Título: Estudio de fase 2b, aleatorizado, doble ciego y controlado con placebo para determinar el rango de dosis y evaluar la eficacia y seguridad de múltiples niveles de dosis de AZD8630 inhalado administrado una vez al día durante 12 semanas en adultos con asma no controlada con riesgo de exacerbaciones (LEVANTE)

Especialidad: Neumología

Código de protocolo: D6830C00003

Número EudraCT: 2024-514228-18-00

Promotor: Astra Zeneca

Investigador principal: Dr. Gustavo de Luiz

Más información:

CRO: IQVIA

Criterios de inclusión: Patient must be 18 to 80 years of age inclusive, at the time of signing the ICF
Pre-BD FEV1 40% at both Visit 1 and Visit 2.
A pre-BD/pre-study intervention dose FEV1 at Visit 2 that has not increased by 400 ml from the pre-BD FEV1 recorded at Visit 1.
Patient has documented evidence of any of the following: (a) A history of 1 severe exacerbation within the last 12 months and either: (i) FeNO 25 ppb at the screening and randomisation visits (Visits 1 and 2) (ii) Eosinophil count 150 cells/µL, recorded at any point in the 12 months up to and including the Screening Visit (local testing can be carried out to confirm eligibility if eosinophil count not available in medical records within the last 12 months). (b) A history of 2 severe exacerbations within 12 months of Visit 1. A severe exacerbation is defined as an episode of symptoms of asthma worsening that results in at least one of the following: OCS use for 3 consecutive days, inpatient ( 24 hours) hospitalisation for asthma or emergency room or equivalent visit for asthma that results in systemic CS use.
At least 80% compliance with usual asthma background medication during the run-in period based on the daily asthma ePROs.
Minimum 80% compliance with daily assessments. Compliance is defined as completing the daily ePROs and PEF measurements (morning and evening) at least 80% of the time during the 14-day period prior to the randomisation visit (minimum of 11 days) preceding Vi
Any patient at GINA step 5 (i.e. on high dose ICS plus LABA) for which an injectable biologic therapy for asthma is indicated (according to local prescribing guidance) must meet the following to be included Be unable or unwilling to receive an injectable biologic, or for whom such treatment is considered contraindicated or inappropriate in the opinion of the investigator. Documentation must be provided in the source records
BMI within the range 18-37 kg/m2 (inclusive) at the time of signing the informed consent at Visit 1 and at Visit 2.
Female patients: (a) All FOCBP must have a negative serum pregnancy test result at the Screening Visit (Visit 1) and a negative urine pregnancy test on the day of randomisation (prior to randomisation; Visit 2) and must not be lactating. (b) Females of non-childbearing potential who are < 55 years old must fulfil one of the following criteria at the Screening Visit: (i) Post-menopausal, defined as amenorrhoea for 12 months following cessation of all exogenous hormonal treatments and FSH levels in the post-menopausal range (historical data for FSH will be accepted). (ii) Permanent sterilisation includes hysterectomy, bilateral oophorectomy, and bilateral salpingectomy at least 6 weeks before screening and is confirmed by the medical records or follow-up hormone level assessment. Bilateral tubal ligation is not acceptable. (c) For females aged 55 years, post-menopausal is defined as having a history of 12 months amenorrhea, without an alternative cause, following cessation of all exogenous hormonal treatments. (d) FOCBP must be willing to use highly effective contraception measures with low user dependency from signing the ICF until 20 days after last dose of study intervention. FOCBP should be stable on their chosen method of birth control for at least 3 months before first dosing.
Male patients: (a) Male patients and their FOCBP partner must be willing to use a highly effective contraception measure and should refrain from donating sperm or fathering a child from the first day of dosing until at least 20 days after last dose of study intervention.
Capable of giving signed informed consent.
Provision of signed and dated written Optional Genomics Initiative Research Information and Consent Form prior to collection of samples for optional genomics initiative research that supports the Genomic Initiative.
Documented physician diagnosis of asthma for at least 12 months, as evidenced by any of the following: (a) Post-BD reversibility of FEV1 12% and 200 mL within 5 years prior to Visit 1, or (b) PEF average daily variability > 10% over a 2-week period within 5 years prior to Visit 1, or (c) Variability of FEV1 > 12% and 200 mL between any 2 clinical visits within 5 years prior to Visit 1, or (d) Positive bronchial challenge test within 5 years prior to Visit 1. A positive test is defined as a fall in FEV1 from pre-challenge of 20% with standard doses of methacholine or 15% with standardised hyperventilation, hypertonic saline, or mannitol challenge, or (e) Positive exercise challenge test within 5 years prior to Visit 1. A positive test is defined as a fall in FEV1 of > 10% and > 200 mL from pre-challenge, or (f) Significant increase in lung function after 4 weeks of anti-inflammatory treatment with ICS-containing treatment (GINA 2023) within 5 years prior to Visit 1, defined as an increase in FEV1 > 12% and 200 mL (or PEF by >20%)
Treated with medium- or high-dose ICS (as per GINA 2023) in combination with LABA (GINA Step 4 or 5 therapy); the dose of ICS must be stable for at least 30 days prior to Visit 1. The ICS can be contained within an ICS-LABA fixed-dose combination product. Note: Treatment with additional asthma controller therapies (eg, LAMA) at a stable dose 30 days prior to Visit 1 is allowed.
Demonstration of uncontrolled asthma through ACQ-6 score 1.5 at both Visit 1 and Visit 2.

