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Trial of Inhaled Molgramostim in CF Subjects With NTM Infection (ENCORE)

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ClinicalTrials.gov Identifier: NCT03597347
Recruitment Status : Recruiting
First Posted : July 24, 2018
Last Update Posted : July 30, 2019
Sponsor:
Information provided by (Responsible Party):
Savara Inc.

Brief Summary:
A study to evaluate the efficacy of inhaled molgramostim administered open-label to adult cystic fibrosis subjects with chronic pulmonary nontuberculous mycobacterial (NTM) infection, with or without ongoing antimycobacterial guideline based combination therapy.

Condition or disease Intervention/treatment Phase
Mycobacterium Infections, Nontuberculous Cystic Fibrosis (CF) Drug: Molgramostim nebulizer solution Device: PARI eFlow nebulizer system Phase 2

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: An Open-label, Non-controlled, Multicenter, Pilot Trial, Using Inhaled Molgramostim in Cystic Fibrosis Subjects With Nontuberculous Mycobacterial (NTM) Infection
Actual Study Start Date : June 20, 2019
Estimated Primary Completion Date : January 15, 2021
Estimated Study Completion Date : June 15, 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Cystic Fibrosis

Arm Intervention/treatment
Experimental: Inhaled molgramostim
Molgramostim nebulizer solution (300 µg/dose) administered once daily for 48 weeks utilizing the PARI eFlow nebulizer system
Drug: Molgramostim nebulizer solution
300 µg / dose molgramostim (recombinant human GM-CSF) for inhalation
Other Name: rhGM-CSF

Device: PARI eFlow nebulizer system
Nebulizer




Primary Outcome Measures :
  1. Sputum NTM culture conversion to negative [ Time Frame: 48 weeks ]
    NTM sputum culture conversion to negative (defined as at least three consecutive negative mycobacterial cultures collected at least 4 weeks apart during the Treatment period).


Secondary Outcome Measures :
  1. NTM sputum culture microbiological cure [ Time Frame: 48 Weeks ]
    NTM sputum culture microbiological cure (defined as multiple consecutive negative but no positive cultures with the causative species after last culture conversion and until the End of Treatment (Week 48).

  2. Time to first NTM sputum culture conversion [ Time Frame: 48 Weeks ]
    Time to first NTM sputum culture conversion during the Treatment period.

  3. Sputum smear conversion to negative [ Time Frame: 48 Weeks ]
    Sputum smear conversion to negative (defined as at least three consecutive negative acid-fast bacilli (AFB) stained sputum smears on microscopy, collected at least 4 weeks apart in subjects who were smear positive at Baseline) during the Treatment period.

  4. Consistent sputum smear conversion to negative Treatment (Week 48) in subjects who were smear positive at Baseline). [ Time Frame: 48 Weeks ]
    Consistent sputum smear conversion to negative (defined as multiple consecutive negative but no positive smears after last smear conversion and until the End of Treatment (Week 48) in subjects who were smear positive at Baseline).

  5. Time to first NTM sputum smear conversion. [ Time Frame: 48 Weeks ]
    Time to first NTM sputum smear conversion during the Treatment period.

  6. Durable NTM sputum microbiological cure [ Time Frame: 12 Weeks after End of Treatment ]
    Durable NTM sputum microbiological cure for the NTM isolate(s) treated without recurrence at Week 12 after End of Treatment.

  7. Durable NTM sputum smear conversion to negative [ Time Frame: 12 Weeks after End of Treatment ]
    Durable NTM sputum smear conversion to negative without subsequent positive smears at Week 12 after End of Treatment.

  8. Change in semi-quantitative grade of number of NTM [ Time Frame: 48 Weeks and 12 Weeks after End of Treatment ]
    Change in semi-quantitative grade of number of NTM on microscopy of AFB stained sputum smears from Baseline to End of Treatment and Week 12 after End of Treatment.

  9. Change in pulmonary function [ Time Frame: 48 weeks and 12 Weeks after End of Treatment ]
    Absolute change in FEV1 (percent predicted) from Baseline to End of Treatment and Week 12 after End of Treatment.

  10. Change in quality of life [ Time Frame: 48 weeks and 12 Weeks after End of Treatment ]
    Change in respiratory domain score assessed by Cystic Fibrosis Questionnaire-Revised (CFQ-R) from Baseline to End of Treatment and Week 12 after End of Treatment.

