Mild Alzheimer's Disease, Mild Cognitive Impairment, Prodromal Alzheimer's Disease
Conditions
Keywords
Dementia, Alzheimer's Disease
Brief summary
This study is a phase 2, randomised, placebo-controlled, multicentre study to investigate the safety and efficacy of Deferiprone in participants with Prodromal Alzheimer's Disease (pAD) and Mild Alzheimer's Disease (mAD). In this phase 2 study, the investigators aim to determine whether Deferiprone (15 mg/kg BID orally) slows cognitive decline in Alzheimer's patients. As secondary outcomes, safety and iron levels in the brain will be evaluated.
Detailed description
This Phase II study is designed as a randomised, double-blinded, placebo controlled, multi-centre study for subjects with evidence of amyloid positive pAD or mAD. Participants will be assigned randomly to two groups (Group 1 Deferiprone (15mg/kg BID orally), Group 2: Placebo). Participants will have a 2 in 3 chance to be placed in the Deferiprone group. The study will enrol approximately 171 participants over 4 sites in Australia. The overall duration for patients will be 54 weeks. This includes a 55-day screening period, and visits on Day 1, weeks 13, 26, 38,52, and a two-week follow-up visit. Participants will be screened for the study after signing the approved informed consent form. As part of the 55-day screening phase, subjects will undertake an extensive medical and neurological assessments as well as a PET scan. At the baseline visit, following the screening phase, blood and urine will be taken for safety monitoring and for measuring APOE-4 gene status. Baseline signs and symptoms will be collected. An MRI will be performed All patients will start with study medication at the Baseline visit. Participants will return to the centre on Weeks 13, 26, 38, 52 (or early termination) to undertake a neurological examination as well as an assessment of blood samples taken at the visit. Participants must also attend weekly blood tests. SAE's, AE's and changes to concomitant medications will be observed and evaluated throughout the study. Each study visit will have a 7-day window after the due date to account for scheduling conflicts/holidays/weekends. Participants will be given additional study product to account for the 7-day window. Participants must attend the weekly pathology visits with a 3-day window of the scheduled date or risk termination from the trial.
Interventions
DRUGDeferiprone 600mg delayed release tablets
The active substance, Deferiprone, is a member of the 3-hydroxypyrid-4-one class of iron chelators, which have a high affinity for ferric iron, binding it in a 3:1 (Deferiprone:iron) molar ratio.
DRUGPlacebo Oral Tablet
The placebo will mimic the Deferiprone arm in every way, except the placebo will not include the active ingredient
Sponsors
The Florey Institute of Neuroscience and Mental Health
Neuroscience Trials Australia
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Caregiver)
Eligibility
Sex/Gender
ALL
Age
65 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Able to provide written informed consent in accordance with federal, local and institutional guidelines. For subjects unable to provide written consent, consent will be provided by the Person Responsible per local regulations. 2. Age ≥65 years, or ≥55 years if they have been diagnosed by a psychiatrist or neurologist with dementia, or if they have a validated previous positive amyloid PET scan. 3. Weight between 40 and 120 kg 4. Have an available caregiver 5. Have ≥ 6 years of education (any) and able to follow testing instructions. 6. Have visual and auditory acuity sufficient to perform neuropsychological testing. 7. Have prior evidence of AD pathology, by a positive amyloid assessment, or amyloid PET scan. 8. Demonstrate abnormal memory function in the last 6 months or at screening: International Shopping List Test (ISLT) \>1.5 SD below the age adjusted mean 9. Subjective or clinical history of retrospective cognitive decline ≥6 months 10. Evidence of mild symptomatology, as defined by a screening MMSE score of ≥ 20 points 11. Meet National Institute on Ageing/Alzheimer's Association Diagnostic Guidelines for Alzheimer's Disease (NIAAA) research criteria for mAD or pAD 12. If receiving medication for symptomatic AD, have a stable dosing regimen for 3 months prior to screening. 13. Females of Child Bearing Potential (FCBP) must have confirmed negative serum pregnancy test within the 21 days prior to randomization. 14. FCBP and male subjects who are sexually active with FCBP must agree to use highly effective contraception during the study and until 90 days after the last dose of treatment (for sexually active male participants whose partners are FCBP) or until 30 days after the last dose of treatment (for women of childbearing potential participants).
Exclusion criteria
1. Clinically significant haematological disorder, including moderate or severe anaemia (blood haemoglobin \<110 g/L, WHO definition) 2. Iron deficiency (serum ferritin \< 10 ng/mL) 3. Clinically significant abnormal haematological results (sufficiently outside the normal range to warrant further investigation). Mild anaemia (haemoglobin ≥110 g/L) is not an exclusion. 4. Clinically significant abnormal renal or liver function results (sufficiently outside the normal range to warrant further investigation) 5. Presence of non-AD condition that may affect cognition, such as but not limited to Parkinson's Disease (PD), normal pressure hydrocephalus, sleep apnoea requiring O2 treatment 6. Clinically evident vascular disease that could potentially affect the brain, such as but not limited to significant carotid or vertebral stenosis, aortic aneurysm, cerebral haemorrhage 7. History of any stroke in the past 2 years, or transient ischemic attack within the last 6 months 8. History of persistent neurologic deficit, intracranial tumour or structural brain damage 9. History of infection that could affect brain function (eg HIV and syphilis) 10. Autoimmune disorders that potentially cause progressive neurologic disease with associated cognitive deficits, such as but not limited to multiple sclerosis, lupus 11. Major psychiatric illness (depression is acceptable if patient has not had an episode within the past year or is considered in remission or controlled by treatment) 12. A history of relapsing neutropenia. 13. Presence of agranulocytosis or with a history of agranulocytosis 14. Known hypersensitivity to DFP or excipients. 15. Alcohol and/or substance abuse 16. MRI evidence of clinically-significant cerebrovascular pathology. Focal white matter lesions, ≤ 2 lacunar infarcts in non-critical sites and other minor pathology assessed by the investigator to not be causing the current cognitive impairment, will not lead to exclusion. 17. Active major medical illness 18. FCBP not using adequate method of contraception or who is pregnant or nursing 19. Inability to provide informed consent 20. Participation in another clinical trial within 3 months prior to inclusion in the study 21. Subjects for whom MRI is contraindicated (severe claustrophobia, pacemaker, incompatible surgical material, unmovable electronic pump implant) 22. Negative amyloid PET scan or CSF in the last 2 years. 23. Hospital Anxiety and Depression Scale (scores \> 8/21 are disqualified). 24. Subject cannot commit to regular blood tests with the interval between tests not exceeding 10 days from the scheduled visit for the duration of the study. 25. Subject has planned surgery which does not permit regular blood tests with the interval between tests not exceeding 10 days from the scheduled visit.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Efficacy of Deferiprone | 12 months | Comparison of the efficacy of Deferiprone (15 mg/kg) administered orally twice a day with a matching placebo in subjects with pAD (MCI with brain amyloid pathology) or mAD at 12 months relative to baseline. This will be measured by a series of paper and electronic assessments called the NTB |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability) | 12 months | Safety and tolerability will be assessed by the incidence and severity of AEs and changes from baseline of all relevant parameters, including clinical laboratory values, vital signs, ECG and other safety biomarkers. Severity of AEs will be assessed according to the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE), Version 4.03. All subjects will be monitored for AEs until resolution. |
| Brain Iron Levels | 12 months | Using MRI to compare iron levels in various brain regions of the Deferiprone and placebo treatment groups at baseline and 12 months. |
Other
| Measure | Time frame | Description |
|---|---|---|
| The effect of Deferiprone on the episodic memory, executive function and attention composites | 12 months | Measured by scores on the NTB at 12 months relative to baseline |
| The Potential for APOE Genotype to be Used to Stratify Responsiveness to Deferiprone | 12 months | Measured by APOE genotype and changes in cognitive ability from baseline at 12 months |
| The Association with Iron levels in the Brain and Cognitive Decline | 12 months | Using MRI to evaluate if cognitive performance is associated with a change in iron levels over a 12-month period relative to baseline. |
| The Potential for Brain Iron Load to be Used to Stratify Responsiveness to Deferiprone | 12 months | Measured by baseline iron MRI and change in cognitive ability from baseline at 12 months. |
Countries
Australia
Outcome results
None listed