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Trial registered on ANZCTR


Registration number
ACTRN12611000514909
Ethics application status
Approved
Date submitted
13/05/2011
Date registered
18/05/2011
Date last updated
10/07/2019
Date data sharing statement initially provided
10/07/2019
Date results information initially provided
10/07/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Does Riluzole reduce the incidence of chemotherapy-induced nerve injury in patients with colorectal cancer?
Scientific title
NEU-HORIZONS: The neuroprotection and therapeutic use of riluzole for the prevention of oxaliplatin neurotoxicity in patients with colorectal cancer
Secondary ID [1] 262128 0
none
Universal Trial Number (UTN)
U1111-1121-2382
Trial acronym
NEU-HORIZONS
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Oxaliplatin-induced neurotoxicity 265801 0
Colorectal cancer 265875 0
Condition category
Condition code
Neurological 265957 265957 0 0
Other neurological disorders
Cancer 266006 266006 0 0
Bowel - Back passage (rectum) or large bowel (colon)

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Patients receiving oxaliplatin chemotherapy for colorectal cancer will be randomised into either the study drug arm or placebo control arm. Participants will be started on either riluzole 50 mg oral tablet twice daily or the twice daily lactose placebo tablet. Following randomisation, therapy will be continued for the duration of oxaliplatin treatment (4-6 months) and for 2 weeks following treatment cessation.
Intervention code [1] 264544 0
Prevention
Comparator / control treatment
Routine clinical care involving standard review by oncology physician and placebo lactose tablet. Symptomatic relief of neuropathic symptoms as required.
Control group
Placebo

Outcomes
Primary outcome [1] 266708 0
To assess whether treatment with riluzole results in a reduction in the development of chronic neuropathy and neuropathic symptoms

The severity of neuropathy will be assessed using the Total Neuropathy Score (TNS). This will be used to evaluate neuropathy in a number of different categories; sensory neuropathic symptoms, examination findings and nerve conduction results.
Timepoint [1] 266708 0
Assessed at 6 monthly intervals following randomisation for 2 years
Secondary outcome [1] 276228 0
1. Nerve conduction measures (sural sensory amplitude).
Timepoint [1] 276228 0
Assessed at baseline, pre cycle 10 and 12, post treatment 4 weeks and 12 weeks.
Secondary outcome [2] 276369 0
2. Peripheral nerve excitability (composite score: threshold electrotonus, refractoriness, superexcitability).
Timepoint [2] 276369 0
Assessed at baseline, 7-10 days after initial dose of riluzole/placebo, pre cycle 10 and 12, post treatment 4 weeks and 12 weeks.
Secondary outcome [3] 276370 0
3. Severity of acute neuropathy: Assessed with the oxaliplatin-specific neurotoxicity scale: Graded from 1 to 4.
Timepoint [3] 276370 0
Assessed at baseline, pre cycle 10 and 12, post treatment 4 weeks and 12 weeks.
Secondary outcome [4] 276371 0
4. Nine-hole pegboard test: measuring upper limb dexterity.
Timepoint [4] 276371 0
Assessed at baseline, pre cycle 10 and 12, post treatment 4 weeks and 12 weeks.
Secondary outcome [5] 276372 0
5. FACT questionnaire (FACT-GOG-NTX-13): a validated13-item questionnaire relating to neuropathy-quality of life
Timepoint [5] 276372 0
Assessed at baseline, pre cycle 10 and 12, post treatment 4 weeks and 12 weeks.
Secondary outcome [6] 276373 0
6. Response rate: assessed qualitatively to ensure that there is no adverse effect of the intervention on cancer-related outcomes.
Timepoint [6] 276373 0
Assessed at baseline, pre cycle 10 and 12, post treatment 4 weeks and 12 weeks.

Eligibility
Key inclusion criteria
1. Receiving oxaliplatin chemotherapy.
2. 18-80 years of age.
3. Able to provide written informed consent.
4. Histological or cytological confirmation of colorectal cancer.
Minimum age
18 Years
Maximum age
80 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Baseline clinical and nerve conduction evidence of pre-existing neuropathy.
2. Past history of neurotoxic chemotherapy treatment.
3. Concurrent use of anticonvulsant medications that modulate axonal Na+ conductances (carbamazepine, topiramate, phenytoin).
4. Evidence of baseline elevation of hepatic transaminases (greater than 3 times the upper limit of normal) on liver function testing.
5. Administration of another investigational drug within 30 days prior to randomisation.
6. A history of severe hypersensitivity reactions to riluzole or any of the tablet components
7. Significant neurological or psychiatric disorders.
8. Pregnancy or lactation. Contraception is required in pre-menopausal female patients.

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)
Stratified random sampling, undertaken by NHMRC clinical trials centre or Prince of Wales Clinical Trial Pharmacy.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomisation will be stratified according to the treatment regime of 2 weekly versus 3 weekly chemotherapy treatment.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint(s)
Efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Completed
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] 14176 0
Prince of Wales Hospital - Randwick
Recruitment postcode(s) [1] 27153 0
2031 - Randwick

Funding & Sponsors
Funding source category [1] 265072 0
Government body
Name [1] 265072 0
National Health and Medical Research Council
Address [1] 265072 0
National Health and Medical Research Council
GPO Box 1421, Canberra ACT 2601
Country [1] 265072 0
Australia
Primary sponsor type
Hospital
Name
Prince of Wales Hospital/South Eastern Sydney Local Health Network
Address
Prince of Wales Hospital, Barker Street, Randwick NSW 2031
Country
Australia
Secondary sponsor category [1] 264165 0
University
Name [1] 264165 0
University of New South Wales
Address [1] 264165 0
Gate 9, High Street
Kensington NSW 2052
Country [1] 264165 0
Australia
Other collaborator category [1] 251992 0
Individual
Name [1] 251992 0
Dr Cindy Lin
Address [1] 251992 0
University of New South Wales and Institute of Neurological Sciences, Prince of Wales Hospital, Barker Street, Randwick NSW 2031
Country [1] 251992 0
Australia
Other collaborator category [2] 251993 0
Individual
Name [2] 251993 0
Prof David Goldstein
Address [2] 251993 0
Department of Medical Oncology, Prince of Wales Hospital, Barker Street, Randwick NSW 2031
Country [2] 251993 0
Australia
Other collaborator category [3] 251994 0
Individual
Name [3] 251994 0
Prof Michael Friedlander
Address [3] 251994 0
Department of Medical Oncology, Prince of Wales Hospital, Barker Street, Randwick NSW 2031
Country [3] 251994 0
Australia
Other collaborator category [4] 251995 0
Individual
Name [4] 251995 0
Dr Andrew Martin
Address [4] 251995 0
NHMRC Clinical Trials Centre Locked Bag 77, Camperdown NSW1450
Country [4] 251995 0
Australia
Other collaborator category [5] 251996 0
Individual
Name [5] 251996 0
Dr Susanna Park
Address [5] 251996 0
University of New South Wales and Institute of Neurological Sciences, Prince of Wales Hospital, Barker Street, Randwick NSW 2031
Country [5] 251996 0
Australia
Other collaborator category [6] 251997 0
Individual
Name [6] 251997 0
Ms Jenna Murray
Address [6] 251997 0
University of New South Wales and Institute of Neurological Sciences, Prince of Wales Hospital, Barker Street, Randwick NSW 2031
Country [6] 251997 0
Australia
Other collaborator category [7] 251998 0
Individual
Name [7] 251998 0
Ms Hannah Pickering
Address [7] 251998 0
University of New South Wales and Institute of Neurological Sciences, Prince of Wales Hospital, Barker Street, Randwick NSW 2031
Country [7] 251998 0
Australia
Other collaborator category [8] 251999 0
Individual
Name [8] 251999 0
Prof Matthew Kiernan
Address [8] 251999 0
University of New South Wales and Institute of Neurological Sciences, Prince of Wales Hospital, Barker Street, Randwick NSW 2031
Country [8] 251999 0
Australia
Other collaborator category [9] 252000 0
Individual
Name [9] 252000 0
Dr Arun Krishnan
Address [9] 252000 0
Room 313, Wallace Wurth Building, University of New South Wales, Sydney 2052
Country [9] 252000 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 267052 0
South Eastern Sydney Local Health Network
Ethics committee address [1] 267052 0
Room G71, East Wing
Edmund Blackett Building
Prince of Wales Hospital
High St Randwick NSW 2031
Ethics committee country [1] 267052 0
Australia
Date submitted for ethics approval [1] 267052 0
14/04/2011
Approval date [1] 267052 0
29/04/2011
Ethics approval number [1] 267052 0
10/236

