Dementia
Conditions
Interventions
Part 1:
A sentinel dosing strategy will be implemented. The first 2 patients at a given
dose level will be assigned 1:1 active:placebo, and at least 1 week must elapse
between initiation of treatmen
Sponsors
Ionis Pharmaceuticals, Inc.
Eligibility
Age
18 Years to 99 Years
Inclusion criteria
Inclusion criteria: Part 1: 1. Patient is able to read, understand, and provide written informed consent (signed and dated) 2. Male or female, aged 50-74 years, inclusive, at Screening 3. AD of mild severity (CDR Global score of 1 or CDR Global Score of 0.5 with a Memory score of 1;; MMSE 20-27, inclusive) at Screening 4. Reduced CSF Aβ42 at Screening, consistent with a diagnosis of mild AD 5. Elevated CSF total tau and p-tau at Screening, consistent with a diagnosis of mild AD 6. Diagnosis of probable AD dementia based on National Institute of Aging-Alzheimer Association (NIA-AA) criteria (may be either amnestic or nonamnestic [Global CDR score of 1.0] presentation) at Screening 7. Body Mass Index (BMI) >= 18 and 50 kg (110 lbs) 9. Able and willing to meet all study requirements, including travel to Study Center, procedures, measurements and visits, including: a. Reside in a proximity to the Study Center that permits prompt appearance at the facility if requested by the Investigator (maximum of 4-hour travel to Study Center), unless neurological examination or admission, if needed, can be arranged promptly at a suitably equipped and staffed alternative facility and these arrangements have been discussed and agreed to by the Ionis Medical Monitor b. Adequately supportive psychosocial circumstances, in the opinion of the Investigator c. Caregiver/trial partner committed to facilitate patient*s involvement in the study who is reliable, competent, at least 18 years of age, willing to accompany the participant to select study visits and to be available to the Study Center by phone if needed and who, in the opinion of the Investigator, is and will remain sufficiently knowledgeable of the patient*s ongoing condition to respond to Study Center inquiries about the patient, such as providing information related to study outcome measures requiring caregiver input d. Adequate visual and auditory acuity for neuropsychological testing 10. Able to read at a level necessary to complete study assessments 11. No evidence or prior diagnosis of general learning disability 12. Females must be non-pregnant, non-lactating and either surgically sterile (e.g., bilateral tubal occlusion, hysterectomy, bilateral salpingectomy, bilateral oophorectomy) or post-menopausal (defined as 12 months of spontaneous amenorrhea without an alternative medical cause and FSH levels in the post-menopausal range for the laboratory involved) 13. Males must be surgically sterile, abstinent or, if engaged in sexual relations with a female of child-bearing potential, must agree to use an acceptable contraceptive method (refer to Section 6.3.1) from the time of signing the informed consent form until at least 13 weeks after the last dose of Study Drug (ISIS 814907 or placebo) or end of the study, whichever is longer, Part 2: 1. Able to read, understand, and provide written informed consent (signed and dated) 2. Able and willing to meet all study requirements in the opinion of the Investigator, including: a. Adequately supportive psychosocial circumstances b. Caregiver/trial partner committed to facilitate patient's involvement in the study who is reliable, competent, at least 18 years of age, willing to accompany the participant to select study visits, and to be available to t
Exclusion criteria
Exclusion criteria: Part 1: 1. First or second degree family member among the investigational or Sponsor staff directly involved in the trial 2. Any contraindication or unwillingness to undergo MRI scanning (e.g., metal implants including MRI incompatible IUDs, claustrophobia, agitation or tremor of a severity that precludes MRI scans) 3. Any contraindication or unwillingness to undergo LP 4. Patient receives daily nursing care due to cognitive condition 5. Evidence of clinically-relevant neurological disease other than the disease being studied, including a. Cerebrovascular disease (history of TIA, stroke, significant vascular disease [large vessel stroke, diffuse white matter hyperintensities {WMHs}, multiple lacunes, bilateral thalamic lesions, and/or > 5 microhemorrhages on brain MRI] or modified 8-item Hachinski Ischemia Scale score >= 4) i. In addition to microhemorrhages, the degree of WMH severity will be centrally rated on T2 FLAIR and GRE T2 star images using the Age Related White Matter Changes (ARWMC) scale (e.g., WMHs > 5 mm, rated on a 4-point scale ranging from 0 (no lesions) to 3 (diffuse involvement of the entire region), within 5 regions in each hemisphere; a score of 3 in a region constitutes the presence of diffuse WMH) ii. Multiple lacunes are rated as the presence of at least 2 lacunes in the basal ganglia and at least 2 lacunes in the frontal white matter. To meet the criterion for the presence of bilateral thalamic lesions, at least 1 lesion must to be present in each thalamus. b. Current infectious/metabolic/systemic diseases affecting CNS c. History of a serious infectious disease affecting the brain in the 5 years prior to Screening d. History of clinically-significant head trauma (i.e., any loss of consciousness for > 5 minutes), including motor vehicle accident and/or concussion in the 3 years prior to Screening e. MRI scan at Screening shows evidence for a potential alternative etiology for dementia (i.e., non-AD etiology) f. History of generalized seizures in the 3 years prior to Screening 6. Psychiatric diagnosis/symptoms interfering with assessment of cognition a. Attempted suicide, suicidal ideation with a plan that required hospital admission and/or change in level of care within 6 months prior to Screening. For patients with (i) a suicide ideation score >= 4 on the Columbia Suicide Severity Rating Scale (C SSRS) within the last 6 months, or (ii) suicidal behaviors within the last 6 months (as measured by the answer *Yes* on any of the C-SSRS Suicidal Behavior Items, a risk assessment should be done by an appropriately-qualified mental health professional (e.g., a Psychiatrist or licensed Clinical Psychologist) to assess whether it is safe for the patient to participate in the study. Patients deemed by the Investigator to be at significant risk of suicide should be excluded b. Major depressive episode within 6 months prior to Screening (with the exception of patients in remission on allowed concomitant antidepressant medication) or at risk for psychosis, confusional state or violent behavior in the opinion of the Investigator c. Geriatric Depression Scale Short Form > 6 d. History of alcohol or drug dependency/abuse within 3 years prior to Screening 7. Clinically-significant cardiac conditions including cardiac failure, angina or previou
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Patient safety will be monitored closely during the study by the Investigator and the FSMG. Further oversight of compliance with study safety procedures will be provided by the Ionis Medical Monitor. Safety and tolerability evaluations include: • Physical examination and standard neurological assessment (including fundi) • Vital signs (Heart Rate, Blood Pressure, orthostatic changes, weight) • ECG • AEs and concomitant medications • Columbia Suicide Severity Rating Scale (C-SSRS) • CSF safety labs (cell counts, protein, glucose) • Plasma laboratory tests (clinical chemistry, hematology) • Urinalysis • Neuroimaging assessments will be conducted using a 3T MRI scanner, and safety scans must be reviewed locally by a trained neuroradiologist: - Safety MRI sequences (GRE T2 star, T2 FLAIR, T2 FSE/TSE, DWI) at Screening and Study Day 169/Week 25 Clinical and volumetric neuroimaging measures will be used to monitor for unexpected deterioration. | — |
Secondary
| Measure | Time frame |
|---|---|
| (1) Pharmacokinetic Evaluations (2) Exploratory Evaluations: - Biochemical: Potential CSF and blood/plasma biomarkers include, but are not limited to neuronal and synaptic injury markers, innate immune activation markers, complement components and lipid-related biomarkers - Neuroimaging: o Structural MRI (hippocampal, whole brain and ventricular volumes) o Arterial Spin Labelling (ASL) o FDG-PET (Cohorts C and D only) - Functioning/ability to perform activities of daily living: Functional Activities Questionnaire (FAQ) - Cognitive: Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and Mini-mental state examination (MMSE) - Neuropsychiatric: Neuropsychiatric Inventory - Questionnaire (NPI-Q) | — |
Countries
Netherlands
Outcome results
None listed