Alzheimer Disease, Healthy Volunteers
Conditions
Brief summary
This study is being done for the following reasons: To determine the safety of LY2886721 and any side effects that may be associated with it and to see how much of the study drug is in the blood and the cerebrospinal fluid (CSF) when one dose is given to healthy participants and participants diagnosed with Alzheimer's disease. It will also look at how safe and tolerable the study drug is when given to healthy participants in higher doses. This research study is being conducted in three groups, referred to as Groups (Cohorts) A, B, or C. Group A will enroll participants with Alzheimer's disease while Groups B and C will enroll healthy participants. For Group A or B, participation in this research study could last up to 34 days. For Group C, participation could last up to 60 days.
Interventions
DRUGLY2886721
DRUGPlacebo
Sponsors
Eli Lilly and Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
* Healthy participants have a body mass index (BMI) of 19 to 32 kilograms per square meter (kg/m\^2), inclusive, at screening. There are no restrictions on BMI in participants diagnosed with Alzheimer's disease. * Healthy participants should not be taking any concomitant medications. For participants with Alzheimer's disease, concomitant medications will be determined by the investigator in consultation with the Lilly clinical pharmacologist on an individual basis. Cohort A: * Participants are defined as otherwise healthy males or females as determined by medical history and physical examination, and a diagnosis of Alzheimer's disease and must be at least 45 years of age. * Meets National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's Disease and Related Disorders Association (NINCDS/ADRDA) criteria for probable Alzheimer's disease, as determined by a clinician approved by the sponsor or designee. * Mini Mental State Examination (MMSE) score of 16 through 28 at screening. * Modified Hachinski Ischemia Scale (MHIS) score of \<4. * Capable of understanding and signing their own informed consent, in the opinion of the investigator, or if the participant has a Legally Authorized Representative (LAR), then the LAR must be capable of understanding and signing the assent form, and the participant may or may not sign the informed consent, as to be determined by the investigator. * If receiving concurrent treatment with an acetylcholinesterase inhibitor (AChEI) and/or memantine, the participant has been on a stable dose for at least 4 weeks before Day 1. Dosing must remain stable throughout the study. Note: If a participant has recently stopped ACHEIs and/or memantine, he or she must have discontinued treatment for at least 4 weeks before Day 1.
Exclusion criteria
* Have an abnormality in the 12-lead electrocardiogram (ECG). * Have abnormal blood pressure. * Have abnormal thyroid function as reflected by thyroid stimulating hormone (TSH) values outside of the normal range. * Show evidence of human immunodeficiency virus (HIV) infection and/or positive HIV antibodies. * Show evidence of hepatitis C and/or positive hepatitis C antibody. * Have had multiple episodes of head trauma, or have a history within the last 5 years of a serious infectious disease affecting the brain. * Have chronic hepatic disease. * Have evidence or history of significant active bleeding or a coagulation disorder. * Cohort A: have any neurological disorders other than Alzheimer's disease. * For healthy participants (Cohorts B and C) only: Use or intend to use over the- counter or prescription medication, including herbal medications within 14 days prior to dosing or during the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetics: Area Under the Curve Extrapolated to Infinity (AUC0-∞) of Cerebrospinal Fluid (CSF) LY2886721 | Predose through 36 hours after administration of study drug | AUC0-∞ following administration of a single dose of 70 mg LY2886721. |
| Pharmacokinetics: Area Under the Curve Extrapolated to Infinity (AUC0-∞) of Plasma LY2886721 | Predose through 96 hours after administration of study drug | AUC0-∞ following administration of a single dose of 70 or 280 mg LY2886721. |
| Pharmacokinetics: Maximum Concentration (Cmax) of Plasma LY2886721 | Predose through 96 hours after administration of study drug | Cmax following administration of a single dose of 70 or 280 mg LY2886721. |
| PD: Cnadir of CSF Aβ 1-40 | Predose up to 36 hours after administration of study drug | Plasma concentration of Aβ1-40 was summarized based on Cnadir following administration of a single dose of 70 mg LY2886721 or a single dose of LY2886721-matching placebo. |
| Pharmacokinetics: Maximum Concentration (Cmax) of CSF LY2886721 | Predose through 36 hours after administration of study drug | Cmax following administration of a single dose of 70 mg LY2886721. |
| Pharmacodynamics (PD): Cnadir of Plasma Amyloid β (Aβ)1-40 | Predose, up to 96 hours after administration of study drug | Plasma concentration of Aβ1-40 was summarized based on lowest observed concentration (Cnadir). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cohort C: Mean QTcF Value at Cmax | Predose up to 48 hours after administration of study drug | The mean QTcF value at Cmax for participants administered a single dose of 280 mg LY2886721 was reported. The QT interval is a measure of the time between the start of the Q wave and the end of the T wave and was calculated from electrocardiogram (ECG) data using Fridericia's formula: QTc = QT/RR\^0.33. Corrected QT (QTc) is the QT interval corrected for heart rate and RR, which is the interval between two R waves. Time matched mean change from baseline in QTcF = time matched plasma concentration + participant + random error. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Cohort A: 70 mg LY2886721 Participants with Alzheimer's disease received a single, 70-mg (1 capsule), oral dose of LY2886721. | 10 |
| Cohort A: Placebo Participants with Alzheimer's disease received a single, oral dose of LY2886721-matching placebo (1 capsule). | 2 |
| Cohort B: 70 mg LY2886721 Healthy participants received a single, 70-mg (1 capsule), oral dose of LY2886721. | 10 |
| Cohort B: Placebo Healthy participants received a single, oral dose of LY2886721-matching placebo (1 capsule). | 2 |
| Cohort C: 280 mg LY2886721 Healthy participants received a single, 280-mg (4 x 70 mg capsules), oral dose of LY2886721. | 9 |
| Cohort C: Placebo Healthy participants received a single, oral dose of LY2886721-matching placebo (4 capsules). | 3 |
| Total | 36 |
Baseline characteristics
| Characteristic | Cohort A: 70 mg LY2886721 | Cohort A: Placebo | Cohort B: 70 mg LY2886721 | Cohort B: Placebo | Cohort C: 280 mg LY2886721 | Cohort C: Placebo | Total |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 70.1 years STANDARD_DEVIATION 12.6 | 67.0 years STANDARD_DEVIATION 18.4 | 59.3 years STANDARD_DEVIATION 6.8 | 54.5 years STANDARD_DEVIATION 3.5 | 29.3 years STANDARD_DEVIATION 11.3 | 21.3 years STANDARD_DEVIATION 0.6 | 51.8 years STANDARD_DEVIATION 20.7 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 10 Participants | 2 Participants | 10 Participants | 2 Participants | 8 Participants | 3 Participants | 35 Participants |
| Region of Enrollment United States | 10 Participants | 2 Participants | 10 Participants | 2 Participants | 9 Participants | 3 Participants | 36 Participants |
| Sex: Female, Male Female | 6 Participants | 1 Participants | 5 Participants | 1 Participants | 1 Participants | 0 Participants | 14 Participants |
| Sex: Female, Male Male | 4 Participants | 1 Participants | 5 Participants | 1 Participants | 8 Participants | 3 Participants | 22 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 4 / 10 | 1 / 2 | 8 / 10 | 0 / 2 | 1 / 9 | 0 / 3 |
| serious Total, serious adverse events | 0 / 10 | 0 / 2 | 0 / 10 | 0 / 2 | 0 / 9 | 0 / 3 |
Outcome results
Primary
PD: Cnadir of CSF Aβ 1-40
Plasma concentration of Aβ1-40 was summarized based on Cnadir following administration of a single dose of 70 mg LY2886721 or a single dose of LY2886721-matching placebo.
Time frame: Predose up to 36 hours after administration of study drug
Population: Participants who received at least one dose of LY2886721 at the 70-mg dose level or placebo and had evaluable CSF Aβ 1-40 data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort A: 70 mg LY2886721 | PD: Cnadir of CSF Aβ 1-40 | 7600 pg/mL | Geometric Coefficient of Variation 30.7 |
| Cohort B: 70 mg LY2886721 | PD: Cnadir of CSF Aβ 1-40 | 19500 pg/mL | — |
| Cohort C: 280 mg LY2886721 | PD: Cnadir of CSF Aβ 1-40 | 4480 pg/mL | Geometric Coefficient of Variation 110 |
| Cohort C: 280 mg LY2886721 | PD: Cnadir of CSF Aβ 1-40 | 12500 pg/mL | — |
Primary
Pharmacodynamics (PD): Cnadir of Plasma Amyloid β (Aβ)1-40
Plasma concentration of Aβ1-40 was summarized based on lowest observed concentration (Cnadir).
Time frame: Predose, up to 96 hours after administration of study drug
Population: Participants who received at least one dose of LY2886721 or placebo and had evaluable plasma Aβ 1-40 data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort A: 70 mg LY2886721 | Pharmacodynamics (PD): Cnadir of Plasma Amyloid β (Aβ)1-40 | 22.2 picograms/milliliter (pg/mL) | Geometric Coefficient of Variation 35.2 |
| Cohort B: 70 mg LY2886721 | Pharmacodynamics (PD): Cnadir of Plasma Amyloid β (Aβ)1-40 | 140 picograms/milliliter (pg/mL) | — |
| Cohort C: 280 mg LY2886721 | Pharmacodynamics (PD): Cnadir of Plasma Amyloid β (Aβ)1-40 | 19.5 picograms/milliliter (pg/mL) | Geometric Coefficient of Variation 11.9 |
| Cohort C: 280 mg LY2886721 | Pharmacodynamics (PD): Cnadir of Plasma Amyloid β (Aβ)1-40 | 11.0 picograms/milliliter (pg/mL) | Geometric Coefficient of Variation 42.2 |
| Cohorts B and C: Placebo | Pharmacodynamics (PD): Cnadir of Plasma Amyloid β (Aβ)1-40 | 162 picograms/milliliter (pg/mL) | Geometric Coefficient of Variation 7.39 |
Primary
Pharmacokinetics: Area Under the Curve Extrapolated to Infinity (AUC0-∞) of Cerebrospinal Fluid (CSF) LY2886721
AUC0-∞ following administration of a single dose of 70 mg LY2886721.
