Study to Assess the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Efficacy of TB006 in Participants With Alzheimer's Disease

TrueBinding, Inc.154 enrolled

Overview

Part 1 of this study will be conducted to determine the safety, tolerability, and pharmacokinetic (PK) profile of multiple doses of TB006, as well as the maximum tolerated dose of TB006, and to assess the immunogenicity of TB006 (production of anti-TB006 antibody). Part 2 of this study will be conducted to determine the clinical efficacy of TB006 in participants with mild to severe Alzheimer's Disease.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

TRIPLE

Enrollment

154

Conditions

Alzheimer's Disease

Interventions

TB006DRUG

intravenous infusion

PlaceboDRUG

intravenous infusion

Eligibility

Sex: ALLMin age: 50 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Body weight of ≥ 50 kilograms (kg) and body mass index (BMI) between 18 and 35 kg/meters squared (m\^2), inclusive * Mini-Mental State Examination (MMSE) score of 24 or less * Must be ambulatory * Clinical diagnosis of Alzheimer's Disease (AD) consistent with the following: 1. Probable AD, according to National Institute of Neurological and Communicative Disorders and Stroke - Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) 2. Meets the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) - Criteria for Major Neurocognitive Disorder (previously dementia) * Participants or caregiver has the ability to understand the purpose and risks of the study and provide signed and dated informed consent which includes compliance with the requirements and restrictions listed in the inform consent form (ICF) and in this protocol. Participants whose caregiver signs the informed consent must provide their assent. Exclusion Criteria: * Any medical or neurological condition other than AD that in the opinion of the investigator could be a contributing cause of the participant's dementia (e.g., medication use, vitamin B12 deficiency, abnormal thyroid function, stroke or other cerebrovascular condition, diffuse Lewy body disease, head trauma) * History within the past 6 months or evidence of clinically significant psychiatric illness (e.g., major depression, schizophrenia, or bipolar affective disorder) * Diagnosis of a dementia-related central nervous system (CNS) disease other than AD (e.g., Parkinson's Disease, Huntington's Disease, frontotemporal dementia, multi-infarct dementia, dementia with Lewy bodies, normal pressure hydrocephalus) * Identification of other known cause of dementia or any other clinically significant contributing co-morbid pathologies at screening magnetic resonance imaging (MRI), in the opinion of the investigator * Participation in any other drug, biologic, device, or clinical study or treatment with any investigational drug or approved therapy for investigational use within 30 days (or 5 half lives, whichever is longer) prior to screening, and/or participation in any other clinical study involving experimental medications for AD within the 60 days (or 5 half lives, whichever is longer) prior to screening

Locations (18)

Clinical Trial Site

Garden Grove, California, United States

Clinical Trial Site

San Diego, California, United States

Outcomes

Primary Outcomes

Part 1: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)

An adverse event is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. An SAE is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, is a congenital anomaly/birth defect, associated with liver injury and impaired liver function or any other situations as per medical or scientific judgement.

Time frame: Up to Day 104

Part 1: Change From Baseline in Clinical Chemistry Parameters: Alanine Aminotransferase (ALT), Alkaline Phosphatase (ALP), Aspartate Aminotransferase (AST) and Creatine Kinase (CK)

Blood samples were collected for analysis of following clinical chemistry parameters including ALT, ALP, AST and CK. Baseline was defined as Day 1. Change from Baseline was obtained by subtracting Baseline value from post-dose visit value.

Time frame: Baseline and up to Day 104

Part 1: Change From Baseline in Clinical Chemistry Parameters: Albumin and Protein

Blood samples were collected for analysis of following clinical chemistry parameters including albumin and protein. Baseline was defined as Day 1. Change from Baseline was obtained by subtracting Baseline value from post-dose visit value.

Time frame: Baseline and up to Day 104

Part 1: Change From Baseline in Chemistry Parameters: Calcium, Cholesterol, Creatinine, Direct Bilirubin, Glucose, HDL (High Density Lipoprotein) Cholesterol, LDL (Low Density Lipoprotein) Cholesterol, Total Bilirubin, Triglycerides and Urea Nitrogen

Blood samples were collected for analysis of following clinical chemistry parameters including Calcium, Cholesterol, Creatinine, Direct Bilirubin, Glucose, HDL Cholesterol, LDL Cholesterol, Total Bilirubin, Triglycerides and Urea Nitrogen. Baseline was defined as Day 1. Change from Baseline was obtained by subtracting Baseline value from post-dose visit value.

