intervention Name(s)
Placebo
Intervention Description
Placebo is a pill or tablet that does not contain any study drug.
Primary Outcome Measure Information:
Title
Within-individual % change in plasma desmosine/isodesmosine
Description
To evaluate the effect of alvelestat (MPH966) administered twice daily (bid) for 12 weeks on blood markers of neutrophil elastase activity, within-individual % change in plasma desmosine/isodesmosine will be measured.
Time Frame
baseline, week 12
Title
Numbers and % of subjects who experience at least 1 treatment-emergent adverse event
Description
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 will be measured.
Time Frame
baseline, week 16

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: 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. Exclusion Criteria: 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) 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)
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Mark T Dransfield, MD
Organizational Affiliation
University of Alabama at Birmingham
Official's Role
Principal Investigator
Facility Information:
Facility Name
The University of Alabama at Birmingham Lung Health Center
City
Birmingham
State/Province
Alabama
ZIP/Postal Code
35294
Country
United States
Facility Name
UCLA
City
Los Angeles
State/Province
California
ZIP/Postal Code
90095
Country
United States
Facility Name
National Jewish Health
City
Denver
State/Province
Colorado
ZIP/Postal Code
80206
Country
United States
Facility Name
Columbia University
City
New York
State/Province
New York
ZIP/Postal Code
10032
Country
United States
Facility Name
University of North Carolina at Chapel Hill
City
Chapel Hill
State/Province
North Carolina
ZIP/Postal Code
27517
Country
United States
Facility Name
Cleveland Clinic
City
Cleveland
State/Province
Ohio
ZIP/Postal Code
44195
Country
United States
Facility Name
Temple University
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19140
Country
United States
Facility Name
Medical University of South Carolina
City
Charleston
State/Province
South Carolina
ZIP/Postal Code
29425-6300
Country
United States
Facility Name
The University of Texas Health Science Center at Tyler
City
Tyler
State/Province
Texas
ZIP/Postal Code
75708
Country
United States
Facility Name
University of Utah
City
Salt Lake City
State/Province
Utah
ZIP/Postal Code
84108
Country
United States

12. IPD Sharing Statement

Learn more about this trial

Alvelestat (MPH966) for the Treatment of ALpha-1 ANTitrypsin Deficiency

We'll reach out to this number within 24 hrs