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Phase I, KM-819 in Healthy Subjects for Parkinson's Disease

NCT03022799 — Phase 1, Completed, 88 participants, Kainos Medicine Inc.
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A First in Human, Randomized, Double-blind, Dose Escalation Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics Following Single and Multiple Oral Doses of KM-819 in Healthy Young Adult and Elderly Subjects

RegistryNCT03022799
StatusCompleted
PhasePhase 1
Study typeInterventional; randomized, parallel, masking: quadruple, basic science
Enrollment88 (Actual)
SponsorKainos Medicine Inc. (Industry)
ConditionsParkinson's Disease
InterventionsKM-819, Placebo (Drug)
Datesstart 2016-11-01, primary completion 2017-09-01, completion 2017-11-01, first posted 2017-01-18, last updated 2020-04-13
Locations1 site in South Korea

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-Summary

This first in human, single-center, randomized, placebo-controlled, double blind, sequential group Phase 1 study in healthy subjects will be conducted to evaluate the safety, tolerability, PK, and PD following the escalation of single and multiple doses of KM-819.

The study will consist of 2 parts. In Part A, up to 5 cohorts of young adult male subjects, and 1 single dose cohort of elderly male or post menopausal female subjects will receive escalating single doses of KM-819. In Part B, up to 4 cohorts of healthy young adult male subjects and 1 multiple dose cohort of elderly male or post menopausal female subjects will receive escalating multiple doses of KM-819. Part B will be conducted after completion of all cohorts of young adult male subjects in Part A.

Dose escalation to the next level will be determined using safety, tolerability, and PK data of the previous cohort.

Part A, Single Ascending Dose (SAD) Up to 40 healthy young adult male subjects and 8 healthy elderly male or post menopausal female subjects will be enrolled and randomized to receive either KM-819 or placebo.

Each of the 5 dose escalation cohorts consists of 8 healthy young adult male subjects; 6 subjects will receive 10, 30, 100, 200, or 400 mg of KM-819 and 2 subjects will receive placebo. In each single dose cohort, dosing of subjects will be sentinel, i.e., 2 subjects will be dosed on the first day (1 subject will receive active treatment and 1 subject will receive placebo) and the remaining 6 subjects will be dosed at least 24 hours after the first 2 subjects.

Cohorts will be dosed sequentially with escalating doses. Eight elderly male or post-menopausal female subjects will be enrolled into an additional cohort; 6 subjects will receive 200 mg KM-819 and 2 subjects will receive placebo.

Part A consists of a Screening period of up to 28 days, and a 3 day Confinement period when subjects are hospitalized for study activities. Subjects are required to return for outpatient visits on Day 4, 7 and for the Follow up Visit on Day 14.

Part B, Multiple Ascending Dose (MAD) Up to 32 healthy young adult male subjects and 8 healthy elderly male or post menopausal female subjects will be enrolled and randomized to receive either KM-819 or placebo.

Each of the 4 dose escalation cohorts consists of 8 healthy young adult male subjects; 6 subjects will receive 30, 100, 200, or 400 mg of KM-819 once a day (QD) for 7 days and 2 subjects will receive placebo. Cohorts will be dosed sequentially with escalating doses.

Eight elderly male or post-menopausal female subjects will be enrolled into an additional cohort; 6 subjects will receive 200 mg KM-819 QD for 7 days and 2 subjects will receive placebo.

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+Arms and interventions

ArmTypeInterventionsDescription
KM-819ExperimentalDrug: KM-819Each cohort consists of 8 subjects; 6 subjects will receive planned dose of KM-819 and 2 subjects will receive placebo.
PlaceboPlacebo comparatorDrug: PlaceboEach cohort consists of 8 subjects; 6 subjects will receive planned dose of KM-819 and 2 subjects will receive placebo.
  • KM-819 (Drug)
  • Placebo (Drug)

+Outcome measures

Primary outcomes

  • Number of Participants With Adverse Events [From screening (Day-28 to Day -2), Day -1 to Day 4, Day 7, and follow-up visit Day 14.]: All AEs will be coded using the latest available version 19.1 of the Medical Dictionary for Regulatory Activities (MedDRA). A treatment-emergent adverse event (TEAE) is defined as an AE that begins or that worsens in severity after at least one dose of the study drug has been administered.

Secondary outcomes

  • Cmax (Maximum Plasma Concentration Determined Directly From the Concentration-time Profile) [Part A: Day1 to Day 4. Part B: Day-1 to Day 8]: To evaluate Cmax of single and multiple ascending oral doses of KM-819 in healthy young adult male subjects and multiple oral doses of KM-819 in elderly male subjects.
  • Tmax (Time to Achieve Maximum Observed Plasma Concentration Determined Directly From the Concentration-time Profile) [Part A:Day 1 to 4; Part B: Day 1 to Day 8]: To evaluate the pharmacokinetics and pharmacodynamics of single and multiple ascending oral doses of KM-819 in healthy young adult male subjects and multiple oral doses of KM-819 in elderly male subjects.
  • t½ (Apparent Terminal Elimination Half Life) [Part A: Day 1 to Day 4. Part B: Day1 to Day 8]: To evaluate the pharmacokinetics and pharmacodynamics of single and multiple ascending oral doses of KM-819 in healthy young adult male subjects. To evaluate the PK and PD of single and multiple oral doses of KM-819 in elderly male subjects.
  • Tlag (Lag Time) [Part A: Day1 to Day 4. Part B: Day 1 to Day 8]: To evaluate the T lag of single and multiple ascending oral doses of KM-819 in healthy young adult male subjects and multiple oral doses of KM-819 in elderly male subjects.
  • AUClast (Area Under the Plasma Concentration-time From Predose (Time 0) to the Last Quantifiable Concentration) [Part A: Day 1 to 4; Part B: Day 1 to Day 8]: To evaluate AUClast of single and multiple ascending oral doses of KM-819 in healthy young adult male subjects and multiple oral doses of KM-819 in elderly male subjects.
  • AUCinf (Area Under the Plasma Concentration-time Curve From Predose (Time 0) Extrapolated to Infinity) [Part A: Day 1 to 4; Part B: Day 1 to Day 8]: To evaluate AUCinf of single and multiple ascending oral doses of KM-819 in healthy young adult male subjects and multiple oral doses of KM-819 in elderly male-subjects.
  • %AUCex (Percentage of AUCinf That is Due to Extrapolation Beyond Tlast) [Part A: Day 1 to 4; Part B: Day 1 to Day 8]: To evaluate %AUCex of single and multiple ascending oral doses of KM-819 in healthy young adult male subjects and multiple oral doses of KM-819 in elderly male subjects.
  • CL/F (Apparent Oral Clearance) [Part A: Day 1 to 4; Part B: Day 1 to Day 8]: To evaluate the CL/F of single and multiple ascending oral doses of KM-819 in healthy young adult male subjects and multiple oral doses of KM-819 in elderly male subjects.
  • Vz/F (Apparent Volume of Distribution) [Part A: Day 1 to 4; Part B: Day 1 to Day 8]: To evaluate Vz/F of single and multiple ascending oral doses of KM-819 in healthy young adult male subjects multiple oral doses of KM-819 in elderly male subjects.
  • AUCtau (Area Under the Plasma Concentration-time Curve for a Dosing Interval) (Part B) [Part B: Day 1 predose (within 30 minutes prior to study drug administration) and 0.25, 0.5, 1, 2, 4, 6, 8, and 12 hours postdose, predose on Days 2, 3, 4, 5, 6, and on Day 7 predose (within 30 minutes prior to study drug administration) and 0.25, 0.5, 1,]: To evaluate the pharmacokinetics and pharmacodynamics of single and multiple ascending oral doses of KM-819 in healthy young adult male subjects multiple oral doses of KM-819 in elderly male subjects.
  • Rac(AUC) (Observed Accumulation by AUC) (Part B) [Part B: Day 1 predose (within 30 minutes prior to study drug administration) and 0.25, 0.5, 1, 2, 4, 6, 8, and 12 hours postdose, predose on Days 2, 3, 4, 5, 6, and on Day 7 predose (within 30 minutes prior to study drug administration) and 0.25, 0.5, 1,]: To evaluate the pharmacokinetics and pharmacodynamics of single and multiple ascending oral doses of KM-819 in healthy young adult male subjects multiple oral doses of KM-819 in elderly male subjects.
  • Rac (Cmax) (Observed Accumulation by Cmax) (Part B) [Part B: Day 1 predose (within 30 minutes prior to study drug administration) and 0.25, 0.5, 1, 2, 4, 6, 8, and 12 hours postdose, predose on Days 2, 3, 4, 5, 6, and on Day 7 predose (within 30 minutes prior to study drug administration) and 0.25, 0.5, 1,]: To evaluate the pharmacokinetics and pharmacodynamics of single and multiple ascending oral doses of KM-819 in healthy young adult male subjects and multiple oral doses of KM-819 in elderly male subjects.
  • AUCtau_D (AUCtau Divided by Dose) (Part B) [Part B: Day 1 predose (within 30 minutes prior to study drug administration) and 0.25, 0.5, 1, 2, 4, 6, 8, and 12 hours postdose, predose on Days 2, 3, 4, 5, 6, and on Day 7 predose (within 30 minutes prior to study drug administration) and 0.25, 0.5, 1,]: To evaluate the pharmacokinetics and pharmacodynamics of single and multiple ascending oral doses of KM-819 in healthy young adult male subjects and multiple oral doses of KM-819 in elderly male subjects.
  • Change From Baseline for Bond and Lader Visual Analogue Scale (VAS) [At Day 1 (3 hours post dose), Day2, Day 3, Day 4, and Day 8.]: The Bond-Lader Visual Analogue Scales (VAS) will be analyzed using 3 factor scores: alertness, contentedness, and calmness. Participants were asked to indicate on the VAS scale ranging from 0 to 100 mm about how they felt at the moment the scale was administered. Baseline is defined as the last available recording prior to dosing on Day 1. 1. Alertness (Range 0 to 100, the higher scores indicated more alertness) 2. Mood (Range 0 to 100, where higher scores indicated elevated mood) 3. Calmness (Range 0 to 100, where higher scores indicated more calmness).
  • Korean Wechsler Adult Intelligence Scale-IV (K-WAIS-IV) [Part A: Day 1; Part B: Day 7]: The K-WAIS-IV consists of an assessment of the cognitive ability using a core battery of 10 unique subtests (Block Design, Similarities, Digit Span, Matrix Reasoning, Vocabulary, Arithmetic, Symbol Search, Visual Puzzles, Information, and Coding) that focus on four specific domains of intelligence: verbal comprehension, perceptual reasoning, working memory, and processing speed. The Verbal Comprehension Index, Perceptual Reasoning Index, Working Memory Index, and Processing Speed Index (standard scores: mean=100, standard deviation=15) that are all based on a number of core and supplemental subtests (scaled scores: mean=15, standard deviation=3) that provide pertinent clinical information and flexibility in implementation. The higher values represent a better outcome.
  • Alpha Synuclein Oligomer in Plasma and CSF (Part B) [Plasma - Part B: Day 7 (at 1 hour after last dosing) / CSF - Part B: Day 7 (at 1 hour after last dosing)]: To evaluate Alpha synuclein oligomer in plasma and CSF of single and multiple ascending oral doses of KM-819 in healthy young adult male subjects and multiple oral doses of KM-819 in elderly male subjects.
  • Change From Baseline Total Tau in CSF (Part B) [CSF - Part B: Day 1 (at -120 minutes to 0 minute prior to the first dosing) and on Day 7 (at 1 hour after last dosing)]: To evaluate Total Tau in CSF of single and multiple ascending oral doses of KM-819 in healthy young adult male subjects and multiple oral doses of KM-819 in elderly male subjects.
  • Change From Baseline Phospho-Tau in CSF (Part B) [CSF - Part B: Day 1 (at -120 minutes to 0 minute prior to the first dosing) and on Day 7 (at 1 hour after last dosing)]: To evaluate Phospho-Tau of single and multiple ascending oral doses of KM-819 in healthy young adult male subjects and multiple oral doses of KM-819 in elderly male subjects.
  • Ratio of CSF Concentration/Plasma Cmax (Part B) [Plasma - Part B: Day 7 (at 1 hour after last dosing) / CSF - Part B: on Day 7 (at 1 hour after last dosing)]: Ratio of CSF concentration/Plasma Cmax

