Chronic Refractory Cough (CRC) With Non-atopic Asthma, CRC With Atopic Asthma, CRC With Chronic Obstructive Pulmonary Disease, CRC With Chronic Obstructive Pulmonary Disease With Chronic Bronchitis, Unexplained Chronic Cough
Conditions
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.
Detailed description
The main study (Part A) enrolled participants with chronic refractory cough (CRC) with asthma with/without atopy as well as participants with unexplained chronic cough (UCC); the substudy (Part B) enrolled participants with chronic obstructive pulmonary disease (COPD) with/without chronic bronchitis (CB). The main objective of the study was was to evaluate the efficacy of GDC-6599, as compared with placebo, in participants with CRC with asthma or UCC (i.e. across all participants in main study - Part A, regardless of the disease background).
Interventions
DRUGGDC-6599
GDC-6599 will be administered Days 1- 14 and on Days 29-42 as film-coated tablets
OTHERGDC-6599-matching placebo
GDC-6599-matching placebo will be administered Days 1- 14 and on Days 29- 42. as film-coated tablets
DIAGNOSTIC_TESTMannitol
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
Sponsors
Genentech, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part A: Cough Frequency Per Hour, Assessed Objectively Over 24 Hours Using VitaloJAK® Cough Recorder | Baseline and Day 14 of Periods 1 and 2 | Cough numbers were assessed by the VitaloJAK semi-automated cough-monitoring system. The VitaloJAK device recorded ambulatory audio for 24 hours from two channels, a lapel microphone (air) and a chest-facing sensor (skin). A software algorithm removed non-cough sounds from the 24-hour audio recordings, compressing the files to less than 10% (on average) of the original length enabling manual analysis to be completed more quickly. The recordings were reviewed by trained Vitalograph analysts who counted individual explosive cough sounds, yielding hourly and 24-hour objective cough count (OCCs). Cough frequency was calculated as the total number of coughs for the full 24 hours recording minus coughs flagged within Mute, Flagged Area, Device Not Attached and Recording Ended Early events divided by the full 24 hours recording minus Mute, Flagged Area, Device Not Attached and Recording Ended Early event time. The standard deviation (SD) reported here is geometric SD. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part A: Change From Baseline in the Severity of Cough, as Assessed Using Participant-reported Cough Severity Visual Analog Scale (VAS) Scores | Baseline to Day 14 of Periods 1 and 2 | Cough severity scores were assessed by the participants using VAS. The VAS was a single-item rating used for the subjective assessment of cough severity. Participants were asked to indicate the severity of their cough by marking a line on a scale between anchor statements of 'no cough' and 'worst cough'. The score was determined by measuring the distance on the line between the anchor and the participant's mark, providing a range of scores from 0-100. A higher score indicates greater severity. |
| Part A: Change From Baseline in the Severity of Cough, as Assessed Using Participant-reported Cough Severity Numeric Response Scale (NRS) Scores | Baseline to Day 14 of Periods 1 and 2 | Cough severity scores were assessed by the participants using the NRS. Participants were asked to rate the severity of their cough in the last 24 hours from 0 (no cough) to 10 (worst cough). Higher scores indicates greater severity. |
| Number of Participants With Adverse Events (AEs) | From signing of informed consent form (ICF) until 28 days after the final dose of study drug (up to approximately 16 weeks) | An AE was any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product, regardless of causal attribution. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. |
| Plasma Concentration of GDC-6599 | Predose and 3 hours post dose on Days 1 and 14 of Periods 1 and 2 and Day 71 (Safety Follow-up Visit) | — |
Countries
Australia, Canada, United Kingdom, United States
Participant flow
Recruitment details
A total of 49 participants with chronic cough took part in the study at 22 investigative sites across Australia, Canada, the United States, and the United Kingdom from 22 March 2023 to 20 October 2024. The study was terminated due to the sponsor's decision to discontinue the clinical development of GDC-6599.
