Trial of Inhaled Molgramostim in Cystic Fibrosis Subjects With Nontuberculous Mycobacterial Infection
Condition: Mycobacterium Infections, Nontuberculous; Cystic Fibrosis (CF)
MeSH terms: Infections; Communicable Diseases; Mycobacterium Infections; Mycobacterium Infections, Nontuberculous; Cystic Fibrosis; Fibrosis
Intervention: Molgramostim nebulizer solution; PARI eFlow nebulizer system
Intervention description: 300 µg / dose molgramostim (recombinant human GM-CSF) for inhalation; PARI eFlow nebulizer system
Intervention MeSH terms: Molgramostim; Sargramostim
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 14.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Nontuberculosis mycobacterial infection; Cystic fibrosis; M. avium complex; M. abscessus complex; Mycobacterium Infections, Nontuberculous

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.
    

Eligibility 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 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.

          4. Subject fulfills criteria for inclusion in one of the following groups:

             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).

          5. Ability to produce sputum or be willing to undergo an induction protocol that produces
             sputum for clinical evaluation.

          6. 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.

          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 at screening that is normalized 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.

               -  Vasectomized partner

               -  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 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.

          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 28 days 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.