GV1001 Subcutaneous for the Treatment of Moderate to Severe Alzheimer's Disease(AD)

Study Overview
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Brief Summary
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The study will be conducted by the Sponsor to evaluate the efficacy and safety of GV1001 (0.56 mg and 1.12 mg) administered subcutaneously as a treatment for moderate to severe Alzheimer's disease (AD). Studies using in vivo and in vitro AD models have shown that GV1001 inhibits neurotoxicity, apoptosis, and the production of reactive oxygen species induced by amyloid beta (Aβ) in neural stem cells by mimicking the extra-telomeric functions of human telomerase reverse transcriptase (hTERT). In nonclinical studies, using both mild (early stage) and severe (late stage) AD mouse models, GV1001 was shown to improve cognitive function and memory, as well as significantly reduce the amount of Aβ and tau proteins. The multifunctional effect of GV1001 makes it a promising therapeutic option for the treatment for AD. In a completed Phase 2 study conducted in Korea, GV1001 showed significant improvement in change from baseline of Severe Impairment Battery score at Week 24 and demonstrated a clinically acceptable safety profile in patients with moderate to severe AD.

Detailed Description
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This is a multi-center, randomized, double-blinded, placebo-controlled, parallel design, prospective phase 3 study in participants with moderate to severe AD. The study will consist of a screening visit (up to 14 days prior to first dose), 24-week double-blind treatment phase, another 24-week open extension phase, and end-of-study (EOS) visits 4 weeks after an end-of-treatment [EOT] visit at each phase. Eligible participants will be randomized in a 1:1:1 ratio to receive GV1001 0.56 mg, GV1001 1.12 mg, or placebo (normal saline) every week for 4 weeks beginning on Day 1 (of Week 1) followed by every 2 weeks for 20 weeks during the double-blind treatment phase. Participants who give consents to enroll in the open extension phase, will receive GV1001 1.12mg every week for 4 weeks beginning on Day 1 (of Week 26) followed by every 2 weeks through Week 49. Yet, the group of participants who received GV1001 in the double-blind treatment phase (either 0.56 mg or 1.12 mg) will receive GV1001 1.12mg and placebo (normal saline) alternately first 4 weeks of the open extension phase. Prior to randomization, eligibility of potential participants will be confirmed through an adjudication process in which screening data (eg, Korea Mini-Mental State Examination [K-MMSE], Global Deterioration Scale [GDS], MRI/CT scans) obtained to evaluate AD status. Results from CT or MRI performed within 1 year prior to screening will also be used to confirm eligibility. If a participant discontinues the study prematurely, the participant will be asked to come for a drop-out [DO] visit for efficacy evaluation are scheduled at an end-of-study [EOS] visit at Week 28 or Week 53. For an individual participant, the maximum duration of study participation is approximately 14 months, including an up to 14-day screening period. Efficacy evaluations will be performed at baseline, 1 Month, 3 Month, 6 Month, 9 Month and 12 Month using the Severe Impairment Battery [SIB] and the Clinical Dementia Rating Scale Sum of Boxes [CDR-SOB], K-MMSE, Neuropsychiatric Inventory Questionnaire [NPI-Q], GDS, and Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory for Severe Alzheimer's Disease [ADCS-ADL-severe]. At the visits where several efficacy assessments are administered, every effort should be made to perform the efficacy evaluations in the same order at each visit. Safety will be assessed throughout the study by monitoring for AEs, laboratory evaluations, vital signs measurements, and physical assessments.

Official Title
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A Multi-center, Randomized, Double-blind, Placebo-controlled, Parallel Design, Prospective, Phase III Clinical Trial to Evaluate the Efficacy and Safety of Subcutaneous Administration of GV1001 in Patients With Moderate to Severe AD

Conditions
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Moderate to Severe Alzheimer's Disease

