Alpha-Lipoic Acid in Preventing Hearing Loss in Cancer Patients Undergoing Treatment With Cisplatin

• Sponsor: US Department of Veterans Affairs (U.S. Fed)
• Overall Status: Completed
• CT.gov ID: NCT00477607
• Collaborator: Oregon Health and Science University (Other)
• Enrollment: 39
• Locations: 2
• Arms: 2
• Duration (Months): 44
• Patients Per Site: 19.5
• Patients Per Site Per Month: 0.4

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Ototoxicity; Unspecified Adult Solid Tumor	Drug: alpha-lipoic acid; Behavioral: Audiology; Biological: laboratory biomarker analysis; Drug: Placebo	Phase 2/Phase 3

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 39 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Supportive Care
• Official Title: Prevention of Cisplatin Ototoxicity With the Antioxidant Alpha-Lipoic Acid
• Study Start Date: Oct 1, 2007
• Actual Primary Completion Date: Mar 1, 2011
• Actual Study Completion Date: Jun 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm 1 Receiving alpha-lipoic acid during cisplatin treatment.	Drug: 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.; Other Names: lipoic acid ; Behavioral: Audiology; otoscopy, immittance screening, noise exposure questionnaire and individualized behavioral pure-tone in the convention and high-frequency ranges.; Other Names: ototoxicity monitoring ; Biological: laboratory biomarker analysis; Plasma concentrations of Malondialdehyde (MDA) will be measures as an indicator of oxidative stress.; Other Names: MDA
Placebo Comparator: Arm 2 Receiving placebo during cisplatin treatment	Behavioral: Audiology; otoscopy, immittance screening, noise exposure questionnaire and individualized behavioral pure-tone in the convention and high-frequency ranges.; Other Names: ototoxicity monitoring ; Biological: laboratory biomarker analysis; Plasma concentrations of Malondialdehyde (MDA) will be measures as an indicator of oxidative stress.; Other Names: MDA ; Drug: Placebo; Placebo will be administered to each patient prior to first cisplatin treatment and continue until 3 months after last treatment.

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.

2. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	VA Medical Center, Portland	Portland	Oregon	United States	97201
2	Oregon Health & Science University	Portland	Oregon	United States	97239

Sponsors and Collaborators

• US Department of Veterans Affairs
• Oregon Health and Science University

Investigators

• Principal Investigator: Dawn L Martin, Portland VA Medical Center, Portland, OR

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: US Department of Veterans Affairs
• ClinicalTrials.gov Identifier: NCT00477607
• Other Study ID Numbers: C4697-R; CDR0000546570; NCRAR-VA-1810; OHSU-3288; NCT00570596
• First Posted: May 24, 2007
• Last Update Posted: Mar 7, 2014
• Last Verified: Feb 1, 2014

• Additional relevant MeSH terms: Ototoxicity; Thioctic Acid

Study Results

Participant Flow

Arm/Group Title	Alpha-lipoic Acid	Placebo
Arm/Group Description	Receiving alpha-lipoic acid during cisplatin treatment. alpha-lipoic acid : Supplements (1200mg once a day) was administered to each patient prior to first cisplatin treatment and continued until 3 months after last treatment.	Receiving placebo during cisplatin treatment Placebo supplements (1200mg once a day) were administered to each patient prior to first cisplatin treatment and continued until 3 months after last treatment.
Period Title: Overall Study
STARTED	19	20
COMPLETED	12	13
NOT COMPLETED	7	7

Baseline Characteristics

Arm/Group Title	Arm 1	Arm 2	Total
Arm/Group Description	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.	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.	Total of all reporting groups
Overall Participants	19	20	39
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	12 63.2%	15 75%	27 69.2%
>=65 years	7 36.8%	5 25%	12 30.8%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	62.0 (10.2)	60.6 (12.3)	61.2 (11.2)
Sex: Female, Male (Count of Participants)
Female	0 0%	1 5%	1 2.6%
Male	19 100%	19 95%	38 97.4%
Region of Enrollment (participants) [Number]
United States	19 100%	20 100%	39 100%

Outcome Measures

1. Primary Outcome

Title	Ototoxicity Measurement
Description	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.

