Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12624000535572p
Ethics application status
Submitted, not yet approved
Date submitted
28/03/2024
Date registered
30/04/2024
Date last updated
30/04/2024
Date data sharing statement initially provided
30/04/2024
Type of registration
Prospectively registered

Titles & IDs
Public title
A Phase I, Randomized, Placebo-Controlled, First in Human Study of the Safety, Tolerability, and Pharmacokinetics of Single and Multiple Ascending Doses of LTSE-2578 in Healthy Participants
Scientific title
A Phase I, Randomized, Placebo-Controlled, First in Human Study of the Safety, Tolerability, and Pharmacokinetics of Single and Multiple Ascending Doses of LTSE-2578 in Healthy Participants
Secondary ID [1] 311582 0
LTSE-2578-01
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Idiopathic pulmonary fibrosis 332963 0
Condition category
Condition code
Respiratory 329676 329676 0 0
Other respiratory disorders / diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The study will be conducted in 2 parts:
Part 1: Single ascending dose (SAD)
Part 2: Multiple ascending dose (MAD)
Decisions about how and when to move between cohorts will be based on reviews of the available safety data (blinded) and pharmacokinetic data.

Part 1: Each cohort will enrol 8 participants with 6 participants randomized to receive LTSE-2578 and 2 participants randomized to receive placebo on Day 1. There will be 5 cohorts and LTSE-2578 oral tablet will be administered at dose levels in the range of 6mg - 250mg.

SAD Cohort 4 – food effect cohort: Single oral dose of LTSE-2578 or placebo administered on Day 1 under fasted conditions and another dose administered on Day 5 under fed conditions (total of 2 doses).

Part 2: LTSE-2578 oral tablet administered twice daily for 14 days at up to 3 dose levels (3 cohorts) in the range from 20 mg to up to 200 mg (total daily dose; actual dosage to be determined based on data from Part 1 and the preceding cohorts in Part 2). Each cohort will enrol 8 participants with 6 participants randomized to receive LTSE-2578 and 2 participants randomized to receive placebo.

Study drug will be administered at the study site by trained study site personnel to ensure compliance.
Intervention code [1] 328036 0
Treatment: Drugs
Comparator / control treatment
Tablets of matching appearance and formulation to the investigational product, however without the LTSE-2578 active ingredient, will be administered as placebo in this study.
Control group
Placebo

Outcomes
Primary outcome [1] 337460 0
Composite outcome: To assess the safety and tolerability of a single dose of LTSE 2578 in healthy adult participants
Timepoint [1] 337460 0
Adverse events - will be graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) (Version 5) and assessed continuously as they are reported or observed and reviewed daily from Day - 1 until Day 15 (End of Study/Early Termination visit [EOS/ETV]).

Vital signs - Blood pressure and heart rate is measured using sphygmomanometer, respiratory rate by manual breath count and temperature by thermometer. Assessed at Screening, Day -1, pre-dose Day 1 0.5, 2, 6 & 12 hrs post-dose, Day 2 24 hrs post-dose, Day 3 48 hrs post-dose, Day 4 72 hrs post-dose and Day 15 (End of Study/Early Termination visit [EOS/ETV]).

Electrocardiogram (ECG) - 12-lead ECG recordings will be obtained in triplicate at Screening, Day -1, Day 3 48 hrs post-dose, Day 4 72 hrs post-dose and Day 15 (End of Study/Early Termination visit [EOS/ETV]).

Clinical laboratory evaluations - blood and urine samples will be collected from Screening, Day -1, Day 1 6 hrs post-dose, Day 2 24 hrs post-dose, Day 3 48 hrs post-dose and Day 15 (End of Study/Early Termination visit [EOS/ETV]).
Primary outcome [2] 337750 0
Composite Outcome: To assess the safety and tolerability of repeat doses of LTSE 2578 in healthy adult participants
Timepoint [2] 337750 0
Adverse events - will be graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) (Version 5) and assessed continuously as they are reported or observed and reviewed daily from Day - 1 until Day 28 (End of Study/Early Termination visit [EOS/ETV]).

Vital signs - Blood pressure and heart rate is measured using sphygmomanometer, respiratory rate by manual breath count and temperature by thermometer. Assessed at Screening, Day -1, pre-dose Day 1 0.5, 2, 6 & 12 hrs post-dose, pre-dose on Day 2 through to Day 14 0.5, 2, 6, 12 hrs post dose, Day 15 24 hrs post dose, Day 16 48 hrs post dose, Day 17 72 hrs post-dose and Day 28 (End of Study/Early Termination visit [EOS/ETV]).

Electrocardiogram (ECG) - 12-lead ECG recordings will be obtained in triplicate at Screening, pre-dose Day 2, pre-dose Day 5, pre-dose Day 8, pre-dose Day 11, Day 16 48 hrs post-last dose, Day 17 72 hrs post-last dose and Day 28 (End of Study/Early Termination visit [EOS/ETV]).

Clinical laboratory evaluations - blood and urine samples will be collected from Screening, Day -1, Day 1 6 hrs post-dose, pre-dose on Days 2, 5, 8 and Day 11, Day 15 24 hrs post-last dose and Day 28 (End of Study/Early Termination visit [EOS/ETV]).
Secondary outcome [1] 431957 0
To describe the PK profile in plasma following a single dose of LTSE 2578 in healthy adult participants
Timepoint [1] 431957 0
Blood samples will be collected as follows: pre-dose Day 1, 0.25hrs, 0.5 hrs, 1 hr, 1.5 hrs, 2 hrs, 3 hrs, 4 hrs, 6 hrs, 8 hrs, 10 hrs and 12 hrs post-dose, Day 2 24 hrs post-dose, Day 3 48 hrs post-dose, Day 4 72 hrs post-dose.
Secondary outcome [2] 433140 0
To describe the PK profile in plasma following repeat doses of LTSE 2578 in healthy adult participants
Timepoint [2] 433140 0
Blood samples will be collected as follows: pre-dose Day 1, 0.25 hrs, 0.5 hrs, 1 hr, 1.5 hrs, 2 hrs, 3 hrs, 4 hrs, 6 hrs, 8 hrs, 10 hrs and 12 hrs post-dose, Day 2 24 hrs post-dose, pre-dose on Days 3, 5, 7, 12 and 13, pre-dose Day 14, 0.25 hrs, 0.5 hrs, 1 hr, 1.5 hrs, 2 hrs, 3 hrs, 4 hrs, 6 hrs, 8 hrs, 10 hrs and 12 hrs post-dose, Day 15 24 hrs post-dose, Day 16 48 hrs post-dose, Day 17 72 hrs post-dose.
Secondary outcome [3] 433141 0
To examine dose proportionality following a single dose of LTSE 2578
Timepoint [3] 433141 0
Blood plasma samples will be collected as follows: pre-dose Day 1, 0.25hrs, 0.5 hrs, 1 hr, 1.5 hrs, 2 hrs, 3 hrs, 4 hrs, 6 hrs, 8 hrs, 10 hrs and 12 hrs post-dose, Day 2 24 hrs post-dose, Day 3 48 hrs post-dose, Day 4 72 hrs post-dose.
Secondary outcome [4] 433142 0
To examine dose proportionality following repeated doses of LTSE 2578
Timepoint [4] 433142 0
