Inhaled Gaseous Nitric Oxide (gNO) for Adults & Adolescents With Non-Tuberculous Mycobacteria Infection (NONTM)

• ClinicalTrials.gov Identifier: NCT03331445
• Recruitment Status: Active, not recruiting
• First Posted: November 6, 2017
• Last Update Posted: October 4, 2018
• Sponsor: University of British Columbia
• Collaborator: Novoteris, LLC
• Information provided by (Responsible Party): Chris Miller, University of British Columbia

Study Description

Brief Summary:

Non tuberculous mycobacteria (NTM) infections in the lung are almost impossible to eradicate with conventional antibiotics. These patients have few options to treat their lung infection. It has been shown that nitric oxide was safe to be inhaled for similar cystic fibrosis patients and reduced drug resistant bacteria in the lungs. Further, research indicates that clinical isolates of NTM can be eradicated by 160ppm NO exposure in the laboratory petri dish. This is not the first time inhaled NO treatment has been used in patients with NTM (case studies). This study will provide more data to see if NO therapy can reduce the NTM bacterial load in the lungs and help the patients breath better.

Condition or disease	Intervention/treatment	Phase
Non-Tuberculous Mycobacterial Pneumonia	Drug: Nitric Oxide 0.5 % / Nitrogen 99.5 % Gas for Inhalation	Phase 2

Detailed Description:

Primary Objective: Assess the safety of inhaled NO (gNO) in adults & adolescents with NTM

Safety will be evaluated by unanticipated adverse events in clinical labs (hematology, coagulation, and serum chemistries); in vitals; in inspired concentration of NO, O2 and NO2 delivered to each subject and; in real time methemoglobin and oxygen saturation levels.

Primary Endpoint:

Determine the safety of gNO in the NTM population,

• as confirmed by no unanticipated adverse events

Secondary safety Endpoint: Determine the efficacy of inhaled NO in adults with NTM.

Efficacy will be evaluated by measuring the change in lung function with spirometry (specifically absolute change in FEV1 % predicted) from baseline to Days 5, 12, 19 and 26 during and after treatment. Because deterioration of lung function is the primary cause of death in patients with NTM, absolute change in FEV1 % predicted has been used to evaluate the clinical efficacy.

Secondary Efficacy Endpoint Determine the presence of an efficacy signal of gNO in the NTM population,

Efficacy will be assessed by the antimicrobial effect of inhaled NO on the density of NTM species and other microorganisms in sputum. Serial measurements of these microbial colony counts in sputum have been previously used as a measure of antimicrobial activity in other clinical trials of antibiotics in NTM.

• as confirmed by an improvement in pre-treatment bacterial colonization and post-treatment bacterial colonization on Day 5, 12, 19 and 26.

Efficacy will be assessed by change in Quality of Life (CRISS) Score.

• as confirmed by an improvement in CRISS Score and post-treatment CRISS Score on Day 5, 12, 19 and 26.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 10 participants
• Intervention Model: Sequential Assignment
• Intervention Model Description: Open label safety study
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open Label Safety Study of Inhaled Gaseous Nitric Oxide (gNO) for Adults & Adolescents With Non-Tuberculous Mycobacteria Infection
• Actual Study Start Date: October 24, 2017
• Estimated Primary Completion Date: December 31, 2018
• Estimated Study Completion Date: December 31, 2018

Arms and Interventions

Arm	Intervention/treatment
Experimental: 160 ppm Nitric Oxide	Drug: Nitric Oxide 0.5 % / Nitrogen 99.5 % Gas for Inhalation; Inhaled Nitric Oxide 160ppm balance air; Other Name: Thiolanox

Outcome Measures

Primary Outcome Measures :

1. Measure the safety of 160ppm inhaled nitric oxide delivery in NTM subjects [ Time Frame: 26 Days ]
   Measure the number of unanticipated adverse events over the duration of the study protocol

Secondary Outcome Measures :

1. Measure the effect of 160ppm inhaled nitric oxide delivery on lung spirometry in NTM subjects [ Time Frame: Day 5,12,19 and 26 ]
   Measure the change in absolute FEV1.0 change from baseline during 160 ppm inhalation therapy
2. Measure the antimicrobial effect of 160ppm inhaled nitric oxide on lung NTM bacterial load in the sputum [ Time Frame: Day 5, 12, 19 and 26 ]
   Measure the difference from baseline NTM species bacterial load (0 to +4) in sputum during 160ppm nitric oxide inhalation therapy
3. Measure the effect of 160ppm inhaled nitric oxide on Quality of Life (CRISS) Score [ Time Frame: Day 5, 12, 19 and 26 ]
   Measure the difference from baseline CRISS (0-100) during 160ppm nitric oxide inhalation therapy (lower score represents higher quality of life)

Eligibility Criteria

• Ages Eligible for Study: 14 Years and older (Child, Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Written informed consent.

• Has been previously diagnosed with NTM.

