ANZCTR - Registration

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Trial registered on ANZCTR

Registration number

ACTRN12621000131853

Ethics application status

Approved

Date submitted

4/02/2021

Date registered

9/02/2021

Date last updated

30/08/2022

Date data sharing statement initially provided

9/02/2021

Type of registration

Prospectively registered

Titles & IDs

Public title

An interventional study to evaluate the safety, tolerability (how well a substance is tolerated by participants), and Pharmacokinetics (PK, the measure of how the human body processes a substance), of different dosages of TTI-0102 when given to healthy participants as either a single oral dose, or as an oral dose give twice daily on one day (as a potential treatment for COVID-19), compared with a single oral dose of the marketed product Cystagon (registered trademark).

Scientific title

An Open-Label, Dose-Escalation Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Oral TTI-0102 (as a potential treatment for COVID-19) compared to Cystagon® in Healthy Adult Male and Female Volunteers

Secondary ID [1]

Nil known

Universal Trial Number (UTN)

Trial acronym

Linked study record

Health condition

Health condition(s) or problem(s) studied:

COVID-19

Condition category

Condition code

Infection

Other infectious diseases

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

TTI-0102 will be given as an oral solution, TTI-0102 drug product (powder) dissolved in 240mL sterile water.
The planned treatments are:
Cohort 1: Cystagon (registered trademark) 600mg once on Day 1, then TTI-0102 1300mg once on Day 3.
Cohort 2: Cystagon (registered trademark) 600mg once on Day 1, then TTI-0102 2600mg once on Day 3.
Cohort 3: Cystagon (registered trademark) 600mg once on Day 1, then TTI-0102 2600mg given as 1300mg in the morning and 1300mg 12 hours later on
Day 3.
The decision to dose escalate to Cohort 2 will be made by the Safety Review Committee (SRC).
The decision to move to twice daily TTI-0102 dosing in Cohort 3 will be made by the SRC.
Adherence to the study treatments will be monitored by inpatient stay and observation; participants will be confined to the study unit from check-in on Day -1 through to discharge on Day 4 (24 hours post last dose).

Intervention code [1]

Treatment: Drugs

Comparator / control treatment

Cystagon (registered trademark) 150mg capsules taken orally.

Control group

Active

Outcomes

Primary outcome [1]

To assess safety and tolerability of different doses of TTI-0102 compared to Cystagon (registered trademark) when administered orally to healthy participants.
This will be assessed by looking at the incidence, severity, causality, and seriousness of adverse events; changes from baseline in clinical laboratory parameters (hematology, serum chemistry, coagulation, and urinalysis); physical examination findings; changes in vital signs parameters, and 12-lead electrocardiogram (ECGs).

Timepoint [1]

Adverse event information will be recorded from the time of admission to the study unit until study Day 7 (4 days after the last dose of study drug).
Clinical laboratory evaluations of hematology, serum chemistry, coagulation, and urinalysis will be performed at Screening, Day -1 (baseline), Day 2, Day 4, and Day 7 (End of Study) or Early Termination visit.
A full physical examination (including at a minimum, assessment of the following: general appearance, Head, Eye, Ear, Nose and Throat [HEENT], mouth/dental [if required], neck [incl thyroid & nodes], cardiovascular, respiratory, gastrointestinal, renal, neurological, musculoskeletal, skin, other) will be conducted at Screening (baseline) and Day 7 (End of Study) or Early Termination visit. A symptom directed physical examination will be conducted pre and post dose on Day 1, Day 2 (24 hours post dose); pre morning and evening (Cohort 3 only) dose on Day 3; post dose (post evening dose for Cohort 3) on Day 3; and Day 4 (24 hours post dose).
Vital signs, including blood pressure, pulse rate, respiration rate and body temperature will be measured at Screening, Day -1, pre dose on Day 1 (baseline); 2, 6 and 12 hours post dose on Day 1; Day 2 (24 hours post dose); pre morning and evening (Cohort 3 only) dose on Day 3; 2, 6 and 12 hours post dose (post evening dose for Cohort 3) on Day 3; Day 4 (24 hours post dose), and Day 7 (End of Study) or Early Termination visit.
Triplicate ECGs will be performed at Screening and pre dose on Day 1 (baseline). Single ECGs will be performed at 2, 6, and 12 hours post dose on Day 1; Day 2 (24 hours post dose); pre morning and evening (Cohort 3 only) dose on Day 3; 2, 6 and 12 hours post dose (post evening dose for Cohort 3) on Day 3; and Day 4 (24 hours post dose).

