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Trial registered on ANZCTR


Registration number
ACTRN12615001072505
Ethics application status
Approved
Date submitted
19/08/2015
Date registered
13/10/2015
Date last updated
2/03/2020
Date data sharing statement initially provided
2/03/2020
Date results information initially provided
2/03/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
A Phase II randomised placebo-controlled, double blind, multisite study of Acetazolamide versus placebo for management of cerebral oedema in recurrent and/or progressive High Grade Glioma requiring treatment with Dexamethasone – The ACED trial
Scientific title
A Phase II randomised placebo-controlled, double blind, multisite study of Acetazolamide versus placebo for management of cerebral oedema in recurrent and/or progressive High Grade Glioma requiring treatment with Dexamethasone – The ACED trial
Secondary ID [1] 286924 0
Nil known
Universal Trial Number (UTN)
Trial acronym
ACED
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Cerebral Oedema in recurrent, progressive and/or persistent High Grade Glioma 294588 0
Condition category
Condition code
Cancer 294888 294888 0 0
Brain

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Eligible participants will be randomised to the study in 1:1 ratio to either study treatment or control.

The study treatment group will receive 1 tablet of 250 mg acetazolamide twice per day for 8 weeks.

The placebo group will receive 1 tablet of placebo twice per day for 8 weeks.

Drug accountability will be checked at each visit with bottle counts.
Intervention code [1] 291495 0
Treatment: Drugs
Comparator / control treatment
The excipients are standard tablet excipients and consist of Microcrystalline Cellulose, Colloidal Silicon Dioxide, Sodium Starch Clycolate, Sodium Strearyl Fumarate
Control group
Placebo

Outcomes
Primary outcome [1] 294644 0
Composite endpoint of dexamethasone dose reduction and stability of neurological function, determined by:

1) At least 50% corticosteroid dose reduction from baseline (baseline dosage is considered the stable dose for at least 3 days prior to randomisation), achieved within 28 days from randomisation and maintained it for > 7 days

AND

2) Without deterioration in neurological function (deterioration is defined as a decrease in Karnofsky Performance Status of 20 points or more)
Timepoint [1] 294644 0
Day 36 from randomisation
Secondary outcome [1] 313787 0
Evaluate symptoms of raised intracranial pressure over the study period.
Symptoms of raised intracranial pressure including nausea, vomiting and headache will be coded and severity rated according to CTCAE v4.03 by the treating specialist during study visits.
Timepoint [1] 313787 0
Week 1, 3, 5, 7 from first study treatment intake
Secondary outcome [2] 313788 0
To document neurological function over the study period
A structured fortnightly neurological examination will assess level of consciousness, mental status, vision, speech, cranial nerve abnormalities, motor and sensory loss in limbs, and gait or limb ataxia. The clinician will rate each variable from normal to severely abnormal according to specific criteria utilized in other studies
Timepoint [2] 313788 0
Week 2, 4, 6, 8 from first study treatment intake
30-42 days post last study treatment intake
Secondary outcome [3] 313789 0
Composite outcome to describe the adverse effects attributable to dexamethasone as reported by clinicians (CTCAE v 4.03) and patient/caregiver self-report (DSQ-Chronic questionnaire)
Timepoint [3] 313789 0
Adverse effect reported by clinicians: first study treatment intake until 30 days from last study treatment intake
Patient caregiver assessment: Week 2, 4, 6, 8 from first study treatment intake
Secondary outcome [4] 313790 0
Composite outcome to describe toxicities attributable to acetazolamide (Worst toxicity as per CTCAE v 4.03) and patient and caregiver rated acetazolamide toxicity as reported by a purpose designed questionnaire)
Timepoint [4] 313790 0
Adverse effect reported by clinicians: first study treatment intake until 30 days from last study treatment intake
Patient caregiver assessment: Week 2, 4, 6, 8 from first study treatment intake
Secondary outcome [5] 315366 0
Assess feasibility of study methodology and measures by assessing the accrual rate and the compliance to the treatment regimen. Patients will complete a daily dexamethasone dose diary.
Timepoint [5] 315366 0
For 8 weeks from baseline

