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Trial registered on ANZCTR


Registration number
ACTRN12620000834954
Ethics application status
Approved
Date submitted
7/08/2020
Date registered
24/08/2020
Date last updated
24/08/2020
Date data sharing statement initially provided
24/08/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
A Randomized, Double-Blind, Placebo-Controlled Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Multiple Ascending Doses of GP1681 in Healthy Adult Participants
Scientific title
A Randomized, Double-Blind, Placebo-Controlled Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Multiple Ascending Doses of GP1681 in Healthy Adult Participants
Secondary ID [1] 301749 0
Nil
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Cytokine Release Syndrome (CRS) 318207 0
COVID-19 318208 0
Condition category
Condition code
Respiratory 316214 316214 0 0
Other respiratory disorders / diseases
Infection 316740 316740 0 0
Studies of infection and infectious agents
Inflammatory and Immune System 316741 316741 0 0
Other inflammatory or immune system disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Intervention: GP1681
Administration: oral (liquid formulation)
Multiple Ascending Dose (MAD) study
Cohort 1: GP1681 5mcg every 8 hours for 7 days (6 active, 2 placebo)
Cohort 2: GP1681 TBC mcg every 8 hours for 7 days (6 active, 2 placebo)
Cohort 3: GP1681 TBC mcg every 8 hours for 7 days (6 active, 2 placebo)

Each cohort will be evaluated for safety by a Dose Escalation Committee (DEC) before escalation to the next dose level cohort. Based on this review, the DEC will decide on the dose level for the next cohort. The next cohort will start 2 weeks after the previous cohort.
Dose escalation will begin at 15 mcg/day and continue until either a maximum tolerated dose (MTD) or a maximum dose of 90 mcg/day is reached or until 3 cohorts have been enrolled.
To monitor any responses and adherence to the intervention, GP1681 will be administered under direct supervision.
Intervention code [1] 318043 0
Treatment: Drugs
Comparator / control treatment
The oral placebo will be 10% w/v polyethylene glycol 400 in phosphate buffered saline (pH 7.4), volume matched and administered in the same way as the IP.
Control group
Placebo

Outcomes
Primary outcome [1] 324399 0
The frequency and severity of treatment-emergent adverse events (TEAEs), including clinically significant abnormal vital signs, ECGs, respiratory monitoring (including O2 saturation and spirometry), laboratory test results (including viral reactivation), cardiac telemetry results, and physical examination (PE) findings.
Timepoint [1] 324399 0
AE: Screening, Baseline, Day 1, Day 2, Day 3, Day 4, Day 5, Day 6, Day 7, Day 8 and Day 14.
Vital signs: Vitals and orthostatic BP will be obtained at Screening, Baseline, predose and 1, 2, 3, 4, 6, and 8 hours post-morning dose on Day 1, predose and 2 hours post-morning dose on Days 2 to 7, prior to discharge on Day 8, and on Day 14.
ECG: ECGs will be recorded at Screening, Baseline, pre-morning dose and at 1, 2, and 4 hours post-morning dose on Day 1, 2 hours post-morning dose on Days 2 to 7, prior to discharge on Day 8, and on Day 14.
O2 Saturation: O2 saturation to be taken at Baseline, predose to dosing and at 2 hours (±30 minutes) post-morning dose on each day of dosing, prior to discharge on Day 8, and on Day 14.
Spirometry: Baseline, Day 8 and Day 14.
Biochemistry, coagulation, hematology: Blood samples will be taken at Screening, Baseline, pre-morning dose on Days 2, 4, and 6, prior to discharge on Day 8, and on Day 14.
Urinalysis (including microscopic examination and examination for casts): Urine samples will be taken at Screening, Baseline, pre-morning dose on Days 2, 4, and 6, prior to discharge on Day 8, and on Day 14.
Viral reactivation (EBV, HSV, VZV, CMV and HBV): Blood samples will be collected at Screening, prior to discharge on Day 8, and on Day 14.
Cardiac telemetry monitoring: Continuous cardiac telemetry will be conducted for 48 hours, from the morning of Baseline (at least 24 hours prior to the first dose) to the morning of Day 2 (24 hours [+30 minutes] post first dose).
Physical Examination: Complete PE during Screening and Symptom-directed PE at Baseline, Day 2, Day 5, Day 7, Day 8 and Day 14.
Primary outcome [2] 324400 0
The frequency and severity of adverse events of special interest (AESIs), including clinically significant changes from baseline in coagulation parameters or platelets or persistent/recurrent symptomatic orthostatic hypotension.
Timepoint [2] 324400 0
AE: Screening, Baseline, Day 1, Day 2, Day 3, Day 4, Day 5, Day 6, Day 7, Day 8 and Day 14.
Vital signs: Vitals and orthostatic BP will be obtained at Screening, Baseline, predose and 1, 2, 3, 4, 6, and 8 hours post-morning dose on Day 1, predose and 2 hours post-morning dose on Days 2 to 7, prior to discharge on Day 8, and on Day 14.
Biochemistry, coagulation, hematology: Blood samples will be taken at Screening, Baseline, pre-morning dose on Days 2, 4, and 6, prior to discharge on Day 8, and on Day 14.
Urinalysis (including microscopic examination and examination for casts): Urine samples will be taken at Screening, Baseline, pre-morning dose on Days 2, 4, and 6, prior to discharge on Day 8, and on Day 14.
Secondary outcome [1] 384559 0
The plasma PK endpoints of the study are:
For initial (single) dosing (Day 1, post first dose):
• Maximum observed concentration (Cmax).
• Time to maximum observed drug concentration (tmax).
• Apparent elimination half life (t½).
• Area under the drug concentration-time curve (AUC) from time zero to 8 hours postdose (AUC0-8).
• AUC from time zero to the last measurable concentration within the first dosing interval based on actual times (AUC0-last).
• AUC from time zero to infinity based on available first dosing interval measurable concentrations (AUC0-inf).
• AUC from time t to infinity as a percentage of the total AUC (%AUCextrap).
• Apparent terminal elimination rate constant (kel).
• Apparent clearance (CL/F).
• Apparent terminal volume of distribution (Vz/F).

