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

Sponsor

Genentech, Inc. (Industry)

Overall Status

Not yet recruiting

CT.gov ID

NCT05660850

Collaborator

(none)

Enrollment

Arms

19.8

Anticipated Duration (Months)

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
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	Drug: GDC-6599 Other: GDC-6599-matching placebo Diagnostic Test: Mannitol	Phase 2

Study Design

Study Type:

Interventional

Anticipated Enrollment :

80 participants

Allocation:

Randomized

Intervention Model:

Crossover Assignment

Masking:

Double (Participant, Investigator)

Primary Purpose:

Treatment

Official Title:

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

Anticipated Study Start Date :

Jan 30, 2023

Anticipated Primary Completion Date :

Sep 15, 2024

Anticipated Study Completion Date :

Sep 24, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Part A: CRC Asthma atopic 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 GDC-6599 will be administered Days 1- 14 and on Days 29-42 as film-coated tablets Other Names: RO7441345 Other: GDC-6599-matching placebo GDC-6599-matching placebo will be administered Days 1- 14 and on Days 29- 42. as film-coated tablets Diagnostic Test: Mannitol 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
Experimental: Part A: CRC Asthma non-atopic 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 GDC-6599 will be administered Days 1- 14 and on Days 29-42 as film-coated tablets Other Names: RO7441345 Other: GDC-6599-matching placebo GDC-6599-matching placebo will be administered Days 1- 14 and on Days 29- 42. as film-coated tablets Diagnostic Test: Mannitol 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
Experimental: Part A: Unexplained Chronic Cough 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 GDC-6599 will be administered Days 1- 14 and on Days 29-42 as film-coated tablets Other Names: RO7441345 Other: GDC-6599-matching placebo GDC-6599-matching placebo will be administered Days 1- 14 and on Days 29- 42. as film-coated tablets Diagnostic Test: Mannitol 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
Experimental: Part B: Chronic Refractory Cough with Chronic Obstructive Pulmonary Disease 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 GDC-6599 will be administered Days 1- 14 and on Days 29-42 as film-coated tablets Other Names: RO7441345 Other: GDC-6599-matching placebo GDC-6599-matching placebo will be administered Days 1- 14 and on Days 29- 42. as film-coated tablets Diagnostic Test: Mannitol 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
Experimental: Part B: Chronic Refractory Cough with Chronic Obstructive Pulmonary Disease with Chronic Bronchitis 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 GDC-6599 will be administered Days 1- 14 and on Days 29-42 as film-coated tablets Other Names: RO7441345 Other: GDC-6599-matching placebo GDC-6599-matching placebo will be administered Days 1- 14 and on Days 29- 42. as film-coated tablets Diagnostic Test: Mannitol 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

Outcome Measures

Primary Outcome Measures

Change in cough frequency per hour, assessed objectively over 24 hours (24-hour OCC) using VitaloJAK cough recorder [From baseline to Day 14]
OCC - objective cough count over 24 hours

Secondary Outcome Measures

Change in the severity of cough, as assessed through the use of the patient-reported cough severity VAS score [From baseline to Day 14]
VAS - visual analog scale
Change in the severity of cough, as assessed through the use of the patient-reported cough severity NRS score [From baseline to Day 14]
NRS - numeric response scale
Change in cough hypersensitivity to mannitol, measured as the CDR to mannitol [From baseline to Day 14]
CDR - coughs-per-dose ratio
Change in mannitol-induced AHR [From baseline to Day 14]
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
Incidence and severity of adverse events, with severity determined according to the DAIDS toxicity grading scale [From baseline to Day 14]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 80 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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