Terbutaline Sulfate in Adults With Asthma (TBS02)

• ClinicalTrials.gov Identifier: NCT04973345
• Recruitment Status: Recruiting
• First Posted: July 22, 2021
• Last Update Posted: January 3, 2024
• Sponsor: Kanecia Obie Zimmerman
• Collaborators: Duke Health; The Emmes Company, LLC
• Information provided by (Responsible Party): Kanecia Obie Zimmerman, Duke University

Tracking Information

• First Submitted Date: July 14, 2021
• First Posted Date: July 22, 2021
• Last Update Posted Date: January 3, 2024
• Actual Study Start Date: July 7, 2023
• Estimated Primary Completion Date: December 2025 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 26, 2021)

• PK: Maximum concentration (CMAX) [ Time Frame: 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, and next calendar day after dose ]
  Describe differences in the PK profiles of terbutaline sulfate administered via the SQ route versus the IV route.
• PK: Time to Research Maximum Concentration (Tmax) [ Time Frame: 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours after dose ]
  Describe differences in the PK profiles of terbutaline sulfate administered via the SQ route versus the IV route.
• PK: Clearance (Cl) [ Time Frame: 5 mins, 15 mins, 30 mins, 45 mins, 1 hr, 2 hrs, 3 hrs, 4 hrs, 6 hrs, after dose ]
  Describe differences in the PK profiles of terbutaline sulfate administered via the SQ route
• PK: Volume of Distribution (Vd) [ Time Frame: 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours after dose ]
  Describe differences in the PK profiles of terbutaline sulfate administered via the SQ route
• PK: Half Life (t1/2) [ Time Frame: 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours after dose ]
  Describe differences in the PK profiles of terbutaline sulfate administered via the SQ route
• Concentration Achieving Maximum FEV1 Improvement (CeMax) [ Time Frame: 0-6 hours ]
  Estimate a target plasma concentration and IV dose which achieves maximum FEV1 improvement from baseline and FEV1 AUC 0 to 6 hours.
• Area Under the Concentration Time Curve (AUC) [ Time Frame: 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, and next calendar day after dose ]
  Describe differences in the PK profiles of terbutaline sulfate administered via the SQ route versus the IV route.
• Forced Expiratory Volume in 1 second (FEV1) [ Time Frame: 0-6 hours ]
  Estimate a target plasma concentration and IV dose which achieves maximum FEV1 improvement from baseline and FEV1 AUC 0 to 6 hours.

Original Primary Outcome Measures (submitted: July 14, 2021)

• PK: Maximum concentration (CMAX) [ Time Frame: 5, 15, 30, 45, 60, 120, 180, 240, 360 minutes, and next calendar day after dose ]
  Describe differences in the PK profiles of terbutaline sulfate administered via the SQ route versus the IV route.
• PK: Time to Research Maximum Concentration (Tmax) [ Time Frame: 5, 15, 30, 45, 60, 120, 180, 240, and 360 minutes after dose ]
  Describe differences in the PK profiles of terbutaline sulfate administered via the SQ route versus the IV route.
• PK: Clearance (Cl) [ Time Frame: 5, 15, 30, 45, 60, 120, 180, 240, and 360 minutes after dose ]
  Describe differences in the PK profiles of terbutaline sulfate administered via the SQ route
• PK: Volume of Distribution (Vd) [ Time Frame: 5, 15, 30, 45, 60, 120, 180, 240, and 360 minutes after dose ]
  Describe differences in the PK profiles of terbutaline sulfate administered via the SQ route
• PK: Half Life (t1/2) [ Time Frame: 5, 15, 30, 45, 60, 120, 180, 240, and 360 minutes after dose ]
  Describe differences in the PK profiles of terbutaline sulfate administered via the SQ route
• Concentration Achieving Maximum FEV1 Improvement (CeMax) [ Time Frame: 0-6 hrs ]
  Estimate a target plasma concentration and IV dose which achieves maximum FEV1 improvement from baseline and FEV1 AUC 0 to 6 hours.
• Area Under the Concentration Time Curve (AUC) [ Time Frame: 5, 15, 30, 45, 60, 120, 180, 240, 360 minutes, and next calendar day after dose ]
  Describe differences in the PK profiles of terbutaline sulfate administered via the SQ route versus the IV route.
• Forced Expiratory Volume in 1 second (FEV1) [ Time Frame: 0-6 hrs ]
  Estimate a target plasma concentration and IV dose which achieves maximum FEV1 improvement from baseline and FEV1 AUC 0 to 6 hours.

Current Secondary Outcome Measures (submitted: July 14, 2021)

• Number of Adverse Events (AEs) [ Time Frame: From baseline through the end of study (Part I up to 60 days, Part II up to 180 days) ]
  Adverse events (AEs) in participants receiving terbutaline sulfate.
• Number of Serious Adverse Events (SAEs) [ Time Frame: From baseline through the end of study (Part I up to 60 days, Part II up to 180 days) ]
  Serious Adverse Events (SAEs) in participants receiving terbutaline sulfate.
• Number of Suspected Unexpected Serious Adverse Reactions (SUSARs) [ Time Frame: From baseline through the end of study (Part I up to 60 days, Part II up to 180 days) ]
  Suspected Unexpected Serious Adverse Reactions (SUSARs) in participants receiving terbutaline sulfate.

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Terbutaline Sulfate in Adults With Asthma
• Official Title: A Prospective, Blinded, Cross-Over Trial of the Exposure-Response Relationship of Terbutaline Sulfate in Adults With Asthma

Brief Summary

The overall aim in Part 1 is to compare the pharmacokinetic (PK)/pharmacodynamics (PD) relationship in intravenous (IV) versus subcutaneous (SQ) terbutaline sulfate to identify the optimal IV dosing range for use in Part 2.

The overall aim in Part 2 is to evaluate the optimal IV dosing of terbutaline sulfate based on PD response and safety data.

Detailed Description

Primary Objectives:

1. Describe differences in the PK profiles of terbutaline sulfate administered via the SQ route versus the IV route.
2. Estimate a target plasma concentration and IV dose which achieves maximum FEV1 improvement from baseline and FEV1 AUC.

Secondary Objective: Describe all adverse events (AEs) in participants receiving terbutaline sulfate.

• Study Type: Interventional
• Study Phase: Phase 2; Phase 3

Study Design

Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description:

A Prospective, Blinded, Cross-over Trial of the Exposure-Response Relationship of Terbutaline Sulfate in Adults with Asthma (TBS02)

Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment

• Condition: Asthma

Intervention

Drug: Terbutaline

management of asthma symptoms

Study Arms

• Experimental: Terbutaline Arm A
  • Arm A: (n=6) IV bolus (0.25 mg) over 5 minutes SQ administration (0.25 mg) Participants in Part 1 Arms A and B (n=12) will be randomized to one of two treatment arms.No masking will be applied for Part 1 or for the SQ dosing in Part 2. All IV treatments in Part 2 will be masked, with exception to the unmasked study pharmacist, refer to the MOP for details.
  Intervention: Drug: Terbutaline
• Experimental: Terbutaline Arm B
  • Arm B: (n=6) SQ administration (0.25 mg) IV bolus (0.25 mg) over 5 minutes Participants in Part 1 Arms A and B (n=12) will be randomized to one of two treatment arms.No masking will be applied for Part 1 or for the SQ dosing in Part 2. All IV treatments in Part 2 will be masked, with exception to the unmasked study pharmacist, refer to the MOP for details.
  Intervention: Drug: Terbutaline
• Experimental: Terbutaline Arm C
  • Arm C: (n=6) SQ (0.25 mg) IV low dose over 5 minutes IV medium dose over 5 minutes IV high dose over 5 minutes Participants in Part 2 (n=18) will be randomized to one of three treatment arms. To maintain masking the first treatment will be 0.25 mg of study drug SQ, followed by one of three IV dose regimes (low, medium, high) below, which are estimated to be 0.1 mg, 0.5 mg, 1.0 mg, but may be adjusted based on the interim analysis completed in Part 1. No masking will be applied for Part 1 or for the SQ dosing in Part 2. All IV treatments in Part 2 will be masked, with exception to the unmasked study pharmacist, refer to the MOP for details.
  Intervention: Drug: Terbutaline
• Experimental: Terbutaline Arm D
  • Arm D: (n=6)SQ (0.25 mg) IV medium dose over 5 minutes IV high dose over 5 minutes IV low dose over 5 minutes Participants in Part 2 (n=18) will be randomized to one of three treatment arms. To maintain masking the first treatment will be 0.25 mg of study drug SQ, followed by one of three IV dose regimes (low, medium, high) below, which are estimated to be 0.1 mg, 0.5 mg, 1.0 mg, but may be adjusted based on the interim analysis completed in Part 1. No masking will be applied for Part 1 or for the SQ dosing in Part 2. All IV treatments in Part 2 will be masked, with exception to the unmasked study pharmacist, refer to the MOP for details.
  Intervention: Drug: Terbutaline
• Experimental: Terbutaline Arm E
  • Arm E: (n=6) SQ (0.25 mg) IV high dose over 5 minutes IV low dose over 5 minutes IV medium dose over 5 minutes Participants in Part 2 (n=18) will be randomized to one of three treatment arms. To maintain masking the first treatment will be 0.25 mg of study drug SQ, followed by one of three IV dose regimes (low, medium, high) below, which are estimated to be 0.1 mg, 0.5 mg, 1.0 mg, but may be adjusted based on the interim analysis completed in Part 1. No masking will be applied for Part 1 or for the SQ dosing in Part 2. All IV treatments in Part 2 will be masked, with exception to the unmasked study pharmacist, refer to the MOP for details.
  Intervention: Drug: Terbutaline

