ANZCTR - Registration

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Trial registered on ANZCTR

Registration number

ACTRN12621000726853

Ethics application status

Approved

Date submitted

22/01/2021

Date registered

10/06/2021

Date last updated

5/06/2024

Date data sharing statement initially provided

10/06/2021

Type of registration

Prospectively registered

Titles & IDs

Public title

Probucol in Alzheimer's Study 2020 (PIA 2020)

Scientific title

A double-blind, placebo controlled, randomised phase II trial of probucol in Alzheimer’s disease: The impact on cognition

Secondary ID [1]

None

Universal Trial Number (UTN)

U1111-1259-0486

Trial acronym

PIA-Study

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Alzheimer's disease

Condition category

Condition code

Neurological

Alzheimer's disease

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

The PIA-Study is a randomised controlled research trial examining whether intervention with Probucol supports cognitive function in AD. Participants are randomly assigned to one of two groups, group 1 (placebo) or group 2 (treatment).
After consenting to participate in the study, screening procedures will occur between Days -56 and -1. All subjects must have measurable mild or moderate Alzheimer’s disease, and accordingly screening procedures will include:
• A positive amyloid biomarker (PET scan) indicative of AD pathology,
• Mini-mental-state examination (MMSE) score of 20 or greater,
• Free and cued selective reminding test (FCSRT) cueing index score of less than or equal to 0.79, OR a free recall of less than or equal to 17.
• Clinical Dementia Rating (CDR) global score of 0.5 or 1.0.

Treatment:
Chemical name: 4,4’-[Propan-2,2-diylbis(sulfandiyl)]bis[2,6-bis(1,1- dimethylethyl) phenol]
The proposed dose of Probucol for this protocol adopts contemporary usage published in contemporary clinical trials at 250 mg twice a day. Probucol will be supplied in a commercially available form known as Lorelco.
Study medication will commence (day 1, week 1) with a single dose escalation design with all participants receiving initially for two-weeks 1 X placebo per day. Unused medication is to be returned at every visit to monitor drug compliance. Thereafter, participants will be randomised into the two groups.
Arm 1 (treatment)
Subjects will be dosed as:
• Week 3: 1 x 250 mg Lorelco™ (or matching placebo) taken in the morning, with food.
• Week 4 – 104: 1 x 250 mg Lorelco™ (or matching placebo) taken in the morning, with food. 1 x 250 mg probucol (or matching placebo) taken in the evening, with food.
Study medication will be dispensed as a 2-week supply for 1 interval (weeks 1 & 2); a 2-week supply for weeks 3 & 4; followed by 2 X 10-week supplies and 6 X 13 week supply dispensed at each visit. Unused medication is to be returned at every visit to monitor drug compliance.

Intervention code [1]

Treatment: Drugs

Comparator / control treatment

Placebo composition: opaque capsules with no active ingredients and a filler of microcrystalline cellulose.
Study medication will commence (day 1, week 1) with a single dose escalation design with all participants receiving initially for two-weeks 1 X placebo per day. Unused tablets are to be returned to monitor drug compliance.
Arm 2 (placebo)
Subjects will be dosed as:
• Week 3: 1 x matching placebo taken in the morning, with food.
• Week 4 – 104: 1 x matching placebo taken in the morning, with food. 1 x matching placebo taken in the evening, with food.
Study medication will be dispensed as a 2-week supply for 1 interval (weeks 1 & 2); a 2-week supply for weeks 3 & 4; followed by 2 X 10-week supplies and 6 X 13 week supply dispensed at each visit. Unused tablets are to be returned at every visit to monitor drug compliance.

Control group

Placebo

Outcomes

Primary outcome [1]

To evaluate the preliminary efficacy of 2x daily 250 mg Lorelco™ on cognitive performance in Alzheimer’s patients over a 102 week treatment period

Timepoint [1]

The Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) will be completed at baseline (week 3, day 1), Week 26 (6 months), week 52 (1 year), week 78 (18 months), and week 104 (2 years; primary endpoint) from randomisation

Secondary outcome [1]

To evaluate cerebral amyloid abundance in the brain of Alzheimer’s Disease patients treated with Lorelco™ over a 102 week treatment period.

Timepoint [1]

PET scan; During screening phase (day -56 to day -1), and week 104 (2 years)

Secondary outcome [2]

To evaluate the Mesial temporal lobe (hippocampus and entorhinal cortex via Scheltens grading) in Alzheimer’s Disease patients treated with Lorelco™ over a 102 week treatment period.

Timepoint [2]

MRI scan: Volumetric isotropic T1 scan During Pre-baseline phase (week 1 to week 3), and week 104 (2 years)

Secondary outcome [3]

Activities of daily living will be assessed using the Alzheimer's Disease Co-operative Study Mild Cognitive Impairment Activities of Daily Living scale (ADCS-MCI-ADL24)

Timepoint [3]

This will be completed at pre-baseline, week 26 (6 months),and week 104 (2 years)

Secondary outcome [4]

Depression, anxiety, and stress will be assessed using Depression Anxiety Stress Scale (DASS-21)

Timepoint [4]

This will be completed at pre-baseline, week 26 (6 months), and week 104 (2 years

Secondary outcome [5]

To assess the safety and tolerability of Lorelco™ in patients with Alzheimer’s Disease via Incidence, type and severity of adverse events.
All AEs will be coded using the current version of the Medical Dictionary of Regulatory Activities (MedDRA). AE's will be assessed using;
-ECG
-Vital signs
-Laboratory evaluations
-Physical examination
-Neurological examination

Possible/know side effects;
diarrhea/loose stools will be self-repored
nausea/vomiting will be self-reported
rash, pruritus and other skin irritations will be assessed via physical assessment
ventricular arrhythmia (torsades de pointes) and QT prolongation will be assessed by ECG
syncope will be assessed via vital signs and physical assessment
gastrointestinal bleeding will be assessed via physical examination and questions about bowel movements
peripheral neuritis will be assessed via neurological examination

Timepoint [5]

Adverse event information is collected at Week 3, Week 4, Week 5, Week 6, Week 15, Week 20, Week 26 (6 months), Week 29, Week 39, Week 47, Week 52 (1 year), Week 55, Week 65, Week 73, Week 78 (18 months), Week 81, Week 91, Week 104 (2 years)

Secondary outcome [6]

To evaluate small vessel ischaemic lesion load in the brain of Alzheimer’s Disease patients treated with Lorelco™ over a 102 week treatment period.

Timepoint [6]

MRI scan: 3D FLAIR scan During Pre-baseline phase (week 1 to week 3), and week 104 (2 years)

Secondary outcome [7]

To evaluate micro bleed load and amyloid angiopathy in the brain of Alzheimer’s Disease patients treated with Lorelco™ over a 102 week treatment period.

Timepoint [7]

MRI scan: Susceptibility weighted imaging During Pre-baseline phase (week 1 to week 3), and week 104 (2 years)

Secondary outcome [8]

To evaluate the preliminary efficacy of 2x daily 250 mg Lorelco™ on cognitive performance in Alzheimer’s patients over a 102 week treatment period

Timepoint [8]

The mini-mental state examination (MMSE) will be completed at screening (day -56 to day -1) and week 104 (2 years)

Secondary outcome [9]

To evaluate global cortical atrophy (Pasquier scale) in the brain of Alzheimer’s Disease patients treated with Lorelco™ over a 102 week treatment period.

Timepoint [9]

MRI scan: Volumetric isotropic T1 scan During Pre-baseline phase (week 1 to week 3), and week 104 (2 years)

Secondary outcome [10]

To evaluate parietal atrophy (Koedam score) in the brain of Alzheimer’s Disease patients treated with Lorelco™ over a 102 week treatment period.

Timepoint [10]

MRI scan: Volumetric isotropic T1 scan During Pre-baseline phase (week 1 to week 3), and week 104 (2 years)

Secondary outcome [11]

To evaluate inferior lateral ventricle size in the brain of Alzheimer’s Disease patients treated with Lorelco™ over a 102 week treatment period.

