Safety and Efficacy Study of ALZT-OP1 in Subjects With Evidence of Early Alzheimer's Disease

This Phase III study is designed as a randomized, double-blinded, placebo-controlled study for subjects with evidence of early AD. The study will evaluate safety and tolerability, efficacy as measured by CDR-SB, and will determine if the combination therapy ALZT-OP1 will slow down, arrests, or reverse cognitive and functional decline in an early stage AD population.

Subjects will be randomly assigned to one of four treatment arms: Group I will consist of ALZT-OP1a (cromolyn) for inhalation, plus an oral placebo tablet; OR the Group II arm, which will consist of ALZT-OP1 combination therapy ALZT-OP1a (cromolyn) for inhalation, plus ALZT-OP1b (ibuprofen) tablet for oral administration; OR to the Group III arm, which will consist of inhaled placebo, plus ALZT-OP1b (ibuprofen) tablet for oral administration; OR to the Group IV placebo arm, which will consist of inhaled placebo plus an oral placebo tablet.

A minimum of 400 evaluable subjects will be randomized to receive one of four possible treatment assignments containing various combinations of active study drug or placebo.

To account for subject dropouts (estimated rate of 30%), it is anticipated that up to 600 (or 150 subjects per treatment arm) may be recruited and randomized, to achieve a minimum of 100 evaluable subjects per treatment arm.

Inclusion criteria

• 55-79 years old;
• ≥ 8 years of education;
• Study partner is available who has frequent contact with the participant (e.g. an average of 10 hours per week or more), and can accompany the participant to all clinic visits for the duration of the protocol;
• Evidence of early AD, as defined by all of the following:

• Memory complaint by subject or study partner that is verified by a study partner;
• Objective memory impairment for age, documented by scoring below the education adjusted cutoff of the Logical Memory II subscale (Delayed Paragraph Recall) from the Wechsler Memory Scale Third Edition (the maximum score is 25):

• ≤ 8 for 16 or more years of education, or
• ≤ 4 for 8-15 years of education;
• Essentially preserved general cognitive function;
• Largely intact functional activities;
• Not demented;
• Cerebrospinal fluid (CSF) biomarker results consistent with early AD, including CSF Aβ-42 levels ≥ 180 pg/mL and ≤ 690 pg/mL;
• Clinical Dementia Rating (Global) = 0.5; Memory Box score must be at least 0.5;
• Must be fluent in the language of the cognitive testing material being administered;
• Stability of permitted medications for 4 weeks prior to study start; subjects receiving acetylcholinesterase inhibitors and/or memantine should be on stable dose of those medications for at least 12 weeks prior to study start with every effort to maintain stable dose for the duration of the study;
• Visual and auditory acuity adequate for neuropsychological testing;
• Good general health with no diseases expected to interfere with the study;
• Must provide written informed consent for APOe4 genotype testing;
• Must provide written informed consent for CSF sampling.

Exclusion criteria

• Any significant neurological disease other than suspected incipient AD, such as Parkinson's disease, multi-infarct dementia, Huntington's disease, normal pressure hydrocephalus, brain tumor, progressive supranuclear palsy, seizure disorder, subdural hematoma, multiple sclerosis, or history of significant head trauma followed by persistent neurologic defaults or known structural brain abnormalities;
• Major depressive episode, as described in the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) within the past 6 months, which could lead to difficulty complying with the protocol;
• History of schizophrenia or bipolar disorder (DSM-IV criteria);
• History of alcohol or substance abuse or dependence within the past 3 years (DSM-IV criteria);
• Currently taking medications that could lead to difficulty complying with the protocol; subjects must be on a stable dose of current medications for 4 weeks prior to study entry, with the exception of acetylcholinesterase inhibitors and/or memantine, which must be on a stable dose for at least 12 weeks prior to study entry;
• Investigational agents are prohibited one month prior to entry and for the duration of the trial;
• Currently taking medications known to be CYP2C9 inducers (i.e. carbamazepine and rifampicin);
• Currently taking cromolyn, or have taken cromolyn, within the past 12 months;
• Chronic daily use of high-dose NSAID for osteoarthritis, rheumatoid arthritis, or other chronic inflammatory diseases ("chronic" defined as 3200 mg/day for >2 weeks);
• Chronic daily use of aspirin exceeding standard of care guidelines for low dose aspirin therapy for prevention of stroke and/or other recommended uses;
• Allergy to cromolyn (also known as Intal®, Nasalcrom®, Opticrom®, Gastrocrom®, etc.);
• Allergies to ibuprofen (Advil®, Motrin®, Nuprin®, etc.) or aspirin;
• Clinically significant respiratory disorders with impaired respiratory effort or difficulty taking inhaled drugs;
• Uncontrolled chronic asthma;
• Abnormal pulmonary function test, defined for this protocol as: FEV1/FVC < predicted value for subject AND FEV1 < 70% of predicted value, indicating moderate or severe respiratory obstruction;
• Taking inhaled protein products on a chronic basis;
• Any significant systemic illness or unstable medical condition which could lead to difficulty complying with the protocol;
• Pregnancy or lactation for female subjects of child-bearing potential (i.e., < two years post-menopausal or not surgically sterile);
• For sexually active male subjects, unwillingness or incapability of using appropriate contraception methods;
• Severe renal or hepatic impairment.