Alzheimer’s disease is a progressive, degenerative disorder that attacks the brain’s neurons resulting in loss of memory, cognitive thinking, and language skills. Common symptoms are also linked to behavioral changes in positively diagnosed patients. The disease is characterized as a condition of a chronic or progressive nature that results in the loss of memory, communication and language, ability to focus and pay attention, reasoning and judgment, and visual perception. Alzheimer’s disease is currently the sixth leading cause of death in the United States and a major public health concern affecting about 47 million people worldwide. Due to this astonishing statistic, it is estimated that the cost of care in the United States is currently $259 billion for those who suffer from the disease. Due to population growth and continuous aging, this number is projected to increase to 76 million by 2030 and is estimated to triple by 2050. As treatments options are limited, research on a variety of medications remains a priority.
Recent therapeutic approaches have been strongly influenced by five neuropathological characteristics of acetylcholine deficiency (AD), glutamate excitotoxicity, extracellular deposition of amyloid-β (AB plague), a formation of intraneuronal neurofibrillary tangles (NTFs), and neuroinflammation. Acetylcholine (ACh) is an important neurotransmitter for memory and patients who are diagnosed with Alzheimer’s have low levels of the enzyme. The lowered concentrations of ACh is associated to a progressive and significant loss of cognitive and behavioral function. Current treatments called acetylcholinesterase inhibitors are drugs that inhibit acetylcholinesterase from breaking down acetylcholine. However, these drugs only alleviate some of the symptoms for some individuals for a limited period of time and they are not restorative.
The use of Intranasal Insulin (INI), a naturally occurring hormone, is a new form of treatment that carries out multiple functions in the brain. Particularly, insulin dysregulation may contribute to the development of Alzheimer’s disease. Areas of the brain that are affected by Alzheimer’s disease have been shown to express insulin receptors. In addition, insulin levels and insulin receptor signaling are thought to be reduced in Alzheimer’s. The physiological impact of insulin in the brain is thought to be associated with synaptic remodeling and glucose utilization. In addition, it is proposed that it plays a role in protecting AB toxicity, tau pathology, neuroinflammation and other aspects of Alzheimer’s physiology. When systemic insulin is administered to elderly non-diabetics it poses unacceptable risks of inadvertent hypoglycemia. However, intranasal delivery directs the insulin into the brain, avoiding systemic side-effects. The use of an intranasal insulin (INI) is thought to be delivered directly into the brain along olfactory perivascular channels to bypass the peripheral bloodstream. Thus, decreasing the amount of unwanted systemic insulin levels. This study will examine the effects of intranasally administered insulin when compared to acetylcholinesterase inhibitor treatment on memory loss in people with mild Alzheimer’s.
Objectives
This clinical trial will examine the comparative effects of intranasal insulin (INI) and acetylcholinesterase inhibitors on memory in adults with a diagnosis of Alzheimer’s disease. The primary endpoint will be measured as a change in daily functioning as measured by the ADCS Activities of Daily Living (ADCS-ADL) and Assessment in the global measure of cognition as measured by the Alzheimer’s Disease Assessment Scale-Cognitive (ADAS-Cog). In addition, measures of lower extremity physical performance will be a secondary endpoint as measured by Short Physical Performance Battery (SPPB). It is hypothesized that after 12 months of treatment with INI compared to acetylcholinesterase inhibitors, subjects treated with INI will improve performance on a global measure of cognition, on a memory composite, and on daily function.
Study Design
This study is proposing a randomized, double-blind, double-dummy, placebo-controlled, parallel group study. The study uses insulin as a therapeutic agent and intranasal administration focusing on the nose to brain transport as a mode of delivery with a parallel comparison of the tablet form of Rivastigmine. In this study, it is anticipated that approximately 260 people with Alzheimer’s disease will be enrolled and will be given either INI or Rivastigmine for 12 months. Men and women with a diagnosis of Alzheimer’s disease will be eligible for the study and will be randomly allocated to one of the two treatment groups; oral Rivastigmine or intranasal insulin. According to the recommended daily dose for Rivastigmine, individuals should be on an active treatment of Rivastigmine prior to the enrollment into the study to ensure tolerance of the medication. 7 Randomization will be completed in permuted blocks using a computer-generated code. Each patient will be given a treatment kit, which will contain a study medication to which they will be assigned and a placebo of the treatment to which they are not assigned. Therefore, a randomly assigned kit will contain the placebo nasal spray and the active Rivastigmine tablet or an active INI and a placebo tablet. The study medication will be self-administered at home. Patients, family members, nurses, clinicians, outcome assessors, and investigators will be unaware of treatment group assignments or block size.
Following screening, patients will be assessed at Day 0 (Baseline), Month 3, Month 6, Month 9, and Month 12. The study physician will assess a change in global measure of cognition as measured by the Alzheimer’s Disease Assessment Scale-Cognitive (ADAS-Cog) at Day 0 (Baseline), Month 3, Month 6, Month 9, and Month 12. In addition, the patients change in daily functioning as measured by the ADCS Activities of Daily Living (ADCS-ADL) will be measured at Day 0, Month 6, and Month 12. The Short Physical Performance Battery (SPPB) will be used throughout this study to measure lower extremity physical performance at Day 0, Month 6, and Month 12. Vital signs such as blood pressure, pulse rate, and weight, will be obtained at each study visit to monitor safety.
End Points
Primary endpoints will include a change in global measure cognition as measured by the Alzheimer’s disease assessment scale. The Alzheimer’s disease Assessment Scale is a two-part scale designed to assess cognitive and non-cognitive symptoms of Alzheimer’s disease by evaluating memory, attention, reasoning, language, orientation, and praxis. The part which measures cognitive faculties is known as the ADAS-Cog. Possible scores range from 70 (severe impairment) to 0 (no impairment). Therefore, a higher score indicates more impairment. Scores from the original portion of the test range from 0 (best) to 70 (worse) and the number of items not recalled ranging from 0-10 is added for a maximum score of 80. A positive change indicates cognitive worsening.
ADCS Activities of Daily Living (ADCS-ADL) will also be used as a primary endpoint. The ADSC-ALD will be utilized as a questionnaire that is aimed at detecting a functional decline in people with Mild Cognitive Impairment (MCI). The questions focus predominantly on instrumental activities of daily living scales. For example, daily living activities such as shopping, preparing meals, using household appliances, keeping appointments, and reading will be assessed. 9 This is a questionnaire of 23 items, with possible scores over a range of 0-78, where 78 indicates full functioning with no impairment. The ADCS-ADL assesses functional capacity across a wide spectrum of severity and will be used as a tool for collecting ADL data for this study population.
Assessment of a standardized measure of lower extremity physical performance measured by Short Physical Performance Battery (SPPB) will be utilized as a secondary endpoint for this study. The SPPB will measure walking, balance, and power tasks. This scale has proven reliable and effective for predicting disability, nursing home placement, hospital admission, and mortality. The SPPB score is based on timed measures of standing balance, walking speed, and repeated chair rises. Scores will range from 0 to 12 with higher scores indicating better function.
