Trial of Inhaled Molgramostim in Cystic Fibrosis Subjects With Nontuberculous Mycobacterial Infection

NCT03597347 | Terminated Phase 2 Results DMC FDA Drug FDA Device

• 1 other identifier: SAV008-02
• Study Type: interventional
• Target: 14
• Locations: 1 country
• Sites: 5

Brief Summary

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

Conditions

Mycobacterium Infections, Nontuberculous; Cystic Fibrosis (CF)

Keywords

Nontuberculosis mycobacterial infection; Cystic fibrosis; M. avium complex; M. abscessus complex; Mycobacterium Infections, Nontuberculous

Outcome Measures

Primary Outcomes (1)

• Number of Participants With Sputum NTM Culture Conversion to Negative

  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).

  48 weeks

Secondary Outcomes (6)

• Number of Participants With NTM Sputum Culture Microbiological Cure

  48 weeks

• Time to First NTM Sputum Culture Conversion

  48 Weeks

• Number of Participants With Sputum Smear Conversion to Negative

  48 weeks

• Number of Participants With Consistent Sputum Smear Conversion to Negative Treatment (Week 48) in Subjects Who Were Smear Positive at Baseline)

  48 weeks

• Time to First NTM Sputum Smear Conversion

  48 weeks

Study Arms (3)

Group 1

EXPERIMENTAL

Participants with chronic pulmonary MAC or MABSC infection who have not consistently achieved negative NTM sputum cultures while currently on a multidrug NTM guideline-based antimycobacterial regimen, which has been ongoing for at least 9 months prior to the Baseline visit.

Drug: Molgramostim nebulizer solution; Device: PARI eFlow nebulizer system

Group 2

EXPERIMENTAL

Participants with chronic pulmonary MAC or MABSC infection who remain sputum culture positive but have stopped a multidrug NTM guideline-based antimycobacterial regimen at least 28 days prior to Screening due to lack of response or intolerance.

Drug: Molgramostim nebulizer solution; Device: PARI eFlow nebulizer system

Group 3

EXPERIMENTAL

Participants with chronic pulmonary MAC or MABSC infection not meeting recommendations for treatment with a multidrug NTM guideline-based antimycobacterial regimen based on failure to meet American Thoracic Society/Infectious Diseases Society of America (ATS/IDSA) criteria for NTM pulmonary disease (i.e. absence of radiologic findings and clinical symptoms beyond what is expected from underlying CF).

Drug: Molgramostim nebulizer solution; Device: PARI eFlow nebulizer system

Interventions

Molgramostim nebulizer solution DRUG

300 µg / dose molgramostim (recombinant human GM-CSF) for inhalation

Also known as: rhGM-CSF

Group 1; Group 2; Group 3

PARI eFlow nebulizer system DEVICE

PARI eFlow nebulizer system

Group 1; Group 2; Group 3

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Written informed consent obtained from participant.
• Confirmed diagnosis of CF according to the Cystic Fibrosis Foundation (CFF) 2017 Consensus Guidelines.
• 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 2 years prior to the screening visit, 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.
• Group 1: Subject with chronic pulmonary MAC or MABSC infection currently on a multidrug NTM guideline-based antimycobacterial regimen, which has been ongoing for at least 9 months prior to the Baseline visit.
• Group 2: Subject with chronic pulmonary MAC or MABSC infection who has stopped a multidrug NTM guideline-based antimycobacterial regimen at least 28 days prior to Screening due to lack of response or intolerance.
• Group 3: Subjects with chronic pulmonary MAC or MABSC 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).
• Ability to produce sputum or be willing to undergo an induction protocol that produces sputum for clinical evaluation.
• An additional sputum culture performed by the central laboratory, which is positive for the same species (MAC) or subspecies (MABSC) of NTM as before the trial within 10 weeks of Baseline.
• CF which in the Investigator's opinion is clinically stable and not expected to require lung transplantation within the next year.
• FEV1 ≥ 30% of predicted at screening that is normalized for age, gender, race, and height, using the Global Lung Function Initiative (GLI) equation.
• 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.
• Female or male ≥18 years of age.
• 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.

You may not qualify if:

• Use of non-maintenance antibiotic for a concurrent pulmonary or extrapulmonary infection within 28 days prior to the Baseline visit.
• 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.
• Prior therapy with inhaled or systemic granulocyte macrophage colony stimulating factor (GM-CSF).
• Subjects with hemoptysis of ≥60 mL in a 24-hour period within 4 weeks prior to Screening.
• Life expectancy of less than 6 months according to Investigator's judgement.
• History of, or present, myeloproliferative disease, leukemia or other hematological malignancy.
• 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.
• Active autoimmune disorder or other condition requiring therapy associated with significant immunosuppression, e.g. such as systemic corticosteroids at a dose equivalent of 10 mg/day or more of prednisolone or other significant immunosuppressant medications, within 3 months prior to Screening or anticipated during the study period. Inhaled or topical corticosteroids, or brief courses (\<14 days) of systemic corticosteroids for pulmonary exacerbations or other self-limited conditions are permitted.
• 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.
• Pulmonary tuberculosis requiring treatment or treated within 2 years prior to Screening.
• History of human immunodeficiency virus (HIV) infection or other disease associated with significant immunodeficiency.
• History of lung or other solid organ transplantation or currently on the list to receive lung or other solid organ transplantation.
• History of congestive heart failure (CHF) New York Heart Association (NYHA) Class III or greater in severity.
• History of cardiovascular ischemic event within 6 months of Baseline.
• Any change in chronic NTM multi-drug antimycobacterial regimen within 28 days prior to Screening.

Sponsors & Collaborators

• Savara Inc.: lead

Study Sites (5)

National Jewish Health

Denver, Colorado, 80206, United States

Location

Central Florida Pulmonary Group

Orlando, Florida, 32803, United States

Location

Northwell Health

New Hyde Park, New York, 11042, United States

Location

University of North Carolina at Chapel Hill - UNC Marisco Clinical Research Center

Chapel Hill, North Carolina, 27517, United States

Location

UT Southwestern Medical Center Dallas

Dallas, Texas, 75390, United States

Location

MeSH Terms

Conditions

Mycobacterium Infections, Nontuberculous; Cystic Fibrosis

Interventions

regramostim

Condition Hierarchy (Ancestors)

Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Pancreatic Diseases; Digestive System Diseases; Lung Diseases; Respiratory Tract Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Infant, Newborn, Diseases

Limitations and Caveats

Due to the early termination of the study, some specified endpoints had insufficient data to be analyzed: \* Durable NTM sputum smear conversion to negative without subsequent positive smears at Week 12 after End of Treatment (EOT). Change from Baseline to EOT and Week 12 after EOT in: * semi-quantitative grade of number of NTM on microscopy of AFB stained sputum smears * FEV1 (percent predicted) * respiratory domain score assessed by CFQ-R * body mass index

Results Point of Contact

• Title: Raymond D Pratt, Chief Medical Officer
• Organization: Savara Inc

ray.pratt@savarapharma.com

+1 512 784 8757

Study Officials

• Jerry Nick, MD

  National Jewish Health

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 12, 2018
• First Posted: July 24, 2018
• Study Start: June 20, 2019
• Primary Completion: October 2, 2020
• Study Completion: October 2, 2020
• Last Updated: January 10, 2023
• Results First Posted: October 11, 2021

Record last verified: 2022-12

Data Sharing

• IPD Sharing: Will not share

Locations

US (5)