Timepoint [11]

MRI scan: Volumetric isotropic T1 scan During Pre-baseline phase (week 1 to week 3), and week 104 (2 years)

Eligibility

Key inclusion criteria

18 years of age or older,
A positive amyloid biomarker (PET scan) indicative of AD pathology,
Mini-mental-state examination (MMSE) score of 20 or greater,
Free and cued selective reminding test (FCSRT) cueing index score of less than or equal to 0.79, OR a free recall of less than or equal to 17.
Clinical Dementia Rating (CDR) global score of 0.5 or 1.0.
A study partner (partner/spouse/carer) consents to the minimum requirements:
Study partner will attend at least one screening visit
Study partner will be available via phone or in person to provide information to the study as required

Minimum age

18 Years

Maximum age

85 Years

Sex

Both males and females

Can healthy volunteers participate?

Key exclusion criteria

A patient who meets any of the following exclusion criteria will not be eligible for inclusion in the study:
1. Recorded number of falls in previous 12 months and during trial. Participants who report multiple falls with potential loss of consciousness will be excluded
2. History of QTc-induced prolongation and willingness to limit use of over-the- counter, or prescription medicines (e.g. anti-histamines) known to prolong QTc interval. Corrected QT interval using Bazett's formula (QTcB) interval > 490 msec for males, or 500 msec for females, as detected by ECG and confirmed by physician. Participants who have a history of QTc-induced prolongation and are unwilling to limit use of medication will be excluded.
3. Evidence of abnormal cardiac function as defined by any of the following:
a. Myocardial infarction within 6 months of Cycle 1, Day 1
b. Symptomatic congestive heart failure (New York Heart Association > Class II)
c. Unstable angina
d. Unstable atrial fibrillation including paroxysmal atrial fibrillation. Medicated, stable atrial fibrillation will be assessed by the study doctor on a case-by-case basis.
e. Frequent multifocal ventricular arrhythmia
4. Unable to swallow oral medications.
5. Gastrointestinal conditions that, in the opinion of the Investigator, could affect the absorption of study drug.
6. Use of any prescription or non-prescription (including herbal) medications, or consumption of foods known to be strong QT prolongation within 7 days prior to the first administration of Lorelco™ and for the duration of the study . These include (but are not limited to):
a. Medications
b. With significant central anticholinergic effects,
c. Sedatives,
d. Antiparkinsonian medications that cannot be stopped prior to study entry,
e. Any investigational treatment for AD
7. ‘Current diagnosis of cancer (within 3 years) and/or undergoing chemotherapy, with exception to cancers of the skin such as basal or squamous cell carcinoma in situ of the skin.
8. Significant head injury within 5 years
9. Electrolyte imbalance (e.g. on high steroids, pituitary tumours, and Addison disease)
10. Hypokalaemia, hypomagnesaemia and hypocalcaemia
11. They have other neurologic or psychiatric diagnosis that in the opinion of the investigator could interfere with cognitive function,
12. Major surgery is planned during the conduct of the trial, or a clinical event has occurred in the six months preceding study inclusion that may compromise ability to participate for the duration of the study,
13. Evidence of stroke where the clinical effects are clearly temporally related to the onset of cognitive impairment.
14. Current diagnosis with a psychiatric disorder, or taking psychotropic medications,
15. Other excluded medications will be those that are;
• Specifically contraindicated with Probucol, based on historic clinical indications for the treatment of cardiovascular disease. Stable use (for at least 3 months) of cholinesterase inhibitors and memantine will be allowed.
• Patients on high dose loop-diuretics or thiazide diuretic medications, will be excluded if taking maximum dose of furosemide or Bendroflumethiazide
16. Self-reported human immunodeficiency virus (HIV-1 or HIV-2), hepatitis B (HBsAg) or hepatitis C virus (HCV).
17. Any inflammatory or chronic pain condition that necessitates regular use of opiates/opioids,
18. Major surgery within 28 days of Cycle 1, Day 1, or minor surgical procedures within 7 days of Cycle 1, Day 1. Exception: no waiting period applies following port-a-cath placement for venous access.
19. For women of childbearing potential, a positive pregnancy test at screening, or on Day 1, prior to dose administration.
20. Pregnant or breast-feeding (or planning to breastfeed) while on study through 15 days after the last dose of study drug.
21. Hypersensitivity or other clinically significant reaction to the study drug or its inactive ingredients.
22. Known substance abuse or medical, psychological, or social conditions that, in the opinion of the Investigator, may interfere with the patient’s participation in the clinical study or evaluation of the clinical study results.
23. Any other condition or prior therapy that in the opinion of the Investigator would make the patient unsuitable for this study, including inability to cooperate fully with the requirements of the study protocol or likelihood of noncompliance with any study requirements

