Terbutaline Sulfate in Adults With Asthma

Study Overview
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Brief Summary
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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
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Primary Objectives: Describe differences in the PK profiles of terbutaline sulfate administered via the SQ route versus the IV route. 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.

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

Conditions
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Asthma

Intervention / Treatment
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* Drug: Terbutaline


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant has provided informed consent History of physician-diagnosed asthma Age ≥18 to <50 at time of consent 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) 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 Willing and able to undergo study procedures and attend required study visits Adequate venous access for blood draws and drug administration, as determined by study investigator, or designee Weight ≥ 40kg FEV1 ≥ 60% predicted on day of terbutaline sulfate dosing Systolic blood pressure (BP) ≤ 150 millimeters of Mercury (mmHg) and diastolic BP ≤ 90 mmHg measured after 10 to 15 minutes of rest Heart rate > 45 and < 110 beats per minute (bpm) measured after 10 to 15 minutes of rest 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: Self-reported pregnancy or lactating or breastfeeding Previous enrollment in the current study (any part) 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 Body Mass Index (BMI) > 35 kg/m2 (class II or III obesity) Moderate to severe renal impairment, defined as estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73m2 Self-reported smoking (including any vaping/e-cigarettes/marijuana) in past 6 months Greater than 10 pack-year smoking history Any history of cardiac disease (e.g. coronary insufficiency, cardiac arrhythmias), non-skin cancer, clinically diagnosed hypertension, hyperthyroidism, diabetes mellitus or epilepsy History of ocular, brain, abdominal or thoracic surgery in the 12 months prior to screening Known hypersensitivity to terbutaline sulfate 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 Self-reported respiratory tract infection in the 14 days prior to Visit 1 Any current chronic condition or past history of disease that, in the opinion of the PI would make the participant unsuitable for the study Baseline prolongation of QTc (QTc ≥ 460 ms by Fridericia's formula) 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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: A Prospective, Blinded, Cross-over Trial of the Exposure-Response Relationship of Terbutaline Sulfate in Adults with Asthma (TBS02)
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Terbutaline Arm A<br>• 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<br>* management of asthma symptoms<br>|
| Experimental: Terbutaline Arm B<br>• 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<br>* management of asthma symptoms<br>|
| Experimental: Terbutaline Arm C<br>• 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<br>* management of asthma symptoms<br>|
| Experimental: Terbutaline Arm D<br>• 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<br>* management of asthma symptoms<br>|
| Experimental: Terbutaline Arm E<br>• 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<br>* management of asthma symptoms<br>|

What is the study measuring?
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Primary Outcome Measures

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

Secondary Outcome Measures

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