Criterios de exclusión: Life-threatening asthma defined as a history of significant asthma episode(s) involving intubation, respiratory arrest, hypoxic seizures, or asthma-related syncopal episode(s).
Patients with recent myocardial infarction, unstable angina pectoris, stroke, or percutaneous coronary intervention within 3 months of Visit 1 or coronary artery bypass grafting within 6 months of Visit 1.
A helminth parasitic infection diagnosed within 24 weeks of Visit 1 that has not been treated, or has not responded to SoC therapy.
Current smokers, former smokers with > 10 pack-years history, or former smokers who stopped smoking < 6 months before Visit 1 (including all forms of tobacco, e-cigarettes [vaping], and other recreational drugs including marijuana).
Known history of drug or alcohol abuse within the 12 months prior to Visit 1, that in the Investigators opinion would preclude participation in the study. The use of oral cannabis is permitted.
Current diagnosis of cancer or unresectable cancer that has not been in complete remission for at least 5 years prior to Visit 1. Note: Squamous cell and basal cell carcinomas of the skin and cervical carcinoma-in-situ that have been treated and considered cured at the time of enrolment are not exclusionary.
Any other clinically relevant abnormal findings on vital signs, physical examination, or clinical laboratory testing including haematology, coagulation, clinical chemistry, or ECG between Visit 1 and Visit 2, that in the opinion of the Investigator or medical monitor might compromise the safety of the patient in the study or interfere with evaluation of the study intervention. Abnormal findings include, but are not limited to: (a) ALT or AST > 2 × ULN (b) TBL > 1.5 × ULN (unless due to Gilberts disease) Treatment with any of the following therapeutic interventions within the specified time before Visit1
Treatment with marketed or investigational biologics for asthma or immunological disease within 4 months or a minimum of 5 half-lives, prior to Visit 1, whichever is longer.
Systemic steroids within 4 weeks prior to Visit 1.
Chronic oral or systemic CS use for asthma or for any other indication (with the exception of stable replacement therapy in adrenal insufficiency).
Completed treatment for respiratory infection and/or asthma exacerbation with systemic corticosteroids and/or antibiotics for > 3 days in the 4 weeks prior to Visit 1.
Clinically important pulmonary disease other than asthma; including but not limited to those with co-existent chronic obstructive pulmonary disease.
Any disorder, including, but not limited to, cardiovascular, gastrointestinal, hepatic, renal, neurological, musculoskeletal, infectious, endocrine, metabolic, haematological, psychiatric, or major physical impairment that is not stable in the opinion of the Investigator and could: (a) Affect the safety of the patient throughout the study (b) Influence the findings of the study or their interpretation (c) Impede the patients ability to complete the entire duration of study
Patients who, in the opinion of the Investigator, have evidence of active TB or are currently on treatment for active or latent TB. Investigation for active or latent TB, with interferon gamma release assay (IGRA) and/or chest X-ray, should only be considered if deemed clinically indicated by the Principal Investigator.
Medical history of or treatment for hepatitis B or hepatitis C, except for cured hepatitis C, as defined by: (a) Positive test for HBsAg (b) Positive test for anti-HBc: Patients who test positive for anti-HBc antibody but negative for HBsAg may be enrolled if their hepatitis B virus DNA test result is negative (c) Positive test for anti-hepatitis C antibody: Patients who test positive for antihepatitis C antibody may be enrolled if their hepatitis C viral RNA test result is negative in the absence of liver cirrhosis
Patients with history of HIV infection or who test positive for HIV.
Congenital long QT syndrome or prolonged QTcF > 470 ms or history of QT prolongation associated with other medications that required discontinuation of that medication.
Current untreated or uncontrolled arrhythmia (eg, multifocal premature ventricular contractions, bigeminy, trigeminy, ventricular tachycardia). Note: Patients with clinically significant sinus nodal disease/bradycardia or type 2 second- or third-degree atrioventricular block can be included if treated with a pacemaker.

Centro: Vithas Xanit Internacional