Pre-assignment details
This study had 2 parts: Part A (main study): chronic refractory cough (CRC) with asthma with/without atopy & unexplained chronic cough (UCC); and Part B (substudy): CRC with chronic obstructive pulmonary disease (COPD) with/without chronic bronchitis (CB). Participants were randomized in 1:1 ratio into 2 crossover sequences (14-day Treatment Periods 1 and 2) to receive GDC-6599 and placebo and were then followed up for safety during the 28-day Safety Follow-up Period.
Participants by arm
| Arm | Count |
|---|---|
| Part A: GDC-6599 - Placebo Participants with CRC-asthma with/without atopy, and UCC received GDC-6599, 50 milligrams (mg) tablets, orally, twice a day (BID) for 14 days in Period 1. Following a 14-day washout period, participants received GDC-6599 matching placebo, BID for 14 days in Period 2. | 24 |
| Part A: Placebo - GDC-6599 Participants with CRC-asthma with/without atopy, and UCC received GDC-6599 matching placebo tablets, orally, BID for 14 days in Period 1. Following a 14-day washout period, participants received GDC-6599, 50 mg, BID for 14 days in Period 2. | 23 |
| Part B: GDC-6599 - Placebo Participants with CRC-COPD with/without CB received GDC-6599, 50 mg tablets, orally, BID for 14 days in Period 1. Following a 14-day washout period, participants received GDC-6599 matching placebo, orally, BID for 14 days in Period 2. | 1 |
| Part B: Placebo - GDC-6599 Participants with CRC-COPD with/without CB received GDC-6599 matching placebo tablets, orally, BID for 14 days in Period 1. Following a 14-day washout period, participants received GDC-6599, 50 mg, BID for 14 days in Period 2. | 1 |
| Total | 49 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Treatment Period 2 | Study Terminated by Sponsor | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Part A: GDC-6599 - Placebo | Total | Part B: Placebo - GDC-6599 | Part B: GDC-6599 - Placebo | Part A: Placebo - GDC-6599 |
|---|---|---|---|---|---|
| Age, Continuous | 62.1 years STANDARD_DEVIATION 9.1 | 60.7 years STANDARD_DEVIATION 11 | 68.0 years | 70.0 years | 58.5 years STANDARD_DEVIATION 12.8 |
| Cohorts CRC Asthma Atopic | 4 Participants | 7 Participants | 0 Participants | 0 Participants | 3 Participants |
| Cohorts CRC Asthma Non-Atopic | 4 Participants | 9 Participants | 0 Participants | 0 Participants | 5 Participants |
| Cohorts CRC COPD | 0 Participants | 2 Participants | 1 Participants | 1 Participants | 0 Participants |
| Cohorts UCC | 16 Participants | 31 Participants | 0 Participants | 0 Participants | 15 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants | 7 Participants | 0 Participants | 0 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 20 Participants | 42 Participants | 1 Participants | 1 Participants | 20 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 23 Participants | 48 Participants | 1 Participants | 1 Participants | 23 Participants |
| Sex: Female, Male Female | 13 Participants | 32 Participants | 1 Participants | 1 Participants | 17 Participants |
| Sex: Female, Male Male | 11 Participants | 17 Participants | 0 Participants | 0 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 49 | 0 / 49 | 0 / 49 |
| other Total, other adverse events | 5 / 49 | 2 / 49 | 0 / 49 |
| serious Total, serious adverse events | 0 / 49 | 0 / 49 | 0 / 49 |
Outcome results
Primary
Part A: Cough Frequency Per Hour, Assessed Objectively Over 24 Hours Using VitaloJAK® Cough Recorder
Cough numbers were assessed by the VitaloJAK semi-automated cough-monitoring system. The VitaloJAK device recorded ambulatory audio for 24 hours from two channels, a lapel microphone (air) and a chest-facing sensor (skin). A software algorithm removed non-cough sounds from the 24-hour audio recordings, compressing the files to less than 10% (on average) of the original length enabling manual analysis to be completed more quickly. The recordings were reviewed by trained Vitalograph analysts who counted individual explosive cough sounds, yielding hourly and 24-hour objective cough count (OCCs). Cough frequency was calculated as the total number of coughs for the full 24 hours recording minus coughs flagged within Mute, Flagged Area, Device Not Attached and Recording Ended Early events divided by the full 24 hours recording minus Mute, Flagged Area, Device Not Attached and Recording Ended Early event time. The standard deviation (SD) reported here is geometric SD.
