A Study of LY3202626 in Healthy Participants and Participants With Alzheimer's Disease

Study Overview
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Brief Summary
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This study involves single and multiple doses of LY3202626 and will evaluate the effects of LY3202626 on the body. There will be 4 parts to this study. In Parts A and B, single increasing doses of LY3202626 will be given in capsule form. Part A will also include itraconazole given orally as a solution. Part A will last approximately 8-12 weeks. Part B will last approximately 5-6 weeks. In Parts C and D, participants will be dosed multiple days with the study drug. Part C will last approximately 11-14 weeks. Part D will last approximately 11-14 weeks and participants must have Alzheimer's Disease. Participants may only enroll in one part.

Official Title
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Single- and Multiple-Ascending Dose, Safety, Tolerability, Pharmacokinetic, and Pharmacodynamic Study of LY3202626

Conditions
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Healthy Volunteers, Alzheimer Disease

Intervention / Treatment
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* Drug: LY3202626
* Drug: Placebo (Part A, B, C)
* Drug: Itraconazole


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: For Parts A, B, and C, are overtly healthy males or females (nonchildbearing potential), as determined by medical history and physical examination Have a body mass index (BMI) of 18 to 32 kilograms per square meter (kg/m^2) For Part D, present with Mild Cognitive Impairment (MCI) due to Alzheimer's Disease (AD) or mild to moderate AD Have venous access sufficient to allow for blood sampling Are reliable and willing to make themselves available for the duration of the study and are willing to follow study procedures and research unit policies Exclusion Criteria: Taking over-the-counter or prescription medication with the exception of vitamins or minerals Smoke more than 10 cigarettes per day Are unwilling or unable to refrain from eating any food or drinking any beverage containing grapefruit or grapefruit juice for at least 2 weeks prior to first dose until completion of the study

