| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| mild to moderate Alzheimer’s disease |
|
| E.1.1.1 | Medical condition in easily understood language |
| mild to moderate Alzheimer’s disease |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10001896 |
| E.1.2 | Term | Alzheimer's disease |
| E.1.2 | System Organ Class | 100000004852 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To assess the efficacy of GV-971 compared with placebo on cognition and global function in participants with mild to moderate Alzheimer’s disease (AD). |
|
| E.2.2 | Secondary objectives of the trial |
1. To assess the effect of GV-971 compared with placebo on behavioral symptoms in participants with mild to moderate AD.
2. To assess the effect of GV-971 compared with placebo on cognitive impairment in participants with mild to moderate AD.
3. To assess the effect of GV-971 compared with placebo on activities of daily living (ADL) in participants with mild to moderate AD.
4. To evaluate short-term efficacy of GV-971 compared with placebo on cognition, function, and global clinical impression in participants with mild to moderate AD.
5. To assess the safety and tolerability of GV-971 compared with placebo in participants with mild to moderate AD.
6. To assess the effect of GV-971 on caregivers/partners of participants with mild to moderate AD.
7. To assess the effect of GV-971 on resource utilization
8. To assess the efficacy and safety of GV-971 throughout the open-label extension (OLE) period.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male and female participants aged 50 to 85 years (inclusive) at the time of screening.
2. Willing and able to give informed consent by GCP and local guidance. If the study participant is not competent to give informed consent, in the opinion of the principal investigator, a legally authorized representative (per applicable laws, rules, and regulations) must provide informed consent on his/her behalf, and the participant must provide assent (or local equivalent).
3. Mild to moderate AD as characterized by the following clinical, cognitive, and functional criteria per National Institute on Aging - Alzheimer’s Association (NIA-AA) diagnostic criteria (refer to Section 10.6 for additional details).
a. Clear history of cognitive and functional decline over at least 1 year that is either (1) documented in medical records or (2) documented by history taken from a study partner or other person who knows the participant well (eg, personal physician).
b. MMSE scores between 11 and 24, inclusive, for those with at least 6 years of education. MMSE range is 11-20 for participants with 5 to 6 years of education.
4. Have a study partner/caregiver who has known the participant for at least 1 year and assists the participant regularly at least 3 times per week and has intimate knowledge of the participant’s cognitive, functional, and emotional states and of the participant’s personal care. The study partner must be willing to accompany the participant to all study visits, assure that all of the participant’s medications and the study drug are stored and dispensed safely, and report adverse events. The study partner must be willing and able to give informed consent for their own participation, be able to read and write, and be capable of providing partner responses to scales such as ADL scales, ADCS-CGIC, and NPI.
5. Have at least 5 years of education and have physical, cognitive, hearing, speech, literacy, and language capacity to participate in all testing.
6. A brain magnetic resonance imaging (MRI) scan during screening or up to 3 months prior to randomization. All imaging is evaluated by a central reader vendor (refer to imaging manual for details). MRI will have oblique coronal hippocampus scan and must show the highest possibility of AD, including:
a. Medial temporal lobe atrophy visual rating scale (MTA) ≥ grade 2 by central read;
b. Fazekas scale for white matter lesions grade < 3;
NOTE: Computerized tomography (CT) may be allowed to substitute with similar review by central reading for MRI contraindications such as heart valve, pacemaker or implants, if medical monitor approves. CT unlike MRI would not be repeated in double-blind or OLE (see Section 8.2.7.5).
7. Female participants should be postmenopausal (menopause > 24 weeks), surgically sterilized, or of childbearing potential who agree to take highly effective contraceptive measures throughout the study (see Section 10.4 for details regarding contraception). Women of childbearing potential (WOCBP) must undergo a urine pregnancy test at screening and result must be negative.
8. May use concomitant medications at screening and during the study (see Table 6-1). These medications must be started at least 30 days before the first dose of study drug and the regimens must be planned to remain constant throughout the study.
9. Participants previously enrolled in an AD clinical study involving a disease modifying or symptomatic therapeutic agent may enroll in this study if: (1) AD vaccine last dose > 12 months before baseline visit; (2) monoclonal antibodies last dose > 6 months before baseline visit; and (3) last symptomatic therapeutic agent ended > 1 month or 5 half-lives (whichever is longer) before baseline visit. These restrictions do not apply if the participant was assigned to placebo treatment and this is documented in the source documents. Previous rejected participants from another study may permitted if their data are discussed with the medical monitor. |
|
| E.4 | Principal exclusion criteria |
1. Diagnosis of a dementia-related central nervous system disease other than AD (eg, Parkinson’s Disease, Huntington’s Disease, frontotemporal dementia, multi-infarct dementia, dementia with Lewy bodies, normal pressure hydrocephalus).
2. Abnormal folate, thyroid, and/or vitamin B12 values that cannot be corrected before baseline visit.
3. Major structural brain disease as judged by central MRI Diagnostic Imaging Review Team (eg, ischemic infarcts, subdural hematoma, hemorrhage, hydrocephalus, brain tumors, multiple subcortical ischemic lesions, or a single lesion in a critical region [eg, thalamus]). CT scan may substitute for MRI atrophy criteria if MRI is not possible.
4. Mental illness determined by Diagnostic and Statistical Manual of Mental Disorders (DSM) V criteria, that is unstable within 12 months, or would interfere with study assessments, including schizophrenia or other psychotic disorders, bipolar disorder, severe depression, or delirium.
