Clinical trial NCT05269173: Efficacy and Safety of Flos Gossypii Flavonoids Tablet in the Treatment of Alzheimer's Disease
Official title: A Randomized, Double-Blind, Placebo-Controlled, Multicenter Phase II Clinical Trial to Evaluate the Efficacy and Safety of Flos Gossypii Flavonoids Tablet in the Treatment of Mild and Moderate Alzheimer's Disease
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Alzheimer Disease
Keywords: medullary sea deficiency
brain collateral stasis syndrome
Lead sponsor: Capital Medical University
Sponsor class: OTHER
Collaborators: name: Xinjiang Uygur Pharmaceutical Co., Ltd.
First posted: 2022-03-07
Enrollment: 240
Sex: ALL
Minimum age (years): 50
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: In clinical trials of preclinical pharmacodynamic studies, Flos Gossypii Flavonoids Tablet has been proved to significantly improve the learning and memory ability of Alzheimer's disease model. Phase I clinical tolerance test is to observe the human body's tolerance to Flos Gossypii Flavonoids Tablet, and provide a basis for the formulation of safe and reasonable dosing regimens for phase II clinical trials. Therefore, a Phase II clinical trial is now being conducted to explore the efficacy and safety of the Flos Gossypii Flavonoids Tablet in the treatment of mild to moderate Alzheimer's disease (marinus sea deficiency/brain collateral stasis syndrome). In this study, the researchers will use a multicenter, randomized, double-blind, placebo-controlled parallel method to recruit AD patients to confirm the efficacy and safety of Flos Gossypii Flavonoids Tablet. Confirmation of drug efficacy will be observed through changes in AD patients' general cognitive and different cognitive domain functions, daily living activities, and symptom severities.

Detailed description: Cotton flower is a Xinjiang Uygur ethnic medicine, and its main active ingredients are flavonoids. Studies have proved that flavonoids have strong characteristics of antioxidant stress and anti-inflammatory response. Preclinical pharmacodynamic studies on rats showed that the Flos Gossypii Flavonoids Tablet could significantly improve the learning and memory ability of AD model caused by different factors, and the mechanism may be related to its inhibition of oxidative stress and inflammatory response. A total of 57 subjects were enrolled in the Phase I tolerance clinical study. The results showed that the experimental drug may temporarily increase the three indexes of glutamic oxaloacetic transaminase, creatine kinase and lactate dehydrogenase, which can self-recovery in a short time. Combined with the safety evaluation results of phase I clinical trial, Flos Gossypii Flavonoids Tablet is a drug with high safety.

Eligibility criteria: Inclusion Criteria:

1. Age 50 to 85 years old (including 50 and 85 years old), male or female;
2. Meet the diagnostic criteria of "likely ad dementia" of the National Institute on aging Alzheimer's disease association (NIA-AA) (2011);
3. The subjects are primary school graduates / graduates and above, and have the ability to complete the cognitive ability test and other tests specified in the program;
4. Memory loss lasted for at least 6 months and tended to worsen gradually;
5. Subjects with mild or moderate illness: 11 ≤ MMSE ≤ 26;
6. Total score of Clinical Dementia Rating Scale (CDR):

   Mild dementia: CDR = 1.0; Moderate dementia: CDR = 2.0;
7. The total score of Hachinski scale(HIS) ≤ 4;
8. The total score of Hamilton Depression Scale (HAMD 17 item version) is ≤ 10;
9. There was no obvious positive sign in nervous system examination;
10. Coronal scanning of head MRI in screening stage: the MTA grade of medial temporal lobe atrophy visual assessment scale is grade 2 or higher, and the signal changes of T2 FLAIR sequence in coronal position of hippocampus. If the subject can provide the head MRI film that meets the requirements within 1 month before screening, it can be used as the basis for enrollment without repeated shooting; If the researcher cannot judge whether the subject's condition has changed, the coronal MRI scan of the head before enrollment can be added;
11. The subjects should have stable and reliable caregivers, who will take care of them at least 3 days a week and at least 2 hours a day. The caregivers will accompany the subjects to participate in the whole process of the study. Caregivers must accompany the subjects to the study visit and assist the investigator in completing the Neuropsychiatric Inventory (NPI), Alzheimer's Disease Collaborative Study-Ability of Daily Living Scale (ADCS-ADL), and Clinician Interview Based Impression of Severity (CIBIC -plus), and other scale scores;
12. Agree to participate and sign the informed consent form by the legal guardian. Due to the subject's limited cognitive ability and other reasons, the subject's signature is allowed to be left blank, and the reason is explained. In addition, the legal guardian shall sign the reason statement, and the legal guardian shall sign the informed consent;
13. Meet the criteria the traditional Chinese medicine of AD which is characterized by the syndrome of insufficient sea of marrow/cerebral collateral stasis. According to the Dementia Syndrome Classification Scale (SDSD), one of the syndromes of insufficient sea of marrow/cerebral collateral stasis can be met.

Exclusion Criteria:

1. During screening, MRI examination showed significant focal lesions, fulfilling one of the following conditions:

   ① There were more than 2 infarcts with diameter \> 2 cm at any site;

   ② MRI examination showed that there were infarcts with arbitrary diameter in key parts (such as thalamus, hippocampus, entorhinal cortex, paraolfactory cortex, angular gyrus, cortex and other subcortical gray matter nuclei);

   ③ Fazekas scale grade of white matter lesions \> 2;

   ④ There are other imaging evidences that do not support mild and moderate AD;
2. Dementia caused by other reasons: vascular dementia, central nervous system infection, Creutzfeldt Jakob disease, Huntington's disease, Parkinson's disease, Lewy body dementia, traumatic dementia, other physical and chemical factors (such as drug poisoning, alcoholism, carbon monoxide poisoning, etc.), important physical diseases (such as hepatic encephalopathy, pulmonary encephalopathy, etc.), intracranial space occupying lesions (such as subdural hematoma, brain tumor), endocrine disorders (such as thyroid disease, parathyroid disease), and vitamin B12, folic acid deficiency or any other known cause;
3. Have suffered from central nervous system diseases (including stroke, optic neuromyelitis, epilepsy, etc.);
4. Subjects who were diagnosed with psychiatric disorders according to DSM-V criteria, including schizophrenia or other mental diseases, bipolar disorder, severe depression or delirium;
5. Abnormal laboratory indexes: liver function (ALT and AST) exceeded 1.5×ULN, renal function (CR) exceeded 1.5×ULN, and creatine kinase exceeded 2×ULN;
6. Untreated hypertensive and hypotensive subjects at screening, or hypertensive subjects with uncontrolled hypertension after treatment; subjects with good blood pressure control after treatment can be determined by the investigator to be suitable for inclusion in this study;
7. Within 1 month of the screening visit, the subject has new or ongoing unstable or serious heart, lung, liver, kidney and hematopoietic diseases according to the judgment of the researcher, and does not meet the conditions for clinical research;
8. Clinically, people with significant allergic reaction history, especially drug allergy history, or known allergy to this product and its excipients;
9. Dyspepsia, esophageal reflux, gastric bleeding or peptic ulcer disease, frequent heartburn (≥ once a week) or any surgical operation that may affect drug absorption (such as partial / total gastrectomy, partial / total small bowel resection and cholecystectomy) within 6 months before screening;
10. Alcohol or drug abusers;
11. Human immunodeficiency virus antibody (ant HIV) and Treponema pallidum antibody (ant TP) are positive;
12. Those who are currently using and cannot stop using drugs for Alzheimer's disease;
13. Screening for cholinesterase inhibitors, N-methyl-D-aspartate receptor antagonists (NMDA antagonists), mental retardants, antiparkinsonian drugs and opioid analgesics taken within 1 month before the visit;
14. There are uncorrectable visual and auditory disorders, and the neuropsychological test and scale evaluation cannot be completed;
15. Female subjects with positive pregnancy test or lactation and subjects unable to take effective contraceptive measures or have family planning;
16. Participated in other clinical trials within 3 months before the screening visit;
17. There are other situations that the researcher believes are not suitable to participate in this study.

Primary outcomes:
measure: Alzheimer's Disease Assessment Scale-Cognitive section(ADAS-cog/11)
timeFrame: Change from baseline in ADAS-cog scores at Week 26
Secondary outcomes:
measure: Mini-mental State Examination (MMSE)
timeFrame: Change from baseline in MMSE scores at Week 26
measure: Alzheimer's Disease Co-operative Study Activities of Daily Living (ADCS-ADL)
timeFrame: Change from baseline in ADCS-ADL scores at Week 26
measure: Clinician Interview Based Impression of Severity (CIBIC-plus)
timeFrame: Change from baseline in CIBIC-plus scores at Week 26
measure: Neuropsychiatric Inventory (NPI)
timeFrame: Change from baseline the scores of 12 behavioral domains in NPI at Week 26.
measure: Neuropsychiatric Inventory (NPI)
timeFrame: Change from baseline in Caregiver Stress Score on the NPI Scale at Week 26
measure: Dementia syndrome classification scale (SDSD)
timeFrame: Change from baseline in SDSD scores at Week 26
Other outcomes:
Locations:
city: Hefei
country: China
facility: Hefei Second People's Hospital
state: Anhui
city: Lu'an
country: China
facility: Lu'an Hospital of traditional Chinese Medicine
state: Anhui
city: Beijing
country: China
facility: Xuanwu Hospital of Capital Medical University
state: Beijing
city: Beijing
country: China
facility: Oriental Hospital of Beijing University of traditional Chinese Medicine
state: Beijing
city: Chongqing
country: China
facility: The First Affiliated Hospital of Chongqing Medical University
state: Chongqing
city: Guangzhou
country: China
facility: Sun Yat Sen Memorial Hospital of Sun Yat sen University
state: Guangdong
city: Chengde
country: China
facility: Affiliated Hospital of Chengde Medical College
state: Hebei
city: Daqing
country: China
facility: Daqing People's Hospital
state: Heilongjiang
city: Luoyang
country: China
facility: Luoyang First Hospital of traditional Chinese Medicine
state: Henan
city: Nanyang
country: China
facility: Jiangsu Hospital of traditional Chinese Medicine
state: Jiangsu
city: Taizhou
country: China
facility: Taizhou Hospital of traditional Chinese Medicine
state: Jiangsu
city: Wuxi
country: China
facility: Wuxi Second People's Hospital
state: Jiangsu
city: Yangzhou
country: China
facility: Yangzhou First People's Hospital
state: Jiangsu
city: Shenyang
country: China
facility: PLA Northern Theater Air Force Hospital
state: Liaoning
city: Taiyuan
country: China
facility: The First Hospital of Shanxi Medical University
state: Shanxi
city: Xi'an
country: China
facility: Shanxi Hospital of traditional Chinese Medicine
state: Shanxi
city: Xi'an
country: China
facility: Xi'an High Tech Hospital
state: Shanxi
city: Xi'an
country: China
facility: Xidian Group Hospital
state: Shanxi
city: Luzhou
country: China
facility: Affiliated Hospital of Southwest Medical University
state: Sichuan
Study officials:
References: