A Clinical Study to Evaluate Z7200 (Budesonide/Formoterol) Pharmacokinetics Profile in Healthy Volunteers

Asthma Clinical Trial

Official title:

An Open-Label, Single-dose, Randomized, Five-Period Cross-over to Compare Pharmacokinetics Profiles of Z7200 and Symbicort Turbohaler, With and Without Charcoal Blockade in Healthy Volunteers.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02237508
• Other study ID #: Z7200J02
• Secondary ID: 2014-002081-69
• Status: Completed
• Phase: Phase 1
• Start date: September 2014
• Est. completion date: February 2015

Study information

• Verified date: February 2022
• Source: Zambon SpA
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The primary objective was:

• to assess the bioequivalence of a single dose (two inhalations) of the test product compared to the reference product, with and without charcoal blockade.

The secondary objectives were:

• to assess the pharmacokinetic profile of budesonide and formoterol in plasma after a single dose (two inhalations) of the test product and the reference product, with and without charcoal blockade.

• to assess the safety and tolerability of the test product and the reference product, with and without charcoal blockade.

Description:

This was a single center, open label, randomized, five-period crossover, single-dose study in healthy volunteers aged 18 to 45 years. A total of 90 volunteers were enrolled, with 9 subjects in each of the 10 treatment sequences.

The study consisted of 5 treatment periods, each lasting approximately 48h, separated by a washout period of a minimum of 5 days. RS01 and/or Symbicort Turbohaler device use training was provided on Day -1 and Day 1 of each treatment period. Subjects were screened for eligibility to participate in the study -28 to -2 days prior to the first treatment period, and were randomized to one of 10 treatment sequencies containing the following 5 treatment arms on Day 1 of the first treatment period:

Treatment A: Z7200 without oral activated charcoal* Treatment B1: Symbicort 1 without oral activated charcoal* Treatment B2: Symbicort 2 without oral activated charcoal* Treatment C: Z7200 with oral activated charcoal** Treatment D: Symbicort with oral activated charcoal**

Subjects were admitted to the clinical unit at 8.00 on the morning of Day -1, and were dosed on the morning of Day 1 following an overnight fast (minimum of 8h). On Day 2, following collection of the 24-h PK blood sample, subjects were discharged.

• Subjects who received treatments A, B1 and B2 rinsed their mouth vigorously with 50 mL water for 3 to 5 sec immediately after the second inhalation.

** A charcoal blockade was used to prevent absorption from oropharyngeal and GI tract, in order to assess the pulmonary deposition of budesonide and formoterol, with periods performed without a charcoal blockade allowing the assessment of the total systemic exposure to the drug.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 90
• Est. completion date: February 2015
• Est. primary completion date: February 2015
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 45 Years

Eligibility

Main Inclusion Criteria:

• Male or female 18 to 45 years of age.

• If female, is currently not pregnant/breast feeding/ or attempting to become pregnant has a negative serum pregnancy test, or is of non-childbearing potential or is of child-bearing potential, willing to commit to using a consistent and acceptable method of birth control or is of child-bearing potential and not sexually active

• Body mass index (BMI) of 18.5 to 29.9 kg/m² inclusive and a body weight =50 kg.

Main Exclusion Criteria:

• FEV1 value less than 80% of the predicted value and FEV1/FVC ratio <0.7.

• History or current evidence of a clinically significant disease or disorder capable of altering the absorption, metabolism, distribution or elimination of drugs.

• History or current evidence of a clinically significant disease including, but not limited to: cardiovascular, hepatic, renal, haematological, neuropsychological, endocrine, gastrointestinal or pulmonary.

• Presence of glaucoma, cataracts, ocular herpes simplex, malignancy, regardless of the clinical significance or current stability of the disease.

• History or presence of silent infections, including positive tests for HIV1, HIV2, Hepatitis B and Hepatitis C.

• Bacterial or viral infection of the upper respiratory tract (including the common cold and flu), sinus, or middle ear within 2 weeks of dosing.

• Lower respiratory tract infection/pneumonia within the past 3 months.

• Presence of any disease or condition or regular concomitant treatment (including vitamins and herbal products) known to interfere with the absorption, distribution, metabolism or excretion of drugs.

• Screening haemoglobin value of less than 1g/dL above the ULN (or 10g/L)

• History of recurrent vasovagal collapses.

• History of anaphylactic/anaphylactoid reactions.

• History of seizures including febrile seizures excluding childhood febrile convulsions.

• Unable to demonstrate proper inhalation techniques involved in using the delivery devices at screening.

• Exposure to any investigational drug within 90 days of the Screening Visit.

• Known or suspected hypersensitivity or idiosyncratic reaction to any steroid, any ß2 agonist,or to lactose monohydrate, leucine or Tween 80.

• History of allergy to milk protein.

• Use of an inhaled corticosteroid within 30 days or systemic corticosteroid within 60 days of the Screening Visit.

• Use of medications or herbal medicines that are strong cytochrome P450 3A4 (CYP3A4) inhibitors or inducers within 30 days prior to Screening Visit

• Any clinically significant abnormal laboratory value or physical finding that may interfere with the interpretation of test results or cause a health risk for the subject if he/she participates in the study.

• Use of caffeine containing beverages more than 600 mg of caffeine/day.

• Current smokers or ex-smokers who have stopped smoking for less than 10 years.

• Recent or current (suspected) drug abuse or positive result in the drugs abuse test.

• Recent or current alcohol abuse (regular drinking more than 21 units per week for males and more than 14 units per week for females [1 unit = 4 cl spirits or equivalent]).

• Predictable poor compliance, intolerance to charcoal solution, or inability to communicate well with the study centre personnel or inability to participate in all treatment periods.

• The subject is not able to understand and comply with protocol requirements, instructions and protocol-stated restrictions, has participated in a clinical research study within the previous three months or has previously been enrolled in this study.

Related Conditions & MeSH terms

• Asthma

Intervention

Drug:
• Z7200 without oral activated charcoal
160 ug budesonide and 4.5 ug formoterol fumarate dihydrate, administered as two inhalations (2 x Z7200 capsules) of budesonide 80 ug/inhalation and formoterol 2.25 ug/inhalation, using an RS01 inhaler (Treatment A).
• Symbicort Turbohaler without oral activated charcoal
320 ug budesonide and 9 ug formoterol fumarate dihydrate, administered as two inhalations of budesonide 160 ug/inhalation and formoterol 4.5 ug/inhalation (Treatments B1 and B2).
• Z7200 with oral activated charcoal
160 ug budesonide and 4.5 ug formoterol fumarate dihydrate, administered as two inhalations (2 x Z7200 capsules) of budesonide 80 ug/inhalation and formoterol 2.25 ug/inhalation, using an RS01 inhaler with a charcoal blockade (Treatment C).
• Symbicort Turbohaler with oral activated charcoal
320 ug budesonide and 9 ug formoterol fumarate dihydrate, administered as two inhalations of budesonide 160 ug/inhalation and formoterol 4.5 ug/inhalation from a Symbicort Turbohaler, with charcoal blockade (Treatment D).

Locations

Country	Name	City	State
United Kingdom	Quotient Clinical Ltd	Ruddington

Sponsors (1)