Eligibility
Key inclusion criteria
1) Adults aged greater than or equal to 18 years;
2) Pathological diagnosis of HGG NOTE: HGG includes glioblastoma multiforme, anaplastic astrocytoma, anaplastic oligodendroglioma, anaplastic ependymoma, anaplastic oligoastrocytoma;
3) Clinically or radiologically diagnosed progressive, recurrent and/or persistent residual disease;
4) Recommencement of dexamethasone, dexamethasone dose increase, or dexamethasone dependent (unable to reduce below 4mg or cease over 8 weeks); for the management of raised ICP (regardless of aetiology);
5) Current dexamethasone dose of a minimum of 4mg per day;
6) Stable dexamethasone dose (after dose increase or recommencement) for at least 72 hours before randomisation;
7) Baseline Karnofsky Performance Status of greater than or equal to 40 at baseline;
8) Ability to swallow oral medication;
9) Adequate liver function (Bilirubin less than or equal to 2.5 times upper limit of normal; Alkaline phosphatase, aspartate transaminase and alanine transaminase less than or equal to 3 times upper limit of normal);
10) Adequate renal function (creatinine clearance > 50 ml/min measured using Cockroft-Gault);
11. Adequate haematological function (Neutrophils greater than or equal to 1.0x10^9 cells/L, Platelets greater than or equal to 100x10^9 cells/L)
12. Serum sodium greater than or equal to 130 mmol/L;
13. Serum potassium between 3-5mmol/L
14. Willing and able to comply with all study requirements, including treatment, timing and/or nature of required assessments;
15. Ability to complete patient-reported measures (in English), or if unable a caregiver who can complete caregiver questionnaires;
16. Signed, written informed consent;
17. Concurrent salvage single or multiple agent chemotherapy including temozolomide (any schedule), carboplatin, a nitrosurea (e.g. CCNU), or etoposide, is permissible.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1) Confirmed allergy to sulphur (sulfonamides) (acetazolamide is a sulfonamide derivative and cross sensitivity between acetazolamide, sulfonamides and other sulfonamide derivatives can occur);
2) Have had any surgery, open biopsy, intracranial biopsy, ventriculoperitoneal shunt or significant traumatic injury within 2 weeks prior to start of treatment on this study or who have not recovered from side effects of such therapy;
3) No further neurosurgical procedure planned for the next 8 weeks;
4) Pre-existing metabolic acidosis (pH < 7.35 and bicarbonate levels <24 mmol/l);
5) History of nephrolithiasis;
6) Systolic Blood Pressure < 100 mmHg;
7) Chronic liver disease (Childs class A or above);
8) Systemic corticosteroid use (dexamethasone or prednisone/prednisolone) required for any indication other than cerebral oedema;
9) Current oral acetazolamide use for any indication;
10) Current bevacizumab therapy or use in prior 4 weeks;
11) Current salvage re-irradiation;
12) Presence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule, including alcohol dependence or drug abuse;
13) Pregnancy, lactation, or inadequate contraception. Women must be post-menopausal, infertile, or use a reliable means of contraception. Women of childbearing potential must have a negative pregnancy test done within 10 days prior to registration. Men must have been surgically sterilised or use a (double if required) barrier method of contraception.

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)
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

Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Stopped early
Data analysis
Data collected is being analysed
Reason for early stopping/withdrawal
Participant recruitment difficulties
Other reasons/comments
Other reasons
Changed prescribing environment.
Date of first participant enrolment
Anticipated
2/11/2015
Actual
19/07/2016
Date of last participant enrolment
Anticipated
Actual
3/06/2019
Date of last data collection
Anticipated
31/03/2020
Actual
Sample size
Target
84
Accrual to date
Final
30
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,TAS,WA,VIC
Recruitment hospital [1] 16034 0
Liverpool Hospital - Liverpool
Recruitment hospital [2] 16035 0
Royal Brisbane & Womens Hospital - Herston
Recruitment hospital [3] 16036 0
St Vincent's Hospital (Melbourne) Ltd - Fitzroy
Recruitment hospital [4] 16037 0
Epworth Richmond - Richmond
Recruitment hospital [5] 16038 0
Sir Charles Gairdner Hospital - Nedlands
Recruitment hospital [6] 16039 0
Royal Hobart Hospital - Hobart
Recruitment hospital [7] 16040 0
Prince of Wales Hospital - Randwick
Recruitment hospital [8] 16041 0
Flinders Medical Centre - Bedford Park
Recruitment hospital [9] 16042 0
The Chris O’Brien Lifehouse - Camperdown
Recruitment hospital [10] 16043 0
St George Hospital - Kogarah
Recruitment hospital [11] 16044 0
St Vincent's Hospital (Darlinghurst) - Darlinghurst
Recruitment postcode(s) [1] 29547 0
2170 - Liverpool
Recruitment postcode(s) [2] 29548 0
4029 - Herston
Recruitment postcode(s) [3] 29549 0
3065 - Fitzroy
Recruitment postcode(s) [4] 29550 0
3121 - Richmond
Recruitment postcode(s) [5] 29551 0
6009 - Nedlands
Recruitment postcode(s) [6] 29552 0
7000 - Hobart
Recruitment postcode(s) [7] 29553 0
2031 - Randwick
Recruitment postcode(s) [8] 29554 0
5042 - Bedford Park
Recruitment postcode(s) [9] 29555 0
2050 - Camperdown
Recruitment postcode(s) [10] 29556 0
2217 - Kogarah
Recruitment postcode(s) [11] 29557 0
2010 - Darlinghurst

Funding & Sponsors
Funding source category [1] 290992 0
Commercial sector/Industry
Name [1] 290992 0
Perpetual Ltd distributes resources on behalf of its trustees
Country [1] 290992 0
Australia
Funding source category [2] 294378 0
Government body
Name [2] 294378 0
Cancer Australia
Country [2] 294378 0
Australia
Primary sponsor type
University
Name
The University of Sydney
Address
NHMRC Clinical Trials Centre
Level 4, 92-94 Parramatta Road,
Camperdown NSW Australia 2050
Country
Australia
Secondary sponsor category [1] 289672 0
None
Name [1] 289672 0
Address [1] 289672 0
Country [1] 289672 0
Other collaborator category [1] 278409 0
Other Collaborative groups
Name [1] 278409 0
Cooperative Trials Group for Neuro-Oncology (COGNO)
Address [1] 278409 0
NHMRC Clinical Trials Centre Level 4, 92-94 Parramatta Road,
Camperdown NSW Australia 2050
Country [1] 278409 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 292582 0
South Western Sydney Local Health District HREC
Ethics committee address [1] 292582 0
Research and Ethics office
Level 2, UNSW Clinical School
Cnr Elizabeth and Goulburn Sts
Liverpool Hospital
NSW 2170
Ethics committee country [1] 292582 0
Australia
Date submitted for ethics approval [1] 292582 0
29/12/2014
Approval date [1] 292582 0
28/07/2015
Ethics approval number [1] 292582 0
14/306

Summary
Brief summary
This study investigates whether addition of the drug acetazolamide to a dexamethasone treatment for controlling raised intracranial pressure symptoms, related to high grade glioma brain tumour (such as headache, nausea and vomiting), will allow the dexamethasone dosage to be reduced, and whether this leads to less dexamethasone-related side-effects.

Who is it for?
You can join this study if you are required to restart or increase a dexamethasone treatment to control recurrent or increased symptoms of intracranial pressure, that may be related to your brain tumour, high grade glioma.

Study details:
If you like to join this study you will first be screened by your specialist to see if you meet the eligibility criteria to participate in this study. If you are deemed eligible to participate you will be randomly (by chance) assigned to
one of two possible treatment groups:
Group 1 will receive 1 tablet of 250mg acetazolamide twice per day for 8 weeks, in addition to the dexamethasone treatment.
Group 2 will receive 1 tablet of placebo twice per day for 8 weeks, in addition to the dexamethasone treatment.
Your chance to receive the group 1 treatment is equally high as to receive the group 2 treatment. You cannot choose to which group you are assigned and both you and your doctor will not know which treatment you received until the study is finished.

Participants will be asked to attend clinic visits every 2 weeks during the treatment period and then 1 more time (about 1 month after having received the last treatment). During these visits the specialist will assess your physical and mental
health, and ask you about your well-being. Participants will also be asked to undergo tests and procedures, such as blood testing, scans, and questionnaire completion.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 56070 0
Prof Meera Agar
Address 56070 0
NHMRC Clinical Trials Centre
Locked Bag 77 Camperdown NSW 1450
Country 56070 0
Australia
Phone 56070 0
+61 (0)2 9562 5000
Fax 56070 0
Email 56070 0
[email protected]
Contact person for public queries
Name 56071 0
Mr ACED Trial Coordinator
Address 56071 0
NHMRC Clinical Trials Centre
Locked Bag 77 Camperdown NSW 1450
Country 56071 0
Australia
Phone 56071 0
+61 (0)2 9562 5000
Fax 56071 0
Email 56071 0
[email protected]
Contact person for scientific queries
Name 56072 0
Dr ACED Trial Coordinator
Address 56072 0
NHMRC Clinical Trials Centre
Locked Bag 77 Camperdown NSW 1450
Country 56072 0
Australia
Phone 56072 0
+61 (0)2 9562 5000
Fax 56072 0
Email 56072 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
No plans to share IPD data at this stage.


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
SourceTitleYear of PublicationDOI
EmbaseAcetazolamide versus placebo for cerebral oedema requiring dexamethasone in recurrent and/or progressive high-grade glioma: phase II randomised placebo-controlled double-blind study.2023https://dx.doi.org/10.1136/spcare-2022-004119
N.B. These documents automatically identified may not have been verified by the study sponsor.