+Eligibility

Sex: All, ages: 19 Years to 45 Years, accepts healthy volunteers

Inclusion Criteria:

1. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved written informed consent and privacy language as per national regulations must be obtained from the subject prior to any study-related procedures (including withdrawal of prohibited medication, if applicable).
2. Male subject should be 19 to 45 years old (for young adult cohorts) or over 60 years old (for elderly cohorts).
3. Subject has a body mass index (BMI) range of 18.5 to 30 kg/m2 inclusive at Screening.
4. Male subject and his female spouse/partner who is of childbearing potential must be using highly effective contraception consisting of 2 forms of birth control (at least one of which must be a barrier method) starting at Screening and continuing throughout the study period and for 90 days after final study drug administration. Highly effective contraception is defined as:

   * Established use of oral, injected, or implanted hormonal methods of contraception
   * Placement of an intrauterine device or intrauterine system
   * Barrier methods of contraception: condom with spermicidal foam, gel, film, cream, suppository or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam, gel, film, cream, or suppository
5. Male subject must not donate sperm starting at Screening, throughout the study period and for at least 90 days after final study drug administration.
6. Female subject must be over 60 years old and post-menopausal (defined as at least 1 year without any menses) prior to Screening.
7. Subject agrees not to participate in another investigational study while on study treatment.

Exclusion Criteria:

1. Subject has a known or suspected hypersensitivity to KM-819, or any components of the formulation(s) used.
2. Subject has previously participated in a clinical study with KM-819.
3. Subject has any of the liver enzymes (aspartate aminotransferase \[AST\], alanine transaminase \[ALT\], alkaline phosphatase, γ glutamyl transferase) or total bilirubin (TBIL) above the ULN. If any liver enzyme is > 1 × ULN but < 1.5 × ULN, the assessment may be repeated once during the Screening period or on check-in. If the repeated assessment is above the ULN, it is exclusionary. If the initial value is > 1.5 × ULN, it cannot be repeated and is exclusionary.
4. Subject has any clinically significant history of allergic conditions (including drug allergies, asthma, eczema, or anaphylactic reactions, but excluding untreated, allergic rhinitis or rhino-conjunctivitis, or house dust mite allergy at time of dosing).
5. Subject with a history of a suicide attempt or suicidal behavior. Any recent suicidal ideation (a level of 4 or 5) within the last 3 months, or having a positive C-SSRS at check-in (Day -1), or who is at significant risk to commit suicide, as judged by the Investigator using the C SSRS at Screening.
6. Subject has/had febrile illness or symptomatic viral, bacterial (including upper respiratory infection) or fungal (non-cutaneous) infection within 1 week before site check-in.
7. Subject has any clinically significant abnormality following the Investigator's review of the physical examination, ECG, and protocol-defined clinical laboratory tests at Screening or site check-in.
8. Subject has a mean pulse < 40 or > 90 beats per minute (bpm); mean systolic blood pressure (SBP) > 140 mmHg; or mean diastolic blood pressure (DBP) > 90 mmHg (measurements taken in triplicate after subject has been resting in the supine position for 5 minutes; pulse will be measured automatically) at Screening or check-in. If the mean pulse, mean SBP, or mean DBP is out of the range specified above, 1 additional triplicate measurement may be taken at Screening and check-in.
9. Subject has a mean QTcF interval of > 430 msec (for males) and > 450 msec (for females) at Screening or check-in. If the mean QTcF exceeds the limits above, 1 additional triplicate ECG can be taken. If this triplicate also gives an abnormal result, the subject should be excluded.
10. Subject has a history of unexplained syncope, cardiac arrest, unexplained cardiac arrhythmias or torsade de pointes, structural heart disease, or a family history of Long QT Syndrome.
11. Subject has use of any prescribed or non-prescribed drugs (including vitamins, hormone replacement therapy, natural and herbal remedies, e.g., St. John's Wort) in the 2 weeks before study drug administration. Acetaminophen up to 2000 mg/day is allowed.
12. Subject has had any use of tobacco- or nicotine-containing products within 6 months prior to Screening.
13. Subject has history of consuming more than 14 units of alcoholic beverages per week within 6 months prior to Screening or has a history of alcoholism or abuse of amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine, and opiates (drugs-of-abuse) within the past 2 years prior to Screening (Note: 1 unit = 355 mL of beer, 118 mL of wine, or 29 mL of spirits/hard liquor) or the subject tests positive at Screening or site admission for alcohol or drugs of-abuse.
14. Subject has used any drugs-of-abuse within 3 months before check in.
15. Subject has used any inducers of metabolism (e.g., barbiturates, rifampin) in the 3 months prior to check-in.
16. Subject has any significant blood loss, donated 1 unit (450 mL) of blood or more, or received a transfusion of any blood, or blood products within 60 days or donated plasma within 7 days before check-in.
17. Subject has a positive serology test for hepatitis B surface antigen (HbsAg), anti hepatitis A virus Immunoglobulin M (HAV IgM), anti-hepatitis C virus (HCV Ab), or anti-human immunodeficiency virus (HIV Ab).
18. Subject has participated in any interventional clinical study or has been treated with any investigational drugs within 3 months or 5 half lives, whichever is longer, before the initiation of Screening.
19. Subject has (recent history of) any other condition which, in the opinion of the Investigator, precludes the subject's participation in the trial.
20. Subject is an employee of the Kainos Medicine, Inc. or vendors involved in the study.

    Additional Exclusion Criteria for Young Adult Subjects
21. For young adult cohorts, subject has any history or evidence of any clinically significant cardiovascular, gastrointestinal, endocrinologic, hematologic, hepatic, immunologic, metabolic, urologic, pulmonary, neurologic, dermatologic, psychiatric, renal, and/or other major disease or malignancy, as judged by the Investigator or designee.

Exclusion Criteria for Elderly Subjects Replacement for Exclusion No. 8 above 8. Subject has a mean pulse < 50 or > 90 bpm; mean SBP > 160 mmHg; mean DBP > 100 mmHg (measurements taken in triplicate after subject has been resting in supine position for 5 minutes; pulse will be measured automatically).

Replacement for Exclusion No. 21 above 21. For elderly cohorts, subject has any history or evidence of any clinically significant cardiovascular, gastrointestinal, endocrinologic, hematologic, hepatic, immunologic, metabolic, urologic, pulmonary, neurologic, dermatologic, psychiatric, renal, and/or other major disease or malignancy that is not well managed and stable, as judged by the Investigator or designee.

Additional Exclusion Criteria 22. Elderly subject is excluded if the Glomerular Filtration Rate (calculated based on Cockcroft-Gault formula) is < 60 mL/min/1.73 m2.

23\. Clinically significant abnormal findings in the lumbar X-ray examination (only for elder subjects for MAD study).

+Posted results

Participant flow

MilestoneKM-819 - 10 mg (Part A)KM-819 - 30 mg (Part A)KM-819 - 100mg (Part A)KM-819 200mg (Part A)KM-819 - 400mg (Part A)KM-819 200mg (Elderly Male Subjects) (Part A)Placebo (Part A)KM-819 30 mg (Part B)KM-819 100 mg (Part B)KM-819 200mg (Part B)KM-819 400mg (Part B)KM-819 200mg (Elderly Male Subjects) (Part B)Placebo (Part B)
Started666666126666610
Completed666666126655610
Not completed0000000001100

