CTRI/2025/12/098902
Recruiting
Phase 2
A Multicentre, Parallel-group, Phase IIb, Randomised, Double-blind, Placebo-controlled, 4-Arm, 24-Week Study to Evaluate the Efficacy and Safety of AZD6793 Tablets in Adult Participants with Moderate to Very Severe Chronic Obstructive Pulmonary Disease (PRESTO)
Overview
- Phase
- Phase 2
- Status
- Recruiting
- Sponsor
- AstraZeneca AB
- Enrollment
- 1,160
- Locations
- 13
- Primary Endpoint
- To evaluate the effect of AZD6793 as compared to placebo on the rate of moderate or severe COPD exacerbations
Overview
Brief Summary
Current COPD therapies include combinations of inhaled long-acting beta two agonists, long-acting muscarinic antagonist, corticosteroids, and add-on oral anti-inflammatory agents such as roflumilast. However, current COPD therapies do not eliminate the symptoms, disability, or exacerbations that are associated with COPD, or significantly alter the course of COPD (Celli and Wedzicha 2019). Thus, a high unmet need remains and novel, more effective therapies are greatly needed. AZD6793 is an orally available, low molecular weight, and potent inhibitor of interleukin-one receptor–associated kinase four (IRAK4). IRAK4 is a key regulator of immune signalling and is expressed by multiple cells including innate and adaptive immune cells. It mediates signal transduction from Toll-like receptors (TLRs) and receptors of the interleukin-one (IL-one) family, including IL-oneR, IL-thirty sixR, and the IL-thirty three receptor suppression of tumorigenicity-two (ST2). AZD6793 has broad anti-inflammatory activity by inhibiting the pathways downstream of ST2 (the receptor for IL-thirty three), IL-one beta, IL-eighteen, and IL-thirty six receptors and various toll-like receptors. Based on data from pre-clinical studies, AZD6793 is expected to reduce both neutrophilic and eosinophilic inflammation and additionally reduce mucus production in the airways of patients with COPD. As exaggerated inflammation and mucus production in COPD airways contribute to the development of acute COPD exacerbations, it is hypothesised that AZD6793 may reduce acute exacerbation rates in patients with COPD also in addition to improving lung function and alleviating the symptom burden associated with COPD. AZD6793 also has the potential to reduce systemic inflammation and thereby reduce the development and progression of comorbidities that are associated with COPD.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Masking
- Participant and Investigator Blinded
Eligibility Criteria
- Ages
- 40.00 Year(s) to 99.00 Year(s) (—)
- Sex
- All
Inclusion Criteria
- •Participants are eligible to be included in the study only if all of the following criteria apply Age
- •Participant must be greater than or equal to 40 years of age at the time of signing the informed consent
- •Documented primary diagnosis of moderate to very severe COPD for at least 12 months prior to enrolment.
- •Pre-BD FEV1 to FVC less than 0.7 at Visit 1 and pre- and post-BD FEV1 to FVC less than 0.7, and post-BD FEV1 greater than or equal to 25 percent to less than 80 percent of predicted normal at Visit
- •If the pre-BD FEV1 to FVC is greater than or equal to 0.7, post-BD spirometry should not be performed.
- •Documented history of greater than or equal to 2 moderate or greater than or equal to 1 severe COPD exacerbations in the 12 months prior to screening (Visit 1). Participants with a documented history of one moderate COPD exacerbation in the 12 months before the screening visit are also eligible (but will be capped at 20 percent of the total sample size). At least one eligible historical COPD exacerbation must have occurred while on the stable maintenance treatment regimen that is required for eligibility. Acceptable documentation is a. Clinic visit or consultation (primary or specialist healthcare provider) notes or emergency room/hospital records providing evidence of the COPD exacerbation event b. Documented prescription of systemic corticosteroids of at least 3 days duration (or one injection of depot formulation) and/or antibiotics for treatment of a COPD exacerbation. In participants with an established self-management plan, documented filling of a prescription to replace an above-listed course of therapy will be considered adequate. c. Discharge summaries from a hospital, emergency room, an urgent care or other equivalent healthcare facility indicating that a participant was hospitalised or treated with systemic corticosteroids or antibiotics for a COPD exacerbation or, d. Evidence from a pharmacy of filled prescription(s) for systemic corticosteroids (3 days duration or one injection of depot formulation) and/or antibiotics
- •Documented stable regimen of inhaled triple maintenance therapy or inhaled dual maintenance therapy (when triple inhaled therapy is not appropriate) for greater than or equal to 3 months prior to screening (Visit 1). Triple therapy may consist of an appropriate combination of ICS plus LABA plus LAMA. Dual therapy consists of either ICS plus LABA, ICS plus LAMA or inhaled LABA plus LAMA when the treating physician deems the participant unsuitable for triple therapy or ICS (for example, blood eosinophil count less than or equal to 100 cells per millilitre on 2 separate occasions, or on the basis of previous or perceived risk of significant AEs from inhaled ICS-based therapy, such as previous episode(s) of pneumonia or significant oral candidiasis). Both triple and dual maintenance therapy may be in the form of separate inhalers or fixed-dose combination inhalers. Documented evidence of prescription for these medications, and/or medications must be provided. A verbal history from the participant is not considered sufficient.