Study design

Purpose of the study

Treatment

Allocation to intervention

Randomised controlled trial

Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)

Permuted block randomisation 1:1 will be utilised to randomly allocate participants via their unique ID to the two treatment arms (treatment vs placebo). Participant IDs will be randomised to either group 1 or group 2 via a computer randomiser. Participant IDs will also be randomised. Participant IDs will be stored (de-identified) at a central administration site. Participant IDs and allocated treatment group will be stored with Oxford Compounding. Only Oxford Compounding will have access to which group a participant belongs to, and may be contacted to disclose information in the event of a severe adverse event.

Methods used to generate the sequence in which subjects will be randomised (sequence generation)

Masking / blinding

Blinded (masking used)

Who is / are masked / blinded?

The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data

Intervention assignment

Parallel

Other design features

Phase

Phase 2

Type of endpoint/s

Efficacy

Statistical methods / analysis

In order to ensure that the study has sufficient power to detect differences in both of the primary outcomes, the sample size chosen is the maximum of that calculated for each primary outcome.
The primary analysis was an intention-to-treat analysis and included all randomized participants. Data will be analysed using both Generalised Estimating Equations (GEE) and Bayesian Analysis.
The analysis of primary endpoints will use linear mixed-effects models, with random slopes and intercepts. For the ADAS-Cog, using mixed model analysis published estimates from the ADNI cohort suggest a sample size of 125 AD participants per trial arm (total N = 250) will be required for power at 0.8 to detect a drug effect of 25% over two years and assuming a decline from baseline of 1.10 standardised units on the composite (SD change = 0.83).
For the MRI markers, Ledig et al. reported the sample sizes required for a 25% intervention reduction over two years based on 322 patients with AD (with 117 followed for 24 months) and a reduction of 10.2% (6.2) for hippocampus. Sample size calculations based on hippocampal volume suggest that 93 subjects per treatment arm are required (total N = 186).
Assuming a 20% attrition rate, a sample of 314 subjects will be recruited for the Cognitive study, and 233 subjects will be randomly chosen for the Imaging study.

Recruitment

Recruitment status

Recruiting

Date of first participant enrolment

Anticipated

12/07/2021

Actual

11/01/2022

Date of last participant enrolment

Anticipated

1/01/2025

Actual

Date of last data collection

Anticipated

1/01/2025

Actual

Sample size

Target

314

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

SA,TAS,WA

Recruitment hospital [1]

The University of Tasmania/Menzies Institute for Medical Research - Hobart

Recruitment hospital [2]

Curtin Health Innovation Research Institute - Curtin University

Recruitment hospital [3]

The Queen Elizabeth Hospital - Woodville

Recruitment postcode(s) [1]

7000 - Hobart

Recruitment postcode(s) [2]

6102 - Curtin University

Recruitment postcode(s) [3]

5011 - Woodville

Funding & Sponsors

Funding source category [1]

Government body

Name [1]

National Health Medicine Research Council

Address [1]

National Health and Medical Research Council
GPO Box 1421
Canberra ACT 2601

Country [1]

