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

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Asthma	Drug: Terbutaline	Phase 2; Phase 3

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 30 participants
• 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
• Official Title: A Prospective, Blinded, Cross-Over Trial of the Exposure-Response Relationship of Terbutaline Sulfate in Adults With Asthma
• Actual Study Start Date: July 7, 2023
• Estimated Primary Completion Date: December 2025
• Estimated Study Completion Date: December 2025

Arms and Interventions

Arm	Intervention/treatment
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.	Drug: Terbutaline; management of asthma symptoms
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.	Drug: Terbutaline; management of asthma symptoms
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.	Drug: Terbutaline; management of asthma symptoms
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.	Drug: Terbutaline; management of asthma symptoms
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.	Drug: Terbutaline; management of asthma symptoms

Outcome Measures

Primary Outcome Measures :

1. 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.
2. 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.
3. 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
4. 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
5. 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
6. 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.
7. 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.
8. 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.

Secondary Outcome Measures :

1. 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.
2. 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.
3. 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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 50 Years (Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Contacts

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

Locations

United States, North Carolina

Duke Early Phase Research Unit (DEPRU); Recruiting

Durham, North Carolina, United States, 27710

Contact: Jane Stiles 919-684-1672

Principal Investigator: Shruti Raja, MD, MHS

Sponsors and Collaborators

Kanecia Obie Zimmerman

Duke Health

The Emmes Company, LLC

Investigators

• Principal Investigator: Jason Lang, MD; Duke University

More Information

• Responsible Party: Kanecia Obie Zimmerman, Associate Professor of Pediatrics, Duke University
• ClinicalTrials.gov Identifier: NCT04973345
• Other Study ID Numbers: Pro00113848; Pro00107910 ( Other Identifier: Duke site protocol number )
• First Posted: July 22, 2021
• Last Update Posted: January 3, 2024
• Last Verified: January 2024

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• 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

Additional relevant MeSH terms:

Asthma; Bronchial Diseases; Respiratory Tract Diseases; Lung Diseases, Obstructive; Lung Diseases; Respiratory Hypersensitivity; Hypersensitivity, Immediate; Hypersensitivity; Immune System Diseases; Terbutaline; Bronchodilator Agents; Autonomic Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Anti-Asthmatic Agents; Respiratory System Agents; Sympathomimetics; Tocolytic Agents; Reproductive Control Agents; Adrenergic beta-2 Receptor Agonists; Adrenergic beta-Agonists; Adrenergic Agonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action