Blood plasma samples will be collected as follows: pre-dose Day 1, 0.25 hrs, 0.5 hrs, 1 hr, 1.5 hrs, 2 hrs, 3 hrs, 4 hrs, 6 hrs, 8 hrs, 10 hrs and 12 hrs post-dose, Day 2 24 hrs post-dose, pre-dose on Days 3, 5, 7, 12 and 13, pre-dose Day 14, 0.25 hrs, 0.5 hrs, 1 hr, 1.5 hrs, 2 hrs, 3 hrs, 4 hrs, 6 hrs, 8 hrs, 10 hrs and 12 hrs post-dose, Day 15 24 hrs post-dose, Day 16 48 hrs post-dose, Day 17 72 hrs post-dose.
Secondary outcome [5] 433143 0
To assess accumulation of LTSE 2578 (Part 1)
Timepoint [5] 433143 0
Blood plasma samples will be collected as follows: pre-dose Day 1, 0.25hrs, 0.5 hrs, 1 hr, 1.5 hrs, 2 hrs, 3 hrs, 4 hrs, 6 hrs, 8 hrs, 10 hrs and 12 hrs post-dose, Day 2 24 hrs post-dose, Day 3 48 hrs post-dose, Day 4 72 hrs post-dose.
Secondary outcome [6] 433144 0
To assess accumulation of LTSE 2578 (Part 2)
Timepoint [6] 433144 0
Blood plasma samples will be collected as follows: pre-dose Day 1, 0.25 hrs, 0.5 hrs, 1 hr, 1.5 hrs, 2 hrs, 3 hrs, 4 hrs, 6 hrs, 8 hrs, 10 hrs and 12 hrs post-dose, Day 2 24 hrs post-dose, pre-dose on Days 3, 5, 7, 12 and 13, pre-dose Day 14, 0.25 hrs, 0.5 hrs, 1 hr, 1.5 hrs, 2 hrs, 3 hrs, 4 hrs, 6 hrs, 8 hrs, 10 hrs and 12 hrs post-dose, Day 15 24 hrs post-dose, Day 16 48 hrs post-dose, Day 17 72 hrs post-dose.
Secondary outcome [7] 433145 0
To assess time to steady-state of LTSE 2578 (Part 2)
Timepoint [7] 433145 0
Blood plasma samples will be collected as follows: pre-dose Days 2 3, 5, 7, 12, 13 and 14.
Secondary outcome [8] 433146 0
To assess the PK of LTSE-2578 in urine following administration of a single oral dose in healthy adult participants (Part 1 SAD only, Cohort 4 – fasted period 1 only).
Timepoint [8] 433146 0
Urine samples will be collected as follows for Part 1 Cohort 4 (fasted period 1 only): Day 1 pre-dose, Day 1 post dose: 0-6 hrs, 6-12 hrs, 12-24 hrs, Day 2 post dose 24-48 hrs, Day 3 post dose 48-72 hrs.
Secondary outcome [9] 433148 0
To assess the effect of food on the PK of LTSE-2578 under fasted and fed conditions (Part 1 SAD Cohort 4 only)
Timepoint [9] 433148 0
Blood samples will be collected as follows for Part 1 Cohort 4: pre-dose Day 1, 0.25 hrs, 0.5 hrs, 1 hr, 1.5 hrs, 2 hrs, 3 hrs, 4 hrs, 6 hrs, 8 hrs, 10 hrs and 12 hrs post-dose, Day 2 24 hrs post-dose, Day 3 48 hrs post-dose, Day 4 72 hrs post-dose, pre-dose Day 5, 0.25 hrs, 0.5 hrs, 1 hr, 1.5 hrs, 2 hrs, 3 hrs, 4 hrs, 6 hrs, 8 hrs, 10 hrs and 12 hrs post-dose, Day 6 24 hrs post-dose, Day 7 48 hrs post-dose, Day 8 72 hrs post-dose,

