A First-In-Human Study of Single and Multiple Ascending Doses of Oral SUL-238 in Healthy Subjects

Healthy Subjects Clinical Trial

Official title:

A Randomized, Double-blind, Placebo-controlled Phase 1 Study to Evaluate the Safety, Tolerability, Pharmacokinetics of Single and Multiple Ascending Oral Doses of SUL-238 in Healthy Subjects

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06277492
• Other study ID #: GN-001
• Status: Recruiting
• Phase: Phase 1
• Start date: February 19, 2024
• Est. completion date: November 8, 2025

Study information

• Verified date: February 2024
• Source: GEN Ilaç ve Saglik Ürünleri A.S.
• Contact: Nadir Ulu, MD, PhD
• Phone: +905334510385
• Email: n.ulu[@]genilac.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The goal of this randomized, double-blind, placebo-controlled, single-center study is to evaluate the safety, tolerability, pharmacokinetics of single and multiple oral doses of SUL-238 in healthy subjects (aged ≥40 years).

Description:

This double-blind placebo-controlled study will be completed in 3 parts.

First part will be single ascending dose in which 6 different oral doses (50 mg, 100 mg, 250 mg, 500 mg, 1000 mg and 2000 mg) will be administered to healthy adult male subjects. Each dosing group, including dose escalations, will be performed as described below:

Dose escalation will be performed until suspected adverse events (AEs) are observed. AEs will be evaluated by the blinded investigator, based on clinical signs detailed in the MedDRA criteria. At each dose level, 2 subjects will be administered SUL-238, whereas 1 subject will be administered the placebo. Escalation to the next higher dose level may occur only if no treatment-emergent AEs are observed in the 2 subjects that received SUL-238. If 1 out of 2 subjects experiences a suspected AE, 5 new subjects will be enrolled at the same dose level (4 subjects will receive one SUL-238 tablet and 1 subject will receive one placebo tablet). If no further suspected AEs occur, escalation to the next higher dose level will be performed. If any additional suspected AE is noted, dose escalation is stopped, and the previous dose level is considered the MTD. If suspected AE are observed in 2 subjects, dose escalation will be stopped and 5 new subjects (4 subjects will receive one SUL-238 tablet and 1 subject will receive one placebo tablet) will be enrolled at the next lower dose level. If no further suspected AE are observed, this dose level is considered the MTD.

The second part of the study will be single dose pharmacokinetics (SDPK) which 1 dose level below that with suspected AEs will be administered to 10 healthy adult male or female subjects (aged ≥40 years). Five male subjects and 5 female subjects will receive SUL-238. After obtaining the initial PK results from Part 1, at least 3 volunteers who accept to be tapped for a Cerebrospinal Fluid (CSF) will provide one CSF sample on Day 1, at the time point of 1 hour after reaching Cmax during Part 2 of the study.

The third part of the study will be multiple ascending oral doses of SUL-238 or placebo which 30 healthy elderly subjects (aged ≥40 years) will be included. There will be 2 dosing groups (n=15 for each) once (or twice) daily (5 male subjects and 5 female subjects) in each dosing group for SUL-238, dosing regimen and doses of SUL-238 will be decided after Part 2.

The maximum tolerated dose (MTD) will be the dose for the first dosing group. The second dosing group will be one below the MTD level (e.g., if MTD is 1000 mg, the second dosing group will receive 500 mg SUL-238). In the first dosing group three 3 male and 2 female subjects and in the second dosing group 2 male and 3 female subjects will receive placebo. PK parameters as well as renal clearance and percentage of drug excreted in urine and feces will be measured in both dosing groups. At least 3 volunteers who agreed to be tapped for a CSF in both dosing groups receiving SUL-238 will provide one CSF sample on day 15, at the time point of CSF sample obtained during Part 2 of the study.

In Part 1 and 2, blood samples will be drawn, before drug administration (0 hours), after 30 minutes and at the following time points: 1, 2, 4, 8, 12, 18, 24, 32, 48 and 72 hours. In Part 3, blood samples will be drawn, before drug administration (0 hours), after 30 minutes and at the following time points: 1, 2, 4, 8, 12, 18, 24, 32, 48 and 72 hours, Days 28 (pre-last dose baseline, post- last dose at 30 minutes, 1, 2, 4, 8, 12 and 18 hours), 29, 30 and 31. The subject randomized to placebo arm will provide blood samples as subjects randomized to active drug.

In Part 1 and Part 2, ambulatory visits will be performed at Day 8, 11, 15, 22 and 29 after dosing on which volunteers will visit the clinical investigational site. The volunteers will be followed up until Day 29. In Part 3, ambulatory visits will be performed at Day 8, 11, 15, 22, 35, 38, 42, 49 and 57 after dosing on which volunteers will visit the clinical investigational site.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 69
• Est. completion date: November 8, 2025
• Est. primary completion date: August 9, 2025
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 40 Years and older

Eligibility

Inclusion Criteria:

1. Healthy as determined by the Investigator, based on a medical evaluation including medical history, physical examination, neurological examination, laboratory tests and cardiac monitoring.

2. Men and women aged=40 years at Screening.

3. Subject must understand the nature of the study and provide signed and dated written informed consent in accordance with local regulations before the conduct of any study-related procedures.

4. Able to complete all study related testing and evaluations.

5. Women and men of child-bearing potential with partners of child-bearing potential must agree to use highly effective contraception. For male subjects, contraception should continue for 90 days after the last dose of investigational medicinal product (IMP, one spermatic cycle).

6. Women of non-childbearing potential must be post-menopausal (the last menstrual period was at least 12 months ago, and follicle-stimulating hormone [FSH] at Screening confirms post-menopausal status), or have no uterus, ovaries, or fallopian tubes (or have their fallopian tubes tied). All women must have a negative pregnancy test result before administration of test article. Women who are surgically sterile must provide documentation of the procedure by an operative report or by ultrasound.

7. Body weight > 50 kg for men and > 50 kg for women and Body Mass Index (BMI) within the range 18.5-30.0 kg/m2, inclusive.

8. Subject must be, in the opinion of the Investigator, able to participate in all scheduled evaluations, likely to complete all required tests, and likely to be compliant.

Exclusion Criteria:

1. A positive urine drug screen/alcohol breath test at Screening or Day -1.

2. Any history of intellectual disability or psychiatric disorders, including substance use disorders, according to the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) criteria, except a history of mild depression/anxiety that has been resolved for at least the past 12 months.

3. A positive Hepatitis B surface antigen, Hepatitis C antibody, or Human Immunodeficiency Virus (HIV) antibody test at Screening.

4. Alanine aminotransferase or aspartate aminotransferase levels greater than 1.5 times the upper limit of normal (ULN) at Screening or between Screening and first dose administration.

5. History of regular alcohol consumption within the last 12 months, defined as an average weekly intake of >21 alcoholic drinks/week for men or >14 alcoholic drinks/week for women.

6. Regularly consumed (e.g., more days than not) excessive quantities of xanthine-containing beverages (e.g., more than five cups of coffee or the equivalent per day) within 30 days prior to Day -1.

7. Received or used an investigational product (including placebo) or device within the following time period prior to Day -1 in the current study: 90 days, 5 half-lives, or twice the duration of the biological effect of the investigational product (whichever is longer).

8. Use of prescription or non-prescription drugs, vitamins, herbal, and dietary supplements within 7 days (or 28 days if the drug is a potential hepatic enzyme inducer) or 5 half-lives (whichever is longer) prior to Day -1.

9. History of clinically significant sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that, in the opinion of the Investigator or Medical Monitor, contraindicates their participation.

10. A positive serum pregnancy test or lactation.

11. A history or presence of any disease, condition, or surgery likely to affect drug absorption, distribution, metabolism, or excretion. Subjects with a history of cholecystectomy should be excluded.

12. A history or presence of a clinically significant hepatic, renal, gastrointestinal, cardiovascular, endocrine, pulmonary, ophthalmologic, immunologic, hematologic, dermatologic, or neurologic abnormality.

13. Any clinically significant abnormalities in rhythm, conduction, or morphology of the resting ECG and any abnormalities in the 12-lead ECG that, in the judgement of the Investigator or Medical Monitor, may interfere with the interpretation of QTc interval changes, including abnormal ST-T-wave morphology or left ventricular hypertrophy.

14. A clinically significant vital signs abnormality at Screening or Day -1 This includes, but is not limited to, the following, in the sitting position (3 measurements, each 5 minutes apart): (a) systolic blood pressure < 90 or >140 mmHg, (b) diastolic blood pressure < 50 or > 95 mmHg, or (c) heart rate < 45 or > 100 beats per minute.

15. Subjects who have previously been enrolled in this study.

16. The subject is, in the opinion of the Investigator or Medical Monitor, unlikely to comply with the protocol or is unsuitable for any reason, e.g., known issues with ability to swallow tablets.

Related Conditions & MeSH terms

• Healthy Subjects

Intervention

Drug:
• Single ascending doses SUL-238
PART 1: SUL-238 single ascending doses
• Single dose Placebo
PART 1: Placebo single dose
• Single dose SUL-238
PART 2: SUL-238 single dose for pharmacokinetics
• Multiple ascending doses SUL-238
PART 3: SUL-238 multiple ascending doses
• Multiple doses Placebo
PART 3: Placebo multiple doses

Locations

Country	Name	City	State
Turkey	Erciyes University IKUM Center	Kayseri

Sponsors (2)

Lead Sponsor	Collaborator
GEN Ilaç ve Saglik Ürünleri A.S.	Sulfateq B.V.

Country where clinical trial is conducted

Turkey, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Incidence of Treatment-Emergent Adverse Events as Measured by NCI-CTCAE criteria	The safety and tolerability of SUL-238 will be assessed by documenting adverse events occurring after single dose administration on Day 1 in Part 1 and Part 2 until Day 29. After once daily continuous dosing of SUL-238 for 28 Days in Part 3, the safety and tolerability of SUL-238 will be assessed by documenting adverse events occurring after during multiple dose administrations until Day 57. There will be no dosing between Day 29 and 57 in Part 3.	Part 1 and Part 2: Up to day 29 and Part 3: Up to day 57
Primary	Incidence of Treatment-Emergent Adverse Events as Measured by Clinical Laboratory Measurements According to Established Clinical Normal Ranges	Clinical laboratory tests include hematology and clinical chemistry including renal function tests, hepatic enzymes, electrolytes and creatine kinase: Change from baseline (pre-dose sample) at 24 hours (Day 2) and at Days 3, 4, 8, 15 and 29 post-dose of SUL-238 (Part 1, Part 2).; Change from baseline (pre-dose sample) at 24 hours (Day 2) and at Days 3, 4, 8, 15 and 28 (1 hour post-last dose), 29 (24 hours post-last dose), 30, 35, 42 and 57 post-dose of SUL-238 for Part 3.; Blood and urine samples will be taken after administration of SUL-238 and values will be compared to baseline and established normal ranges to determine how SUL-238 administration impacts normal body function.	Part 1 and Part 2: Up to day 29 and Part 3: Up to day 57
Primary	Incidence of Treatment-Emergent Adverse Events as Measured by ECG	As compared to baseline (an ECG taken at 60 minutes pre-dose); ECG evaluations will be performed at 30 minutes, 1 hour, 12 hours post-dose and Days 2 (24 hours), 3, 4, 8, 15 and 29 post-dose of SUL-238 occurring after single dose administration (Part 1 and Part 2).; As compared to baseline (an ECG taken at 60 minutes pre-dose); ECG evaluations will be performed at 30 minutes, 1 hour, 12 hours post-dose 2 and Days 2 (24 hours), 3, 4, 8, 28 (1-hour post-last dose), 29, 30, 35, 42 and 57 post-dose of SUL-238. ECG parameters including QT interval corrected for heart rate using Fridericia's formula (QTcF) will be used to measure changes to the heart rate after administration of SUL-238.	Part 1 and Part 2: Up to day 29 and Part 3: Up to day 57
Primary	Incidence of Treatment-Emergent Adverse Events as Measured by physical examination and vital signs	Vital signs include blood pressure, heart rate and oral temperature. Change from baseline at every time points defined until Day 29 for Part 1 and 2, and until Day 57 for Part 3 post-dose of SUL-238.	Part 1 and Part 2: Up to day 29 and Part 3: Up to day 57
Primary	Incidence of Treatment-Emergent Adverse Events as Measured by central nervous system (CNS) and autonomic nervous system (ANS) examination.	After each dose of SUL-238 through completion of dosing, up to Day 29 in Part 1 and Part 2 and up to Day 57 in Part 3, at all time points defined for the evaluation of adverse events, CNS and ANS examinations will be performed and outcomes will be documented. CNS examinations should include evaluation of mental status, cranial and peripheral nerves, muscle strength, gait and coordination, sensations and reflexes. For the evaluation of ANS, the presence of postural hypotension, heart rate changes, pupil reflex change to light and signs and symptoms of decreased or absent sweating should be checked.	Part 1 and Part 2: Up to day 29 and Part 3: Up to day 57
Secondary	PK parameter: Maximum drug concentration in plasma (Cmax) of SUL-238 after a single ascending dose (Part 1 and Part 2).	Blood collection on Days 1, 2, 3 and 4. On Day 1 (pre-dose baseline, post-dose at 30 minutes, 1, 2, 4, 8, 12 and 18 hours), and Days 2 (24 and 32 hours post-dose), 3 (48 hours post-dose), and 4 (72 hours post-dose).	Part 1 and Part 2: Up to day 4
Secondary	PK parameter: Maximum drug concentration in plasma (Cmax) of SUL-238 after multiple ascending doses (Part 3).	Blood collection on Days 1, 2, 3, 4, 28, 29, 30 and 31. On Day 1 (pre-first dose baseline, post-first dose at 30 minutes, 1, 2, 4, 8, 12 and 18 hours), Days 2 (24 and 32 hours post-first dose), 3 (48 hours post-first dose), 4 (72 hours post-first dose), 28 (pre-last dose baseline, post-last dose at 30 minutes, 1, 2, 4, 8, 12 and 18 hours), 29, 30 and 31.	Part 3: Up to day 31
Secondary	PK parameter: Area under the concentration-time curve in plasma (AUC) of SUL-238 after single ascending dose (Part 1 and Part 2).	Blood collection on Days 1, 2, 3 and 4. On Day 1 (pre-dose baseline, post-dose at 30 minutes, 1, 2, 4, 8, 12 and 18 hours), Days 2 (24 and 32 hours post-dose), 3 (48 hours post-dose), and 4 (72 hours post-first dose). The determination of the Area under the concentration-time curve will be made from the data of pre-dose (time 0) to the time of the last quantifiable concentration (tlast) and from pre-dose (time 0) extrapolated to infinite time (AUClast + Clast/?z) calculated using the linear-log trapezoidal rule.	Part 1 and Part 2: Up to day 4
Secondary	PK parameter: Area under the concentration-time curve in plasma (AUC) of SUL-238 after multiple ascending doses (Part 3).	Blood collection on Days 1, 2, 3, 4, 28, 29, 30, and 31. On Day 1 (pre-first dose baseline, post-first dose at 30 minutes, 1, 2, 4, 8, 12 and 18 hours), Days 2 (24 and 32 hours post-first dose), 3 (48 hours post-first dose), 4 (72 hours post-dose), 28 (pre-last dose baseline, post-last dose at 30 minutes, 1, 2, 4, 8, 12 and 18 hours), 29, 30 and 31. The determination of the area under the concentration-time curve will be made from the data of pre-dose (time 0) to the time of the last quantifiable concentration (tlast) and from pre-dose (time 0) extrapolated to infinite time (AUClast + Clast/?z) calculated using the linear-log trapezoidal rule.	Part 3: Up to day 31
Secondary	Renal clearance and percentage of drug excreted in urine after single and multiple ascending doses of SUL-238.	Part 1 and 2: On Day 1 (pre-dose baseline), and 0-4, 4-8, 8-12, 12-24 hours and on Day 2 (24-48 hours) in 24 hours urine samples post-dose.; Part 3: On Day 1, (pre-dose baseline), and 0-4, 4-8, 8-12, 12-24 hours and post-dose on Days 2 (24-48 hours) in 24 hours urine samples, 8, 15, 28, 29 and 30 (post-dose in 24 hours urine samples). The renal clearance and amount of SUL-238 excreted in urine will be determined.	Part 1 and Part 2: Up to day 2 and Part 3: Up to day 30
Secondary	Percentage of drug excreted in feces after multiple ascending doses of SUL-238.	Part 3: Baseline (pre-first dose), Days 1 (24 hours post first-dose), 30, 35, 42 and 57 (after dosing). The amount of SUL-238 excreted in feces will be determined.	Part 3: Up to day 57
Secondary	The cerebrospinal fluid (CSF) levels of SUL-238	Based on the time to reach Cmax value obtained in Part 1, the cerebrospinal fluid (CSF) levels of SUL-238 will be evaluated through collection of CSF samples and evaluation of SUL-238 concentrations during Part 2 and Part 3 of the study. The CSF collections will be performed on Day 1 (dosing day) in Part 2 at a time point which will be defined as one hour after the time point when the Cmax is reached (Tmax) and on Day 15 (post-first dose) in Part 3 at the same time point of CSF sampling in Part 2. Due to its invasive nature, this evaluation will only be performed based on the acceptance of the healthy volunteers and CSF samples will be collected from the volunteers receiving SUL-238.	Part 2: Day 1 and Part 3: Days 1 and 15