Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12618001980224
Ethics application status
Approved
Date submitted
4/12/2018
Date registered
10/12/2018
Date last updated
22/05/2019
Date data sharing statement initially provided
10/12/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
A placebo controlled phase 1 study to determine the safety and tolerability of ascending doses of GT-1 (a new antibiotic) in healthy adult participants following intravenous infusion.
Scientific title
A Phase 1, Randomized, Double-blind, Placebo-controlled, Dose Escalation Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of GT-1 in Healthy Adult Subjects.
Secondary ID [1] 296726 0
GT1-001
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Gram-negative Infections 310589 0
Condition category
Condition code
Infection 309301 309301 0 0
Studies of infection and infectious agents

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This study will comprise of 64 healthy adult participants who will receive GT-1 (a new antibiotic) or placebo (saline) by intravenous (IV) infusion. The study is split into two parts: Part 1 and Part 2.

Part 1
Part 1 will be split into 5 groups (cohorts) of 8 participants in each group. In each group 2 participants will be sentinel participants meaning they will be dosed and assessed for safety prior to the rest of the group receiving the study treatment. One (1) sentinel participant will be randomised to receive GT-1 and the other sentinel participant will receive placebo. After 24-48 hours, following a positive safety review, the remaining 6 participants will receive the study drug. Of these 6 participants, 5 will receive GT-1 and 1 will receive placebo.
Five dose levels of GT-1 will be assessed in Part 1 according to an ascending single-dose regimen (0.5, 1, 2, 3, and 4 g). The starting dose is based on safety results from nonclinical studies. An extra dose cohort may be added in Part 1 if all 5 previous dosages are well tolerated and all accumulated pharmacokinetic (PK) and safety data appear to support the addition of a higher dose. The dose for this cohort is to be determined but will be between 4.5g and 6.0g administered by IV administration.

Participants in Part 1 will be admitted to the Clinical Unit for 3 days from 1 day prior to dosing until 2 days after dosing after which they will return to the Clinical Unit on Day 7 for a follow-up visit.

Part 2
Part 2 will be split into 3 groups of 8 participants in each group. There are no sentinel participants in the Part 2 groups. In each group participants will be randomised to receive multiple IV infusions of GT-1 or placebo over 7 calendar days. The amount of GT-1 to be infused in each group and the number of infusions will be determined based on the safety information obtained in Part 1. In each group, 6 participants will receive GT-1 infusions and 2 participants will receive placebo infusions.
Participants in Part 2 will be admitted to the Clinical Unit for 9 days from 1 day prior to dosing until Day 8 (at least 24 hours after the last dose) after which they will return to the Clinical Unit on Day 12 for a follow-up visit.
Intervention code [1] 313034 0
Treatment: Drugs
Comparator / control treatment
The placebo consists of 0.9% saline. It will be administered as a single IV infusion for participants in Part 1. Placebo Participants in Part 2 will receive multiple IV infusions of 0.9% saline.
Control group
Placebo

Outcomes
Primary outcome [1] 308268 0
To assess the safety of GT-1 following single ascending doses and multiple ascending doses by IV infusion in healthy adult subjects. This will be assessed by clinical laboratory testing, physical examination, vital sign assessments, ECGs and by noting the frequency and types of adverse events.
.
Timepoint [1] 308268 0
Participants will be confined in the Phase 1 unit for 48 hours after dosing in Part 1 and 24 hours after doing in Part 2 for continuous observation and regular safety assessments. The participants return to the Phase 1 unit on Day 7 for Part 1 and Day 12 for Part 2.

Primary outcome [2] 308269 0
To assess the PK characteristics in plasma and urine of GT-1 following single ascending doses and multiple ascending doses by IV infusion in healthy adult subjects. This is a composite outcome.
The following PK parameters will be determined:
• Maximum plasma concentration (Cmax)
• Time to maximum plasma concentration (Tmax)
• Area under the curve (AUC) to the last measurable (ie, above the lower limit of quantification) concentration
• Clearance
• Volume of distribution (Vz)
• Elimination rate constant (lambda z)
• Terminal half-life (t1/2)

For data from Part 2 (MAD), the following plasma PK parameters will also be estimated:
• Minimum concentration over the inter-dosing interval (Cmin)
• AUC over the inter-dosing interval (AUCtau)
• Percent fluctuation over the inter-dosing interval (%Fluc)
• Average drug concentration at steady-state (Cssave)
• Accumulation index (AI)

Urine concentration data will be used in the determination of renal excretion and drug recovery rate in the urine.
Timepoint [2] 308269 0
Blood draws to assess PK measurements will be taken both pre and post dose at the following time-points:

Part 1
- pre-dose
- 30 , 60, 75 and 90 minutes post-dose
- 2, 2.5, 3, 4, 6, 8, 10, 12, 24 and 48 hours post-dose

Part 2
- pre-dose
- 30, 60, 75 and 90 minutes post first dose
- 2, 2.5, 3, 4, 6 and 8 hours post first dose
- pre-dose on Days 2, 4, 6 and 7
- 30, 60, 75 and 90 minutes post last dose
- 2, 2.5, 3, 4, 6, 8, 10, 12 and 24 hours post last dose

Urine PK samples will be collected both pre and post-dose at the following time-points:

Part 1
- pre-dose
- 0-2, >2-4, >4-8, >8-12, >12-24 hours (Days 1-2) and >24-48 hours (Days 2-3) post-dose

Part 2
- pre-dose
- 0-8 post first dose
- 0-8 hours post last dose
Secondary outcome [1] 354544 0
N/A
Timepoint [1] 354544 0
N/A

Eligibility
Key inclusion criteria
1. Healthy male or female 18 to 50 years of age, inclusive, at time of consent
2. Female subjects of child-bearing potential, if sexually active with a male partner, must agree to and comply with using 1 barrier method (eg, female condom or male partner using a condom) plus 1 other highly effective method of birth control (eg, oral contraceptive, implant, injectable, indwelling intrauterine device, vasectomized partner), or sexual abstinence, for the duration of the study (from signing of consent to FU visit) and for 30 days after last study drug administration. Females of child-bearing potential must also agree not to donate ova or oocytes (ie, human eggs) during the study. To be considered not of childbearing potential, a female must have either a tubal ligation, hysterectomy, bilateral salpingo-oophrectomy, or menopause (last menstruation >12 months and follicle-stimulating hormone in menopausal range).
3. Male subjects, if sexually active with a female partner, must agree to and comply with using 1 barrier method of birth control (eg, male condom) plus 1 other highly effective method of birth control in their partner (eg, oral contraceptive; implant, injectable, indwelling intrauterine device), or sexual abstinence, and must not donate sperm, for the duration of the study (from signing of consent to FU visit) and for 90 days after last study drug administration
4. Agrees to be available for all study visits and cooperate fully with the requirements of the study protocol, including the schedule of assessments
5. Normal clinical examination including:
a. No physical examination findings that PI determines would interfere with interpretation of study results
b. Screening visit triplicate ECG without clinically significant abnormalities, including a QTcF interval duration less than or equal to 450 msec obtained as an average from the triplicate screening ECGs after at least 5 minutes in a semi-supine quiet rest position
c. Hemoglobin/hematocrit, white blood cell count, and platelet count within the normal range of the reference laboratory, unless deemed not clinically significant by the Investigator (eg, asymptomatic Gilbert’s disease)
d. Serum creatinine, urea, alanine aminotransferase, and aspartate aminotransferase equal to or less than the upper limit of normal for the reference laboratory; results of all other clinical chemistry and urine analytes without any clinically significant abnormality
e. Estimated creatinine clearance (CrCl) greater than or equal to 80 mL/min as determined by the Cockcroft-Gault formula
6. Body mass index greater than or equal to 18.0 and less than or equal to 30.0 kg/m2
7. Willing to refrain from over-the-counter (OTC) or prescription medications or nutritional supplements from Screening visit until discharge from the CRU
8. Willing to refrain from strenuous physical activity that could cause muscle aches or injury, including contact sports, at any time from Screening visit until completion of the study (FU visit)
9. Willing and able to provide written informed consent
Minimum age
18 Years
Maximum age
50 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. Women who are pregnant and/or nursing
2. History of any intolerance, hypersensitivity, or allergic reaction to any ß-lactam antibiotic
3. History of QT prolongation, clinically significant hypokalemia, or other proarrhythmic conditions
4. History of a known or suspected central nervous system disorders, such as hallucinations, suicidal thoughts, suicidal acts, or of a central nervous system disorder that may predispose to seizures or lower the seizure threshold
5. History of Clostridium difficile infection
6. Hypertension (confirmed systolic BP >140 mm Hg or diastolic BP >90 mm Hg), bradycardia (heart rate <50 bpm), or tachycardia (HR >100 bpm) measured after 10 to 15 minutes of rest at Screening visit
7. Surgery within the 3 months before randomization determined by the PI to be clinically relevant
8. Experiencing symptoms of acute illness or chronic disease within 30 days before randomization
9. History of recent vaccination within 14 days of first dose of study medication
10. Positive screen for hepatitis B virus surface antigen, hepatitis C virus antibody, or human immunodeficiency virus (HIV) antibody
11. Received any prescription or OTC medications, or herbal, nutritional, and dietary supplements within 7 days before randomization, with the exception of hormonal contraception per Inclusion Criterion #2
12. Received any systemic antibiotic within 30 days before randomization
13. Smoker or nicotine user within the 3 months before randomization
14. History of substance abuse or alcohol abuse defined as an average daily intake >3 units, or an average weekly intake >21 units, where 1 unit is equivalent to 1 can or bottle (12 oz) of beer, or 1 measure (1.5 oz) of spirits, or 1 glass (5 oz) of wine within the previous 2 years
15. Positive breath test for alcohol or urine screen for drugs of abuse
16. Donation of blood or plasma within 30 days before randomization, or loss of whole blood of more than 50 mL within the 30 days before randomization, or receipt of a blood transfusion within 1 year of study enrollment
17. Previous participation in this study or previous participation in another study within 30 days (or <5 half-lives of the study drug, whichever is longer) of Day 1; prior participation at any time in non-invasive methodology trials in which no drugs were given is acceptable
18. Employee or family member of an employee of the Sponsor, CRU, or clinical research organization at which the study will be conducted
19. Unable to cooperate fully with the requirements of the study protocol, including the schedule of assessments, or likely to be non-compliant with any study requirements
20. Any disease or condition (medical or surgical) that, by the determination of the PI, might compromise interpretation of safety or PK data, or would place the subject at risk as a result of participation in the study