Eligibility
Key inclusion criteria
1. Adult males and females, 18 to 65 years of age (inclusive) at screening.
2. Body mass index (BMI) greater than or equal to 18.0 and less than or equal to 30.0 kg/m2, with a body weight (to 1 decimal place) greater than or equal to 40 kg at screening.
3. Medically healthy (in the opinion of the Investigator) at screening, as determined by pre-study medical history, and without clinically significant abnormalities including:
a. Physical examination without any clinically relevant findings;
b. Systolic blood pressure in the range of 90 to 140 mmHg and diastolic blood pressure in the range of 50 to 90 mmHg after 5 minutes in supine or semi-supine position.
c. Pulse rate in the range of 40 to 100 bpm after 5 minutes rest in supine or semi-supine position.
d. Body temperature (tympanic), between 35.5°C and 37.5°C.
e. Electrocardiogram (ECG) without clinically significant abnormalities including QRS interval >120 msec on the screening ECG (measurements are the mean of 3 ECGs), QT interval corrected for Fredericia (QTcF) <450 msec for male subjects and <470 msec for female subjects.
f. No clinically significant findings in serum chemistry, haematology, coagulation and urinalysis tests including the following specific findings:
i. Alanine aminotransferase (ALT) <1.5 x ULN, aspartate aminotransferase (AST) <1.5 x ULN, gamma-glutamyl transferase (GGT) <1.5 x ULN, or alkaline phosphatase <1.5 x ULN .
4. Female volunteers (Childbearing or non-childbearing potential):
a. Non-childbearing potential is defined as surgically sterilized (hysterectomy, bilateral salpingectomy, bilateral oophorectomy) at least 6 weeks before the screening visit or postmenopausal (where postmenopausal is defined as no menses for 12 months without an alternative medical cause and a follicle-stimulating hormone (FSH) level consistent with postmenopausal status, per local laboratory guidelines), or
b. If of child-bearing potential, must:
i. Have a negative pregnancy test at the screening visit and on admission to the clinic on Day-1.
ii. Agree not to attempt to become pregnant or donate ova from signing the consent form until at least 90 days after the last dose of study drug.
iii. If not exclusively in a same-sex relationship or abstinent as a committed lifestyle, agree to use adequate contraception (defined as use of a condom by the male partner combined with use of a highly effective method of contraception from one month prior to screening until at least 90 days after the last dose of study drug.
5. Male volunteers, must:
a. Agree not to donate sperm from signing the consent form until at least 90 days after the last dose of study drug.
b. If engaging in sexual intercourse with a female partner who could become pregnant, agree to use adequate contraception (defined as use of a condom combined with use of a highly effective method of contraception from signing the consent form until at least 90 days after the last dose of study drug.
c. If engaging in sexual intercourse with a female partner who is not of childbearing potential or a same-sex partner, agree to use a condom from signing the consent form until at least 90 days after the last dose of study drug.
Minimum age
18 Years
Maximum age
65 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. Known hypersensitivity to any of the study drug ingredients.
2. Demonstrated clinically significant (required intervention, e.g., emergency room visit, epinephrine administration) allergic reactions (e.g., food, drug, or atopic reactions, asthmatic episodes) which, in the opinion of the Investigator, would interfere with the volunteer’s ability to participate in the trial.
3. History or presence of clinically significant cardiovascular, pulmonary, hepatic, renal, haematological, gastrointestinal, endocrine, immunologic, dermatologic, psychiatric or neurological disease/disorder, including any acute illness, within the past 3 months determined by the Investigator to be clinically relevant.
4. History of surgery or hospitalization within 2 months prior to screening, or surgery planned during the study.
5. Any history of malignant disease in the last 5 years (excludes surgically resected skin squamous cell, basal cell carcinoma and cervical cancer in situ).
6. History of risk factors for torsade de pointes (including a family history of long QT syndrome or sudden cardiac death) or a known arrythmia.
7. Presence or having sequelae of gastrointestinal, liver (including Gilbert’s syndrome), kidney, or other conditions known to interfere with the absorption, distribution, metabolism, or excretion of drugs.
8. Estimated creatinine clearance (CrCl) < 60 mL/min using the Cockcroft-Gault formula or serum creatinine more than 1.5-fold above the ULN at screening.
9. Positive test results for active human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg) or hepatitis C virus (HCV) antibodies at the screening visit.
10. Positive drugs of abuse test, cotinine test or alcohol breath test results at the screening visit or on admission to the clinic on Day -1.
11. Regular consumption of more than 10 standard alcoholic drinks/week, 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], or 30 mL spirit [40% Alc/Vol]).
12. Any history of smoking or nicotine use (e.g., cigarettes, e-cigarettes/vaping, marijuana, cigars, chewing, or nicotine replacement therapy) within 3 months prior to screening .
13. Consumption of grapefruit, tangelo, or Seville orange (or products containing grapefruit or Seville orange) within 10 days prior to dosing (Day 1).
14. Females who are breastfeeding or planning to breastfeed.
15. Use of any prescription or over-the-counter medication (including herbal products, diet aids, vitamins, and hormone supplements) within 10 days or 5 half-lives of the medication (whichever is longer) prior to the first dose of study drug, except use of contraceptives and the occasional use of paracetamol (up to 2 g per day).
16. Current infection that requires systemically absorbed antibiotic, antifungal, antiparasitic or antiviral medication within 10 days prior to first dose of study drug.
17. Use of any vaccinations within 30 days prior to screening.
18. Donation of blood or plasma within 30 days prior to first dose of study drug, or loss of whole blood of more than 500 mL within 30 days prior to first dose of study drug, or receipt of a blood transfusion within 1 year of the first dose 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)
Participants will be randomized to receive LTSE-2578 or Placebo according to the randomisation schedule and plan prepared prior to study start. Code-break tamper-evident envelopes containing treatment allocation per participant will be provided to the study site for emergency unblinding if required.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Participants who meet the study eligibility criteria will be assigned a randomisation number pre-dose on Day 1, which corresponds to a study treatment (LTSE-2578 or placebo). The allocation to LTSE-2578 or placebo will be performed using a block randomisation algorithm and will be documented in the study randomisation schedule.
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
Not yet recruiting
Date of first participant enrolment
Anticipated
11/06/2024
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
64
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 26209 0
Scientia Clinical Research - Randwick
Recruitment postcode(s) [1] 42085 0
2031 - Randwick

