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Safety and Pharmacokinetics of Single Ascending Doses and Multiple Ascending Doses of CS6253 in Healthy Volunteers

Primary Purpose

Alzheimer's Disease

Status
Recruiting
Phase
Early Phase 1
Locations
Spain
Study Type
Interventional
Intervention
CS6253 Solution for Injection
Placebo
Sponsored by
Artery Therapeutics, Inc.
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Alzheimer's Disease

Eligibility Criteria

18 Years - 80 Years (Adult, Older Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria: Male HVs at least 18 years old. a) Cohort 5 only: Male and female HVs at least 50 years old and if female be of non-childbearing potential, i.e. meet at least one of the following criteria: postsurgical sterilization (hysterectomy or bilateral oophorectomy or tubal ligation) or postmenopausal (amenorrheic for at least 2 years and a serum follicle-stimulating hormone (FSH) > 30 IU/L). b) If subject is male, must be willing to use acceptable contraception from Day 1 until 30 days after the last dose of study drug. The subject has a body mass index (BMI) within 18-32 kg/m² (inclusive). The subject is in reasonably good health as determined by medical history and physical examination and clinical laboratory tests. The subject is willing and able to speak, read, and understand Spanish and give signed informed consent. The subject must agree to comply with a lumbar catheterization and collection of blood and CSF samples (SAD Cohorts 3-5 only and MAD cohorts). The subject is willing and able to comply with all testing and requirements defined in the protocol. The subject is willing, deemed compliant, and able to remain at the Clinical Research Unit (CRU) for the duration of the confinement period and return for all outpatient visits. Phase 1B MAD The eligibility criteria for the Phase 1B MAD study are the same as described for Phase 1A SAD, with the following exceptions: At least 50 years old and female need to be of non-childbearing potential Known to have at least 1 APOE4 allele (homozygous or heterozygous). Note: this criterion applies to on average for the MAD at least 4 APOE4 subjects per cohort. Exclusion Criteria: Subjects who meet any of the following criteria will not be enrolled: The subject has any clinically significant deviations from normal in physical examination, ECG, or clinical laboratory tests, as determined by the investigator. The subject has an increased bleeding risk or is treated with anti-coagulation therapies including but not limited to aspirin, coumarin, warfarin and heparin. The subject has had a clinically significant illness within 30 days of check-in, as determined by the investigator. The subject has a history of significant neurological, hepatic, renal, endocrine, cardiovascular, gastrointestinal, pulmonary, or metabolic disease. History of Type 2 diabetes mellitus or hemoglobin A1c (HbA1c) > 7%. Fasting triglycerides > 400 mg/dL Estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2 (Cockcroft-Gault formula) The subject has changed the frequency or dose of chronic medication within the last 8 weeks. The subject has a history of substance abuse or a positive alcohol or urine drug screen at screening or at check-in. The subject has a positive serum hepatitis B surface antigen or positive anti-hepatitis C virus test at the Screening Visit. Have positive test results for, or evidence of active infection with, human immunodeficiency virus type 1 or 2, or hepatitis B, or C. The subject has received an investigational drug within 30 days of Check-in.

Sites / Locations

  • La Paz University HospitalRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

CS6253 Solution for Injection

Placebo

Arm Description

SAD: Single ascending doses: CS6253 Solution for Injection dosing, 50 mg/mL, will be weight based and provided from single use 2 mL vials containing approximately 100 mg CS6253 in phosphate buffered saline (PBS) solution MAD: Multiple ascending doses (4x every 72 hours): CS6253 Solution for Injection dosing, 50 mg/mL, will be weight based and provided from single use 2 mL vials containing approximately 100 mg CS6253 in phosphate buffered saline (PBS) solution

SAD and MAD: Placebo control will be provided from vials containing physiological saline for injection in an equal amount as necessary for the active arm.

Outcomes

Primary Outcome Measures

Safety and tolerability of CS6253
All treatment emerging Adverse Events (TAEs) will be recorded until the SAD: Day 4 and MAD: Day 13
SAD-Plasma: AUC0-last
Area under the concentration-time curve until the last quantifiable concentration
SAD-Plasma: AUC0-inf
Area under the concentration time curve from time 0 extrapolated to infinity
SAD-Plasma: Cmax
Maximum observed plasma concentration (eg C0)
SAD-Plasma: Kel
Terminal elimination rate constant
SAD-Plasma: t1/2
Terminal elimination half-life
SAD-Plasma: Clearance (CL/F)
Apparent clearance
SAD-Plasma: Vd/F
Apparent volume of distribution
SAD-Cerebrospinal Fluid (CSF): AUC0-last
In cohorts 3-5:Area under the concentration-time curve in CSF until the last quantifiable concentration
SAD-CSF: Cmax
In cohorts 3-5:Maximum observed CSF concentration (eg C0)concentration
MAD-Plasma: AUC0-last
Area under the concentration-time curve until the last quantifiable concentration
MAD-Plasma: Cmax
Maximum observed plasma concentration (eg C0)
MAD-CSF:AUC0-last
Area under the concentration-time curve until the last quantifiable concentration
MAD-CSF: Cmax
Maximum observed CSF concentration (eg C0)