Time frame: Baseline and Day 14 of Periods 1 and 2
Population: ITT population included all participants who received any amount of GDC-6599 or placebo. Number analyzed is the number of participants with data available for analysis at the specified timepoint. As prespecified in the protocol participants were grouped according to the treatment received in Part A to compare results between GDC-6599 \& placebo regardless of treatment period \& disease cohort.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| GDC-6599 | Part A: Cough Frequency Per Hour, Assessed Objectively Over 24 Hours Using VitaloJAK® Cough Recorder | Baseline | 14.88 coughs/hour |
| GDC-6599 | Part A: Cough Frequency Per Hour, Assessed Objectively Over 24 Hours Using VitaloJAK® Cough Recorder | Day 14 | 12.61 coughs/hour |
| Placebo | Part A: Cough Frequency Per Hour, Assessed Objectively Over 24 Hours Using VitaloJAK® Cough Recorder | Baseline | 17.30 coughs/hour |
| Placebo | Part A: Cough Frequency Per Hour, Assessed Objectively Over 24 Hours Using VitaloJAK® Cough Recorder | Day 14 | 13.21 coughs/hour |
Secondary
Number of Participants With Adverse Events (AEs)
An AE was any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product, regardless of causal attribution. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.
Time frame: From signing of informed consent form (ICF) until 28 days after the final dose of study drug (up to approximately 16 weeks)
Population: Safety population included all randomized participants who received at least one dose of study drug. As prespecified in the protocol participants in Part A and Part B were grouped according to the treatment received to compare results between GDC-6599 \& placebo regardless of treatment period \& disease cohort.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| GDC-6599 | Number of Participants With Adverse Events (AEs) | 18 Participants |
| Placebo | Number of Participants With Adverse Events (AEs) | 13 Participants |
Secondary
Part A: Change From Baseline in the Severity of Cough, as Assessed Using Participant-reported Cough Severity Numeric Response Scale (NRS) Scores
Cough severity scores were assessed by the participants using the NRS. Participants were asked to rate the severity of their cough in the last 24 hours from 0 (no cough) to 10 (worst cough). Higher scores indicates greater severity.
Time frame: Baseline to Day 14 of Periods 1 and 2
Population: ITT population included all participants who received any amount of GDC-6599 or placebo. Overall number analyzed is the number of participants with data available for analysis. As prespecified in the protocol participants were grouped according to the treatment received in Part A to compare results between GDC-6599 \& placebo regardless of treatment period \& disease cohort.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| GDC-6599 | Part A: Change From Baseline in the Severity of Cough, as Assessed Using Participant-reported Cough Severity Numeric Response Scale (NRS) Scores | -1.237 score on a scale | Standard Deviation 1.676 |
| Placebo | Part A: Change From Baseline in the Severity of Cough, as Assessed Using Participant-reported Cough Severity Numeric Response Scale (NRS) Scores | -1.022 score on a scale | Standard Deviation 1.56 |
Secondary
Part A: Change From Baseline in the Severity of Cough, as Assessed Using Participant-reported Cough Severity Visual Analog Scale (VAS) Scores
Cough severity scores were assessed by the participants using VAS. The VAS was a single-item rating used for the subjective assessment of cough severity. Participants were asked to indicate the severity of their cough by marking a line on a scale between anchor statements of 'no cough' and 'worst cough'. The score was determined by measuring the distance on the line between the anchor and the participant's mark, providing a range of scores from 0-100. A higher score indicates greater severity.