- •Individual component changes or switches between devices are allowed as long as the participant remains on the same class therapies in equivalent doses.
- •SAMA taken at regular scheduled intervals (at a minimum frequency of 3 times daily) will be considered equivalent to LAMA.
- •If a participant is being treated with oral COPD maintenance therapy (for example, azithromycin, roflumilast), these treatments must also be stable for at least 3 months prior to screening (Visit 1)
Exclusion Criteria
- •Participants are excluded from the study if any of the following criteria apply Medical Conditions 1 Clinically important pulmonary disease other than COPD (eg, asthma [current diagnosis per GINA or other accepted guidelines], active pulmonary infection, clinically significant bronchiectasis when bronchiectasis is the predominant diagnosis, pulmonary fibrosis, cystic fibrosis, hypoventilation syndrome associated with obesity, lung cancer, alpha-1 antitrypsin deficiency or primary ciliary dyskinesia). A prior misdiagnosis of asthma or a history of asthma is not exclusionary. 2 Radiological findings suggestive of a respiratory disease other than COPD that is significantly contributing to the participant’s respiratory symptoms. (a) Radiological findings of pulmonary nodule(s) suspicious for lung cancer, as per applicable guidance (eg, ACR Lung-RADS v2022,) without appropriate follow-up before Visit
- •(b) Recent lung imaging result that requires immediate diagnostic investigation or follow-up. If initial repeat surveillance imaging has been undertaken, and the abnormality is considered as low risk for malignancy, the participant may be eligible for enrolment. Applicable also for participants taking part in the optional HRCT scan sub-study. 3 Any unstable disorder, including, but not limited to, CV, gastrointestinal, hepatic, renal, neurological, musculoskeletal, infectious, endocrine, metabolic, haematological, psychiatric disorder, major physical and/or cognitive impairment that, in the opinion of the investigator, could: (a) Affect the safety of the participant throughout the study. (b) Influence the findings of the study or their interpretation. (c) Impede the participant’s ability to complete the entire duration of the study and/or comply with the study visit schedule and procedures. 4 Participants with the following medical conditions (a) Significant left heart failure (ie, New York Heart Association Functional Classification class III and IV or left ventricular ejection fraction less than 40 percentage on echocardiogram or cardiac MRI, if such results are available). (b) Unstable angina, acute coronary syndrome/acute myocardial infarction or coronary intervention with percutaneous coronary intervention/coronary artery bypass graft within 6 months of randomisation, uncontrolled arrhythmia, or cardiomyopathy, clinically significant aortic stenosis, or signs of pulmonary oedema or volume overload(c) Pulmonary arterial hypertension, either idiopathic or due to connective tissue or thromboembolic disease. Note: Participants with pulmonary arterial hypertension due to chronic lung disease are eligible. (d) History of another underlying condition that predisposes the participant to infections (eg, history of splenectomy, known primary or secondary immune deficiency syndromes). (e) History of ulcerative colitis, Crohn s disease, or microscopic colitis diagnosed by either a gastroenterologist or by histopathology. (f) Presence of greater that 10percentage BSA depigmentation (eg, vitiligo or other causes of hypopigmentation) at baseline (Visit 3), at the discretion of the investigator. 5 The following abnormal laboratory findings at screening: (a) ALT or AST greater than 2 × ULN (b) TBL greater than 2 × ULN (unless due to Gilbert s disease) (c) Hb less than 120 g/L (males); Hb less than 110 g/L (females) (d) WBC less than LLN, neutrophil count less than 2.5 × 109/L, platelet count less than 150 × 109/L (e) Estimated glomerular filtration rate less than 45 mL/min/1.73 m2 by Chronic Kidney Disease Epidemiology Collaboration formula. Note: Abnormal laboratory values can be repeated once during screening (unless the sample was clotted, delayed in processing, otherwise mishandled, or a laboratory error is suspected, then additional repeat testing is allowed). 6 Any clinically significant abnormalities in the 12-lead ECG that, in the investigator s opinion, would put the participant at increased risk. Atrial fibrillation is not exclusionaryif the rate is well controlled, and the participant has been on stable anticoagulant therapy for at least 8 weeks. 7 Participants with evidence of active liver disease and/or evidence of chronic liver disease. Any of the following would exclude the participant from the study: (a) Participants who test positive for hepatitis C antibody, unless HCV RNA levels are undetectable prior to randomisation. Please note that if the participant has undergone treatment for HCV, then the RNA level must be assessed more than 12 weeks following the end of treatment. (b) Positive hepatitis B surface antigen or a positive medical history for hepatitis B. Participants with a history of hepatitis B vaccination without history of hepatitis B are allowed to enrol. 8 Participants with history of HIV infection or who test positive for HIV. 9 History of a clinically significant infection (viral, bacterial, or fungal; defined as requiring systemic antibiotics, antiviral, or antifungal medication for greater than 7 days) within 4 weeks prior to Day 1 (Visit 3) (including unexplained diarrhoea) or clinical suspicion of infection at the time of dosing. Participants can rescreen after the infection has resolved. 10 History of lung volume reduction surgery. 11 History of bronchial thermoplasty or endobronchial valves within 6 months prior to Visit