Time frame: Predose through 36 hours after administration of study drug
Population: Participants who received at least one dose of LY2886721 at the 70-mg dose level and with evaluable CSF LY2886721-concentration data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort A: 70 mg LY2886721 | Pharmacokinetics: Area Under the Curve Extrapolated to Infinity (AUC0-∞) of Cerebrospinal Fluid (CSF) LY2886721 | 458 ng*h/mL | Geometric Coefficient of Variation 16 |
| Cohort B: 70 mg LY2886721 | Pharmacokinetics: Area Under the Curve Extrapolated to Infinity (AUC0-∞) of Cerebrospinal Fluid (CSF) LY2886721 | 410 ng*h/mL | Geometric Coefficient of Variation 16 |
Primary
Pharmacokinetics: Area Under the Curve Extrapolated to Infinity (AUC0-∞) of Plasma LY2886721
AUC0-∞ following administration of a single dose of 70 or 280 mg LY2886721.
Time frame: Predose through 96 hours after administration of study drug
Population: Participants who received at least one dose of LY2886721 and with evaluable plasma LY2886721-concentration data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort A: 70 mg LY2886721 | Pharmacokinetics: Area Under the Curve Extrapolated to Infinity (AUC0-∞) of Plasma LY2886721 | 2800 nanograms*hours/milliliter (ng*h/mL) | Geometric Coefficient of Variation 25 |
| Cohort B: 70 mg LY2886721 | Pharmacokinetics: Area Under the Curve Extrapolated to Infinity (AUC0-∞) of Plasma LY2886721 | 2580 nanograms*hours/milliliter (ng*h/mL) | Geometric Coefficient of Variation 20 |
| Cohort C: 280 mg LY2886721 | Pharmacokinetics: Area Under the Curve Extrapolated to Infinity (AUC0-∞) of Plasma LY2886721 | 10500 nanograms*hours/milliliter (ng*h/mL) | Geometric Coefficient of Variation 22 |
Primary
Pharmacokinetics: Maximum Concentration (Cmax) of CSF LY2886721
Cmax following administration of a single dose of 70 mg LY2886721.
Time frame: Predose through 36 hours after administration of study drug
Population: Participants who received at least one dose of LY2886721 at the 70-mg dose level and with evaluable CSF LY2886721-concentration data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort A: 70 mg LY2886721 | Pharmacokinetics: Maximum Concentration (Cmax) of CSF LY2886721 | 24.0 ng/mL | Geometric Coefficient of Variation 18 |
| Cohort B: 70 mg LY2886721 | Pharmacokinetics: Maximum Concentration (Cmax) of CSF LY2886721 | 24.4 ng/mL | Geometric Coefficient of Variation 19 |
Primary
Pharmacokinetics: Maximum Concentration (Cmax) of Plasma LY2886721
Cmax following administration of a single dose of 70 or 280 mg LY2886721.
Time frame: Predose through 96 hours after administration of study drug
Population: Participants who received at least one dose of LY2886721 and with evaluable plasma LY2886721-concentration data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort A: 70 mg LY2886721 | Pharmacokinetics: Maximum Concentration (Cmax) of Plasma LY2886721 | 183 nanograms/milliliter (ng/mL) | Geometric Coefficient of Variation 41 |
| Cohort B: 70 mg LY2886721 | Pharmacokinetics: Maximum Concentration (Cmax) of Plasma LY2886721 | 180 nanograms/milliliter (ng/mL) | Geometric Coefficient of Variation 17 |
| Cohort C: 280 mg LY2886721 | Pharmacokinetics: Maximum Concentration (Cmax) of Plasma LY2886721 | 888 nanograms/milliliter (ng/mL) | Geometric Coefficient of Variation 11 |
Secondary
Cohort C: Mean QTcF Value at Cmax
The mean QTcF value at Cmax for participants administered a single dose of 280 mg LY2886721 was reported. The QT interval is a measure of the time between the start of the Q wave and the end of the T wave and was calculated from electrocardiogram (ECG) data using Fridericia's formula: QTc = QT/RR\^0.33. Corrected QT (QTc) is the QT interval corrected for heart rate and RR, which is the interval between two R waves. Time matched mean change from baseline in QTcF = time matched plasma concentration + participant + random error.
Time frame: Predose up to 48 hours after administration of study drug
Population: Participants who received at least one dose of LY2886721 at the 280-mg dose level and with evaluable mean QTcF data.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Cohort A: 70 mg LY2886721 | Cohort C: Mean QTcF Value at Cmax | 28.3 milliseconds (ms) |