Study to Assess the Safety, Tolerability and Pharmacokinetics of Single Ascending Oral Doses of J147

Study Overview
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Brief Summary
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This Phase I clinical study is a randomized, double-blind, placebo-controlled, parallel-design study to thoroughly assess the safety profile and PK properties of J147 in healthy subjects. The study will include single ascending dose (SAD) in healthy young and elderly subjects.

Detailed Description
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This Phase I clinical study is a randomized, double-blind, placebo-controlled, parallel-design study to thoroughly assess the safety profile and PK properties of J147 in healthy subjects and to perform a preliminary assessment of the effect of food on safety and PK parameters of J147. The study will include single ascending dose (SAD) in healthy young and elderly subjects. Approximately 64 subjects may be included in the study, with an additional 24 to be added depending on the emerging data. Six cohorts of 8 healthy young male subjects and 2 cohorts of 8 healthy elderly male and female subjects are planned. Depending on emerging safety, tolerability and PK data, 2 additional cohorts of 8 healthy young male subjects in each cohort and 1 additional cohort of 8 elderly male and female subjects may be enrolled. In each cohort, 6 subjects will be randomized to receive a single dose of J147 orally and 2 subjects will be randomized to receive a matching dose of placebo. All cohorts will consist of 2 sentinel subjects of whom 1 subject will receive J147 and 1 subject will receive matching placebo. The remaining 6 subjects of whom 5 subjects will receive J147 and 1 subject will receive matching placebo will be dosed at least 24 hours following the sentinel subjects. Healthy elderly subjects will receive doses that have been found to be safe in healthy young subjects.

Official Title
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A Phase I, Randomized, Double-Blind, Placebo-Controlled Study to Assess the Safety, Tolerability and Pharmacokinetics of Single Ascending Oral Doses of J147 in Healthy Young Volunteers and Healthy Elderly Volunteers

Conditions
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Alzheimer's Disease

Intervention / Treatment
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* Drug: J147
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provide voluntarily agreement to participate in this study and signs an IRB/IEC-approved informed consent prior to performing any of the screening procedures Healthy male subjects, between 18 to 50 years of age, inclusive, at the time of signing the informed consent; OR, Healthy male and female subjects, between 60 to 85 years of age, inclusive, at the time of signing the informed consent If male, subjects with partners of child bearing potential must be practicing abstinence, part of an abstinent life style or agree to use a highly effective contraception method during the intervention period and for at least 3 months after the last dose of study medication and refrain from donating sperm during this period. Because of the unacceptable failure rate of barrier (chemical and/or physical) methods, the barrier method of contraception must only be used in combination with a highly effective method. Post coital methods of contraception are not permitted. If female, must not be pregnant, must not be lactating, and must be of non-childbearing potential (surgically sterile [hysterectomy or bilateral tubal ligation] or postmenopausal ≥ 1 year. Body mass index (BMI) between 18.0 and 30.0 kg/m2, inclusive, at screening with a weight of at least 50 kg Nonsmokers (or other nicotine use) as determined by history (no nicotine use over the past year) and by urine cotinine concentration (< 200 ng/mL) at the screening visit and admission Exclusion Criteria: Has clinically significant history or evidence of cardiovascular, endocrine, hematologic, immune, gastrointestinal, genitourinary or other body system disease as determined by an Investigator Has clinically significant history or evidence of disease or dysfunction in neurological or psychiatric system that is likely to affect the results of the study in the opinion of an Investigator Has any disorder that would interfere with the absorption, distribution, metabolism or excretion of drugs Subject has any concurrent disease or condition that, in the opinion of the Principal Investigator, would make the subject unsuitable for participation in the clinical study Has positive test for hepatitis B surface antigen (HBsAg), hepatitis C antibody (HCV) or human immunodeficiency virus (HIV) antibodies Has a urine blood test for ethanol or cotinine at the screening visit or admission Has a positive urine drug test (e.g., cocaine, amphetamines, barbiturates, opiates, benzodiazepines, cannabinoids) at the screening visit or admission Females who are breastfeeding Is unwilling to or has not avoided consumption of grapefruit, grapefruit juice, Seville oranges, Seville orange marmalade or other products containing grapefruit or Seville oranges within 14 days of dosing with study medication Has history of alcohol and/or illicit drug abuse within 1 year of entry or is unwilling to avoid use of alcohol or alcohol-containing foods, medications or beverages, within 48 hours prior to admission until discharge from the clinical unit Has donated blood (> 500 mL) or blood products within 30 days prior to first day of dosing Requires treatment with any medication, prescription or over-the-counter (OTC) medications (including vitamins [mega doses], dietary supplements or herbal medications), prescription medications within 14 days prior to administration of study medication. By exception, acetaminophen ≤ 1000 mg per day and vitamin products at recommended daily doses are permitted Has received any known hepatic or renal clearance altering agents (e.g., erythromycin, cimetidine, barbiturates, phenothiazines or herbal/plant-derived preparations such as St. John's wort) for a period of 30 days prior to dosing Has used an investigational drug within 30 days prior to screening Has a history of hypersensitivity or allergies to J147, any components of formulated J147, or any drug within the same class; minor drug allergies to a drug in another drug class may be approved by an Investigator if not considered of clinical relevance Has clinically significant abnormal vital signs, 12-lead ECGs, physical examination, clinical laboratory, or other safety variable, as judged by an Investigator Is considering or has scheduled any surgical procedure during study participation Requires a special diet or has a significant food allergy or intolerance; if the subject or patient is vegetarian, he or she may be enrolled at an Investigator's discretion Is unable to understand the protocol requirements, instructions and study related restrictions, the nature, scope and possible consequences of the clinical study Is unlikely to comply with the protocol requirements, instructions and study related restrictions; e.g., uncooperative attitude, inability to return for follow-up visits and improbability of completing the clinical study Has previously been enrolled in this clinical study or is currently enrolled in another clinical study For the elderly subjects, there must be no evidence of cognitive decline that has been greater than expected for age and no evidence of changes in their level of independence in everyday life. Is judged by an Investigator or Sponsor to be inappropriate for the study