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: July 14, 2021): 30
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: December 2025
• Estimated Primary Completion Date: December 2025 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Participant has provided informed consent
2. History of physician-diagnosed asthma
3. Age ≥18 to <50 at time of consent

4. Past evidence of airway reactivity (within 12 months of consent), defined as:

   • Documentation of ≥10% FEV1 improvement following bronchodilator OR
   • Positive methacholine challenge (20% or more FEV1 decrease at ≤ 16 mg/mL)

5. Evidence of recent asthma symptoms, defined as either:

   • Self-reported use of short-acting beta-agonist (SABA) for asthma symptoms at least twice/week on average over the past month OR
   • Asthma Control Questionnaire, 5-item version (ACQ - 5) ≥ 1.25
6. Willing and able to undergo study procedures and attend required study visits
7. Adequate venous access for blood draws and drug administration, as determined by study investigator, or designee
8. Weight ≥ 40kg
9. FEV1 ≥ 60% predicted on day of terbutaline sulfate dosing
10. Systolic blood pressure (BP) ≤ 150 millimeters of Mercury (mmHg) and diastolic BP ≤ 90 mmHg measured after 10 to 15 minutes of rest
11. Heart rate > 45 and < 110 beats per minute (bpm) measured after 10 to 15 minutes of rest
12. Female participants of child-bearing potential: negative pregnancy test (urine hCG) and agreement to use effective contraception (complete abstinence from vaginal intercourse, combination barrier and spermicide, partner vasectomy, bilateral tubal ligation, intrauterine device (IUD), progestin implants, or hormonal) during study participation

Exclusion Criteria:

1. Self-reported pregnancy or lactating or breastfeeding
2. Previous enrollment in the current study (any part)
3. Any chronic respiratory condition besides asthma (including, but not limited to Chronic Obstructive Pulmonary Disease (COPD), emphysema, or interstitial lung disease) that in the opinion of the Principal Investigator (PI) or clinical site investigator, would make the participant unsuitable for the study
4. Body Mass Index (BMI) > 35 kg/m2 (class II or III obesity)
5. Moderate to severe renal impairment, defined as estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73m2
6. Self-reported smoking (including any vaping/e-cigarettes/marijuana) in past 6 months
7. Greater than 10 pack-year smoking history
8. Any history of cardiac disease (e.g. coronary insufficiency, cardiac arrhythmias), non-skin cancer, clinically diagnosed hypertension, hyperthyroidism, diabetes mellitus or epilepsy
9. History of ocular, brain, abdominal or thoracic surgery in the 12 months prior to screening
10. Known hypersensitivity to terbutaline sulfate
11. Use of any medications from the following classes within 28 days prior to Visit 1: monoamine oxidase inhibitors, tricyclic antidepressants, beta blockers, antihypertensive diuretics, or systemic corticosteroids
12. Self-reported respiratory tract infection in the 14 days prior to Visit 1
13. Any current chronic condition or past history of disease that, in the opinion of the PI would make the participant unsuitable for the study
14. Baseline prolongation of QTc (QTc ≥ 460 ms by Fridericia's formula)
15. Participation in another research study that includes use of any investigational drug treatment within the 30 days prior to Visit 1, or planned participation during the study period.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 50 Years (Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Talaya McCright-Gill, MA; 321 566 3091; talaya.mccright-gill@duke.edu

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT04973345
• Other Study ID Numbers: Pro00113848; Pro00107910 ( Other Identifier: Duke site protocol number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Kanecia Obie Zimmerman, Duke University
• Original Responsible Party: Kanecia Zimmerman, MD MPH, Duke University, Associate Professor of Pediatrics
• Current Study Sponsor: Kanecia Obie Zimmerman
• Original Study Sponsor: Kanecia Zimmerman, MD MPH

Collaborators

• Duke Health
• The Emmes Company, LLC

Investigators

• Principal Investigator: Jason Lang, MD; Duke University

• PRS Account: Duke University
• Verification Date: January 2024