For multiple doses at steady state (SS) (Day 7):
• Maximum SS plasma concentration during a dosing interval (Cmax,ss).
• Time to maximum concentration at SS (tmax,ss).
• Lowest concentration in a dosing interval (Cmin,ss).
• Average concentration during a dosing interval (Cav,ss).
• Concentration at the end of the dosing interval (Ctrough).
• AUC during a dosage interval (AUC0-tau) including AUC0-last, AUC0-inf, and AUC%extrap at SS.
• AUC from time zero to 8 hours post dose (AUC0-8).
• Apparent terminal elimination rate constant at SS (kel,ss).
• Apparent clearance at SS (CL/Fss).
• Apparent terminal volume of distribution at SS (Vz/Fss).
• Accumulation ratio (RA) for Cmax and AUCtau.
Timepoint [1] 384559 0
PK blood samples: Day 1 (pre-dose, 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 3, 4, 6, 8, 8.75, 16, 16.75 and 24 hours post-morning dose), Day 2 (pre-morning dose), Day 3 (pre-morning dose), Day 4 (pre-morning dose), Day 5 (pre-morning dose), Day 6 (pre-morning dose), Day 7 (pre-dose, 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 3, 4, 6, 8, 8.75, 16, 16.75 and 24 hours post-morning dose) and Day 8
Secondary outcome [2] 384560 0
The PD endpoints of the study are:
• Actual values and change from baseline in plasma cytokine levels.
Timepoint [2] 384560 0
PD (cytokine): Blood samples will be collected on Day 1 pre-morning dose, and at 1 and 11 hours post-morning dose on Day 1, pre-morning dose on Days 2, 4, and 6, prior to discharge on Day 8, and on Day 14.

Eligibility
Key inclusion criteria
To be eligible for this study, participants must meet all of the following criteria:
1. Healthy male and female volunteers aged >= 18 to <= 65 years at the time of informed consent.
2. In good health as determined by medical history and PE at Screening and Admission to the CRU.
3. Must have a minimum body weight of >=45 kg and <=100 kg and a BMI between 18 and 30 kg/m2, inclusive, at Screening.
4. Must have clinical laboratory values within normal range as specified by the testing laboratory, unless deemed not clinically significant by the Investigator or their delegate.
5. Negative test for drugs of abuse at Screening and Admission to the CRU.
6. Negative test for alcohol use (breathalyzer) at Screening and Admission to the CRU.
7. Women of childbearing potential must use an acceptable, highly effective double barrier contraception from Screening until study completion, including the follow-up period. Double contraception is defined as a condom AND one other form of the following:
a. Established hormonal contraception (oral contraceptive pill, long-acting implantable hormones, injectable hormones).
b. A vaginal ring or an IUD).
c. Documented evidence of surgical sterilization at least 6 months prior to Screening (e.g., tubal occlusion, hysterectomy, bilateral salpingectomy, or bilateral oophorectomy for women or vasectomy for men [with appropriate post-vasectomy documentation of the absence of sperm in semen] provided the male partner is a sole partner).
Women not of childbearing potential must be postmenopausal for >=12 months at Screening. Postmenopausal status will be confirmed through testing of FSH levels >= 40 IU/mL at Screening for amenorrheic female participants. Females who are abstinent from heterosexual intercourse will also be eligible.
Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not considered highly effective methods of birth control. Participants who practice complete abstinence as part of their usual and preferred lifestyle will be eligible.
Female participants who are in same sex relationships are not required to use contraception.
WOCBP must have a negative pregnancy test at Screening and prior to administration of the initial dose of study drug and must be willing to have additional pregnancy tests as required throughout the study.
Males must be surgically sterile (>30 days since vasectomy with no viable sperm), abstinent, or, if engaged in sexual relations with a WOCBP, his partner must be surgically sterile (e.g., tubal occlusion, hysterectomy, bilateral salpingectomy, bilateral oophorectomy) or the participant and his partner must be using an acceptable, highly effective double barrier contraceptive method from Screening until study completion, including the follow-up period. Acceptable methods of contraception include the use of condoms AND the use of an effective contraceptive for the female partner that includes: OCPs, long-acting implantable hormones, injectable hormones, a vaginal ring, or an IUD. Participants with same sex partners (abstinence from penile-vaginal intercourse) are eligible when this is their preferred and usual lifestyle.
8. Male participants must not donate sperm for at least 90 days after the last dose of study drug.
9. Must have the ability and willingness to attend the necessary visits to the CRU.
10. Must be willing and able to provide written informed consent after the nature of the study has been explained and prior to the commencement of any study procedures.
Minimum age
18 Years
Maximum age
65 Years
Gender
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
A participant who meets any of the following criteria must be excluded from the study:
1. Pregnant or lactating at Screening or planning to become pregnant (self or partner) at any time during the study, including the follow-up period, until study completion.
2. Prior or ongoing medical conditions, medical history, physical findings, or laboratory abnormality that, in the Investigator’s (or delegate’s) opinion, could adversely affect the safety of the participant. Participants with history of the following will be excluded: irritable bowel syndrome, menorrhagia, fainting spells or dizzy spells or syncope, chronic abdominal or pelvic pain, hemoptysis, gastric ulcers, or anemia. Transient hemorrhage (e.g., infrequent epistaxis, normal menstrual bleeding, gingival bleeding, hemorrhoidal bleeding, etc.) would not preclude enrollment.
3. Presence of any underlying physical or psychological medical condition that, in the opinion of the Investigator, would make it unlikely that the participant will comply with the protocol or complete the study per protocol.
4. Any surgical or medical condition that could interfere with the absorption, distribution, metabolism, or excretion of the study drug.
5. Fever (body temperature >38°C) or symptomatic viral or bacterial infection within 2 weeks prior to Admission to the CRU.
6. Any acute illness within 30 days prior to Admission to the CRU.
7. History of severe allergic or anaphylactic reactions, determined at the discretion of the Investigator.
8. Known or suspected intolerance or hypersensitivity to the IP, closely related compounds, or any of the stated ingredients.
9. History of malignancy except for non-melanoma skin cancer excised more than 2 years ago and cervical intraepithelial neoplasia that has been successfully cured more than 5 years prior to Screening.
10. Abnormal ECG findings at Screening or Admission that are considered by the Investigator to be clinically significant.
11. History or presence of a condition associated with significant immunosuppression.
12. History of life-threatening infection (e.g., meningitis) within 5 years prior to Screening.
13. Infections requiring parenteral antibiotics within the 6 months prior to Screening.
14. Vaccination with a live-attenuated vaccine within the 4 weeks prior to Screening through to the EOS.
15. Exposure to any significantly immunosuppresive drug (including experimental therapies as part of a clinical trial) within the 4 months prior to Screening or five half-lives, whichever is longer. Topical steroids are allowed at the discretion of the Investigator.
16. Positive hepatitis panel (including HBsAg, HBcAb or anti-HCV), or a positive HIV antibody screen.
17. A BP value outside the specified range of 90 mm Hg to 160 mmHg (for SBP) and 50 mm Hg to 95 mmHg (for DBP; both inclusive) at Screening or Admission (can be repeated once at Screening at the Investigator’s discretion).
18. A history of substance abuse or dependency or history of recreational IV drug use over the last 5 years (by self-declaration).
19. Regular alcohol consumption defined as >14 alcohol units per week (where 1 unit = 284 mL of beer, 25 mL of 40% spirit, or a 125 mL glass of wine) within 6 months of Screening. Participant is unwilling to abstain from alcohol beginning 48 hours prior to each visit and during the confinement period.
20. Regularly consume more than 8 cups (i.e., 2 L) daily of beverage containing caffeine and unable to abstain from caffeine- or xanthine-containing products for at least 24 hours prior to Admission to the CRU and during confinement.
21. Currently smoke (including tobacco, marijuana, e-cigarettes, vaping, nicotine gum, etc.) or have used such products within 2 weeks prior to Screening.
22. Have undergone major surgery or have donated blood within 12 weeks prior to the start of the study.
23. A history of bleeding diathesis or other bleeding disorders.
24. Use of any prescription medications/products (other than hormonal contraception: OCPs, long-acting implantable hormones, injectable hormones, vaginal ring, or IUD) within 30 days prior to Screening, unless reviewed and approved by the Investigator in consultation with the Sponsor. Simple analgesia (NSAID or paracetamol) may be permitted at the discretion of the Investigator).
25. Use of any OTC, non-prescription preparations (including vitamins, minerals, phytotherapeutic/herbal/plant-derived preparations) within 14 days prior to Admission to the CRU.
26. A history of orthostatic hypotension or evidence of orthostatic hypotension at Screening that may make participation in the study inappropriate, as determined by the Investigator or delegate.

