Relative Bioavailability Study to Compare Inhalation of Terbutaline Sulphate 1,5mg Via Turbuhaler M3 With Turbuhaler M2

• Sponsor: AstraZeneca (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02178059
• Collaborator: (none)
• Enrollment: 34
• Location: 1
• Arms: 2
• Duration (Months): 3
• Patients Per Site Per Month: 11.2

Study Details

Study Description

Brief Summary

Relative bioavailability study to compare inhalation of Terbutaline Sulphate 1,5mg via current version of Turbuhaler with inhalation via a new version

Condition or Disease	Intervention/Treatment	Phase
Healthy Volunteers	Drug: terbutaline sulphate delivered dose; Drug: terbutaline sulphate metered dose	Phase 1

Detailed Description

An Open-label, Single-dose, 2-period Cross over Study in Healthy Male and Female Volunteers to Assess Relative Bioavailability of Terbutaline Sulphate 1.5 mg after Inhalation via the M3 Turbuhaler (New Version) Compared with the M2 Turbuhaler (Current Version)

Study Design

• Study Type: Interventional
• Actual Enrollment: 34 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Basic Science
• Official Title: An Open-label, Single-dose, 2-period Cross Over Study in Healthy Volunteers to Assess Relative Bioavailability of Terbutaline Sulphate 1.5 mg After Inhalation Via the M3 Turbuhaler Compared With the M2 Turbuhaler
• Study Start Date: Aug 1, 2014
• Actual Primary Completion Date: Nov 1, 2014
• Actual Study Completion Date: Nov 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Bricanyl Turbuhaler M3 0.4 mg terbutaline sulphate (delivered dose) per inhalation	Drug: terbutaline sulphate delivered dose; 0.4 mg terbutaline sulphate (delivered dose) per inhalation; Other Names: Turbuhaler New Version
Active Comparator: Bricanyl Turbuhaler M2 0.5 mg terbutaline sulphate (metered dose) per inhalation	Drug: terbutaline sulphate metered dose; 0.5 mg terbutaline sulphate (metered dose) per inhalation; Other Names: Turbuhaler Current Version

Outcome Measures

Primary Outcome Measures

1. Area Under the Plasma Concentration-time Curve From Zero to the Time of Last Measurable Concentration [AUC(0-t)] [Samples will be taken at predose, and at 5, 10, 20, 40, 80, 100 minutes and at 2, 4, 6, 9, 12, 18, 24, 30, and 36 hours postdose]

   These will be taken at each treatment period

2. Maximum Observed Plasma Concentration (Cmax) [Samples will be taken at predose, and at 5, 10, 20, 40, 80, 100 minutes and at 2, 4, 6, 9, 12, 18, 24, 30, and 36 hours postdose]

   These will be taken at each treatment period

Secondary Outcome Measures

1. Time to Reach Maximum Observed Plasma Concentration (Tmax) [Samples will be taken at predose, and at 5, 10, 20, 40, 80, 100 minutes and at 2, 4, 6, 9, 12, 18, 24, 30, and 36 hours postdose]

   These will be taken at each treatment period

2. Area Under the Plasma Concentration-time Curve From Zero Extrapolated to Infinity (AUC) [Samples will be taken at predose, and at 5, 10, 20, 40, 80, 100 minutes and at 2, 4, 6, 9, 12, 18, 24, 30, and 36 hours postdose]

   These will be taken at each treatment period

3. Area Under the Plasma Concentration-time Curve From Zero to 36 Hours Postdose [AUC(0-36)] [Samples will be taken at predose, and at 5, 10, 20, 40, 80, 100 minutes and at 2, 4, 6, 9, 12, 18, 24, 30, and 36 hours postdose]

   These will be taken at each treatment period

4. Terminal Half-life (t1/2) [Samples will be taken at predose, and at 5, 10, 20, 40, 80, 100 minutes and at 2, 4, 6, 9, 12, 18, 24, 30, and 36 hours postdose]

   These will be taken at each treatment period

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

1. Female and male volunteers aged between 18 and 65 years, both inclusive

2. Healthy as judged by the Principal Investigator after medical history, physical examination, 12-lead ECG, laboratory tests (including HIV, HBsAg and hepatitis C antibody tests) and assessments of pulse rate and blood pressure

3. Ability to use a Turbuhaler according to the provided instructions, as judged by the Principal Investigator or the study nurse

4. Have a body mass index (BMI) between 18 and 30 kg/m2 inclusive and weighing at least 50 kg and no more than 100 kg -

Exclusion Criteria:

1. History or presence of respiratory, gastrointestinal, hepatic or renal disease or any other condition known to interfere with absorption, distribution, metabolism or excretion of drugs (except for cholecystectomy)

2. Current smokers or those who have smoked or used nicotine products within the previous 3 months should be excluded

3. Plasma donation within 1 month of screening or any blood donation or blood loss of more than 500 mL during the 3 months prior to screening

4. History of severe allergy/hypersensitivity or ongoing allergy/hypersensitivity, as judged by the Principal Investigator or history of hypersensitivity to terbutaline (or drugs of a similar chemical structure or class) or inhaled lactose

5. Positive screen for drugs of abuse and/or alcohol and/or cotinine at screening (Visit

1. or on admission to the study centre (Day -1) prior to administration of the investigational medical product (IMP) on Day 1 -

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	London		United Kingdom

Sponsors and Collaborators

• AstraZeneca

Investigators

• Principal Investigator: Amitava Ganguli, MB ChB, MRCP, Quintiles London United Kingdom
• Study Director: Göran Eckervall, MD, Astrazeneca Mölndal, Sweden
• Study Chair: Ola Beckman, MD, Astrazeneca Mölndal, Sweden

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT02178059
• Other Study ID Numbers: D4711C00002
• First Posted: Jun 30, 2014
• Last Update Posted: Mar 1, 2017
• Last Verified: Jan 1, 2017

• Keywords provided by AstraZeneca: Healthy volunteers, pharmacokinetic, inhalation
• Additional relevant MeSH terms: Respiratory Aspiration; Terbutaline

Study Results

Participant Flow

Recruitment Details	This was a single centre study conducted in the UK.
Pre-assignment Detail	Healthy subjects were assessed for eligibility at a screening visit (Visit 1) within 28 days of administration of the first dose of terbutaline via Bricanyl Turbuhaler M2 or Bricanyl Turbuhaler M3 (Visit 2). Subjects were randomly assigned to 1 of 2 treatment sequences: M3 then M2 or M2 then M3

Arm/Group Title	M3 First, Then M2	M2 First, Then M3
Arm/Group Description	Sequence 1: M3 first then M2	Sequence 2: M2 first, then M3
Period Title: First Intervention
STARTED	17	17
COMPLETED	17	17
NOT COMPLETED	0	0
Period Title: First Intervention
STARTED	17	17
COMPLETED	16	17
NOT COMPLETED	1	0
Period Title: First Intervention
STARTED	16	17
COMPLETED	16	17
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Randomized Subjects
Arm/Group Description	All randomized subjects
Overall Participants	34
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	42 (11)
Gender (Count of Participants)
Female	18 52.9%
Male	16 47.1%

Outcome Measures

1. Primary Outcome

Title	Area Under the Plasma Concentration-time Curve From Zero to the Time of Last Measurable Concentration [AUC(0-t)]
Description	These will be taken at each treatment period
Time Frame	Samples will be taken at predose, and at 5, 10, 20, 40, 80, 100 minutes and at 2, 4, 6, 9, 12, 18, 24, 30, and 36 hours postdose

Outcome Measure Data

Analysis Population Description

The PK analysis set included all healthy subjects who received at least 1 dose of the IMP and had at least 1 postdose PK measurement without important protocol deviations/violations or events thought to significantly affect the PK of the IMP.

Arm/Group Title	Bricanyl Turbuhaler M3	Bricanyl Turbuhaler M2
Arm/Group Description	Bricanyl Turbuhaler M3: 0.4 mg terbutaline sulphate (delivered dose) per inhalation	Bricanyl Turbuhaler M2: 0.5 mg terbutaline sulphate (metered dose) per inhalation
Measure Participants	34	33
Geometric Mean (95% Confidence Interval) [nmol*h/L]	89.04	100.9

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bricanyl Turbuhaler M3, Bricanyl Turbuhaler M2
	Comments	No increase in the exposure of plasma terbutaline after administration of Bricanyl Turbuhaler M3 will be concluded if the upper bound of the 90% CIs for the ratios of AUC and Cmax are both below 1.25
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Approximately 34 healthy volunteers will be entered into the study in order to complete 30 evaluable volunteers. Based on the study SD-001-0268, a residual intra-individual standard deviation of 0.300/sqrt(2) = 0.212 can be expected on the natural log scale. With 30 completed volunteers there will be a 93% chance that the upper limits of two-sided 90% CI for Cmax and AUC ratios are <1.25 provided that the true mean ratios are <1.05.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of geometric means (%)
	Estimated Value	88.20
	Confidence Interval	(2-Sided) 90%; 81.03 to 96.02
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison of Bricanyl Turbuhaler M3 (test) to Bricanyl Turbuhaler M2 (reference)

2. Secondary Outcome

Title	Time to Reach Maximum Observed Plasma Concentration (Tmax)
Description	These will be taken at each treatment period
Time Frame	Samples will be taken at predose, and at 5, 10, 20, 40, 80, 100 minutes and at 2, 4, 6, 9, 12, 18, 24, 30, and 36 hours postdose

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Bricanyl Turbuhaler M3	Bricanyl Turbuhaler M2
Arm/Group Description	Bricanyl Turbuhaler M3: 0.4 mg terbutaline sulphate (delivered dose) per inhalation	Bricanyl Turbuhaler M2: 0.5 mg terbutaline sulphate (metered dose) per inhalation
Measure Participants	34	33
Median (95% Confidence Interval) [hour]	1.33	1.33

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bricanyl Turbuhaler M3, Bricanyl Turbuhaler M2
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.8052
	Comments
	Method	Wilcoxon signed rank test
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	0.00
	Confidence Interval	(2-Sided) 90%; -0.17 to 0.17
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Area Under the Plasma Concentration-time Curve From Zero Extrapolated to Infinity (AUC)
Description	These will be taken at each treatment period
Time Frame	Samples will be taken at predose, and at 5, 10, 20, 40, 80, 100 minutes and at 2, 4, 6, 9, 12, 18, 24, 30, and 36 hours postdose

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Bricanyl Turbuhaler M3	Bricanyl Turbuhaler M2
Arm/Group Description	Bricanyl Turbuhaler M3: 0.4 mg terbutaline sulphate (delivered dose) per inhalation	Bricanyl Turbuhaler M2: 0.5 mg terbutaline sulphate (metered dose) per inhalation
Measure Participants	34	33
Geometric Mean (95% Confidence Interval) [nmol*h/L]	96.63	109.7

4. Secondary Outcome

Title	Area Under the Plasma Concentration-time Curve From Zero to 36 Hours Postdose [AUC(0-36)]
Description	These will be taken at each treatment period
Time Frame	Samples will be taken at predose, and at 5, 10, 20, 40, 80, 100 minutes and at 2, 4, 6, 9, 12, 18, 24, 30, and 36 hours postdose

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Bricanyl Turbuhaler M3	Bricanyl Turbuhaler M2
Arm/Group Description	Bricanyl Turbuhaler M3: 0.4 mg terbutaline sulphate (delivered dose) per inhalation	Bricanyl Turbuhaler M2: 0.5 mg terbutaline sulphate (metered dose) per inhalation
Measure Participants	34	33
Geometric Mean (Geometric Coefficient of Variation) [nmol*h/L]	89.0 (29.5)	101 (27.8)

