Healthy Elderly, Mild-Moderate Alzheimer's Disease
Conditions
Brief summary
The purpose of this study is to assess the safety, drug levels and effects on the body of 1 or 3 injections of MEDI1814, in people with mild to moderate Alzhiemer's Disease or healthy elderly people.
Interventions
BIOLOGICALMEDI1814 for IV injection
Monoclonal antibody for IV Injection
BIOLOGICALMEDI1814 for Subcutaneous Injection
Monoclonal antibody for subcutaneous injection
BIOLOGICALIV Placebo
Placebo for IV injection
BIOLOGICALPlacebo for Subcutaneous Injection
Subcutaneous Placebo Injection
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
55 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
Male and female (non child bearing potential) subjects Mild-moderate Alzheimer's Disease
Exclusion criteria
History or evidence of significant autoimmune disease Presence of psychiatric disorder which would affect completion of the study Current serious or unstable clinically important illness
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Tolerability as Measured by Participant Withdrawal for an Adverse Event | 4 months SAD; 7 months MAD | Tolerability measured by participant withdrawal for an adverse event from randomization through end of study |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Plasma Concentration (Cmax) of Medi1814 | 1 month | Maximum plasma concentration (Cmax) of Medi1814 during 28 day period after dose administration start (prior to dosing, during infusion, 1, 2, 4, 8, 24, 48 hr, 7, 14,21, and 28 days) |
| Mean Termination Half Life (t 1/2) of Medi1814 | 1 month | Mean termination half life (t 1/2) of Medi1814 during 28 day period after dose administration start (SAD Day 1 dose, MAD 3rd dose) |
| Biomarkers: Amyloid-beta in Cerebral Spinal Fluid (Two Amyloid Bets Peptides of 40 and 42 Amino Acids Were Assessed) | Day 29 in SAD; Day 85 in MAD | Biomarkers: Amyloid-beta in cerebral spinal fluid, mean percent change from baseline |
| Area Under the Concentration Time Curve (AUC) Time 0 to t (28 Days After 1st Dose SAD and MAD and After 3rd Dose in MAD, Day 57) | 1 month | Area Under the Concentration time curve (AUC) time 0 to t; calculated from Just prior to dose administration start to 28th day after dose (pre infusion, during infusion, 1,2,4,8,24,48 hr 7, 14, 21, and 28 day) |
| Medi1814 Concentration in CSF Samples | SAD Day 29; MAD Day 85 | Medi1814 concentration in CSF Samples; number of sampled subjects with a value above the lower limit of quantification |
| Immunogenicity: Anti-drug Antibody Titer | 4 months SAD (6 tests over 4 months; week 1, 2, 4, 8, 12, 16); 7 months MAD (7 monthly tests) | Immunogenicity: Anti-drug antibody titer, subject counted if titer 50 or greater on any test, else 0 if all \<50 |
| Biomarker: Total Amyloid-beta 1-42 in Plasma | Day 29 in SAD; Day 85 in MAD | Biomarker: Total Amyloid-beta 1-42 in plasma, mean percent change from baseline |
Countries
United States
Participant flow
Recruitment details
261 screening visits in 193 individuals were required to randomize 45 subjects into 6 Single Ascending Dose (SAD) cohorts and 32 subjects into 4 Multiple Ascending Dose (MAD) cohorts.
Pre-assignment details
Due to population (mild to moderate Alzheimer's disease) and duration (6 or 9 months) per cohort, rescreening was permitted. SAD had 128 screeings in105 subjects (23 rescreens); MAD had 133 screenings in 88 subjects, (22 rescreens from SAD and 23 rescreens from MAD). Note: 11 of 32 randomized MAD subjects had previously completed a SAD cohort.
Participants by arm
| Arm | Count |
|---|---|
| Placebo: SAD Placebo: pooled SAD pooled cohorts 1, 2, 3, 4, 5 IV & 6 SC (2 subjects each) | 12 |
| Medi1814 25 mg IV: SAD Medi1814 25 mg IV: SAD cohort 1 | 3 |
| Medi1814 100 mg IV: SAD Medi1814 100 mg IV: SAD cohort 2 | 6 |
| Medi1814 300 mg IV: SAD Medi1814 300 mg IV: SAD cohort 3 | 6 |
| Medi1814 900 mg IV: SAD Medi1814 900 mg IV: SAD cohort 4 | 6 |
| Medi1814 1800 mg IV: SAD Medi1814 1800 mg IV: SAD cohort 5 | 6 |
| Medi1814 100 mg SC: SAD Medi1814 100 mg SC: CAD cohort 6 | 6 |
| Placebo: MAD Placebo: MAD pooled cohorts 7, 8, 9 IV & 10 SC (2 subjects each) | 8 |
| Medi1814 300 mg IV: MAD Medi1814 300 mg IV: MAD cohort 7 | 6 |
| Medi 1814 900 mg IV: MAD Medi1814 900 mg IV: MAD cohort 8 | 6 |
| Medi1814 1800 mg IV: MAD Medi1814 1800 mg IV: MAD cohort 9 | 6 |
| Medi1814 200 mg SC: MAD Medi1814 200 mg SC: MAD cohort 10 | 6 |
| Total | 77 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 | FG010 | FG011 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| SAD Cohorts : Study Part 1 | Lost to Follow-up | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 |
| SAD Cohorts : Study Part 1 | Withdrawal by Subject | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Placebo: SAD | Medi1814 25 mg IV: SAD | Medi1814 100 mg IV: SAD | Medi1814 300 mg IV: SAD | Medi1814 900 mg IV: SAD | Medi1814 1800 mg IV: SAD | Medi1814 100 mg SC: SAD | Placebo: MAD | Medi1814 300 mg IV: MAD | Medi 1814 900 mg IV: MAD | Medi1814 1800 mg IV: MAD | Medi1814 200 mg SC: MAD | Total |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 66.3 years STANDARD_DEVIATION 7.22 | 74.0 years STANDARD_DEVIATION 8.89 | 66.8 years STANDARD_DEVIATION 1.94 | 69.0 years STANDARD_DEVIATION 6.1 | 71.8 years STANDARD_DEVIATION 5.15 | 64.8 years STANDARD_DEVIATION 5.91 | 69.3 years STANDARD_DEVIATION 4.84 | 70.0 years STANDARD_DEVIATION 5.9 | 71.7 years STANDARD_DEVIATION 6.62 | 70.8 years STANDARD_DEVIATION 6.62 | 62.5 years STANDARD_DEVIATION 6.16 | 69.3 years STANDARD_DEVIATION 8.71 | 68.5 years STANDARD_DEVIATION 6.55 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 8 Participants | 0 Participants | 5 Participants | 4 Participants | 1 Participants | 6 Participants | 1 Participants | 5 Participants | 5 Participants | 5 Participants | 6 Participants | 6 Participants | 52 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants | 3 Participants | 1 Participants | 2 Participants | 5 Participants | 0 Participants | 5 Participants | 3 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 25 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Mini Mental State Exam (MMSE) | 21.8 MMSE score STANDARD_DEVIATION 3.02 | 22.0 MMSE score STANDARD_DEVIATION 2.65 | 22.3 MMSE score STANDARD_DEVIATION 3.27 | 22.5 MMSE score STANDARD_DEVIATION 3.73 | 22.2 MMSE score STANDARD_DEVIATION 2.99 | 21.0 MMSE score STANDARD_DEVIATION 2 | 23.2 MMSE score STANDARD_DEVIATION 2.04 | 22.1 MMSE score STANDARD_DEVIATION 2.48 | 19.8 MMSE score STANDARD_DEVIATION 2.58 | 20.2 MMSE score STANDARD_DEVIATION 1.72 | 20.0 MMSE score STANDARD_DEVIATION 2.45 | 22.5 MMSE score STANDARD_DEVIATION 2.59 | 21.6 MMSE score STANDARD_DEVIATION 3.07 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 2 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 7 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 10 Participants | 1 Participants | 6 Participants | 4 Participants | 5 Participants | 6 Participants | 5 Participants | 8 Participants | 5 Participants | 6 Participants | 6 Participants | 5 Participants | 67 Participants |
| Sex: Female, Male Female | 7 Participants | 0 Participants | 6 Participants | 5 Participants | 4 Participants | 1 Participants | 3 Participants | 5 Participants | 3 Participants | 2 Participants | 3 Participants | 5 Participants | 44 Participants |
| Sex: Female, Male Male | 5 Participants | 3 Participants | 0 Participants | 1 Participants | 2 Participants | 5 Participants | 3 Participants | 3 Participants | 3 Participants | 4 Participants | 3 Participants | 1 Participants | 33 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 | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk | EG011 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 12 | 0 / 3 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 8 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 |
| other Total, other adverse events | 5 / 12 | 1 / 3 | 3 / 6 | 3 / 6 | 6 / 6 | 1 / 6 | 4 / 6 | 3 / 8 | 4 / 6 | 3 / 6 | 2 / 6 | 2 / 6 |
| serious Total, serious adverse events | 0 / 12 | 0 / 3 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 8 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 |
Outcome results
Primary
Tolerability as Measured by Participant Withdrawal for an Adverse Event
Tolerability measured by participant withdrawal for an adverse event from randomization through end of study
Time frame: 4 months SAD; 7 months MAD
Population: Safety Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo: SAD | Tolerability as Measured by Participant Withdrawal for an Adverse Event | 0 Participants |
| Medi1814 25 mg IV: SAD | Tolerability as Measured by Participant Withdrawal for an Adverse Event | 0 Participants |