Funding & Sponsors
Funding source category [1] 315884 0
Commercial sector/Industry
Name [1] 315884 0
Lhotse Bio, Inc.
Country [1] 315884 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
Lhotse Bio, Inc.
Address
Country
United States of America
Secondary sponsor category [1] 318028 0
Commercial sector/Industry
Name [1] 318028 0
Avance Clinical Pty Ltd
Address [1] 318028 0
Country [1] 318028 0
Australia

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 314730 0
Bellberry Human Research Ethics Committee D
Ethics committee address [1] 314730 0
https://bellberry.com.au/
Ethics committee country [1] 314730 0
Australia
Date submitted for ethics approval [1] 314730 0
10/04/2024
Approval date [1] 314730 0
Ethics approval number [1] 314730 0

Summary
Brief summary
This is a double-blind, randomized, placebo-controlled study which is subdivided in 2 parts, Part 1 (SAD) and Part 2 (MAD). Decisions about how and when to move between cohorts will be based on reviews of the available blinded safety data and available pharmacokinetic (PK) data; this data will be reviewed by a prespecified Safety Review Committee (SRC). In Part 1, healthy volunteers will be enrolled to receive single ascending doses of LTSE-2578 or placebo. In Part 2, healthy volunteers will be enrolled to receive once or twice daily doses of LTSE-2578 or placebo for fourteen consecutive days.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 132550 0
Dr Christopher Argent
Address 132550 0
Scientia Clinical Research, 5th Floor Bright Building, Corner High and Avoca Street, Randwick NSW 2031
Country 132550 0
Australia
Phone 132550 0
+61 02 9382 5844
Fax 132550 0
Email 132550 0
[email protected]
Contact person for public queries
Name 132551 0
Christopher Argent
Address 132551 0
Scientia Clinical Research, 5th Floor Bright Building, Corner High and Avoca Street, Randwick NSW 2031
Country 132551 0
Australia
Phone 132551 0
+61 02 9382 5844
Fax 132551 0
Email 132551 0
[email protected]
Contact person for scientific queries
Name 132552 0
Christopher Argent
Address 132552 0
Scientia Clinical Research, 5th Floor Bright Building, Corner High and Avoca Street, Randwick NSW 2031
Country 132552 0
Australia
Phone 132552 0
+61 02 9382 5844
Fax 132552 0
Email 132552 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


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.