Data from ClinicalTrials.gov

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Clinical Trial Site

Delray Beach, Florida, United States

Clinical Trial Site

Lady Lake, Florida, United States

Clinical Trial Site #1

Maitland, Florida, United States

Clinical Trial Site

Maitland, Florida, United States

Clinical Trial Site

Miami, Florida, United States

Clinical Trial Site

Miami, Florida, United States

Clinical Trial Site

Miami, Florida, United States

Clinical Trial Site

Miami, Florida, United States

...and 8 more locations

Time frame: Baseline and up to Day 104

Part 1: Change From Baseline in Clinical Chemistry Parameter: Hemoglobin A1C

Blood samples were collected for analysis of following clinical chemistry parameters including Hemoglobin A1C. Baseline was defined as Day 1. Change from Baseline was obtained by subtracting Baseline value from post-dose visit value.

Time frame: Baseline and up to Day 104

Part 1: Change From Baseline in Clinical Chemistry Parameters: Potassium and Sodium

Blood samples were collected for analysis of following clinical chemistry parameters including Potassium and Sodium. Baseline was defined as Day 1. Change from Baseline was obtained by subtracting Baseline value from post-dose visit value.

Time frame: Baseline and up to Day 104

Part 1: Change From Baseline in Clinical Chemistry Parameter: Thyrotropin

Blood samples were collected for analysis of following clinical chemistry parameters including Thyrotropin. Baseline was defined as Day 1. Change from Baseline was obtained by subtracting Baseline value from post-dose visit value.

Time frame: Baseline and up to Day 104

Part 1: Change From Baseline in Hematology Parameters: Basophils, Eosinophils, Leukocytes, Lymphocytes, Monocytes, Neutrophils and Platelets

Blood samples were collected for analysis of following hematology parameters including Basophils, Eosinophils, Leukocytes, Lymphocytes, Monocytes, Neutrophils and Platelets. Baseline was defined as Day 1. Change from Baseline was obtained by subtracting Baseline value from post-dose visit value.

Time frame: Baseline and up to Day 104

Part 1: Change From Baseline in Hematology Parameter: Erythrocyte. Mean Corpuscular Hemoglobin (Ery. MCH)

Blood samples were collected for analysis of following hematology parameter: Ery. MCH. Baseline was defined as Day 1. Change from Baseline was obtained by subtracting Baseline value from post-dose visit value.

Time frame: Baseline and up to Day 104

Part 1: Change From Baseline in Hematology Parameter: Hematocrit

Blood samples were collected for analysis of following hematology parameter: Hematocrit. Baseline was defined as Day 1. Change from Baseline was obtained by subtracting Baseline value from post-dose visit value.

Time frame: Baseline and up to Day 104

Part 1: Change From Baseline in Hematology Parameter: Erythrocytes and Reticulocytes

Blood samples were collected for analysis of following hematology parameter: Erythrocytes and Reticulocytes. Baseline was defined as Day 1. Change from Baseline was obtained by subtracting Baseline value from post-dose visit value.

Time frame: Baseline and up to Day 104

Part 1: Change From Baseline in Hematology Parameter: Erythrocyte. Mean Corpuscular Volume (Ery. MCV)

Blood samples were collected for analysis of following hematology parameter: Ery. MCV. Baseline was defined as Day 1. Change from Baseline was obtained by subtracting Baseline value from post-dose visit value.

Time frame: Baseline and up to Day 104

Part 1: Change From Baseline in Hematology Parameter: Hemoglobin

Blood samples were collected for analysis of following hematology parameter: Baseline was defined as Day 1. Change from Baseline was obtained by subtracting Baseline value from post-dose visit value.

Time frame: Baseline and up to Day 104

Part 1: Change From Baseline in Urine Potential of Hydrogen (pH)

Urine samples were collected for analysis of Urine pH. Baseline was defined as Day 1. Change from Baseline was obtained by subtracting Baseline value from post-dose visit value.

Time frame: Baseline and up to Day 104

Part 1: Change From Baseline in Urine Specific Gravity

Urine samples were collected for analysis of Urine specific gravity. Baseline was defined as Day 1. Change from Baseline was obtained by subtracting Baseline value from post-dose visit value.

Time frame: Baseline and up to Day 104

Part 1: Change From Baseline in Urobilinogen

Urine samples were collected for analysis of Urobilinogen. Baseline was defined as Day 1. Change from Baseline was obtained by subtracting Baseline value from post-dose visit value.

Time frame: Baseline and up to Day 104

Part 1: Change From Baseline in Diastolic Blood Pressure (DBP) and Systolic Blood Pressure (SBP)

Vital signs including DBP and SBP was measured by at least 5 minutes of rest with the participant in a quiet setting without distractions (eg, television, cell phones). Blood pressure measurements were taken with the participant in the sitting position. Baseline was defined as the last available value prior to the participant receiving the first study drug infusion on Day 1. Change from Baseline was obtained by subtracting the Baseline value from post-dose visit value.

Time frame: Baseline and Up to Day 104

Part 1: Change From Baseline in Respiratory Rate

Vital signs including respiratory rate was measured by at least 5 minutes of rest with the participant in a quiet setting without distractions (eg, television, cell phones). Baseline was defined as the last available value prior to the participant receiving the first study drug infusion on Day 1. Change from Baseline was obtained by subtracting the Baseline value from post-dose visit value.

Time frame: Baseline and Up to Day 104

Part 1: Change From Baseline in Temperature

Vital signs including temperature was measured by at least 5 minutes of rest with the participant in a quiet setting without distractions (eg, television, cell phones). Baseline was defined as the last available value prior to the participant receiving the first study drug infusion on Day 1. Change from Baseline was obtained by subtracting the Baseline value from post-dose visit value.

Time frame: Baseline and Up to Day 104

Part 1: Change From Baseline in Heart Rate

Vital signs including heart rate was measured by at least 5 minutes of rest with the participant in a quiet setting without distractions (eg, television, cell phones). Baseline was defined as the last available value prior to the participant receiving the first study drug infusion on Day 1. Change from Baseline was obtained by subtracting the Baseline value from post-dose visit value.

Time frame: Baseline and Up to Day 104

Part 1: Change From Baseline in Electrocardiogram (ECG) Mean Heart Rate

12-lead ECG measurements was obtained using an ECG machine that automatically calculates the heart rate. Baseline was defined as the last available value prior to the participant receiving the first study drug infusion on Day 1. Change from Baseline was obtained by subtracting the Baseline value from post-dose visit value value.

Time frame: Baseline and Up to Day 104

Part 1: Change From Baseline in ECG Parameters

12-lead ECG measurements was obtained using an ECG machine that automatically calculates the PR interval, QRS duration, QT interval and QT Corrected using Bazett's formula (QTcB). Baseline was defined as the last available value prior to the participant receiving the first study drug infusion on Day 1. Change from Baseline was obtained by subtracting the Baseline value from post-dose visit value.

Time frame: Baseline and Up to Day 104

Part 1: Number of Participants With Suicidal Ideation or Suicidal Behavior as Measured Using Columbia Suicide Severity Rating Scale (C-SSRS)

The C-SSRS is an interview-based instrument to systematically assess suicidal ideation and suicidal behavior. Number of participants that have an affirmative response to the 5 items for suicidal ideation (1. Wish to be dead, 2. Non-specific active suicidal thoughts, 3. Active suicidal ideation with any methods without intent to act, 4. Active suicidal ideation with some intent to act, without specific plan, 5. Active suicidal ideation with specific plan and intent) and/or to the 5 items for suicidal behavior (1. Preparatory acts or behavior, 2. Aborted attempt, 3. Interrupted attempt, 4. Actual attempt, 5. Completed suicide) were reported. The total score ranges from 0 (no ideation present) to 5 (active suicidal ideation with specific plan and intent); higher scores indicate worse symptoms.

