<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03234686</url>
  </required_header>
  <id_info>
    <org_study_id>DEF001</org_study_id>
    <nct_id>NCT03234686</nct_id>
  </id_info>
  <brief_title>Deferiprone to Delay Dementia (The 3D Study)</brief_title>
  <official_title>Deferiprone to Delay Dementia (The 3D Study): a Clinical Proof of Concept Study</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Neuroscience Trials Australia</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>The Florey Institute of Neuroscience and Mental Health</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Neuroscience Trials Australia</source>
  <oversight_info>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This study is a phase 2, randomised, placebo-controlled, multicentre study to investigate the&#xD;
      safety and efficacy of Deferiprone in participants with Prodromal Alzheimer's Disease (pAD)&#xD;
      and Mild Alzheimer's Disease (mAD). In this phase 2 study, the investigators aim to determine&#xD;
      whether Deferiprone (15 mg/kg BID orally) slows cognitive decline in Alzheimer's patients. As&#xD;
      secondary outcomes, safety and iron levels in the brain will be evaluated.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This Phase II study is designed as a randomised, double-blinded, placebo controlled,&#xD;
      multi-centre study for subjects with evidence of amyloid positive pAD or mAD.&#xD;
&#xD;
      Participants will be assigned randomly to two groups (Group 1 Deferiprone (15mg/kg BID&#xD;
      orally), Group 2: Placebo). Participants will have a 2 in 3 chance to be placed in the&#xD;
      Deferiprone group.&#xD;
&#xD;
      The study will enrol approximately 171 participants over 4 sites in Australia. The overall&#xD;
      duration for patients will be 54 weeks. This includes a 55-day screening period, and visits&#xD;
      on Day 1, weeks 13, 26, 38,52, and a two-week follow-up visit.&#xD;
&#xD;
      Participants will be screened for the study after signing the approved informed consent form.&#xD;
      As part of the 55-day screening phase, subjects will undertake an extensive medical and&#xD;
      neurological assessments as well as a PET scan.&#xD;
&#xD;
      At the baseline visit, following the screening phase, blood and urine will be taken for&#xD;
      safety monitoring and for measuring APOE-4 gene status. Baseline signs and symptoms will be&#xD;
      collected. An MRI will be performed All patients will start with study medication at the&#xD;
      Baseline visit.&#xD;
&#xD;
      Participants will return to the centre on Weeks 13, 26, 38, 52 (or early termination) to&#xD;
      undertake a neurological examination as well as an assessment of blood samples taken at the&#xD;
      visit.&#xD;
&#xD;
      Participants must also attend weekly blood tests.&#xD;
&#xD;
      SAE's, AE's and changes to concomitant medications will be observed and evaluated throughout&#xD;
      the study. Each study visit will have a 7-day window after the due date to account for&#xD;
      scheduling conflicts/holidays/weekends.&#xD;
&#xD;
      Participants will be given additional study product to account for the 7-day window.&#xD;
&#xD;
      Participants must attend the weekly pathology visits with a 3-day window of the scheduled&#xD;
      date or risk termination from the trial.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">January 19, 2018</start_date>
  <completion_date type="Anticipated">September 2023</completion_date>
  <primary_completion_date type="Anticipated">September 2022</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Double (Participant, Care Provider)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Efficacy of Deferiprone</measure>
    <time_frame>12 months</time_frame>
    <description>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</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability)</measure>
    <time_frame>12 months</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Brain Iron Levels</measure>
    <time_frame>12 months</time_frame>
    <description>Using MRI to compare iron levels in various brain regions of the Deferiprone and placebo treatment groups at baseline and 12 months.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>The effect of Deferiprone on the episodic memory, executive function and attention composites</measure>
    <time_frame>12 months</time_frame>
    <description>Measured by scores on the NTB at 12 months relative to baseline</description>
  </other_outcome>
  <other_outcome>
    <measure>The Association with Iron levels in the Brain and Cognitive Decline</measure>
    <time_frame>12 months</time_frame>
    <description>Using MRI to evaluate if cognitive performance is associated with a change in iron levels over a 12-month period relative to baseline.</description>
  </other_outcome>
  <other_outcome>
    <measure>The Potential for Brain Iron Load to be Used to Stratify Responsiveness to Deferiprone</measure>
    <time_frame>12 months</time_frame>
    <description>Measured by baseline iron MRI and change in cognitive ability from baseline at 12 months.</description>
  </other_outcome>
  <other_outcome>
    <measure>The Potential for APOE Genotype to be Used to Stratify Responsiveness to Deferiprone</measure>
    <time_frame>12 months</time_frame>
    <description>Measured by APOE genotype and changes in cognitive ability from baseline at 12 months</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">171</enrollment>
  <condition>Mild Cognitive Impairment</condition>
  <condition>Prodromal Alzheimer's Disease</condition>
  <condition>Mild Alzheimer's Disease</condition>
  <arm_group>
    <arm_group_label>Deferiprone</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients will orally receive the equivalent 15 mg/kg of 600mg delayed release Deferiprone tablets twice daily.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Patients will receive matching placebo tablets designed to mimic the experimental treatment, twice daily</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Deferiprone 600mg delayed release tablets</intervention_name>