| Medi1814 100 mg IV: SAD | Tolerability as Measured by Participant Withdrawal for an Adverse Event | 0 Participants |
| Medi1814 300 mg IV: SAD | Tolerability as Measured by Participant Withdrawal for an Adverse Event | 0 Participants |
| Medi1814 900 mg IV: SAD | Tolerability as Measured by Participant Withdrawal for an Adverse Event | 0 Participants |
| Medi1814 1800 mg IV: SAD | Tolerability as Measured by Participant Withdrawal for an Adverse Event | 0 Participants |
| Medi1814 100 mg SC : SAD | Tolerability as Measured by Participant Withdrawal for an Adverse Event | 0 Participants |
| Placebo: MAD | Tolerability as Measured by Participant Withdrawal for an Adverse Event | 0 Participants |
| Medi1814 300 mg IV: MAD | Tolerability as Measured by Participant Withdrawal for an Adverse Event | 0 Participants |
| Medi1814 900 mg IV: MAD | Tolerability as Measured by Participant Withdrawal for an Adverse Event | 0 Participants |
| Medi1814 1800 mg IV: MAD | Tolerability as Measured by Participant Withdrawal for an Adverse Event | 0 Participants |
| Medi1814 200 mg SC: MAD | Tolerability as Measured by Participant Withdrawal for an Adverse Event | 0 Participants |
Secondary
Area Under the Concentration Time Curve (AUC) Time 0 to t (28 Days After 1st Dose SAD and MAD and After 3rd Dose in MAD, Day 57)
Area Under the Concentration time curve (AUC) time 0 to t; calculated from Just prior to dose administration start to 28th day after dose (pre infusion, during infusion, 1,2,4,8,24,48 hr 7, 14, 21, and 28 day)
Time frame: 1 month
Population: Pharmacokinetic Population (subjects treated with Medi1814)
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo: SAD | Area Under the Concentration Time Curve (AUC) Time 0 to t (28 Days After 1st Dose SAD and MAD and After 3rd Dose in MAD, Day 57) | First Dose (day 1-29) | 80.5 ng x day/mL | Geometric Coefficient of Variation 61.1 |
| Placebo: SAD | Area Under the Concentration Time Curve (AUC) Time 0 to t (28 Days After 1st Dose SAD and MAD and After 3rd Dose in MAD, Day 57) | Third dose (day 57-85) | NA ng x day/mL | — |
| Medi1814 25 mg IV: SAD | Area Under the Concentration Time Curve (AUC) Time 0 to t (28 Days After 1st Dose SAD and MAD and After 3rd Dose in MAD, Day 57) | First Dose (day 1-29) | 455 ng x day/mL | Geometric Coefficient of Variation 19.7 |
| Medi1814 25 mg IV: SAD | Area Under the Concentration Time Curve (AUC) Time 0 to t (28 Days After 1st Dose SAD and MAD and After 3rd Dose in MAD, Day 57) | Third dose (day 57-85) | NA ng x day/mL | — |
| Medi1814 100 mg IV: SAD | Area Under the Concentration Time Curve (AUC) Time 0 to t (28 Days After 1st Dose SAD and MAD and After 3rd Dose in MAD, Day 57) | First Dose (day 1-29) | 1550 ng x day/mL | Geometric Coefficient of Variation 26.3 |
| Medi1814 100 mg IV: SAD | Area Under the Concentration Time Curve (AUC) Time 0 to t (28 Days After 1st Dose SAD and MAD and After 3rd Dose in MAD, Day 57) | Third dose (day 57-85) | NA ng x day/mL | — |
| Medi1814 300 mg IV: SAD | Area Under the Concentration Time Curve (AUC) Time 0 to t (28 Days After 1st Dose SAD and MAD and After 3rd Dose in MAD, Day 57) | First Dose (day 1-29) | 4040 ng x day/mL | Geometric Coefficient of Variation 28 |
| Medi1814 300 mg IV: SAD | Area Under the Concentration Time Curve (AUC) Time 0 to t (28 Days After 1st Dose SAD and MAD and After 3rd Dose in MAD, Day 57) | Third dose (day 57-85) | NA ng x day/mL | — |
| Medi1814 900 mg IV: SAD | Area Under the Concentration Time Curve (AUC) Time 0 to t (28 Days After 1st Dose SAD and MAD and After 3rd Dose in MAD, Day 57) | Third dose (day 57-85) | NA ng x day/mL | — |
| Medi1814 900 mg IV: SAD | Area Under the Concentration Time Curve (AUC) Time 0 to t (28 Days After 1st Dose SAD and MAD and After 3rd Dose in MAD, Day 57) | First Dose (day 1-29) | 4420 ng x day/mL | Geometric Coefficient of Variation 30.7 |
| Medi1814 1800 mg IV: SAD | Area Under the Concentration Time Curve (AUC) Time 0 to t (28 Days After 1st Dose SAD and MAD and After 3rd Dose in MAD, Day 57) | Third dose (day 57-85) | NA ng x day/mL | — |
| Medi1814 1800 mg IV: SAD | Area Under the Concentration Time Curve (AUC) Time 0 to t (28 Days After 1st Dose SAD and MAD and After 3rd Dose in MAD, Day 57) | First Dose (day 1-29) | 120 ng x day/mL | Geometric Coefficient of Variation 51.9 |
| Medi1814 100 mg SC : SAD | Area Under the Concentration Time Curve (AUC) Time 0 to t (28 Days After 1st Dose SAD and MAD and After 3rd Dose in MAD, Day 57) | Third dose (day 57-85) | 1150 ng x day/mL | Geometric Coefficient of Variation 37.9 |
| Medi1814 100 mg SC : SAD | Area Under the Concentration Time Curve (AUC) Time 0 to t (28 Days After 1st Dose SAD and MAD and After 3rd Dose in MAD, Day 57) | First Dose (day 1-29) | 710 ng x day/mL | Geometric Coefficient of Variation 24.2 |
| Placebo: MAD | Area Under the Concentration Time Curve (AUC) Time 0 to t (28 Days After 1st Dose SAD and MAD and After 3rd Dose in MAD, Day 57) | First Dose (day 1-29) | 1690 ng x day/mL | Geometric Coefficient of Variation 75.3 |
| Placebo: MAD | Area Under the Concentration Time Curve (AUC) Time 0 to t (28 Days After 1st Dose SAD and MAD and After 3rd Dose in MAD, Day 57) | Third dose (day 57-85) | 2680 ng x day/mL | Geometric Coefficient of Variation 74 |
| Medi1814 300 mg IV: MAD | Area Under the Concentration Time Curve (AUC) Time 0 to t (28 Days After 1st Dose SAD and MAD and After 3rd Dose in MAD, Day 57) | First Dose (day 1-29) | 4490 ng x day/mL | Geometric Coefficient of Variation 24.2 |
| Medi1814 300 mg IV: MAD | Area Under the Concentration Time Curve (AUC) Time 0 to t (28 Days After 1st Dose SAD and MAD and After 3rd Dose in MAD, Day 57) | Third dose (day 57-85) | 7150 ng x day/mL | Geometric Coefficient of Variation 27.3 |
| Medi1814 900 mg IV: MAD | Area Under the Concentration Time Curve (AUC) Time 0 to t (28 Days After 1st Dose SAD and MAD and After 3rd Dose in MAD, Day 57) | First Dose (day 1-29) | 162 ng x day/mL | Geometric Coefficient of Variation 69.2 |
| Medi1814 900 mg IV: MAD | Area Under the Concentration Time Curve (AUC) Time 0 to t (28 Days After 1st Dose SAD and MAD and After 3rd Dose in MAD, Day 57) | Third dose (day 57-85) | 134 ng x day/mL | Geometric Coefficient of Variation 57 |
95% CI: [0.82, 1.04]Regression, Linear
95% CI: [0.71, 1.3]Regression, Linear
Secondary
Biomarkers: Amyloid-beta in Cerebral Spinal Fluid (Two Amyloid Bets Peptides of 40 and 42 Amino Acids Were Assessed)
Biomarkers: Amyloid-beta in cerebral spinal fluid, mean percent change from baseline
Time frame: Day 29 in SAD; Day 85 in MAD
Population: Pharmacodynamic population (with non zero baseline values)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo: SAD | Biomarkers: Amyloid-beta in Cerebral Spinal Fluid (Two Amyloid Bets Peptides of 40 and 42 Amino Acids Were Assessed) | Free amyloid-beta 1-42 | 28.6 % change | Standard Deviation 113.7 |
| Placebo: SAD | Biomarkers: Amyloid-beta in Cerebral Spinal Fluid (Two Amyloid Bets Peptides of 40 and 42 Amino Acids Were Assessed) | Total amyloid-beta 1-40 | 122.9 % change | Standard Deviation 426.51 |
| Placebo: SAD | Biomarkers: Amyloid-beta in Cerebral Spinal Fluid (Two Amyloid Bets Peptides of 40 and 42 Amino Acids Were Assessed) | Total amyloid-beta 1-42 | 25.3 % change | Standard Deviation 100.71 |
| Medi1814 25 mg IV: SAD | Biomarkers: Amyloid-beta in Cerebral Spinal Fluid (Two Amyloid Bets Peptides of 40 and 42 Amino Acids Were Assessed) | Free amyloid-beta 1-42 | -33.9 % change | Standard Deviation 13.98 |
| Medi1814 25 mg IV: SAD | Biomarkers: Amyloid-beta in Cerebral Spinal Fluid (Two Amyloid Bets Peptides of 40 and 42 Amino Acids Were Assessed) | Total amyloid-beta 1-42 | 52.0 % change | Standard Deviation 104.35 |
| Medi1814 25 mg IV: SAD | Biomarkers: Amyloid-beta in Cerebral Spinal Fluid (Two Amyloid Bets Peptides of 40 and 42 Amino Acids Were Assessed) | Total amyloid-beta 1-40 | -15.9 % change | Standard Deviation 20.57 |
| Medi1814 100 mg IV: SAD | Biomarkers: Amyloid-beta in Cerebral Spinal Fluid (Two Amyloid Bets Peptides of 40 and 42 Amino Acids Were Assessed) | Free amyloid-beta 1-42 | -54.3 % change | Standard Deviation 39.96 |
| Medi1814 100 mg IV: SAD | Biomarkers: Amyloid-beta in Cerebral Spinal Fluid (Two Amyloid Bets Peptides of 40 and 42 Amino Acids Were Assessed) | Total amyloid-beta 1-42 | 41.7 % change | Standard Deviation 38.68 |
| Medi1814 100 mg IV: SAD | Biomarkers: Amyloid-beta in Cerebral Spinal Fluid (Two Amyloid Bets Peptides of 40 and 42 Amino Acids Were Assessed) | Total amyloid-beta 1-40 | -21.0 % change | Standard Deviation 19.57 |
| Medi1814 300 mg IV: SAD | Biomarkers: Amyloid-beta in Cerebral Spinal Fluid (Two Amyloid Bets Peptides of 40 and 42 Amino Acids Were Assessed) | Free amyloid-beta 1-42 | -57.2 % change | Standard Deviation 55.8 |
