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Inhaled Gaseous Nitric Oxide (gNO) Antimicrobial Treatment of Difficult Bacterial and Viral Lung (COVID-19) Infections

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ClinicalTrials.gov Identifier: NCT03331445
Recruitment Status : Terminated (Covid Incidence too low and Funding Completed)
First Posted : November 6, 2017
Last Update Posted : July 16, 2021
Sponsor:
Collaborator:
Mallinckrodt
Information provided by (Responsible Party):
Chris Miller, Nitric Solutions Inc.

Tracking Information
First Submitted Date  ICMJE October 25, 2017
First Posted Date  ICMJE November 6, 2017
Last Update Posted Date July 16, 2021
Actual Study Start Date  ICMJE October 24, 2017
Actual Primary Completion Date June 30, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 31, 2017)
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
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: March 24, 2020)
  • 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
  • Measure the antimicrobial effect of 160ppm inhaled nitric oxide on lung NTM bacterial load in the sputum [ Time Frame: Day 19 and 26 ]
    Measure the difference from baseline NTM species bacterial load (0 to +4) in sputum during 160ppm nitric oxide inhalation therapy
  • Measure the effect of 160ppm inhaled nitric oxide on Quality of Life (CRISS) Score [ Time Frame: Day 19 and 26 ]
    Measure the difference from baseline CRISS (0-100) during 160ppm nitric oxide inhalation therapy (lower score represents higher quality of life)
Original Secondary Outcome Measures  ICMJE
 (submitted: October 31, 2017)
  • 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 from baseline during 160 ppm inhalation therapy
  • Measure the antimicrobial effect of 160ppm inhaled nitric oxide on lung NTM bacterial load in the lung [ Time Frame: Day 5, 12, 19 and 26 ]
    Measure the difference from baseline NTM species bacterial load in sputum during 160ppm nitric oxide inhalation therapy
Current Other Pre-specified Outcome Measures
 (submitted: March 24, 2020)
  • Sub-Study Primary Endpoint(s): Efficacy to reduce respiratory interventions [ Time Frame: Day 26 ]
    Measuring reduction in the incidence of mechanical assistance including oxygen therapy, BIPAP, CPAP, intubation and mechanical ventilation during the study period.
  • Efficacy in reduction of mortality [ Time Frame: Day 26 ]
    Measured by death from all causes
  • Antiviral effect [ Time Frame: Day 26 ]
    Assessed by time to negative conversion of COVID-19 RT-PCR from upper respiratory tract
  • Efficacy on clinical improvement [ Time Frame: Day 26 ]
    Time to clinical recovery as measured by resolution of clinical signs
  • Efficacy on the respiratory symptoms [ Time Frame: Day 26 ]
    Measured by change in the Modified Jackson Cold Score
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Inhaled Gaseous Nitric Oxide (gNO) Antimicrobial Treatment of Difficult Bacterial and Viral Lung (COVID-19) Infections
Official Title  ICMJE An Open Label Safety Study of Inhaled Gaseous Nitric Oxide (gNO) for Adults & Adolescents With Non-Tuberculous Mycobacteria, Burkholderia Spp, Aspergillus Spp and Corona-like Viral (Sub-Study) Infections
Brief Summary Non tuberculous mycobacteria (NTM), Burkholdria spp, Aspergillus in the lung are almost impossible to eradicate with conventional antibiotics. In addition COVID-19 has know current treatment. These patients have few options to treat their lung infection. Nitric oxide has broad bactericidal and virucidal properties. 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, Burkholderia spp, Aspergillus spp and Corona-like viruses 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 difficult lung infections. This study will provide more data to see if NO therapy can reduce the bacterial load in the lungs, help the patients breath better; and in the case of COVID-19 act as a anti-viral agent resulting in the reduction of incidence of oxygen therapy, mechanical assistance of BIPAP, CPAP, intubation and mechanical ventilation during the study period.
Detailed Description

Main Study

Primary Objective: Assess the safety of inhaled NO (gNO) in adults & adolescents with NTM, Burkholderia, Aspergillus Lung Infections and Viral Lung (COVID-19) Infections

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
  • Absence of a deleterious mean change in FEV1% predicted (absolute) from baseline

Secondary safety Endpoint: Determine the efficacy of inhaled NO in adults with NTM, Burkholderia and Aspergillus Lung Infections

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.

Secondary Efficacy Endpoint Determine the presence of an efficacy signal of gNO in the NTM, Burkholderia and Aspergillus Lung Infections

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 Days 19 and 26 as compared to baseline.

