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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT04759365

Registration number

NCT04759365

Ethics application status

Date submitted

15/02/2021

Date registered

18/02/2021

Date last updated

17/01/2023

Titles & IDs

Public title

Safety, Tolerability, Pharmacokinetic, and Pharmacodynamic Study of Oral ASN51 in Healthy Subjects and Subjects With Alzheimer's Disease

Scientific title

A Randomized, Double-Blind, Placebo-Controlled, Phase 1 Safety, Tolerability, Pharmacokinetics and Pharmacodynamics Study of Oral ASN51 in Healthy Young Adult and Elderly Subjects and Elderly Subjects With Alzheimer's Disease

Secondary ID [1]

ASN51-101

Universal Trial Number (UTN)

Trial acronym

Linked study record

Health condition

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

Alzheimer Disease

Condition category

Condition code

Neurological

Alzheimer's disease

Neurological

Dementias

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

Treatment: Drugs - ASN51
Treatment: Drugs - Placebo

Experimental: ASN51 - ASN51 will be administered as an oral capsule

Placebo comparator: Placebo - Placebo will be administered as an oral capsule

Treatment: Drugs: ASN51
ASN51 formulation for oral capsule

Treatment: Drugs: Placebo
Placebo formulation for oral capsule

Intervention code [1]

Treatment: Drugs

Comparator / control treatment

Control group

Outcomes

Primary outcome [1]

Incidence of Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)

Timepoint [1]

Up to 38 days

Secondary outcome [1]

PK parameter: The area under the concentration-time curve from time zero to time t of the last measured concentration above the limit of quantification (AUC0-t) in plasma

Timepoint [1]

Up to 10 days

Secondary outcome [2]

PK parameter: The area under the concentration-time curve from zero to infinity (AUC0-inf) in plasma

Timepoint [2]

Up to 10 days

Secondary outcome [3]

PK parameter: The maximum concentration (Cmax) at steady state in plasma

Timepoint [3]

Up to 10 days

Secondary outcome [4]

PK parameter: The time to reach maximum concentration (tmax) in plasma

Timepoint [4]

Up to 10 days

Secondary outcome [5]

PK parameter: The terminal elimination rate constant (?Z) with the respective half-life (t½) in plasma

Timepoint [5]

Up to 10 days

Secondary outcome [6]

PK parameter: The percentage of the extrapolated AUC in plasma

Timepoint [6]

Up to 10 days

Secondary outcome [7]

PK parameter: Area under the concentration-time curve from time zero to the end of the dosing interval (AUCtau) in plasma (Part 2 Day 1 only)

Timepoint [7]

Up to 1 day

Secondary outcome [8]

PK parameter: The minimal observed trough concentration (Cmin) at steady state in plasma

Timepoint [8]

Up to 10 days

Secondary outcome [9]

PK parameter: The average concentration (Cavg) at steady state in plasma

Timepoint [9]

Up to 10 days

Secondary outcome [10]

PK parameter: Accumulation Ratio: AUCtau at Day 10/ AUCtau at Day 1 in plasma

Timepoint [10]

Up to 10 days

Secondary outcome [11]

PK parameter: The mean cumulative amounts excreted (both in % of the administered dose and in mg ASN51) will be calculated both for Fe(0-72h) and Fe(0-tau) and Ae(0-72h) and Ae(0-tau), respectively

Timepoint [11]

Up to 10 days

Secondary outcome [12]

PK parameter: The area under the plasma concentration-time curve from time zero to time t of the last measured concentration above the limit of quantification (AUC0-t) in cerebrospinal fluid (CSF)

Timepoint [12]

Up to 10 days

Secondary outcome [13]

PK parameter: The area under the plasma concentration-time curve from zero to infinity (AUC0-8) in CSF

Timepoint [13]

Up to 10 days

Secondary outcome [14]

PK Parameter: The maximum plasma concentration (Cmax) in CSF

Timepoint [14]

Up to 10 days

Secondary outcome [15]

PK parameter: The time to reach maximum plasma concentration (tmax) in CSF

Timepoint [15]

Up to 10 days

Secondary outcome [16]

PK parameter: The terminal elimination rate constant (?Z) with the respective half-life (t½) in CSF

