Clinical Study to Evaluate Z7200 Pharmacokinetics Profile

Zambon

Status and phase: Completed; Phase 1

Conditions: Asthma

Treatments: Drug: Z7200 with oral activated charcoal; Drug: Z7200 without oral activated charcoal; Drug: Symbicort Turbohaler with oral activated charcoal; Drug: Symbicort Turbohaler without oral activated charcoal

Study type: Interventional

Funder types: Industry

Identifiers

NCT02631941

Z7200J04

2015-003233-95 (EudraCT Number)

Details and patient eligibility

About

Brief 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.

Full 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 planned to be 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 sequences 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.

Enrollment: 91 patients

Sex: All

Ages: 18 to 45 years old

Volunteers: Accepts Healthy Volunteers

Inclusion and exclusion criteria

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 18.0 to 32.0 kg/m² inclusive and a body weight ≥50 kg.
• 10 years or more past history of cigarette, <=5 pack year

Main Exclusion Criteria:

• Forced Expiratory Volume in 1 sec (FEV1) value less than 80% of the predicted value and FEV1/FVC (Forced Vital Capacity) 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.
• positive tests for Human Immunodeficiency Virus (HIV), 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 Lower Limit of Normality
• 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 β2 agonist; 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 5 cups/day.
• 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)
• 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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Crossover Assignment

Masking: None (Open label)

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91 participants in 10 patient groups

A-B1-B2-C-D

Experimental group

Description:

Subjects were dosed on Day 1 of each treatment period with one of the following 5 treatments according to the randomization schedule using a Williams Latin Square design: 1. Treatment A: Z7200 without oral activated charcoal 2. Treatment B1: Symbicort 1 without oral activated charcoal 3. Treatment B2: Symbicort 2 without oral activated charcoal 4. Treatment C: Z7200 with oral activated charcoal 5. Treatment D: Symbicort with oral activated charcoal A washout period of a minimum of 5 days followed treatment periods 1 to 4. Treatment B1 and B2 denote Symbicort without oral activated charcoal administered in two different period, designated as Symbicort 1 and Symbicort 2.

Treatment:

Drug: Symbicort Turbohaler without oral activated charcoal

Drug: Symbicort Turbohaler with oral activated charcoal

Drug: Z7200 with oral activated charcoal

Drug: Z7200 without oral activated charcoal

B1-C-A-D-B2

Experimental group

Description:

Subjects were dosed on Day 1 of each treatment period with one of the following five treatments according to the randomization schedule using a Williams Latin Square design: 1. Treatment A: Z7200 without oral activated charcoal 2. Treatment B1: Symbicort 1 without oral activated charcoal 3. Treatment B2: Symbicort 2 without oral activated charcoal 4. Treatment C: Z7200 with oral activated charcoal 5. Treatment D: Symbicort with oral activated charcoal A washout period of a minimum of 5 day followed treatment periods 1 to 4. Treatment B1 and B2 denote Symbicort without oral activated charcoal administered in two different period, designated as Symbicort 1 and Symbicort 2.

Treatment:

Drug: Symbicort Turbohaler without oral activated charcoal

Drug: Symbicort Turbohaler with oral activated charcoal

Drug: Z7200 with oral activated charcoal

Drug: Z7200 without oral activated charcoal

C-D-B1-B2-A

Experimental group

Description:

Subjects were dosed on Day 1 of each treatment period with one of the following five treatments according to the randomization schedule using a Williams Latin Square design: 1. Treatment A: Z7200 without oral activated charcoal 2. Treatment B1: Symbicort 1 without oral activated charcoal 3. Treatment B2: Symbicort 2 without oral activated charcoal 4. Treatment C: Z7200 with oral activated charcoal 5. Treatment D: Symbicort with oral activated charcoal A washout period of a minimum of 5 day followed treatment periods 1 to 4. Treatment B1 and B2 denote Symbicort without oral activated charcoal administered in two different period, designated as Symbicort 1 and Symbicort 2.

Treatment:

Drug: Symbicort Turbohaler without oral activated charcoal

Drug: Symbicort Turbohaler with oral activated charcoal

Drug: Z7200 with oral activated charcoal

Drug: Z7200 without oral activated charcoal

D-B2-C-A-B1

Experimental group

Description:

Subjects were dosed on Day 1 of each treatment period with one of the following five treatments according to the randomization schedule using a Williams Latin Square design: 1. Treatment A: Z7200 without oral activated charcoal 2. Treatment B1: Symbicort 1 without oral activated charcoal 3. Treatment B2: Symbicort 2 without oral activated charcoal 4. Treatment C: Z7200 with oral activated charcoal 5. Treatment D: Symbicort with oral activated charcoal A washout period of a minimum of 5 day followed treatment periods 1 to 4. Treatment B1 and B2 denote Symbicort without oral activated charcoal administered in two different period, designated as Symbicort 1 and Symbicort 2.

Treatment:

Drug: Symbicort Turbohaler without oral activated charcoal

Drug: Symbicort Turbohaler with oral activated charcoal

Drug: Z7200 with oral activated charcoal

Drug: Z7200 without oral activated charcoal

B2-A-D-B1-C

Experimental group

Description:

Subjects were dosed on Day 1 of each treatment period with one of the following five treatments according to the randomization schedule using a Williams Latin Square design: 1. Treatment A: Z7200 without oral activated charcoal 2. Treatment B1: Symbicort 1 without oral activated charcoal 3. Treatment B2: Symbicort 2 without oral activated charcoal 4. Treatment C: Z7200 with oral activated charcoal 5. Treatment D: Symbicort with oral activated charcoal A washout period of a minimum of 5 day followed treatment periods 1 to 4. Treatment B1 and B2 denote Symbicort without oral activated charcoal administered in two different period, designated as Symbicort 1 and Symbicort 2.

