IV Gallium Study for Patients with Cystic Fibrosis Who Have NTM (ABATE Study)

The purpose of this study is to assess the safety and tolerability of two 5-day infusion cycles of IV gallium in adult patients with CF who are infected with NTM.

Funding Source - FDA Office of Orphan Products Development (OOPD)

This is a prospective, multicenter open-label study in adults with CF who are colonized with M. avium complex and/or M. abscessus complex.

Participants are enrolled into one of the two cohorts:

1. Treatment-Naïve NTM Cohort: participants with persistently positive NTM culture results (either M. avium complex, M. abscessus complex, or both M. avium and M. abscessus) who had never been treated for current NTM species or previous treatment was associated with clearance of NTM.
2. Treatment-Refractory NTM Cohort: participants with persistently positive NTM culture results (either M. avium complex, M. abscessus complex, or both M. avium and M. abscessus) whose treatment failed to respond to 12 months of NTM guideline-based therapy or currently receiving treatment with guideline-based antibiotics for \> 12 months.

Subjects will receive two 5-day infusion cycles of IV gallium. The study will evaluate the safety and antimycobacterial effect of two 5-day infusions of IV gallium.

Eligibility Criteria:
Inclusion Criteria for Treatment-Naïve NTM Cohort

1. Written informed consent obtained from participant or participant's legal representative
2. Be willing and able to adhere to the study visit schedule and other protocol requirements
3. All genders ≥ 18 years of age at Visit 1
4. Documentation of a CF diagnosis as evidenced by one or more clinical features consistent with the CF phenotype
5. Documentation of persistently positive NTM culture results that are positive for the same species or sub-species (either M. avium complex, M. abscessus complex, or both M. avium and M. abscessus). Persistently positive cultures are those which meet ONE of the following criteria, after first ignoring any negative culture results that occur within 7 days of a positive culture:

   1. The two most recent NTM culture results from sputum or BAL taken at least 28 days apart are positive.

      OR
   2. At least one NTM culture result in the previous 4 months from sputum or BAL is positive. If there are four or more cultures in the last 12-months at least 3 out of the 4 most recent cultures must be positive for NTM. If there are three or fewer cultures in the past 12 months, then at least 2 of the 3 most recent cultures must be positive for NTM even if some of those cultures are more than 12 months ago.
6. Current NTM species or subspecies has never been treated or previous treatment was associated with clearance of NTM and completed \> 2 years prior to Day 1
7. FEV1 ≥ 25 % of predicted value at Screening
8. Able to expectorate sputum
9. Clinically stable with no significant changes in health status within 7 days prior to Day 1
10. Enrolled in the CFF Patient Registry (CFF PR)
11. Willing to discontinue chronic azithromycin use for the duration of the study

Inclusion Criteria for Treatment-Refractory NTM Cohort

1. Written informed consent obtained from participant or participant's legal representative
2. Be willing and able to adhere to the study visit schedule and other protocol requirements
3. All genders ≥ 18 years of age at Visit 1
4. Documentation of a CF diagnosis as evidenced by one or more clinical features consistent with the CF phenotype
5. History of current or prior treatment for NTM pulmonary disease with M. abscessus or M avium (or both M. avium and M. abscessus)

   1. Previously received treatment with guideline-based antibiotics for \>12 months without having treatment discontinued for reasons of culture clearance OR
   2. Currently receiving treatment with guideline-based antibiotics for \>12 months
6. FEV1 ≥ 25 % of predicted value at Screening
7. Able to expectorate sputum
8. Not hospitalized within 7 days prior to Day 1
9. Enrolled in the CFF Patient Registry (CFF PR)
10. Be willing and able to continue guideline-based antibiotic therapy for M. abscessus or M avium (or both M. avium and M. abscessus) concurrent with IV gallium, if currently on treatment

Exclusion Criteria Treatment-Naïve NTM Cohort

1. Any of the following abnormal lab values at screening:

   * Hemoglobin \<10g/dL
   * Platelets \<100,000/mm3
   * Absolute neutrophil count \< 1500/mm3
   * Aspartate transaminase (AST), alanine transaminase (ALT), gamma-glutamyl transferase (GGT), alkaline phosphatase (ALP), or total bilirubin ≥3 x upper limit of normal
   * Serum creatinine \> 2.0 mg/dl and ≥1.5 x upper limit of normal
   * Ionized calcium ≤ lower limit of normal (only performed if total calcium is ≤ lower limit of normal)
2. History of solid organ or hematological transplantation
3. Use of bisphosphonates within 7 days prior to Day 1
4. Known sensitivity to gallium
5. Use of any investigational drug and/or participated in any interventional clinical trial within 28 days prior to Day 1
6. In the opinion of the Investigator, features of active NTM disease are present (e.g., clinical worsening is likely due to NTM disease despite definitive treatment of co-pathogens and/or acute exacerbations)
7. Undergoing treatment for NTM disease or anticipate beginning treatment within 3 months
8. Current diagnosis of osteoporosis
9. For people of childbearing potential:

   * Positive pregnancy test at Visit 1 or
   * Lactating or
   * Unwilling to practice a medically acceptable form of contraception (acceptable forms of contraception: abstinence, hormonal birth control, intrauterine device, or barrier method plus a spermicidal agent), unless surgically sterilized or postmenopausal during the study
10. For people able to father a child: unwilling to use adequate contraception (as determined by the investigator) during the study
11. Has any other condition that, in the opinion of the Site Investigator/designee, would preclude informed consent or assent, make study participation unsafe, complicate interpretation of study outcome data, or otherwise interfere with achieving the study objectives
12. New initiation of chronic CF therapy (e.g., CFTR modulators, ibuprofen, azithromycin, inhaled tobramycin, Cayston, etc.) within 28 days prior to Visit 1 (Day 1)
13. Use of azithromycin within 14 days prior to the screening visit

Exclusion Criteria Treatment-Refractory NTM Cohort

1. Any of the following abnormal lab values at screening:

   * Hemoglobin \<10g/dL
   * Platelets \<100,000/mm3
   * Absolute neutrophil count \< 1500/mm3
   * Aspartate transaminase (AST), alanine transaminase (ALT), gamma-glutamyl transferase (GGT), alkaline phosphatase (ALP), or total bilirubin ≥3 x upper limit of normal
   * Serum creatinine \> 2.0 mg/dL and ≥1.5 x upper limit of normal
   * Ionized calcium ≤ lower limit of normal (only performed if total calcium is ≤ lower limit of normal)
2. History of solid organ or hematological transplantation
3. Use of bisphosphonates within 7 days prior to Day 1
4. Known sensitivity to gallium
5. Use of any investigational drug and/or participated in any interventional clinical trial within 28 days prior to Day 1
6. Current diagnosis of osteoporosis
7. For people of childbearing potential:

   * Positive pregnancy test at Visit 1 (Day 1) or
   * Lactating or
   * Unwilling to practice a medically acceptable form of contraception (acceptable forms of contraception: abstinence, hormonal birth control, intrauterine device, or barrier method plus a spermicidal agent), unless surgically sterilized or postmenopausal during the study
8. For people able to father a child: unwilling to use adequate contraception (as determined by the investigator) during the study
9. Has any other condition that, in the opinion of the Site Investigator/designee, would preclude informed consent or assent, make study participation unsafe, complicate interpretation of study outcome data, or otherwise interfere with achieving the study objectives
10. New initiation of chronic CF therapy (e.g., CFTR modulators, ibuprofen, inhaled tobramycin, Cayston, etc.) within 28 days prior to Visit 1 (Day 1)