Efficacy and Safety Evaluation of GSK4527226 in Early Alzheimer's Disease: A Randomized, Double-Blind, Placebo-Controlled, Multicenter Phase 2 Study
- Trial ID
- 2023-505083-11-01
- Protocol
- 219867
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **efficacy** of GSK4527226 dose 1 compared to placebo in participants with early Alzheimer's disease, as measured by the Clinical Dementia Rating-Sum of Boxes (CDR-SB). This assessment is clinically relevant as it provides a comprehensive measure of cognitive and functional performance, which is crucial for understanding the progression of Alzheimer's disease and the potential impact of the treatment.
Secondary objectives include evaluating the efficacy of GSK4527226 dose 1 compared to placebo through cognitive and functional assessments in participants with early Alzheimer's disease. These assessments aim to provide additional insights into the treatment's impact on cognitive functions and daily living activities, further supporting the primary objective's findings.
Participants
The clinical trial involves a total of **142 participants** diagnosed with **Alzheimer's Disease**. The study population includes both male and female subjects, aged between 50 to 85 years. Participants are required to be in the Alzheimer's continuum, as defined by the 2018 NIA-AA Research Framework, and must have evidence of cerebral amyloidosis. The trial population was selected based on specific inclusion criteria, including a Mini-Mental State Examination (MMSE) score between 21 and 29, and a Clinical Dementia Rating-Global Score (CDR-GS) of 0.5 to 1.0. Participants must have a stable dosing regimen of symptomatic Alzheimer's medications, if applicable, for at least 12 weeks prior to screening. The study also considers lifestyle factors such as body weight, which must be between 45 kg and 120 kg, with a BMI ranging from 17 to 34.9 kg/m². Both male and female participants must adhere to contraception requirements as outlined in the protocol. The trial includes a vulnerable population, and participants must be willing and able to provide informed consent, with the availability of an adult person who can provide accurate information regarding their cognitive and functional abilities.
Plans and Procedures
The clinical trial is designed as a **randomized**, **double-blind**, **placebo-controlled**, 3-arm, multicenter study to evaluate the efficacy and safety of GSK4527226 [AL101] intravenous infusion compared with placebo in patients with early **Alzheimer's Disease**. The trial will involve participants aged 50 to 85 years who meet specific inclusion criteria, including evidence of cerebral amyloidosis and defined clinical severity. The trial is expected to commence recruitment on December 19, 2023, and conclude by December 15, 2026, with an estimated duration of 18 months for each participant's involvement.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on the inclusion criteria. This will be followed by regular follow-up visits to monitor the primary endpoint, which is the change from baseline in the Clinical Dementia Rating-Sum of Boxes (CDR-SB) across Weeks 52, 64, and 76. Secondary endpoints include changes in iADRS, ADAS-Cog14, ADCS-iADL component of ADCS-ADL-MCI, ADCS-ADL-MCI, and ADCOMS over the same period. The end-of-study visit will occur at the conclusion of the participant's involvement, ensuring all data is collected and any necessary follow-up care is arranged.
The expected length of participant involvement is approximately 18 months, with conditions for early termination including withdrawal of consent, significant protocol deviations, or adverse events that compromise participant safety. The trial will utilize intravenous administration of the investigational product, with a maximum treatment period of 18 months. Participants will be closely monitored throughout the study to ensure adherence to the protocol and to assess the safety and efficacy of the treatment.
Treatment
The clinical trial involves the administration of several experimental and non-experimental treatments. **VIZAMYL** 400 MBq/mL solution for injection is an experimental medication containing the active substance **flutemetamol (18F)**. It is provided in a solution for injection form and is administered via **intravenous use**. The maximum daily dose is 185 MBq, with a total maximum dose of 370 MBq over a treatment period of up to 2 days. This product is manufactured by GE Healthcare AS and is not a pediatric formulation.
**Amyvid** is another experimental treatment used in the trial, available in two concentrations: 1900 MBq/mL and 800 MBq/mL, both containing the active substance **florbetapir (18F)**. These solutions for injection are also administered intravenously. The maximum daily dose for both concentrations is 370 MBq, with a total maximum dose of 740 MBq over a 2-day treatment period. Amyvid is produced by Eli Lilly Nederland B.V.
**GSK4527226**, a solution for infusion, is the primary experimental medication in this study. It is administered intravenously, with a treatment period extending up to 18 weeks. The active substance is a protein-based compound, and the product is developed by GlaxoSmithKline. The dosing schedule and specific dosage amounts are determined based on the study protocol, and participant compliance is monitored throughout the trial.
**Neuraceq** 300 MBq/mL solution for injection, containing **florbetaben (18F)**, is another experimental treatment. It is administered intravenously, with a maximum daily dose of 300 MBq and a total maximum dose of 600 MBq over a 2-day period. This product is manufactured by Life Radiopharma Berlin GmbH.
**Florquinitau (18F)**, also known as [18F]MK-6240, is provided as a solution for injection and is administered intravenously. The maximum daily dose is 185 MBq, with a total maximum dose of 370 MBq over a 2-day treatment period. This compound is developed by GlaxoSmithKline.
The trial also includes the use of **0.9% (w/v) sodium chloride (Normal Saline)** as a non-experimental treatment, serving as a placebo. This solution is used to maintain blinding in the study and is administered as per the study protocol. The administration route and dosing schedule for the placebo are consistent with those of the experimental treatments to ensure the integrity of the trial design.
Efficacy
The efficacy of the investigational product GSK4527226 in patients with early Alzheimer's disease will be assessed using the **Clinical Dementia Rating-Sum of Boxes (CDR-SB)** as the primary endpoint. The primary efficacy parameter will be the change from baseline in CDR-SB scores measured at Weeks 52, 64, and 76. Secondary endpoints will include changes from baseline across the same timepoints in the following assessments: the integrated Alzheimer's Disease Rating Scale (iADRS), Alzheimer's Disease Assessment Scale-Cognitive Subscale 14 (ADAS-Cog14), Alzheimer's Disease Cooperative Study-Activities of Daily Living Inventory-Mild Cognitive Impairment (ADCS-ADL-MCI), and the Alzheimer's Disease Composite Score (ADCOMS).
These efficacy parameters will be collected and analyzed at specified intervals to evaluate the treatment's impact on cognitive and functional abilities. The assessments will be conducted using validated scales and instruments appropriate for measuring cognitive decline and daily living activities in Alzheimer's disease. The trial is designed as a Phase 2, parallel group, randomized, double-blind, placebo-controlled, 3-arm, multicenter study, ensuring rigorous evaluation of the investigational product's efficacy compared to placebo.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Participant must be 50 to 85 years of age, inclusive. 2. Participant must be in the Alzheimer’s continuum as defined by the 2018 NIA-AA Research Framework corresponding to the clinical categories of MCI due to AD and mild AD dementia. 3. Participant must have evidence of cerebral amyloidosis (A+) by either positive amyloid PET scan read by central imaging lab or CSF amyloid beta test result indicative of amyloid positivity. 4. Participant must meet the following inclusion criteria to define clinical severity: a. MMSE score of between 21 and 29 points b. CDR-GS of 0.5 to 1.0. c. CDR Memory Box score >0.5 d. WMS-IV LMII score at least 1 standard deviation below age-adjusted mean i. ≤ 15 for age 50 to 64 years ii. ≤12 for age 65 to 69 years iii. ≤11 for age 70 to 74 years iv. ≤9 for age 75 to 79 years v. ≤7 for age 80 to 90 years 5. If the participant is receiving symptomatic AD medications such as an acetyl choline esterase inhibitor, (e.g. donepezil, rivastigmine, galantamine), or memantine, the dosing regimen must have been stable for at least 12 weeks prior to screening and is not expected to change during study participation. 6. If the participant is receiving other medications for AD related symptoms or associated conditions, the dosing regimen must have been stable for at least 4 weeks prior to screening and not expected to change during study participation. Symptoms must be considered adequately and stably controlled by the investigator, without marked changes in medication anticipated for the duration of the study.
- Body weight ≥45 kg to ≤120 kg with BMI between 17 and 34.9 kg/m2, inclusive. 8. A female participant is eligible to participate if she is not pregnant or breastfeeding, and if she is of child-bearing potential follows contraception requirements outlined in the protocol. 9. A male participant is eligible to participate if he follows contraception requirements outlined in the protocol. 10. Participant is willing and able to give informed consent which includes compliance with the requirements and restrictions listed in the ICF. 11. Availability of an adult person who has frequent and sufficient contact with the participant is able to provide accurate information regarding the participant’s cognitive and functional abilities, agrees to provide information at clinic visits, and signs the ICF of the study partner.
Exclusion Criteria
- Evidence of any neurological condition other than AD that may contribute to cognitive impairment 2. History or presence of vascular disease that has the potential to affect cognitive function. 3. History or presence of stroke within the past 1 year or recent transient ischemic attack within 180 days before screening. 4. History of severe, clinically significant CNS trauma. 5. History or presence of intracranial tumor. 6. Presence of ongoing infection(s) that may affect brain function, or history of infections that resulted in neurologic sequelae. 7. History of primary psychiatric diagnosis that the investigator considers may interfere with study assessments 8. Columbia Suicide Severity Rating Scale (C-SSRS) suicidal ideation Type 4 or 5, suicidal behaviour or participant has been assessed to be at risk of suicide, in the opinion of the investigator within 6 months before Screening through the Baseline Visit, or has been hospitalized or treated for suicidal behaviour in the past 2 years
- Participant has history of alcohol or moderate to severe substance use disorder within the past 2 years. 10. MRI evidence based on central read of: a. >3 lacunar infarcts. b. Stroke involving a major vascular territory, severe small vessel, or white matter disease. c. Any territorial/Cortical/Other infarct >1 cm3. d. White matter hyperintense lesions on the FLAIR sequence that correspond to an overall Fazekas score of 3. e. >4 microhemorrhages. f. Any areas of superficial hemosiderosis. g. A single macrohmorrhage greater than 10 mm at greatest diameter. h. Vasogenic edema. i. Cerebral contusion, encephalomalacia, aneurysms, vascular malformations, or infective lesions. j. Space occupying lesions or brain tumors. k. Significant cerebral vascular pathology. l. Hydrocephalus/Normal pressure hydrocephalus. m. Other MRI findings contraindicating participation in the study such as subarachnoid hemorrhage. 11. Unable to tolerate MRI procedures or has a contraindication to MRI. 12. History suggestive of exposure to, or past tuberculosis (TB) infection should undergo screening for TB disease 13. Chronic active immune disorder requiring systemic immunosuppressive therapy within 6 months prior to Screening 14. Serum vitamin B12 concentration < LLN or in the low normal range 15. Folate < LLN or TSH > ULN 16. Hemoglobin A1c >8% or poorly controlled diabetes during the last 12 weeks.
- History of cancer 18. Known history of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric, human, or humanized antibodies or fusion proteins. 19. Planned surgery during the study which requires general, spinal, or epidural anesthesia that would take place during the study. 20. Key exclusionary medications include: a. antipsychotics, opiates/opioids, cannabinoids, hypnotics, antidepressants, mood stabilizers, or stimulants that are used on a chronic basis, are exclusionary if not consistent with the following rule: treatment has to have been at a stable dose for at least 4 weeks before screening and should remain stable during the study b. Any biologic drugs with systemic exposure, whether investigational or approved, used within 6 months before screening. c. Any disease modification drug for AD, such as aducanumab and lecanemab, whether investigational or approved, used within 6 months before screening. d. Anticoagulation medications within 90 days of screening and during the study e. Systemic immunosuppressive therapy within 6 months before screening and during the study 21. Impaired coagulation or platelet count <50,000/uL. 22. Participant resides in a skilled nursing facility, convalescent home, or longterm care facility. 23. If at screening, a participant with comorbidities that are likely to require non-study related medical procedures with additional radiation exposure is identified, the investigator must discuss with the medical monitor to determine if the total radiation exposure would be deemed to exceed maximum radioactive exposure allowed by country-specific regulations or 40 mSv for the study (whichever is the lower value). 24. Known genetic predisposition for clotting disorder or hemorrhagic disease.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Finland | Not Recruiting | 19 Dec 2023 | 20 |
 France | Not Recruiting | 19 Dec 2023 | 24 |
 Germany | Not Recruiting | 19 Dec 2023 | 6 |
 Italy | Not Recruiting | 19 Dec 2023 | 25 |
 The Netherlands | Not Recruiting | 19 Dec 2023 | — |
 Norway | Not Recruiting | 19 Dec 2023 | 16 |
 Spain | Not Recruiting | 19 Dec 2023 | 30 |
 Sweden | Not Recruiting | 19 Dec 2023 | 16 |
| Netherlands | — | — | 3 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Amyvid 1900 MBq/mL solution for injection | Other | SOLUTION FOR INJECTION | INTRAVENOUS USE | 370 | 2 | PRD757923 |
Neuraceq 300 MBq/mL solution for injection | Other | SOLUTION FOR INJECTION | INTRAVENOUS USE | 300 | 2 | PRD6020031 |
0.9% (w/v) sodium chlorideNormal Saline | Placebo | N/A | — | — | — | N/A |
VIZAMYL 400 MBq/mL solution for injection | Other | SOLUTION FOR INJECTION | INTRAVENOUS USE | 185 | 2 | PRD1651609 |
Amyvid 800 MBq/mL solution for injection | Other | SOLUTION FOR INJECTION | INTRAVENOUS USE | 370 | 2 | PRD755239 |