Secondary Outcome Measures

Full Information

First Posted
January 26, 2023
Last Updated
October 23, 2023
Sponsor
Artery Therapeutics, Inc.
Collaborators
National Institute on Aging (NIA)
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1. Study Identification

Unique Protocol Identification Number
NCT05965414
Brief Title
Safety and Pharmacokinetics of Single Ascending Doses and Multiple Ascending Doses of CS6253 in Healthy Volunteers
Official Title
A Phase 1 Randomized, Double-Blind, Placebo Controlled Study to Evaluate the Safety and Pharmacokinetics of Single Ascending Doses and Multiple Ascending Doses of CS6253 in Healthy Volunteers and in APOE4 Carriers
Study Type
Interventional

2. Study Status

Record Verification Date
October 2023
Overall Recruitment Status
Recruiting
Study Start Date
October 23, 2023 (Anticipated)
Primary Completion Date
September 30, 2024 (Anticipated)
Study Completion Date
September 30, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Artery Therapeutics, Inc.
Collaborators
National Institute on Aging (NIA)

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Phase 1A SAD: Five or more cohorts of 8 healthy volunteers (HVs) will receive a single IV bolus injection of study drug or placebo. The first 4 cohorts will be male only. The last cohort will be repeated with the max safe dose of the previous cohorts in healthy elderly subjects (male and female of non childbearing potential, > 50years) Phase 1B MAD: Two or more cohorts of 8 male and female HVs will receive multiple (4) IV bolus injections of study drug or placebo every 72 hours.
Detailed Description
This is a randomized, double-blind, placebo-controlled study in HV and in APOE4 carriers. Phase 1A Single Ascending Dose (SAD): In 5 or more sequential SAD cohorts of 8 (6 active:2 placebo) HVs a single IV bolus injection (CS6253 1, 2.4, 6, and 10 mg/kg or placebo) will be administered and PK, safety, and biomarkers will be assessed. The first 4 cohorts will include males only. In the fifth cohort 8 (6 active:2 placebo) subjects, male and female of non-childbearing potential and at least 50 years old, will be administered CS6253 at equal to or lower doses than the maximum safe SAD dose in HV. CSF will not be collected in the first 2 SAD cohorts. In the following cohorts, CSF will be collected before dosing and over 24 hours after dosing. Additional cohorts may be added as needed and deemed safe and appropriate by the Data Safety Monitoring Board (DSMB). Phase 1B Multiple Ascending Dose (MAD): In 2 or more sequential MAD cohorts of 8 (6 active:2 placebo) male and female HVs at least 50 years old on average ≥ 3/sex/cohort; ≥ 4 APOE4 carriers/cohort, will be administered multiple IV bolus injections. Cohort 1 will be administered CS6253 at 75% of the maximum safe SAD dose in subjects at least 50 years old or placebo, and if no Treatment Emerging Adverse Events (TEAEs), in Cohort 2 at 100% of the maximum safe SAD dose or placebo will be administered every 72 hours x 4 doses and PK, safety, and biomarkers will be assessed. Plasma PK will be assessed after first and fourth dose in all cohorts. CSF will be collected before dosing and over 24 hours in conjunction with the fourth dose. Cohorts of 8 subjects (6 active:2 placebo) may be added at doses equal to or lower than the maximum safe MAD dose to further explore CS6253 brain exposure and Pharmacodynamics (PD) dependency on APOE4 isoform and sex.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Alzheimer's Disease