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

  • as assessed by an improvement in CRISS Score on Day 5, 19 and 26 as compared to baseline measurement;
  • as determined by improvement in six-minute walk test with one minute recovery as compared to baseline measurement.

COVID-19 Substudy

Primary Endpoint:

Efficacy will be evaluated by measuring reduction in the incidence of mechanical assistance of BIPAP, CPAP, intubation and mechanical ventilation during the study period.

Secondary Endpoints:

  1. Proportion of patients with mild COVID2019 who deteriorate to a severe form of the disease requiring mechanical intervention like BIPAP/CPAP, intubation and mechanical ventilation;
  2. Mortality from all causes during the study period;
  3. Negative conversion of COVID-19 RT-PCR from upper respiratory tract measured as the proportion of patients with a negative conversion of RT-PCR from an oropharyngeal or a nasopahryngeal swab;
  4. Time to clinical recovery defined as the time from initiation of the study to discharge or to normalization of fever (defined as <36.6°C from axillary site, or < 37.2°C from oral site or < 37.8°C from rectal or tympanic site), respiratory rate (< 24 bpm while breathing room air);
  5. Alleviation of symptoms recorded in the Modified Jackson Cols score with particular definition of cough (defined as mild or absent in a patient reported scale of severity).
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Sequential Assignment
Intervention Model Description:
Open label safety study (COVID-19 Sub-study)
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Respiratory Tract Infections
  • Corona Virus Infection
Intervention  ICMJE Drug: Nitric Oxide 0.5 % / Nitrogen 99.5 % Gas for Inhalation
Inhaled Nitric Oxide 160ppm balance air
Other Name: Thiolanox
Study Arms  ICMJE Experimental: 160 ppm Nitric Oxide
Intervention: Drug: Nitric Oxide 0.5 % / Nitrogen 99.5 % Gas for Inhalation
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: July 12, 2021)
13
Original Estimated Enrollment  ICMJE
 (submitted: October 31, 2017)
10
Actual Study Completion Date  ICMJE June 30, 2021
Actual Primary Completion Date June 30, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

COVID SubStudy Inclusion Criteria

  • Capable of understanding and providing signed informed consent and ability to adhere to the requirements and restrictions of this protocol;
  • Men and Women ≥ 19 years of age unless local laws dictate otherwise;
  • English speaking;
  • Suspected of exposure to SARS-CoV-2 with fatigue and at least a fever (>37.90 C) or cough or sore throat or a positive swab for SAR-CoV-2 within 5 days of the of enrollment;
  • Must be willing to use an adequate form of contraception (or abstinence) from the time of the first dose with the IMP until after the last dose of IMP.

Exclusion Criteria

  • Prior Tracheostomy;
  • Concomitant treatment involving high flow nasal cannula;
  • Any clinical contraindications, as judged by the attending physician;
  • Mentally or neurologically disabled patients who are considered not fit to consent to their participation in the study;
  • Prior COVID-19 infection or a positive swab for SARS-CoV-2 greater than 5 days from enrollment;
  • Family members in the same household already on the study;
  • Hydroxychloroquine, colchicine and other experimental antiviral medications;
  • unwilling to practice a medically acceptable form of contraception from screening to Day 26 (acceptable forms of contraception: abstinence, hormonal birth control, intrauterine device, or barrier method plus a spermicidal agent).

Recruitment on hold for following Criteria during COVID-19 Pandemic

Inclusion Criteria:

  • Written informed consent.
  • Has been previously diagnosed with NTM, Burkholderia spp and Aspergillus spp. or Corona-like viral infection:

    1. NTM, Burkholderia spp and Aspergillus spp defined as positive culture(s) of at least one species of Mycobacterium avium Complex (MAC) or Mycobacterium abscessus Complex (MABSCor Burkholderia spp and Aspergillus spp) or Corona-like viral infection:
    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. c. Suspected corona-like viral infection
  • 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:

  • 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 or antivirals 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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 19 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Canada
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03331445
Other Study ID Numbers  ICMJE NTM-CTP-01: H17-02107
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Chris Miller, Nitric Solutions Inc.
Study Sponsor  ICMJE Chris Miller
Collaborators  ICMJE Mallinckrodt
Investigators  ICMJE
Principal Investigator: Jeremy D Road, MD MD
PRS Account Nitric Solutions Inc.
Verification Date July 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP