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| Name | Class |
|---|---|
| Thrasher Research Fund | OTHER |
| University of Florida | OTHER |
| Florida Hospital for Children | OTHER |
| University of California, San Francisco |
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This is a phase I/II open-label study to determine the lowest, safe, effective dose of budesonide given with calfactant as the vehicle.
This is a phase I/II open-label study to determine the lowest safe, effective dose of budesonide given with calfactant as the vehicle; the investigators will perform an unblinded dose escalation study. The investigators will administer four dosing levels of budesonide suspended in calfactant beginning with 0.025 mg/kg of budesonide administered to 8 extremely low gestational age newborns (ELGANs) who are intubated at 3-10 days of age. Daily doses (at the same dosage) will be administered to infants who remain intubated for a potential of 5 total doses in each patient. Subsequent groups of 8 infants each will receive 0.05 mg/kg, 0.10 mg/kg, and 0.15 mg/kg of budesonide in calfactant (up to 5 total doses in each patient). A total of up to 32 infants will be enrolled in the trial. The investigators will evaluate the clinical, laboratory and safety data from each group of treated infants to 28 days of age before moving to the next dosing level of budesonide.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 0.025 mg/kg Budesonide | Experimental | 0.025 mg/kg Budesonide in Calfactant |
|
| 0.050 mg/kg Budesonide | Experimental | 0.050 mg/kg Budesonide in Calfactant |
|
| 0.10 mg/kg Budesonide | Experimental | 0.10 mg/kg Budesonide in Calfactant |
|
| 0.15 mg/kg Budesonide | Experimental | 0.15 mg/kg Budesonide in Calfactant |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Budesonide in Calfactant | Drug | Budesonide in Calfactant |
|
| Measure | Description | Time Frame |
|---|---|---|
| Number of ELGANs With Clinical and Anti-inflammatory Efficacy of Escalating Doses of Budesonide Determined by Monitoring Respiratory Severity Score (RSS) | Dose escalation will be defined as effective at the dose level in which 5 of 8 infants achieve the following:
AND a > 50% suppression of the tracheal aspirate interleukin-8 (IL-8) or CCL2 (chemokine ligand 2) at 24-72 hours (or prior to extubation if occurs at <24 hours after dosing) after the initial dose in 5 of 8 of the infants (this may be a different combination of 5 patients than those who met the above criteria). | 28 days of life for each dosing group |
| The Clinical and Anti-inflammatory Efficacy of Escalating Doses of Budesonide Suspended in Calfactant and Given Into the Lungs of ELGANs by Monitoring Tracheal Aspirate Cytokine Levels. | Number of ELGANS with a clinical AND Cytokine response: a > 50% suppression of the tracheal aspirate interleukin-8 or chemokine ligand 2 at 24-72 hours (or prior to extubation if occurs at <24 hours after dosing) after the initial dose in 5 of 8 of the infants | 28 days of life for each dosing group |
| Measure | Description | Time Frame |
|---|---|---|
| Adverse Events/Subject Safety | Safety assessments will include the subject's vital signs, clinical laboratory testing, morbidities associated with prematurity, morbidities associated with administration of budesonide in calfactant, and Adverse Events (AE)s. Clinical parameters/ AEs of interest are those potentially consistent with elevated glucocorticoid levels and will be specifically evaluated. A Data and Safety Monitoring Board (DSMB) will be established to review safety data. All of the data will be reviewed to monitor subject safety. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Cynthia McEvoy, MD, MCR | Oregon Health and Science University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of California, San Francisco | San Francisco | California | 94143 | United States | ||
| University of Florida, Jacksonville |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 26351971 | Background | Yeh TF, Chen CM, Wu SY, Husan Z, Li TC, Hsieh WS, Tsai CH, Lin HC. Intratracheal Administration of Budesonide/Surfactant to Prevent Bronchopulmonary Dysplasia. Am J Respir Crit Care Med. 2016 Jan 1;193(1):86-95. doi: 10.1164/rccm.201505-0861OC. | |
| 18426851 | Background | Yeh TF, Lin HC, Chang CH, Wu TS, Su BH, Li TC, Pyati S, Tsai CH. Early intratracheal instillation of budesonide using surfactant as a vehicle to prevent chronic lung disease in preterm infants: a pilot study. Pediatrics. 2008 May;121(5):e1310-8. doi: 10.1542/peds.2007-1973. Epub 2008 Apr 21. |
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| ID | Title | Description |
|---|---|---|
| FG000 | 0.025 mg/kg Budesonide | 0.025 mg/kg Budesonide in Calfactant Budesonide in Calfactant: Budesonide in Calfactant |
| FG001 | 0.050 mg/kg Budesonide | 0.050 mg/kg Budesonide in Calfactant Budesonide in Calfactant: Budesonide in Calfactant |
| FG002 | 0.10 mg/kg Budesonide | 0.10 mg/kg Budesonide in Calfactant Budesonide in Calfactant: Budesonide in Calfactant |
| FG003 | 0.15 mg/kg Budesonide | 0.15 mg/kg Budesonide in Calfactant Budesonide in Calfactant: Budesonide in Calfactant |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
Study ended prior to dosing level 4 (0.15 mg/kg).