Summary
Brief summary
This study aims to determine whether a drug called Riluzole can prevent chemotherapy-induced nerve injury in patients with colorectal cancer.

Who is it for?
You can join this study if you are aged 18-80 years and are scheduled to undergo chemotherapy with the drug, oxaliplatin, for the treatment of colorectal cancer.

Trial details
In this study, participants are randomly (by chance) divided into two groups. One group will take the study drug, Riluzole, at a dose of 50 mg oral tablet twice daily for the duration of chemotherapy treatment (4-6 months), and for 2 weeks following treatment cessation. The other group will receive a placebo (sham) treatment consisting of lactose tablets. During the trial, participants will not know whether they are receiving the active drug or placebo.

Participants will be assessed at regular intervals over 2 years to assess their nerve function, quality of life, and cancer-related outcomes.
Trial website
Trial related presentations / publications
1. Park SB, Goldstein D, Lin CSY, Krishnan AV, Friedlander ML & Kiernan MC (In press) Neuroprotection for Oxaliplatin-induced neurotoxicity: What happened to objective assessment? Journal of Clinical Oncology.

2. Park SB, Lin CS, Krishnan AV, Goldstein D, Friedlander ML & Kiernan MC (In press) Long-term Neuropathy after Oxaliplatin Treatment: Challenging the Dictum of Reversibility? The Oncologist.

3. Park SB, Lin CS, Krishnan AV & Kiernan MC (In Press) The contributions of SK3 polymorphisms to acute oxaliplatin-induced neurotoxicity: Direct or indirect effects? Cancer, Chemotherapy, and Pharmcology.

4. Park SB, Lin CSY, Krishnan AV, Goldstein D, Friedlander ML & Kiernan MC (2011) Dose effects of oxaliplatin on persistent and transient Na+ conductances and the development of Neurotoxicity. PLoS ONE 6(4): e18469.

5. Park SB, Lin CS, Krishnan AV, Goldstein D, Friedlander ML, & Kiernan MC. (2011) Utilizing natural activity to dissect the pathophysiology of acute oxaliplatin-induced neuropathy. Experimental Neurology. 227(1): 120-127.

6. Park SB, Lin CS, Krishnan AV, Goldstein D, Friedlander ML & Kiernan MC. (2009). Oxaliplatin-induced neurotoxicity: changes in axonal excitability precede development of neuropathy. Brain 132: 2712-2723.

7. Park SB, Goldstein D, Lin CSY, Krishnan AV, Friedlander ML & Kiernan MC. (2009) Acute abnormalities of sensory nerve function associated wtih oxaliplatin-induced neurotoxicity. Journal of Clinical Oncology 27(8): 1243-1249.

8. Park SB, Lin CSY, Krishnan AV, Goldstein D, Friedlander ML & Kiernan MC. (2009) Oxaliplatin-induced Lhermitte’s phenomenon as a manifestation of severe generalized nerve dysfunction. Oncology 77:342 – 348.