Ages Eligible for Study
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Minimum Age: 20 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: Basic Science
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Part A Cohort 1 Sequence1: 0.1mg, 1.6mg, Placcebo; 15mg<br>Part A Cohort 1 involved healthy participants and was comprised of 4 treatment periods with a washout period of approximately 14 days between doses. Period 1: 0.1mg LY3202626 Period 2: 1.6mg LY3202626 Period 3: 15 mg placebo (PBO) Period 4: 15mg LY3202626. | Drug: LY3202626<br>* administered orally<br>Drug: Placebo (Part A, B, C)<br>* administered orally<br>|
| Experimental: Part A Cohort 1 Sequence 2: 0.1mg, PBO, 15mg, 15mg<br>Part A Cohort 1 involved healthy participants and comprised of 4 treatment periods with a washout period of approximately 14 days between doses. Period 1: 0.1mg Period 2: PBO Period 3: 15mg LY3202626 Period 4: 15mg LY3202626. | Drug: LY3202626<br>* administered orally<br>Drug: Placebo (Part A, B, C)<br>* administered orally<br>|
| Experimental: Part A Cohort 1 Sequence 3: PBO, 1.6mg, 15mg, Placebo<br>Part A Cohort 1 involved healthy participants and comprised of 4 treatment periods with a washout period of approximately 14 days between doses. Period 1: PBO Period 2: 1.6mg LY3202626 Period 3: 15mg LY3202626 Period 4: PBO. | Drug: LY3202626<br>* administered orally<br>Drug: Placebo (Part A, B, C)<br>* administered orally<br>|
| Experimental: Part A Cohort 2 Sequence 1:0.4mg, 5mg, PBO, 0.4mg/Itraconazole<br>Part A Cohort 2 involved healthy participants and comprised of 4 treatment periods with a washout period of approximately 14 days between doses. Period 1: 0.4mg LY3202626 Period 2: 5mg LY3202626 Period 3: 45mg, PBO Period 4: 0.4mg LY3202626/200mg Itraconazole. | Drug: LY3202626<br>* administered orally<br>Drug: Placebo (Part A, B, C)<br>* administered orally<br>|
| Experimental: Part A Cohort 2 Sequence 2: 0.4mg, PBO, 45mg. 0.4mg/Itra<br>Part A Cohort 2 involved healthy participants and comprised of 4 treatment periods with a washout period of approximately 14 days between doses. Period 1: 0.4mg LY3202626 Period 2: 5mg, PBO Period 3: 45mg LY3202626 Period 4: 0.4mg LY3202626/200mg Itraconazole. | Drug: LY3202626<br>* administered orally<br>Drug: Placebo (Part A, B, C)<br>* administered orally<br>Drug: Itraconazole<br>* administered orally<br>|
| Experimental: Part A Cohort 2 Sequence 3:PBO, 5mg, 45mg,0.4mg/200mg Itra<br>Part A Cohort 2 involved healthy participants and was comprised of 4 treatment periods with a washout period of approximately 14 days between doses. Period 1: 0.4mg, PBO Period 2: 5mg LY3202626 Period 3: 45mg LY3202626 Period 4: 0.4mg LY3202626/200mg Itraconazole. | Drug: LY3202626<br>* administered orally<br>Drug: Placebo (Part A, B, C)<br>* administered orally<br>Drug: Itraconazole<br>* administered orally<br>|
| Experimental: Part A Cohort 3 Sequence 1: Food Effect Fed/Fasted<br>Part A Cohort 3 involved healthy participants and was comprised of two treatment periods with a washout period of approximately 14 days between doses. Single dose of 10mg LY3202626 given PO in Period 1 and 2. Period 1: Fed 2: Fasted. | Drug: LY3202626<br>* administered orally<br>|
| Experimental: Part A Cohort 3 Sequence 2: Food Effect Fasted/Fed<br>Part A Cohort 3 involved healthy participants and was comprised of two treatment periods with a washout period of approximately 14 days between doses. Single dose 10mg LY3202626 given PO in Period 1 and 2. Period 1: Fasted 2: Fed. | Drug: LY3202626<br>* administered orally<br>|
| Experimental: Part B Cohort 4: 1.6mg<br>Part B Cohort 4 involved healthy participants and was comprised of one period. Single dose of 1.6mg LY3202626 given PO in Period 1. Dose determined by Part A. | Drug: LY3202626<br>* administered orally<br>|
| Experimental: Part B Cohort 5: 10mg<br>Part B Cohort 5 involved healthy participants and was comprised of one period. Single dose of 10mg LY3202626 given PO in Period 1. Dose determined by Part A. | Drug: LY3202626<br>* administered orally<br>|
| Experimental: Part B Cohort 6: 26mg<br>Part B Cohort 6 involved healthy participants and was comprised of one period. Single dose of 26mg LY3202626 given PO in Period 1. Dose determined by Part A. | Drug: LY3202626<br>* administered orally<br>|
| Placebo Comparator: Part B Cohort 4, 5, 6: Placebo Comparator<br>Part B Cohort 4,5,6 involved healthy participants and was comprised of one period. Single dose of PBO given PO in Period 1. | Drug: Placebo (Part A, B, C)<br>* administered orally<br>|
| Experimental: Part C Cohort 7: 1mg<br>Part C Cohort 7 involved healthy participants and was comprised of one period. 1mg LY3202626 given PO once daily for 14 days. Dose determined by Part B. | Drug: LY3202626<br>* administered orally<br>|
| Experimental: Part C Cohort 8: 6mg<br>Part C Cohort 8 involved healthy participants and was comprised of one period. 6mg LY3202626 was given PO once daily for 14 days. Dose determined by Part B. | Drug: LY3202626<br>* administered orally<br>|
| Experimental: Part C Cohort 9: 26mg<br>Part C Cohort 9 included healthy participants and was comprised of one period. 26mg LY3202626 was given PO once daily for 14 days. Dose determined by Part B. | Drug: LY3202626<br>* administered orally<br>|
| Placebo Comparator: Part C Cohort 7, 8 ,9: Placebo Comparator<br>Part C Cohort 7,8,9 involved healthy participants and was comprised of one period. Placebo given PO once daily for 14 days. | Drug: Placebo (Part A, B, C)<br>* administered orally<br>|
| Experimental: Part D Cohort 10: 6mg<br>Part D Cohort 10 involved participants with Alzheimer's disease and was comprised of one period. 6mg LY3202626 was given PO once daily for 14 days. Dose determined by Part B. | Drug: LY3202626<br>* administered orally<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With One or More Serious Adverse Event(s) (SAEs) Considered by the Investigator to be Related to Study Drug Administration | A summary of other nonserious Adverse Events (AE's), and all SAE's, regardless of causality, is located in the Reported Adverse Events section. | Baseline to Study Completion (up to 14 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics (PK): Maximum Drug Concentration (Cmax) of LY3202626 | Summary of PK parameters of LY3202626 in plasma following oral administration of single doses for Parts A and B and multiple doses for Part C. | Part A and B Day 1:Predose, 0.5,1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, and 120 hours postdose; Part C Day 1:Predose, 0.5,1, 2, 4, 6, 8, and 12 hours postdose; Part C Day 14:Predose, 0.5,1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 168, and 216 hours postdose | 
| PK: Area Under the Concentration Time Curve (AUC) of LY3202626 | Pharmacokinetic parameters for Part A and B were assessed on Day 1 using AUC 0-infinity (AUC0-inf). Pharmacokinetic parameters for Part C were assessed on Day 1 using AUC zero to time to last (AUC0-tlast), Day 14 using AUC steady state. | Part A and B Day 1: Predose, 0.5,1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, and 120 hours postdose; Part C Day 1:Presdose, 0.5,1, 2, 4, 6, 8,12 hours postdose; Day 14: Predose, 0.5,1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 168, and 216 hours postdose | 
| Pharmacodynamic(PD) Biomarker: Plasma Minimum Amyloid-Beta Peptide (A-beta) 1-40 Concentration | Plasma minimum A-beta 1-40 concentration or nadir concentration (Cnadir) is defined as the lowest concentration of plasma A-beta 1-40 following dose administration. | Part A Day 1: Predose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, and 120 postdose; Part C Day 14: Predose 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 120, 168, and 216 postdose | 
| PD Biomarker: Cerebral Spinal Fluid (CSF) Minimum Amyloid-beta Peptide (A-beta) 1-40 Concentration | CSF minimum A-beta 1-40 concentration or nadir concentration (Cnadir) is defined as the lowest concentration of CSF A-beta 1-40 following dose administration. | Part B: -4, -2, Predose, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, 24, 28, 32, and 36 hours postdose | 
| PK: CSF Concentration of LY3202626 |  | Part C: Day 15 at 24 hours +/- 4 hours (hr) postdose | 
| PD Biomarker: Change From Baseline in Cerebrospinal Fluid (CSF) Amyloid-beta Peptide (A-beta) 1-40 Concentration | CSF Aβ1-40 change from baseline at Day 15 endpoint, 24 hours postdose (+/- 4 hours) following multiple doses of LY3202626. | Parts C: Baseline, Day 15 |