Secondary outcome [1]

To assess the PK of cysteamine following administration of oral TTI-0102 compared to Cystagon (registered trademark).
Blood samples will be collected and the following PK parameters will be assessed in plasma:
• Cmax
• Time of the maximum drug concentration (tmax), obtained without interpolation. If the maximum value occurs at more than 1 timepoint, tmax is defined as the first timepoint with this value
• Area under the drug concentration-time curve, calculated using linear trapezoidal summation, from time zero to time of the last measurable drug concentration (AUC0–last)
• Apparent elimination rate constant (delta z), calculated by linear regression of the terminal linear portion of the log concentration versus time curve, where delta z = - slope
• Area under the drug concentration-time curve from time zero to infinity (AUC0–inf) calculated as AUC0-t + Ct/delta z, where delta z is the apparent terminal elimination rate constant
• Area under the drug concentration-time curve from time zero to 24 hours following dose administration (AUC0-24)
• Apparent total clearance of the drug from plasma following oral administration (CL/F), calculated as dose/AUC0-inf
• Apparent terminal elimination half-life (t 1/2), calculated as ln(2)/ delta z;
• Apparent volume of distribution Vd/F; calculated as (CL)/ delta z.

Timepoint [1]

Blood samples for PK will be collected at the following timepoints:
Day 1 – pre dose, and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 9, 12, 15, and 18 hours post dose.
Day 2 (24 hours post dose).
Day 3 (Cohorts 1 & 2) – pre dose, and 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 9, 12, 15, and 18 hours post dose.
Day 3 (Cohort 3) – pre morning dose, and 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 9, 12 (pre evening dose), 12.25, 12.5, 12.75, 13, 13.25, 13.5, 14, 15, 16, 18, and 21 hours post morning dose.
Day 4 (24 hours post morning dose).

Secondary outcome [2]

To assess the PK of taurine following administration of oral TTI-0102 compared to Cystagon®.
Blood samples will be collected and the following PK parameters will be assessed in plasma:
• Cmax
• Time of the maximum drug concentration (tmax), obtained without interpolation. If the maximum value occurs at more than 1 timepoint, tmax is defined as the first timepoint with this value
• Area under the drug concentration-time curve, calculated using linear trapezoidal summation, from time zero to time of the last measurable drug concentration (AUC0–last)
• Apparent elimination rate constant (delta z), calculated by linear regression of the terminal linear portion of the log concentration versus time curve, where delta z = - slope
• Area under the drug concentration-time curve from time zero to infinity (AUC0–inf) calculated as AUC0-t + Ct/delta z, where delta z is the apparent terminal elimination rate constant
• Area under the drug concentration-time curve from time zero to 24 hours following dose administration (AUC0-24)
• Apparent total clearance of the drug from plasma following oral administration (CL/F), calculated as dose/AUC0-inf
• Apparent terminal elimination half-life (t1/2), calculated as ln(2)/ delta z;
• Apparent volume of distribution Vd/F; calculated as (CL)/ delta z.

Timepoint [2]

Secondary outcome [3]

To assess the PK of pantothenic acid (Vitamin B5) following administration of oral TTI-0102 compared to Cystagon®.
Blood samples will be collected and the following PK parameters will be assessed in plasma:
• Cmax
• Time of the maximum drug concentration (tmax), obtained without interpolation. If the maximum value occurs at more than 1 timepoint, tmax is defined as the first timepoint with this value
• Area under the drug concentration-time curve, calculated using linear trapezoidal summation, from time zero to time of the last measurable drug concentration (AUC0–last)
• Apparent elimination rate constant (delta z), calculated by linear regression of the terminal linear portion of the log concentration versus time curve, where delta z = - slope
• Area under the drug concentration-time curve from time zero to infinity (AUC0–inf) calculated as AUC0-t + Ct/delta z, where delta z is the apparent terminal elimination rate constant
• Area under the drug concentration-time curve from time zero to 24 hours following dose administration (AUC0-24)
• Apparent total clearance of the drug from plasma following oral administration (CL/F), calculated as dose/AUC0-inf
• Apparent terminal elimination half-life (t1/2), calculated as ln(2)/ delta z;
• Apparent volume of distribution Vd/F; calculated as (CL)/ delta z.