7. Study Design

Primary Purpose
Treatment
Study Phase
Early Phase 1
Interventional Study Model
Parallel Assignment
Model Description
SAD: 5 cohorts 8 of healthy volunteers each will receive single ascending doses of either study drug or placebo (6 active:2 placebo). MAD: 2 or more cohorts 8 of healthy male and female volunteers each will receive single ascending doses of either study drug or placebo (6 active:2 placebo). The subjects will be stratified on their APOE4 status. Each cohort needs to have at least 4 APOE4 carriers.
Masking
ParticipantInvestigator
Masking Description
Neither the investigator nor the subject will know who has received the study drug or the placebo, The injections will be prepared by an unblinded pharmacist according to the randomization list.
Allocation
Randomized
Enrollment
64 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
CS6253 Solution for Injection
Arm Type
Active Comparator
Arm Description
SAD: Single ascending doses: CS6253 Solution for Injection dosing, 50 mg/mL, will be weight based and provided from single use 2 mL vials containing approximately 100 mg CS6253 in phosphate buffered saline (PBS) solution MAD: Multiple ascending doses (4x every 72 hours): CS6253 Solution for Injection dosing, 50 mg/mL, will be weight based and provided from single use 2 mL vials containing approximately 100 mg CS6253 in phosphate buffered saline (PBS) solution
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
SAD and MAD: Placebo control will be provided from vials containing physiological saline for injection in an equal amount as necessary for the active arm.
Intervention Type
Drug
Intervention Name(s)
CS6253 Solution for Injection
Intervention Description
Solution for intra-venous injection, 50mg CS6253 /mL. Single-use vials containing 100 mg CS6253 (2 mL of 50 mg/mL concentration)
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Physiological saline solution for intra-venous injection
Primary Outcome Measure Information:
Title
Safety and tolerability of CS6253
Description
All treatment emerging Adverse Events (TAEs) will be recorded until the SAD: Day 4 and MAD: Day 13
Time Frame
SAD: After dosing and until 72 hours after dosing; MAD: After dosing until day 13 (72 hours after the last dosing on day 10)
Title
SAD-Plasma: AUC0-last
Description
Area under the concentration-time curve until the last quantifiable concentration
Time Frame
Pharmacokinetics (PK) samples will be collected at predose and at 0.16, 0.5, 1, 2, 4, 8, 12, 24, 48, and 72 hours postdose; MAD:
Title
SAD-Plasma: AUC0-inf
Description
Area under the concentration time curve from time 0 extrapolated to infinity
Time Frame
PK samples will be collected at predose and at 0.16, 0.5, 1, 2, 4, 8, 12, 24, 48, and 72 hours postdose; MAD:
Title
SAD-Plasma: Cmax
Description
Maximum observed plasma concentration (eg C0)
Time Frame
PK samples will be collected at predose and at 0.16, 0.5, 1, 2, 4, 8, 12, 24, 48, and 72 hours postdose; MAD:
Title
SAD-Plasma: Kel
Description
Terminal elimination rate constant
Time Frame
PK samples will be collected at predose and at 0.16, 0.5, 1, 2, 4, 8, 12, 24, 48, and 72 hours postdose; MAD:
Title
SAD-Plasma: t1/2
Description
Terminal elimination half-life
Time Frame
PK samples will be collected at predose and at 0.16, 0.5, 1, 2, 4, 8, 12, 24, 48, and 72 hours postdose; MAD:
Title
SAD-Plasma: Clearance (CL/F)
Description
Apparent clearance
Time Frame
PK samples will be collected at predose and at 0.16, 0.5, 1, 2, 4, 8, 12, 24, 48, and 72 hours postdose; MAD:
Title
SAD-Plasma: Vd/F
Description
Apparent volume of distribution
Time Frame
PK samples will be collected at predose and at 0.16, 0.5, 1, 2, 4, 8, 12, 24, 48, and 72 hours postdose; MAD:
Title
SAD-Cerebrospinal Fluid (CSF): AUC0-last
Description
In cohorts 3-5:Area under the concentration-time curve in CSF until the last quantifiable concentration
Time Frame
PK samples will be collected by lumbar catheter starting predose, and at 0.5, 2, 8, 12 and 24 hours postdose.
Title
SAD-CSF: Cmax
Description
In cohorts 3-5:Maximum observed CSF concentration (eg C0)concentration
Time Frame
PK samples will be collected by lumbar catheter starting predose, and at 0.5, 2, 8, 12 and 24 hours postdose.
Title
MAD-Plasma: AUC0-last
Description
Area under the concentration-time curve until the last quantifiable concentration
Time Frame
PK samples will be collected after the first and fourth doses (Day 1 and Day 10) at predose and at 0.16, 0.5, 1, 2, 4, 8, 12, 24, 48 and 72 hours postdose.
Title
MAD-Plasma: Cmax
Description
Maximum observed plasma concentration (eg C0)
Time Frame
PK samples will be collected after the first and fourth doses (Day 1 and Day 10) at predose and at 0.16, 0.5, 1, 2, 4, 8, 12, 24, 48 and 72 hours postdose.
Title
MAD-CSF:AUC0-last
Description
Area under the concentration-time curve until the last quantifiable concentration
Time Frame
CSF collection by lumbar puncture (LP) will be performed before the first dose. At the fourth dose, on Day 10, serial CSF samples will be collected by lumbar catheter starting predose, and at 0.5, 2, 8, 12 and 24 hours postdose.
Title
MAD-CSF: Cmax
Description
Maximum observed CSF concentration (eg C0)
Time Frame
CSF collection by lumbar puncture (LP) will be performed before the first dose. At the fourth dose, on Day 10, serial CSF samples will be collected by lumbar catheter starting predose, and at 0.5, 2, 8, 12 and 24 hours postdose.