- •12 Use, or need for chronic use, of any NIPPV. Stable use of non-invasive ventilation for the treatment of obstructive sleep apnoea is permitted. 13 Current or history of malignancy within 5 years before the screening visit with the following exceptions: (a) Low risk prostate cancer under active surveillance (b) Completely treated in situ carcinoma of the cervix (c) Ductal carcinoma in situ of the breast or localised medullary cancer of the thyroid successfully treated with surgery with no evidence of recurrence for at least one year (d) Participants with basal cell or superficial squamous skin cancer 14 History of, or a reason to believe a participant has a history of, drug or alcohol abuse within the past one year prior to screening. 15 Participants who, as judged by the investigator, have evidence of active TB, either treated or untreated, or latent TB without completion of an appropriate course of treatment or appropriate ongoing prophylactic treatment. Evaluation will be according to the local SoC as determined by local guidelines and may consist of history and physical examinations, chest X-ray, or TB test (eg, purified protein derivative or QuantiFERON® test). 16 Male or female participants who wish to conceive a child or donate sperm or ova during the study and for the 2 weeks after the last dose of IMP. Prior/Concomitant Therapy 1 Participants currently receiving background therapy for COPD that is not approved by regulatory authorities in the country of study (with the exception of nicotine vaping products or patches). 2 Major surgery within 8 weeks prior to screening or planned inpatient surgery or hospitalisation during the study period. 3 Treatment with a broad-spectrum antibiotic (excluding long-term azithromycin) within 28 days (4 weeks) prior to randomisation (Visit 3). 4 Donation of blood or blood products within 3 months prior to screening. 5 History of allogeneic bone marrow transplant. 6 Participant who is going to start a COPD rehabilitation programme at any time during the study period. Participants can be recruited immediately following the completion of their COPD rehabilitation programme. Ongoing maintenance programs will be permitted. 7 Receiving any of the prohibited concomitant medications as specified in the CSP: (a) Acute systemic (oral or injectable) corticosteroids within 28 days (4 weeks) of Visit
- •(b) Any other immunosuppressive therapy (including methotrexate, cyclosporine, tacrolimus, azathioprine, or maintenance systemic steroid treatment) within 3 months of randomisation. Courses of systemic corticosteroids not exceeding 8 weeks for the treatment of acute or self-limiting conditions that ended before 4 weeks of Visit 1 are permitted. (c) Immunoglobulin, interferon gamma, or blood products within 28 days (4 weeks) of Visit
- •(d) Certain CYP-interacting medications 14 days (2 weeks) prior to Visit
- •(e) Metformin 14 days (2 weeks) prior to randomisation (Visit 3). (f) IMPs within 4 months or 5 half-lives of randomisation, whichever is longer. (g) Marketed biologics for respiratory diseases within 4 months or 5 half-lives prior to the date informed consent is obtained, whichever is longer. Note: Participants on stable therapy for at least 8 weeks prior to randomisation who intend to stay on treatment throughout the study with marketed biologics for non-respiratory diseases that are not likely to interfere with the assessment of safety and/or efficacy of AZD6793 (eg, for the treatment of osteoporosis, migraine, pain, diabetes, obesity, ocular, CV, or metabolic diseases) can participate in the study. (h) Long-term-oxygen therapy greater than 4.0 L/minute. While breathing supplemental oxygen, participants must demonstrate an oxyhaemoglobin saturation greater than or equal to 89percentage. To be admitted to the study, participants on long-term oxygen therapy must be ambulatory and able to attend clinic visits. Note: As-needed oxygen use is allowed. 17 Any concomitant medications known to be associated with Torsades de Pointes. Prior/Concurrent Clinical Study Experience 18 Participants with a known hypersensitivity to AZD6793 or any of the excipients of the product. 19 Concurrent enrolment in another clinical study involving an investigational treatment. Other Exclusions 20 Participant is an investigator, sub-investigator, study coordinator, or employee of the participating site or AstraZeneca or is a first-degree relative of the aforementioned. 21 Inability to perform technically acceptable spirometry. 22 Randomisation of participant is not permitted due to closure of stratum. 23 Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site). 24 Judgement by the investigator that the participant should not participate in the study if the participant is unlikely to comply with study procedures, restrictions, and requirements. 25 Previous enrolment or randomisation in the present study or previous treatment with AZD
- •26 For females only.