5. Secondary Outcome

Title	Terminal Half-life (t1/2)
Description	These will be taken at each treatment period
Time Frame	Samples will be taken at predose, and at 5, 10, 20, 40, 80, 100 minutes and at 2, 4, 6, 9, 12, 18, 24, 30, and 36 hours postdose

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Bricanyl Turbuhaler M3	Bricanyl Turbuhaler M2
Arm/Group Description	Bricanyl Turbuhaler M3: 0.4 mg terbutaline sulphate (delivered dose) per inhalation	Bricanyl Turbuhaler M2: 0.5 mg terbutaline sulphate (metered dose) per inhalation
Measure Participants	34	33
Geometric Mean (Geometric Coefficient of Variation) [hour]	11.7 (8.9)	11.8 (10.9)

6. Primary Outcome

Title	Maximum Observed Plasma Concentration (Cmax)
Description	These will be taken at each treatment period
Time Frame	Samples will be taken at predose, and at 5, 10, 20, 40, 80, 100 minutes and at 2, 4, 6, 9, 12, 18, 24, 30, and 36 hours postdose

Outcome Measure Data

Analysis Population Description

The PK analysis set included all healthy subjects who received at least 1 dose of the IMP and had at least 1 postdose PK measurement without important protocol deviations/violations or events thought to significantly affect the PK of the IMP.

Arm/Group Title	Bricanyl Turbuhaler M3	Bricanyl Turbuhaler M2
Arm/Group Description	Bricanyl Turbuhaler M3: 0.4 mg terbutaline sulphate (delivered dose) per inhalation	Bricanyl Turbuhaler M2: 0.5 mg terbutaline sulphate (metered dose) per inhalation
Measure Participants	34	33
Geometric Mean (95% Confidence Interval) [nmol/L]	12.00	13.12

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bricanyl Turbuhaler M3, Bricanyl Turbuhaler M2
	Comments	No increase in the exposure of plasma terbutaline after administration of Bricanyl Turbuhaler M3 will be concluded if the upper bound of the 90% CIs for the ratios of AUC and Cmax are both below 1.25
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Approximately 34 healthy volunteers will be entered into the study in order to complete 30 evaluable volunteers. Based on the study SD-001-0268, a residual intra-individual standard deviation of 0.300/sqrt(2) = 0.212 can be expected on the natural log scale. With 30 completed volunteers there will be a 93% chance that the upper limits of two-sided 90% CI for Cmax and AUC ratios are <1.25 provided that the true mean ratios are <1.05.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of geometric means (%)
	Estimated Value	91.44
	Confidence Interval	(2-Sided) 90%; 84.82 to 98.58
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison of Bricanyl Turbuhaler M3 (test) to Bricanyl Turbuhaler M2 (reference)

Adverse Events

Arm/Group Title	Bricanyl Turbuhaler M3		Bricanyl Turbuhaler M2
Arm/Group Description	Bricanyl Turbuhaler M3: 0.4 mg terbutaline sulphate (delivered dose) per inhalation		Bricanyl Turbuhaler M2: 0.5 mg terbutaline sulphate (metered dose) per inhalation
All Cause Mortality
	Bricanyl Turbuhaler M3		Bricanyl Turbuhaler M2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Bricanyl Turbuhaler M3		Bricanyl Turbuhaler M2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/34 (0%)		0/33 (0%)
Other (Not Including Serious) Adverse Events
	Bricanyl Turbuhaler M3		Bricanyl Turbuhaler M2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	12/34 (35.3%)		11/33 (33.3%)
Musculoskeletal and connective tissue disorders
Back Pain	2/34 (5.9%)	2	0/33 (0%)	0
Nervous system disorders
Headache	9/34 (26.5%)	10	7/33 (21.2%)	8
Dizziness	2/34 (5.9%)	2	4/33 (12.1%)	4

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

If a publication (e.g., in a scientific journal) based on the results of this study is envisaged, approval from AstraZeneca will be obtained and a draft manuscript will be submitted to AstraZeneca for scrutiny and comment. The choice of conduit will be mutually agreed on by the Principal Investigator and AstraZeneca.