Clinical trial NCT03234686: Deferiprone to Delay Dementia (The 3D Study)
Official title: Deferiprone to Delay Dementia (The 3D Study): a Clinical Proof of Concept Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Mild Cognitive Impairment
Prodromal Alzheimer's Disease
Mild Alzheimer's Disease
Keywords: Dementia
Alzheimer's Disease
Lead sponsor: Neuroscience Trials Australia
Sponsor class: OTHER
Collaborators: name: The Florey Institute of Neuroscience and Mental Health
First posted: 2017-07-31
Enrollment: 81
Sex: ALL
Minimum age (years): 65
Standard ages: OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Efficacy of Deferiprone
timeFrame: 12 months
Secondary outcomes:
measure: Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability)
timeFrame: 12 months
measure: Brain Iron Levels
timeFrame: 12 months
Other outcomes:
measure: The effect of Deferiprone on the episodic memory, executive function and attention composites
timeFrame: 12 months
measure: The Association with Iron levels in the Brain and Cognitive Decline
timeFrame: 12 months
measure: The Potential for Brain Iron Load to be Used to Stratify Responsiveness to Deferiprone
timeFrame: 12 months
measure: The Potential for APOE Genotype to be Used to Stratify Responsiveness to Deferiprone
timeFrame: 12 months
Locations:
city: Macquarie Park
country: Australia
facility: KaRa Institute of Neurological Diseases
state: New South Wales
city: Waratah
country: Australia
facility: Hunter New England Local Health District
state: New South Wales
city: Box Hill
country: Australia
facility: Box Hill Hospital
state: Victoria
city: Heidelberg
country: Australia
facility: Austin Health
state: Victoria
city: Melbourne
country: Australia
facility: Alfred Hospital
state: Victoria
city: Noble Park
country: Australia
facility: NeuroCentrix
state: Victoria
city: Parkville
country: Australia
facility: Royal Melbourne Hospital
state: Victoria
city: Nedlands
country: Australia
facility: Australian Alzheimer's Research Foundation
state: Western Australia
Study officials:
affiliation: The Florey Institute of Neuroscience and Mental Health
name: Ashley I. Bush
role: PRINCIPAL_INVESTIGATOR
References: