ANZCTR - Registration

Registration number

ACTRN12622000743763

Ethics application status

Approved

Date submitted

11/04/2022

Date registered

24/05/2022

Date last updated

20/05/2024

Date data sharing statement initially provided

24/05/2022

Date results information initially provided

1/03/2024

Type of registration

Prospectively registered

Titles & IDs

Public title

A Three Part, Randomized, Double-Blind, Placebo-Controlled, Phase I Study to evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Ascending Doses of GXV-001 in Healthy Volunteers

Scientific title

A Three Part, Randomized, Double-Blind, Placebo-Controlled, Phase I Study to evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Ascending Doses of GXV-001 in Healthy Volunteers

Secondary ID [1]

GXV-001-1001-AU

Universal Trial Number (UTN)

Trial acronym

Linked study record

Health condition

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

Rett Syndrome

Fragile X Syndrome

Neurodevelopmental disorders

Condition category

Condition code

Neurological

Other neurological disorders

Mental Health

Other mental health disorders

Human Genetics and Inherited Disorders

Other human genetics and inherited disorders

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

This is a randomised double-blind, placebo controlled, ascending dose, multi-cohort trial.
The study will be conducted in three parts:

Part A: A single ascending dose (SAD) part where dose levels will be evaluated in a sequential manner starting at the proposed lowest dose level in healthy volunteers.

40 healthy volunteers will be enrolled in a total of 5 cohorts. Each cohort will enrol 8 participants with 6 participants randomized to receive GXV-001 and 2 participants randomized to receive placebo.

GXV-001 will be provided as an oral solution. The starting dose, dose increments and dose range to be evaluated are based on available nonclinical data. In Part A, GXV-001 dose levels in the range of 3 to 200 mg are planned to be investigated.

Single dose of double blinded GXV-001 or placebo administered on Day 1.

Part B: A multiple ascending dose (MAD) part where dose levels and final numbers of subjects will be evaluated depending on SAD results in healthy volunteers.

Up to 48 healthy volunteers will be enrolled in a total of 3 cohorts. Each cohort will enrol a minimum of 8 and a maximum of 16 participants with up to 12 participants randomised to receive GXV-001 and 4 participants randomized to receive placebo depending on the variability of exposure and pharmacodynamic (PD) assessments in Part A.

The starting dose for each cohort in Part B was selected following completion of Part A based upon safety/tolerability/PK and available biomarker data. In Part B, GXV-001 dose levels in the range of 30 to 200 mg are planned to be investigated.

GXV-001 or placebo administered once daily (QD) for 7 days (total of 7 doses).

Part C: (Elderly Cohort) Evaluation of a single dose in healthy male and female volunteers between 50 and 75 years of age.

Approximately 8 healthy volunteers between 50 and 75 years of age (inclusive) will be enrolled in a single cohort, with 6 participants randomized to receive GXV-001 and 2 participants randomized to receive placebo. In Part C, GXV-001 at a dose level of 30mg is planned to be investigated.

Single dose of double blinded GXV-001 or placebo administered on Day 1.

The GXV-001 and placebo doses to be administered to participants will be dissolved in 60mls of water.

Adherence to the intervention will be done via supervised drug administration.

Intervention code [1]

Treatment: Drugs

Comparator / control treatment

Matching placebo to GXV-001. The placebo will contain sodium bicarbonate and FlavorSweet.

Control group

Placebo

Outcomes

Primary outcome [1]

To assess the safety and tolerability of single oral doses of GXV-001 in healthy volunteers.

Timepoint [1]

Measured by change from baseline and where appropriate overtime include:
• Incidence, severity, and relationship of AEs/SAEs graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) (Version 5). Timepoints: Monitored continuously from Day -1 (Check-in) to Day 6, and Day 7 End of Study (EOS)/Early Termination Visit (ETV)
• Change in vital signs, Blood pressure and heart rate is assessed using a sphygmomanometer and e-Celsius Performance used to measure temperature of participants under controlled conditions.. Timepoints: Screening, Day -1 (Check-in) and Day 1 (pre-dose, 1,2,4 and 12 hours post-dose), Day 2 (24 hours post dose) and Day 7 EOS/ETV
• Change in electrocardiogram (ECG) parameters – 12 Lead ECG usedin triplicate and single. Timepoints: Screening, Day -1 (Check-in) and Day 1 (pre-dose, 1, 4 and 12 hours post-dose), Day 2 (24 hours post dose) and Day 7 EOS/ETV
• Change in clinical laboratory parameters (haematology, serum chemistry, coagulation (blood samples) and urinalysis (urine sample) Timepoints: Screening, Day -1 (Check-in), Day 1 (1 hour post-dose), Day 2 (24 hours post-dose) and Day 7 EOS/ETV

Primary outcome [2]

To assess the safety and tolerability of 7-day repeat oral doses of GXV-001 in healthy volunteers.

Timepoint [2]

Measured by change from baseline and where appropriate overtime include: • Incidence, severity, and relationship of AEs/SAEs graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) (Version 5). Timepoints: Monitored continuously from Day 1 (Check-in) to Day 7, Day 8, Day 9 to Day 14, and Day 15 EOS/ETV • Change in vital signs, Blood pressure and heart rate is assessed using a sphygmomanometer. Timepoints: Screening, Day 1 (Check-in), Day 7 (pre-dose, 1,2,4 and 12 hours post-dose), Day 2 to Day 6 (pre-dose), Day 8 and Day 15 EOS/ETV • Change in electrocardiogram (ECG) parameters – 12 Lead ECG used in triplicate and single. Timepoints: Screening, Day 1 (Check-in) (pre-dose, 1, 4 and 12 hours post-dose), Day 7 (pre-dose,1 4 and 12 hours post dose), Day 2 to Day 6 (pre-dose) Day 8 and Day 15 EOS/ETV • Change in clinical laboratory parameters (haematology, serum chemistry, coagulation (blood samples) and urinalysis (urine sample) Timepoints: Screening, Day 1 (Check-in), Daily from Day 2 to Day 6 (pre-dose), Day 8 and Day 15 EOS/ETV

Secondary outcome [1]

To assess the pharmacokinetics (PK) of GXV-001 in plasma following administration of single oral doses in healthy volunteers.

Timepoint [1]

PK parameters to be calculated include (but are not limited to): Maximum observed plasma concentration (Cmax), Time to Cmax (Tmax), Area under the plasma concentration-time curve from time 0 to time of last quantifiable concentration (AUC0-t), Area under the plasma concentration-time curve from time 0 extrapolated to infinity (AUC0-inf), Apparent terminal elimination half-life (T1/2), Terminal elimination rate constant (Terminal elimination rate constant (kel), Apparent clearance (CL/F), Apparent volume of distribution (Vz/F)
Timepoints: Day 1: pre-dose, 0, 0.5, 1, 2, 4, 6, 12 and 24 hours post dose

Secondary outcome [2]

To assess the pharmacokinetics (PK) of GXV-001 in plasma following administration of 7-day repeat oral doses in healthy volunteers.

Timepoint [2]

PK parameters to be calculated include (but are not limited to): Maximum observed plasma concentration (Cmax), Time to Cmax (Tmax), Trough concentrations, Minimum observed concentration Cmin (Day 7, Part B only), Area under the plasma concentration-time curve from time 0 to time of last quantifiable concentration (AUC0-t), Area under the plasma concentration-time curve from time 0 to tau (AUCtau), Area under the plasma concentration-time curve from time 0 extrapolated to infinity (AUC0-inf), Apparent terminal elimination half-life (T1/2), Terminal elimination rate constant (Terminal elimination rate constant (kel), Apparent clearance (CL/F), Apparent steady state volume of distribution (Vss/F) following multiple oral administration, Accumulation ratio of AUCtau, Accumulation ratio of Cmax
Timepoints: Day 1 and Day 7: pre-dose, 0, 0.5, 1, 2, 4, 6, 12 and 24 hours post dose, Day 2 to Day 6: pre-dose

Secondary outcome [3]

To assess the PK of GXV-001 in urine following administration of a single oral dose in healthy adult volunteers

Timepoint [3]

Urine PK endpoints include (but are not limited to): Cumulative amount of unchanged drug excreted in urine (Ae), Renal clearance (CLr).
Timepoints: Day 1: pre-dose, 0 to 12 hours post-dose, 12 to 24 hours post-dose

Secondary outcome [4]

To assess the PK of GXV-001 in urine following administration of a 7-day repeat oral doses in healthy adult volunteers

Timepoint [4]

Urine PK endpoints include (but are not limited to): Cumulative amount of unchanged drug excreted in urine (Ae), Renal clearance (CLr).
Timepoints: Day 1 & Day 7: pre-dose, 0 to 12 hours post-dose, 12 to 24 hours post-dose

Eligibility

Key inclusion criteria

Part A: Healthy volunteers will be included in Part A of the study if they satisfy all the following criteria:
1. Participants 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. Assessed to have a usual sleeping pattern that meets the following criteria as judged by the PI following discussion with the participant:
a. no use of sleep aids (homeopathic/natural remedies such as over-the-counter melatonin, valerian and sleep vitamins) during last 3 months,
b. generally regular bedtime between 10 pm and midnight,
c. generally regular wake up times between 6 am and 9 am,
d. sleep latency time usually no longer than 1 hour
e. generally, sleep duration of 6-10 hours per day.
3. Willingness to comply with a structured sleeping pattern for 7 days prior to drug administration and during all confinement periods with bedtime between 11 pm and 12 am and waketime between 7 am to 8 am each day and agree to abstain for exercise or exposure to excessive sunlight on the day of admission.
4. Based upon data from the actigraphy device worn continuously during the 7 days prior to Day -1, have bedtime confirmed to be between 11 pm and 12 am with waketime between 7am and 8am for at least 5 out of 7 nights with at least 2 sequential nights prior to Day -1.
5. Adult males and females between 18 to 40 years of age (inclusive) at screening;
6. Body Mass Index (BMI) greater than or equal to 18.0 and less than or equal to 32.0 kg/m2, with a body weight greater than or equal to 45 kg at screening;
7. Medically healthy without clinically significant abnormalities at screening, at Check-in on Day -1;
8. Female volunteers must:
a. Be of nonchildbearing potential i.e., be surgically sterilized (hysterectomy, bilateral salpingectomy, bilateral oophorectomy at least 6 weeks before screening) or be postmenopausal, where menopause is defined as 12 months of amenorrhea in the absence of other biological causes (females under the age of 50 years must have a documented serum follicle stimulating hormone (FSH) level > 40mIU/mL to confirm menopause);
b. If of childbearing potential (defined as any female who has experienced menarche and who has not undergone surgical sterilisation and is not postmenopausal), the participant:
• Must have a negative serum test at the screening visit and a negative urine pregnancy test within 24 hours prior to the start of study drug;
• Must not be breastfeeding, lactating, or planning pregnancy during the study period;
• Must agree not to attempt to become pregnant;
• If heterosexual and sexually active, agree to use double barrier contraceptives including non-hormonal containing IUD and one other additional barrier contraception (mandatory use of a condom by the male partner) after signing consent, during the study, and at least 35 days after the last dose of study drug (women in a same sex relationship do not need to use contraception)
• Must agree to not donate ova for at least 35 days after the last dose of study drug;
9. Male participants, if not surgically sterilized, must agree to:
a. Not donate sperm after signing consent, during the study, and at least 95 days after the last dose of study drug;
b. If engaging in sexual intercourse with a female partner who could become pregnant, use a condom in addition to having the female partner use a highly effective contraceptive method;
c. If engaging in sexual intercourse with a male partner, a condom should be used for 35 days after the last dose of study drug;
10. Have suitable venous access for blood sampling;
11. Be willing and able to comply with all study assessments and adhere to the protocol schedule and restrictions.

Part B: Healthy volunteers will be included in Part B of the study if they satisfy all the following criteria:
1. Participants 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 between 18 to 40 years of age (inclusive) at screening;
3. Body mass index (BMI) greater than or equal to 18.0 and less than or equal to 32.0 kg/m2, with a body weight greater than or equal to 45 kg at screening;
4. Medically healthy without clinically significant abnormalities at screening, at Check-in on Day 1;
5. Female volunteers must:
a. Be of nonchildbearing potential i.e., be surgically sterilized (hysterectomy, bilateral salpingectomy, bilateral oophorectomy at least 6 weeks before screening) or be postmenopausal, where menopause is defined as 12 months of amenorrhea in the absence of other biological causes (females must have a documented serum follicle stimulating hormone (FSH) level > 40mIU/mL to confirm menopause);
b. If of childbearing potential (defined as any female who has experienced menarche and who has not undergone surgical sterilization and is not postmenopausal), the participant:
• Must have a negative serum test at the screening visit and a negative urine pregnancy test within 24 hours prior to the start of study drug;
• Must not be breastfeeding, lactating, or planning pregnancy during the study period;
• Must agree not to attempt to become pregnant;
• If heterosexual and sexually active, agree to use double barrier contraceptives including non-hormonal containing IUD and one other additional barrier contraception (as mandatory use of a condom by the male partner) after signing consent, during the study, and at least 35 days after the last dose of study drug (women in a same sex relationship do not need to use contraception)
• Must agree to not donate ova for at least 35 days after the last dose of study drug;
6. Male participants, if not surgically sterilized, must agree to:
a. Not donate sperm after signing consent, during the study, and at least 95 days after the last dose of study drug;
b. If engaging in sexual intercourse with a female partner who could become pregnant, use a condom in addition to having the female partner use a highly effective contraceptive method;
c. If engaging in sexual intercourse with a male partner, a condom should be used from signing consent until at least 35 days after the last dose of study drug;
7. Have suitable venous access for blood sampling;
8. Be willing and able to comply with all study assessments and adhere to the protocol schedule and restrictions.

Part C: Healthy volunteers will be included in Part C of the study if they satisfy all the following criteria:
1. Participants 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. Healthy adult males and females, and otherwise healthy adult males and females with a stable chronic disease or condition between 50 to 75 years of age (inclusive) at screening.
3. Medically healthy or with stable chronic disease or condition. Adults with stable chronic disease or condition includes adults with no new diagnosis, hospitalisation or changes in medication in the 3 months prior to first dose on study Day 1. Ongoing concomitant medications associated with the stable disease or condition, including prescription medications, OTC medications and herbal/vitamin supplements taken by volunteers, will be recorded and reviewed by the Investigator to determine whether the volunteer is suitable for inclusion in the study. In conducting this review, the Investigator must consider Exclusion Criteria 6, 9, 18 and 26;
4. Body mass index greater than or equal to 18.0 and less than or equal to 32.0 kg/m2, with a body weight greater than or equal to 45 kg at screening;
5. Female volunteers must be of non-childbearing potential i.e., be surgically sterilized (hysterectomy, bilateral salpingectomy, bilateral oophorectomy at least 6 weeks before screening) or be postmenopausal, where menopause is defined as 12 months of amenorrhea in the absence of other biological causes (females must have a documented serum FSH level > 40 mIU/mL to confirm menopause);
6. Male participants, if not surgically sterilized, must agree to:
a. Not donate sperm after signing consent, during the study, and at least 95 days after the last dose of study drug;
b. If engaging in sexual intercourse with a female partner who could become pregnant, use a condom in addition to having the female partner use a highly effective contraceptive method;
c. If engaging in sexual intercourse with a male partner, use a condom from signing consent until at least 35 days after the last dose of study drug;
7. Have suitable venous access for blood sampling;
8. Be willing and able to comply with all study assessments and adhere to the protocol schedule and restrictions.

Minimum age

18 Years

Maximum age

75 Years

Sex

Both males and females

Can healthy volunteers participate?

Yes

Key exclusion criteria

Part A: Healthy volunteers will be excluded from this study if there is evidence of any of the following at the screening visit, Check-in on Day -1 or prior to administration of the first dose on study Day 1:
1. History or presence of significant cardiovascular, pulmonary, hepatic, renal, hematological, gastrointestinal, endocrine, immunologic, dermatologic, or neurological disease, including any acute illness or major surgery within the past 3 months determined by the PI to be clinically significant (participants with resolved childhood asthma may be included in the study)
a. Systolic blood pressure in the range of >140 mmHg and diastolic blood pressure in the range of >90 mmHg) after 5 minutes in semi-supine position at screening;
b. Heart rate in the range of >100 beats/min (inclusive) after 5 minutes rest in semi-supine position;
c. Body temperature (tympanic or oral), outside the range of 35.0°C and 37.5°C (inclusive);
d. The Screening 12-lead ECG outside the normal range (QTcF males less than or equal to 450 msec; females less than or equal to 470 msec) or with abnormalities, which are hazardous to the participant according to the opinion of the Investigator at screening;
e. Any clinically relevant findings in biochemistry, hematology, coagulation, and urinalysis examinations as judged by the Investigator at screening;
2. Any finding in the participant’s medical history, physical examination, or safety laboratory tests giving reasonable suspicion of disease that would contraindicate taking GXV-001, or a similar drug in the same class, or that might interfere with the conduct of the study. This includes but is not limited to, peptic ulcer disease, seizure disorders, and cardiac arrythmia;
3. People with or presenting a risk of intestinal disorders that can lead to obstruction of the digestive tract, including diverticula.
4. People with motility disorders of the gastrointestinal tract or gastrointestinal surgery.
5. People with known swallowing disorders.
6. Current infection that requires systemically absorbed antibiotic, antifungal, antiparasitic or antiviral medications;
7. Any history of malignant disease in the last 10 years (excludes surgically resected skin squamous cell or basal cell carcinoma);