Treatment:

Drug: Symbicort Turbohaler without oral activated charcoal

Drug: Symbicort Turbohaler with oral activated charcoal

Drug: Z7200 with oral activated charcoal

Drug: Z7200 without oral activated charcoal

D-C-B2-B1-A

Experimental group

Description:

Subjects were dosed on Day 1 of each treatment period with one of the following five treatments according to the randomization schedule using a Williams Latin Square design: 1. Treatment A: Z7200 without oral activated charcoal 2. Treatment B1: Symbicort 1 without oral activated charcoal 3. Treatment B2: Symbicort 2 without oral activated charcoal 4. Treatment C: Z7200 with oral activated charcoal 5. Treatment D: Symbicort with oral activated charcoal A washout period of a minimum of 5 day followed treatment periods 1 to 4. Treatment B1 and B2 denote Symbicort without oral activated charcoal administered in two different period, designated as Symbicort 1 and Symbicort 2.

Treatment:

Drug: Symbicort Turbohaler without oral activated charcoal

Drug: Symbicort Turbohaler with oral activated charcoal

Drug: Z7200 with oral activated charcoal

Drug: Z7200 without oral activated charcoal

B2-D-A-C-B1

Experimental group

Description:

Subjects were dosed on Day 1 of each treatment period with one of the following five treatments according to the randomization schedule using a Williams Latin Square design: 1. Treatment A: Z7200 without oral activated charcoal 2. Treatment B1: Symbicort 1 without oral activated charcoal 3. Treatment B2: Symbicort 2 without oral activated charcoal 4. Treatment C: Z7200 with oral activated charcoal 5. Treatment D: Symbicort with oral activated charcoal A washout period of a minimum of 5 day followed treatment periods 1 to 4. Treatment B1 and B2 denote Symbicort without oral activated charcoal administered in two different period, designated as Symbicort 1 and Symbicort 2.

Treatment:

Drug: Symbicort Turbohaler without oral activated charcoal

Drug: Symbicort Turbohaler with oral activated charcoal

Drug: Z7200 with oral activated charcoal

Drug: Z7200 without oral activated charcoal

A-B2-B1-D-C

Experimental group

Description:

Subjects were dosed on Day 1 of each treatment period with one of the following five treatments according to the randomization schedule using a Williams Latin Square design: 1. Treatment A: Z7200 without oral activated charcoal 2. Treatment B1: Symbicort 1 without oral activated charcoal 3. Treatment B2: Symbicort 2 without oral activated charcoal 4. Treatment C: Z7200 with oral activated charcoal 5. Treatment D: Symbicort with oral activated charcoal A washout period of a minimum of 5 day followed treatment periods 1 to 4. Treatment B1 and B2 denote Symbicort without oral activated charcoal administered in two different period, designated as Symbicort 1 and Symbicort 2.

Treatment:

Drug: Symbicort Turbohaler without oral activated charcoal

Drug: Symbicort Turbohaler with oral activated charcoal

Drug: Z7200 with oral activated charcoal

Drug: Z7200 without oral activated charcoal

B1-A-C-B2-D

Experimental group

Description:

Subjects were dosed on Day 1 of each treatment period with one of the following five treatments according to the randomization schedule using a Williams Latin Square design: 1. Treatment A: Z7200 without oral activated charcoal 2. Treatment B1: Symbicort 1 without oral activated charcoal 3. Treatment B2: Symbicort 2 without oral activated charcoal 4. Treatment C: Z7200 with oral activated charcoal 5. Treatment D: Symbicort with oral activated charcoal A washout period of a minimum of 5 day followed treatment periods 1 to 4. Treatment B1 and B2 denote Symbicort without oral activated charcoal administered in two different period, designated as Symbicort 1 and Symbicort 2.

Treatment:

Drug: Symbicort Turbohaler without oral activated charcoal

Drug: Symbicort Turbohaler with oral activated charcoal

Drug: Z7200 with oral activated charcoal

Drug: Z7200 without oral activated charcoal

C-B1-D-A-B2

Experimental group

Description:

Subjects were dosed on Day 1 of each treatment period with one of the following five treatments according to the randomization schedule using a Williams Latin Square design: 1. Treatment A: Z7200 without oral activated charcoal 2. Treatment B1: Symbicort 1 without oral activated charcoal 3. Treatment B2: Symbicort 2 without oral activated charcoal 4. Treatment C: Z7200 with oral activated charcoal 5. Treatment D: Symbicort with oral activated charcoal A washout period of a minimum of 5 day followed treatment periods 1 to 4. Treatment B1 and B2 denote Symbicort without oral activated charcoal administered in two different period, designated as Symbicort 1 and Symbicort 2.

Treatment:

Drug: Symbicort Turbohaler without oral activated charcoal

Drug: Symbicort Turbohaler with oral activated charcoal

Drug: Z7200 with oral activated charcoal

Drug: Z7200 without oral activated charcoal