| Medi1814 300 mg IV: SAD | Biomarkers: Amyloid-beta in Cerebral Spinal Fluid (Two Amyloid Bets Peptides of 40 and 42 Amino Acids Were Assessed) | Total amyloid-beta 1-40 | 8.72 % change | Standard Deviation 31.69 |
| Medi1814 300 mg IV: SAD | Biomarkers: Amyloid-beta in Cerebral Spinal Fluid (Two Amyloid Bets Peptides of 40 and 42 Amino Acids Were Assessed) | Total amyloid-beta 1-42 | 192.8 % change | Standard Deviation 127.96 |
| Medi1814 900 mg IV: SAD | Biomarkers: Amyloid-beta in Cerebral Spinal Fluid (Two Amyloid Bets Peptides of 40 and 42 Amino Acids Were Assessed) | Total amyloid-beta 1-40 | 2.0 % change | Standard Deviation 29.21 |
| Medi1814 900 mg IV: SAD | Biomarkers: Amyloid-beta in Cerebral Spinal Fluid (Two Amyloid Bets Peptides of 40 and 42 Amino Acids Were Assessed) | Total amyloid-beta 1-42 | 414.7 % change | Standard Deviation 292.18 |
| Medi1814 900 mg IV: SAD | Biomarkers: Amyloid-beta in Cerebral Spinal Fluid (Two Amyloid Bets Peptides of 40 and 42 Amino Acids Were Assessed) | Free amyloid-beta 1-42 | -81.65 % change | Standard Deviation 21.67 |
| Medi1814 1800 mg IV: SAD | Biomarkers: Amyloid-beta in Cerebral Spinal Fluid (Two Amyloid Bets Peptides of 40 and 42 Amino Acids Were Assessed) | Free amyloid-beta 1-42 | -15.2 % change | Standard Deviation 189.05 |
| Medi1814 1800 mg IV: SAD | Biomarkers: Amyloid-beta in Cerebral Spinal Fluid (Two Amyloid Bets Peptides of 40 and 42 Amino Acids Were Assessed) | Total amyloid-beta 1-40 | 10.2 % change | Standard Deviation 98.14 |
| Medi1814 1800 mg IV: SAD | Biomarkers: Amyloid-beta in Cerebral Spinal Fluid (Two Amyloid Bets Peptides of 40 and 42 Amino Acids Were Assessed) | Total amyloid-beta 1-42 | 376.1 % change | Standard Deviation 295.92 |
| Medi1814 100 mg SC : SAD | Biomarkers: Amyloid-beta in Cerebral Spinal Fluid (Two Amyloid Bets Peptides of 40 and 42 Amino Acids Were Assessed) | Total amyloid-beta 1-42 | 5.87 % change | Standard Deviation 24.52 |
| Medi1814 100 mg SC : SAD | Biomarkers: Amyloid-beta in Cerebral Spinal Fluid (Two Amyloid Bets Peptides of 40 and 42 Amino Acids Were Assessed) | Total amyloid-beta 1-40 | -14.6 % change | Standard Deviation 23.69 |
| Medi1814 100 mg SC : SAD | Biomarkers: Amyloid-beta in Cerebral Spinal Fluid (Two Amyloid Bets Peptides of 40 and 42 Amino Acids Were Assessed) | Free amyloid-beta 1-42 | -19.0 % change | Standard Deviation 17.69 |
| Placebo: MAD | Biomarkers: Amyloid-beta in Cerebral Spinal Fluid (Two Amyloid Bets Peptides of 40 and 42 Amino Acids Were Assessed) | Total amyloid-beta 1-42 | -29.4 % change | Standard Deviation 55.9 |
| Placebo: MAD | Biomarkers: Amyloid-beta in Cerebral Spinal Fluid (Two Amyloid Bets Peptides of 40 and 42 Amino Acids Were Assessed) | Free amyloid-beta 1-42 | -2.5 % change | Standard Deviation 62.66 |
| Placebo: MAD | Biomarkers: Amyloid-beta in Cerebral Spinal Fluid (Two Amyloid Bets Peptides of 40 and 42 Amino Acids Were Assessed) | Total amyloid-beta 1-40 | 4.96 % change | Standard Deviation 90.19 |
| Medi1814 300 mg IV: MAD | Biomarkers: Amyloid-beta in Cerebral Spinal Fluid (Two Amyloid Bets Peptides of 40 and 42 Amino Acids Were Assessed) | Total amyloid-beta 1-42 | 633.6 % change | Standard Deviation 471.79 |
| Medi1814 300 mg IV: MAD | Biomarkers: Amyloid-beta in Cerebral Spinal Fluid (Two Amyloid Bets Peptides of 40 and 42 Amino Acids Were Assessed) | Total amyloid-beta 1-40 | 638.5 % change | Standard Deviation 1054.28 |
| Medi1814 300 mg IV: MAD | Biomarkers: Amyloid-beta in Cerebral Spinal Fluid (Two Amyloid Bets Peptides of 40 and 42 Amino Acids Were Assessed) | Free amyloid-beta 1-42 | 11.6 % change | Standard Deviation 167.59 |
| Medi1814 900 mg IV: MAD | Biomarkers: Amyloid-beta in Cerebral Spinal Fluid (Two Amyloid Bets Peptides of 40 and 42 Amino Acids Were Assessed) | Free amyloid-beta 1-42 | -96.3 % change | Standard Deviation 2.26 |
| Medi1814 900 mg IV: MAD | Biomarkers: Amyloid-beta in Cerebral Spinal Fluid (Two Amyloid Bets Peptides of 40 and 42 Amino Acids Were Assessed) | Total amyloid-beta 1-40 | -17.9 % change | Standard Deviation 34.08 |
| Medi1814 900 mg IV: MAD | Biomarkers: Amyloid-beta in Cerebral Spinal Fluid (Two Amyloid Bets Peptides of 40 and 42 Amino Acids Were Assessed) | Total amyloid-beta 1-42 | 197.5 % change | Standard Deviation 115.25 |
| Medi1814 1800 mg IV: MAD | Biomarkers: Amyloid-beta in Cerebral Spinal Fluid (Two Amyloid Bets Peptides of 40 and 42 Amino Acids Were Assessed) | Total amyloid-beta 1-40 | -36.96 % change | Standard Deviation 46.82 |
| Medi1814 1800 mg IV: MAD | Biomarkers: Amyloid-beta in Cerebral Spinal Fluid (Two Amyloid Bets Peptides of 40 and 42 Amino Acids Were Assessed) | Free amyloid-beta 1-42 | -95.0 % change | Standard Deviation 1.88 |
| Medi1814 1800 mg IV: MAD | Biomarkers: Amyloid-beta in Cerebral Spinal Fluid (Two Amyloid Bets Peptides of 40 and 42 Amino Acids Were Assessed) | Total amyloid-beta 1-42 | 915.5 % change | Standard Deviation 1361.86 |
| Medi1814 200 mg SC: MAD | Biomarkers: Amyloid-beta in Cerebral Spinal Fluid (Two Amyloid Bets Peptides of 40 and 42 Amino Acids Were Assessed) | Free amyloid-beta 1-42 | -57.7 % change | Standard Deviation 29.76 |
| Medi1814 200 mg SC: MAD | Biomarkers: Amyloid-beta in Cerebral Spinal Fluid (Two Amyloid Bets Peptides of 40 and 42 Amino Acids Were Assessed) | Total amyloid-beta 1-40 | 38.06 % change | Standard Deviation 47.51 |
| Medi1814 200 mg SC: MAD | Biomarkers: Amyloid-beta in Cerebral Spinal Fluid (Two Amyloid Bets Peptides of 40 and 42 Amino Acids Were Assessed) | Total amyloid-beta 1-42 | 87.8 % change | Standard Deviation 124.68 |
Secondary
Biomarker: Total Amyloid-beta 1-42 in Plasma
Biomarker: Total Amyloid-beta 1-42 in plasma, mean percent change from baseline
Time frame: Day 29 in SAD; Day 85 in MAD
Population: Pharmacodynamic population (with non zero baseline values)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo: SAD | Biomarker: Total Amyloid-beta 1-42 in Plasma | 19.6 % change | Standard Deviation 34.51 |
| Medi1814 25 mg IV: SAD | Biomarker: Total Amyloid-beta 1-42 in Plasma | 40132.5 % change | Standard Deviation 4379.93 |
| Medi1814 100 mg IV: SAD | Biomarker: Total Amyloid-beta 1-42 in Plasma | 41107.0 % change | Standard Deviation 43509.89 |
| Medi1814 300 mg IV: SAD | Biomarker: Total Amyloid-beta 1-42 in Plasma | 46667.9 % change | Standard Deviation 29628.09 |
| Medi1814 900 mg IV: SAD | Biomarker: Total Amyloid-beta 1-42 in Plasma | 78534.5 % change | Standard Deviation 22773.96 |
| Medi1814 1800 mg IV: SAD | Biomarker: Total Amyloid-beta 1-42 in Plasma | 44050.9 % change | Standard Deviation 15776.4 |
| Medi1814 100 mg SC : SAD | Biomarker: Total Amyloid-beta 1-42 in Plasma | 45404.0 % change | Standard Deviation 1808.13 |
| Placebo: MAD | Biomarker: Total Amyloid-beta 1-42 in Plasma | -32.0 % change | Standard Deviation 45.65 |
| Medi1814 300 mg IV: MAD | Biomarker: Total Amyloid-beta 1-42 in Plasma | 30272.4 % change | Standard Deviation 14834.8 |
| Medi1814 900 mg IV: MAD | Biomarker: Total Amyloid-beta 1-42 in Plasma | 84652.8 % change | Standard Deviation 44649.16 |
| Medi1814 1800 mg IV: MAD | Biomarker: Total Amyloid-beta 1-42 in Plasma | 43415.3 % change | Standard Deviation 13760.07 |
| Medi1814 200 mg SC: MAD | Biomarker: Total Amyloid-beta 1-42 in Plasma | 97140.1 % change | Standard Deviation 34151.47 |
Secondary
Immunogenicity: Anti-drug Antibody Titer
Immunogenicity: Anti-drug antibody titer, subject counted if titer 50 or greater on any test, else 0 if all \<50
Time frame: 4 months SAD (6 tests over 4 months; week 1, 2, 4, 8, 12, 16); 7 months MAD (7 monthly tests)
Population: Safety Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo: SAD | Immunogenicity: Anti-drug Antibody Titer | 0 Participants |
| Medi1814 25 mg IV: SAD | Immunogenicity: Anti-drug Antibody Titer | 0 Participants |
| Medi1814 100 mg IV: SAD | Immunogenicity: Anti-drug Antibody Titer | 0 Participants |
| Medi1814 300 mg IV: SAD | Immunogenicity: Anti-drug Antibody Titer | 0 Participants |
| Medi1814 900 mg IV: SAD | Immunogenicity: Anti-drug Antibody Titer | 0 Participants |
| Medi1814 1800 mg IV: SAD | Immunogenicity: Anti-drug Antibody Titer | 0 Participants |
| Medi1814 100 mg SC : SAD | Immunogenicity: Anti-drug Antibody Titer | 0 Participants |
| Placebo: MAD | Immunogenicity: Anti-drug Antibody Titer | 0 Participants |
| Medi1814 300 mg IV: MAD | Immunogenicity: Anti-drug Antibody Titer | 0 Participants |
| Medi1814 900 mg IV: MAD | Immunogenicity: Anti-drug Antibody Titer | 0 Participants |
| Medi1814 1800 mg IV: MAD | Immunogenicity: Anti-drug Antibody Titer | 0 Participants |
| Medi1814 200 mg SC: MAD | Immunogenicity: Anti-drug Antibody Titer | 0 Participants |
