Alzheimer Disease
Conditions
Brief summary
A two-year safety study of simufilam (PTI-125) 100 mg oral tablets twice daily for participants of the previous simufilam studies as wells as additional new mild-to-moderate Alzheimer's disease subjects for a total of 200 participants. All participants will receive simufilam 100 mg tablets twice daily for one year, followed by a 6-month randomized, double-blind period where subjects will either continue on active treatment or be switched to placebo. The study concludes with an additional 6-month open-label treatment period. Clinic visits are every month or month and a half in the first year, and every 3 months in the second year with an additional visit at Month 13. Cognition and neuropsychiatric symptoms are evaluated.
Detailed description
The objectives of this study are to build the safety database for simufilam (PTI-125) and to investigate its effects on biomarkers, cognition and neuropsychiatric symptoms during 12-month twice-daily administration in mild-to-moderate AD patients. Additional objectives are to assess differences in cognition and neuropsychiatric symptoms between active and placebo arms in the 6-month randomized period. All subjects will undergo lumbar puncture at screening for baseline testing of cerebrospinal fluid (CSF) total tau and Abeta42, and the first 50 subjects will also provide a CSF sample at Month 6 or Month 12 for evaluation of change from baseline in CSF biomarkers. CSF will not be required of subjects with prior CSF, PET or MRI evidence of Alzheimer's disease. Plasma biomarkers will be evaluated in all subjects. Safety will be assessed by blood tests, electrocardiograms, adverse event monitoring and, at Months 12 and 24, full physical examinations.
Interventions
DRUGSimufilam 100 mg oral tablet
Simufilam 100 mg oral tablet for b.i.d. administration
DRUGPlacebo
Matching placebo oral tablets
Sponsors
National Institute on Aging (NIA)
Cassava Sciences, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Matching placebo for the 6-month randomized period (Month 12 to Month 18)
Intervention model description
Approximately two hundred (200) patients will be enrolled into the study. All participants will receive open-label simufilam 100 mg b.i.d. for a year. At Month12, participants will be randomized (1:1) to continue taking simufilam 100 mg b.i.d. or to be switched to placebo for 6 months. At Month 18, all participants will enter a final 6-month treatment period of open-label simufilam 100 mg b.i.d.
Eligibility
Sex/Gender
ALL
Age
50 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
1. Informed consent form (ICF) signed by the subject or legally acceptable representative. 2. Patient has a caregiver or legal representative responsible for administering the drug and recording the time. 3. Ages ≥ 50 and ≤ 85 years 4. Clinical diagnosis of dementia due to possible or probable AD consistent with criteria established by a workgroup of the National Institute on Aging and the Alzheimer's Disease Association. 5. If female, postmenopausal for at least 1 year 6. Patient living at home, senior residential setting, or an institutional setting without the need for continuous (i.e. 24-h) nursing care 7. General health status acceptable for participation in the study 8. Fluency (oral and written) in English or Spanish 9. If receiving memantine, rivastigmine, galantamine or an AChEI, receiving a stable dose for at least 3 months (90 days) before screening. If receiving donepezil, receiving any dose lower than 23 mg once daily. Multiple medications are allowed. 10. The patient is a non-smoker for at least 3 years. 11. The patient or legal representative must agree to comply with the drawing of blood samples for the PK assessments, laboratory assessments and SavaDx. 12. MMSE-2 score ≥ 16 and ≤ 26 at screening, OR if \> 26, must have evidence of AD pathology such as a prior CSF total tau/Aβ42 ratio ≥ 0.28, an amyloid positive PET scan or hippocampal volume loss consistent with AD.
Exclusion criteria
1. Anything that in the opinion of the Investigator would preclude participation in a 2-year study. 2. BMI \< 18.5 3. Positive urine drug screen. 4. Positive HIV, HCV or HbsAg screen. 5. Suicidality on C-SSRS 6. Exposure to an experimental drug other than simufilam, experimental biologic or experimental medical device within 3 months before screening 7. A medical condition that would interfere with a lumbar puncture 8. Residence in a skilled nursing facility and requiring 24 h care. 9. Clinically significant laboratory test results 10. Clinically significant untreated hypothyroidism (if treated, thyroid-stimulating hormone level and thyroid supplementation dose must be stable for at least 6 months before screening) 11. Insufficiently controlled diabetes mellitus, including requiring insulin or metformin \>1000 mg/day. 12. Renal insufficiency (serum creatinine \> ULN and clinically significant in the opinion of PI and/or Sponsor OR eGFR \<60 ml/min/m2 as estimated by either the MDRD or CKD-EPI equation) 13. Malignant tumor within 3 years before screening (except squamous and basal cell carcinoma or cervical carcinoma in situ or localized prostate cancer or localized stage 1 bladder cancer) 14. History of ischemic colitis or ischemic enterocolitis 15. Unstable medical condition that is clinically significant in the judgment of the investigator 16. Alanine transaminase (ALT) or aspartate transaminase (AST) \> ULN or total bilirubin \> ULN and clinically significant in the opinion of PI and/or Sponsor. 17. History of myocardial infarction or unstable angina within 6 months before screening 18. History of more than 1 myocardial infarction within 5 years before screening 19. Clinically significant cardiac arrhythmia (including atrial fibrillation), cardiomyopathy, or cardiac conduction defect (patients with a pacemaker are acceptable) 20. Symptomatic hypotension, or uncontrolled hypertension 21. Clinically significant abnormality on screening electrocardiogram (ECG), including but not necessarily limited to a confirmed QTc (Fridericia correction method) value ≥ 450 msec for males or ≥ 470 msec for females. 22. Stroke within 18 months before screening, or history of a stroke concomitant with onset of dementia 23. History of brain tumor or other clinically significant space-occupying lesion on CT or MRI 24. Head trauma with clinically significant loss of consciousness within 12 months before screening or concurrent with the onset of dementia 25. Onset of dementia secondary to cardiac arrest, surgery with general anesthesia, or resuscitation 26. Specific degenerative CNS disease diagnosis other than AD (e.g., Huntington's disease, Creutzfeld-Jacob disease, Down's syndrome, Frontotemporal Dementia, Parkinson's disease) 27. Wernicke's encephalopathy 28. Active acute or chronic CNS infection 29. Donepezil 23 mg or greater QD currently or within 3 months prior to randomization 30. Discontinued AChEI \< 30 days prior to randomization 31. Antipsychotics; low doses are allowed only if given for sleep disturbances, agitation and/or aggression, and only if the subject has received a stable dose for at least 3 months before randomization 32. Tricyclic antidepressants and monoamine oxidase inhibitors; all other antidepressants are allowed only if the subject has received a stable dose for at least 3 months before randomization 33. Anxiolytics or sedative-hypnotics, including barbiturates (unless given in low doses for benign tremor); low doses of benzodiazepines and zolpidem are allowed only if given for insomnia/sleep disturbance, and only if the subject has received a stable dose for at least 3 months before randomization 34. Immunosuppressants, including systemic corticosteroids, if taken in clinically immunosuppressive doses (Steroid use for allergy or other inflammation is permitted.) 35. Antiepileptic medications if taken for control of seizures 36. Chronic intake of opioid-containing analgesics 37. Sedating H1 antihistamines 38. Nicotine therapy (all dosage forms including a patch), varenicline (Chantix), or similar therapeutic agent within 30 days before screening 39. Clinically significant illness within 30 days of enrollment 40. History of significant neurological, hepatic, renal, endocrine, cardiovascular, gastrointestinal, pulmonary, or metabolic disease 41. Loss of a significant volume of blood (\> 450 mL) within 4 weeks prior to the study 42. COVID-19 infection within 3 months
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety and Tolerability (Randomize Withdraw Abnormal Clinical Laboratory Results) | Month 12 to Month 18 | Treatment Emergent Adverse Events when two or more subjects reported abnormal clinical laboratory results while on simufilam (PTI-125) or placebo during the randomized withdraw portion of the study: Month 12 to Month 18 |
| Safety and Tolerability (Open Label Electrocardiogram Results) | Day 1 to Month 12 and month 18 to month 24 | The number of subjects that had Treatment Emergent Adverse Events indicative of abnormal Electrocardiogram results while on simufilam (PTI-125) during the open label portion of the study: Open-label period 1 (Day 1 to Month 12) and open-label period 2 (Month 18 to Month 24) |
| Safety and Tolerability (Randomize Withdraw Electrocardiogram Results) | Month 12 to Month 18 | The number of subjects that had Treatment Emergent Adverse Events indicative of abnormal Electrocardiogram results while on simufilam (PTI-125) or placebo during the randomized withdraw portion of the study: Month 12 to Month 18 |
| Safety and Tolerability (Open Label Abnormal Physical Examination) | Day 1 to Month 12 and month 18 to month 24 | The most frequently reported Treatment Emergent Adverse Events indicative of abnormal physical examination (weight increase or weight decrease) while administered simufilam (PTI-125) during the open label portion of the study: Open-label period 1 (Day 1 to Month 12) and open-label period 2 (Month 18 to Month 24) |
| Safety and Tolerability (Randomize Withdraw Abnormal Physical Examination Findings) | Month 12 to Month 18 | The number of subjects that had Treatment Emergent Adverse Events of indicative of abnormal physical examination while on simufilam (PTI-125) or placebo during the randomized withdraw portion of the study: Month 12 to Month 18 |
| Safety and Tolerability (Open Label Abnormal Clinical Laboratory Results) | Day 1 to Month 12 and month 18 to month 24 | Treatment Emergent Adverse Events when three or more subjects reported abnormal clinical laboratory results while on simufilam (PTI-125) during the open label portion of the study: Open-label period 1 (Day 1 to Month 12) and open-label period 2 (Month 18 to Month 24) |
| Change From Baseline in ADAS-Cog-11 | Day 1 to Month 24 | Alzheimer's Disease Assessment Scale-Cognitive Subscale 11-item: Change from baseline in cognition over the course of 24 months Possible range in score: 0-70; Subscales are summed; Higher values represent a more cognitively impaired participant Decrease in mean value represents improvement in cognition from one timepoint to the next. |
| Change From Baseline in ADAS-Cog-11 (Month 12 to Month 24) | Month 12 to Month 24 | Alzheimer's Disease Assessment Scale-Cognitive Subscale 11-item: Change from baseline in cognition Starting at month 12 through month 24; Possible range in score: 0-70; Higher values represent a more cognitively impaired participant; Decrease in mean value represents improvement in cognition from one timepoint to the next. |
| Safety and Tolerability (Open Label Abnormal Vital Signs) | Day 1 to Month 12 and month 18 to month 24 | The most frequently reported Treatment Emergent Adverse Events indicative of abnormal vital signs (hypertension/worsening of hypertension and blood pressure increase) of simufilam (PTI-125) during the open label portion of the study: Open-label period 1 (Day 1 to Month 12) and open-label period 2 (Month 18 to Month 24) |
| Safety and Tolerability (Randomize Withdraw Abnormal Vital Signs) | Month 12 to month 18 | The most frequently reported Treatment Emergent Adverse Event indicative of abnormal vital signs (hypotension) of simufilam (PTI-125) or placebo during the randomized withdraw portion of the study : Month 12 to Month 18 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Month 12 in Cerebral Spinal Fluid for Tau Protein Mean Concentration (pg/mL) | Day 1 to Month 12 | Change from baseline to month 12 in Cerebral Spinal Fluid for Tau Protein Mean Concentration (pg/mL) (samples stored at -70 degrees Celsius; assays performed at Abilene Christian University Bioanalytics Laboratory) |
| Change From Baseline to Month 12 in Cerebral Spinal Fluid for Neurogranin Mean Concentration (pg/mL) | Day 1 to Month 12 | Change from baseline to month 12 in Cerebral Spinal Fluid for Neurogranin Mean Concentration (pg/mL) (samples stored at -70 degrees Celsius; assays performed at Abilene Christian University Bioanalytics Laboratory) |
| Change From Baseline to Month 12 in Cerebral Spinal Fluid for Neurofilament Light Chain Protein Mean Concentration (pg/mL) | Day 1 to Month 12 | Change from baseline to month 12 in Cerebral Spinal Fluid for Neurofilament Light Chain Protein Mean Concentration (pg/mL) (samples stored at -70 degrees Celsius; assays performed at Abilene Christian University Bioanalytics Laboratory) |
| Change From Baseline to Month 12 in Cerebral Spinal Fluid for Glial Fibrillary Acidic Protein Mean Concentration (pg/mL) | Day 1 to Month 12 | Change from baseline to month 12 in Cerebral Spinal Fluid for Glial Fibrillary Acidic Protein Mean Concentration (pg/mL) (samples stored at -70 degrees Celsius; assays performed at Abilene Christian University Bioanalytics Laboratory) |
| Change From Baseline to Month 12 in Cerebral Spinal Fluid for Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) Mean Concentration (pg/mL) | Day 1 to Month 12 | Change from baseline to month 12 in Cerebral Spinal Fluid for Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) Mean Concentration (pg/mL) (samples stored at -70 degrees Celsius; assays performed at Abilene Christian University Bioanalytics Laboratory) |
Countries
Canada, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Moderate Alzheimer's Disease Subjects with a Mini Mental State Examination (MMSE) score of \<=20 are included in Moderate group | 85 |
| Mild Alzheimer's Disease Subjects with a Mini Mental State Examination (MMSE) score of \>=21 are included in Mild group | 134 |
| Total | 219 |
Baseline characteristics
| Characteristic | Moderate Alzheimer's Disease | Mild Alzheimer's Disease | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 63 Participants | 108 Participants | 171 Participants |
| Age, Categorical Between 18 and 65 years | 22 Participants | 26 Participants | 48 Participants |
| Age, Continuous | 70.5 years STANDARD_DEVIATION 8.7 | 70.8 years STANDARD_DEVIATION 7.93 | 70.7 years STANDARD_DEVIATION 8.21 |
| Body Mass Index (kg/m^2) | 25.52 kg/m2 STANDARD_DEVIATION 4.046 | 28.44 kg/m2 STANDARD_DEVIATION 5.74 | 27.33 kg/m2 STANDARD_DEVIATION 5.333 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 9 Participants | 39 Participants | 48 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 76 Participants | 95 Participants | 171 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 6 Participants | 0 Participants | 6 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 4 Participants | 6 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 76 Participants | 129 Participants | 205 Participants |
| Sex: Female, Male Female | 55 Participants | 68 Participants | 123 Participants |
| Sex: Female, Male Male | 30 Participants | 66 Participants | 96 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 77 | 1 / 220 |
| other Total, other adverse events | 12 / 77 | 113 / 220 |
| serious Total, serious adverse events | 5 / 77 | 25 / 220 |
Outcome results
Primary
Change From Baseline in ADAS-Cog-11
Alzheimer's Disease Assessment Scale-Cognitive Subscale 11-item: Change from baseline in cognition over the course of 24 months Possible range in score: 0-70; Subscales are summed; Higher values represent a more cognitively impaired participant Decrease in mean value represents improvement in cognition from one timepoint to the next.
Time frame: Day 1 to Month 24
Population: Full Analysis set; Overall number of participants is the number for each arm that completed a ADAS-Cog-11 assessment at baseline and month 24.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Moderate Alzheimer's Disease, 24 Months of Simufilam | Change From Baseline in ADAS-Cog-11 | 11.05 Change in scale units | Standard Error 1.19 |
| Mild Alzheimer's Disease, 24 Months of Simufilam | Change From Baseline in ADAS-Cog-11 | 0.07 Change in scale units | Standard Error 1.15 |
| Moderate Alzheimer's Disease, Interrupted Simufilam Placebo Administration From Month 12 to Month 18 | Change From Baseline in ADAS-Cog-11 | 14.26 Change in scale units | Standard Error 1.79 |
| Mild Alzheimer's Disease, Interrupted Simufilam Placebo Administration From Month 12 to Month 18 | Change From Baseline in ADAS-Cog-11 | 1.04 Change in scale units | Standard Error 1.65 |
Primary
Change From Baseline in ADAS-Cog-11 (Month 12 to Month 24)
Alzheimer's Disease Assessment Scale-Cognitive Subscale 11-item: Change from baseline in cognition Starting at month 12 through month 24; Possible range in score: 0-70; Higher values represent a more cognitively impaired participant; Decrease in mean value represents improvement in cognition from one timepoint to the next.
Time frame: Month 12 to Month 24
Population: Full Analysis set; Overall number of participants is the number for each arm/group that completed a ADAS-Cog-11 assessment at month 12 and month 24.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Moderate Alzheimer's Disease, 24 Months of Simufilam | Change From Baseline in ADAS-Cog-11 (Month 12 to Month 24) | 7.39 Change in scale units | Standard Error 1.447 |
| Mild Alzheimer's Disease, 24 Months of Simufilam | Change From Baseline in ADAS-Cog-11 (Month 12 to Month 24) | 1.93 Change in scale units | Standard Error 1.128 |
| Moderate Alzheimer's Disease, Interrupted Simufilam Placebo Administration From Month 12 to Month 18 | Change From Baseline in ADAS-Cog-11 (Month 12 to Month 24) | 6.97 Change in scale units | Standard Error 1.404 |
| Mild Alzheimer's Disease, Interrupted Simufilam Placebo Administration From Month 12 to Month 18 | Change From Baseline in ADAS-Cog-11 (Month 12 to Month 24) | 2.45 Change in scale units | Standard Error 1.225 |
Primary
Safety and Tolerability (Open Label Abnormal Clinical Laboratory Results)
Treatment Emergent Adverse Events when three or more subjects reported abnormal clinical laboratory results while on simufilam (PTI-125) during the open label portion of the study: Open-label period 1 (Day 1 to Month 12) and open-label period 2 (Month 18 to Month 24)
Time frame: Day 1 to Month 12 and month 18 to month 24
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Moderate Alzheimer's Disease, 24 Months of Simufilam | Safety and Tolerability (Open Label Abnormal Clinical Laboratory Results) | Hyperkalaemia | 3 Participants |
| Moderate Alzheimer's Disease, 24 Months of Simufilam | Safety and Tolerability (Open Label Abnormal Clinical Laboratory Results) | Hyperlipidaemia | 3 Participants |
| Moderate Alzheimer's Disease, 24 Months of Simufilam | Safety and Tolerability (Open Label Abnormal Clinical Laboratory Results) | Hypophosphataemia | 3 Participants |
| Moderate Alzheimer's Disease, 24 Months of Simufilam | Safety and Tolerability (Open Label Abnormal Clinical Laboratory Results) | Subjects that reported 2 or less TEAEs indicative of clinical laboratory results | 162 Participants |
Primary
Safety and Tolerability (Open Label Abnormal Physical Examination)
The most frequently reported Treatment Emergent Adverse Events indicative of abnormal physical examination (weight increase or weight decrease) while administered simufilam (PTI-125) during the open label portion of the study: Open-label period 1 (Day 1 to Month 12) and open-label period 2 (Month 18 to Month 24)
Time frame: Day 1 to Month 12 and month 18 to month 24
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Moderate Alzheimer's Disease, 24 Months of Simufilam | Safety and Tolerability (Open Label Abnormal Physical Examination) | Weight decrease | 4 Participants |
| Moderate Alzheimer's Disease, 24 Months of Simufilam | Safety and Tolerability (Open Label Abnormal Physical Examination) | Weight increase | 2 Participants |
| Moderate Alzheimer's Disease, 24 Months of Simufilam | Safety and Tolerability (Open Label Abnormal Physical Examination) | Number of subjects that reported TEAEs not indicative of weight change | 165 Participants |
Primary
Safety and Tolerability (Open Label Abnormal Vital Signs)
The most frequently reported Treatment Emergent Adverse Events indicative of abnormal vital signs (hypertension/worsening of hypertension and blood pressure increase) of simufilam (PTI-125) during the open label portion of the study: Open-label period 1 (Day 1 to Month 12) and open-label period 2 (Month 18 to Month 24)
Time frame: Day 1 to Month 12 and month 18 to month 24
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Moderate Alzheimer's Disease, 24 Months of Simufilam | Safety and Tolerability (Open Label Abnormal Vital Signs) | Hypertension/worsening hypertension | 13 Participants |
| Moderate Alzheimer's Disease, 24 Months of Simufilam | Safety and Tolerability (Open Label Abnormal Vital Signs) | Blood pressure increase | 6 Participants |
| Moderate Alzheimer's Disease, 24 Months of Simufilam | Safety and Tolerability (Open Label Abnormal Vital Signs) | The number of subjects that did not report hypertension or did not have worsening of hypertension | 152 Participants |
Primary
Safety and Tolerability (Open Label Electrocardiogram Results)
The number of subjects that had Treatment Emergent Adverse Events indicative of abnormal Electrocardiogram results while on simufilam (PTI-125) during the open label portion of the study: Open-label period 1 (Day 1 to Month 12) and open-label period 2 (Month 18 to Month 24)
Time frame: Day 1 to Month 12 and month 18 to month 24
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Moderate Alzheimer's Disease, 24 Months of Simufilam | Safety and Tolerability (Open Label Electrocardiogram Results) | Acute left ventricular failure | 1 Participants |
| Moderate Alzheimer's Disease, 24 Months of Simufilam | Safety and Tolerability (Open Label Electrocardiogram Results) | Acute myocardial infarction | 3 Participants |
| Moderate Alzheimer's Disease, 24 Months of Simufilam | Safety and Tolerability (Open Label Electrocardiogram Results) | Angina pectoris | 2 Participants |
| Moderate Alzheimer's Disease, 24 Months of Simufilam | Safety and Tolerability (Open Label Electrocardiogram Results) | Aortic valve incompetence | 1 Participants |
| Moderate Alzheimer's Disease, 24 Months of Simufilam | Safety and Tolerability (Open Label Electrocardiogram Results) | Atrial fibrillation | 4 Participants |
| Moderate Alzheimer's Disease, 24 Months of Simufilam | Safety and Tolerability (Open Label Electrocardiogram Results) | Atrial tachycardia | 1 Participants |
| Moderate Alzheimer's Disease, 24 Months of Simufilam | Safety and Tolerability (Open Label Electrocardiogram Results) | Bradycardia | 3 Participants |
| Moderate Alzheimer's Disease, 24 Months of Simufilam | Safety and Tolerability (Open Label Electrocardiogram Results) | Cardiogenic shock | 1 Participants |
| Moderate Alzheimer's Disease, 24 Months of Simufilam | Safety and Tolerability (Open Label Electrocardiogram Results) | Coronary artery disease | 2 Participants |
| Moderate Alzheimer's Disease, 24 Months of Simufilam | Safety and Tolerability (Open Label Electrocardiogram Results) | Mitral valve incompetence | 2 Participants |
| Moderate Alzheimer's Disease, 24 Months of Simufilam | Safety and Tolerability (Open Label Electrocardiogram Results) | Sinus tachycardia | 1 Participants |
| Moderate Alzheimer's Disease, 24 Months of Simufilam | Safety and Tolerability (Open Label Electrocardiogram Results) | Subjects that reported TEAEs that were not related to Electrocardiogram results | 150 Participants |
Primary
Safety and Tolerability (Randomize Withdraw Abnormal Clinical Laboratory Results)
Treatment Emergent Adverse Events when two or more subjects reported abnormal clinical laboratory results while on simufilam (PTI-125) or placebo during the randomized withdraw portion of the study: Month 12 to Month 18
Time frame: Month 12 to Month 18
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Moderate Alzheimer's Disease, 24 Months of Simufilam | Safety and Tolerability (Randomize Withdraw Abnormal Clinical Laboratory Results) | Leukocytosis | 0 Participants |
| Moderate Alzheimer's Disease, 24 Months of Simufilam | Safety and Tolerability (Randomize Withdraw Abnormal Clinical Laboratory Results) | Haematuria | 2 Participants |
| Moderate Alzheimer's Disease, 24 Months of Simufilam | Safety and Tolerability (Randomize Withdraw Abnormal Clinical Laboratory Results) | Two subjects or less that report TEAEs of abnormal clinical laboratory results or none at all. | 43 Participants |
| Mild Alzheimer's Disease, 24 Months of Simufilam | Safety and Tolerability (Randomize Withdraw Abnormal Clinical Laboratory Results) | Leukocytosis | 2 Participants |
| Mild Alzheimer's Disease, 24 Months of Simufilam | Safety and Tolerability (Randomize Withdraw Abnormal Clinical Laboratory Results) | Haematuria | 1 Participants |
| Mild Alzheimer's Disease, 24 Months of Simufilam | Safety and Tolerability (Randomize Withdraw Abnormal Clinical Laboratory Results) | Two subjects or less that report TEAEs of abnormal clinical laboratory results or none at all. | 34 Participants |
Primary
Safety and Tolerability (Randomize Withdraw Abnormal Physical Examination Findings)
The number of subjects that had Treatment Emergent Adverse Events of indicative of abnormal physical examination while on simufilam (PTI-125) or placebo during the randomized withdraw portion of the study: Month 12 to Month 18
Time frame: Month 12 to Month 18
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Moderate Alzheimer's Disease, 24 Months of Simufilam | Safety and Tolerability (Randomize Withdraw Abnormal Physical Examination Findings) | Weight decrease | 0 Participants |
| Moderate Alzheimer's Disease, 24 Months of Simufilam | Safety and Tolerability (Randomize Withdraw Abnormal Physical Examination Findings) | Subjects that did not report TEAEs of abnormal weight decrease | 45 Participants |
| Mild Alzheimer's Disease, 24 Months of Simufilam | Safety and Tolerability (Randomize Withdraw Abnormal Physical Examination Findings) | Weight decrease | 2 Participants |
| Mild Alzheimer's Disease, 24 Months of Simufilam | Safety and Tolerability (Randomize Withdraw Abnormal Physical Examination Findings) | Subjects that did not report TEAEs of abnormal weight decrease | 35 Participants |
Primary
Safety and Tolerability (Randomize Withdraw Abnormal Vital Signs)
The most frequently reported Treatment Emergent Adverse Event indicative of abnormal vital signs (hypotension) of simufilam (PTI-125) or placebo during the randomized withdraw portion of the study : Month 12 to Month 18
Time frame: Month 12 to month 18
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Moderate Alzheimer's Disease, 24 Months of Simufilam | Safety and Tolerability (Randomize Withdraw Abnormal Vital Signs) | Number of subjects that reported hypotension | 2 Participants |
| Moderate Alzheimer's Disease, 24 Months of Simufilam | Safety and Tolerability (Randomize Withdraw Abnormal Vital Signs) | Number of subjects that did not report hypotension | 43 Participants |
| Mild Alzheimer's Disease, 24 Months of Simufilam | Safety and Tolerability (Randomize Withdraw Abnormal Vital Signs) | Number of subjects that reported hypotension | 0 Participants |
| Mild Alzheimer's Disease, 24 Months of Simufilam | Safety and Tolerability (Randomize Withdraw Abnormal Vital Signs) | Number of subjects that did not report hypotension | 37 Participants |
Primary
Safety and Tolerability (Randomize Withdraw Electrocardiogram Results)
The number of subjects that had Treatment Emergent Adverse Events indicative of abnormal Electrocardiogram results while on simufilam (PTI-125) or placebo during the randomized withdraw portion of the study: Month 12 to Month 18
Time frame: Month 12 to Month 18
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Moderate Alzheimer's Disease, 24 Months of Simufilam | Safety and Tolerability (Randomize Withdraw Electrocardiogram Results) | Acute Myocardial Infarction | 1 Participants |
| Moderate Alzheimer's Disease, 24 Months of Simufilam | Safety and Tolerability (Randomize Withdraw Electrocardiogram Results) | Arrhymia | 0 Participants |
| Moderate Alzheimer's Disease, 24 Months of Simufilam | Safety and Tolerability (Randomize Withdraw Electrocardiogram Results) | Atrial Fibrillation | 1 Participants |
| Moderate Alzheimer's Disease, 24 Months of Simufilam | Safety and Tolerability (Randomize Withdraw Electrocardiogram Results) | Atrioventricular block first degree | 0 Participants |
| Moderate Alzheimer's Disease, 24 Months of Simufilam | Safety and Tolerability (Randomize Withdraw Electrocardiogram Results) | Cardiomegaly | 0 Participants |
| Moderate Alzheimer's Disease, 24 Months of Simufilam | Safety and Tolerability (Randomize Withdraw Electrocardiogram Results) | Subjects that had TEAEs that were not related Electrocadiogram results | 43 Participants |
| Mild Alzheimer's Disease, 24 Months of Simufilam | Safety and Tolerability (Randomize Withdraw Electrocardiogram Results) | Cardiomegaly | 1 Participants |