8. Presence of clinically relevant immunosuppression from, but not limited to, immunodeficiency conditions such as common variable hypogammaglobulinemia;
9. Use of or plans to use systemic immunosuppressive (e.g., corticosteroids, methotrexate, azathioprine, cyclosporine) or immunomodulating medications (e.g., interferon) during the study or within 3 months prior to the first study drug administration (prior use of nasal sprays for hay fever may be permitted at the discretion of the PI);
10. History of risk factors for torsade de pointes (including a family history of long QT syndrome or sudden cardiac death) or a known arrythmia;
11. Liver function test results elevated more than 1.5-fold above the upper limit of normal (ULN) for gamma glutamyl transferase (GGT), bilirubin (total, conjugated and unconjugated), alkaline phosphatase (ALP), aspartate aminotransferase (AST) or alanine aminotransferase (ALT). Volunteers with ALP and/or ALT/AST above the limits specified may be included, at the discretion of the Investigator, if the levels are unaccompanied by clinical signs and are determined to be normal variants;
12. Smokers, who smoked within the last 14 days and do not pass the urine cotinine test at screening or at Check-in on Day -1;
13. Positive test results for active, human immunodeficiency virus (HIV-1 or HIV-2), hepatitis B surface antigen (HBsAg) or hepatitis C virus (HCV) antibodies at the screening visit;
14. Presence or having sequelae of gastrointestinal, liver, kidney, or other conditions known to interfere with the absorption, distribution, metabolism, or excretion of drugs (prior gall bladder and/or appendix removal is not exclusionary if deemed appropriate by the PI);
15. Estimated creatinine clearance (CrCl) < 60 mL/min using the Cockcroft-Gault formula or serum creatinine more than 1.5-fold above the ULN;
16. History of substance abuse or alcohol abuse within 12 months prior to the screening visit (defined as more than an average of 14 standard drinks per week or regular consumption of 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]);
17. Positive drugs of abuse or alcohol breath test results at the screening visit or at check-in on Day -1;
18. Use of any prescription or over-the-counter medication (including herbal products, and hormone supplements or oral contraceptive pill) and > 400mg of ibuprofen within 10 days or 5 half-lives of the medication (whichever is longer) prior to the first study drug administration – exceptions include occasional use of ibuprofen during the study to manage AEs whereby up to a total of 400mg is allowed in the morning (before 12pm), topical ointments, and vitamins or dietary supplements;
19. Consumption of grapefruit or Seville orange (or products containing grapefruit or Seville orange) within 10 days prior to the first administration of study drug;
20. Cruciferous vegetables (such as; arugula, bok choy, broccoli, brussel sprouts, cabbage, cauliflower and collard greens), poppy seeds, or charbroiled foods (i.e., cooking foods at high temperatures resulting in charred food) are prohibited within 72 hours prior to Check-in on Day -1 and for the duration of the study;
21. 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;
22. Known hypersensitivity to any of the study drug ingredients or to the actigraphy watch;
23. Known hypersensitivity to melatonin agonists such as melatonin, ramelteon, tasimelteon, or agomelatine;
24. Use of any vaccinations within 14 days prior to the first study drug administration;
25. For women of childbearing potential, a positive serum pregnancy test at the screening visit or a positive urine pregnancy test (with confirmatory serum pregnancy test) at check-in on Day -1;
26. Females who are breastfeeding or planning to breast feed at any time during the study;
27. 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 first study drug administration, or receipt of a blood transfusion within 1 year of first study drug administration;
28. Treatment with an investigational drug in another clinical trial within 30 days or 5 half-lives of the other investigational drug (whichever is longer) prior to the first administration of study drug in this trial;
29. Volunteer has a risk of suicide according to the Investigator’s clinical judgement or has made a suicide attempt in the previous 6 months;
30. Volunteer has worked as shift worker or had a trans meridian travel during the last 4 weeks before study start.
31. Any other condition or prior therapy that in the opinion of the Investigator 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.