Lead Sponsor	Collaborator
Zambon SpA

Country where clinical trial is conducted

United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	AUC0-t of Budesonide With and Without Charcoal Blockade	Area under the plasma concentration-time curve from time zero to the last detectable level calculations were performed using the linear trapezoidal rule.; Participants for the Treatment B are counted for both Symbicort 1 and Symbicort 2, together.	0-24h (0, 2, 5, 10, 15, 20, 30, 45, 60, 90, 120, 180, 240, 360, 480, 600, 720, and 1440 min)
Primary	AUC0-t of Formoterol With and Without Charcoal Blockade	Area under the plasma concentration-time curve from time zero to the last detectable level calculations were performed using the linear trapezoidal rule.; Participants for the Treatment B are counted for both Symbicort 1 and Symbicort 2, together.	0-24h (0, 2, 5, 10, 15, 20, 30, 45, 60, 90, 120, 180, 240, 360, 480, 600, 720, and 1440 min)
Primary	Cmax of Budesonide With and Without Charcoal Blockade	Maximum plasma level of budesonide with and without charcoal blockade. Participants for the Treatment B are counted for both Symbicort 1 and Symbicort 2, together.	0-24h (0, 2, 5, 10, 15, 20, 30, 45, 60, 90, 120, 180, 240, 360, 480, 600, 720, and 1440 min)
Primary	Cmax of Formoterol With and Without Charcoal Blockade	Maximum plasma level of formoterol with and without charcoal blockade. Participants for the Treatment B are counted for both Symbicort 1 and Symbicort 2, together.	0-24h (0, 2, 5, 10, 15, 20, 30, 45, 60, 90, 120, 180, 240, 360, 480, 600, 720, and 1440 min)
Secondary	AUC0-30 of Budesonide With and Without Charcoal Blockade.	Area under the plasma concentration-time curve from time zero to 30 minutes calculations were performed using the linear trapezoidal rule.; Participants for the Treatment B are counted for both Symbicort 1 and Symbicort 2, together.	0-30 min (0, 2, 5, 10, 15, 20, and 30 min)
Secondary	AUC0-30 of Formoterol With and Without Charcoal Blockade.	Area under the plasma concentration-time curve from time zero to 30 minutes calculations were performed using the linear trapezoidal rule.; Participants for the Treatment B are counted for both Symbicort 1 and Symbicort 2, together.	0-30 min (0, 2, 5, 10, 15, 20, and 30 min)
Secondary	AUC0-8 of Budesonide With and Without Charcoal Blockade	Area under the plasma concentration-time curve from time zero to infinity calculations were performed using the linear trapezoidal rule.; Participants for the Treatment B are counted for both Symbicort 1 and Symbicort 2, together.	0-24h (0, 2, 5, 10, 15, 20, 30, 45, 60, 90, 120, 180, 240, 360, 480, 600, 720, and 1440 min)
Secondary	AUC0-8 of Formoterol With and Without Charcoal Blockade	Area under the plasma concentration-time curve from time zero to infinity calculations were performed using the linear trapezoidal rule.; Participants for the Treatment B are counted for both Symbicort 1 and Symbicort 2, together.	0-24h (0, 2, 5, 10, 15, 20, 30, 45, 60, 90, 120, 180, 240, 360, 480, 600, 720, and 1440 min)
Secondary	Tmax for Budesonide With and Without Charcoal Blockade	Time at which the maximum plasma level (Cmax) occurred with and without charcoal blockade.; Participants for the Treatment B are counted for both Symbicort 1 and Symbicort 2, together.	0-24h (0, 2, 5, 10, 15, 20, 30, 45, 60, 90, 120, 180, 240, 360, 480, 600, 720, and 1440 min)
Secondary	Tmax for Formoterol With and Without Charcoal Blockade	Time at which the maximum plasma level (Cmax) occurred with and without charcoal blockade.; Participants for the Treatment B are counted for both Symbicort 1 and Symbicort 2, together.	0-24h (0, 2, 5, 10, 15, 20, 30, 45, 60, 90, 120, 180, 240, 360, 480, 600, 720, and 1440 min)
Secondary	t1/2 for Budesonide With and Without Charcoal Blockade	Apparent elimination half-life calculated as 0.693/lambda zeta, with and without charcoal blockade.; Participants for the Treatment B are counted for both Symbicort 1 and Symbicort 2, together.	0-24h (0, 2, 5, 10, 15, 20, 30, 45, 60, 90, 120, 180, 240, 360, 480, 600, 720, and 1440 min)
Secondary	t1/2 for Formoterol With and Without Charcoal Blockade	Apparent elimination half-life calculated as 0.693/lambda zeta, with and without charcoal blockade.; Participants for the Treatment B are counted for both Symbicort 1 and Symbicort 2, together.	0-24h (0, 2, 5, 10, 15, 20, 30, 45, 60, 90, 120, 180, 240, 360, 480, 600, 720, and 1440 min)
Secondary	Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1)	FEV1 refers to the volume of air that an individual can exhale during a forced breath in 1 second.; Participants for the Treatment B are counted for both Symbicort 1 and Symbicort 2, together.; and Symbicort 2, together. Please note that, within the safety population, 90 subjects received Treatment B. This would mean that theorically 180 participants received Symbicort 1 and Symbicort 2, together.; But some subjects were excluded from the statistical analysis for various reasons so that the total number included in the statistical anlysis for treatment B is 174.	At 75 min (1.25 hours) post-dose
Secondary	Change From Baseline in the Ratio of Forced Expiratory Volume in 1 Second to Forced Vital Capacity (FEV1/FVC)	FVC = Forced vital capacity. It is the full amount of air that can be exhaled with effort in a complete breath.; FEV1/FVC = Tiffenau-Pinelli Index. This parameter represents the measurement of the amount of air an individual can forcefully exhale from his/her lungs.; Participants for the Treatment B are counted for both Symbicort 1 and Symbicort 2, together.; Please note that, within the safety population, 90 subjects received Treatment B. This would mean that theorically 180 participants received Symbicort 1 and Symbicort 2, together.; But 6 subjects were excluded from the statistical analysis for various reasons so that the total number included in the statistical anlysis for treatment B is 174.	At 75 min (1.25 hours) post-dose
Secondary	Change From Baseline in Peak Expiratory Flow Rate (PEFR)	PEFR is the highest rate at which gases can be expelled from the lungs via an open mouth. Its measurement is a simple procedure in which an individual takes a full inspiration and blows out as forcibly as possible into an instrument called a peak flow meter, which measures the maximal gas flow in an exhalation in liters per minute.; Participants for the Treatment B are counted for both Symbicort 1 and Symbicort 2, together.Please note that, within the safety population, 90 subjects received Treatment B. This would mean that theorically 180 participants received Symbicort 1 and Symbicort 2, together. But 6 subjects were excluded from the statistical analysis for various reasons so that the total number included in the statistical anlysis for treatment B is 174.	At 75 min (1.25 hours) post-dose