    <description>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.</description>
    <arm_group_label>Deferiprone</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo Oral Tablet</intervention_name>
    <description>The placebo will mimic the Deferiprone arm in every way, except the placebo will not include the active ingredient</description>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Able to provide written informed consent in accordance with federal, local and&#xD;
             institutional guidelines. For subjects unable to provide written consent, consent will&#xD;
             be provided by the Person Responsible per local regulations.&#xD;
&#xD;
          2. Age ≥65 years, or ≥55 years if they have been diagnosed by a psychiatrist or&#xD;
             neurologist with dementia, or if they have a validated previous positive amyloid PET&#xD;
             scan.&#xD;
&#xD;
          3. Weight between 40 and 120 kg&#xD;
&#xD;
          4. Have an available caregiver&#xD;
&#xD;
          5. Have ≥ 6 years of education (any) and able to follow testing instructions.&#xD;
&#xD;
          6. Have visual and auditory acuity sufficient to perform neuropsychological testing.&#xD;
&#xD;
          7. Have prior evidence of AD pathology, by a positive amyloid assessment, or amyloid PET&#xD;
             scan.&#xD;
&#xD;
          8. Demonstrate abnormal memory function in the last 6 months or at screening:&#xD;
             International Shopping List Test (ISLT) &gt;1.5 SD below the age adjusted mean&#xD;
&#xD;
          9. Subjective or clinical history of retrospective cognitive decline ≥6 months&#xD;
&#xD;
         10. Evidence of mild symptomatology, as defined by a screening MMSE score of ≥ 20 points&#xD;
&#xD;
         11. Meet National Institute on Ageing/Alzheimer's Association Diagnostic Guidelines for&#xD;
             Alzheimer's Disease (NIAAA) research criteria for mAD or pAD&#xD;
&#xD;
         12. If receiving medication for symptomatic AD, have a stable dosing regimen for 3 months&#xD;
             prior to screening.&#xD;
&#xD;
         13. Females of Child Bearing Potential (FCBP) must have confirmed negative serum pregnancy&#xD;
             test within the 21 days prior to randomization.&#xD;
&#xD;
         14. FCBP and male subjects who are sexually active with FCBP must agree to use highly&#xD;
             effective contraception during the study and until 90 days after the last dose of&#xD;
             treatment (for sexually active male participants whose partners are FCBP) or until 30&#xD;
             days after the last dose of treatment (for women of childbearing potential&#xD;
             participants).&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Clinically significant haematological disorder, including moderate or severe anaemia&#xD;
             (blood haemoglobin &lt;110 g/L, WHO definition)&#xD;
&#xD;
          2. Iron deficiency (serum ferritin &lt; 10 ng/mL)&#xD;
&#xD;
          3. Clinically significant abnormal haematological results (sufficiently outside the&#xD;
             normal range to warrant further investigation). Mild anaemia (haemoglobin ≥110 g/L) is&#xD;
             not an exclusion.&#xD;
&#xD;
          4. Clinically significant abnormal renal or liver function results (sufficiently outside&#xD;
             the normal range to warrant further investigation)&#xD;
&#xD;
          5. Presence of non-AD condition that may affect cognition, such as but not limited to&#xD;
             Parkinson's Disease (PD), normal pressure hydrocephalus, sleep apnoea requiring O2&#xD;
             treatment&#xD;
&#xD;
          6. Clinically evident vascular disease that could potentially affect the brain, such as&#xD;
             but not limited to significant carotid or vertebral stenosis, aortic aneurysm,&#xD;
             cerebral haemorrhage&#xD;
&#xD;
          7. History of any stroke in the past 2 years, or transient ischemic attack within the&#xD;
             last 6 months&#xD;
&#xD;
          8. History of persistent neurologic deficit, intracranial tumour or structural brain&#xD;
             damage&#xD;
&#xD;
          9. History of infection that could affect brain function (eg HIV and syphilis)&#xD;
&#xD;
         10. Autoimmune disorders that potentially cause progressive neurologic disease with&#xD;
             associated cognitive deficits, such as but not limited to multiple sclerosis, lupus&#xD;
&#xD;
         11. Major psychiatric illness (depression is acceptable if patient has not had an episode&#xD;
             within the past year or is considered in remission or controlled by treatment)&#xD;
&#xD;
         12. A history of relapsing neutropenia.&#xD;
&#xD;
         13. Presence of agranulocytosis or with a history of agranulocytosis&#xD;
&#xD;
         14. Known hypersensitivity to DFP or excipients.&#xD;
&#xD;
         15. Alcohol and/or substance abuse&#xD;
&#xD;
         16. MRI evidence of clinically-significant cerebrovascular pathology. Focal white matter&#xD;
             lesions, ≤ 2 lacunar infarcts in non-critical sites and other minor pathology assessed&#xD;
             by the investigator to not be causing the current cognitive impairment, will not lead&#xD;
             to exclusion.&#xD;
&#xD;
         17. Active major medical illness&#xD;
&#xD;
         18. FCBP not using adequate method of contraception or who is pregnant or nursing&#xD;
&#xD;
         19. Inability to provide informed consent&#xD;
&#xD;
         20. Participation in another clinical trial within 3 months prior to inclusion in the&#xD;
             study&#xD;
&#xD;
         21. Subjects for whom MRI is contraindicated (severe claustrophobia, pacemaker,&#xD;
             incompatible surgical material, unmovable electronic pump implant)&#xD;
&#xD;
         22. Negative amyloid PET scan or CSF in the last 2 years.&#xD;
&#xD;
         23. Hospital Anxiety and Depression Scale (scores &gt; 8/21 are disqualified).&#xD;
&#xD;
         24. Subject cannot commit to regular blood tests with the interval between tests not&#xD;
             exceeding 10 days from the scheduled visit for the duration of the study.&#xD;
&#xD;
         25. Subject has planned surgery which does not permit regular blood tests with the&#xD;
             interval between tests not exceeding 10 days from the scheduled visit.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>65 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Ashley I. Bush</last_name>
    <role>Principal Investigator</role>
    <affiliation>The Florey Institute of Neuroscience and Mental Health</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>KaRa Institute of Neurological Diseases</name>
      <address>
        <city>Macquarie Park</city>
        <state>New South Wales</state>
        <zip>2113</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hunter New England Local Health District</name>
      <address>
        <city>Waratah</city>
        <state>New South Wales</state>
        <zip>2298</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Box Hill Hospital</name>
      <address>
        <city>Box Hill</city>
        <state>Victoria</state>
        <zip>3128</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Austin Health</name>
      <address>
        <city>Heidelberg</city>
        <state>Victoria</state>
        <zip>3084</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Alfred Hospital</name>
      <address>
        <city>Melbourne</city>
        <state>Victoria</state>
        <zip>3004</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>NeuroCentrix</name>
      <address>
        <city>Noble Park</city>
        <state>Victoria</state>
        <zip>3174</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Royal Melbourne Hospital</name>
      <address>
        <city>Parkville</city>
        <state>Victoria</state>
        <zip>3050</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Australian Alzheimer's Research Foundation</name>
      <address>
        <city>Nedlands</city>
        <state>Western Australia</state>
        <zip>6009</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Australia</country>
  </location_countries>
  <verification_date>December 2021</verification_date>
  <study_first_submitted>July 23, 2017</study_first_submitted>
  <study_first_submitted_qc>July 26, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">July 31, 2017</study_first_posted>
  <last_update_submitted>March 8, 2022</last_update_submitted>
  <last_update_submitted_qc>March 8, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">March 23, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Dementia</keyword>
  <keyword>Alzheimer's Disease</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Alzheimer Disease</mesh_term>
    <mesh_term>Dementia</mesh_term>
    <mesh_term>Cognitive Dysfunction</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Deferiprone</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03234686
org study id: DEF001
nct id: NCT03234686
lead sponsor: 
collaborator: 
is fda regulated drug: No
is fda regulated device: No
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.
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.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Double (Participant, Care Provider)
measure: Efficacy of Deferiprone
time frame: 12 months
description: 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
measure: Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability)
time frame: 12 months
description: 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.
measure: Brain Iron Levels
time frame: 12 months
description: Using MRI to compare iron levels in various brain regions of the Deferiprone and placebo treatment groups at baseline and 12 months.
measure: The effect of Deferiprone on the episodic memory, executive function and attention composites
time frame: 12 months
description: Measured by scores on the NTB at 12 months relative to baseline
measure: The Association with Iron levels in the Brain and Cognitive Decline
time frame: 12 months
description: Using MRI to evaluate if cognitive performance is associated with a change in iron levels over a 12-month period relative to baseline.
measure: The Potential for Brain Iron Load to be Used to Stratify Responsiveness to Deferiprone
time frame: 12 months
description: Measured by baseline iron MRI and change in cognitive ability from baseline at 12 months.
measure: The Potential for APOE Genotype to be Used to Stratify Responsiveness to Deferiprone
time frame: 12 months
description: Measured by APOE genotype and changes in cognitive ability from baseline at 12 months
arm group label: Deferiprone
arm group type: Experimental
description: Patients will orally receive the equivalent 15 mg/kg of 600mg delayed release Deferiprone tablets twice daily.
arm group label: Placebo
arm group type: Placebo Comparator
description: Patients will receive matching placebo tablets designed to mimic the experimental treatment, twice daily
intervention type: Drug
intervention name: Deferiprone 600mg delayed release tablets
description: 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.
arm group label: Deferiprone
intervention type: Drug
intervention name: Placebo Oral Tablet
description: The placebo will mimic the Deferiprone arm in every way, except the placebo will not include the active ingredient
arm group label: Placebo
criteria: 
gender: All
minimum age: 65 Years
maximum age: N/A
healthy volunteers: No
last name: Ashley I. Bush
role: Principal Investigator
affiliation: The Florey Institute of Neuroscience and Mental Health
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: Australia
responsible party type: Sponsor
mesh term: Alzheimer Disease
mesh term: Dementia
mesh term: Cognitive Dysfunction
mesh term: Deferiprone