Does Aspirin Have a Protective Role Against Chemotherapeutically Induced Ototoxicity?
Primary Purpose
Hearing Loss, Ototoxicity
Status
Unknown status
Phase
Not Applicable
Locations
Canada
Study Type
Interventional
Intervention
aspirin
placebo
Sponsored by
About this trial
This is an interventional prevention trial for Hearing Loss focused on measuring hearing loss, ototoxicity, cisplatin
Eligibility Criteria
Inclusion Criteria:
Patients undergoing cisplatin treatment for the following malignancies:
- germ-cell
- bladder
- head and neck (Only head and neck patients requiring only 2 cycles of post-operative chemo-radiotherapy, and therefore not requiring a gastrostomy tube, will be enrolled.)
- Over 18 years of age
- Normal otoscopic examination
- Informed consent
Exclusion Criteria:
Patients with the following will be excluded:
- Not able to grasp the study implications or unable to consent.
- History of peptic ulcer disease
- Severe renal impairment (U&E, Cr clearance)
- Haemophilia
- Severe hepatic impairment
- Cerebrovascular haemorrhage
- Acute gout
- Hypersensitivity to NSAIDs
Sites / Locations
- Princess Margaret Hospital
Arms of the Study
Arm 1
Arm 2
Arm Type
Placebo Comparator
Experimental
Arm Label
2
1
Arm Description
placebo OD during course of chemotherapy
325mg ASA OD during course of chemotherapy
Outcomes
Primary Outcome Measures
hearing loss
Secondary Outcome Measures
hearing loss and tinnitus questionnaires
Full Information
NCT ID
NCT00578760
First Posted
December 18, 2007
Last Updated
December 19, 2007
Sponsor
University Health Network, Toronto
1. Study Identification
Unique Protocol Identification Number
NCT00578760
Brief Title
Does Aspirin Have a Protective Role Against Chemotherapeutically Induced Ototoxicity?
Official Title
Does Aspirin Have a Protective Role Against Chemotherapeutically Induced Ototoxicity?
Study Type
Interventional
2. Study Status
Record Verification Date
December 2007
Overall Recruitment Status
Unknown status
Study Start Date
February 2008 (undefined)
Primary Completion Date
undefined (undefined)
Study Completion Date
February 2010 (Anticipated)
3. Sponsor/Collaborators
Name of the Sponsor
University Health Network, Toronto
4. Oversight
Data Monitoring Committee
No
5. Study Description
Brief Summary
Aspirin (ASA) has been shown, in an animal model, to attenuate the ototoxic properties of cisplatin. The researchers plan to investigate this in patients undergoing cisplatin chemotherapy.
The researchers hypothesise that low-dose aspirin can prevent cisplatin induced ototoxicity in the clinical setting.
Detailed Description
Cisplatin has the highest ototoxic potential of all platinum containing compounds. It is used in the treatment of squamous cell carcinoma of the head and neck, germ cell tumours of the testis and bladder carcinoma.
42% of 400 patients receiving high-dose cisplatin (70-85 mg/m2, median cumulative dose 420mg) experienced common toxicity criteria (CTC: appendix 1) grade 3 or 4 symptoms (De Jongh 2003). Ototoxicity is dose related: 75-100% of patients receiving a very high dose and 20-40% with a low dose regime will develop significant ototoxic symptoms. In one study, 50% of head and neck cancer patients treated with cisplatin develop ototoxicity (Blakley 1994).
Cisplatin ototoxicity can present as a variable collection of symptoms and signs. These include bilateral and symmetrical hearing loss that is permanent and irreversible. High frequency sensorineural hearing loss with progression towards lower frequencies. Tinnitus, that is also permanent and irreversible.
There are a number of known factors that can predispose to cisplatin ototoxicity. They include: Dose, duration and mode of administration, age extremes, previous or concurrent cranial irradiation, previous history of hearing loss, renal disease, concomitant use of other ototoxic drugs, noise exposure with concomitant cisplatin administration, decreased serum albumin level, low hemoglobin level, low red blood cell count and a low haematocrit. Interestingly, cisplatin ototoxicity is considered to be exclusively confined to the cochlear, the vestibular system is unaffected (Myers 1993).
Ototoxicity from chemotherapeutic agents is due, in part, to reactive oxygen species. Reactive oxygen species can be attenuated by antioxidants. Salicylates are antioxidants that can be administered as aspirin.
It has been shown, in an animal model, that aspirin can protect hearing from cisplatin induced ototoxicity (Li 2002). In this set of experiments, the rat was used to evaluate the protective role of aspirin in both the acute and chronic setting. Auditory evoked brain stem responses were used to determine pre- and post-intervention hearing thresholds. In the acute experiments (n=23), one dose of cisplatin (16mg/kg) was administered and the animals were given aspirin (100mg/kg) starting the day before cisplatin treatment and continuing 4 days thereafter. There was a significant difference in hearing thresholds between the treatment and control groups at 3, 8 and 14kHz.
In the chronic experiments cisplatin was given on days 1, 4 and 7 (5mg/kg). Aspirin was given from 2 days before to 3 days after cisplatin treatment (100mg/kg bd). The hearing thresholds were compared before the first dose and 10 days after the last treatment. In those animals treated concurrently with aspirin, their hearing did not differ form control animals at 16 and 24 kHz. This was correlated to a significant reduction in inner hair cell loss from 20% (cisplatin) to 8% (cisplatin and aspirin).
Salicylates also protected renal function as determined by both plasma blood urea nitrogen and creatinine levels.
Salicylates did not affect tumour mass or metastasis. The rats were inoculated with malignant breast cancer cells (metastatic mammary adenocarcinoma). Aspirin protected against cisplatin-induced ototoxicity, without affecting the oncolytic action of the cisplatin.
Gentamicin and cisplatin both have a similar ototoxic mechanism of action. Aspirin has been shown to prevent gentamicin-induced hearing loss without compromising its anti-bacterial efficacy in both animal models and the clinical setting (Sha 2006, Chen 2007). Sha's group reported a prospective, randomized, double-blind trial with 200 patients. The patients all required gentamycin for clinical indications. In the 'treatment' arm of the study, the patients also received aspirin (1g tds for 14 days). A significant difference in hearing was shown at 6 and 8kHz of >15dB if aspirin was not given.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hearing Loss, Ototoxicity
Keywords
hearing loss, ototoxicity, cisplatin
7. Study Design
Primary Purpose
Prevention
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
110 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
2
Arm Type
Placebo Comparator
Arm Description
placebo OD during course of chemotherapy
Arm Title
1
Arm Type
Experimental
Arm Description
325mg ASA OD during course of chemotherapy
Intervention Type
Drug
Intervention Name(s)
aspirin
Intervention Description
325mg ASA OD for the duration of the cisplatin
Intervention Type
Drug
Intervention Name(s)
placebo
Intervention Description
OD for course of cisplatin chemotherapy
Primary Outcome Measure Information:
Title
hearing loss
Time Frame
before and after chemotherapy
Secondary Outcome Measure Information:
Title
hearing loss and tinnitus questionnaires
Time Frame
before and after cisplatin treatment
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Patients undergoing cisplatin treatment for the following malignancies:
germ-cell
bladder
head and neck (Only head and neck patients requiring only 2 cycles of post-operative chemo-radiotherapy, and therefore not requiring a gastrostomy tube, will be enrolled.)
Over 18 years of age
Normal otoscopic examination
Informed consent
Exclusion Criteria:
Patients with the following will be excluded:
Not able to grasp the study implications or unable to consent.
History of peptic ulcer disease
Severe renal impairment (U&E, Cr clearance)
Haemophilia
Severe hepatic impairment
Cerebrovascular haemorrhage
Acute gout
Hypersensitivity to NSAIDs
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Emma Barker, FRCS, PhD
Phone
001-416-946-4501
Ext
4353
Email
emmabarker@doctors.org.uk
Facility Information:
Facility Name
Princess Margaret Hospital
City
Toronto
State/Province
Ontario
Country
Canada
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Emma Barker, FRCS, PhD
12. IPD Sharing Statement
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Does Aspirin Have a Protective Role Against Chemotherapeutically Induced Ototoxicity?
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