Outcome results

  • Number of Participants With Adverse Events (Primary), Number, participants: KM-819 - 10 mg (Part A) 2; KM-819 - 30 mg (Part A) 2; KM-819 - 100mg (Part A) 2; KM-819 200mg (Part A) 1; KM-819 - 400mg (Part A) 0; KM-819 200mg (Elderly Male Subjects) (Part A) 2; Placebo (Part A) 3; KM-819 30 mg (Part B) 2; KM-819 100 mg (Part B) 4; KM-819 200mg (Part B) 5; KM-819 400mg (Part B) 5; KM-819 200mg (Elderly Male Subjects) (Part B) 3; Placebo (Part B) 5
  • Cmax (Maximum Plasma Concentration Determined Directly From the Concentration-time Profile) (Secondary), Geometric mean, ng/mL: KM-819 - 10 mg (Part A) 244.1 +/- 31.4; KM-819 - 30 mg (Part A) 503.6 +/- 28.0; KM-819 - 100mg (Part A) 1152 +/- 36.7; KM-819 200mg (Part A) 1879 +/- 55.3; KM-819 - 400mg (Part A) 2767 +/- 43.4; KM-819 200mg (Elderly Male Subjects) (Part A) 1766 +/- 26.0; KM-819 30 mg (Part B) 512.0 +/- 30.9; KM-819 100 mg (Part B) 1009 +/- 33.0; KM-819 200mg (Part B) 1465 +/- 77.2; KM-819 400mg (Part B) 3163 +/- 50.7; KM-819 200mg (Elderly Male Subjects) (Part B) 3542 +/- 76.4
  • Tmax (Time to Achieve Maximum Observed Plasma Concentration Determined Directly From the Concentration-time Profile) (Secondary), Median, hours: KM-819 - 10 mg (Part A) 1.500 (0.50 to 2.00); KM-819 - 30 mg (Part A) 1.000 (0.50 to 2.00); KM-819 - 100mg (Part A) 2.000 (1.00 to 4.00); KM-819 200mg (Part A) 2.008 (1.00 to 4.00); KM-819 - 400mg (Part A) 4.000 (2.00 to 4.00); KM-819 200mg (Elderly Male Subjects) (Part A) 2.000 (1.00 to 4.00); KM-819 30 mg (Part B) ; KM-819 100 mg (Part B) ; KM-819 200mg (Part B) ; KM-819 400mg (Part B) ; KM-819 200mg (Elderly Male Subjects) (Part B)
  • t½ (Apparent Terminal Elimination Half Life) (Secondary), Geometric mean, Hours: KM-819 - 10 mg (Part A) 1.786 +/- 28.3; KM-819 - 30 mg (Part A) 4.791 +/- 25.0; KM-819 - 100mg (Part A) 9.159 +/- 41.2; KM-819 200mg (Part A) 9.010 +/- 71.6; KM-819 - 400mg (Part A) 8.527 +/- 63.2; KM-819 200mg (Elderly Male Subjects) (Part A) 10.55 +/- 28.5; KM-819 30 mg (Part B) ; KM-819 100 mg (Part B) ; KM-819 200mg (Part B) ; KM-819 400mg (Part B) ; KM-819 200mg (Elderly Male Subjects) (Part B)
  • Tlag (Lag Time) (Secondary), Mean, Hours: KM-819 - 10 mg (Part A) 0.08333 +/- 0.1291; KM-819 - 30 mg (Part A) 0 +/- 0; KM-819 - 100mg (Part A) 0 +/- 0; KM-819 200mg (Part A) 0.04167 +/- 0.1021; KM-819 - 400mg (Part A) 0 +/- 0; KM-819 200mg (Elderly Male Subjects) (Part A) 0 +/- 0; KM-819 30 mg (Part B) ; KM-819 100 mg (Part B) ; KM-819 200mg (Part B) ; KM-819 400mg (Part B) ; KM-819 200mg (Elderly Male Subjects) (Part B)
  • AUClast (Area Under the Plasma Concentration-time From Predose (Time 0) to the Last Quantifiable Concentration) (Secondary), Mean, h*ng/mL: KM-819 - 10 mg (Part A) 597.5 +/- 140.5; KM-819 - 30 mg (Part A) 1726 +/- 289.7; KM-819 - 100mg (Part A) 4479 +/- 1423; KM-819 200mg (Part A) 8210 +/- 2912; KM-819 - 400mg (Part A) 12770 +/- 4321; KM-819 200mg (Elderly Male Subjects) (Part A) 10880 +/- 1108; KM-819 30 mg (Part B) ; KM-819 100 mg (Part B) ; KM-819 200mg (Part B) ; KM-819 400mg (Part B) ; KM-819 200mg (Elderly Male Subjects) (Part B)
  • AUCinf (Area Under the Plasma Concentration-time Curve From Predose (Time 0) Extrapolated to Infinity) (Secondary), Geometric mean, h*ng/mL: KM-819 - 10 mg (Part A) 594.2 +/- 24.4; KM-819 - 30 mg (Part A) 1731 +/- 17.3; KM-819 - 100mg (Part A) 4872 +/- 30.8; KM-819 200mg (Part A) 7338 +/- 51.9; KM-819 - 400mg (Part A) 12640 +/- 36.1; KM-819 200mg (Elderly Male Subjects) (Part A) 10970 +/- 9.8; KM-819 30 mg (Part B) ; KM-819 100 mg (Part B) ; KM-819 200mg (Part B) ; KM-819 400mg (Part B) ; KM-819 200mg (Elderly Male Subjects) (Part B)
  • %AUCex (Percentage of AUCinf That is Due to Extrapolation Beyond Tlast) (Secondary), Geometric mean, percentage of AUC: KM-819 - 10 mg (Part A) 1.664 +/- 50.5; KM-819 - 30 mg (Part A) 1.331 +/- 51.2; KM-819 - 100mg (Part A) 1.338 +/- 19.0; KM-819 200mg (Part A) 0.7787 +/- 65.4; KM-819 - 400mg (Part A) 0.4833 +/- 164.4; KM-819 200mg (Elderly Male Subjects) (Part A) 0.9795 +/- 77.9; KM-819 30 mg (Part B) ; KM-819 100 mg (Part B) ; KM-819 200mg (Part B) ; KM-819 400mg (Part B) ; KM-819 200mg (Elderly Male Subjects) (Part B)
  • CL/F (Apparent Oral Clearance) (Secondary), Geometric mean, mL/h: KM-819 - 10 mg (Part A) 16830 +/- 24.4; KM-819 - 30 mg (Part A) 17340 +/- 17.3; KM-819 - 100mg (Part A) 20530 +/- 30.8; KM-819 200mg (Part A) 27260 +/- 51.9; KM-819 - 400mg (Part A) 31650 +/- 36.1; KM-819 200mg (Elderly Male Subjects) (Part A) 18230 +/- 9.8; KM-819 30 mg (Part B) ; KM-819 100 mg (Part B) ; KM-819 200mg (Part B) ; KM-819 400mg (Part B) ; KM-819 200mg (Elderly Male Subjects) (Part B)