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| ID | Title | Description |
|---|---|---|
| BG000 | 0.025 mg/kg Budesonide | 0.025 mg/kg Budesonide in Calfactant Budesonide in Calfactant: Budesonide in Calfactant |
| BG001 | 0.050 mg/kg Budesonide | 0.050 mg/kg Budesonide in Calfactant Budesonide in Calfactant: Budesonide in Calfactant |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Number of ELGANs With Clinical and Anti-inflammatory Efficacy of Escalating Doses of Budesonide Determined by Monitoring Respiratory Severity Score (RSS) | Dose escalation will be defined as effective at the dose level in which 5 of 8 infants achieve the following:
AND a > 50% suppression of the tracheal aspirate interleukin-8 (IL-8) or CCL2 (chemokine ligand 2) at 24-72 hours (or prior to extubation if occurs at <24 hours after dosing) after the initial dose in 5 of 8 of the infants (this may be a different combination of 5 patients than those who met the above criteria). | Extremely low gestational age infants (ELGANs), born before 28 weeks gestation. | Posted | Count of Participants | Participants | 28 days of life for each dosing group |
Adverse event data was collected through 28 days of life.
Adverse Event Definition:
Any untoward medical occurrence in a patient or clinical investigation in which a subject is given a pharmaceutical product; does not necessarily have a causal relationship with such treatment, or Any unfavorable and unintended sign (including abnormal laboratory findings),symptom, or disease temporally associated with the use of a medicinal (investigational) product; not necessarily related to the product.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 0.025 mg/kg Budesonide | 0.025 mg/kg Budesonide in Calfactant Budesonide in Calfactant: Budesonide in Calfactant |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Severe Respiratory Decompensation | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Apnea | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
Early termination of the study is not due to any safety concerns, but rather enrollment challenges and lack of response in patients. The FDA and IRB were notified and approved.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Cindy McEvoy | Oregon Health & Science University | 5034945598 | mcevoyc@ohsu.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Oct 16, 2017 | Mar 20, 2019 | Prot_SAP_000.pdf |
Not provided
| ID | Term |
|---|---|
| D001997 | Bronchopulmonary Dysplasia |
| ID | Term |
|---|---|
| D055397 | Ventilator-Induced Lung Injury |
| D055370 | Lung Injury |
| D008171 | Lung Diseases |
| D012140 | Respiratory Tract Diseases |
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| ID | Term |
|---|---|
| D019819 | Budesonide |
| C117342 | calfactant |
| ID | Term |
|---|---|
| D011282 | Pregnenediones |
| D011283 | Pregnenes |
| D011278 | Pregnanes |
| D013256 | Steroids |
| D000072473 |
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| OTHER |
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|
| Through 28 days of life |
| Serial Budesonide Levels, Peak | The research team will obtain dried blood spot samples at 15 minutes, and 1 and 4 hours after the first dose of budesonide in calfactant for budesonide levels. Trough concentrations (Cmin) will be drawn before potential subsequent daily doses. | At 15 minutes, 1 and 4 hours after first dose and prior to each additional dose |
| Serial Budesonide Levels, T 1/2 | The research team will obtain dried blood spot samples at 15 minutes, and 1 and 4 hours after the first dose of budesonide in calfactant for budesonide levels. Trough concentrations (Cmin) will be drawn before potential subsequent daily doses. | At 15 minutes, 1 and 4 hours after first dose and prior to each additional dose |
| Serial Budesonide Levels, AUC | The research team will obtain dried blood spot samples at 15 minutes, and 1 and 4 hours after the first dose of budesonide in calfactant for budesonide levels. Trough concentrations (Cmin) will be drawn before potential subsequent daily doses. | At 15 minutes, 1 and 4 hours after first dose and prior to each additional dose |