- •currently pregnant (confirmed with positive pregnancy test) or breastfeeding. All WOCBP participants must have a negative pregnancy test result at Visit 1 (serum) and Visit 3 (urine). 1.1 Lifestyle Considerations 1.1.1 Meals and Dietary Restrictions Participants should avoid eating a large meal for at least 2 hours prior to spirometry. Grapefruit juice should be avoided for 14 days (2 weeks) prior to Visit 3, during the study and for 2 days following discontinuation of AZD
- •1.1.2 Caffeine, Alcohol, and Tobacco.
- •CYP1A2 is the main enzyme catalysing the metabolism of caffeine (more than 95percentage). Downregulation of CYP1A2 mRNA levels in hepatocytes in the presence of AZD6793 has been observed in vitro, but whether this finding translates to a clinically relevant DDI is currently unknown. Excessive use of caffeine during the study should be discouraged if it causes caffeine related symptoms such as tremors, palpitations, restlessness, and insomnia.
Outcomes
Primary Outcomes
To evaluate the effect of AZD6793 as compared to placebo on the rate of moderate or severe COPD exacerbations
Time Frame: To evaluate the effect of AZD6793 as compared to placebo on the rate of moderate or severe COPD exacerbations
Secondary Outcomes
- To evaluate the effect of AZD6793 as compared to placebo on COPD exacerbations(Time to first moderate or severe COPD exacerbation.)
- To evaluate the effect of AZD6793 as compared to placebo on COPDCompEx events(Annualised rate of COPDCompEx events)
- To evaluate the effect of AZD6793 compared to placebo on measures of lung function(Change from baseline in pre-BD FEV1 at Week 12 and Week 24)
- To evaluate the effect of AZD6793 compared to placebo on symptoms and HRQoL(Change from baseline over 24 weeks in each of the following)
- To assess the PK of AZD6793 in participants with moderate to very severe COPD(AZD6793 plasma concentrations at specific timepoints.)
Investigators
Tapankumar M Shah
AstraZeneca Pharma India Ltd,
Study Sites (13)
Loading locations...
Similar Trials
Not yet recruiting
Not Applicable
A Phase II Clinical Study Evaluating the Combination Therapy of JS212 in Patients With Advanced Lung CancerNCT07309276Shanghai Junshi Bioscience Co., Ltd.864
Not yet recruiting
Phase 2
QLS12010 Capsules in Adults With Moderate to Severe Hidradenitis SuppurativaNCT07417917Qilu Pharmaceutical Co., Ltd.102
Recruiting
Phase 2
A Study Evaluating the Efficacy and Safety of ABP1011T Tablets in Patients With Advanced Solid TumorsNCT07321574Shanghai AB PharmaTech Ltd.110
Recruiting
Phase 1
Adebrelimab Combined With Gemcitabine, Cisplatin, and Simvastatin for Advanced Biliary Tract CancerNCT07392541Tongji Hospital29
Not yet recruiting
Not Applicable
Study of QLC5513 in Combination With Epalolimab Tovolimab (QL1706) ± Platinum in Patients With Advanced or Metastatic Malignant Solid TumorsNCT07272590Qilu Pharmaceutical Co., Ltd.290