Deferiprone to Delay Dementia (The 3D Study)

• ClinicalTrials.gov Identifier: NCT03234686
• Recruitment Status: Active, not recruiting
• First Posted: July 31, 2017
• Last Update Posted: March 23, 2022
• Sponsor: Neuroscience Trials Australia
• Collaborator: The Florey Institute of Neuroscience and Mental Health
• Information provided by (Responsible Party): Neuroscience Trials Australia

Tracking Information

• First Submitted Date: July 23, 2017
• First Posted Date: July 31, 2017
• Last Update Posted Date: March 23, 2022
• Actual Study Start Date: January 19, 2018
• Estimated Primary Completion Date: September 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 10, 2017)

Efficacy of Deferiprone [ Time Frame: 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

Original Primary Outcome Measures (submitted: July 26, 2017)

Efficacy of Deferiprone [ Time Frame: 12 months ]

Comparison of the efficacy of DFP (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

Current Secondary Outcome Measures (submitted: September 10, 2017)

• Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability) [ Time Frame: 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 [ Time Frame: 12 months ]
  Using MRI to compare iron levels in various brain regions of the Deferiprone and placebo treatment groups at baseline and 12 months.

Original Secondary Outcome Measures (submitted: July 26, 2017)

• Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability) [ Time Frame: 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 [ Time Frame: 12 months ]
  Using MRI to compare iron levels in various brain regions of the DFP and placebo treatment groups at baseline and 12 months.

Current Other Pre-specified Outcome Measures (submitted: September 10, 2017)

• The effect of Deferiprone on the episodic memory, executive function and attention composites [ Time Frame: 12 months ]
  Measured by scores on the NTB at 12 months relative to baseline
• The Association with Iron levels in the Brain and Cognitive Decline [ Time Frame: 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 [ Time Frame: 12 months ]
  Measured by baseline iron MRI and change in cognitive ability from baseline at 12 months.
• The Potential for APOE Genotype to be Used to Stratify Responsiveness to Deferiprone [ Time Frame: 12 months ]
  Measured by APOE genotype and changes in cognitive ability from baseline at 12 months

Original Other Pre-specified Outcome Measures (submitted: July 26, 2017)

• The effect of DFP on the episodic memory, executive function and attention composites [ Time Frame: 12 months ]
  Measured by scores on the NTB at 12 months relative to baseline
• The Association with Iron levels in the Brain and Cognitive Decline [ Time Frame: 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 DFP [ Time Frame: 12 months ]
  Measured by baseline iron MRI and change in cognitive ability from baseline at 12 months.
• The Potential for APOE Genotype to be Used to Stratify Responsiveness to DFP [ Time Frame: 12 months ]
  Measured by APOE genotype and changes in cognitive ability from baseline at 12 months

Descriptive Information

• Brief Title: Deferiprone to Delay Dementia (The 3D Study)
• Official Title: Deferiprone to Delay Dementia (The 3D Study): a Clinical Proof of Concept Study
• 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.

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Care Provider); Primary Purpose: Treatment

Condition

• Mild Cognitive Impairment
• Prodromal Alzheimer's Disease
• Mild Alzheimer's Disease

Intervention

• Drug: Deferiprone 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.
• Drug: Placebo Oral Tablet
  The placebo will mimic the Deferiprone arm in every way, except the placebo will not include the active ingredient

Study Arms

• Experimental: Deferiprone
  Patients will orally receive the equivalent 15 mg/kg of 600mg delayed release Deferiprone tablets twice daily.
  Intervention: Drug: Deferiprone 600mg delayed release tablets
• Placebo Comparator: Placebo
  Patients will receive matching placebo tablets designed to mimic the experimental treatment, twice daily
  Intervention: Drug: Placebo Oral Tablet

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Estimated Enrollment (submitted: July 26, 2017): 171
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: September 2023
• Estimated Primary Completion Date: September 2022 (Final data collection date for primary outcome measure)

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 65 Years and older (Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia

Administrative Information

• NCT Number: NCT03234686
• Other Study ID Numbers: DEF001
• Has Data Monitoring Committee: Not Provided

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Neuroscience Trials Australia
• Original Responsible Party: Same as current
• Current Study Sponsor: Neuroscience Trials Australia
• Original Study Sponsor: Same as current
• Collaborators: The Florey Institute of Neuroscience and Mental Health

Investigators

• Principal Investigator: Ashley I. Bush; The Florey Institute of Neuroscience and Mental Health

• PRS Account: Neuroscience Trials Australia
• Verification Date: December 2021