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria: Male HVs at least 18 years old. a) Cohort 5 only: Male and female HVs at least 50 years old and if female be of non-childbearing potential, i.e. meet at least one of the following criteria: postsurgical sterilization (hysterectomy or bilateral oophorectomy or tubal ligation) or postmenopausal (amenorrheic for at least 2 years and a serum follicle-stimulating hormone (FSH) > 30 IU/L). b) If subject is male, must be willing to use acceptable contraception from Day 1 until 30 days after the last dose of study drug. The subject has a body mass index (BMI) within 18-32 kg/m² (inclusive). The subject is in reasonably good health as determined by medical history and physical examination and clinical laboratory tests. The subject is willing and able to speak, read, and understand Spanish and give signed informed consent. The subject must agree to comply with a lumbar catheterization and collection of blood and CSF samples (SAD Cohorts 3-5 only and MAD cohorts). The subject is willing and able to comply with all testing and requirements defined in the protocol. The subject is willing, deemed compliant, and able to remain at the Clinical Research Unit (CRU) for the duration of the confinement period and return for all outpatient visits. Phase 1B MAD The eligibility criteria for the Phase 1B MAD study are the same as described for Phase 1A SAD, with the following exceptions: At least 50 years old and female need to be of non-childbearing potential Known to have at least 1 APOE4 allele (homozygous or heterozygous). Note: this criterion applies to on average for the MAD at least 4 APOE4 subjects per cohort. Exclusion Criteria: Subjects who meet any of the following criteria will not be enrolled: The subject has any clinically significant deviations from normal in physical examination, ECG, or clinical laboratory tests, as determined by the investigator. The subject has an increased bleeding risk or is treated with anti-coagulation therapies including but not limited to aspirin, coumarin, warfarin and heparin. The subject has had a clinically significant illness within 30 days of check-in, as determined by the investigator. The subject has a history of significant neurological, hepatic, renal, endocrine, cardiovascular, gastrointestinal, pulmonary, or metabolic disease. History of Type 2 diabetes mellitus or hemoglobin A1c (HbA1c) > 7%. Fasting triglycerides > 400 mg/dL Estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2 (Cockcroft-Gault formula) The subject has changed the frequency or dose of chronic medication within the last 8 weeks. The subject has a history of substance abuse or a positive alcohol or urine drug screen at screening or at check-in. The subject has a positive serum hepatitis B surface antigen or positive anti-hepatitis C virus test at the Screening Visit. Have positive test results for, or evidence of active infection with, human immunodeficiency virus type 1 or 2, or hepatitis B, or C. The subject has received an investigational drug within 30 days of Check-in.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Nikola Helmberg, PhD
Phone
+4366488397558
Email
nhelmberg@neuroscios.com
First Name & Middle Initial & Last Name or Official Title & Degree
Barbara Fridrich
Phone
+4366488869909
Email
bfridrich@neuroscios.com
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Alberto M. Borobia Perez, MD, Ass.Prof
Organizational Affiliation
Universidad Autónoma de Madrid, Farmacología y Terapéutica / Facultad de Medicina
Official's Role
Principal Investigator
Facility Information:
Facility Name
La Paz University Hospital
City
Madrid
ZIP/Postal Code
28046
Country
Spain
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Alberto M. Borobia-Perez, Ass. Prof.
Phone
+34 6061
Ext
26606
Email
a.borobia@gmail.com

12. IPD Sharing Statement

Plan to Share IPD
No
IPD Sharing Plan Description
No individual participant data will be shared

Learn more about this trial

Safety and Pharmacokinetics of Single Ascending Doses and Multiple Ascending Doses of CS6253 in Healthy Volunteers

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