A Study of MP-101 in Dementia-Related Psychosis and/or Agitation and Aggression

Study Overview
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Brief Summary
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A ten-week study to assess MP-101 in Dementia-Related Psychosis and/or Agitation and Aggression

Official Title
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Tolerability, Pharmacokinetics, and Efficacy of MP-101 in the Treatment of Patients With Dementia-Related Psychosis and/or Agitation and Aggression

Conditions
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Psychosis, Dementia, Aggression, Agitation, Alzheimer Dementia

Intervention / Treatment
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* Drug: MP-101
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Females must be of non-childbearing potential, defined as women greater than or equal to (≥) 60 years of age, postmenopausal women ≥50 and less than (<) 60 years of age who have had a cessation of menses for at least 12 months, or women who are congenitally or surgically sterile Males must agree to use 2 forms of highly effective birth control with female partners of childbearing potential while enrolled in the study, and for at least 28 days following the last dose Ambulatory (with or without walking device) with a stable gait Have a Mini-Mental State Examination (MMSE) score of 10 to 24 Meet clinical criteria for one of the following disorders: dementia associated with Parkinson's disease, dementia with Lewy bodies, possible or probable Alzheimer's disease, frontotemporal degeneration spectrum disorders, vascular dementia Able to communicate verbally Have an NPI score of ≥4 on either individual item (delusions or hallucinations) or ≥6 on the Psychosis Subscale (combined delusions and hallucinations), or an NPI score of ≥4 on agitation/aggression domain Have a reliable caregiver who provides written informed consent to participate and who is in frequent contact with the patient (defined as spending at least 4 hours/day at least 4 days/week with the patient and who is knowledgeable about the patient's daytime and nighttime behaviors). The caregiver must be able to communicate with site personnel, and opinion of the investigator, must understand the written protocol-specified questionnaires. If a caregiver cannot continue, one replacement caregiver will be allowed if the above criterion is met Must be on a stable dose of cholinesterase inhibitor and/or memantine, if applicable If taking antipsychotic drugs or any drug intended to treat psychosis, must be on a stable treatment regimen for ≥1 month prior to the study Have venous access sufficient to allow for blood sampling per the protocol Have clinical laboratory test results within normal reference range for the population or investigative site Are capable of participating in all study assessments Are able and willing to provide consent (patients and caregivers) Exclusion Criteria: Have a history of significant psychotic disorders (including, schizophrenia, delusional disorder, substance abuse psychosis that lasted over 6 months, major depressive disorder or bipolar disorder with psychotic episodes) Has a history of ischemic stroke within the last 12 months or any evidence of hemorrhagic stroke Have renal impairment as defined by Estimated Glomerular Filtration Rate (eGFR) <45 milliliters per minute per 1.73 square meters (ml/min/1.73m2) Have significant cardiovascular, respiratory, gastrointestinal, renal, hematologic, or oncologic comorbidities that could impact patient safety and study participation over 10 weeks Have a history of seizures or other condition that would place the patient at increased risk of seizures. Are, in the investigator's judgment, at risk for suicide, or as indicated by the Columbia Suicide Severity Rating Scale (C-SSRS) Have a Fridericia's corrected QT interval (QTcF) greater than (>) 450 milliseconds (ms) for males or 470 ms for females Are currently enrolled in any other clinical trial involving an investigational product or any other type of medical research judged not to be scientifically or medically compatible with this study Have participated, within the last 30 days, in a clinical trial involving an investigational product. If the previous investigational product has a long half-life, at least 3 months (or more) must have passed In the opinion of the investigator or sponsor, are unsuitable for inclusion in the study

