Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
CT1812 · 10 trials · 7 indications
The Clinical Dementia Rating (CDR) is a clinical scale that describes 5 levels of impairment in performance on each of 6 categories of function including memory, orientation, judgment and problem solving, community affairs, home and hobbies, and personal care. The ratings of degree of impairment obtained on each of the 6 categories of function are synthesized into 1 global rating of dementia as absent, questionable, mild, moderate, or severe (global CDR scores of 0, 0.5, 1, 2, or 3, respectively). The score is based on interviews with the participant and study partner, using a structured interview. A sum of boxes score (CDR-SB) provides an additional measure of change where each category has a maximum possible score of 3 points and the total score is a sum of the category scores giving a total possible score of 0 to 18 with higher scores indicating more impairment.
All adverse events (AE) summaries were restricted to TEAEs, which were defined as those AEs that occurred on or after the date of first dose and those existing AEs that worsened during the study. If it could not be determined whether the AE was treatment-emergent due to a partial onset date, then it was counted as such. Verbatim terms were mapped to System Organ Class (SOC) and preferred terms using MedDRA version 24.1.
Adverse events were captured from the start of study-related procedures at Visit 1 (including diagnostic assessments or signing of ICF) onward during the course of this study. Adverse events were coded using MedDRA Version 22.0
Global relative theta power was quantified and summarized descriptively (observed values, change from the pre-treatment values) by treatment and time point using the Safety Population. The change from period baseline in global relative theta power within each period was analyzed using a linear mixed model with fixed effects for treatment group (CT1812 or placebo), sequence, and period, and a random effect for subject within sequence. The analysis was conducted using PROC MIXED. The ability of CT1812 to rapidly restore synapse number to normal was expected to result in a decrease in EEG theta power in AD patients in response to short-term treatment with CT1812. Thus, a decrease in the Global Relative Theta Power represents better outcomes, while high values in the Global Relative Theta Power represent worse outcomes. The unit is represented by uV\^2/Hz (microvolt squared per frequency). This is a common unit for spectral power density, and how relative power measures are displayed.
For the measurements of pre-dose and post-dose plasma concentrations of CT1812, samples were collected 1± 0.25 hour predose. Single concentrations of CT1812 at selected predose and post-dose time points were reported.
Adverse events were captured from the start of study-related procedures at Visit 1 (including diagnostic assessments or signing of ICF) onward during the course of this study. Adverse events were coded using MedDRA Version 27.0.TEAEs are events that occurred or worsened on or after the first application of study drug. Participants are counted once for each system organ class (SOC) and once for each preferred term (PT).
Cmax: Maximum observed plasma concentration occurring at Tmax
Cmax - Maximum observed plasma concentration occurring at Tmax.
CSF/plasma ratio - Pre-dose on Day 13 and 3h (±15 min) post-dose on Day 15
Plasma concentrations of CT1812 were determined using a validated liquid chromatography with tandem mass spectrometry (LC-MS/MS) following a single oral dose of 300 mg (\~1 μCi) \[14C\]-CT1812 administered in healthy adult male subjects.
Plasma concentrations of M6/CP199 were determined using a validated liquid chromatography with tandem mass spectrometry (LC-MS/MS) following a single oral dose of 300 mg (\~1 μCi) \[14C\]-CT1812 administered in healthy adult male subjects.
Plasma Total Radioactivity Concentration of CT1812-Equivalents was performed using Liquid Scintillation Counting (LSC) method following a single oral dose of 300 mg (\~1 μCi) \[14C\]-CT1812 administered in healthy adult male subjects.
The analysis of Whole Blood Total Radioactivity Concentration of CT1812-Equivalents was performed using combustion followed by Liquid Scintillation Counting (LSC) method following a single oral dose of 300 mg (\~1 μCi) \[14C\]-CT1812 administered in healthy adult male subjects.
Cumulative radioactive dose (Cum%Dose) excreted in the urine was determined using Liquid Scintillation Counting (LSC) following a single oral dose of 300 mg (\~1 μCi) \[14C\]-CT1812 administered in healthy adult male subjects.
Cumulative radioactive dose (Cum%Dose) excreted in the feces was performed using combustion followed by Liquid Scintillation Counting (LSC) method following a single oral dose of 300 mg (\~1 μCi) \[14C\]-CT1812 administered in healthy adult male subjects.
Plasma CT1812 Concentration were measured using the area under the concentration-time curve, from time 0 to the last observed non-zero concentration, as calculated by the linear trapezoidal method following a single oral dose of 300 mg (\~1 μCi) \[14C\]-CT1812 administered in healthy adult male subjects. Plasma concentrations of CT1812 were determined using a validated liquid chromatography with tandem mass spectrometry (LC-MS/MS).
M6/CP199 Plasma Concentration was measured using the area under the concentration-time curve, from time 0 to the last observed non-zero concentration, as calculated by the linear trapezoidal method following a single oral dose of 300 mg (\~1 μCi) \[14C\]-CT1812 administered in healthy adult male subjects. M6/CP199 plasma concentrations were determined using a validated liquid chromatography with tandem mass spectrometry (LC-MS/MS).
Plasma Total Radioactivity was measured using the area under the concentration-time curve, from time 0 to the last observed non-zero concentration, as calculated by the linear trapezoidal method following a single oral dose of 300 mg (\~1 μCi) \[14C\]-CT1812 administered in healthy adult male subjects. Plasma Total Radioactivity Concentration of CT1812-Equivalents was performed using Liquid Scintillation Counting (LSC).
Whole Blood Total Radioactivity was measured using the area under the concentration-time curve, from time 0 to the last observed non-zero concentration, as calculated by the linear trapezoidal method following a single oral dose of 300 mg (\~1 μCi) \[14C\]-CT1812 administered in healthy adult male subjects. Plasma Total Radioactivity Concentration of CT1812-Equivalents was performed using Liquid Scintillation Counting (LSC)
evidence of oligomer displacement as demonstrated by a clear rise in CSF oligomer concentration relative to baseline and placebo
Single dose (Day -2 and Day 6) pharmacokinetic parameter Area under the plasma-concentration time curve
Treatment Emergent Adverse Events will be assessed by reviewing: Physical Exams; monitoring of vital signs, ECGs, and clinical and laboratory assessments
Treatment Emergent Adverse Events will be assessed by reviewing: * physical examinations, * monitoring vital signs, * monitoring clinical and laboratory assessments, * monitoring ECGs.
| Arm | Type | Description |
|---|---|---|
| CT1812 100 mg | ACTIVE_COMPARATOR | CT1812 at a dose of 100 n=180 group |
| CT1812 200 mg | ACTIVE_COMPARATOR | CT1812 at a dose of 300mg, n=180 group |
| Placebo | PLACEBO_COMPARATOR | Placebo, n=180 group |
| CT1812 300 mg | ACTIVE_COMPARATOR | CT1812 300 mg |
| Active Treatment- CT1812 | EXPERIMENTAL | Active Treatment- CT1812 at a dose of 300mg |
| Control - Placebo | PLACEBO_COMPARATOR | Drug: Placebo Non-active study drug |
| Active Treatment- CT1812 100 mg | ACTIVE_COMPARATOR | CT1812 at a dose of 100 mg |
| Active Treatment- CT1812 300 mg | ACTIVE_COMPARATOR | CT1812 at a dose of 300mg |
| Placebo Comparator - Placebo | PLACEBO_COMPARATOR | Placebo |
| 150 mg QD | EXPERIMENTAL | CT1812 150 mg QD |
| 150 mg BID | EXPERIMENTAL | CT1812 150 mg BID |
| 300 mg QD | EXPERIMENTAL | CT1812 300 mg QD |
| CT1812 | EXPERIMENTAL | Investigational Drug |
| Active Treatment- CT1812 560 mg | ACTIVE_COMPARATOR | - |
| Active Treatment- CT1812 280 mg | ACTIVE_COMPARATOR | - |
| Active Treatment- CT1812 90 mg | ACTIVE_COMPARATOR | - |
| Active Treatment-Low | ACTIVE_COMPARATOR | 6 subjects randomized to 280 mg (Low) CT1812 |
| Active Treatment-High | ACTIVE_COMPARATOR | 6 subjects randomized to 560 mg (High) CT1812 |
| Matching Placebo | PLACEBO_COMPARATOR | In cohorts 1-6, 8 subjects will be enrolled. 6 subjects will receive matching placebo. |
| Name | Type | Description |
|---|---|---|
| CT1812 | DRUG | Study Drug |
| Placebo | DRUG | Non-active study drug |
| 300 mg [C14] CT1812 | DRUG | Single dose of 300 mg CT1812 with microtracer dose of \[C14\] |
| tolbutamide | DRUG | Single-sequence drug-drug interaction study to determine the effect of CT1812 (560 mg) once daily on the pharmacokinetics of tolbutamide |
| dextromethorphan | DRUG | Single-sequence drug-drug interaction study to determine the effect of CT1812 (560 mg) once daily on the pharmacokinetics of dextromethorphan |
| Omeprazole | DRUG | Single-sequence drug-drug interaction study to determine the effect of CT1812 (560 mg) once daily on the pharmacokinetics of omeprazole |
| midazolam | DRUG | Single-sequence drug-drug interaction study to determine the effect of CT1812 (560 mg) once daily on the pharmacokinetics of midazolam |
Inclusion Criteria: 1. Ages 50-85 years. 2. Diagnosis of either MCI due to AD or mild AD dementia. 3. MMSE 20-30 (inclusive). 4. Amyloid PET scan of the brain or CSF biomarkers consistent with AD. 5. Neuroimaging (MRI) obtained during screening consistent with the clinical diagnosis of Alzheimer's ...