| Mild Alzheimer's Disease, 24 Months of Simufilam | Safety and Tolerability (Randomize Withdraw Electrocardiogram Results) | Acute Myocardial Infarction | 0 Participants |
| Mild Alzheimer's Disease, 24 Months of Simufilam | Safety and Tolerability (Randomize Withdraw Electrocardiogram Results) | Atrioventricular block first degree | 1 Participants |
| Mild Alzheimer's Disease, 24 Months of Simufilam | Safety and Tolerability (Randomize Withdraw Electrocardiogram Results) | Arrhymia | 1 Participants |
| Mild Alzheimer's Disease, 24 Months of Simufilam | Safety and Tolerability (Randomize Withdraw Electrocardiogram Results) | Subjects that had TEAEs that were not related Electrocadiogram results | 33 Participants |
| Mild Alzheimer's Disease, 24 Months of Simufilam | Safety and Tolerability (Randomize Withdraw Electrocardiogram Results) | Atrial Fibrillation | 1 Participants |
Secondary
Change From Baseline to Month 12 in Cerebral Spinal Fluid for Glial Fibrillary Acidic Protein Mean Concentration (pg/mL)
Change from baseline to month 12 in Cerebral Spinal Fluid for Glial Fibrillary Acidic Protein Mean Concentration (pg/mL) (samples stored at -70 degrees Celsius; assays performed at Abilene Christian University Bioanalytics Laboratory)
Time frame: Day 1 to Month 12
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Moderate Alzheimer's Disease, 24 Months of Simufilam | Change From Baseline to Month 12 in Cerebral Spinal Fluid for Glial Fibrillary Acidic Protein Mean Concentration (pg/mL) | -84.946 pg/mL | Standard Deviation 118.736 |
Secondary
Change From Baseline to Month 12 in Cerebral Spinal Fluid for Neurofilament Light Chain Protein Mean Concentration (pg/mL)
Change from baseline to month 12 in Cerebral Spinal Fluid for Neurofilament Light Chain Protein Mean Concentration (pg/mL) (samples stored at -70 degrees Celsius; assays performed at Abilene Christian University Bioanalytics Laboratory)
Time frame: Day 1 to Month 12
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Moderate Alzheimer's Disease, 24 Months of Simufilam | Change From Baseline to Month 12 in Cerebral Spinal Fluid for Neurofilament Light Chain Protein Mean Concentration (pg/mL) | -10.00 pg/mL | Standard Deviation 95.504 |
Secondary
Change From Baseline to Month 12 in Cerebral Spinal Fluid for Neurogranin Mean Concentration (pg/mL)
Change from baseline to month 12 in Cerebral Spinal Fluid for Neurogranin Mean Concentration (pg/mL) (samples stored at -70 degrees Celsius; assays performed at Abilene Christian University Bioanalytics Laboratory)
Time frame: Day 1 to Month 12
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Moderate Alzheimer's Disease, 24 Months of Simufilam | Change From Baseline to Month 12 in Cerebral Spinal Fluid for Neurogranin Mean Concentration (pg/mL) | -115.15 pg/mL | Standard Deviation 237.256 |
Secondary
Change From Baseline to Month 12 in Cerebral Spinal Fluid for Tau Protein Mean Concentration (pg/mL)
Change from baseline to month 12 in Cerebral Spinal Fluid for Tau Protein Mean Concentration (pg/mL) (samples stored at -70 degrees Celsius; assays performed at Abilene Christian University Bioanalytics Laboratory)
Time frame: Day 1 to Month 12
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Moderate Alzheimer's Disease, 24 Months of Simufilam | Change From Baseline to Month 12 in Cerebral Spinal Fluid for Tau Protein Mean Concentration (pg/mL) | -12.26 pg/mL | Standard Deviation 96.238 |
Secondary
Change From Baseline to Month 12 in Cerebral Spinal Fluid for Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) Mean Concentration (pg/mL)
Change from baseline to month 12 in Cerebral Spinal Fluid for Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) Mean Concentration (pg/mL) (samples stored at -70 degrees Celsius; assays performed at Abilene Christian University Bioanalytics Laboratory)
Time frame: Day 1 to Month 12
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Moderate Alzheimer's Disease, 24 Months of Simufilam | Change From Baseline to Month 12 in Cerebral Spinal Fluid for Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) Mean Concentration (pg/mL) | -4093.31 pg/mL | Standard Deviation 4730.736 |