A Study To Evaluate The Efficacy, Safety, Pharmacokinetics, And Pharmacodynamic Effects Of GDC-6599 In Patients With Chronic Cough

Study Overview
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Brief Summary
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This Phase IIa, multicenter, randomized, double-blind, placebo-controlled, crossover study will evaluate the efficacy, safety, pharmacokinetics, and pharmacodynamic (PD) effects of GDC-6599 compared with placebo in patients with a history of chronic cough.

Official Title
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A Phase IIa, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Crossover Study To Evaluate The Efficacy, Safety, Pharmacokinetics, And Pharmacodynamic Effects Of GDC-6599 In Patients With Chronic Cough

Conditions
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Chronic Refractory Cough (CRC) With Non-atopic Asthma, CRC With Atopic Asthma, Unexplained Chronic Cough, CRC With Chronic Obstructive Pulmonary Disease, CRC With Chronic Obstructive Pulmonary Disease With Chronic Bronchitis

Intervention / Treatment
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* Drug: GDC-6599
* Other: GDC-6599-matching placebo
* Diagnostic Test: Mannitol


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Previous diagnosis of CRC, despite optimized treatment for asthma or COPD, or UCC for at least 1 year Chest X-ray or computed tomography (CT) scan thorax within 5 years prior to screening visit that confirms the absence of any clinically significant abnormality contributing to the chronic cough in the opinion of the investigator Cough severity VAS score ≥ 40 at screening visit Pre-bronchodilator forced expiratory volume in 1 second (FEV1) ≥ 60% of predicted at screening Mannitol CDR ≥ 12 coughs/100 mg determined at screening visit mannitol challenge test For women of childbearing potential: agreement to remain abstinent or use contraception For men: agreement to remain abstinent or use a condom, and agreement to refrain from donating sperm Inclusion Criteria for Patients with CRC with Atopic Asthma or Patients with CRC with Non-Atopic Asthma (Part A) Physician diagnosis of asthma for ≥ 12 months based upon GINA STEP 2-5 Stable treatment with ICS therapy (GINA STEP 2) or ICS therapy and at least one additional controller (GINA STEP 3- 5) for ≥ 3 months Patients with atopic asthma (n = 20), based upon historic record of positive test for atopy (if available), or confirmed at screening by positive fluorescence enzyme immunoassay for specific IgE against at least one of the following five perennial aeroallergens: animal (cat dander, dog dander, cockroach), dust mite (Dermatophagoides farinae, Dermatophagoides pteronyssinus), and mold mix Patients with non-atopic asthma (n = 20), based upon historic record of negative test for atopy (if available), or confirmed at screening by negative ImmunoCAP test result for all five perennial aeroallergens: animal (cat dander, dog dander, cockroach), dust mite (Dermatophagoides farinae, Dermatophagoides pteronyssinus), and mold mix, and relevant local allergens, and no history of symptoms suggesting atopy Never or former smoker (≥ 6 months prior to screening) with < 20 pack-years or equivalent history Inclusion Criteria for Patients with CRC COPD-CB or Patients with CRC COPD (Part B) Diagnosis of COPD GOLD I-II ± CB Stable background treatment consisting of a bronchodilator medication and or stable ICS therapy for ≥ 12 weeks prior to screening visit Former smoker with ≥ 10 pack-years or equivalent history within 6 months of screening Post-bronchodilator FEV1/ forced vital capacity (FVC) ratio ≤ 0.70 at screening Chest X-ray or CT scan within 6 months prior to screening visit or during the screening period (prior to randomization [Study Visit 2]), that confirms the absence of clinically significant lung disease besides COPD Exclusion Criteria: Pregnant or breastfeeding, or intention of becoming pregnant during the study or within 28 days after the final dose of GDC-6599 History of diagnosed bleeding diathesis or easy bruising or bleeding Post-bronchodilator FEV1/ FVC ratio < 0.60 at screening visit (patients with CRC asthma and UCC only: Part A) History of significant hepatic impairment History of aspiration or recurrent pneumonia Respiratory infection (including upper respiratory infection) within 8 weeks prior to screening Treatment with any strong inhibitor or inducer of CYP3A within 28 days or 5 drug-elimination half-lives, whichever is longer, prior to initiation of study drug Treatment with angiotensin-converting enzyme (ACE) inhibitor within 12 weeks prior to screening (Study Visit 1) through completion of the study Treatment with opioids (including codeine), pregabalin, gabapentin, amitriptyline, or nortriptyline for the treatment of cough within 2 weeks prior to screening (Study Visit 1) through completion of the study Treatment with cough suppressant medication within 2 weeks prior to screening (Study Visit 1) through completion of the study Known coronavirus 2019 (COVID-19) infection, persistent symptoms of known prior COVID-19 infection, and/or known positive COVID-19 test within at least 8 weeks prior to screening and randomization Clinical laboratory value outside the reference range for the test laboratory at screening Any serious medical condition or abnormality in clinical laboratory tests that, in the investigator's judgment, precludes the patient's safe participation in and completion of the study History of malignancy within 5 years prior to screening, except for appropriately treated carcinoma in situ of the cervix or non-melanoma skin carcinoma