Intervention / Treatment
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* Drug: GV1001 Placebo
* Drug: GV1001 0.56mg
* Drug: GV1001 1.12mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects aged ≥ 55 to ≤ 85 years Subjects who meet the DSM-IV criteria for diagnosing dementia Subjects who are clinically diagnosed with probable Alzheimer's disease as defined in the NINCDS-ADRDA criteria Subjects with a K-MMSE score ≤ 19 at the screening visit Subjects with GDS (Global Deterioration Scale) grade 5 to 6 Subjects who have no other diseases to cause dementia other than AD as a result of MRI or CT scan within 12 months from the screening visit Subjects who are taking donepezil alone or donepezil and memantine in combination at a stable dose without a dose change over 3 months before screening Subjects who are not illiterate Subjects who can walk with or without assist device to visit hospitals or clinics to undergo cognitive tests and other tests Subjects with caregiver who can accompany all visits with the subjects as scheduled for this trial, supervise subject's compliance for the tests and examination process and provide information about the subject's indications, and who give written consent Subjects and/or caregivers who voluntarily agreed in written to participate in the clinical trial Exclusion Criteria: Subjects who have other causes of dementia as listed below according to CT/MRI test and neurologic examination within 12 months of screening or at the time of screening. Subjects with possible, probable or definite vascular dementia according to NINDS-AIREN criteria Subjects with other central nervous system diseases that can cause the impairment of cognitive function (cerebrovascular disease including cerebrovascular dementia, Parkinsonism, Huntington's disease, subdural hematoma, normal pressure hydrocephalus, brain tumor, Creutzfeldt-Jakob disease, etc.) Subjects with neuropathy such as delusion, delirium, epilepsy, etc. Subjects who have abnormal test results which are considered to contribute to the severity of their dementia or be the cause of dementia in the vitamin B12, folic acid, the syphilis serology, and the thyroid stimulating hormone (TSH) tests Subjects who have a history of significant psychiatric illness such as schizophrenia or bipolar affective disorders which may interfere with the participation of this clinical trial according to the investigator's judgment or who are suffering from depression Subjects with a history of known or suspected seizures including febrile seizure, recent loss of consciousness which is not explained or history of significant head trauma accompanied by loss of consciousness Subjects in any medical condition that may interfere with the evaluation and progression of the clinical trial according to the investigator's judgment (acute or unstable cardiovascular disease, uncontrolled hypertension (>160/100 mmHg) at Visit 1 and Visit 2, insulin-dependent or uncontrolled diabetes at Visit 1 (HbA1c> 8% on screening test), etc.). Subjects who are hypersensitive to the components of the investigational product. Subjects with a history of alcohol and drug abuse or dependence (except nicotine dependence) within the last 2 years. Subjects with a history of cancer within the past 5 years (however, non-metastatic skin basal cell carcinoma and/or skin squamous cell carcinoma, carcinoma in suit of uterine cervix or non-progressive prostate cancer may be acceptable and If cancer is considered to have been treated at the judgement of the investigator, if subjects are not taking anticancer or radiation therapy and are considered that treatment is not required for the next 5 years at the discretion of the investigator, enrollment is possible) Subjects with renal dysfunction (Creatinine Clearance (Clcr) < 30 mL/min) Subjects with serious hepatic dysfunction (ALT or AST ≥ 2.0 normal upper limit) Subjects who are taking prohibited drugs or expected to be administered during clinical trial period Drugs for the treatment of Alzheimer's Disease or other cognitive impairment other than donepezil and memantine Anticholinergic drugs, antidepressant drugs (tricyclic antidepressants, MAO inhibitors), orthopedic antipsychotic drugs, etc. Subjects with previous administration of all clinical trial vaccines for Alzheimer's disease Subjects who consented to lumbar puncture (LP) for CSF examination only check the following exclusion criteria - Subjects who are not contraindicated (e.g. platelet count <100,000/μL, lumbar deformity, etc.) for performing lumbar puncture. Subjects can participate in clinical trials even if they are contraindicated in performing a lumbar puncture. Female subjects with childbearing potential who do not agree to contraception using a medically accepted method (surgical sterilization, intrauterine device or Intrauterine system), fallopian tube ligation, double blocking (combined use of blocking methods such as male condom, female condom, cervical cap, contraceptive diaphragm, contraceptive sponge), single blocking method using spermicide during the clinical trial period and until 90 days after clinical trial end(stop). Pregnant or lactating women Subjects who participated in another clinical trial within 4 weeks before participation in this clinical trial Subjects in less than 12 months after the administration of the Investigational product for this clinical trial Subjects who participated in any clinical trial for Alzheimer type dementia treatment within 6 months at screening Subjects who are judged by the investigator to be ineligible for participation in this clinical trial