Timepoint [16]

Up to 10 days

Secondary outcome [17]

PK parameter: The percentage of the extrapolated AUC in CSF

Timepoint [17]

Up to 10 days

Secondary outcome [18]

PK parameter: Area under the concentration-time curve from time zero to the end of the dosing interval (AUCtau) in CSF

Timepoint [18]

Up to 10 days

Secondary outcome [19]

PD parameter: Change from baseline in total and phosphorylated CSF tau

Timepoint [19]

Up to 10 days

Secondary outcome [20]

PD parameter: Change from baseline in quantitative electroencephalography power and the P300 event related potential (ERP)

Timepoint [20]

Up to 10 days

Eligibility

Key inclusion criteria

Part 1 and Part 2 Only:

1. Healthy as determined by the Investigator, based on a medical evaluation including medical history, physical examination, neurological examination, laboratory tests and cardiac monitoring. A subject with a clinical abnormality or laboratory parameters outside the reference range for the population being studied may be included only if, in the opinion of the Investigator, the finding is (a) unlikely to introduce additional risk to the subject, (b) will not interfere with study procedures or confound study results, and (c) is not otherwise exclusionary (see

Minimum age

18 Years

Maximum age

85 Years

Sex

Both males and females

Can healthy volunteers participate?

Yes

Key exclusion criteria

Exclusion Criteria).
2. Men and women aged 18-55 years, inclusive, at Screening (Part 1) or 55-80 years, inclusive, at Screening (Part 2)
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 (Part 1 only) and men of child-bearing potential with partners of child-bearing potential must agree to use highly effective contraception. Contraception should consist of: (1) a condom for the male participant or partner of a female participant, combined with (2) a highly effective method of contraception (e.g., a hormonal method associated with suppression of ovulation, an intrauterine device [IUD]) for the female participant or partner of a male participant. Abstinence from heterosexual intercourse should only be used in place of contraception when this is consistent with the usual and preferred lifestyle of the participant. For male subjects, contraception should continue for 90 days after the last dose of investigational medicinal product (IMP, one spermatic cycle). Male subjects should agree to refrain from sperm donation throughout this same period.
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 > 50.0 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.
9. Subjects is fluent in the local language.
10. Subject agrees not to post any personal medical data related to the study or information related to the study on any website or social media site (e.g., Facebook, Twitter, etc.) until the trial has been completed, this does not include information about participating in a clinical study in general.
11. [Part 2 only] Subject is able to undergo Lumbar Puncture (LP)

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. Frequent use of any tobacco-containing (e.g., cigar, cigarette, or snuff) or nicotine-containing product (e.g., nicotine chewing gum, nicotine plasters, or other product used for smoking cessation) within 3 months prior to 1 week before study drug administration. Frequent use is defined as more than 10 cigarettes or equivalent per week. Use of any tobacco or nicotine-containing product is prohibited from 1 week prior to study drug administration throughout the study (final visit).
6. 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.
7. 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.
8. 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).
9. Use of prescription or non-prescription drugs, vitamins, herbal, and dietary supplements (including St John's Wort) 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.
10. 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.
11. Loss of more than 400 mL of blood within 3 months prior to Day -1, i.e., blood donor
12. A positive serum pregnancy test or lactation.
13. Hearing test result considered unacceptable for auditory ERP P300 assessment.
14. 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.
15. A history or presence of a clinically significant hepatic, renal, gastrointestinal, cardiovascular, endocrine, pulmonary, ophthalmologic, immunologic, hematologic, dermatologic, or neurologic abnormality.
16. A clinically significant abnormality on physical examination, neurological examination, electrocardiogram (ECG), or laboratory evaluations at Screening or between Screening and first dose administration.
17. A corrected QT interval measurement corrected according to the Fridericia rule (QTcF) > 450 msec during controlled rest at screening or between screening and first dose administration, or family history of long QT syndrome.
18. 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.
19. PR (PQ) interval shortening < 120 msec (PR < 120 msec but > 110 msec is acceptable if there is no evidence of ventricular pre-excitation).
20. PR (PQ) interval prolongation (> 220 msec), intermittent second- (Wenckebach block while asleep or in deep rest is not exclusionary) or third-degree AV block.
21. Persistent or intermittent complete bundle branch block (BBB), incomplete bundle branch block (IBBB), or intraventricular conduction delay (IVCD) with QRS > 120 msec.
22. 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.
23. Significant (> 10%) weight loss or gain within 30 days prior to Day -1
24. A history of seizure.
25. A history of head trauma, with loss of consciousness, except for minor head trauma that occurred at least 20 years prior to first dose.
26. A history of symptomatic orthostatic hypotension (i.e., postural syncope) or symptomatic orthostatic hypotension at Screening.
27. A history of neuroleptic malignant syndrome.
28. A history of chronic urinary tract infections.
29. 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 size 00 capsules.
30. Currently employed by Asceneuron SA or by a clinical trial site participating in this study, or a first-degree relative of an Asceneuron SA employee or of an employee at a participating clinical trial site.
31. Unsatisfactory venous access.
32. Identification of suicide risk in the Columbia-Suicide Severity Rating Scale (C-SSRS).
33. Part 2 only: Abnormal exercise ECG in relation to age.

Part 3 Only:

Inclusion Criteria

1. Between 55-85 years of age, inclusive.
2. Mild cognitive impairment due to AD or Mild-to-moderate AD dementia, Mini-Mental State Examination (MMSE) 14-27 and Clinical Dementia Rating (CDR) 0.5, 1 or 2 at the Screening Visit.
3. Clinical diagnosis of mild cognitive impairment or dementia, due probably to AD, by Revised National Institute on Aging-Alzheimer's Association criteria.
4. Reliable and capable support person/caregiver.
5. Able to undergo Lumbar Puncture (LP) and complete all study related testing and evaluations.
6. Women of non-childbearing potential must be post-menopausal [the last menstrual period was at least 12 months ago, and 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. Women and men of child-bearing potential with partners of child-bearing potential must agree to use highly effective contraception. Contraception should consist of: (1) a condom for the male participant or partner of a female participant, combined with (2) a highly effective method of contraception (e.g., a hormonal method associated with suppression of ovulation, an IUD) for the female participant or partner of a male participant. Abstinence from heterosexual intercourse should only be used in place of contraception when this is consistent with the usual and preferred lifestyle of the participant. For male subjects, contraception should continue for 90 days after the last dose of IMP (one spermatic cycle). Male subjects should agree to refrain from sperm donation throughout this same period.
8. Treatment-free or receiving stable acetylcholinesterase inhibitor (AChEI) treatment, defined as:

* Subjects who are taking an approved AChEI for at least 2 weeks prior to the first Screening biomarker for efficacy assessment at a dose that is not anticipated to change through the study follow-up period, OR
* Subjects who received an AChEI in the past and discontinued, e.g., due to tolerability issues, at least 5 half-lives or 30 days before the first Screening biomarker or efficacy assessment, whichever is longer.

1. Receipt of any investigational drug or device within 8 weeks or 4 half-lives, whichever is longer, prior to randomization.
2. History of cardiovascular disease or at risk of stroke or heart attack, peripheral vascular intervention, atrial fibrillation, clinically relevant cardiac arrhythmias, or uncontrolled hypertension.
3. History within 2 years of Screening, or current diagnosis of the any of the following psychiatric disorders: Schizophrenia, schizoaffective disorder, bipolar disorder I, or alcohol abuse or dependence per DSM-5 criteria.
4. History of unexplained loss of consciousness, and seizures (excluding infant febrile seizures)
5. Ongoing infectious, metabolic, or systemic diseases affecting the central nervous system (CNS) (e.g. syphilis, untreated hypothyroidism, current vitamin B12 or folate deficiency, potentially clinically significant serum electrolyte disturbances, unstable diabetes mellitus (HbA1c > 10.5%); or other similar conditions.
6. History within 2 years of Screening, or current diagnosis of a chronic inflammatory disease (i.e., rheumatoid arthritis, systemic lupus, erythematosus, Crohn's disease, etc.).
7. A positive Hepatitis B surface antigen, Hepatitis C antibody, or Human Immunodeficiency Virus (HIV) antibody test at Screening.
8. The subject has received active amyloid or tau immunization at any time, or passive immunization within 12 months of Screening.
9. Intake of any of the prohibited medications listed below within the past 30 days or 5 half-lives, whichever is longer. Subjects need to stay off the medication during the trial.

