Ototoxicity, Unspecified Adult Solid Tumor
Conditions
Brief summary
RATIONALE: Alpha-lipoic acid may prevent or lessen hearing loss caused by cisplatin. PURPOSE: This randomized clinical trial is studying the effectiveness of alpha-lipoic acid in preventing hearing loss in cancer patients undergoing treatment with cisplatin.
Detailed description
OBJECTIVES: Primary Determine the ability of alpha-lipoic acid supplementation to prevent or reduce the incidence and severity of hearing loss in cancer patients undergoing treatment with cisplatin. Secondary Determine if this drug improves the oxidative state, as measured by a malondialdehyde measurement of oxidative stress, thereby protecting the patient against ototoxic-induced hearing loss. OUTLINE: This is a placebo-controlled, double-blind, randomized, multicenter study. Patients are stratified by cancer stage and institution. Patients are randomized to 1 of 2 treatment arms. Arm I: Patients receive oral alpha-lipoic acid supplement once a day beginning 1 week before the start of cisplatin treatment and continuing for up to 1 month after the completion of cisplatin. During cisplatin treatment, patients discontinue supplement 1 day prior to the cisplatin treatment and resume daily supplements 2 days post treatment. Arm II: Patients receive oral placebo supplement once a day beginning 1 week before the start of cisplatin and continuing for up to 1 month after the completion of cisplatin. During cisplatin treatment, patients discontinue supplement 1 day prior to the cisplatin treatment and resume daily supplements 2 days post treatment. Hearing and ototoxicity are assessed at baseline, on each day of chemotherapy, and at 1 and 3 months post chemotherapy. Blood samples are collected periodically to measure malondialdehyde and alpha-lipoic acid levels. After completion of treatment with cisplatin, patients are followed for 3 months.
Interventions
Supplements (1200mg once a day) or placebo will be administered to each patient prior to first cisplatin treatment and continue until 3 months after last treatment.
BEHAVIORALAudiology
otoscopy, immittance screening, noise exposure questionnaire and individualized behavioral pure-tone in the convention and high-frequency ranges.
BIOLOGICALlaboratory biomarker analysis
Plasma concentrations of Malondialdehyde (MDA) will be measures as an indicator of oxidative stress.
DRUGPlacebo
Placebo will be administered to each patient prior to first cisplatin treatment and continue until 3 months after last treatment.
Sponsors
Oregon Health and Science University
US Department of Veterans Affairs
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
SUPPORTIVE_CARE
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Diagnosis of cancer * Receiving therapeutic treatment with cisplatin * Fertile patients must use effective contraception during and for 3 months after completion of study treatment * Cognitively and physically able to participate in the study * Must be able to provide reliable behavioral threshold responses (patient must meet intra-session reliability criterion of +/- 5 dB) * At least 6 months since prior treatment with cisplatin or other ototoxic medications (e.g., aminoglycoside antibiotics) * At least 6 months since prior and no concurrent radiotherapy for head and neck tumors * Concurrent radiotherapy targeted below the neck allowed * More than 1 month since prior alpha-lipoic acid supplements
Exclusion criteria
* No aggressive behavior as indicated in electronic chart notes * No documented dementia * No Alzheimer's disease * No severe psychosocial disorder * No active or recent history of middle ear disorder based on otoscopy, tympanometry, immittance, or notes in patient chart * No renal disease * No Meniere's disease or retrocochlear disorder based on patient report or notes in patient's chart * Not receiving treatment for diabetes mellitus * No concurrent vincristine or vinblastine * No other concurrent investigational therapy * No other concurrent antioxidants or vitamin E \> 100 IU per day
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Ototoxicity Measurement | Baseline measurement occurred prior to first cisplatin treatment session. Follow-up measurements occurred up to 3 months after last cisplatin treatment. | Any American Speech and Hearing Association (ASHA)-significant hearing loss in the Sensitive Region for Ototoxicity frequencies between baseline measurement and any follow-up measurement. ASHA criteria are defined as * 20 decibel (dB) increase at any test frequency, * 10 dB increase at any two consecutive test frequencies, or loss of response where there was previously a response at any three test frequencies. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Malondialdehyde (MDA) Levels | Baseline measurement occurred prior to first cisplatin treatment session. Follow-up measurements occurred up to 3 months after last cisplatin treatment. | Computed maximum increase relative to baseline for each subject = (max MDA during treatment) - baseline MDA level. |
| Total Amount of Prescribed Cisplatin Dose Administered | cisplatin treatment period between 10 weeks and up to 16 weeks. | Maximum cumulative dose of cisplatin (mg/m\^2) administered during the course of chemotherapy. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arm 1 Receiving alpha-lipoic acid during cisplatin treatment.
laboratory biomarker analysis : Plasma concentrations of Malondialdehyde (MDA) will be measures as an indicator of oxidative stress.
alpha-lipoic acid : Supplements (1200mg once a day) or placebo will be administered to each patient prior to first cisplatin treatment and continue until 3 months after last treatment.
Audiology : otoscopy, immittance screening, noise exposure questionnaire and individualized behavioral pure-tone in the convention and high-frequency ranges. | 19 |
| Arm 2 Receiving placebo during cisplatin treatment
Audiology : otoscopy, immittance screening, noise exposure questionnaire and individualized behavioral pure-tone in the convention and high-frequency ranges.
alpha-lipoic acid : Supplements (1200mg once a day) or placebo will be administered to each patient prior to first cisplatin treatment and continue until 3 months after last treatment.
laboratory biomarker analysis : Plasma concentrations of Malondialdehyde (MDA) will be measures as an indicator of oxidative stress. | 20 |
| Total | 39 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 7 | 7 |
Baseline characteristics
| Characteristic | Arm 2 | Arm 1 | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 5 Participants | 7 Participants | 12 Participants |
| Age, Categorical Between 18 and 65 years | 15 Participants | 12 Participants | 27 Participants |
| Age, Continuous | 60.6 years STANDARD_DEVIATION 12.3 | 62.0 years STANDARD_DEVIATION 10.2 | 61.2 years STANDARD_DEVIATION 11.2 |
| Region of Enrollment United States | 20 participants | 19 participants | 39 participants |
| Sex: Female, Male Female | 1 Participants | 0 Participants | 1 Participants |
| Sex: Female, Male Male | 19 Participants | 19 Participants | 38 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 3 / 19 | 2 / 20 |
| serious Total, serious adverse events | 5 / 19 | 6 / 20 |
Outcome results
Primary
Ototoxicity Measurement
Any American Speech and Hearing Association (ASHA)-significant hearing loss in the Sensitive Region for Ototoxicity frequencies between baseline measurement and any follow-up measurement. ASHA criteria are defined as * 20 decibel (dB) increase at any test frequency, * 10 dB increase at any two consecutive test frequencies, or loss of response where there was previously a response at any three test frequencies.
Time frame: Baseline measurement occurred prior to first cisplatin treatment session. Follow-up measurements occurred up to 3 months after last cisplatin treatment.
Population: Intent-to-treat (ITT)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm 1 | Ototoxicity Measurement | 7 participants |
| Arm 2 | Ototoxicity Measurement | 7 participants |
Comparison: H0: pr(Hearing loss arm 1) = pr(Hearing loss arm 2)p-value: 0.8995% CI: [0.4, 11.4]Fisher Exact
Secondary
Malondialdehyde (MDA) Levels
Computed maximum increase relative to baseline for each subject = (max MDA during treatment) - baseline MDA level.
Time frame: Baseline measurement occurred prior to first cisplatin treatment session. Follow-up measurements occurred up to 3 months after last cisplatin treatment.
Population: Non-missing MDA measurements from 23 subjects in primary outcome analysis
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm 1 | Malondialdehyde (MDA) Levels | 0.27 uM=micro-moles/liter | Standard Deviation 1 |
| Arm 2 | Malondialdehyde (MDA) Levels | 0.47 uM=micro-moles/liter | Standard Deviation 0.83 |
Comparison: H0: mean (MDA arm 1) = mean (MDA Arm 2)p-value: 0.6395% CI: [-1.03, 0.64]t-test, 2 sided
Secondary
Total Amount of Prescribed Cisplatin Dose Administered
Maximum cumulative dose of cisplatin (mg/m\^2) administered during the course of chemotherapy.
Time frame: cisplatin treatment period between 10 weeks and up to 16 weeks.
Population: Subjects from the original 39 recruited who had sufficient chemotherapy data recorded to measure cumulative dose.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm 1 | Total Amount of Prescribed Cisplatin Dose Administered | 239.7 mg/m^2 | Standard Deviation 92.6 |
| Arm 2 | Total Amount of Prescribed Cisplatin Dose Administered | 191.5 mg/m^2 | Standard Deviation 110.5 |
Comparison: H0: mean(max dose arm 1) = mean(max dose arm 2)p-value: 0.1595% CI: [-18.1, 114.6]t-test, 2 sided