Time frame: Up to Day 104

Part 1: Number of Participants With Clinically Significant Physical Examination Findings

A complete physical examination included, at a minimum, assessment of the Cardiovascular, Respiratory, Gastrointestinal and Neurological systems. This analysis was planned but data was not captured in the database. Abnormal changes were captured as adverse events if they were clinically significant.

Time frame: Up to Day 104

Part 1: Number of Participants With Clinically Significant Neurological Examination Findings

The neurological examination assessed mental status, motor and sensory skills, hearing and speech, vision, coordination, and balance. This analysis was planned but data was not captured in the database. Abnormal changes were captured as adverse events if they were clinically significant.

Time frame: Up to Day 104

Part 1: Dose Normalized Area Under the Concentration Time Curve Over a Dosing Interval (AUCtau) of TB006

Blood samples were collected at indicated time points for pharmacokinetic (PK) analysis of TB006. PK parameters were analyzed using standard non-compartmental analysis. AUCtau normalized to the actual administered dose is presented. The AUCtau was divided by the actual dose strength to get the normalized area under the concentration-time curve.

Time frame: Day 1 and Day 29

Part 1: Time at Which Maximum Plasma Concentration Occurs (Tmax) of TB006

Blood samples were collected at indicated time points for PK analysis of TB006. PK parameters were analyzed using standard non-compartmental analysis.

Time frame: At Days 1, 8 and 29

Part 1: Dose Normalized Maximum Observed Plasma Concentration (Cmax) of TB006

Blood samples were collected at indicated time points for PK analysis of TB006. PK parameters were analyzed using standard non-compartmental analysis. Cmax normalized to the actual administered dose is presented. The Cmax was divided by the actual dose strength to get the normalized maximum observed plasma concentration.

Time frame: At Days 1, 8 and 29

Part 1: Concentration at the End of a Dosing Interval (Ctrough) of TB006

Blood samples were collected at indicated time points for PK analysis of TB006. PK parameters were analyzed using standard non-compartmental analysis.

Time frame: Day 8 and Day 29

Part 1: Terminal Elimination Phase Half-life (t1/2) of TB006

Blood samples were collected at indicated time points for PK analysis of TB006. PK parameters were analyzed using standard non-compartmental analysis.

Time frame: At Day 29

Part 1: Total Clearance (CL) of TB006

Blood samples were collected at indicated time points for PK analysis of TB006. PK parameters were analyzed using standard non-compartmental analysis.

Time frame: At Day 29

Part 1: Volume of Distribution (Vd) of TB006

Blood samples were collected at indicated time points for PK analysis of TB006. PK parameters were analyzed using standard non-compartmental analysis.

Time frame: At Day 29

Part 1: Number of Participants With Anti-TB006 Antibodies (Immunogenicity of TB006)

Plasma samples were collected at indicated time points for the determination of anti-TB006 antibodies. Plasma samples were screened for antibodies binding to TB006 and the titer of confirmed positive samples has been reported.

Time frame: Day 1 (Predose), Day 8 (Predose), Day 36 and Day 104

Part 2: Change From Baseline Through Day 104 on the Clinical Dementia Rating Scale - Sum of Boxes Total Score

The Clinical Dementia Rating was obtained through semi-structured interviews of participants and informants, and cognitive functioning was rated in six domains of functioning: memory, orientation, judgement and problem solving, community affairs, home and hobbies, and personal care. Each domain was rated on a five-point scale of functioning as follows: 0: no impairment; 0.5: questionable impairment; 1: mild impairment; 2: moderate impairment; and 3: severe impairment. The Clinical Dementia Rating Scale - Sum of Boxes was based on summing each of the domain box scores with total scores ranging from 0-18, where lower total scores represent better outcomes, and higher total scores represent worse outcomes. Baseline was defined as the last available value prior to the subject receiving the first study drug infusion on Day 1. Change from Baseline value was obtained by subtracting Baseline value from post-dose visit value.

Time frame: Baseline through Day 104

Secondary Outcomes

Part 2: Change From Baseline Through Day 36 on the Clinical Dementia Rating Scale - Sum of Boxes Total Score

Time frame: Baseline through Day 36

Part 2: Percentage of Responders on the Clinical Dementia Rating Scale - Sum of Boxes

The Clinical Dementia Rating is obtained through semi-structured interviews of participants and informants, and cognitive functioning is rated in six domains of functioning: memory, orientation, judgement and problem solving, community affairs, home and hobbies, and personal care. Each domain is rated on a five-point scale of functioning as follows: 0, no impairment; 0.5, questionable impairment; 1, mild impairment; 2, moderate impairment; and 3, severe impairment. The Clinical Dementia Rating Scale - Sum of Boxes is based on summing each of the domain box scores with total scores ranging from 0-18, where lower total scores represent better outcomes, and higher total scores represent worse outcomes. A responder was defined as a participant with at least 1 point improvement from Baseline on the Sum of Boxes score. Percentage of responders on the Clinical Dementia Rating Scale - Sum of Boxes has been presented.

Time frame: At Days 36 and 104

Part 2: Change From Baseline on Mini-Mental State Examination (MMSE) Score

The MMSE was used to measure cognitive impairment. The MMSE can evaluate overall cognitive function, and is widely used for the assessment of cognitive impairment in dementia participants. The questionnaire consists of 11 items, and each item aims to evaluate different cognitive domains such as orientation, memory, attention, and construction. The score ranged from 0 to 30, with a higher score indicating better function. A positive change score indicated improvement from Baseline. Baseline was defined as Day 1. Change from Baseline was obtained by subtracting Baseline value from post-dose visit value.

Time frame: Baseline and at Days 36 and 104

Part 2: Change From Baseline on the Neuropsychiatric Inventory (NPI) Score

The NPI was a questionnaire that quantified psychiatric symptoms and behavioral disorders in dementia. A total of 12 items (the original NPI-10 consisting of 10 behavioral domains: delusions, hallucinations, agitation/aggression, dysphoria, anxiety, euphoria, apathy, disinhibition, irritability/lability, and aberrant motor behavior, The NPI total score was calculated by adding the scores of the domains (each domain scores ranges from 0 to 12). The NPI total score ranges from 0 to 120 with higher scores indicating greater behavioral impairment. Baseline was defined as Day 1. Change from Baseline was obtained by subtracting Baseline value from post-dose visit value.

Time frame: Baseline and at Days 36 and 104

Part 2: Number of Participants With AEs and SAEs

Time frame: Up to Day 104

Part 2: Change From Baseline in Clinical Chemistry Parameters: ALT, ALP, AST and CK

Time frame: Baseline and up to Day 104

Part 2: Change From Baseline in Clinical Chemistry Parameters: Albumin and Protein

Time frame: Baseline and up to Day 104

Part 2: Change From Baseline in Chemistry Parameters: Calcium, Cholesterol, Creatinine, Direct Bilirubin, Glucose, HDL Cholesterol, LDL Cholesterol, Total Bilirubin, Triglycerides and Urea Nitrogen

Time frame: Baseline and up to Day 104

Part 2: Change From Baseline in Clinical Chemistry Parameter: Hemoglobin A1C

Blood samples were collected for analysis of following clinical chemistry parameter including Hemoglobin A1C. Baseline was defined as Day 1. Change from Baseline was obtained by subtracting Baseline value from post-dose visit value.

Time frame: Baseline and up to Day 104

Part 2: Change From Baseline in Clinical Chemistry Parameters: Potassium and Sodium

Time frame: Baseline and up to Day 104

Part 2: Change From Baseline in Clinical Chemistry Parameter: Thyrotropin

Blood samples were collected for analysis of following clinical chemistry parameter including Thyrotropin. Baseline was defined as Day 1. Change from Baseline was obtained by subtracting Baseline value from post-dose visit value.

Time frame: Baseline and up to Day 104

Part 2: Change From Baseline in Hematology Parameters: Basophils, Eosinophils, Leukocytes, Lymphocytes, Monocytes, Neutrophils and Platelets

Time frame: Baseline and up to Day 104

Part 2: Change From Baseline in Hematology Parameter: Ery. MCH

Time frame: Baseline and up to Day 104

Part 2: Change From Baseline in Hematology Parameter: Ery. MCV

Time frame: Baseline and up to Day 104

Part 2: Change From Baseline in Hematology Parameter: Erythrocytes and Reticulocytes

Time frame: Baseline and up to Day 104

Part 2: Change From Baseline in Hematology Parameter: Hematocrit

Time frame: Baseline and up to Day 104

Part 2: Change From Baseline in Hematology Parameter: Hemoglobin

Blood samples were collected for analysis of following hematology parameter: Hemoglobin. Baseline was defined as Day 1. Change from Baseline was obtained by subtracting Baseline value from post-dose visit value.