  11. Change in body mass index (BMI) [ Time Frame: 48 weeks and 12 Weeks after End of Treatment ]
    Change in BMI from Baseline to End of Treatment and Week 12 after End of Treatment.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Written informed consent obtained from participant.
  2. Confirmed diagnosis of CF according to the Cystic Fibrosis Foundation (CFF) 2017 Consensus Guidelines.
  3. History of chronic pulmonary infection with M. avium complex (MAC) or M. abscessus complex (MABSC) (defined as at least three positive NTM cultures (sputum or BAL for the same species (MAC) or subspecies (MABSC) within the past 2 years, with at least one positive within the past 6 months and a minimum of 50% of NTM cultures positive over the past 2 years) that does not demonstrate response to current treatment course based on decreasing NTM burden or frequency of positive cultures, and in the opinion of the Investigator is unlikely to resolve with current treatment course.
  4. Subject fulfills one of the following criteria:

    • Subject currently on a multidrug NTM guideline-based antimycobacterial regimen, which has been ongoing for at least 9 months prior to the Baseline visit.
    • Subject who has stopped a multidrug NTM guideline-based antimycobacterial regimen at least 28 days prior to Screening due to lack of response or intolerance.
    • Subjects with chronic NTM infection not meeting recommendations for treatment with a multidrug NTM guideline-based antimycobacterial regimen based on failure to meet ATS/IDSA criteria for NTM pulmonary disease (i.e. absence of radiologic findings and clinical symptoms beyond what is expected from underlying CF).
  5. Ability to produce sputum or be willing to undergo an induction protocol that produces sputum for clinical evaluation.
  6. An additional sputum culture, which is positive for the same species (MAC) or subspecies (MABSC) of NTM as before the trial within 10 weeks of Baseline.
  7. CF which in the Investigator's opinion is clinically stable and not expected to require lung transplantation within the next year.
  8. FEV1 ≥ 30% of predicted that is normal for age, gender, race, and height, using the Global Lung Function Initiative (GLI) equation.
  9. Subjects who are co-infected with a respiratory pathogen, e.g. P. aeruginosa or S. aureus, must either be stable on a regular suppression antibiotic regimen or must be, in the opinion of the Investigator, stable despite the lack of such treatment.
  10. Female or male ≥18 years of age.
  11. If female, subjects who have been post-menopausal for more than 1 year or females of childbearing potential after a confirmed menstrual period using a highly efficient method of contraception (i.e. a method with less than 1% failure rate) during and until 30 days after last dose of trial treatment, having a negative serum pregnancy test at Screening (Visit 1) and a negative urine pregnancy test at dosing at Baseline (Visit 2) and must not be lactating.

    For purposes of this study, the Sponsor defines "acceptable methods of contraception" as:

    • Oral birth control pills administered for at least 1 monthly cycle prior to administration of the study drug.
    • A synthetic progestin implanted rod (eg, Implanon®) for at least 1 monthly cycle prior to the study drug administration but not beyond the 4th successive year following insertion.
    • Intrauterine devices (IUDs), inserted by a qualified clinician for at least 1 monthly cycle prior to study drug administration.
    • Medroxyprogesterone acetate (eg, Depo-Provera®) administered for a minimum of 1 monthly cycle prior to administration of the study drug and continuing through 1 month following study completion.
    • Hysterectomy or surgical sterilization.
    • Abstinence.

    Double barrier method (diaphragm with spermicidal gel or condoms with contraceptive foam) is not considered an acceptable form of contraception.

    NOTE: For subjects prescribed Orkambi: Orkambi may substantially decrease hormonal contraceptive exposure, reducing the effectiveness and increasing the incidence of menstruation-associated adverse reactions. Hormonal contraceptives, including oral, injectable, transdermal, and implantable, should not be relied upon as an effective method of contraception when co-administered with Orkambi.

  12. If male, subjects who, if sexually active of reproductive potential and non-sterile (i.e., male who has not been sterilized by vasectomy for at least 6 months and not diagnosed with infertility through demonstration of azoospermia in a semen sample and/or absence of vas deferens through ultrasound) are willing to use a barrier method of contraception, or their female partner must use an acceptable method of contraception, during the study and until 30 days after last dose of medication.
  13. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other trial procedures specified in the protocol as judged by the Investigator.