Secondary
Maximum Plasma Concentration (Cmax) of Medi1814
Maximum plasma concentration (Cmax) of Medi1814 during 28 day period after dose administration start (prior to dosing, during infusion, 1, 2, 4, 8, 24, 48 hr, 7, 14,21, and 28 days)
Time frame: 1 month
Population: Pharmacokinetic population (subjects dosed with Medi1814)
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo: SAD | Maximum Plasma Concentration (Cmax) of Medi1814 | First dose (day 1-29) | 10.2 ng/ml | Geometric Coefficient of Variation 42.7 |
| Placebo: SAD | Maximum Plasma Concentration (Cmax) of Medi1814 | Third dose (day 57-85) | NA ng/ml | — |
| Medi1814 25 mg IV: SAD | Maximum Plasma Concentration (Cmax) of Medi1814 | First dose (day 1-29) | 38.7 ng/ml | Geometric Coefficient of Variation 30.9 |
| Medi1814 25 mg IV: SAD | Maximum Plasma Concentration (Cmax) of Medi1814 | Third dose (day 57-85) | NA ng/ml | — |
| Medi1814 100 mg IV: SAD | Maximum Plasma Concentration (Cmax) of Medi1814 | First dose (day 1-29) | 102 ng/ml | Geometric Coefficient of Variation 14.7 |
| Medi1814 100 mg IV: SAD | Maximum Plasma Concentration (Cmax) of Medi1814 | Third dose (day 57-85) | NA ng/ml | — |
| Medi1814 300 mg IV: SAD | Maximum Plasma Concentration (Cmax) of Medi1814 | First dose (day 1-29) | 341 ng/ml | Geometric Coefficient of Variation 19.3 |
| Medi1814 300 mg IV: SAD | Maximum Plasma Concentration (Cmax) of Medi1814 | Third dose (day 57-85) | NA ng/ml | — |
| Medi1814 900 mg IV: SAD | Maximum Plasma Concentration (Cmax) of Medi1814 | Third dose (day 57-85) | NA ng/ml | — |
| Medi1814 900 mg IV: SAD | Maximum Plasma Concentration (Cmax) of Medi1814 | First dose (day 1-29) | 424 ng/ml | Geometric Coefficient of Variation 36.1 |
| Medi1814 1800 mg IV: SAD | Maximum Plasma Concentration (Cmax) of Medi1814 | Third dose (day 57-85) | NA ng/ml | — |
| Medi1814 1800 mg IV: SAD | Maximum Plasma Concentration (Cmax) of Medi1814 | First dose (day 1-29) | 3.59 ng/ml | Geometric Coefficient of Variation 51.4 |
| Medi1814 100 mg SC : SAD | Maximum Plasma Concentration (Cmax) of Medi1814 | Third dose (day 57-85) | 96.7 ng/ml | Geometric Coefficient of Variation 38.3 |
| Medi1814 100 mg SC : SAD | Maximum Plasma Concentration (Cmax) of Medi1814 | First dose (day 1-29) | 83.9 ng/ml | Geometric Coefficient of Variation 22.3 |
| Placebo: MAD | Maximum Plasma Concentration (Cmax) of Medi1814 | First dose (day 1-29) | 172 ng/ml | Geometric Coefficient of Variation 77.2 |
| Placebo: MAD | Maximum Plasma Concentration (Cmax) of Medi1814 | Third dose (day 57-85) | 185 ng/ml | Geometric Coefficient of Variation 110 |
| Medi1814 300 mg IV: MAD | Maximum Plasma Concentration (Cmax) of Medi1814 | First dose (day 1-29) | 496 ng/ml | Geometric Coefficient of Variation 24.4 |
| Medi1814 300 mg IV: MAD | Maximum Plasma Concentration (Cmax) of Medi1814 | Third dose (day 57-85) | 536 ng/ml | Geometric Coefficient of Variation 32.3 |
| Medi1814 900 mg IV: MAD | Maximum Plasma Concentration (Cmax) of Medi1814 | First dose (day 1-29) | 10.1 ng/ml | Geometric Coefficient of Variation 81.4 |
| Medi1814 900 mg IV: MAD | Maximum Plasma Concentration (Cmax) of Medi1814 | Third dose (day 57-85) | 7.56 ng/ml | Geometric Coefficient of Variation 38.5 |
95% CI: [0.81, 0.98]Regression, Linear
95% CI: [0.65, 1.27]Regression, Linear
Secondary
Mean Termination Half Life (t 1/2) of Medi1814
Mean termination half life (t 1/2) of Medi1814 during 28 day period after dose administration start (SAD Day 1 dose, MAD 3rd dose)
Time frame: 1 month
Population: Pharmacokinetic population (subjects dosed with Medi1814)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo: SAD | Mean Termination Half Life (t 1/2) of Medi1814 | First dose (day 1-29) | 17.2 days | Standard Deviation 0.94 |
| Placebo: SAD | Mean Termination Half Life (t 1/2) of Medi1814 | Third dose (day 57-85) | NA days | — |
| Medi1814 25 mg IV: SAD | Mean Termination Half Life (t 1/2) of Medi1814 | First dose (day 1-29) | 17.0 days | Standard Deviation 2.16 |
| Medi1814 25 mg IV: SAD | Mean Termination Half Life (t 1/2) of Medi1814 | Third dose (day 57-85) | NA days | — |
| Medi1814 100 mg IV: SAD | Mean Termination Half Life (t 1/2) of Medi1814 | First dose (day 1-29) | 17.1 days | Standard Deviation 2.78 |
| Medi1814 100 mg IV: SAD | Mean Termination Half Life (t 1/2) of Medi1814 | Third dose (day 57-85) | NA days | — |
| Medi1814 300 mg IV: SAD | Mean Termination Half Life (t 1/2) of Medi1814 | First dose (day 1-29) | 19.0 days | Standard Deviation 2.23 |
| Medi1814 300 mg IV: SAD | Mean Termination Half Life (t 1/2) of Medi1814 | Third dose (day 57-85) | NA days | — |
| Medi1814 900 mg IV: SAD | Mean Termination Half Life (t 1/2) of Medi1814 | Third dose (day 57-85) | NA days | — |
| Medi1814 900 mg IV: SAD | Mean Termination Half Life (t 1/2) of Medi1814 | First dose (day 1-29) | 18.3 days | Standard Deviation 7.69 |
| Medi1814 1800 mg IV: SAD | Mean Termination Half Life (t 1/2) of Medi1814 | Third dose (day 57-85) | NA days | — |
| Medi1814 1800 mg IV: SAD | Mean Termination Half Life (t 1/2) of Medi1814 | First dose (day 1-29) | 19.8 days | Standard Deviation 3.56 |
| Medi1814 100 mg SC : SAD | Mean Termination Half Life (t 1/2) of Medi1814 | Third dose (day 57-85) | 14.2 days | Standard Deviation 1.86 |
| Medi1814 100 mg SC : SAD | Mean Termination Half Life (t 1/2) of Medi1814 | First dose (day 1-29) | NA days | — |
| Placebo: MAD | Mean Termination Half Life (t 1/2) of Medi1814 | First dose (day 1-29) | NA days | — |
| Placebo: MAD | Mean Termination Half Life (t 1/2) of Medi1814 | Third dose (day 57-85) | 16.2 days | Standard Deviation 1.61 |
| Medi1814 300 mg IV: MAD | Mean Termination Half Life (t 1/2) of Medi1814 | First dose (day 1-29) | NA days | — |
| Medi1814 300 mg IV: MAD | Mean Termination Half Life (t 1/2) of Medi1814 | Third dose (day 57-85) | 20.4 days | Standard Deviation 5.38 |
| Medi1814 900 mg IV: MAD | Mean Termination Half Life (t 1/2) of Medi1814 | First dose (day 1-29) | NA days | — |
| Medi1814 900 mg IV: MAD | Mean Termination Half Life (t 1/2) of Medi1814 | Third dose (day 57-85) | 16.4 days | Standard Deviation 3.29 |
Secondary
Medi1814 Concentration in CSF Samples
Medi1814 concentration in CSF Samples; number of sampled subjects with a value above the lower limit of quantification
Time frame: SAD Day 29; MAD Day 85
Population: Pharmacokinetic population (subjects dosed with Medi1814)
| Arm | Measure | Group | Value (NUMBER) | Dispersion |
|---|---|---|---|---|
| Placebo: SAD | Medi1814 Concentration in CSF Samples | Third dose (day 57-85) | NA Participants | — |
| Placebo: SAD | Medi1814 Concentration in CSF Samples | First dose (day 1-29) | 0 Participants | 0.94 |
| Medi1814 25 mg IV: SAD | Medi1814 Concentration in CSF Samples | First dose (day 1-29) | 0 Participants | 2.16 |
| Medi1814 25 mg IV: SAD | Medi1814 Concentration in CSF Samples | Third dose (day 57-85) | NA Participants | — |
| Medi1814 100 mg IV: SAD | Medi1814 Concentration in CSF Samples | First dose (day 1-29) | 1 Participants | 2.78 |
| Medi1814 100 mg IV: SAD | Medi1814 Concentration in CSF Samples | Third dose (day 57-85) | NA Participants | — |
| Medi1814 300 mg IV: SAD | Medi1814 Concentration in CSF Samples | First dose (day 1-29) | 2 Participants | 2.23 |
| Medi1814 300 mg IV: SAD | Medi1814 Concentration in CSF Samples | Third dose (day 57-85) | NA Participants | — |
| Medi1814 900 mg IV: SAD | Medi1814 Concentration in CSF Samples | Third dose (day 57-85) | NA Participants | — |
| Medi1814 900 mg IV: SAD | Medi1814 Concentration in CSF Samples | First dose (day 1-29) | 4 Participants | 7.69 |
| Medi1814 1800 mg IV: SAD | Medi1814 Concentration in CSF Samples | First dose (day 1-29) | 0 Participants | 3.56 |
| Medi1814 1800 mg IV: SAD | Medi1814 Concentration in CSF Samples | Third dose (day 57-85) | NA Participants | — |
| Medi1814 100 mg SC : SAD | Medi1814 Concentration in CSF Samples | Third dose (day 57-85) | 1 Participants | 1.86 |
| Medi1814 100 mg SC : SAD | Medi1814 Concentration in CSF Samples | First dose (day 1-29) | NA Participants | — |
| Placebo: MAD | Medi1814 Concentration in CSF Samples | First dose (day 1-29) | NA Participants | — |
| Placebo: MAD | Medi1814 Concentration in CSF Samples | Third dose (day 57-85) | 5 Participants | 1.61 |
| Medi1814 300 mg IV: MAD | Medi1814 Concentration in CSF Samples | First dose (day 1-29) | NA Participants | — |
| Medi1814 300 mg IV: MAD | Medi1814 Concentration in CSF Samples | Third dose (day 57-85) | 6 Participants | 5.38 |
| Medi1814 900 mg IV: MAD | Medi1814 Concentration in CSF Samples | First dose (day 1-29) | NA Participants | — |
| Medi1814 900 mg IV: MAD | Medi1814 Concentration in CSF Samples | Third dose (day 57-85) | 0 Participants | 3.29 |