Timepoint [3]

Eligibility

Key inclusion criteria

1. Must have given written informed consent before any study-related activities are carried out and must be able to understand the full nature and purpose of the trial, including possible risks and adverse effects.
2. Adult males and females, 18 to 64 years of age (inclusive) at screening.
3. Body mass index greater than or equal to 19.0 and less than or equal to 31.0 kg/metres squared, with a body weight greater than or equal to 60.0 and less than or equal to 85.0 kg at screening.
4. Be nonsmokers (including tobacco, e-cigarettes and marijuana) for at least 1 month prior to first study drug administration.
5. Medically healthy without clinically significant (in the opinion of the Investigator) abnormalities at screening and pre-dose on Day 1, including:
a. Physical examination without any clinically relevant findings;
b. Systolic blood pressure in the range of 90 to 160 mmHg and diastolic blood pressure in the range of 50 to 95 mmHg after 5 minutes in supine position;
c. Heart rate (HR) in the range of 45 to 100 bpm after 5 minutes rest in supine position;
d. Body temperature, between 35.5°C and 37.7°C;
e. No clinically significant findings in serum chemistry, hematology, coagulation and urinalysis tests as judged by the investigator.
6. Conventional 12-lead electrocardiogram (ECG) recording in triplicate (the mean of triplicate measurements will be used to determine eligibility at screening and pre-dose on Day 1) consistent with the PI assessment of a normal cardiac conduction and function, including the following criteria:
a. Normal sinus rhythm with HR between 45 and 100 bpm, inclusive;
b. QT interval corrected using the Fridericia method (QTcF) less than or equal to 450 msec for males or less than or equal to 470 msec for females;
c. QRS duration of less than 120 msec;
d. PR interval of less than or equal to 220 msec;
e. Electrocardiogram morphology consistent with healthy cardiac ventricular conduction and normal rhythm, and with measurement of the QT interval;
f. No family history of short or long QT syndrome;
g. No history of risk factors for torsade de pointes or the diagnosis;
7. Female participants must:
a. Be of nonchildbearing potential (i.e., surgically sterilised [hysterectomy, bilateral salpingectomy, bilateral oophorectomy at least 6 weeks before screening]) or postmenopausal (where postmenopausal is defined as no menses for 12 months without an alternative medical cause, and a follicle-stimulating hormone [FSH] level greater than 40 IU/L at the screening visit), or
b. If of childbearing potential, must agree not to donate ova, not to attempt to become pregnant and, if engaging in sexual intercourse with a male partner, must agree to use an acceptable method of contraception (refer to Appendix 5) from signing the consent form until at least 30 days after the last dose of the study drug.
8. Male participants, if not surgically sterilized, must be willing not to donate sperm and, if engaging in sexual intercourse with a female partner who could become pregnant, must be willing to use a condom in addition to having the female partner use a highly effective contraceptive method from signing the consent form until at least 90 days after the last dose of study drug.
9. Have suitable venous access for blood sampling.
10. Be willing and able to comply with all study assessments and adhere to the protocol schedule and restrictions.

Minimum age

18 Years

Maximum age

64 Years

Sex

Both males and females

Can healthy volunteers participate?

Yes

Key exclusion criteria

1. Allergy to any medicine containing mercaptamine, penicillamine or known hypersensitivity to any of the study drug ingredients.
2. Evidence of or verbal attestation of Helicobacter pylori infection, presently, or within the last 90 days prior to Screening.
3. Participants who have had a kidney transplant or are planning or are a registered candidate for a kidney transplant within 3 months of the Screening or have a serum creatinine that is not within local lab normal range or less than or equal to 1.5x ULN.
4. Participants with known hypersensitivity to cysteamine.
5. Patients with a haemoglobin level that is not within local lab normal range or less than or equal to 1.5x ULN.
6. History or presence of significant cardiovascular, pulmonary, hepatic, renal, hematological, gastrointestinal, endocrine, immunologic, dermatologic or neurological disease, including any acute illness or surgery within the past 3 months determined by the PI to be clinically relevant.
7. Current infection that requires antibiotic, antifungal, antiparasitic or antiviral medications.
8. Any history of malignant disease in the last 10 years (excludes surgically resected skin squamous cell or basal cell carcinoma).
9. Liver function test results (ie, aspartate aminotransferase [AST], alanine aminotransferase [ALT], and gamma glutamyl transferase [GGT]) and total bilirubin must not be elevated more than within local lab normal range or more than 1.5-fold above the upper limit of normal (ULN).
10. Positive test results for active human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg) or hepatitis C virus (HCV) antibodies.
11. Presence or having sequelae of gastrointestinal, liver, kidney, or other conditions known to interfere with the absorption, distribution, metabolism, or excretion of drugs.
12. Estimated creatinine clearance (CrCl) less than 60 mL/min using the Cockcroft-Gault formula.
13. History of substance abuse or alcohol abuse (defined as more than 10 standard drinks per week or regularly consuming more than 4 standard drinks on any one day; where 1 standard drink is 10 g of pure alcohol and is equivalent to 285 mL beer [4.9% Alc./Vol], 100 mL wine [12% Alc./Vol], 30 mL spirit [40% Alc./Vol]) during less than or equal to 12 months prior to the screening visit.
14. Positive drug or alcohol test results at the screening visit or at check-in (Day -1) (may be repeated once, if a positive test was recorded in the first instance, at the discretion of the PI).
15. Use of any prescription or over-the-counter medication (including herbal products, diet aids, and hormone supplements) within 10 days or 5 half-lives of the medication (whichever is longer) prior to the first study drug administration, except occasional use of paracetamol.
16. Use of any live vaccinations within 30 days prior to the first study drug administration except for the influenza vaccine.
17. For women of childbearing potential, a positive serum pregnancy test at screening or a positive urine pregnancy test with confirmatory serum pregnancy test on Day -1.
18. Donation of blood or plasma within 30 days prior to first study drug administration, or loss of whole blood of more than 500 mL within 30 days prior to randomization, or receipt of a blood transfusion within 1 year of first study drug administration.
19. Participation in another investigational clinical trial within 60 days prior to the first study drug administration.
20. Any other condition or prior therapy that in the opinion of the PI would make the volunteer unsuitable for this study, including inability to cooperate fully with the requirements of the study protocol or likelihood of noncompliance with any study requirements.

Study design

Purpose of the study

Treatment

Allocation to intervention

Non-randomised trial

Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)

Allocation is not concealed.

Methods used to generate the sequence in which subjects will be randomised (sequence generation)

Not applicable

Masking / blinding

Open (masking not used)

Who is / are masked / blinded?

Intervention assignment

Other

Other design features

Participants will be assigned to different dosages depending on which cohort they are enrolled into.

Phase

Phase 1

Type of endpoint/s

Safety

Statistical methods / analysis

Total enrolment of participants in the planned three dose cohorts is 12 (4 participants per cohort).
The sample size for this study is based on clinical and practical considerations and not on a formal statistical power calculation.

Recruitment

Recruitment status

Completed

Date of first participant enrolment

Anticipated

19/04/2021

Actual

15/05/2021

Date of last participant enrolment

Anticipated

25/05/2021

Actual

16/07/2021

Date of last data collection

Anticipated

31/05/2021

Actual

22/07/2021

Sample size

Target

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

Recruitment hospital [1]

CMAX Clinical Research Pty Ltd - Adelaide

Recruitment postcode(s) [1]

5000 - Adelaide

Funding & Sponsors

Funding source category [1]

Commercial sector/Industry

Name [1]

Thiogenesis Therapeutics, Inc.

Address [1]

4795 Keswick Court, San Diego CA 92130

Country [1]

United States of America

Primary sponsor type

Commercial sector/Industry

Name

Thiogenesis Therapeutics, Inc.

Address

4795 Keswick Court, San Diego CA 92130

Country

United States of America

Secondary sponsor category [1]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Bellberry Limited

Ethics committee address [1]

123 Glen Osmond Road, Eastwood SA 5063

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

17/02/2021

Approval date [1]

15/04/2021

Ethics approval number [1]

2020-12-1307

Summary

Brief summary

This research project is being conducted to look at the safety, tolerability and pharmacokinetics (PK, how the human body processes a substance) of TTI-0102 when given to healthy volunteers orally as a single dose, compared with a single oral dose of the marketed product Cystagon (registered trademark).
It is proposed that TTI-0102 could be used as a treatment for acute respiratory distress syndrome (ARDS) related to COVID-19 infection.

Trial website

Trial related presentations / publications

Public notes

Contacts

Principal investigator

Name

Dr Paul Wabnitz, MBBS, FRACP

Address

CMAX Clinical Research,
Level 5, 18a North Terrace
Adelaide, SA 5000

Country

Australia

Phone

+61 8 7088 7900

Fax

[email protected]

Contact person for public queries

Name

Paul Wabnitz, MBBS, FRACP

Address

CMAX Clinical Research,
Level 5, 18a North Terrace
Adelaide, SA 5000

Country

Australia

Phone

+61 8 7088 7900

Fax

[email protected]

Contact person for scientific queries

Name

Paul Wabnitz, MBBS, FRACP

Address

CMAX Clinical Research,
Level 5, 18a North Terrace
Adelaide, SA 5000

Country

Australia

Phone

+61 8 7088 7900

Fax

[email protected]

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

Yes

What data in particular will be shared?

Individual participant data underlying published results only

When will data be available (start and end dates)?

6 months after publication; no end date determined

Available to whom?

Case-by-case basis at the discretion of Primary Sponsor

Available for what types of analyses?

Only to achieve the aims in the approved proposal

How or where can data be obtained?

Access subject to approvals by Principal Investigator - [email protected]

What supporting documents are/will be available?

Doc. No.	Type	Email
10438	Study protocol	[email protected]
10439	Informed consent form	[email protected]
10440	Ethical approval	[email protected]

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.

Trial Review

Documents added manually

Documents added automatically