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A: CRC Asthma atopic<br>Patients with CRC atopic asthma will be randomized in a 1:1 ratio to receive GDC-6599 or placebo for 14 days during the first study period (Treatment Period 1, Study Visits 2-4). Following a 14-day washout period, patients will cross over to the second study period (Treatment Period 2, Study Visits 5-7) and will receive the alternate treatment (GDC-6599 or placebo) for 14 days starting at Study Visit 5 | Drug: GDC-6599<br>* GDC-6599 will be administered Days 1- 14 and on Days 29-42 as film-coated tablets<br>* Other names: RO7441345;Other: GDC-6599-matching placebo<br>* GDC-6599-matching placebo will be administered Days 1- 14 and on Days 29- 42. as film-coated tablets<br>Diagnostic Test: Mannitol<br>* Mannitol challenge tests will be performed during screening and at least 2.5 hours following study drug administration at Study Visits 2, 4, 5 and 7<br>|
| Experimental: Part A: CRC Asthma non-atopic<br>Patients with CRC non-atopic asthma will be randomized in a 1:1 ratio to receive GDC-6599 or placebo for 14 days during the first study period (Treatment Period 1, Study Visits 2-4). Following a 14-day washout period, patients will cross over to the second study period (Treatment Period 2, Study Visits 5-7) and will receive the alternate treatment (GDC-6599 or placebo) for 14 days starting at Study Visit 5 | Drug: GDC-6599<br>* GDC-6599 will be administered Days 1- 14 and on Days 29-42 as film-coated tablets<br>* Other names: RO7441345;Other: GDC-6599-matching placebo<br>* GDC-6599-matching placebo will be administered Days 1- 14 and on Days 29- 42. as film-coated tablets<br>Diagnostic Test: Mannitol<br>* Mannitol challenge tests will be performed during screening and at least 2.5 hours following study drug administration at Study Visits 2, 4, 5 and 7<br>|
| Experimental: Part A: Unexplained Chronic Cough<br>Patients with Unexplained Chronic Cough will be randomized in a 1:1 ratio to receive GDC-6599 or placebo for 14 days during the first study period (Treatment Period 1, Study Visits 2-4). Following a 14-day washout period, patients will cross over to the second study period (Treatment Period 2, Study Visits 5-7) and will receive the alternate treatment (GDC-6599 or placebo) for 14 days starting at Study Visit 5 | Drug: GDC-6599<br>* GDC-6599 will be administered Days 1- 14 and on Days 29-42 as film-coated tablets<br>* Other names: RO7441345;Other: GDC-6599-matching placebo<br>* GDC-6599-matching placebo will be administered Days 1- 14 and on Days 29- 42. as film-coated tablets<br>Diagnostic Test: Mannitol<br>* Mannitol challenge tests will be performed during screening and at least 2.5 hours following study drug administration at Study Visits 2, 4, 5 and 7<br>|
| Experimental: Part B: Chronic Refractory Cough with Chronic Obstructive Pulmonary Disease<br>Patients with Chronic Obstructive Pulmonary Disease will be randomized in a 1:1 ratio to receive GDC-6599 or placebo for 14 days during the first study period (Treatment Period 1, Study Visits 2-4). Following a 14-day washout period, patients will cross over to the second study period (Treatment Period 2, Study Visits 5-7) and will receive the alternate treatment (GDC-6599 or placebo) for 14 days starting at Study Visit 5. | Drug: GDC-6599<br>* GDC-6599 will be administered Days 1- 14 and on Days 29-42 as film-coated tablets<br>* Other names: RO7441345;Other: GDC-6599-matching placebo<br>* GDC-6599-matching placebo will be administered Days 1- 14 and on Days 29- 42. as film-coated tablets<br>Diagnostic Test: Mannitol<br>* Mannitol challenge tests will be performed during screening and at least 2.5 hours following study drug administration at Study Visits 2, 4, 5 and 7<br>|
| Experimental: Part B: Chronic Refractory Cough with Chronic Obstructive Pulmonary Disease with Chronic Bronchitis<br>Patients with Chronic Obstructive Pulmonary Disease with Chronic Bronchitis will be randomized in a 1:1 ratio to receive GDC-6599 or placebo for 14 days during the first study period (Treatment Period 1, Study Visits 2-4). Following a 14-day washout period, patients will cross over to the second study period (Treatment Period 2, Study Visits 5-7) and will receive the alternate treatment (GDC-6599 or placebo) for 14 days starting at Study Visit 5. | Drug: GDC-6599<br>* GDC-6599 will be administered Days 1- 14 and on Days 29-42 as film-coated tablets<br>* Other names: RO7441345;Other: GDC-6599-matching placebo<br>* GDC-6599-matching placebo will be administered Days 1- 14 and on Days 29- 42. as film-coated tablets<br>Diagnostic Test: Mannitol<br>* Mannitol challenge tests will be performed during screening and at least 2.5 hours following study drug administration at Study Visits 2, 4, 5 and 7<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in cough frequency per hour, assessed objectively over 24 hours (24-hour OCC) using VitaloJAK cough recorder | OCC - objective cough count over 24 hours | From baseline to Day 14 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in the severity of cough, as assessed through the use of the patient-reported cough severity VAS score | VAS - visual analog scale | From baseline to Day 14 | 
| Change in the severity of cough, as assessed through the use of the patient-reported cough severity NRS score | NRS - numeric response scale | From baseline to Day 14 | 
| Change in cough hypersensitivity to mannitol, measured as the CDR to mannitol | CDR - coughs-per-dose ratio | From baseline to Day 14 | 
| Change in mannitol-induced AHR | AHR - airway hyperresponsiveness calculated as maximum percent decrease in FEV1 after the last dose of mannitol divided by cumulative dose of mannitol administered during mannitol challenge test | From baseline to Day 14 | 
| Incidence and severity of adverse events, with severity determined according to the DAIDS toxicity grading scale |  | From baseline to Day 14 |