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

NCT03656042 | Completed Phase 2 DMC

• 1 other identifier: 96-0272A-ASAD-061202
• Study Type: interventional
• Target: 21
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Alzheimer's Disease

Keywords

Dementia; Alzheimer's disease; Granulocyte-colony stimulating factor

Outcome Measures

Primary Outcomes (1)

• Alzheimer's Disease Assessment Scale, Cognitive subscale - Chinese version (ADAS-Cog-C)

  The total score ranges from 0 to 75 and the higher the score, the greater the impairment. ADAS-Cog-C has 11 items and each has its score range: Word Recall Task: maximum score = 10 Naming Task: maximum score = 5 Commands: maximum score = 5 Constructional Praxis: maximum score = 5 Ideational Praxis: maximum score = 5 Orientation: maximum score = 8 Word Recognition: maximum score = 12 Remembering Test Instructions: maximum score = 5 Spoken Language Ability: maximum score = 5 Word-Finding Difficulty: maximum score = 5 Comprehension: maximum score = 5 We measure the change from baseline in ADAS-Cog at 24-week visit.

  24 weeks

Secondary Outcomes (9)

• Mini-mental State Examination (MMSE)

  Baseline, 12 weeks, 24 weeks and 48 weeks

• Clinical Dementia Rating Scale (CDR)

  Baseline, 12 weeks, 24 weeks and 48 weeks

• AD Cooperative Study - Clinical Global Impression of change (ADCS-CGIC )

  Baseline, 12 weeks, 24 weeks and 48 weeks

• Lawton and Brody Scale for Instrumental Activities of Daily Living (IADL)

  Baseline, 12 weeks, 24 weeks and 48 weeks

• Neuropsychiatric Inventory (NPI)

  Baseline, 12 weeks, 24 weeks and 48 weeks

Study Arms (2)

G-CSF

EXPERIMENTAL

Subjects in the treatment group will receive Filgrastim (75mcg/0.3ml, NEUPOGEN®), 10 mic/kg/day, by sc, for 5 continuous days for the first week, rest for 11 weeks. Filgrastim will be given 12-weekly ( 12 weeks/cycle ) for 2 cycles.

Drug: Filgrastim (75mcg/0.3ml)

No-treatment

NO INTERVENTION

No-treatment group is used to control evaluation bias and potential time effect.

Interventions

Filgrastim (75mcg/0.3ml) DRUG

Subjects who meet all eligible requirements for entry into the study will be randomized into one of the two treatment groups in 1:1 ratio as shown below: 1. 10 microgram/kg/day, by sc, for 5 continuous days for the first week, rest for 11 weeks; repeat dosing regimen every 12-weekly (12 weeks / cycle) for 2 cycles 2. Non-treatment

Also known as: NEUPOGEN®

G-CSF

Eligibility Criteria

• Age: 50 Years - 85 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Subject with age of at lease 50 years old and no more than 85 years old
• 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.
• Subject with Mini-Mental Examination (MMSE) scores of 12 to 26 (inclusive).
• Subject with Clinical Dementia Rating (CDR) score of 1 (mild) or 2 moderate).
• Subject with Modified Hachinski Ischemic score of 4.
• Subject with a Hamilton Psychiatric Rating Scale for Depression score of 12.
• 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).
• Subject and subject's legally acceptable representative have given written informed consent.
• A reliable caregiver is sufficiently familiar with the subject (as determined by the investigator) and is willing to provide accurate data.

You may not qualify if:

• Subject has underwent any of the following treatment modalities with the respective time frames:
• Anti-epileptic agents: Within 12 weeks of the screening visit,
• Narcotic: within 12 weeks of the screening visit,
• Immunosuppressants: within 12 weeks of the screening visit,
• Hypnotics: within 24 hours of the screening visit or the randomization visit,
• Lithium: within 2 weeks of the randomization visit,
• Succinylcholine-type muscle relaxants: within 2 weeks of the randomization visit,
• Drugs or treatments known to cause major organ system toxicity: within 42 weeks of the randomization visit,
• Tricyclic and tetracyclic anti-depressants: within 4 weeks of the screening visit,
• 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),
• 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).
• Subject is lactating, pregnant or plans to become pregnant,
• Subject is cared primarily by nursing home,
• Subject's AST or ALT is greater than 2 times of the upper limit or normal range.
• Subject with diabetic history and with HbA1c \> 8.5 %.

Sponsors & Collaborators

• Chang Gung Memorial Hospital: lead

Study Sites (1)

Chang Gung Memorial Hospital

Taoyuan District, Taiwan R.o.c, 333, Taiwan

Location

Related Publications (9)

• Alzheimer's Association. 2016 Alzheimer's disease facts and figures. Alzheimers Dement. 2016 Apr;12(4):459-509. doi: 10.1016/j.jalz.2016.03.001.

  PMID: 27570871 BACKGROUND

• Scheltens P, Blennow K, Breteler MM, de Strooper B, Frisoni GB, Salloway S, Van der Flier WM. Alzheimer's disease. Lancet. 2016 Jul 30;388(10043):505-17. doi: 10.1016/S0140-6736(15)01124-1. Epub 2016 Feb 24.

  PMID: 26921134 BACKGROUND

• Braak H, Del Tredici K. The preclinical phase of the pathological process underlying sporadic Alzheimer's disease. Brain. 2015 Oct;138(Pt 10):2814-33. doi: 10.1093/brain/awv236. Epub 2015 Aug 17.

  PMID: 26283673 BACKGROUND

• Chartier-Harlin MC, Crawford F, Houlden H, Warren A, Hughes D, Fidani L, Goate A, Rossor M, Roques P, Hardy J, et al. Early-onset Alzheimer's disease caused by mutations at codon 717 of the beta-amyloid precursor protein gene. Nature. 1991 Oct 31;353(6347):844-6. doi: 10.1038/353844a0.

  PMID: 1944558 BACKGROUND

• Tigue CC, McKoy JM, Evens AM, Trifilio SM, Tallman MS, Bennett CL. Granulocyte-colony stimulating factor administration to healthy individuals and persons with chronic neutropenia or cancer: an overview of safety considerations from the Research on Adverse Drug Events and Reports project. Bone Marrow Transplant. 2007 Aug;40(3):185-92. doi: 10.1038/sj.bmt.1705722. Epub 2007 Jun 11.

  PMID: 17563736 BACKGROUND

• Yanqing Z, Yu-Min L, Jian Q, Bao-Guo X, Chuan-Zhen L. Fibronectin and neuroprotective effect of granulocyte colony-stimulating factor in focal cerebral ischemia. Brain Res. 2006 Jul 7;1098(1):161-9. doi: 10.1016/j.brainres.2006.02.140. Epub 2006 Jul 11.

  PMID: 16814750 BACKGROUND

• Schneider A, Kruger C, Steigleder T, Weber D, Pitzer C, Laage R, Aronowski J, Maurer MH, Gassler N, Mier W, Hasselblatt M, Kollmar R, Schwab S, Sommer C, Bach A, Kuhn HG, Schabitz WR. The hematopoietic factor G-CSF is a neuronal ligand that counteracts programmed cell death and drives neurogenesis. J Clin Invest. 2005 Aug;115(8):2083-98. doi: 10.1172/JCI23559. Epub 2005 Jul 7.

  PMID: 16007267 BACKGROUND

• Tsai KJ, Tsai YC, Shen CK. G-CSF rescues the memory impairment of animal models of Alzheimer's disease. J Exp Med. 2007 Jun 11;204(6):1273-80. doi: 10.1084/jem.20062481. Epub 2007 May 21.

  PMID: 17517969 BACKGROUND

• Sanchez-Ramos J, Song S, Sava V, Catlow B, Lin X, Mori T, Cao C, Arendash GW. Granulocyte colony stimulating factor decreases brain amyloid burden and reverses cognitive impairment in Alzheimer's mice. Neuroscience. 2009 Sep 29;163(1):55-72. doi: 10.1016/j.neuroscience.2009.05.071. Epub 2009 Jun 14.

  PMID: 19500657 BACKGROUND

MeSH Terms

Conditions

Alzheimer Disease; Dementia

Interventions

Filgrastim

Condition Hierarchy (Ancestors)

Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tauopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Granulocyte Colony-Stimulating Factor; Colony-Stimulating Factors; Glycoproteins; Glycoconjugates; Carbohydrates; Hematopoietic Cell Growth Factors; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors

Study Officials

• Wen-Chuin Hsu, M.S.

  Chang Gung Memorial Hospital, Linkou medical center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 23, 2018
• First Posted: September 4, 2018
• Study Start: March 1, 2009
• Primary Completion: July 1, 2014
• Study Completion: August 1, 2014
• Last Updated: September 4, 2018

Record last verified: 2017-02

Locations

TW (1)