Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12619000227190
Ethics application status
Approved
Date submitted
12/02/2019
Date registered
18/02/2019
Date last updated
24/01/2022
Date data sharing statement initially provided
18/02/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Phase I trial to evaluate the safety and tolerability of GDC-4379 in healthy volunteers and patients with mild asthma
Scientific title
A Phase I study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of inhaled gdc-4379 conducted in three parts: a single ascending dose study in healthy volunteers, a multiple ascending dose study in healthy volunteers, and a proof-of-activity study in patients with mild asthma
Secondary ID [1] 297334 0
none
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Asthma 311443 0
Condition category
Condition code
Respiratory 310081 310081 0 0
Asthma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
For Part A, healthy volunteers will receive a single inhaled dose of GDC-4379 or placebo. The starting dose will be 1 mg inhaled. A total of 6 dose cohorts are planned: Cohort A, B, C, D, H and I. The dose will be increased by approximately 2- to 3-fold (i.e., half-log or less) increments for each successive cohort. Actual doses may be adjusted depending on the outcome of preceding cohorts. Doses will be escalated based on safety, tolerability, and available PK data.

For Part B, healthy volunteers will receive an inhaled dose of GDC-4379 or placebo once or twice daily for a total of 14 days. A total of 4 dose cohorts are planned: Cohort E, F, Q and L. The dose will be increased by approximately 2- to 3-fold (i.e., half-log or less) increments for each successive cohort. Actual doses may be adjusted depending on the outcome of preceding cohorts. Doses will be escalated based on safety, tolerability, and available PK data. Daily dose will not exceed those evaluated in Part A.

For Part C, patients with mild asthma will receive an inhaled dose of GDC-4379 or placebo once or twice daily for 14 days. A total of 3 dose cohorts are planned: Cohort M, S, and either P or T. The final dose cohort (P or T) will be determined after the completion of Part B Cohort L. Doses will be escalated based on safety, tolerability, and available PK/PD data. Dose and duration will not exceed those evaluated in Part B.

For parts A, B and C all dosing will be done in clinic under the supervision of qualified medical staff.

A Safety Monitoring committee that will include at minimum the Medical Monitor, a drug safety scientist, and a biostatistician from the Sponsor; and will be responsible for dose-escalation decisions, with consent from the investigator.

NOTE: There have been several protocol amendments and study design iterations throughout the study, which resulted in cohorts G, J, K, N, O, R (each with varying doses) being eliminated from the study. These cohorts were never enrolled. To avoid potential confusion, any newly added cohorts were assigned the next available letter in the alphabet, rather than re-assigning a previously used letter from an eliminated cohort.
Intervention code [1] 313583 0
Treatment: Drugs
Comparator / control treatment
Placebo treatment is an inhaled capsule containing lactose monohydrate with no active substance.
Control group
Placebo

Outcomes
Primary outcome [1] 318977 0
The primary objective of this study is to characterize the safety profile associated with GDC-4379. This will be measured through the incidence and the severity of any adverse events, and change from baseline in vital signs, physical exam, laboratory test results, ECG, or spirometry. As a first-in-human study, the risks at this time are unknown. All adverse events (patient or investigator reported) will be classified using MedDRA coding system and the WHO Toxicity Grading Scale.
Timepoint [1] 318977 0
Adverse events will be reported after any occurrence after the first dose. Vital signs will be collected at each study visit for part A (visit days 1 through 15). For part B and C they will be collected on visit days (1-17, 21, 28, 35 and 42).
Secondary outcome [1] 366559 0
To characterize the PK profile of GDC-4379, Plasma concentrations of GDC-4379 will be assessed and pharmacokinetic parameters such as through AUC, tmax, Cmax, and half-life will be calculated.
Timepoint [1] 366559 0
To characterize the PK profile of GDC 4379 16 plasma samples will be assessed for GDC-0214 concentrations during the course of the SAD in order to sufficiently characterize PK parameters such as Tmax, Cmax,t1/2, and AUC. Individual PK parameters will not be assessed at specific time points since they require the totality of the data. PK will be collected on Day 1 (pre-dose, (5 min, 15 min and 30 min post-dose and 1, 2, 4, 8, and 12 hours post-dose) ). On Day 2 (24h and 36h post-dose). On Day 3 (48hr post-dose). On Day 4 (72h post-dose) and anytime during visit days 6, 10 and 15.

Eligibility
Key inclusion criteria
Inclusion Criteria for Healthy Volunteers
• Signed Informed Consent Form
• Age 18-65 years
• Body mass index of 18-37 kg/m2
• Weight of 50-120 kg
• In good health, determined by no clinically significant findings from medical history, 12-lead ECG, and vital signs.
• First forced expiratory volume (FEV1) >70 % predicted
• Forced vital capacity (FVC) >2.0 L
• Ability to demonstrate sufficient inspiratory effort using the inhaler training
• Ability to comply with the study protocol, including all study procedures
• Agreement to remain abstinent or use contraceptive methods
• FeNO >25 ppb at screening for one specific cohort

