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Trial record 6 of 10 for:    Alpha-1-proteinase inhibitor AND ELANE

Alvelestat (MPH996) for the Treatment of ALpha-1 ANTitrypsin Deficiency (ATALANTa)

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ClinicalTrials.gov Identifier: NCT03679598
Recruitment Status : Recruiting
First Posted : September 20, 2018
Last Update Posted : June 14, 2019
Sponsor:
Collaborators:
National Institutes of Health (NIH)
Mereo BioPharma
Information provided by (Responsible Party):
Mark Dransfield, MD, University of Alabama at Birmingham

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 (MPH996) in subjects with confirmed alpha-1 (Alpha-1 ZZ genotype (Pi*ZZ), Alpha-1 SZ genotype (Pi*SZ), or Alpha -1 Null phenotype (Pi*Null phenotype)) antitrypsin deficiency (AATD)-related emphysema.

Condition or disease Intervention/treatment Phase
Alpha-1 Antitrypsin Deficiency (AATD) Pi*ZZ, Pi*SZ, or Pi*Null Phenotype Emphysema or COPD Drug: Alvelestat (MPH996) Other: Placebo Phase 2

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 does not definitively slow the rate of emphysema progression and is very expensive. Alvelestat (MPH996, 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 (MPH996) in patients with AATD.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 66 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: randomized (1:1), placebo-controlled
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Masking Description: double blind
Primary Purpose: Treatment
Official Title: A First in Class Disease Modifying Therapy to Treat Alpha-1 Antitrypsin Deficiency a Genetically Linked Orphan Disease
Actual Study Start Date : April 8, 2019
Estimated Primary Completion Date : August 2021
Estimated Study Completion Date : August 2021


Arm Intervention/treatment
Active Comparator: Alvelestat (MPH996)
Alvelestat (MPH996) 120mg (4 30mg tablets) twice daily by mouth for 12 weeks
Drug: Alvelestat (MPH996)
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.

Placebo Comparator: Placebo
4 Placebo tablets twice daily by mouth for 12 weeks
Other: Placebo
Placebo is a pill or tablet that does not contain any study drug.




Primary Outcome Measures :
  1. Within-individual % change in plasma desmosine/isodesmosine [ Time Frame: baseline, week 12 ]
    To evaluate the effect of alvelestat (MPH996) administered twice daily (bid) for 12 weeks on blood markers of neutrophil elastase activity, within-individual % change in plasma desmosine/isodesmosine will be measured.

  2. 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 (MPH996) administered twice daily (bid) for 12 weeks treatment numbers and % of subjects who experience at least 1 treatment-emergent adverse event will be measured.



Information from the National Library of Medicine

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Ages Eligible for Study:   25 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

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

Type of Participant and Disease Characteristics

  1. Capable of giving signed informed consent , which includes compliance with the requirements and restrictions listed in the informed consent form and in this protocol
  2. Age ≥25 and ≤80 years
  3. Patients with a diagnosis or confirmation of AATD (Pi*ZZ, Pi*SZ, or Pi*NullNull genotype/phenotype)
  4. FEV1 ≥30% predicted
  5. Computed tomography (CT) scan evidence of emphysema by visual reading by local investigator
  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 OR ii. A woman of childbearing potential who agrees to follow the specified contraceptive guidance 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 other AATD phenotypes/genotypes including Pi*MZ
  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. Significant liver fibrosis as evidenced by Fibrosis-4 (FIB-4) score >3.25
  9. Cirrhosis
  10. Hyperlipidemia requiring statins, where treatment would be initiated during the study treatment period (subjects on established treatment >28 days will not be excluded)
  11. 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
  12. Congestive heart failure (New York Heart Association III/IV) with left ventricular ejection fraction < 40%
  13. 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
  14. History of cancer within the last 5 years, except for well-treated basal cell carcinoma and squamous cell carcinoma of the skin
  15. 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:

  16. Theophylline, roflumilast, daily use of macrolide antibiotics, daily use of prednisone (>10mg daily) or other systemic glucocorticoids, and use of other immunosuppressant therapies are prohibited
  17. Immunomodulating monoclonal antibodies within 6 months prior to screening are prohibited
  18. AAT augmentation therapy will be discontinued during the run-in period and will not be permitted until after completion of the week 12 study visit
  19. Daily use of acetaminophen ≥2g/day or daily use of non-steroidal anti-inflammatory drugs (NSAIDs) is prohibited
  20. Initiation of treatment with drugs known for hepatotoxic potential (including but not restricted to statins, anti-epileptics, antibiotics such as amoxicillin, amoxicillin/clavulanate, and NSAIDs) within 1 month prior to screening is prohibited
  21. Requirement for medications mainly metabolized by CYP2C9 and with narrow therapeutic index (eg, warfarin) 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 Known hypersensitivity to medications used in the study procedures (e.g. midazolam, fentanyl, and lidocaine for bronchoscopy)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03679598


Contacts
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Contact: Mark T Dransfield, MD 205-934-5555 mdransfield@uabmc.edu
Contact: James M Wells, MD 205-934-5555 jmwells@uabmc.edu

Locations
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United States, Alabama
The University of Alabama at Birmingham Lung Health Center Recruiting
Birmingham, Alabama, United States, 35294
Contact: Mark M Dransfield, MD    205-934-5555    mdransfield@uabmc.edu   
United States, Colorado
National Jewish Health Not yet recruiting
Denver, Colorado, United States, 80206
Contact: Robert Sandhaus, MD    303-398-1518    RSandhaus@alphanet.org   
United States, Ohio
Cleveland Clinic Not yet recruiting
Cleveland, Ohio, United States, 44195
Contact: Umur Hatipoglu, M.D    216-444-1150    hatipou@ccf.org   
United States, Pennsylvania
Temple University Not yet recruiting
Philadelphia, Pennsylvania, United States, 19140
Contact: Wissam Chatila, MD    215-707-3332    Wissam.Chatila@tuhs.temple.edu   
United States, South Carolina
Medical University of South Carolina Not yet recruiting
Charleston, South Carolina, United States, 29425-6300
Contact: Charles Strange, MD    843-792-8438    strangec@musc.edu   
United States, Texas
The University of Texas Health Science Center at Tyler Not yet recruiting
Tyler, Texas, United States, 75708
Contact: James Stocks, MD    903-877-8246    james.stocks@uthct.edu   
Sponsors and Collaborators
University of Alabama at Birmingham
National Institutes of Health (NIH)
Mereo BioPharma
Investigators
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Principal Investigator: Mark T Dransfield, MD University of Alabama at Birmingham

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Responsible Party: Mark Dransfield, MD, Professor, University of Alabama at Birmingham
ClinicalTrials.gov Identifier: NCT03679598     History of Changes
Other Study ID Numbers: IRB-300002338
4UH3TR002450-02 ( U.S. NIH Grant/Contract )
First Posted: September 20, 2018    Key Record Dates
Last Update Posted: June 14, 2019
Last Verified: June 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Alpha 1-Antitrypsin Deficiency
Alpha 1-Antitrypsin
Protein C Inhibitor
Trypsin Inhibitors
Serine Proteinase Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Emphysema
Pathologic Processes
Lung Diseases
Respiratory Tract Diseases
Liver Diseases
Digestive System Diseases
Genetic Diseases, Inborn
Subcutaneous Emphysema
Molecular Mechanisms of Pharmacological Action