5. History of suicidal actions within the past 12 months or current suicide risk determined by a positive response (‘Yes’) to either Question 4 or Question 5 on the suicidal ideation portion of the Columbia-Suicide Severity Rating Scale (C-SSRS) at Screening.
6. DSM V diagnosis of alcohol or other substance abuse dependence within the last 12 months.
7. Gastrointestinal illness that may impact absorption as Crohn’s, gastric bypass or recurrent diarrhea.
8. History or current diagnosis of significant cardiac arrhythmias, myocardial infarction, transient ischemic attack, or cerebrovascular accident, uncompensated congestive heart failure New York Heart Association class III and IV.
9. A resting heart rate of < 50 beats per minute (bpm) after 5 minutes of rest in sitting or supine position.
10. Major medical illness or unstable medical condition within 6 months of screening that in the opinion of the investigator may interfere with the participant’s ability to comply with study procedures and abide by study restrictions, or with the ability to interpret safety data, including any physical disability (eg, blindness, deafness, non-AD-related speech impairment, sensory or motor dysfunction) that would prevent completion of study procedures or assessments.
11. Cancer except:
a. History of any cancer that has been in remission (no evidence of recurrence) for > 3 years from the screening.
b. Participants with basal cell or stage 1 squamous cell carcinoma of the skin, stable untreated cancer as prostate or meningioma.
12. Any participants who have previously been treated with GV-971 but discontinued due to safety issues or lack of efficacy.
13. Any participants who have taken any dose of GV-971 within 6 months prior to screening.
14. Use of antibiotics for more than 10 consecutive days in the last 12 weeks prior to baseline or as much as can be any projected need for more than 10 consecutive days during the course of the study. If needed for an unexpected AE during the study, the participant may continue.
15. May not be on AChEI or memantine for at least 4 weeks prior to first MMSE and ADAS-cog/11 at start of run-in period and throughout the study.
16. Past or intended use of over-the-counter or prescription medication (including herbal medications) as defined in protocol
17. Participants are excluded if they:
a. have participated in any other clinical study (excluding non-drug interventional clinical study) within 4 weeks prior to screening visit
b. have participated in another GV-971 clinical study at any time
c. plan to take part in another clinical study during this study.
18. Geriatric Depression Scale-15 (GDS-15) total score > 7 at screening
19. Inadequate hepatic function, defined in protocol
20. Inadequate organ function, defined in protocol
21. After resting for at least 5 minutes in the supine position, 3 averaged ECG shows clinically significant abnormalities or QTcF > 450 ms for male participants and > 470 ms female participants. Exclusion applies if the average of the 3 exceeds these limits.
22. After at least 5 minutes of rest in sitting or supine position:
a. systolic blood pressure (BP) > 180 mmHg
b. diastolic BP > 100 mmHg or < 50 mmHg
23. Poor venous access for blood samples
24. Female participants who are pregnant or lactating. NOTE: Does not apply to female partners of male participants.
25. Wherever residing, participants must have a reliable caregiver/study partner and be able to perform basic ADL (eg, washing and eating) without nursing supervision.
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1 Change from baseline to End of Double-blind Study (EODB) in Alzheimer’s Disease Assessments Scale – cognitive subscale/11-item (ADAS-cog/11) score.
2 Alzheimer's Disease Cooperative Study - Clinical Global Impression of Change (ADCS-CGIC) scale total score at EODB. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1. Change from baseline to Weeks 36, and 52 in Neuropsychiatric Inventory (NPI) score.
2. Change from baseline to EODB in Mini Mental State Examination (MMSE) score.
3. End point
• Change from baseline to Weeks 36 and 52 in Alzheimer’s Disease Cooperative Study – Activities of Daily Living; 23-item Scale (ADCS-ADL23).
• Change from baseline to Weeks 36 and 52 in Amsterdam Instrumental Activities of Daily Living scale (A-IADL).
4. Change from baseline to Weeks 12, 24, and 36 in ADAS-cog/11 and ADCS-CGIC scores.
5. end point
• Incidence of adverse events (AEs)
• Vital signs
• Clinical laboratory values
• Physical exam findings
• Electrocardiogram (ECG)
• Use of concomitant and rescue medications
• Columbia-Suicide Severity Rating Scale (C-SSRS)
• Change from baseline in Zarit Burden Interview (ZBI).
• Change from baseline in NPI caregiver items.
6. End point
• Change from baseline in the primary and secondary caregiver time components of the Resource Utilization in Dementia (RUD) – Lite Version
• The change from baseline in the RUD-Lite total score
7. Changes from baseline through End of Study (EOS) and from Week 52 to Week 78 in:
o ADAS-cog/11,
o ADCS-CGIC,
o NPI,
o MMSE,
o ADCS-ADL23,
o A-IADL,
o Incidence of adverse events (AEs),
o Vital signs,
o Clinical laboratory values,
o Physical exam findings,
o Electrocardiogram (ECG),
o Use of concomitant and rescue medications,
o Columbia-Suicide Severity Rating Scale (C-SSRS).
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary endpoint ;
1 baseline to week 36 and 52
2 baseline to week 54
3 baseline to Weeks 36 and 52
4 baseline to Weeks 12, 24, and 36
5 to 6 baseline to End of Study
7 baseline through End of Study |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 14 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 63 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Canada |
| China |
| Czechia |
| France |
| Germany |
| Hong Kong |
| Italy |
| Netherlands |
| Poland |
| Spain |
| Taiwan |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 1 |
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