Ages Eligible for Study
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Minimum Age: 50 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: MP-101<br>Week 0: Participants received 20 milligrams (mg) MP-101 orally QD (1 x 20-mg caps) and 2 placebo caps. Week 1: Participants received 40 mg MP-101 orally QD (2 x 20-mg caps) and 1 placebo caps. Week 2 through Week 9: Participants received 60 mg MP-101 orally QD (3 x 20-mg caps ). | Drug: MP-101<br>* Capsules<br>* Other names: LY2812223;|
| Placebo Comparator: Placebo<br>Participants received 3 capsules (caps) of placebo orally once daily (QD) during Week 0, Week 1, and Week 2 through Week 9. | Drug: Placebo<br>* Capsules<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With 30% Improvement From Baseline in the Neuropsychiatric Inventory (NPI) - Psychosis Subscale or Aggression/Agitation Subscale Score | The NPI is a questionnaire that quantifies behavioral changes in dementia. For each of 12 domains there are 4 scores: Frequency (scale:1=occasionally to 4=very frequently), Severity (scale:1=Mild to 3=Severe), Total (frequency x severity), Caregiver distress (scale: 0=not at all distressing to 5=extremely distressing). An NPI response was defined as at least a 30% improvement from baseline on the NPI Psychosis sub-score (for participants with a psychosis diagnosis (Delusions and Hallucinations)) or the NPI Aggression/Agitation sub-score (for participants with an agitation/aggression diagnosis). The delusions, hallucinations, and aggression/agitation domain scores were added together to form a core total score with score range of 0 to 36. Lower score=less severity. A negative change score from baseline indicates improvement. | Week 10 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Improvement From Baseline in the Clinical Global Impression of Improvement (CGI-I) at Week 10 | The CGI rating scale, which measures symptom severity, treatment response and the efficacy of treatments, is used in clinical studies on mental disorders. CGI Improvement scale is a 7 point scale that requires the clinician to assess how much the participant's illness has improved or worsened relative to a baseline state at the beginning of the intervention: 1=very much improved; 2=much improved; 3=minimally improved; 4=no change; 5=minimally worse; 6=much worse; 7=very much worse. | Week 10 | 
| Change From Baseline in NPI Total Score | The NPI is a questionnaire that quantifies behavioral changes in dementia. For each of 12 domains there are 4 scores: Frequency (scale: 1=occasionally to 4=very frequently), Severity (scale:1=Mild to 3=Severe), Total (frequency x severity), Caregiver distress (scale: 0=not at all distressing to 5=extremely distressing). The NPI Total Score is calculated by adding the Individual Item Scores for all 12 domains, to yield a possible NPI Total Score of 0 to 144. Lower score=less severity. A negative change score from baseline indicates improvement. | Baseline, Week 10 | 
| Change From Baseline in NPI Core Total Score | The NPI is a questionnaire that quantifies behavioral changes in dementia. For each of 12 behavioral domains there are 4 scores: Frequency (scale: 1=occasionally to 4=very frequently), Severity (scale:1=Mild to 3=Severe), Total (frequency x severity), Caregiver distress (scale: 0=not at all distressing to 5=extremely distressing). The NPI CoreTotal Score is calculated by adding the Individual Item Scores for all 3 domains (hallucinations, delusions, and agitation/aggression) to yield a possible NPI Core Total Score of 0 to 36. Lower score=less severity. A negative change score from baseline indicates improvement. | Baseline, Week 10 | 
| Number of Participants With NPI Caregiver Distress | The NPI is a questionnaire that quantifies behavioral changes in dementia. For each of 12 domains there are 4 scores: Frequency (scale:1=occasionally to 4=very frequently), Severity (scale:1=Mild to 3=Severe), Total (frequency x severity), Caregiver distress (scale:0=not at all distressing to 5=extremely distressing). The NPI Psychosis Subscale Caregiver Distress Score is calculated by adding Individual Item Scores for the domains of Delusions and Hallucinations, to yield a possible total score of 0 to 10. Lower score=less severity. A negative change score from baseline=improvement. | Week 10 | 
| Change From Baseline in NPI Domains - Anxiety | The 12 individual items in NPI that quantify changes in dementia are delusions, hallucinations, agitation, depression, anxiety, apathy, disinhibition, irritability, euphoria, aberrant motor behavior, nighttime behaviors, and appetite. For each of 12 behavioral domains there are 4 scores: Frequency (scale:1=occasionally to 4=very frequently), Severity (scale:1=Mild to 3=Severe), Total (frequency x severity), Caregiver distress (scale: 0=not at all distressing to 5=extremely distressing). The NPI Psychosis Subscale Anxiety consists of anxiety item to yield a possible NPI Score of 0 to 12. Lower score=less severity. A negative change score from baseline indicates improvement. | Baseline, 10 Weeks | 
| Number of Participants With Any Treatment Emergent Adverse Event | Number of participants with untoward medical occurrences that emerge during the treatment period, having been absent pretreatment, or worsen relative to the pretreatment state, which do not necessarily have a causal relationship with this treatment. A summary of serious adverse events (SAEs) and other non-serious adverse events (AEs) is located in the reported adverse events module. | Baseline Up to 10 Weeks | 
| Change From Baseline in the Unified Parkinson's Disease Rating Scale (UPDRS) Part III | Part III of the UPDRS is an investigator-scored scale used to assess the motor symptoms of patients with Parkinson's disease. The investigator rates the patient on 14 items based on observation or the performance of a task the patient performs (even in the context of any comorbidities) on a 5-point scale. The scores range from 0 to 4, with higher scores indicating greater impairment. The total UPDRS score was calculated as the sum of all items, ranging from 0 to 56 with higher scores indicating greater impairment. If any individual item was missing, the UPDRS score was be set to missing. | Baseline, Week 10 | 
| Population Pharmacokinetics (PK): Plasma Levels of MP-101 and Metabolite | Summary statistics of sparse blood concentration samples at weeks 2, 4, 6, 10 and Early Termination obtained utilizing a population PK approach. | Week 2: 4-8 hours post-dose; Week 4: Predose, 0-2 hours postdose; Week 6: 8-12 hours postdose; Week 10: 2- 4 hours;Early Termination | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Psychotic Disorders