  1. NTM defined as positive culture(s) of at least one species of Mycobacterium avium Complex (MAC) or Mycobacterium abscessus Complex (MABSC)
  2. History of repeatedly positive cultures (2 or more), irregardless of therapy
• Male or female ≥14 years of age.
• Female not pregnant at time of study.
• Has an FEV1 ≥ 30 % of predicted.

• Oxygen saturation on room air >92% at screening.

  a. Able to breathe without supplemental oxygen for 60 minutes

• Non-smoker for at least 6 months prior to screening and agrees not to smoke during the study.
• Willing and able to comply with the treatment schedule and procedures.

Exclusion Criteria:

Inclusion Criteria:

• Written informed consent.

• Has been previously diagnosed with NTM.

  1. NTM defined as positive culture(s) of at least one species of Mycobacterium avium Complex (MAC) or Mycobacterium abscessus Complex (MABSC)
  2. History of repeatedly positive cultures (2 or more), irregardless of therapy
• Male or female ≥14 years of age.
• Female not pregnant at time of study.
• Has an FEV1 ≥ 30 % of predicted.

• Oxygen saturation on room air >92% at screening.

  o Able to breathe without supplemental oxygen for 60 minutes

• Non-smoker for at least 6 months prior to screening and agrees not to smoke during the study.
• Willing and able to comply with the treatment schedule and procedures.

Exclusion Criteria:

• Use of an investigational drug within 30 days of screening
• History of frequent epistaxis (>1 episode/month)
• Significant hemoptysis within 30 days (≥ 5 mL of blood in one coughing episode or > 30 mL of blood in a 24 hour period)
• History of reactive pulmonary vascular hypertension
• Methemoglobin >3% at screening
• Liver function insufficiency (ALT/ AST >3 of normal values)
• Hemoglobin <11 g/dl
• Thrombocytopenia (platelet count <100,000/mm3) at screening
• Prothrombin time international ratio (INR) > 1.3 at screening
• Changes to antibiotics (e.g. azithromycin) from 7 days prior to screening through last treatment day. (Subjects may be taking antibiotics during this time period, but they cannot start, stop or change doses during this time period)
• On supplemental oxygen during gNO treatment (SaO2 < 90% for 50 minutes while resting in a chair).

• For women of child bearing potential:

  1. positive pregnancy test at screening or
  2. lactating or
  3. unwilling to practice a medically acceptable form of contraception from screening to Day 36 (acceptable forms of contraception: abstinence, hormonal birth control, intrauterine device, or barrier method plus a spermicidal agent)
• Presence of a condition or abnormality that in the opinion of the Investigator would compromise the safety of the patient or the quality of the data.

Contacts and Locations

Locations

Canada, British Columbia

Diamond Centre

Vancouver, British Columbia, Canada, V5Z-1L8

Sponsors and Collaborators

University of British Columbia

Novoteris, LLC

Investigators

• Principal Investigator: Jeremy D Road, MD; Professor

More Information

Publications:

Deppisch C, Herrmann G, Graepler-Mainka U, Wirtz H, Heyder S, Engel C, Marschal M, Miller CC, Riethmüller J. Gaseous nitric oxide to treat antibiotic resistant bacterial and fungal lung infections in patients with cystic fibrosis: a phase I clinical study. Infection. 2016 Aug;44(4):513-20. doi: 10.1007/s15010-016-0879-x. Epub 2016 Feb 9.

Miller C, Miller M, McMullin B, Regev G, Serghides L, Kain K, Road J, Av-Gay Y. A phase I clinical study of inhaled nitric oxide in healthy adults. J Cyst Fibros. 2012 Jul;11(4):324-31. doi: 10.1016/j.jcf.2012.01.003. Epub 2012 Apr 18.

Yaacoby-Bianu K, Gur M, Toukan Y, Nir V, Hakim F, Geffen Y, Bentur L. Compassionate Nitric Oxide Adjuvant Treatment of Persistent Mycobacterium Infection in Cystic Fibrosis Patients. Pediatr Infect Dis J. 2018 Apr;37(4):336-338. doi: 10.1097/INF.0000000000001780.

• Responsible Party: Chris Miller, Principal Investigator, University of British Columbia
• ClinicalTrials.gov Identifier: NCT03331445 History of Changes
• Other Study ID Numbers: NTM-CTP-01: H17-02107
• First Posted: November 6, 2017
• Last Update Posted: October 4, 2018
• Last Verified: October 2018

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Chris Miller, University of British Columbia:

inhaled nitric oxide; non tuberculous mycobacteria; drug resistant pneumonia

Additional relevant MeSH terms:

Mycobacterium Infections; Mycobacterium Infections, Nontuberculous; Pneumonia; Lung Diseases; Respiratory Tract Diseases; Respiratory Tract Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Nitric Oxide; Bronchodilator Agents; Autonomic Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Anti-Asthmatic Agents; Respiratory System Agents; Free Radical Scavengers; Antioxidants; Molecular Mechanisms of Pharmacological Action; Neurotransmitter Agents; Endothelium-Dependent Relaxing Factors; Vasodilator Agents; Gasotransmitters; Protective Agents