Exclusion criteria:

  1. Use of non-maintenance antibiotic for a concurrent pulmonary or extrapulmonary infection within 28 days prior to the Baseline visit.
  2. Use of a maintenance antibiotic regimen containing azithromycin for a concurrent non-NTM pulmonary infection within 28 days prior to the Baseline visit. For subjects in Group 1, azithromycin is allowed if part of ongoing multidrug NTM guideline-based antimycobacterial regimen.
  3. Prior therapy with inhaled or systemic granulocyte macrophage colony stimulating factor (GM-CSF).
  4. Subjects with hemoptysis of ≥60 mL in a 24-hour period within 4 weeks prior to Screening.
  5. Life expectancy of less than 6 months according to Investigator's judgement.
  6. History of, or present, myeloproliferative disease, leukemia or other hematological malignancy.
  7. Active pulmonary malignancy (primary or metastatic); or any malignancy requiring chemotherapy or radiation therapy within 1 year prior to Screening or anticipated during the study period.
  8. Active allergic bronchopulmonary mycosis or connective tissue disease, inflammatory bowel disease or other autoimmune disorder requiring therapy associated with significant immunosuppression, such as systemic corticosteroids at a dose equivalent of 10 mg/day or more of prednisolone, within 3 months prior to Screening or anticipated during the study period.
  9. Changes in antimicrobial, bronchodilator, anti-inflammatory or corticosteroid medications, or changes in Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) modulators, within 28 days prior to the Baseline visit.
  10. Pulmonary tuberculosis requiring treatment or treated within 2 years prior to Screening.
  11. History of human immunodeficiency virus (HIV) infection or other disease associated with significant immunodeficiency.
  12. History of lung or other solid organ transplantation or currently on the list to receive lung or other solid organ transplantation.
  13. History of congestive heart failure (CHF) New York Heart Association (NYHA) Class III or greater in severity.
  14. History of cardiovascular ischemic event within 6 months of Baseline.
  15. Any change in chronic NTM multi-drug antimycobacterial regimen within 28 days prior to Screening.
  16. Treatment with any investigational medicinal product within 3 months of Screening.
  17. Previous experience of severe and unexplained side-effects during aerosol delivery of any kind of medicinal product.
  18. Any other condition that, in the opinion of the Investigator, would preclude informed consent or assent, make study participation unsafe, complicate interpretation of study outcome data, or otherwise interfere with achieving the study objectives.

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): NCT03597347


Contacts
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Contact: Amy Beasley 512-851-1346 amy.beasley@savarapharma.com
Contact: Jessica Jackson 512-851-1361 jessica.jackson@savarapharma.com

Locations
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United States, Colorado
National Jewish Health Recruiting
Denver, Colorado, United States, 80206
Contact: Alexandria Leonhardt    303-398-1453    leonhardta@njhealth.org   
Principal Investigator: Jerry Nick, MD         
United States, Florida
Central Florida Pulmonary Group Recruiting
Orlando, Florida, United States, 32803
Contact: Kenneth (Bert) Kesser    407-841-1100 ext 118    bkesser@cfpulmonary.com   
Principal Investigator: Daniel T. Layish, MD         
United States, Minnesota
Mayo Clinic Recruiting
Rochester, Minnesota, United States, 55905
Contact: Boleyn Andrist    507-284-9946    Andrist.boleyn@mayo.edu   
Principal Investigator: Mark E. Wylam, MD         
United States, New York
Northwell Health Recruiting
New Hyde Park, New York, United States, 11042
Contact: Andrea Sookchan    516-465-5412    asookchan1@northwell.edu   
Contact: Susan Galvin    516-321-8606    sgalvin@northwell.edu   
Principal Investigator: Janice Wang, MD         
United States, North Carolina
University of North Carolina at Chapel Hill - UNC Marisco Clinical Research Center Recruiting
Chapel Hill, North Carolina, United States, 27517
Contact: Alexandria "Alex" Nesbit    984-974-2967    alexandria_nesbit@med.unc.edu   
Principal Investigator: Jennifer Goralski, MD         
Sponsors and Collaborators
Savara Inc.
Investigators
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Principal Investigator: Jerry Nick, MD National Jewish Health

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Responsible Party: Savara Inc.
ClinicalTrials.gov Identifier: NCT03597347     History of Changes
Other Study ID Numbers: SAV008-02
First Posted: July 24, 2018    Key Record Dates
Last Update Posted: July 30, 2019
Last Verified: July 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: Yes
Device Product Not Approved or Cleared by U.S. FDA: No
Keywords provided by Savara Inc.:
Nontuberculosis mycobacterial (NTM) infection
Cystic Fibrosis (CF)
M. avium complex (MAC)
M. abscessus complex (MABSC)
Mycobacterium Infections, Nontuberculous
Additional relevant MeSH terms:
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Infection
Communicable Diseases
Mycobacterium Infections
Mycobacterium Infections, Nontuberculous
Cystic Fibrosis
Fibrosis
Pathologic Processes
Pancreatic Diseases
Digestive System Diseases
Lung Diseases
Respiratory Tract Diseases
Genetic Diseases, Inborn
Infant, Newborn, Diseases
Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial Infections
Molgramostim
Antineoplastic Agents