A Study to Evaluate the Efficacy and Safety of Semorinemab in Patients With Prodromal to Mild Alzheimer's Disease

Study Overview
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Brief Summary
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This was a phase II, randomized, placebo-controlled, double-blind study to evaluate the efficacy and safety of Semorinemab in participants with prodromal to mild Alzheimer's disease. An optional 96-week open-label extension period was available to participants who completed the double-blind treatment period and who, in the judgment of the investigator, would potentially benefit from open-label Semorinemab treatment.

Official Title
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A Phase II, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Efficacy, and Safety Study of MTAU9937A in Patients With Prodromal to Mild Alzheimer's Disease

Conditions
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Alzheimer's Disease

Intervention / Treatment
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* Drug: Semorinemab
* Drug: Placebo
* Drug: [18F]GTP1


Participation Criteria
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Eligibility Criteria
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Inclusion criteria Age between 50 and 80 years National Institute on Aging/Alzheimer's Association core clinical criteria for probable Alzheimer's disease (AD) dementia or mild cognitive impairment (prodromal AD) Evidence of the AD pathological process, by a positive amyloid assessment either on cerebrospinal fluid Aβ1-42 OR amyloid positron emission tomography (PET) scan. Historical amyloid PET scans may be accepted in some cases Mild AD symptomatology, as defined by a screening Mini-Mental State Examination score of >= 20 points and Clinical Dementia Rating (CDR) -Global Score of 0.5 or 1 Abnormal memory function at screening Availability of a person with sufficient contact with the participant to be able to provide accurate information on the participant's cognitive and functional ability Exclusion criteria Pregnant or breastfeeding Inability to tolerate magnetic resonance imaging (MRI) procedures or contraindication to MRI Contraindications to both PET imaging and lumbar dural puncture (must be able to undergo at least one of these procedures to be eligible) Residence in a skilled nursing facility Any serious medical condition or abnormality in clinical laboratory tests that remains abnormal on retest and, in the investigator's judgment, precludes the patient's safe participation in and completion of the study, or bias the assessment of the clinical or mental status of the participant to a significant degree Any evidence of a condition other than AD that may affect cognition Alcohol or substance abuse within the past 2 years Use of any experimental therapy within 90 days or 5 half-lives prior to screening, whichever is greater and any passive immunotherapy (immunoglobulin) against tau, except use of RO7105705 in Genentech Study GN39058, as long as the last dose was at least 90 days prior to screening Use of any passive immunotherapy (immunoglobulin) against Aβ, unless the last dose was at least 1 year prior to screening and any active immunotherapy (vaccine) that is under evaluation to prevent or postpone cognitive decline Any previous treatment with medications specifically intended to treat Parkinsonian symptoms or any other neurodegenerative disorder within 1 year of screening Systemic immunosuppressive therapy within 12 months of screening through the entire study period Typical antipsychotic or neuroleptic medication within 6 months of screening Daily treatment with any of the following classes of medication, except for intermittent short-term use, which is permitted except within 2 days or 5 half-lives (whichever is longer) prior to any COA: atypical antipsychotics, opiates or opioids, benzodiazepines, barbiturates, hypnotics, or any medication with clinically significant centrally-acting antihistamine or anticholinergic activity Stimulant medications, unless the dose has been stable within the 6 months prior to screening and is expected to be stable throughout the study

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose 1 Semorinemab<br> | Drug: Semorinemab<br>* Participants will receive Semorinemab intravenously (IV).<br>* Other names: RO7105705;Drug: [18F]GTP1<br>* [18F]GTP1 will be administered as a solution for intravenous (IV) use, as part of positron emission tomography (PET) imaging.<br>* Other names: RO6880276;|
| Experimental: Dose 2 Semorinemab<br> | Drug: Semorinemab<br>* Participants will receive Semorinemab intravenously (IV).<br>* Other names: RO7105705;Drug: [18F]GTP1<br>* [18F]GTP1 will be administered as a solution for intravenous (IV) use, as part of positron emission tomography (PET) imaging.<br>* Other names: RO6880276;|
| Experimental: Dose 3 Semorinemab<br> | Drug: Semorinemab<br>* Participants will receive Semorinemab intravenously (IV).<br>* Other names: RO7105705;Drug: [18F]GTP1<br>* [18F]GTP1 will be administered as a solution for intravenous (IV) use, as part of positron emission tomography (PET) imaging.<br>* Other names: RO6880276;|
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* Matching placebo doses of Semorinemab given intravenously (IV).<br>Drug: [18F]GTP1<br>* [18F]GTP1 will be administered as a solution for intravenous (IV) use, as part of positron emission tomography (PET) imaging.<br>* Other names: RO6880276;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline on the CDR-SB | The Clinical Dementia Rating-Sum of Boxes (CDR-SB) rates impairment in 6 categories (memory, orientation, judgement and problem solving, community affairs, home and hobbies and personal care) on a 5-point scale in which no impairment = 0, questionable impairment = 0.5 and mild, moderate and severe impairment = 1, 2 and 3 respectively. The score range is from 0 to 18 with a high score indicating a high disease severity. The difference in mean change from Baseline to Week 73 between Semorinemab doses and Placebo treated participants was estimated. The difference in mean change from Baseline to Week 73 between Semorinemab doses and Placebo treated participants was estimated. | Baseline and 73 Weeks | 
| Percentage of Participants With Adverse Events | Percentage of participants with at least one adverse event | Up to the data cutoff date 15 January 2021 (up to approximately 39 months) | 
| Change From Baseline on the C-SSRS | Categories are as defined in the Classification Algorithm for Suicide Assessment (CASA) based on the Columbia Suicide Severity Rating Scale (C-SSRS) questionnaire. SI1: Passive category is Wish to be dead, SI2: Active-Nonspecific (no method, intent or plan), SI3: Active-Method, but no intent or Plan, SI4: Active-Method and intent, but no plan in C-SSRS. The worst post-baseline suicidal ideation is the highest across post-baseline visits, with highest as SI5 and lowest as SI1. Percentages are based on the total number of subjects in a treatment group. Baseline is the last observation prior to initiation of study drug. | Baseline to data cutoff date 15 January 2021 (up to approximately 39 months) | 
| Other Abnormal MRI Findings | Other abnormal MRI findings by visit. For the Double Blind Period, baseline is defined as last results prior to initiation of study drug. For the Open Label Extension Period, baseline is defined as last results prior to entering the open label period. | Baseline, Week 9, Week 49, Week 73, Study Treatment Discontinuation, and Week 89 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline on the Repeatable Battery for Assessment of Neuropsychological Status (RBANS) | The RBANS is a validated neuropsychological assessment has been shown to be a useful tool in both clinical and research settings. The RBANS consists of ten subtests that are combined to provide five indices, one for each of the five domains tested (immediate memory, visuospatial/constructional, language, attention, and delayed memory). Scores range from 40 to 160 and a higher score indicates better cognitive functioning. A decrease in the outcome measure from baseline corresponds to disease worsening. The difference in mean change from Baseline to Week 73 between Semorinemab doses and Placebo treated participants was estimated. | Baseline and 73 weeks | 
| Change From Baseline on the Alzheimer's Disease Assessment Scale-Cognitive Subscale 13 (ADAS-Cog-13) Subscale Score | The ADAS-Cog-13 assesses multiple cognitive domains including memory, comprehension, praxis, orientation, and spontaneous speech. Most of these are assessed by tests although some are rated by the clinician on a 5-point scale. The ADAS-Cog-13 is the ADAS-Cog-11 with 2 further items: delayed word recall and total digit cancellation. The score range for ADAS-Cog-13 is from 0 to 85 with high scores representing severe dysfunction. The difference in mean change from Baseline to Week 73 between Semorinemab doses and Placebo treated participants was estimated. | Baseline and 73 weeks | 
| Change From Baseline on the Amsterdam Instrumental Activity of Daily Living (iADL) Questionnaire | The Amsterdam iADL questionnaire is an informant-based instrument for measuring iADL problems in participants with dementia. This instrument consists of 70 items, scored on a 5-point scale, that uses item response theory for scoring. Items presented to the informant are tailored to responses to earlier items; thus each administration of the Amsterdam iADL may consist of less than the total of 70 items. The resulting score ranges from 20 to 80 with lower scores indicating poorer performance. A decrease in the outcome measure from baseline corresponds to disease worsening. The difference in mean change from Baseline to Week 73 between Semorinemab doses and Placebo treated participants was estimated. | Baseline and 73 weeks | 
| Change From Baseline on the Alzheimer's Disease Cooperative Study Group-Activities of Daily Living Inventory | The ADCS-ADL (Alzheimer's Disease Cooperative Study-Activities of Daily Living) is the scale most widely used to assess functional outcomes in participants with AD. The ADCS-ADL covers both basic ADL (e.g., eating and toileting) and more complex 'instrumental' ADL or iADL (e.g., using the telephone, managing finances and preparing a meal). The ADCS-ADL consists of 23 questions with a score range of 0 to 78 where a higher score represents better function. The difference in mean change from Baseline to Week 73 between Semorinemab doses and Placebo treated participants was estimated. | Baseline and 73 weeks | 
| Serum Concentrations of Semorinemab at Specified Timepoints | Serum concentrations of Semorinemab at specified timepoints. | Up to 109 weeks | 
| Presence of Anti-drug Antibodies During the Study Relative to Their Presence at Baseline | Presence of anti-drug antibodies during the study relative to their presence at baseline. | Up to 109 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Alzheimer Disease, Brain Diseases, Dementia, Neurodegenerative Diseases, Neurocognitive Disorders