* For memantine, a 1-month drug-free period is required between the last dose received and Screening
* Anticonvulsants
* Neuroleptics (quetiapine and clozapine are allowed)
* Centrally active anti-hypertensive drugs (e.g., clonidine, alpha-methyldopa, guanidine, or guanfacine)
* Immunosuppressants or systemic corticosteroids >10 mg/day prednisone or equivalent
* Anticoagulants

9. History or presence of brain MRI scans indicative of a neurologic disease other than AD or any other significant abnormality.

10. Subject has an atypical variant presentation of AD, if known from medical history, particularly non-amnestic AD.

11. History of treatment for cancer within the past 2 years. Subjects who have undergone curative excision of basal cell carcinoma or squamous cell carcinoma of the skin within the past 2 years are permitted.

12. Blood pressure and ECG parameters at Screening:

* Seated systolic blood pressure < 90 mmHg or > 150 mmHg; or diastolic blood pressure < 50 mmHg or > 95 mmHg
* ECG abnormalities on the screening ECG including: clinically significant conduction abnormalities, ischemic changes (e.g., prior Q-wave myocardial infarction and/or marked ischemic ST- and T-wave), arrhythmias (e.g., persistent or paroxysmal ventricular or supraventricular arrhythmias, including atrial fibrillation), or other ECG abnormalities that would pose unnecessary risk in the opinion of the Investigator
* QTc interval > 450 in males or > 470 in females utilizing Fredericia's correction (QTcF)

13. Abnormal stress ECG in relation to age at Screening.

14. Renal insufficiency (serum creatinine >177 µmol/L).

15. Hepatic impairment with alanine aminotransferase or aspartate aminotransferase > 1.5 times the upper limit of normal, or Child-Pugh class B or C.

16. Hearing test result considered unacceptable for auditory ERP P300 assessment.

17. Positive urine or serum pregnancy test, lactating, or plans to become pregnant during the trial.

18. Significant suicide risk as assessed by C-SSRS.

19. Any condition that in the judgement of the Investigator would interfere with the ability to complete the trial, pose significant risk to subject safety, or potentially confound interpretation of trial results, e.g., known issues with ability to swallow size 5 capsules.

Study design

Purpose of the study

Treatment

Allocation to intervention

Randomised controlled trial

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

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

Masking / blinding

Blinded (masking used)

Who is / are masked / blinded?

The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data

Intervention assignment

Other

Other design features

Phase

Phase 1

Type of endpoint/s

Statistical methods / analysis

Recruitment

Recruitment status

Stopped early

Data analysis

Reason for early stopping/withdrawal

Other reasons

Date of first participant enrolment

Anticipated

Actual

2/06/2021

Date of last participant enrolment

Anticipated

Actual

Date of last data collection

Anticipated

Actual

1/08/2022

Sample size

Target

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

VIC

Recruitment hospital [1]

Nucleus Network - Melbourne

Recruitment postcode(s) [1]

3004 - Melbourne

Funding & Sponsors

Primary sponsor type

Commercial sector/industry

Name

Asceneuron Pty Ltd.

Address

Country

Other collaborator category [1]

Commercial sector/industry

Name [1]

Asceneuron S.A.

Address [1]

Country [1]

Other collaborator category [2]

Other

Name [2]

Neuroscience Trials Australia

Address [2]

Country [2]

Ethics approval

Ethics application status

Summary

Brief summary

ASN51-101 is a randomized, double-blind, placebo-controlled, phase 1 first in human (FIH) safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) study of oral ASN51 in healthy young adult and elderly subjects and elderly subjects with AD. The study is comprised of three parts (Part 1, Part 2, and Part 3).

Trial website

https://clinicaltrials.gov/study/NCT04759365

Trial related presentations / publications

Public notes

Contacts

Principal investigator

Name

Address

Country

Phone

Fax

Contact person for public queries

Name

Address

Country

Phone

Fax

Contact person for scientific queries

Summary Results

For IPD and results data, please see https://clinicaltrials.gov/study/NCT04759365

Trial Review

Did you know?

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT04759365