9. Park SB, Krishnan AV, Lin CSY, Goldstein D, Friedlander ML & Kiernan MC. (2008) Mechanisms underlying chemotherapy-induced neurotoxicity and the potential for neuroprotective strategies. Current Medicinal Chemistry 15(29):3081 – 3094. (Invited Review)
Public notes

Contacts
Principal investigator
Name 32580 0
Prof Arun Krishnan
Address 32580 0
Prince of Wales Hospital
Department of Neurological Sciences
Level 2, room G104 High Street,
Randwick 2031
NSW, Australia
Country 32580 0
Australia
Phone 32580 0
+61 2 9382 2414
Fax 32580 0
Email 32580 0
arun.krishnan@unsw.edu.au
Contact person for public queries
Name 15827 0
Prof Arun Krishnan
Address 15827 0
Prince of Wales Hospital
Department of Neurological Sciences
Level 2, room G104 High Street,
Randwick 2031
NSW, Australia
Country 15827 0
Australia
Phone 15827 0
+61 2 9382 2414
Fax 15827 0
+61 2 9382 2428
Email 15827 0
arun.krishnan@unsw.edu.au
Contact person for scientific queries
Name 6755 0
Prof Arun Krishnan
Address 6755 0
Prince of Wales Hospital
Department of Neurological Sciences
Level 2, room G104 High Street,
Randwick 2031
NSW, Australia
Country 6755 0
Australia
Phone 6755 0
+61 2 9382 2414
Fax 6755 0
+61 2 9382 2428
Email 6755 0
arun.krishnan@unsw.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
This was a preliminary study in a small cohort. It cannot be translated in clinical practice and has no direct benefit for participants.
What supporting documents are/will be available?
Study protocol
Statistical analysis plan
Informed consent form
Ethical approval
How or where can supporting documents be obtained?
Type [1] 2808 0
Study protocol
Citation [1] 2808 0
Link [1] 2808 0
Email [1] 2808 0
Other [1] 2808 0
Type [2] 2809 0
Statistical analysis plan
Citation [2] 2809 0
Link [2] 2809 0
Email [2] 2809 0
Other [2] 2809 0
Type [3] 2810 0
Informed consent form
Citation [3] 2810 0
Link [3] 2810 0
Email [3] 2810 0
Other [3] 2810 0
Type [4] 2811 0
Ethical approval
Citation [4] 2811 0
Link [4] 2811 0
Email [4] 2811 0
Other [4] 2811 0
Summary results
Have study results been published in a peer-reviewed journal?
No
Other publications
Have study results been made publicly available in another format?
No
Results – basic reporting
Results – plain English summary
Oxaliplatin has demonstrated superior activity as a first-line treatment in advanced colorectal cancer and as adjuvant treatment, and now represents a central component of colorectactal cancer treatment. However, the dose-limiting toxicity of oxaliplatin treatment is related to the development of peripheral neuropathy, present in up to 50% of patients at higher doses. Paraesthesia is the most commonly reported outcome representing a significant limitation to treatment, as end organ neurotoxicity and neuropathy may require discontinuation of effective therapy. Previous studies using nerve excitability techniques have provided insight into the pathophysiology of oxaliplatin induced neuropathy revealing prominent alterations in sodium channel function. The present study investigated the neuroprotective potential of riluzole, a drug currently used for the treatment of amyotrophic lateral sclerosis where it has demonstrated neuroprotective effects by blocking certain sodium channels.
Fifty-two patients were recruited and randomised into either a treatment or control group. The treatment group received 50 mg of riluzole twice daily prior to oxaliplatin treatment until the end of the chemotherapy regime and the control group received matched lactose placebo. Neurophysiological and functional testing were conducted including the Total Neuropathy Score, nerve excitability measures and 9-hole pegboard test.
A major limitation of this study was that the recruitment target was not reached and accordingly, a post-hoc repeated measures analyses was employed to address the limited sample size. The results indicated there was no benefit of riluzole on the development of neuropathy during chemotherapy treatment and up to 12 weeks post-treatment. Although the current study was underpowered, the authors observed no indication that would suggest further investigation is warranted.