Key Inclusion Criteria for Patients with Mild Asthma
• Signed Informed Consent Form
• Age 18-65 years
• Body mass index of 18-37 kg/m2
• Weight of 50-120 kg
• Documented physician-diagnosed mild asthma for at least 6 months prior to screening, defined as: Asthma that is controlled with as-needed reliever medication with or without a leukotriene receptor antagonist
• No use of inhaled corticosteroids within 60 days prior to initiation of study drug
• FeNO >40 ppb at screening and at pre-randomization visit
• No clinically significant ECG abnormalities
• Clinical laboratory evaluations should be within the reference range for the test laboratory unless deemed not clinically significant by the investigator and Sponsor.
• FEV1 >70 % predicted
• FVC >2.0 L
• Ability to demonstrate sufficient inspiratory effort using the inhaler training device
• Ability to comply with the study protocol, including all study procedures
• Agreement to remain abstinent or use contraceptive methods
Minimum age
18 Years
Maximum age
65 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Key Exclusion Criteria for Healthy Volunteers
Subjects who meet any of the following criteria will be excluded from Parts A and B:
• History or clinical manifestations of significant metabolic, hepatic, renal, pulmonary, cardiovascular, gastrointestinal, urologic, neurologic, or psychiatric disorders, in the investigator’s judgment
•History of malignancy, except completely excised basal cell carcinoma or squamous cell carcinoma of the skin
• History of nasal polyposis or nasal polyps identified during screening physical examination
• History of anaphylaxis, hypersensitivity, or significant drug allergies
• History of severe hypersensitivity to milk proteins
• History or presence of an abnormal ECG that is clinically significant
• Any medical condition or abnormality in clinical laboratory tests that, in the investigator’s judgment, precludes the subject’s safe participation in and completion of the study
• Illicit drug or alcohol abuse within 12 months prior to initiation of study drug
• Positive alcohol screen at screening or pre-randomization
• Recent history of smoking within the 30 days prior to initiation of study drug
• Smokers not able to pass the tobacco-related screening and who cannot refrain from smoking during the study
• Positive urine test for selected drugs of abuse at screening
• Pregnant or breastfeeding, or intending to become pregnant during the study
• Women of childbearing potential must have a negative pregnancy test result at screening or pre-randomization.
• Use of any prescription medications and products within 7 days prior to initiation of study drug and throughout the study
• Use of a investigational drug or recent participation in an investigational study
• Positive for hepatitis panel at screening

Exclusion Criteria for Patients with Mild Asthma
Subjects who meet any of the following criteria will be excluded from Part C:
• Any of the exclusion criteria for healthy volunteers above
• Use of ICS therapy within 60 days prior to initiation of study drug
• Lack of asthma control defined as respiratory symptoms requiring use of a reliever inhaler (e.g., 2 puffs of SABA) more than twice a day on a regular basis within 4 weeks prior to initiation of study drug (not including reliever medication used to prevent symptoms)
• Recent asthma exacerbation requiring oral corticosteroid use or urgent medical care for asthma within 12 weeks prior to initiation of study drug
• Any asthma-related history, symptoms, or findings that precludes the subject’s safe participation in and completion of the study in the investigator’s judgment
• Positive nasopharyngeal PCR test for SARS-COV-2 within 10 days prior to initiation of study drug

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Phase 1
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
3/06/2019
Actual
10/06/2019
Date of last participant enrolment
Anticipated
14/10/2020
Actual
5/03/2021
Date of last data collection
Anticipated
15/12/2020
Actual
17/04/2021
Sample size
Target
136
Accrual to date
Final
128
Recruitment outside Australia
Country [1] 21276 0
New Zealand
State/province [1] 21276 0

Funding & Sponsors
Funding source category [1] 301896 0
Commercial sector/Industry
Name [1] 301896 0
Genentech, Inc.
Country [1] 301896 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
Genentech
Address
1 DNA Way, South San Francisco CA 94080
Country
United States of America
Secondary sponsor category [1] 301688 0
None
Name [1] 301688 0
Address [1] 301688 0
Country [1] 301688 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 302586 0
Standing Committee on Therapeutic Trials (SCOTT)
Ethics committee address [1] 302586 0
Ethics committee country [1] 302586 0
New Zealand
Date submitted for ethics approval [1] 302586 0
28/02/2019
Approval date [1] 302586 0
28/02/2019
Ethics approval number [1] 302586 0

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 90734 0
Dr Chris Wynne
Address 90734 0
Christchurch Clinical Studies Trust Ltd
Level 4, 264 Antigua Street, Christchurch 8011
Country 90734 0
New Zealand
Phone 90734 0
+64 3 372 9478
Fax 90734 0
Email 90734 0
[email protected]
Contact person for public queries
Name 90735 0
Margit Bode
Address 90735 0
Genentech
1 DNA way, South San Francisco CA 94080
Country 90735 0
United States of America
Phone 90735 0
+14153178617
Fax 90735 0
Email 90735 0
[email protected]
Contact person for scientific queries
Name 90736 0
Rebecca Kunder
Address 90736 0
Genentech, Inc. 1 DNA Way, South San Francisco, CA 94080
Country 90736 0
United States of America
Phone 90736 0
+16504678708
Fax 90736 0
Email 90736 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Individual Participant Data (IPD) will not be shared. However a Lay Person Summary will be posted and shared with sites.


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseEffects of inhaled JAK inhibitor GDC-4379 on exhaled nitric oxide and peripheral biomarkers of inflammation.2022https://dx.doi.org/10.1016/j.pupt.2022.102133
N.B. These documents automatically identified may not have been verified by the study sponsor.