To Evaluate the Efficacy and Safety/Tolerability Profiles of G-CSF in Subjects With Mild to Moderate Alzheimer's Disease

A Open-label, No-treatment-controlled, Parallel, Pilot Phase Ⅱ Study to Evaluate the Efficacy and Safety/Tolerability Profiles of G-CSF in Subjects With Mild to Moderate Alzheimer's Disease

With the enrichment of living environment and the progress of medicine, the scale of aging population has increased in many countries of the world. Alzheimer's disease (AD), the leading cause of dementia, counts for approximately 60% to 70% in dementia in aged population. AD is a well-known neurodegenerative disease and characterized by the formation of neurofibrillary tangles and deposition of amyloid in the brain. It also affects more than 12 million patients worldwide and puts a tremendous burden on family caregivers and causes high nursing home costs for society. So far, the mechanisms of AD have not been elucidated and currently no curable treatment exists. Thus, clinical trials concerning the treatment of AD are in urgent expectation.

Granulocyte-colony stimulating factor (G-CSF) is a growth factor that presents in human body in small quantity and is known to promote the blood cell proliferation and differentiation. Previous studies showed injection of G-CSF could help release hematopoietic stem cell (HSCs) from bone marrow to the peripheral blood, and then migrate to repair damaged areas, e.g. heart tissue and ischemia brain tissue. We have found that G-CSF triggering release of stem cells from bone marrow shows the potential as an effective reagent for treatment of AD by using two AD mouse models. The one was generated by injecting the brains of normal mice with amyloid and another was by using a strain of transgenic mice which naturally exhibit Alzheimer's disease-like neuronal apoptosis and memory loss. Subcutaneous administration of G-CSF into mice significantly rescued their cognitive/memory functions.

G-CSF has already been widely used in clinical practice, for example, neutropenia caused by chemotherapy in cancer and bone marrow transplantation. The new finding shows G-CSF can release HSCs from bone marrow and these cells not only can pass through the blood-brain barrier but can selectively migrate to the region of damaged brain to improve neurological recovery. Thus, we conduct this clinical trial to investigate the potential effect of G-CSF for the cognitive function of AD patients. If successful, G-CSF could open up a new window for AD treatment which is less invasive and more effective than the current therapies.

This is a randomized open-label Phase 2 trial with parallel design using no-treatment group as control. Subjects in the treatment arm will receive subcutaneous G-CSF with the dosage of 10 microgram/kg/day, for 5 continuous days in the first week. The second dosage will be given in the 12 week. If subjects has received Donepezil already, the Donepezil will be concomitantly used in a stable dose (the same dose as pre-entering this study) during the study.

Background data and general medical history will be registered on the screening visit (Visit 1, started four weeks or less before Visit 2). Subjects fulfil the inclusion criteria 1) age between 50 to 85 years old; 2) those who were diagnosed as AD and the supporting evidences from the brain computed tomography or Magnetic Resonance Imaging scan within 12-months; 3) Mini-Mental State Examination scores of 10 to 26, and, 4) Clinical Dementia Rating score of 1 or 2. Subjects with clinically significant medical or neurological disorders, other than AD, that may affect cognition will be excluded Additional inclusion criteria included Modified Hachinski Ischemic score of ≤ 4, Hamilton Psychiatric Rating Scale for Depression score of ≤ 12and a reliable caregiver who is sufficiently familiar with the subject and is willing to provide the accurate data.

Participants will receive standard physical examination in all visits. Serum tests include complete blood count (CBC),total bilirubin, creatinine, blood urea nitrogen (BUN), uric acid, aspartate transaminase (AST), alanine transaminase (ALT), total protein, albumin, Vitamin B12, folate, T4, thyroid-stimulating hormone (TSH), HbA1c, rapid plasmin reagin (RPR)/Treponema pallidum haemagglutination (TPHA) will be also obtained.

Inclusion Criteria:

1. Subject with age of at lease 50 years old and no more than 85 years old
2. Subject diagnosed of Alzheimer's disease; based on the criteria of The Diagnostic and Statistical Manual of Mental Disorders (DSM)-Ⅳ for dementia and those of National Institute of Neurological and Communicative Disorders and Stroke - Alzheimer's Dementia and Related Disorder Association (NINCDS - ADRDA) and within 12-months CT/MRI brain scan supporting evidences.
3. Subject with Mini-Mental Examination (MMSE) scores of 12 to 26 (inclusive).
4. Subject with Clinical Dementia Rating (CDR) score of 1 (mild) or 2 moderate).
5. Subject with Modified Hachinski Ischemic score of 4.
6. Subject with a Hamilton Psychiatric Rating Scale for Depression score of 12.
7. Female subject with child-bearing potential agrees to take reliable contraceptive method during the participation of the study (Females with no child-bearing potential have to be surgically sterilized or at least 2 years after post-menopausal).
8. Subject and subject's legally acceptable representative have given written informed consent.
9. A reliable caregiver is sufficiently familiar with the subject (as determined by the investigator) and is willing to provide accurate data.

Exclusion Criteria:

1. Subject has underwent any of the following treatment modalities with the respective time frames:

   1. Anti-epileptic agents: Within 12 weeks of the screening visit,
   2. Narcotic: within 12 weeks of the screening visit,
   3. Immunosuppressants: within 12 weeks of the screening visit,
   4. Hypnotics: within 24 hours of the screening visit or the randomization visit,
   5. Lithium: within 2 weeks of the randomization visit,
   6. Succinylcholine-type muscle relaxants: within 2 weeks of the randomization visit,
   7. Drugs or treatments known to cause major organ system toxicity: within 42 weeks of the randomization visit,
   8. Tricyclic and tetracyclic anti-depressants: within 4 weeks of the screening visit,
   9. Antiparkinsonian: Within12 weeks of the screening visit (Not including dopaminergic agent or peripheral anticholinergic agent at stable dose for at least 4 weeks of randomization visit),
   10. Any medications for cognition enhancement: Within13 weeks of the screening visit(except for donepezil that has been maintained with a stable regimen for at least 12 weeks).

2. Subject is lactating, pregnant or plans to become pregnant,

3. Subject is cared primarily by nursing home,

4. Subject's AST or ALT is greater than 2 times of the upper limit or normal range.

5. Subject with diabetic history and with HbA1c > 8.5 %.

6. Subject with clinically significant medical or neurological disorders, other than AD, that may affect cognition (e.g., abnormal thyroid function tests, Vitamin B12 or folate deficiency, post-traumatic conditions Huntington's disease, Parkinson's disease, syphilis, probable/possible vascular dementia according to NINDS-AIREN criteria, active/uncontrolled seizure).

7. Subject with major psychiatric disorders.

8. Subject with spleen related disorders.

9. Subject with sickle cell disease.

10. Subject with myelodysplastic syndrome.

11. Subject with current diagnosis of acute stroke or history of acute stroke within 1 year.

12. Subject with allergy history to E. coli-derived proteins or G-CSF or donepezil.

13. Subject with cancer history and has received related therapy(ies) with in 2 years of entering this study.

14. Subject has participated other investigational study within 4 weeks of entering this study.