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Subjects will receive a single dose of J147 or placebo in a fasted state. The dose levels are planned to be administered in ascending order. Progression to the next dose level, and dose selection, will be based on all available safety and tolerability data up to at least 48 hours post-dose and available PK data (up to at least 24 hours post-dose) from a minimum of 6 subjects (J147 n ≥4) in the preceding dose cohort. Healthy elderly subjects will receive doses that have been found to be safe in healthy young subjects.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Study Drug<br>Healthy young male subjects will receive a single ascending oral dose of J147 following an overnight fast of at least 8 hours. Healthy elderly subjects will receive doses that have been found to be safe in healthy young subjects. | Drug: J147<br>* Single oral dose of J147<br>|
| Placebo Comparator: Placebo<br>Subjects will receive a single oral dose of placebo with 240 mL non-carbonated water in the morning following an overnight fast of at least 8 hours. | Drug: Placebo<br>* Single oral dose of corn oil<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of treatment-emergent adverse events | Nature, frequency and severity of adverse events | from pre-dose to 7+/-2 days post dose | 
| Number of subjects with abnormal electrocardiogram | 12-lead electrocardiogram measurement | from pre-dose to 7+/-2 days post dose | 
| Incidence of clinically significant changes in serum biomarker levels in a standard serum chemistry panel | Changes in standard serum chemistry measures will be assessed. | from pre-dose to 7+/-2 days post dose | 
| Incidence of clinically significant changes in hematological biomarker levels in a standard hematology panel | Changes in standard hematology measures will be assessed. | from pre-dose to 7+/-2 days post dose | 
| Incidence of clinically significant changes in urine biomarker levels in a standard urinalysis panel | Changes in standard urinalysis measures will be assessed. | from pre-dose to 7+/-2 days post dose | 
| Number of patients exhibiting changes in standard Physical Examination results |  | from pre-dose to 7+/-2 days post dose | 
| Number of patients exhibiting changes in standard Neurological Examination results |  | from pre-dose to 7+/-2 days post dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum plasma concentration (Cmax) |  | 0-48 hours post dose | 
| Time to Cmax (Tmax) |  | 0-48 hours post dose | 
| Area under the plasma concentration vs. time curve (AUC) |  | 0-48 hours post dose | 
| Terminal rate constant |  | 0-48 hours post dose | 
| Terminal half-life (t1/2) |  | 0-48 hours post dose | 
| Apparent plasma clearance (CL/F) |  | 0-48 hours post dose | 
| Renal clearance (CLr) |  | 0-48 hours post dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Dementia, Neurodegenerative Disease