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Trial registered on ANZCTR


Registration number
ACTRN12619000566134p
Ethics application status
Submitted, not yet approved
Date submitted
2/04/2019
Date registered
10/04/2019
Date last updated
10/04/2019
Date data sharing statement initially provided
10/04/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
OXTOX: Can Oxaliplatin neurotoxicity be reduced with ibudilast in people with metastatic colorectal cancer – a phase II randomised study
Scientific title
OXTOX: Can Oxaliplatin neurotoxicity be reduced with ibudilast in people with metastatic colorectal cancer – a phase II randomised study
Secondary ID [1] 297865 0
None
Universal Trial Number (UTN)
U1111-1231-0304
Trial acronym
OXTOX
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Neurotoxicity caused by oxaliplatin in patients with metastatic colorectal cancer 312239 0
Condition category
Condition code
Cancer 310786 310786 0 0
Bowel - Back passage (rectum) or large bowel (colon)
Neurological 310788 310788 0 0
Other neurological disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Ibudilast 30mg oral twice a day for prevention of acute neurotoxicity for the duration of taking oxaliplatin chemotherapy commencing 2 days prior to starting oxaliplatin.
Intervention code [1] 314098 0
Treatment: Drugs
Comparator / control treatment
Placebo microcellulose capsule
Control group
Placebo

Outcomes
Primary outcome [1] 319633 0
Acute neurotoxicity assessed by the Oxaliplatin Acute Symptom Questionnaire
Timepoint [1] 319633 0
Day 3 of week 4 for CAPOX and day 3 of week 5 for FOLFOX.
Secondary outcome [1] 368941 0
Chemotherapy-induced peripheral neuropathy. Assessed by the Total Neuropathy Score, Grooved Pegboard, NCI-CTCAE-neuropathy sensory sub scale, FACT-GOG-Ntx questionnaire,, Rasch-built Overall Disability Scale for CIPN (CIPN-R-ODS)



Timepoint [1] 368941 0
During oxaliplatin -every 3 -4 weeks depending on chemotherapy regimen
Post oxaliplatin: 1, 3, 6, 9, 12 months after oxaliplatin
Secondary outcome [2] 368991 0
Changes in acute neurotoxicity - assessed by the Oxaliplatin Acute Symptom Questionnaire scores for individual subscales
Timepoint [2] 368991 0
Day 1 and day 3 of oxaliplatin chemotherapy
Secondary outcome [3] 368992 0
Quality of life - FACT-G questionnaire
Timepoint [3] 368992 0
Day 1 of each chemotherapy cycle and 1, 3, 6, 9 and 12 months after chemotherapy
Secondary outcome [4] 368993 0
Chemotherapy-induced peripheral neuropathy/chemotherapy cycle
Measured by FACT-GOG-Ntx Questionnaire and Total Neuropathy Score (TNSc) vs number of chemotherapy cycles achieved
Timepoint [4] 368993 0
1 and 3 months after oxaliplatin
Secondary outcome [5] 368994 0
Treatment adherence to oxaliplatin and ibudilast.
Adherence to ibudilast - patient questionnaire and pill count.
Adherence to oxaliplatin - amount of chemotherapy delivered
Both questionnaires designed specifically for this study.
Amount of chemotherapy -is collected in a study specific questionnaire and is abstracted from the medical record
Timepoint [5] 368994 0
Day 1 of each cycle of chemotherapy and 1 month post chemotherapy

Eligibility
Key inclusion criteria
Diagnosis of histologically confirmed metastatic adenocarcinoma CRC who are to commence chemotherapy with oxaliplatin (i.e. FOLFOX or CAPOX).
Speak and read sufficient English to answer the questionnaires.
Adequate organ function, defined as renal function with glomerular filtration rate >50mL/min, adequate bone marrow (platelets>100 X 109 L-1, neutrophil count >1.5 X 109 L-1), and hepatic (<1.5 X the upper limit of normal (ULN), with the exception that GGT may be elevated <3 X ULN as long as bilirubin is within normal range).
Give written informed consent.
Concomittant use of analgesics that are being used for purposes other than peripheral neuropathy but that have efficacy in neuropathy pain such as gabapentin and pregabalin and selective serotonin reuptake inhibitors (SSRIs), are allowed as long as the dose is expected to be consistent throughout the trial.

Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
ECOG Performance Status of 3 or above.
Existing peripheral neuropathy of any grade (e.g. due to diabetes mellitus, B12 deficiency, alcohol abuse, or use of nucleoside reverse transcriptase inhibitors).
Prior treatment with oxaliplatin within the past 6 months.
Any major active psychiatric illness, dementia, or alcohol abuse that in the opinion of the principal investigator may interfere with their ability to complete neurotoxicity assessments.
Any contraindication to taking ibudilast, including uncontrolled nausea or vomiting with chemotherapy.
Inability to swallow capsules.

Study design
Purpose of the study
Prevention
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Central randomisation by computer
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Dynamic (adaptive) random allocation method with Minimisation
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)
Safety/efficacy
Statistical methods / analysis
Intention to treat analysis.
A sample size of 90 participants (45/group) gives 81% power to detect a difference of 0.6 standard deviations using a 2 sample t-test to compare the mean scores in the two groups, and 80% power to detect a reduction from a significant neuropathic symptom rate of 62% in the control group (score of 10 or more out of 30 for the sum of the three key OASQ items) versus 33% in the experimental group with two-sided type 1 error of 0.05. A total of 100 patients will be recruited to take into account treatment attrition.
Continuous variables will be summarised in terms of means and standard deviation (SD) where appropriate or median (range), categorical variables will be presented as frequency (percentage). For continuous variables, differences between randomisation groups will be assessed using appropriate tests (such as a t-test) and where normality assumptions are not met appropriate transformations of the data may be applied or other strategies (use of categories and/or non-parametric tests) may be employed. Differences between groups with respect to categorical variables will be evaluated using the chi-squared or an appropriate exact test.
Proportions are summarised alongside the corresponding 95% confidence interval. Logistic regression will be used to investigate the association of baseline demographics on acute neuropathy and CIPN. Longitduinal analyses will be used on the patient reported outcomes, investigating the time-by-intervention interaction where appropriate.

Estimates of progression-free survival over time will be calculated using the method of Kaplan and Meier to determine overall activity. Comparisons will be made using the log-rank test and proportional hazards regression. Analysis of safety endpoints (i.e. toxicity) will be according to treatment received. The proportions of patients experiencing Grade 3/4 toxicities will be presented with 95% CIs.
Qualitative interviews will be audio-recorded and transcribed. Qualitative data will be subjected to thematic analysis.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 13533 0
Concord Repatriation Hospital - Concord
Recruitment hospital [2] 13534 0
Royal North Shore Hospital - St Leonards
Recruitment hospital [3] 13535 0
Wollongong Hospital - Wollongong
Recruitment hospital [4] 13536 0
Orange Health Service - Orange
Recruitment hospital [5] 13537 0
Nepean Hospital - Kingswood
Recruitment postcode(s) [1] 26156 0
2139 - Concord
Recruitment postcode(s) [2] 26157 0
2065 - St Leonards
Recruitment postcode(s) [3] 26158 0
2500 - Wollongong
Recruitment postcode(s) [4] 26159 0
2800 - Orange
Recruitment postcode(s) [5] 26160 0
2747 - Kingswood

Funding & Sponsors
Funding source category [1] 302388 0
Other Collaborative groups
Name [1] 302388 0
Australasian Gastro-Intestinal Trials Group
Address [1] 302388 0
GI Cancer Institute
143.119 Missenden Rd
Camperdown NSW 2050
Country [1] 302388 0
Australia
Primary sponsor type
Other Collaborative groups
Name
Australasian Gastro-Intestinal Trials Group
Address
GI Cancer Institute
143.119 Missenden Rd
Camperdown NSW 2050
Country
Australia
Secondary sponsor category [1] 302279 0
None
Name [1] 302279 0
Address [1] 302279 0
Country [1] 302279 0

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 303061 0
Sydney Local Health District Human Research Ethics Committee- Concord Repatriation General Hospital
Ethics committee address [1] 303061 0
Concord Repatriation General Hospital
Hospital Rd
Concord, 2139, NSW
Ethics committee country [1] 303061 0
Australia
Date submitted for ethics approval [1] 303061 0
03/04/2019
Approval date [1] 303061 0
Ethics approval number [1] 303061 0

Summary
Brief summary
Oxaliplatin chemotherapy improves survival but causes acute neuropathy (paraesthesias or dysesthesias) and chronic chemotherapy-induced peripheral neuropathy (CIPN) in almost all patients. CIPN can last for months to years, and can have a major impact on quality of life. It is suggested that ibudilast can prevent and treat this neurotoxicity.

The purpose of this study is to determine if ibudilast can safely and effectively decrease neurotoxicity in patients receiving chemotherapy.

Who is it for?

You may be eligible for this study if you are an adult who has been diagnosed with metastatic colorectal cancer, and will be commencing chemotherapy with oxaliplatin.

Study details

Participants in this study will continue with their prescribed chemotherapy. As part of this study, participants will be randomly allocated to one of two groups:
1. Ibudilast taken twice a day for the duration of oxaliplatin, and
2. Placebo capsules, taken twice a day for the same period.
Participants will complete questionnaires and be examined by their usual oncologist. Results of usual blood tests and imaging will be reviewed.
It is hoped that this research will help determine if ibudilast can be effective in reducing neurotoxicity in participants. If it is shown to be effective, it may allow more chemotherapy to be delivered, and therefore may improve survival rates in people with colorectal cancer.
Trial website
N/A
Trial related presentations / publications
N/A
Public notes

Contacts
Principal investigator
Name 92326 0
Prof Janette Vardy
Address 92326 0
Concord Cancer Centre
Concord Repatriation General Hospital
Hospital Rd
Concord, 2139, NSW
Country 92326 0
Australia
Phone 92326 0
+61 02 9767 5000
Fax 92326 0
Email 92326 0
janette.vardy@sydney.edu.au
Contact person for public queries
Name 92327 0
Ms Anne Warby
Address 92327 0
University of Sydney
Concord Clinical School
Asbestos Diseases Research Institute
Hospital Rd
Concord, 2139, NSW
Country 92327 0
Australia
Phone 92327 0
+61 02 9767 9816
Fax 92327 0
Email 92327 0
anne.warby@sydney.edu.au
Contact person for scientific queries
Name 92328 0
Prof Janette Vardy
Address 92328 0
Concord Cancer Centre
Concord Repatriation General Hospital
Hospital Rd
Concord, 2139, NSW
Country 92328 0
Australia
Phone 92328 0
+61 02 9767 5000
Fax 92328 0
Email 92328 0
janette.vardy@sydney.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
What supporting documents are/will be available?
No other documents available
Summary results
No Results