Time frame: Baseline to Day 14 of Periods 1 and 2
Population: ITT population included all participants who received any amount of GDC-6599 or placebo. Overall number analyzed is the number of participants with data available for analysis. As prespecified in the protocol participants were grouped according to the treatment received in Part A to compare results between GDC-6599 \& placebo regardless of treatment period \& disease cohort.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| GDC-6599 | Part A: Change From Baseline in the Severity of Cough, as Assessed Using Participant-reported Cough Severity Visual Analog Scale (VAS) Scores | -11.218 score on a scale | Standard Deviation 17.408 |
| Placebo | Part A: Change From Baseline in the Severity of Cough, as Assessed Using Participant-reported Cough Severity Visual Analog Scale (VAS) Scores | -9.642 score on a scale | Standard Deviation 16.56 |
Secondary
Plasma Concentration of GDC-6599
Time frame: Predose and 3 hours post dose on Days 1 and 14 of Periods 1 and 2 and Day 71 (Safety Follow-up Visit)
Population: Pharmacokinetic (PK) population included all participants with sufficient data to enable estimation of key parameters with participants grouped according to treatment received. Number analyzed is the number of participants with data available for analysis at the specified time point. As prespecified in the protocol participants in Part A and Part B were grouped according to the sequence in which they received treatment regardless of treatment period \& disease cohort.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| GDC-6599 | Plasma Concentration of GDC-6599 | 3 Hour Post dose on Day 1 Period 1 | 404 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 71.4 |
| GDC-6599 | Plasma Concentration of GDC-6599 | 3 Hour Post dose on Day 1 Period 2 | 0.250 nanograms per milliliter (ng/mL) | — |
| GDC-6599 | Plasma Concentration of GDC-6599 | 3 Hour Post dose on Day 14 Period 1 | 745 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 52.2 |
| GDC-6599 | Plasma Concentration of GDC-6599 | Predose on Day 14 Period 2 | 0.250 nanograms per milliliter (ng/mL) | — |
| GDC-6599 | Plasma Concentration of GDC-6599 | Predose on Day 14 Period 1 | 364 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 126.4 |
| GDC-6599 | Plasma Concentration of GDC-6599 | 3 Hour Post dose on Day 14 Period 2 | 0.250 nanograms per milliliter (ng/mL) | — |
| GDC-6599 | Plasma Concentration of GDC-6599 | Predose on Day 1 Period 2 | 0.250 nanograms per milliliter (ng/mL) | — |
| GDC-6599 | Plasma Concentration of GDC-6599 | Day 71 (Safety Follow-up Visit) | 0.250 nanograms per milliliter (ng/mL) | — |
| GDC-6599 | Plasma Concentration of GDC-6599 | Predose on Day 1 Period 1 | NA nanograms per milliliter (ng/mL) | — |
| Placebo | Plasma Concentration of GDC-6599 | Day 71 (Safety Follow-up Visit) | 0.250 nanograms per milliliter (ng/mL) | — |
| Placebo | Plasma Concentration of GDC-6599 | Predose on Day 1 Period 1 | NA nanograms per milliliter (ng/mL) | — |
| Placebo | Plasma Concentration of GDC-6599 | 3 Hour Post dose on Day 1 Period 1 | 0.250 nanograms per milliliter (ng/mL) | — |
| Placebo | Plasma Concentration of GDC-6599 | Predose on Day 14 Period 1 | 0.250 nanograms per milliliter (ng/mL) | — |
| Placebo | Plasma Concentration of GDC-6599 | 3 Hour Post dose on Day 14 Period 1 | 0.250 nanograms per milliliter (ng/mL) | — |
| Placebo | Plasma Concentration of GDC-6599 | Predose on Day 1 Period 2 | 0.250 nanograms per milliliter (ng/mL) | — |
| Placebo | Plasma Concentration of GDC-6599 | 3 Hour Post dose on Day 1 Period 2 | 521 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 37 |
| Placebo | Plasma Concentration of GDC-6599 | Predose on Day 14 Period 2 | 199 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 512.3 |
| Placebo | Plasma Concentration of GDC-6599 | 3 Hour Post dose on Day 14 Period 2 | 758 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 42.2 |