  • Vz/F (Apparent Volume of Distribution) (Secondary), Geometric mean, mL: KM-819 - 10 mg (Part A) 43370 +/- 18.8; KM-819 - 30 mg (Part A) 119800 +/- 23.5; KM-819 - 100mg (Part A) 271200 +/- 56.6; KM-819 200mg (Part A) 354300 +/- 114.0; KM-819 - 400mg (Part A) 389300 +/- 49.5; KM-819 200mg (Elderly Male Subjects) (Part A) 277500 +/- 27.3; KM-819 30 mg (Part B) ; KM-819 100 mg (Part B) ; KM-819 200mg (Part B) ; KM-819 400mg (Part B) ; KM-819 200mg (Elderly Male Subjects) (Part B)
  • AUCtau (Area Under the Plasma Concentration-time Curve for a Dosing Interval) (Part B) (Secondary), Mean, h*ng/mL: KM-819 30 mg (Part B) 1612 (1130 to 2320); KM-819 100 mg (Part B) 3521 (2760 to 4290); KM-819 200mg (Part B) 8039 (7670 to 8770); KM-819 400mg (Part B) 22830 (11000 to 34700); KM-819 200mg (Elderly Male Subjects) (Part B) 17020 (11000 to 25800)
  • Rac(AUC) (Observed Accumulation by AUC) (Part B) (Secondary), Geometric mean, ratio: KM-819 30 mg (Part B) 0.8926 (0.70 to 1.13); KM-819 100 mg (Part B) 0.9727 (0.69 to 1.37); KM-819 200mg (Part B) 0.7568 (0.57 to 1.00); KM-819 400mg (Part B) 1.485 (0.86 to 2.56); KM-819 200mg (Elderly Male Subjects) (Part B) 0.9241 (0.67 to 1.28)
  • Rac (Cmax) (Observed Accumulation by Cmax) (Part B) (Secondary), Geometric mean, ratio: KM-819 30 mg (Part B) 0.8173 (0.53 to 1.26); KM-819 100 mg (Part B) 1.003 (0.73 to 1.39); KM-819 200mg (Part B) 0.6227 (0.55 to 0.71); KM-819 400mg (Part B) 1.117 (1.00 to 1.25); KM-819 200mg (Elderly Male Subjects) (Part B) 0.9122 (0.53 to 1.58)
  • AUCtau_D (AUCtau Divided by Dose) (Part B) (Secondary), Mean, (h*ng/mL)/mg: KM-819 30 mg (Part B) 53.74 (37.7 to 77.4); KM-819 100 mg (Part B) 35.21 (27.6 to 42.9); KM-819 200mg (Part B) 40.19 (38.3 to 43.6); KM-819 400mg (Part B) 57.08 (27.5 to 86.6); KM-819 200mg (Elderly Male Subjects) (Part B) 85.09 (55.1 to 129)
  • Change From Baseline for Bond and Lader Visual Analogue Scale (VAS) (Secondary), Mean, units on a scale: KM-819 - 10 mg (Part A) -0.482 +/- 3.6349; KM-819 - 30 mg (Part A) -4.315 +/- 8.8671; KM-819 - 100mg (Part A) 0.720 +/- 7.2589; KM-819 200mg (Part A) -3.610 +/- 9.4171; KM-819 - 400mg (Part A) -2.333 +/- 6.4200; KM-819 200mg (Elderly Male Subjects) (Part A) 3.093 +/- 3.7733; Placebo (Part A) -2.926 +/- 11.4835; KM-819 30 mg (Part B) 7.058 +/- 12.2168; KM-819 100 mg (Part B) 3.445 +/- 11.1990; KM-819 200mg (Part B) 9.264 +/- 21.4350; KM-819 400mg (Part B) -4.668 +/- 4.6964; KM-819 200mg (Elderly Male Subjects) (Part B) -0.128 +/- 8.7694; Placebo (Part B) 2.088 +/- 8.4283
  • Korean Wechsler Adult Intelligence Scale-IV (K-WAIS-IV) (Secondary), Mean, Intelligence quotient (IQ): KM-819 - 10 mg (Part A) 6.2 +/- 10.05; KM-819 - 30 mg (Part A) -0.3 +/- 8.73; KM-819 - 100mg (Part A) -3.8 +/- 16.18; KM-819 200mg (Part A) 2.2 +/- 8.04; KM-819 - 400mg (Part A) 4.8 +/- 6.94; KM-819 200mg (Elderly Male Subjects) (Part A) 3.3 +/- 5.24; Placebo (Part A) 2.5 +/- 8.87; KM-819 30 mg (Part B) 1.7 +/- 5.50; KM-819 100 mg (Part B) 4.3 +/- 6.41; KM-819 200mg (Part B) 2.0 +/- 15.12; KM-819 400mg (Part B) 1.2 +/- 4.09; KM-819 200mg (Elderly Male Subjects) (Part B) 1.2 +/- 4.45; Placebo (Part B) -1.6 +/- 16.19
  • Alpha Synuclein Oligomer in Plasma and CSF (Part B) (Secondary), Mean, pg/mL: KM-819 30 mg (Part B) 49.9424 (1.118 to 188.833); KM-819 100 mg (Part B) -252.5578 (-1565.068 to 47.610); KM-819 200mg (Part B) 0.6012 (-25.141 to 24.998); KM-819 400mg (Part B) 18.2112 (-121.943 to 163.679); KM-819 200mg (Elderly Male Subjects) (Part B) 34.8672 (-22.683 to 95.017); Placebo (Part B) 20.3025 (-82.488 to 145.654)
  • Change From Baseline Total Tau in CSF (Part B) (Secondary), Mean, pg/mL: KM-819 30 mg (Part B) 60.3043 (-23.213 to 145.209); KM-819 100 mg (Part B) 9.2313 (-9.048 to 33.901); KM-819 200mg (Part B) -3.1593 (-15.058 to 22.546); KM-819 400mg (Part B) 27.8648 (-32.813 to 134.771); KM-819 200mg (Elderly Male Subjects) (Part B) 29.2961 (-52.079 to 203.508); Placebo (Part B) 20.8198 (-13.358 to 82.099)
  • Change From Baseline Phospho-Tau in CSF (Part B) (Secondary), Mean, pg/mL: KM-819 30 mg (Part B) 6.4132 (-13.590 to 42.811); KM-819 100 mg (Part B) 0.2072 (-1.154 to 2.231); KM-819 200mg (Part B) 4.4672 (-1.534 to 18.292); KM-819 400mg (Part B) 6.7032 (-2.773 to 19.666); KM-819 200mg (Elderly Male Subjects) (Part B) 5.1606 (-5.717 to 23.325); Placebo (Part B) 5.3123 (-3.592 to 23.931)
  • Ratio of CSF Concentration/Plasma Cmax (Part B) (Secondary), Mean, Ratio: KM-819 100 mg (Part B) 0.00067004 (0.00040485 to 0.00085699); KM-819 200mg (Part B) 0.00074179 (0.00047881 to 0.00090404); KM-819 400mg (Part B) 0.00048832 (0.00011022 to 0.0013316); KM-819 200mg (Elderly Male Subjects) (Part B) 0.00031749 (0.00018612 to 0.00045000)

Adverse events

Time frame: From screening (Day-28 to Day -2), Day -1 to Day 4, Day 7, and follow-up visit Day 14.

ArmDeathsSerious adverse eventsOther adverse events
Placebo (Part A)0/12 (0.0%)0/12 (0.0%)4/12 (33.3%)
KM-819 - 10 mg (Part A)0/6 (0.0%)0/6 (0.0%)2/6 (33.3%)
KM-819 - 30 mg (Part A)0/6 (0.0%)0/6 (0.0%)2/6 (33.3%)
KM-819 - 100mg (Part A)0/6 (0.0%)0/6 (0.0%)3/6 (50.0%)
KM-819 200mg (Part A)0/6 (0.0%)0/6 (0.0%)1/6 (16.7%)
KM-819 - 400mg (Part A)0/6 (0.0%)0/6 (0.0%)0/6 (0.0%)
KM-819 200mg (Elderly Male Subjects) (Part A)0/6 (0.0%)0/6 (0.0%)4/6 (66.7%)
Placebo (Part B)0/10 (0.0%)0/10 (0.0%)10/10 (100.0%)
KM-819 30 mg (Part B)0/6 (0.0%)0/6 (0.0%)6/6 (100.0%)
KM-819 100 mg (Part B)0/6 (0.0%)0/6 (0.0%)5/6 (83.3%)
KM-819 200mg (Part B)0/6 (0.0%)1/6 (16.7%)6/6 (100.0%)
KM-819 400mg (Part B)0/6 (0.0%)0/6 (0.0%)6/6 (100.0%)
KM-819 200mg (Elderly Male Subjects) (Part B)0/6 (0.0%)0/6 (0.0%)6/6 (100.0%)

Serious adverse events by term

TermOrgan systemPlacebo (Part A)KM-819 - 10 mg (Part A)KM-819 - 30 mg (Part A)KM-819 - 100mg (Part A)KM-819 200mg (Part A)KM-819 - 400mg (Part A)KM-819 200mg (Elderly Male Subjects) (Part A)Placebo (Part B)KM-819 30 mg (Part B)KM-819 100 mg (Part B)KM-819 200mg (Part B)KM-819 400mg (Part B)KM-819 200mg (Elderly Male Subjects) (Part B)
HeadacheNervous system disorders0/120/60/60/60/60/60/60/100/60/61/60/60/6

Other adverse events by term

TermOrgan systemPlacebo (Part A)KM-819 - 10 mg (Part A)KM-819 - 30 mg (Part A)KM-819 - 100mg (Part A)KM-819 200mg (Part A)KM-819 - 400mg (Part A)KM-819 200mg (Elderly Male Subjects) (Part A)Placebo (Part B)KM-819 30 mg (Part B)KM-819 100 mg (Part B)KM-819 200mg (Part B)KM-819 400mg (Part B)KM-819 200mg (Elderly Male Subjects) (Part B)
Eye swellingEye disorders1/120/60/60/60/60/60/60/100/60/60/60/60/6
Abdominal discomfortGastrointestinal disorders0/120/60/60/61/60/60/61/100/60/61/60/60/6
HyperbilirubinaemiaHepatobiliary disorders0/122/60/61/60/60/60/61/100/60/61/60/60/6
InfluenzaInfections and infestations1/120/60/60/60/60/60/60/100/60/60/60/60/6
Face injuryInjury, poisoning and procedural complications0/120/60/60/60/60/61/60/100/60/60/60/60/6
Pain in extremityMusculoskeletal and connective tissue disorders0/120/61/60/60/60/60/60/100/60/60/60/60/6
HeadacheNervous system disorders1/120/60/60/60/60/62/62/102/61/65/64/60/6
HypoaesthesiaNervous system disorders0/120/60/61/60/60/60/61/100/60/62/60/60/6
SyncopeNervous system disorders0/120/61/60/60/60/60/60/100/60/60/60/60/6
ProteinuriaRenal and urinary disorders0/120/60/61/60/60/60/60/100/60/60/60/60/6
CoughRespiratory, thoracic and mediastinal disorders1/120/60/60/60/60/60/60/100/60/60/60/60/6
Hot flushVascular disorders0/120/60/60/60/60/61/60/100/60/60/60/60/6
Erythema of eyelidEye disorders0/120/60/60/60/60/60/60/100/60/60/61/60/6
Abdominal painGastrointestinal disorders0/120/60/60/60/60/60/60/100/60/60/60/61/6
DiarrhoeaGastrointestinal disorders0/120/60/60/60/60/60/61/100/60/60/60/61/6
NauseaGastrointestinal disorders0/120/60/60/60/60/60/60/102/61/64/60/60/6
VomitingGastrointestinal disorders0/120/60/60/60/60/60/60/102/60/64/60/60/6
Back painMusculoskeletal and connective tissue disorders0/120/60/60/60/60/60/63/100/62/61/61/62/6
Muscle haemorrhageMusculoskeletal and connective tissue disorders0/120/60/60/60/60/60/60/100/60/60/60/61/6
Musculoskeletal stiffnessMusculoskeletal and connective tissue disorders0/120/60/60/60/60/60/60/100/60/61/61/60/6
Neck painMusculoskeletal and connective tissue disorders0/120/60/60/60/60/60/60/100/60/60/60/61/6
DizzinessNervous system disorders0/120/60/60/60/60/60/62/101/61/62/60/60/6
AnxietyPsychiatric disorders0/120/60/60/60/60/60/61/100/60/60/60/60/6
InsomniaPsychiatric disorders0/120/60/60/60/60/60/60/100/60/60/60/61/6
EpistaxisRespiratory, thoracic and mediastinal disorders0/120/60/60/60/60/60/60/100/60/60/61/60/6
Oropharyngeal painRespiratory, thoracic and mediastinal disorders0/120/60/60/60/60/60/60/100/60/61/60/60/6
ErythemaSkin and subcutaneous tissue disorders0/120/60/60/60/60/60/61/100/60/60/60/60/6
HyperhidrosisSkin and subcutaneous tissue disorders0/120/60/60/60/60/60/61/100/60/60/61/60/6

+Locations (1)

FacilityCityCountryStatus
CHA Bundang Medical Center, CHA UniversitySeongnam-si, Gyeonggi-doSouth Korea

+Study documents

+Investigators

My Notes