Time frame: Baseline and up to Day 104

Part 2: Change From Baseline in Urine pH

Urine samples were collected for analysis of Urine pH. Baseline was defined as Day 1. Change from Baseline was obtained by subtracting Baseline value from post-dose visit value.

Time frame: Baseline and up to Day 104

Part 2: Change From Baseline in Urine Specific Gravity

Urine samples were collected for analysis of Urine specific gravity. Baseline was defined as Day 1. Change from Baseline was obtained by subtracting Baseline value from post-dose visit value.

Time frame: Baseline and up to Day 104

Part 2: Change From Baseline in Urobilinogen

Urine samples were collected for analysis of Urobilinogen. Baseline was defined as Day 1. Change from Baseline was obtained by subtracting Baseline value from post-dose visit value.

Time frame: Baseline and up to Day 104

Part 2: Change From Baseline in DBP and SBP

Time frame: Baseline and Up to Day 104

Part 2: Change From Baseline in Respiratory Rate

Vital signs including respiratory rate was measured by at least 5 minutes of rest with the participant in a quiet setting without distractions (eg, television, cell phones). Blood pressure measurements were taken with the participant in the sitting position. Baseline was defined as the last available value prior to the participant receiving the first study drug infusion on Day 1. Change from Baseline was obtained by subtracting the Baseline value from post-dose visit value.

Time frame: Baseline and Up to Day 104

Part 2: Change From Baseline in Temperature

Vital signs including temperature was measured by at least 5 minutes of rest with the participant in a quiet setting without distractions (eg, television, cell phones). Blood pressure measurements were taken with the participant in the sitting position. Baseline was defined as the last available value prior to the participant receiving the first study drug infusion on Day 1. Change from Baseline was obtained by subtracting the Baseline value from post-dose visit value.

Time frame: Baseline and Up to Day 104

Part 2: Change From Baseline in Heart Rate

Vital signs including heart rate was measured by at least 5 minutes of rest with the participant in a quiet setting without distractions (eg, television, cell phones). Blood pressure measurements were taken with the participant in the sitting position. Baseline was defined as the last available value prior to the participant receiving the first study drug infusion on Day 1. Change from Baseline was obtained by subtracting the Baseline value from post-dose visit value.

Time frame: Baseline and Up to Day 104

Part 2: Change From Baseline in ECG Parameters

12-lead ECG measurements was obtained using an ECG machine that automatically calculates the PR interval, QRS duration, QT interval and QTcB. Baseline was defined as the last available value prior to the participant receiving the first study drug infusion on Day 1. Change from Baseline was obtained by subtracting the Baseline value from post-dose visit value.

Time frame: Baseline and Up to Day 104

Part 2: Change From Baseline in ECG Mean Heart Rate

Time frame: Baseline and Up to Day 104

Part 2: Number of Participants With Suicidal Ideation or Suicidal Behavior as Measured Using C-SSRS

Time frame: Up to Day 104

Part 2: Number of Participants With Clinically Significant Physical Examination Findings

Time frame: Up to Day 104

Part 2: Number of Participants With Clinically Significant Neurological Examination Findings

Time frame: Up to Day 104

Part 2: Ctrough of TB006

Blood samples were collected at indicated time points for PK analysis of TB006. PK parameters were analyzed using standard non-compartmental analysis.

Time frame: Day 29

Part 2: t1/2 of TB006

Blood samples were collected at indicated time points for PK analysis of TB006. PK parameters were analyzed using standard non-compartmental analysis.

Time frame: Day 29

Part 2: Cmax of TB006

Blood samples were collected at indicated time points for PK analysis of TB006. PK parameters were analyzed using standard non-compartmental analysis.

Time frame: Day 1 and Day 29