| Eligibility |
Inclusion Criteria:
Informed consent
- Capable of giving signed informed consent which includes compliance with the
requirements and restrictions listed in the informed consent form (ICF) and in this
Clinical Study Protocol (CSP).
- Provision of signed and dated, written ICF prior to any mandatory study specific
procedures, sampling, and analyses.
- Provision of signed and dated written Genetic ICF prior to collection of samples for
genetic analysis (if subject agrees to take part in this optional assessment).
Age • Subject must be 18 to 65 years of age (inclusive) at the time of signing the ICF.
Type of subject and disease characteristics
- Individuals who are determined as healthy by the Investigator, based on medical
evaluations including, but not limited to, medical history, physical examination,
laboratory tests, vital signs, and electrocardiogram (ECG).
- Subjects have mild, stable, allergic asthma with episodic wheeze and shortness of
breath. Asthma therapy is limited to inhaled, short-acting ß2 agonists (should not be
used on more than 2 occasions in a week, excluding for prophylactic treatment).
- Subjects have no current exposure to allergens to which the subject experiences
asthmatic responses (except for the house dust mite).
- Positive methacholine challenge (PC20 =16 mg/mL) at screening (Visit 2).
- Positive skin-prick test to at least one common aeroallergen at screening (Visit 1).
- Positive early and late airway responses during the screening allergen challenge. The
EAR will be a fall in FEV1 of =20% during the 2 hours after allergen challenge. The
LAR will be defined as a fall in FEV1 of =15% during the 3-7 hours after allergen
challenge.
- Pre-bronchodilator FEV1 at screening (Visit 1) =70% of predicted normal value.
Weight
• Body mass index (BMI) within the range 18 to 35 kg/m2 (inclusive).
Sex • Male or female
Reproduction
- Negative serum pregnancy test for female subjects at Screening Visit 1.
- WOCBP should be stable on their chosen method of highly effective birth control for a
minimum of 3 months prior to Visit 1, and willing to use this for the entire duration
of the study (from the time they sign the ICF), and for 1 month after the last dose of
study treatment. With the exception of abstinence, addition of a barrier method (such
as a condom) must be used from Visit 1 until 1 month after the last dose of study
treatment. Female subjects must not donate ova for the same time period
- Male subjects must be surgically sterile or using an acceptable method of
contraception for the duration of the study (from the time they sign consent) and for
1 month after the last dose of study treatment to prevent pregnancy in a partner
(unless the partner is considered postmenopausal). Male subjects must not donate or
bank sperm during this same time period.
Additionally, for randomization into the study (baseline Visit 6), the subject must fulfil
the following additional criteria:
- Negative urine pregnancy test for female subjects, confirmed pre dose prior to
randomization.
- Visit 6 pre dose methacholine PC20 =1 doubling concentration lower than the
corresponding baseline value at Visit 2.
- Ability to produce a sputum sample and viable cytospin for assessment of the cell
differential count at the screening allergen challenge. The purpose of this analysis
is to support exploratory endpoints only and is not related to treatment decisions.
- A Visit 6 pre-dose FEV1 that is not more than 10% lower than that measured at the
screening Visit 2, to demonstrate asthma stability.
Exclusion criteria
Medical conditions
- A worsening of asthma or a respiratory tract infection from 6 weeks prior to Visit 1
or during the screening period, requiring a change of treatment.
- Any history of life-threatening asthma attack or asthma attack requiring admission to
an intensive care unit and/or ventilation.
- A medical history or evidence of medical conditions which in the Investigator's
opinion makes it undesirable for the subject to participate in the study, including
but not limited to:
1. lung disease (excluding sleep apnea) other than mild allergic asthma
2. history of diabetes, metabolic syndrome, Gilbert syndrome, hepatic impairment,
hypertriglyceridemia, or familial lipid disorders
3. clinically significant hypotensive episodes or symptoms of fainting, dizziness,
or light headedness
4. cardiovascular disease, particularly coronary artery disease, hypertension,
congestive heart failure or any clinically important abnormalities in rhythm,
conduction or morphology of the ECG at rest that may interfere with the
interpretation of QT interval corrected (QTc) interval changes.
5. significant neurologic disease, including transient ischemic attack, stroke, or
seizure disorder
6. alcoholism, drug dependency or abuse
7. latent or chronic infection (eg, recurrent sinusitis, genital or ocular herpes,
urinary tract infection) or at risk of infection (eg, surgery) within 90 days of
screening
8. malignancy in the previous 5 years other than superficial basal cell carcinoma.
- Prolonged QT interval corrected using Fridericia's formula (QTcF) >450 milliseconds
(ms) based on ECG (at Visit 1 or Visit 6 pre-dose) or family history of long QT
syndrome
- Persistent or intermittent bundle branch block, intermittent second or third degree
atrial ventricular (AV) block or AV dissociation (at Visit 1 or Visit 6).
- Current smokers. Ex-smokers must not have smoked or used nicotine or cannabis products
(including e-cigarettes) for a minimum of 6 months prior to enrolment and should not
have a smoking history =10 pack years.
- Excessive intake of caffeine-containing drinks or food (eg, coffee, tea, chocolate) as
judged by the Investigator.
Prior/concomitant therapy
- Intention to use any concomitant medication that is not permitted or failure to
undergo the required washout period for a prohibited medication.
- Chronic use of any other medication for treatment of allergic lung disease other than
short acting ß2-agonist.
- Subject who has a scheduled in-patient surgery or hospitalization during the study.
- Previous use of a mechanistic target of rapamycin (mTOR) antagonist (eg, rapamycin,
everolimus) or PI3K inhibitor (selective or non-selective PI3K inhibitor).
Prior/concurrent clinical study experience
• Participation in another clinical study with an investigational product administered from
30 days (or 5 half lives) before Visit 1.
Note: refer to prohibited/restricted medications list for required washouts from previous
investigational treatments.
- Subjects with a known hypersensitivity (as judged by the Investigator) to drugs with a
similar class to AZD8154.
- Previously received AZD8154 or randomized to treatment in the present study.
Diagnostic assessments
- Clinically significant abnormalities in laboratory test results at Visit 1 or during
the screening period as judged by the Investigator.
- Any values outside the normal range for the following parameters at Visit 1:
1. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level =1.5
times the upper limit of normal (ULN).
2. Absolute neutrophil count =1.5 x 109/L.
- Positive serology at Visit 1 (HIV-1; HIV-2; Hepatitis B & C).
- Subjects with latent or active tuberculosis (TB), as confirmed by a positive
QuantiFERON® - TB Gold test or as judged by the Investigator at Visit 1.
Note: subjects will be allowed to continue with screening and baseline assessments whilst
the results are pending but must not be randomized into the study until the test results
confirm the subject does not have TB.
Other exclusions
- Involvement in the planning and/or conduct of the study (applies to both AstraZeneca
staff, staff at the study site, and other third party staff involved in the study).
- Judgement by the Investigator that the subject should not participate in the study if
the subject is unlikely or unwilling to comply with study procedures, restrictions and
requirements.
- Female subjects who are currently pregnant (confirmed with positive pregnancy test) or
breast feeding or planning a pregnancy (also applies to male subjects), within the
study period or 1 month following the last dose of study treatment.
- If a subject agrees to participate in the optional genetic research, the following
exclusion criteria will apply:
1. Previous allogeneic bone marrow transplant.
2. Non-leukocyte depleted whole blood transfusion within 120 days of the date of the
genomic sample collection.
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