| Respiratory Severity Score: Mean Airway Pressure and Oxygen Requirement at 28 Days of Age | Clinical respiratory status (RSS and oxygen requirement) around dosing and at 28 days of age will be compared between dosing groups and also compared to the matched historical control patients from the "Trial of Late Surfactant:(TOLSURF) study. The respiratory severity score (RSS) is a simplified severity score consisting of the mean airway pressure (MAP) multiplied by the fraction of inspired oxygen (FiO2). This score ranges from 0 to 12, with a higher score indicating more severe disease. | 28 days of life for each dosing group |
| Jacksonville |
| Florida |
| 32209 |
| United States |
| Florida Hospital for Children | Orlando | Florida | 32803 | United States |
| Oregon Health ans Science University | Portland | Oregon | 97239 | United States |
| Vanderbilt Children's Hospital | Nashville | Tennessee | 37232 | United States |
| 26416605 | Background | Roberts JK, Stockmann C, Dahl MJ, Albertine KH, Egan E, Lin Z, Reilly CA, Ballard PL, Ballard RA, Ward RM. Pharmacokinetics of Budesonide Administered with Surfactant in Premature Lambs: Implications for Neonatal Clinical Trials. Curr Clin Pharmacol. 2016;11(1):53-61. doi: 10.2174/1574884710666150929100210. |
| 27281349 | Background | Barrette AM, Roberts JK, Chapin C, Egan EA, Segal MR, Oses-Prieto JA, Chand S, Burlingame AL, Ballard PL. Antiinflammatory Effects of Budesonide in Human Fetal Lung. Am J Respir Cell Mol Biol. 2016 Nov;55(5):623-632. doi: 10.1165/rcmb.2016-0068OC. |
| 32006953 | Result | McEvoy CT, Ballard PL, Ward RM, Rower JE, Wadhawan R, Hudak ML, Weitkamp JH, Harris J, Asselin J, Chapin C, Ballard RA. Dose-escalation trial of budesonide in surfactant for prevention of bronchopulmonary dysplasia in extremely low gestational age high-risk newborns (SASSIE). Pediatr Res. 2020 Oct;88(4):629-636. doi: 10.1038/s41390-020-0792-y. Epub 2020 Feb 1. |
| BG002 | 0.10 mg/kg Budesonide | 0.10 mg/kg Budesonide in Calfactant Budesonide in Calfactant: Budesonide in Calfactant |
| BG003 | 0.15 mg/kg Budesonide | 0.15 mg/kg Budesonide in Calfactant Budesonide in Calfactant: Budesonide in Calfactant |
| BG004 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | Mean | Standard Deviation | gestational age in weeks |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| Number of participants that completed study | Count of Participants | Participants |
|
| ID |
|---|
| Title |
|---|
| Description |
|---|
| OG000 | 0.025 mg/kg Budesonide | 0.025 mg/kg Budesonide in Calfactant Budesonide in Calfactant: Budesonide in Calfactant |
| OG001 | 0.050 mg/kg Budesonide | 0.050 mg/kg Budesonide in Calfactant Budesonide in Calfactant: Budesonide in Calfactant |
| OG002 | 0.10 mg/kg Budesonide | 0.10 mg/kg Budesonide in Calfactant Budesonide in Calfactant: Budesonide in Calfactant |
| OG003 | 0.15 mg/kg Budesonide | 0.15 mg/kg Budesonide in Calfactant Budesonide in Calfactant: Budesonide in Calfactant |
|
|
| Primary | The Clinical and Anti-inflammatory Efficacy of Escalating Doses of Budesonide Suspended in Calfactant and Given Into the Lungs of ELGANs by Monitoring Tracheal Aspirate Cytokine Levels. | Number of ELGANS with a clinical AND Cytokine response: a > 50% suppression of the tracheal aspirate interleukin-8 or chemokine ligand 2 at 24-72 hours (or prior to extubation if occurs at <24 hours after dosing) after the initial dose in 5 of 8 of the infants | No patient at the 0.025 mg/kg or at the 0.05 mg/kg or at the 0.10 mg/kg dosing level met the criteria for the primary outcome of a clinical and cytokine response. Due to this lack of response, we were approved by the Thrasher Foundation to not perform the dosing at the 0.15 mg/kg dosing level. | Posted | Count of Participants | Participants | 28 days of life for each dosing group |
|
|
|
| Secondary | Adverse Events/Subject Safety | Safety assessments will include the subject's vital signs, clinical laboratory testing, morbidities associated with prematurity, morbidities associated with administration of budesonide in calfactant, and Adverse Events (AE)s. Clinical parameters/ AEs of interest are those potentially consistent with elevated glucocorticoid levels and will be specifically evaluated. A Data and Safety Monitoring Board (DSMB) will be established to review safety data. All of the data will be reviewed to monitor subject safety. | No SAEs were considered to be treatment related. | Posted | Count of Participants | Participants | Through 28 days of life |
|
|
|
| Secondary | Serial Budesonide Levels, Peak | The research team will obtain dried blood spot samples at 15 minutes, and 1 and 4 hours after the first dose of budesonide in calfactant for budesonide levels. Trough concentrations (Cmin) will be drawn before potential subsequent daily doses. | Posted | Mean | 54% Confidence Interval | ng/mL | At 15 minutes, 1 and 4 hours after first dose and prior to each additional dose |