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT)

Arm/Group Title	Arm 1	Arm 2
Arm/Group Description	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.	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.
Measure Participants	10	13
Number [participants]	7 36.8%	7 35%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm 1, Arm 2
	Comments	H0: pr(Hearing loss arm 1) = pr(Hearing loss arm 2)
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.89
	Comments
	Method	Fisher Exact
	Comments	No adjustments. Right one-sided p-value.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2
	Confidence Interval	(2-Sided) 95%; 0.4 to 11.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Malondialdehyde (MDA) Levels
Description	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.

Outcome Measure Data

Analysis Population Description

Non-missing MDA measurements from 23 subjects in primary outcome analysis

Arm/Group Title	Arm 1	Arm 2
Arm/Group Description	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.	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.
Measure Participants	10	11
Mean (Standard Deviation) [uM=micro-moles/liter]	0.27 (1.00)	0.47 (0.83)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm 1, Arm 2
	Comments	H0: mean (MDA arm 1) = mean (MDA Arm 2)
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.63
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.195
	Confidence Interval	(2-Sided) 95%; -1.03 to 0.64
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.3999
	Estimation Comments

3. Secondary Outcome

Title	Total Amount of Prescribed Cisplatin Dose Administered
Description	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.

Outcome Measure Data

Analysis Population Description

Subjects from the original 39 recruited who had sufficient chemotherapy data recorded to measure cumulative dose.

Arm/Group Title	Arm 1	Arm 2
Arm/Group Description	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.	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.
Measure Participants	19	20
Mean (Standard Deviation) [mg/m^2]	239.7 (92.6)	191.5 (110.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm 1, Arm 2
	Comments	H0: mean(max dose arm 1) = mean(max dose arm 2)
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.15
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	48.2
	Confidence Interval	(2-Sided) 95%; -18.1 to 114.6
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 32.7
	Estimation Comments

Adverse Events

Arm/Group Title	Arm 1		Arm 2
Arm/Group Description	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.		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.
All Cause Mortality
	Arm 1		Arm 2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Arm 1		Arm 2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/19 (26.3%)		6/20 (30%)
Blood and lymphatic system disorders
Neutropenia	1/19 (5.3%)	1	2/20 (10%)	2
Blood transfusion	1/19 (5.3%)	1	1/20 (5%)	1
Endocrine disorders
Pancreatitis	0/19 (0%)	0	1/20 (5%)	1
Gastrointestinal disorders
Nausea/vomitting	1/19 (5.3%)	1	0/20 (0%)	0
Esophagitis	1/19 (5.3%)	1	0/20 (0%)	0
Infections and infestations
sceptic shock	1/19 (5.3%)	1	0/20 (0%)	0
Renal and urinary disorders
Acute Renal Failure	0/19 (0%)	0	3/20 (15%)	3
Respiratory, thoracic and mediastinal disorders
hypoxic respiratory failure	0/19 (0%)	0	1/20 (5%)	1
Other (Not Including Serious) Adverse Events
	Arm 1		Arm 2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/19 (15.8%)		2/20 (10%)
Cardiac disorders
Atrial Fibrillation	1/19 (5.3%)	1	0/20 (0%)	0
Gastrointestinal disorders
Small bowel obstruction	0/19 (0%)	0	1/20 (5%)	1
Distended abdomen	1/19 (5.3%)	1	0/20 (0%)	0
Musculoskeletal and connective tissue disorders
Spine pain	0/19 (0%)	0	1/20 (5%)	1
Muscle Weakness	1/19 (5.3%)	1	0/20 (0%)	0

Limitations/Caveats

Missing data constraints have the number of subjects in the study being different for different outcomes.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.