Australia

Primary sponsor type

University

Name

Curtin University

Address

Curtin Health Innovation Research Institute
Kent St
Bentley, WA, 6102

Country

Australia

Secondary sponsor category [1]

Charities/Societies/Foundations

Name [1]

Alzheimer's Research Australia

Address [1]

Clinical Trials Division
Suite 17, Hollywood Specialist Centre,
95 Monash Avenue,
Nedlands, WA, 6009

Country [1]

Australia

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Bellberry

Ethics committee address [1]

123 Glen Osmond Road
Eastwood, SA, 5063

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

02/10/2020

Approval date [1]

04/05/2021

Ethics approval number [1]

HREC2019-11-1063

Summary

Brief summary

The aim of this study is to understand whether or not treatment with Probucol supports cognitive function in participants with MCI/mild-dementia due to AD. The trial is specifically designed to provide evidence that treatment with Probucol may slow the decline of cognitive ability and functional state. The presence of cognitive impairment will be assessed using neuro-cognitive assessments. Participants will be randomly assigned to one of two groups, group 1 (placebo) or group 2 (treatment). This is a double-blind trial meaning the participant and study doctor will not be aware which group the participant has been randomised to. The study will be 104 weeks in duration (2 years). Participants will be required to take one tablet a day (with food) for the first three weeks, and then two tablets a day (morning and night, with food) for the remainder of the trial.
During the screening/pre-baseline phase participants will be asked about their medical history, complete a physical and neurological examination, an Electrocardiogram (ECG), and a blood test. Participants will also complete Neuro-cognitive assessments (memory and thinking tasks), as well as a Magnetic Resonance Imaging (MRI) scan and/or a Positron emission tomography (PET) scan.
During the treatment phase, participants will be required to visit the study doctor on 10 separate occasions (once a week for the first 3 weeks, and then at approximately 3 monthly intervals). Each visit will involve a health and safety assessment. Neuro-cognitive assessments will also be conducted at week 26 (6 months), 52 (12 months), and 78 (18 months). A blood sample will also be taken at each visit.
At completion of the treatment phase (week 104), participants will recomplete the Neuro-cognitive assessments, MRI and/or PET scan, and provide a final blood sample.
During the course of the trial, participants will be required to nominate a 'study partner' (spouse/partner/carer). The study partner will need to attend at least one screening visit. In addition, study partners should make themselves available by phone or preferably in person, to provide information to the study as required. Participants will need to identify a study partner to be eligible to take part in this study.

Trial website

www.piastudy.com.au

Trial related presentations / publications

Public notes

Contacts

Principal investigator

Name

Prof Roger Clarnette

Address

Australian Alzheimer’s Research Foundation
Suite 17, Hollywood Specialist Centre,
95 Monash Avenue,
Nedlands, WA 6009

Country

Australia

Phone

+61 08 9389 6433

Fax

[email protected]

Contact person for public queries

Name

Ms PIA Study Coordinator

Address

Curtin Health Innovation Research Institute
Curtin University, Building 305
Kent St
Bentley, WA, 6102

Country

Australia

Phone

+61 0468 532 458

Fax

[email protected]

Contact person for scientific queries

Name

Prof John Mamo

Address

Curtin Health Innovation Research Institute
Curtin University, Building 305
Kent St
Bentley, WA, 6102

Country

Australia

Phone

+61 08 9266 7232

Fax

[email protected]

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

No/undecided IPD sharing reason/comment

What supporting documents are/will be available?

No Supporting Document Provided

Results publications and other study-related documents

Documents added manually

No documents have been uploaded by study researchers.

Documents added automatically

Source	Title	Year of Publication	DOI
Embase	Efficacy of probucol on cognitive function in Alzheimer's disease: Study protocol for a double-blind, placebo-controlled, randomised phase II trial (PIA study).	2022	https://dx.doi.org/10.1136/bmjopen-2021-058826

N.B. These documents automatically identified may not have been verified by the study sponsor.

Trial Review

Documents added manually

Documents added automatically