A Comparison of VR647 and Conventionally Nebulized Budesonide in Healthy Volunteers and Adult Asthma Subjects

A Randomized, Open-label, Crossover Trial to Compare the Pharmacokinetics, Safety and Tolerability of Single Doses of VR647 Inhalation Suspension Delivered by the VR647 Inhalation System (VR647) With Single Doses of Budesonide Delivered by a Conventional Jet Nebulizer in Healthy Adult Volunteers and Adult Asthma Subjects

This is a three part, randomized, open-label, crossover, Phase 1 trial in adults. Parts 1 and 2 will enroll healthy male and female subjects. Part 3 will enroll subjects with mild asthma. This study will assess the pharmacokinetics, safety and tolerability of single doses of budesonide delivered by VR647 Inhalation System (AKITA® JET) with mouthpiece or face mask to single doses of budesonide delivered by a conventional jet nebulizer (PARI VIOS®) with mouthpiece or face mask.

For all parts of the study, subjects in the VR647 group will receive VR647 Inhalation Suspension delivered by the VR647 Inhalation System (AKITA JET) with either a mouthpiece or a facemask. Similarly, for all parts of the study, subjects in the comparator group will receive approved doses of budesonide (Pulmicort Respules®) delivered by a conventional jet nebulizer (PARI VIOS) with either a mouthpiece or a facemask.

Part 1:

Subjects who fulfill the enrollment criteria will progress to a comparative single dose, 6-treatment, 6-period crossover trial. Subjects will receive 4 dose levels of VR647 Inhalation Suspension delivered by the VR647 Inhalation System (AKITA JET) (5, 10, 15 and 25 breaths, with targeted doses of 30, 60, 120 and 240 µg) and 2 dose levels of budesonide delivered by a conventional jet nebulizer (PARI VIOS) (0.5 and 1 mg). There will be a Washout Period between each dose of approximately 48 hours. Each subject will be randomized to treatment.

Part 2:

Following an approximate 7-day washout, the same cohort of subjects from Part 1 will progress to a comparative single dose, 6-treatment, 6-period crossover trial. There will be a Washout Period between each dose of approximately 48 hours. Each subject will be randomized to treatment in a 6-way crossover.

Part 3:

Subjects with mild asthma who fulfill the enrollment criteria (including those criteria specific to Part 3) will progress to a comparative single dose, 4-treatment, 4-period crossover trial conducted at a separate clinic from Parts 1 and 2. There will be a Washout Period between each dose of approximately 48 hours. This part of the trial can start before completion of Parts 1 and 2.

Inclusion Criteria:

• Male or female subject

• Female subjects must have a negative pregnancy test at the Screening and Day -1 Visits (prior to dosing), must be using a reliable form of contraception throughout the trial, or must be of non-childbearing potential as follows:

  • Be post-menopausal (their last menstrual period was at least 12 months ago), and have a serum follicle-stimulating hormone (FSH) level consistent with postmenopausal status as determined by the investigator, or
  • Have undergone a hysterectomy, a bilateral oophorectomy or a bilateral salpingectomy

• Aged 18 to 55 years

• Hemoglobin level of ≥11.5 g/dL for females and ≥13.0 g/dL for males

• Weigh at least 50 kg, and body mass index (Quetelet index) in the range 18.0-32.0 kg/m2, inclusive

• Forced expiratory volume in 1 second (FEV1) of more than 1.69 L at the Screening Visit

• Ability to comprehend the nature of the trial and any hazards of participating in it. Ability to communicate satisfactorily with the investigator and to participate in, and comply with the requirements of, the entire trial

• Give written consent to participate after reading the consent form, and after having the opportunity to discuss the trial with the investigator or his/her delegate

Additional Inclusion Criteria for Part 3:

• Documented clinical history of mild asthma (mild as defined by the National Asthma Evaluation and Prevention Program (NAEPP) guidelines) for at least 6 months before the Screening Visit, but otherwise healthy
• FEV1 reversibility (increase of at least 12% and 200 mL in absolute FEV1 from pre bronchodilator value within 15±5 minutes post bronchodilator) at the Screening Visit or during past 12 months
• Values for FEV1 of at least 80% of predicted value and normal FEV1/forced vital capacity (FVC; as defined by NAEPP guidelines). Assessment should be performed without treatment with β2-agonists. If a subject's FEV1 is outside that range at the Screening Visit, the test may be repeated once on another day during the Screening Period

Exclusion Criteria:

• Clinically relevant abnormal medical history, physical findings, ECG, or laboratory values at the screening assessment that could interfere with the objectives of the trial or the safety of the subject (excluding mild asthma in Part 3)

• Subjects who have impaired cardiovascular, endocrine, autoimmune, metabolic, neurological, renal, respiratory (excluding mild asthma in Part 3), gastrointestinal, hepatic, hematological or any other system abnormalities

• Respiratory tract infection within 4 weeks before the Screening Visit

• History of surgery or medical intervention within 6 weeks before the Screening Visit, or planned surgery or medical intervention, that could interfere with the objectives of the trial or the safety of the subject

• Regular treatment (more than 1 month duration) with oral or parenteral corticosteroids in the last year prior to the Screening Visit

• Use of the following prescription medications within 28 days prior to the first dose:

  • corticosteroids by any route, androgenic steroids (e.g., testosterone), ritonavir and similar drugs for HIV prophylaxis, ketoconazole, itraconazole or similar azole anti-fungal drugs and macrolide antibiotics (e.g., erythromycin)

• Presence or history of severe adverse reaction to any drug, or sensitivity to components of the trial medication

• Use of a prescription or over-the-counter medicine, nutritional and vitamin supplements, with the exception of acetaminophen and hormonal contraceptives, during the 7 days before the first dose of trial medication. For Part 3 only, inhaled short-acting β2-agonists in addition to acetaminophen and hormonal contraceptives are permitted

• Participation in another clinical trial of a new chemical entity, new device, or a prescription medicine within the 3 months before dosing, or participation within 5 half-lives of receiving an experimental drug (whichever is longer)

• Presence or history of drug or alcohol abuse, or intake of more than 21 units (14 units for women) of alcohol weekly

• Evidence of drug abuse on urine testing, or a positive test for alcohol

• Current smoker; or ex-smokers who (a) gave up less than 1 year ago, or (b) who have a history of more than 10 pack years. A pack year is calculated as the number of cigarettes per day multiplied by number of years smoked divided by 20

• Blood pressure and heart rate at the screening examination outside the ranges 90-140 mmHg systolic, 40-90 mm Hg diastolic, heart rate 40-100 beats/min

• Loss of more than 400 mL blood, e.g., as a blood donor, or donation of blood products, during the 3 months before the Screening Visit

• Positive test for hepatitis B, hepatitis C, or HIV

• History of, or latent, tuberculosis (TB) infection

• Evidence of any other clinically significant infection, including bacterial or viral infections

• Possibility that the subject will not cooperate with the requirements of the protocol, including effective use of the nebulizer

• Employee of the investigational site or the Sponsor, who is directly involved in the trial, or a family member of such a person

Additional Exclusion Criteria for Part 3:

• Any life-threatening asthmatic episode in the past
• Asthmatic episode or respiratory tract infection requiring systemic steroid treatment or hospitalization 3 months prior to the Screening Visit
• Use of inhaled short-acting β2-agonists for > 2 days/week for symptom relief during 28 days prior to the Screening Visit