Part B: Healthy volunteers will be excluded from this study if there is evidence of any of the following at the screening visit or check-in on Day 1:
1. History or presence of significant cardiovascular, pulmonary, hepatic, renal, haematological, gastrointestinal, endocrine, immunologic, dermatologic, or neurological disease, including any acute illness or major surgery within the past 3 months determined by the PI to be clinically significant (participants with resolved childhood asthma may be included in the study) including:
a. Systolic blood pressure in the range of >140 mmHg and diastolic blood pressure in the range of >90 mmHg after 5 minutes in semi-supine position;
b. Heart rate in the range of >100 beats/min (inclusive) after 5 minutes rest in semi-supine position;
c. Body temperature (tympanic or oral), outside the range of 35.0°C and 37.5°C (inclusive);
d. The screening 12-lead ECG outside the normal range (QT interval corrected using the Fridericia method (QTcF) males less than or equal to 450 msec; females less than or equal to 470 msec) or with abnormalities, which are hazardous to the participant according to the opinion of the Investigator;
e. Any clinically relevant findings in biochemistry, haematology, coagulation, and urinalysis examinations as judged by the Investigator;
2. Any finding in the participant’s medical history, physical examination, or safety laboratory tests giving reasonable suspicion of disease that would contraindicate taking GXV-001, or a similar drug in the same class, or that might interfere with the conduct of the study. This includes but is not limited to, peptic ulcer disease, seizure disorders, and cardiac arrythmia;
3. People with or presenting a risk of intestinal disorders that can lead to obstruction of the digestive tract, including diverticula.
4. People with motility disorders of the gastrointestinal tract or gastrointestinal surgery.
5. People with known swallowing disorders.
6. Current infection that requires systemically absorbed antibiotic, antifungal, antiparasitic or antiviral medications;
7. Any history of malignant disease in the last 10 years (excludes surgically resected skin squamous cell or basal cell carcinoma);
8. Presence of clinically relevant immunosuppression from, but not limited to, immunodeficiency conditions such as common variable hypogammaglobulinemia;
9. Use of or plans to use systemic immunosuppressive (e.g., corticosteroids, methotrexate, azathioprine, cyclosporine) or immunomodulating medications (e.g., interferon) during the study or within 3 months prior to the first study drug administration (prior use of nasal sprays for hay fever may be permitted at the discretion of the Investigator);
10. History of risk factors for torsade de pointes (including a family history of long QT syndrome or sudden cardiac death) or a known arrythmia;
11. Liver function test results elevated more than 1.5-fold above the upper limit of normal (ULN) for gamma glutamyl transferase (GGT), bilirubin (total, conjugated and unconjugated), alkaline phosphatase (ALP), aspartate aminotransferase (AST) or alanine aminotransferase (ALT). Volunteers with ALP and/or ALT/AST above the limits specified may be included, at the discretion of the Investigator, if the levels are unaccompanied by clinical signs and are determined to be normal variants;
12. Smokers, who smoked within 14 days before screening and do not pass the urine cotinine test at Screening or at Check-in on Day 1;
13. Positive test results for active, human immunodeficiency virus (HIV-1 or HIV-2), hepatitis B surface antigen (HBsAg) or hepatitis C virus (HCV) antibodies at the screening visit;
14. Presence or having sequelae of gastrointestinal, liver, kidney, or other conditions known to interfere with the absorption, distribution, metabolism, or excretion of drugs (prior gall bladder and/or appendix removal is not exclusionary if deemed appropriate by the PI);
15. Estimated creatinine clearance (CrCl) < 60 mL/min using the Cockcroft-Gault formula or serum creatinine more than 1.5-fold above the ULN;
16. History of substance abuse or alcohol abuse within 12 months prior to the screening visit (defined as more than an average of 14 standard drinks per week or regular consumption of 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]);
17. Positive drugs of abuse or alcohol breath test results at the screening visit or at check-in on Day 1;
18. Use of any prescription or over-the-counter medication (including herbal products, and hormone supplements or oral contraceptive pill) and > 400 mg/day of ibuprofen within 10 days or 5 half-lives of the medication (whichever is longer) prior to the first study drug administration – exceptions include occasional use of ibuprofen during the study to manage AEs whereby up to a total of 400 mg is allowed in the morning (before 12 pm), topical ointments, and vitamins or dietary supplements;
19. Consumption of grapefruit or Seville orange (or products containing grapefruit or Seville orange) within 10 days prior to the first administration of study drug;
20. Cruciferous vegetables (such as; rocket, bok choy, broccoli, brussel sprouts, cabbage, cauliflower and collard greens), poppy seeds, or charbroiled foods (i.e., cooking foods at high temperatures resulting in charred food) are prohibited within 72 hours prior to check-in on Day 1 and for the duration of the study;
21. 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;
22. Known hypersensitivity to any of the study drug ingredients;
23. Known hypersensitivity to melatonin agonists such as melatonin, ramelteon, tasimelteon, or agomelatine;
24. Use of any vaccinations within 14 days prior to the first study drug administration;
25. For women of childbearing potential, a positive serum pregnancy test at the screening visit or a positive urine pregnancy test (with confirmatory serum pregnancy test) at check-in Day 1;
26. Females who are breastfeeding or planning to breast feed at any time during the study;
27. 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 first study drug administration, or receipt of a blood transfusion within 1 year of first study drug administration;
28. Treatment with an investigational drug in another clinical trial within 30 days or 5 half-lives of the other investigational drug (whichever is longer) prior to the first administration of study drug in this trial;
29. Volunteer has a risk of suicide according to the Investigator’s clinical judgement (i.e., per Columbia-Suicide Severity Rating Scale [C-SSRS]) or has made a suicide attempt in the previous 6 months;
30. Any other condition or prior therapy that in the opinion of the Investigator 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.

Part C: Healthy volunteers will be excluded from this study if there is evidence of any of the following at the screening visit or check-in on Day 1:
1. History or presence of significant cardiovascular, pulmonary, hepatic, renal, haematological, gastrointestinal, endocrine, immunologic, dermatologic, neurological, oncologic, or psychiatric disease, or any other condition that, in the opinion of the Investigator, would jeopardise the safety of the participant or validity of study results (participants with resolved childhood asthma may be included in the study). Participants must present without any clinically significant (CS) abnormalities, including:
a. Systolic BP in the range of >145 mmHg and diastolic BP in the range of >95 mmHg after 5 minutes in semi-supine position;
b. Heart rate in the range of >100 beats/min (inclusive) after 5 minutes rest in semi-supine position;
c. Body temperature (tympanic or oral), outside the range of 35.0°C and 37.5°C (inclusive);
d. The screening 12-lead ECG outside the normal range QTcF (males less than or equal to 450 msec; females less than or equal to 470 msec) or with abnormalities, which are hazardous to the participant according to the opinion of the Investigator;
e. Any clinically relevant findings in biochemistry, haematology, coagulation, and urinalysis examinations as judged by the Investigator;
2. Any finding in the participant’s medical history, physical examination, or safety laboratory tests giving reasonable suspicion of disease that would contraindicate taking GXV-001, or a similar drug in the same class, or that might interfere with the conduct of the study. This includes but is not limited to, peptic ulcer disease, seizure disorders, and cardiac arrythmia;
3. People with or presenting a risk of intestinal disorders that can lead to obstruction of the digestive tract, including diverticula.
4. People with motility disorders of the gastrointestinal tract or gastrointestinal surgery.
5. People with known swallowing disorders.
6. Current infection that requires systemically absorbed antibiotic, antifungal, antiparasitic or antiviral medications;
7. Any history of malignant disease in the last 5 years (excludes surgically resected skin squamous cell or basal cell carcinoma);
8. Presence of clinically relevant immunosuppression from, but not limited to, immunodeficiency conditions such as common variable hypogammaglobulinemia;
9. Use of or plans to use systemic immunosuppressive (e.g., corticosteroids, methotrexate, azathioprine, cyclosporine) or immunomodulating medications (e.g., interferon) during the study or within 3 months prior to the first study drug administration (prior use of nasal sprays for hay fever may be permitted at the discretion of the Investigator);
10. History of risk factors for torsade de pointes (including a family history of long QT syndrome or sudden cardiac death) or a known arrythmia;
11. Liver function test results elevated more than 1.5-fold above the ULN for GGT, bilirubin (total, conjugated and unconjugated), ALP, AST or ALT. Volunteers with ALP and/or ALT/AST above the limits specified may be included, at the discretion of the Investigator, if the levels are unaccompanied by clinical signs and are determined to be normal variants;
12. Smokers, who smoked within 14 days before screening and do not pass the urine cotinine test at Screening or at check-in on Day 1;
13. Positive test results for active, HIV-1 or HIV-2, HBsAg or HCV antibodies at the screening visit or a positive COVID-19 test;
14. Presence or having sequelae of gastrointestinal, liver, kidney, or other conditions known to interfere with the absorption, distribution, metabolism, or excretion of drugs (prior gall bladder and/or appendix removal is not exclusionary if deemed appropriate by the Investigator);
15. Estimated CrCl < 60 mL/min using the Cockcroft-Gault formula or serum creatinine more than 1.5-fold above the ULN;
16. History of substance abuse or alcohol abuse within 12 months prior to the screening visit (defined as more than an average of 14 standard drinks per week or regular consumption of 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]);
17. Positive drugs of abuse or alcohol breath test results at the screening visit or at check-in on Day 1;
18. Use of any prescription or OTC medication (including herbal products, and hormone supplements or oral contraceptive pill) and > 400 mg/day of ibuprofen within 10 days or 5 half-lives of the medication (whichever is longer) prior to the first study drug administration. The volunteer may be enrolled if the medication or residual drug present is not expected to interfere with participant safety or study results - exceptions include occasional use of ibuprofen during the study to manage AEs whereby up to a total of 400 mg is allowed in the morning (before 12 noon), topical ointments, and vitamins or dietary supplements. Medications associated with a stable disease or condition (including prescription medications, OTC medications and herbal/vitamin supplements) may be permitted if not expected to interfere with participant safety or study results;
19. Consumption of grapefruit or Seville orange (or products containing grapefruit or Seville orange) within 10 days prior to the first administration of study drug;
20. Cruciferous vegetables (such as; rocket, bok choy, broccoli, Brussels sprouts, cabbage, cauliflower and collard greens), poppy seeds, or charbroiled foods (i.e., cooking foods at high temperatures resulting in charred food) are prohibited within 72 hours prior to check-in on Day 1 and for the duration of the study;
21. 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;
22. Known hypersensitivity to any of the study drug ingredients;
23. Known hypersensitivity to melatonin agonists such as melatonin, ramelteon, tasimelteon, or agomelatine;
24. Use of any vaccinations within 14 days prior to the first study drug administration;
25. 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 first study drug administration, or receipt of a blood transfusion within 1 year of first study drug administration;
26. Treatment with an investigational drug in another clinical trial within 30 days or 5 half-lives of the other investigational drug (whichever is longer) prior to the first administration of study drug in this trial;
27. Volunteer has a risk of suicide according to the Investigator’s clinical judgement (i.e., per C-SSRS) or has made a suicide attempt in the previous 6 months;
28. Any other condition or prior therapy that in the opinion of the Investigator 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

Statistical methods / analysis

No formal sample size calculation was performed.

The Full Analysis Set will include all randomised participants who receive at least one dose of study drug (GXV-001 or placebo) and have at least one post-dose assessment.
Participant disposition and background data, including demographics, relevant background, participation, compliance, and concomitant medication data, will be presented for all participants in the full analysis set.

The Safety Analysis Set will include all participants who receive at least 1 dose of study drug (GXV-001 or placebo) and have at least 1 post-dose safety assessment.
Safety and tolerability data will be presented for all participants in the safety set.

The PK Analysis Set will include all participants in the Safety Analysis Set who have sufficient plasma concentration data to derive at least one PK parameter.

Recruitment

Recruitment status

Completed

Date of first participant enrolment

Anticipated

20/06/2022

Actual

21/06/2022

Date of last participant enrolment

Anticipated

Actual

3/01/2024

Date of last data collection

Anticipated

Actual

26/01/2024

Sample size

Target

88

Accrual to date

Final

86

Recruitment in Australia

Recruitment state(s)

QLD

Recruitment hospital [1]

Q-Pharm Pty - Clive Berghofer Research Centre (CBCRC) - Herston

Recruitment postcode(s) [1]

4006 - Herston

Funding & Sponsors

Funding source category [1]

Commercial sector/Industry

Name [1]

GEXVal AU PTY LTD

Country [1]

Australia

Primary sponsor type

Commercial sector/Industry

Name

GEXVal AU PTY LTD

Country

Australia

Secondary sponsor category [1]

Commercial sector/Industry

Name [1]

Avance Clinical Pty Ltd

Country [1]

Australia

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Alfred Hospital Ethics Committee

Ethics committee address [1]

The Alfred Hospital
55 Commercial Rd,
Melbourne VIC 3004

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

04/05/2022

Approval date [1]

10/06/2022

Ethics approval number [1]

Summary

Brief summary

This is a randomised double-blind, placebo controlled, ascending dose, multi-cohort trial.
The study will be conducted in three parts:

• Part A: A single ascending dose (SAD) part where dose levels will be evaluated in a sequential manner starting at the proposed lowest dose level in healthy volunteers.
• Part B: A multiple ascending dose (MAD) part where dose levels and final numbers of subjects will be evaluated depending on SAD results in healthy volunteers.
• Part C: Evaluation of a single dose in healthy male and female volunteers between 50 and 75 years of age.

Part A will enrol up to 40 healthy volunteers in a total of 5 cohorts. Each cohort will enrol 8 participants with 6 participants randomised to receive GXV-001 and 2 participants randomised to receive placebo.

Part B will enrol up to 48 healthy volunteers will be enrolled in a total of 3 cohorts. Each cohort will enrol a minimum of 8 and a maximum of 16 participants with up to 12 participants randomised to receive GXV-001 and 4 participants randomised to receive placebo.

Part C (Elderly Cohort) will enrol approximately 8 healthy volunteers between 50 and 75 years of age (inclusive) in a single cohort, with 6 participants randomized to receive GXV-001 and 2 participants randomized to receive placebo.

Up to three dose levels will be evaluated in Part B. The starting dose and number of participants enrolled in MAD cohorts for Part B will be selected following completion of Part A.

The total maximum study duration for participants in Part A is 43 days (for SAD Cohorts 1, 2, 3, 4 and 5), inclusive of visit windows. For SAD Cohorts 1, 2, 3, 4 and 5, this includes a screening period of up to 28 days (Day -35 to Day -8), outpatient sleep control period (actigraphy) from Day -8 to Day -1, confinement to the clinical facility over 2 nights (Days -1 to Day 2) and one outpatient visit at the end of the study (Day 7 ±1 day).

The total maximum study duration for participants in Part B is 44 days (for MAD Cohorts 6, 7 and 8), inclusive of visit windows. This includes a screening period of up to 28 days (Day -28 to Day -1), confinement to the clinical facility over 7 nights (Days 1 to Day 8) and one outpatient visit at the end of the study (Day 15 ±1 day).

The total maximum study duration for participants in Part C is 36 days inclusive of visit windows. This includes a screening period of up to 28 days (Day -28 to Day -1), confinement to the clinical facility on Day 1 and one outpatient visit at the end of the study (Day 7 ±1 day).

Trial website

Public notes

Participants excluded if use of any vaccinations within 14 days prior to the first study drug administration (including COVID-19 vaccinations)

A critical part of the study design is a single blind placebo run in where subjects are not aware of the exact assignment on Day -1 for Part A only. It is imperative to the analysis of PD markers to have this as a baseline and imparts an efficient part to the study design reducing requirement for more subjects in the randomised part of the study. This is an accepted study design used in prior studies in this area.

Contacts

Principal investigator

Name

Dr Richard Friend

Address

Level 5 Clive Berghofer Cancer Centre Research Centre
300 Herston Road, Herston, QLD 4006

Country

Australia

Phone

+61 7 3707 2720

Email

r.friend@nucleusnetwork.com.au

Contact person for public queries

Name

Dr Nucleus Network Brisbane

Address

Level 5 Clive Berghofer Cancer Centre Research Centre,
300 Herston Road, Herston, QLD 4006

Country

Australia

Phone

+61 1800 243 733

Email

brisbane@nucleusnetwork.com

Contact person for scientific queries

Name

Dr Takashi Arima

Address

GEXVal AU PTY Ltd
Level 2, 169 Pirie Street, Adelaide, SA 5000, Australia

Country

Australia

Phone

+61 410 714 052

Email

takashi.arima@gexval.com

Trial Review

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