Study of Daratumumab in Patients With Mild to Moderate Alzheimer's Disease

Study Overview
=================
Brief Summary
-----------------
This is an open-label, pilot study designed to explore whether daratumumab may have a clinically meaningful effect in patients with mild to moderate Alzheimer's disease.

Detailed Description
-----------------
Daratumumab is a human antibody that targets CD38. It is FDA-approved for the treatment of multiple myeloma, has broad-ranging immunomodulatory effects on nonplasma cells that express CD38, and is able to cross the blood-brain barrier. CD38 expression on CD8+ T-cells is significantly increased in the blood of early AD patients as compared with age-matched controls, and activated T-cells are capable of trafficking into the central nervous system and exerting toxic effects. This study is designed to explore whether treatment with Daratumumab may have a clinically meaningful effect on patients with mild to moderate Alzheimer's disease.

Official Title
-----------------
An Open-Label, Pilot Study of Daratumumab SC in Patients With Mild to Moderate Alzheimer's Disease

Conditions
-----------------
Alzheimer Disease

Intervention / Treatment
-----------------
* Drug: Daratumumab Injection


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Each subject must be ≥ 55 to ≤ 85 years of age at the screening visit. Each subject must have a diagnosis of probable AD dementia according to National Institute on Aging-Alzheimer's Association (NIA-AA) criteria. Each subject must have a Mini-Mental State Examination (MMSE) score ≥ 15 and ≤ 26 at the screening visit. Each subject must have a Magnetic Resonance Imaging (MRI) scan performed during the screening period that is consistent with a diagnosis of AD. Each subject must have a positive amyloid Positron Emission Tomography (PET) scan, either performed during the screening period, or previously performed provided that the scan and result are considered acceptable by the investigator. If the subject is receiving a cholinesterase inhibitor (donepezil, rivastigmine, or galantamine) and/or memantine, the dose must have been stable for at least 12 weeks before the screening visit, and the subject must be willing to remain on the same dose for the duration of the trial. Each subject must have a study partner who is reliable and competent. The study partner must have a close relationship with the subject, have face to face contact at least 3 days/week for a minimum of 6 waking hours/week, and be willing to accompany the subject to all required study visits. Each subject must have no clinically significant abnormal laboratory test results [complete blood count (CBC), prothrombin time (PT)/international normalized ratio (INR), activated partial thromboplastin time (APTT), comprehensive metabolic panel (CMP), thyroid stimulating hormone (TSH), and vitamin B12 level] at the screening visit. Each subject must have results of a physical and neurological examination and vital signs within normal limits or clinically acceptable to the investigator at the screening visit. If female, the subject must be postmenopausal defined as: No menses for 12 or more months without an alternative medical cause OR permanently surgically sterile (bilateral oophorectomy, bilateral salpingectomy, or hysterectomy). Exclusion Criteria: The subject has a Rosen-modified Hachinski Ischemia Score > 4 at the screening visit. The subject has a known history of stroke or evidence from screening MRI that is clinically significant in the investigator's opinion. The subject has evidence of a clinically relevant neurological disorder other than probable AD at the screening visit, including: vascular dementia, Parkinson's disease, dementia with Lewy bodies, frontotemporal dementia, progressive supranuclear palsy, corticobasal degeneration, amyotrophic lateral sclerosis, Huntington's disease, multiple sclerosis, mental retardation, hypoxic cerebral damage, or head trauma with loss of consciousness that led to persistent cognitive deficits. The subject has evidence of a clinically relevant or unstable psychiatric disorder, based on DSM-5 criteria, including schizophrenia or other psychotic disorder, bipolar disorder, delirium, or major depression. (Major depression in remission is not exclusionary.) A score on the 15-item Geriatric Depression Scale (GDS) of 5 or more requires an assessment by an appropriate health care professional to evaluate for the presence of major depression. Subjects with a score of 5 or more who are not diagnosed with major depression following such an assessment may be included in the trial. The subject has a history of alcoholism or drug dependency/abuse within the last 5 years before screening. The subject has been treated with any investigational product within 60 days or 5 half-lives (whichever is longer) prior to the screening visit. The subject has been treated with anti-amyloid-beta or anti-tau protein monoclonal antibodies within one year prior to the screening visit. The subject has been treated with an active vaccine targeting amyloid-beta or tau protein. The subject has received a live/live-attenuated bacterial or viral vaccine within 3 months prior to the screening visit. The subject has been treated with immunosuppressive medications, such as azathioprine, cyclosporine, methotrexate, tacrolimus, or mycophenylate, within 2 months prior to the screening visit. The subject has been treated with a course of corticosteroids longer than 5 days within 2 months prior to the screening visit. The subject is taking or is anticipated to require treatment with estrogens. The subject is taking or is anticipated to require treatment with an anticoagulant medication, including warfarin, dabigatran, rivaroxaban, apixaban, edoxaban, heparin, or enoxaparin. The subject is taking or is anticipated to require treatment with aspirin at a dose higher than 325 mg daily. The subject has a history of asthma or chronic obstructive pulmonary disease. The subject has had a myocardial infarction, unstable angina, stroke, transient ischemic attack or required intervention for any of these conditions (e.g., coronary artery bypass graft, percutaneous coronary intervention via cardiac catheterization, thrombolytic therapy) within 6 months prior to the screening visit. The subject has had an infection requiring medical intervention within 30 days prior to the screening visit. The subject has serologic evidence of current or prior hepatitis B virus (HBV) infection based on hepatitis B surface antigen or hepatitis core antibody blood tests at the screening visit. The subject has serologic evidence of hepatitis C virus (HCV) infection based on hepatitis C antibody blood test at the screening visit. The subject has serologic evidence of human immunodeficiency virus (HIV) infection based on HIV antigen/antibody test at the screening visit. The subject has a platelet count less than 50,000 per microliter (mL) at the screening visit. The subject has a creatinine clearance less than 30 mL/minute at the screening visit. The subject has a history or evidence of a malignancy (except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or localized prostate carcinoma) within the 2 years prior to the screening visit. The subject has had any other unstable/uncontrolled medical illness within 12 weeks prior to the screening visit such that, in the judgment of the investigator, participation in the trial would pose a significant medical risk to the subject. The subject has significant visual or auditory impairment, or limited English proficiency, that in the investigator's opinion would preclude collection of outcome measures. The subject has any contraindication to or inability to tolerate brain MRIs (e.g., a pacemaker or any other implanted device or condition that would preclude proximity to a strong magnetic field). The subject has any contraindication to or inability to tolerate a PET scan (includes current or recent participation in any procedures involving radioactive agents such that the total radiation dose exposure to the subject in any given year would exceed acceptable limits of annual and total dose). The subject has a history of allergy to dexamethasone, diphenhydramine, acetaminophen, montelukast, or acyclovir.

Ages Eligible for Study
-----------------
Minimum Age: 55 Years
Maximum Age: 85 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Open-label treatment group.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Open-label Treatment<br>This is an open-label pilot study designed to explore whether daratumumab may have a clinically meaningful effect in patients with mild to moderate Alzheimer's disease. During the treatment phase, eligible subjects will receive daratumumab SC 1800 mg (daratumumab 1800 mg with rHuPH20 30,000 units) subcutaneous infusion over 3-5 minutes (15 mL) once weekly for 8 weeks followed by daratumumab SC 1800 mg every 2 weeks for 16 weeks. | Drug: Daratumumab Injection<br>* Daratumumab SC 1800 mg (daratumumab 1800 mg with rHuPH20 30,000 units) subcutaneous infusion<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With an Improvement of ≥ 4 Points on the ADAS-cog/11 | The standard 11-item version of the Alzheimer's Disease Assessment Scale, cognitive subscale score (ADAS-cog/11) includes both subject-completed tests and observer-based assessments. Specific tasks include Word Recall, Naming Objects and Fingers, Commands, Constructional Praxis, Ideational Praxis, Orientation, Word Recognition, and Language. The score ranges from 0 to 70 with each point representing a performance error and higher scores reflecting worse performance. An improvement (decrease) of ≥ 4 points in ADAS-cog/11 score has been deemed to be clinically meaningful. | 25 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Number of Subjects Who Are Unchanged or Improved From Baseline on ADAS-cog/12 Score | The 12-item version of the Alzheimer's Disease Assessment Scale, cognitive subscale (ADAS-Cog/12) adds a delayed word recall task, scored from 0 to 10. The ADAS-Cog/12 score is the total of the ADAS-Cog/11 plus the delayed recall score, and therefore has a range of 0 to 80. Higher scores reflect worse performance. | 25 weeks | 
| The Number of Subjects Who Are Unchanged or Improved From Baseline on the MMSE | The Mini-Mental State Examination (MMSE) is a 30-point scale that measures orientation to time and place, registration, immediate and delayed recall, attention, language, and drawing. Scores range from 0 (most impaired) to 30 (no impairment). | 25 weeks | 
| The Number of Subjects Who Are Unchanged or Improved From Baseline on the CDR-SB | The Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) is a clinical global rating scale requiring the interviewing of both the subject and a study partner who knows and has contact with the subject. The CDR-SB is a clinician-directed assessment of both cognition and function, and is intended to capture the state and therefore the disease stage of the individual. The range of scores is from 0-18, with higher scores being worse. | 25 weeks | 
| The Number of Subjects Who Are Unchanged or Improved From Baseline on the ADCOMS | The AD Composite Score (ADCOMS) is derived from a weighted combination of selected items from the ADAS-cog/12, MMSE, and CDR-SB. The range of the ADCOMS is between 0 and 1.97. A higher score is indicative of greater impairment. | 25 weeks | 
| Treatment Emergent Adverse Effects | The proportion of subjects with treatment-emergent adverse effects from initial treatment through final follow-up study visit. | 35 weeks | 
| Treatment Emergent Serious Adverse Effects | The proportion of subjects with treatment-emergent serious adverse effects from initial treatment through final follow-up study visit. | 35 weeks |