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
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Other design features
Phase
Phase 1
Type of endpoint/s
Safety
Statistical methods / analysis
This is an exploratory study and, therefore, it is not powered for inferential statistical analyses.

Data will be summarized and listed separately for each study part. Continuous data will be summarized using the number of subjects, mean, standard deviation, median, minimum and maximum values for continuous variables, whilst categorical data will present the number and percentage of subjects within each category. Summaries will be provided by dose level (each GT-1 dose level or placebo) for each study part. Data on subjects receiving placebo will be pooled across SAD cohorts and will also be pooled across MAD cohorts. All data will be summarized separately by dose level for each study part. Listings of individual subject data will also be produced, for each study part

Recruitment
Recruitment status
Stopped early
Data analysis
No data analysis planned
Reason for early stopping/withdrawal
Safety concerns
Date of first participant enrolment
Anticipated
6/03/2019
Actual
14/03/2019
Date of last participant enrolment
Anticipated
18/07/2019
Actual
2/04/2019
Date of last data collection
Anticipated
30/07/2019
Actual
11/04/2019
Sample size
Target
64
Accrual to date
Final
8
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 12578 0
Nucleus Network - Melbourne
Recruitment postcode(s) [1] 24955 0
3004 - Melbourne

Funding & Sponsors
Funding source category [1] 301307 0
Commercial sector/Industry
Name [1] 301307 0
Geom Therapeutics Australia Pty Ltd
Country [1] 301307 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Clinical Network Services (CNS) Pty Ltd
Address
Level 4, 88 Jephson Street
Toowong, QLD 4066
Country
Australia
Secondary sponsor category [1] 300988 0
Commercial sector/Industry
Name [1] 300988 0
Geom Therapeutics Australia Pty Ltd
Address [1] 300988 0
Level 4, 88 Jephson Street
Toowong, QLD 4066
Country [1] 300988 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 302048 0
Alfred Hospital Ethics Committee
Ethics committee address [1] 302048 0
Ethics committee country [1] 302048 0
Australia
Date submitted for ethics approval [1] 302048 0
10/12/2018
Approval date [1] 302048 0
07/02/2019
Ethics approval number [1] 302048 0

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

Contacts
Principal investigator
Name 88954 0
Dr Ben Snyder
Address 88954 0
Centre for Clinical Studies
Nucleus Network Limited,
Level 5 Burnet Building AMREP Precinct
89 Commercial Rd
Melbourne Vic 3004
Country 88954 0
Australia
Phone 88954 0
+61 3 8593 9800
Fax 88954 0
Email 88954 0
[email protected]
Contact person for public queries
Name 88955 0
Brendan Hannah
Address 88955 0
Geom Therapeutics
PO Box 330365
San Francisco, CA 94133
Country 88955 0
United States of America
Phone 88955 0
+1 619 990 8136
Fax 88955 0
Email 88955 0
[email protected]
Contact person for scientific queries
Name 88956 0
Brendan Hannah
Address 88956 0
Geom Therapeutics
PO Box 330365
San Francisco, CA 94133
Country 88956 0
United States of America
Phone 88956 0
+1 619 990 8136
Fax 88956 0
Email 88956 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
The data sharing statement was marked 'No' with the reason being that this is a healthy volunteer study and the individual participant results are not useful to the participants or to others outside of the Sponsor.


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
No additional documents have been identified.