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)
A randomization list will be prepared using a statistical software package by a Biostatistician and will be transferred electronically to the pharmacist on site.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s

Intervention assignment
Other design features
Phase
Phase 1
Type of endpoint(s)
Safety
Statistical methods / analysis
Continuous and categorical safety data will be analyzed using standard methods. Pharmacokinetic data will be analyzed using standard WinNonlin methods. Pharmacodynamic data will be listed and summarized descriptively.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
SA
Recruitment hospital [1] 17067 0
CMAX Clinical Research Pty Ltd - Adelaide
Recruitment postcode(s) [1] 30740 0
5000 - Adelaide

Funding & Sponsors
Funding source category [1] 306181 0
Commercial sector/Industry
Name [1] 306181 0
CytoAgents Pty Ltd
Address [1] 306181 0
58 Gipps Street
Collingwood VIC 3066, Australia


Country [1] 306181 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
CytoAgents, Inc
Address
100 S. Commons Suite 102
Pittsburgh, PA 15212
Country
United States of America
Secondary sponsor category [1] 306655 0
None
Name [1] 306655 0
Address [1] 306655 0
Country [1] 306655 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 306394 0
Bellberry Limited
Ethics committee address [1] 306394 0
123 Glen Osmond Road
Eastwood, South Australia 5063
Ethics committee country [1] 306394 0
Australia
Date submitted for ethics approval [1] 306394 0
13/07/2020
Approval date [1] 306394 0
21/08/2020
Ethics approval number [1] 306394 0

Summary
Brief summary
CytoAgents Inc is developing GP1681, an effective immunomodulary agent whose parent compound (Beraprost Sodium, i.e., BPS) has the advantage of an excellent safety record over many years of clinical use. This study will determine the safety, tolerability, pharmacokinetics and pharmacodynamics of GP1681 in healthy adults, with the aim of developing GP1681 to treat patients admitted to the hospital with COVID-19 disease.
This study will be conducted in up to 24 healthy volunteers who meet all of the inclusion criteria and none of the exclusion criteria.
The study is a double-blinded, randomized, placebo-controlled, multiple ascending dose (MAD) study of GP1681 as compared with placebo to be conducted in three sequential cohorts of healthy volunteers.
Participants will receive study drug (GP1681 or placebo) every 8 hours (q8h) within 30 minutes of eating a meal or snack, for a total of 7 consecutive days (Day 1 to Day 7, inclusive) while domiciled at the clinical research unit (CRU).
The first cohort will receive the predefined dose of 5 mcg q8h (15 mcg/day). Subsequent dose levels will be determined by the Dose Escalation Committee until either an MTD or a maximum dose of 90 µg/day is reached or until 3 cohorts have been enrolled.


Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 103730 0
Dr Angela Molga
Address 103730 0
CMAX Clinical Research
Level 5, 18a North Terrace
Adelaide, South Australia 5000
Country 103730 0
Australia
Phone 103730 0
+61 424 666 247
Fax 103730 0
Email 103730 0
angela.molga@sa.gov.au
Contact person for public queries
Name 103731 0
Dr Angela Molga
Address 103731 0
CMAX Clinical Research
Level 5, 18a North Terrace
Adelaide, South Australia 5000
Country 103731 0
Australia
Phone 103731 0
+61 424 666 247
Fax 103731 0
Email 103731 0
angela.molga@sa.gov.au
Contact person for scientific queries
Name 103732 0
Dr Jere Fellmann
Address 103732 0
TekTeam
2225 East Bayshore Road
Palo Alto, CA 94303
Country 103732 0
United States of America
Phone 103732 0
+1 510 918 3975
Fax 103732 0
Email 103732 0
jere@tekteam.net

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
This is a healthy volunteer study and the individual participant results are not useful to the participants or to others outside of the sponsor and the Sponsors authorized representatives.
What supporting documents are/will be available?
No other documents available
Summary results
No Results