|
|
|
| Secondary | Serial Budesonide Levels, T 1/2 | The research team will obtain dried blood spot samples at 15 minutes, and 1 and 4 hours after the first dose of budesonide in calfactant for budesonide levels. Trough concentrations (Cmin) will be drawn before potential subsequent daily doses. | Posted | Mean | 50% Confidence Interval | h | At 15 minutes, 1 and 4 hours after first dose and prior to each additional dose |
|
|
|
| Secondary | Serial Budesonide Levels, AUC | The research team will obtain dried blood spot samples at 15 minutes, and 1 and 4 hours after the first dose of budesonide in calfactant for budesonide levels. Trough concentrations (Cmin) will be drawn before potential subsequent daily doses. | Posted | Mean | 48% Confidence Interval | ng*h/mL | At 15 minutes, 1 and 4 hours after first dose and prior to each additional dose |
|
|
|
| Secondary | Respiratory Severity Score: Mean Airway Pressure and Oxygen Requirement at 28 Days of Age | Clinical respiratory status (RSS and oxygen requirement) around dosing and at 28 days of age will be compared between dosing groups and also compared to the matched historical control patients from the "Trial of Late Surfactant:(TOLSURF) study. The respiratory severity score (RSS) is a simplified severity score consisting of the mean airway pressure (MAP) multiplied by the fraction of inspired oxygen (FiO2). This score ranges from 0 to 12, with a higher score indicating more severe disease. | Posted | Mean | Standard Deviation | Respiratory Severity Score | 28 days of life for each dosing group |
|
|
|
| 0 |
| 8 |
| 1 |
| 8 |
| 8 |
| 8 |
| EG001 | 0.050 mg/kg Budesonide | 0.050 mg/kg Budesonide in Calfactant Budesonide in Calfactant: Budesonide in Calfactant | 0 | 8 | 1 | 8 | 7 | 8 |
| EG002 | 0.10 mg/kg Budesonide | 0.10 mg/kg Budesonide in Calfactant Budesonide in Calfactant: Budesonide in Calfactant | 3 | 9 | 4 | 9 | 8 | 9 |
| EG003 | 0.15 mg/kg Budesonide | 0.15 mg/kg Budesonide in Calfactant Budesonide in Calfactant: Budesonide in Calfactant | 0 | 0 | 0 | 0 | 0 | 0 |
| Sepsis | Infections and infestations | Systematic Assessment |
|
| Necrotizing Enterocolitis | Gastrointestinal disorders | Systematic Assessment |
|
| Anemia | Blood and lymphatic system disorders | Systematic Assessment |
|
| Bradycardia | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Cardiopulmonary arrest | Cardiac disorders | Systematic Assessment |
|
| Elevated blood gas | Metabolism and nutrition disorders | Systematic Assessment |
|
| Hyperkalemia | Metabolism and nutrition disorders | Systematic Assessment |
|
| Hyponatremia | Metabolism and nutrition disorders | Systematic Assessment |
|
| Increased urine output | Renal and urinary disorders | Systematic Assessment |
|
| Intraventricular hemorrhage | Nervous system disorders | Systematic Assessment |
|
| Metabolic acidosis | Metabolism and nutrition disorders | Systematic Assessment |
|
| Presumed formula aspiratiom | General disorders | Systematic Assessment |
|
| Reflux into ETT during dosing | Injury, poisoning and procedural complications | Systematic Assessment |
|
| PDA requiring treatment | Cardiac disorders | Systematic Assessment |
|
| Pulmonary decompensation | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Re-intubation during study | General disorders | Systematic Assessment |
|
| Renal insufficiency | Renal and urinary disorders | Systematic Assessment |
|
| Respiratory failure | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Sepsis | Infections and infestations | Systematic Assessment |
|
| Severe hypotension | Blood and lymphatic system disorders | Systematic Assessment |
|
| Severe respiratory decompensation | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Severe pulmonary hemorrhage | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Supraventricular tachycardia | Cardiac disorders | Systematic Assessment |
|
| Uncontrolled hyperglycemia | Metabolism and nutrition disorders | Systematic Assessment |
|
Not provided
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| D007235 |
| Infant, Premature, Diseases |
| D007232 | Infant, Newborn, Diseases |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| Fused-Ring Compounds |
| D011083 | Polycyclic Compounds |