Ages Eligible for Study
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Minimum Age: 55 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo (with extention period: GV1001 1.12mg)<br>Placebo SC injection will be administered once weekly for 4 weeks then every 2 weeks through Week 24 for double blind phase. Then GV1001 1.12 mg will be administered once weekly for 4 weeks (from Week 26 to Week 29) then every 2 weeks through Week 49 for open extension phase. | Drug: GV1001 Placebo<br>* 0.9% normal saline<br>* Other names: Normal saline;Drug: GV1001 1.12mg<br>* Lyophilized peptide from hTERT<br>* Other names: Tertomotide 1.68mg;|
| Experimental: GV1001 0.56 mg (with extention period: Placebo&GV1001 1.12mg)<br>GV1001 0.56 mg SC injection will be administered once weekly for 4 weeks then every 2 weeks through Week 24 for double blind phase. Placebo and GV1001 1.12 mg will be administered alternately every week for 4 weeks (from Week 26 to Week 29), then GV1001 1.12 mg will be administered every 2 weeks through Week 49 for open extension phase. | Drug: GV1001 Placebo<br>* 0.9% normal saline<br>* Other names: Normal saline;Drug: GV1001 0.56mg<br>* Lyophilized peptide from hTERT<br>* Other names: Tertomotide 0.84mg;Drug: GV1001 1.12mg<br>* Lyophilized peptide from hTERT<br>* Other names: Tertomotide 1.68mg;|
| Experimental: GV1001 1.12 mg (with extention period: Placebo&GV1001 1.12mg)<br>GV1001 1.12 mg SC injection administered once weekly for 4 weeks then every 2 weeks through Week 24 for double blind phase. Placebo and GV1001 1.12 mg will be administered alternately every week for 4 weeks (from Week 26 to Week 29), then GV1001 1.12 mg will be administered every 2 weeks through Week 49 for open extension phase. | Drug: GV1001 Placebo<br>* 0.9% normal saline<br>* Other names: Normal saline;Drug: GV1001 1.12mg<br>* Lyophilized peptide from hTERT<br>* Other names: Tertomotide 1.68mg;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in SIB(Severe Impairment Battery) score | SIB includes 51 questions to assess cognition in an individual. SIB consists of nine symptom domains such as attention, language, orientation, memory, praxis, visuospatial perception, construction, social skills and orientating head to name. The possible total scores range from 0 to 100 with a higher score indicating greater cognitive function. | 6 months | 
| Change from baseline in CDR-SOB(Clinical Dementia Rating Scale Sum of Boxes) score | CDR-SOB evaluates cognitive and functional performance in six domains related to AD including memory, orientation, judgment and problem solving, community affairs, home and hobbies, and personal care. Each domain is rated from 0 to 5 points (0, 0.5, 1, 2, 3, 4, and 5) with a lower total score indicating severely impaired cognitive function. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in SIB(Severe Impairment Battery) score | SIB includes 51 questions to assess cognition in an individual. SIB consists of nine symptom domains such as attention, language, orientation, memory, praxis, visuospatial perception, construction, social skills and orientating head to name. The possible total scores range from 0 to 100 with a higher score indicating greater cognitive function. | 1 month and 3 months | 
| Change from baseline in CDR-SOB(Clinical Dementia Rating Scale Sum of Boxes) score | CDR-SOB evaluates cognitive and functional performance in six domains related to AD including memory, orientation, judgment and problem solving, community affairs, home and hobbies, and personal care. Each domain is rated from 0 to 5 points (0, 0.5, 1, 2, 3, 4, and 5) with a lower total score indicating severely impaired cognitive function. | 1 month and 3 months | 
| Change from baseline in K-MMSE(Korea Mini-Mental State Examination) score | K-MMSE assesses an individual's cognitive function by asking questions about time orientation, spatial orientation, memory registration, attention and calculation, memory recall, language, and space-time configuration. It creates the possible total score from 0 to 30, with a lower total score indicating greater severity in cognitive impairment. | 1 month, 3 months, and 6 months | 
| Change from baseline in NPI-Q(Neuropsychiatric Inventory Questionnaire) score | NPI-Q consists of questions to evaluate degrees of behavioral disturbance in 12 domains. It includes delusions, hallucinations, agitation/aggression, depression/dysphoria, anxiety, elation/euphoria, apathy/indifference, disinhibition, irritability/lability, motor disturbance, nighttime behaviors, and appetite/eating. The severity scale has scores ranging from 1 to 3 points (1=mild and 3=severe) and the scale for assessing caregiver distress has scores ranging from 0 to 5 points (0=no distress and 5=extreme distress). The higher sum of the NPI-Q severity score represents greater severity of the individual's symptoms, and the higher sum of the NPI-Q distress score indicates greater severity of caregiver's distress associated with the symptoms. | 1 month, 3 months, and 6 months | 
| Change from baseline in GDS(Global Deterioration Scale) score | GDS provides the stages for the severity of cognitive function of the individual with AD. It is brown down into seven stages (stage1=no cognitive decline and 7=very severe cognitive decline). | 1 month, 3 months, and 6 months | 
| Change from baseline in ADCS-ADL-severe(Alzheimer's Disease Cooperative Study-Activities of Daily Living scale-severe) score | ADCS-ADL-severe consists of 19 items that can access the competence of individuals with AD in activities of daily living. The maximum possible total score is 54, with a higher score indicating lesser severity in AD. | 1 month, 3 months, and 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Alzheimer's Disease, GV1001