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This study is being done because peripheral neuropathy, a condition that interrupts sensation in your limbs, is a common side effect of paclitaxel. There is some evidence that alpha lipoic acid (ALA), an antioxidant compound, protects neurons after exposure to paclitaxel. The purpose of this study is to assess the safety and tolerability of ALA and to find the best dose of ALA in patients that receive chemotherapy.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Alpha lipoic acid | Experimental | Oral administration three times daily (morning, mid-day, night) |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Alpha lipoic acid | Drug | The baseline dose is 100 mg three times daily for four months. Dose escalation will occur until a maximum tolerated dose is found. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Identification of the Optimal Dose of ALA Based on Acceptable Adverse Event(AE) Profile | Based on acceptable adverse event (AE) profile and continual reassessment method dose escalation. | 4 months |
| Measure | Description | Time Frame |
|---|---|---|
| Proportion of Patients Who Complete the Proposed Regimen of Daily ALA | 4 months | |
| Cumulative Rate of Adverse Events | 4 months | |
| Total Neuropathy Score (TNS) |
Not provided
Inclusion Criteria
Diagnosis of Breast cancer.
Breast cancer must meet the following criteria:
Must be receiving single agent paclitaxel in their prescribed chemotherapy regimen.
Age > 18 years. There is no upper age limit for participation in this study.
Required lab values: AST, ALT, creatinine
Women of childbearing potential and sexually active males must agree to use contraception while on study.
ECOG performance status 0,1,2
All patients must have given signed, informed consent.
Exclusion Criteria
Breast cancer meeting the following criteria:
Evidence of pre-existing peripheral neuropathy as determined by baseline Michigan neuropathy screening instrument score > 2.
Previous chemotherapy treatment of any kind.
AST and ALT >2 times upper limit of normal; Creatinine > 2.0 mg/dL.
Current use of medications or substances known to be associated with peripheral neuropathy.
Use of ALA or other anti-oxidant supplements during the prior three months.
Diabetes mellitus or use of medications known to lower blood sugar.
Participation in any other experimental trial.
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| Name | Affiliation | Role |
|---|---|---|
| Jeffrey A. Allen, MD | Northwestern University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Northwestern Medical Faculty Foundation | Chicago | Illinois | 60611 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 16797537 | Background | Siau C, Xiao W, Bennett GJ. Paclitaxel- and vincristine-evoked painful peripheral neuropathies: loss of epidermal innervation and activation of Langerhans cells. Exp Neurol. 2006 Oct;201(2):507-14. doi: 10.1016/j.expneurol.2006.05.007. Epub 2006 Jun 22. | |
| 18789599 | Background | McCarty MF, Barroso-Aranda J, Contreras F. The "rejuvenatory" impact of lipoic acid on mitochondrial function in aging rats may reflect induction and activation of PPAR-gamma coactivator-1alpha. Med Hypotheses. 2009 Jan;72(1):29-33. doi: 10.1016/j.mehy.2008.07.043. Epub 2008 Sep 11. |
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| ID | Title | Description |
|---|---|---|
| FG000 | Alpha Lipoic Acid | Oral administration three times daily (morning, mid-day, night) Alpha lipoic acid: The baseline dose is 100 mg three times daily for four months. Dose escalation will occur until a maximum tolerated dose is found. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Cohort 1: Dose Level 1 (ALA 300mg Daily) |
| |||||||||||||
| Cohort 2: Dose Level 2 (ALA 600mg Daily) |
| |||||||||||||
| Cohort 3: Dose Level 3 (ALA 400mg Daily) |
| |||||||||||||
| Cohort 4: Dose Level 4 (ALA 500mg Daily) |
| |||||||||||||
| Cohort 5: Dose Level 2 (ALA 600mg Daily) |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Alpha Lipoic Acid | Oral administration three times daily (morning, mid-day, night) Alpha lipoic acid: The baseline dose is 100 mg three times daily for four months. Dose escalation will occur until a maximum tolerated dose is found. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Identification of the Optimal Dose of ALA Based on Acceptable Adverse Event(AE) Profile | Based on acceptable adverse event (AE) profile and continual reassessment method dose escalation. | Although our dose finding analysis suggested a maximum tolerated dose of 500mg daily, it should be noted that we failed to fully complete the Continual Reassessment Method (CRM) dose finding portion of the study. As such, we can not make confident dose finding statements on the basis of this trial. | Number | mg | 4 months |
|
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Alpha Lipoic Acid | Oral administration three times daily (morning, mid-day, night) Alpha lipoic acid: The baseline dose is 100 mg three times daily for four months. Dose escalation will occur until a maximum tolerated dose is found. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Nausea | Gastrointestinal disorders | Systematic Assessment | mild - probably related to study drug Moderate - possibly related to study drug Severe - possibly related to study drug |
The small number of enrolled patients precluded any meaningful ALA dose finding or neuropathy prevention efficacy statements. A formal statistical analysis of the data was not able to be performed.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Jeffrey Allen M.D. | Northwestern University | 312-695-8636 | jallen1@nmff.org |
Not provided
| ID | Term |
|---|---|
| D010523 | Peripheral Nervous System Diseases |
| D001943 | Breast Neoplasms |
| ID | Term |
|---|---|
| D009468 | Neuromuscular Diseases |
| D009422 | Nervous System Diseases |
| D009371 | Neoplasms by Site |
| D009369 | Neoplasms |
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| ID | Term |
|---|---|
| D008063 | Thioctic Acid |
| ID | Term |
|---|---|
| D002264 | Carboxylic Acids |
| D009930 | Organic Chemicals |
| D013876 | Thiophenes |
| D013457 | Sulfur Compounds |
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|
The Total Neuropathy score (TNS) is a validated score that combines signs, symptoms, and very limited nerve conduction studies (NCS). It was designed to assess peripheral nerve function and has been used as an endpoint in clinical trials of toxic neuropathy. The TNS is a composite scale with a range of values from 0 (normal) to 28 (severely affected). It includes data from 7 different categories. Patients are asked to assess the severity of sensory symptoms on a scale of 0 (no symptoms) to 4 (symptoms above knees or elbows, or functionally disabling). Next, 4 examination categories are assessed. These include pin sensation, vibration sensation, deep tendon reflexes, and strength. Signs are scored from 0 to 4 depending on severity. The nerve conduction portion of the scale consists of measurements of a motor (peroneal) and sensory (sural) nerve. Motor and sensory responses are graded on a scale of 0 to 4 depending on the severity of an abnormality. |
| 4 months |
| 18809400 | Background | Melli G, Taiana M, Camozzi F, Triolo D, Podini P, Quattrini A, Taroni F, Lauria G. Alpha-lipoic acid prevents mitochondrial damage and neurotoxicity in experimental chemotherapy neuropathy. Exp Neurol. 2008 Dec;214(2):276-84. doi: 10.1016/j.expneurol.2008.08.013. Epub 2008 Sep 9. |
| 17065669 | Background | Ziegler D, Ametov A, Barinov A, Dyck PJ, Gurieva I, Low PA, Munzel U, Yakhno N, Raz I, Novosadova M, Maus J, Samigullin R. Oral treatment with alpha-lipoic acid improves symptomatic diabetic polyneuropathy: the SYDNEY 2 trial. Diabetes Care. 2006 Nov;29(11):2365-70. doi: 10.2337/dc06-1216. |
| 16904799 | Background | Cremer DR, Rabeler R, Roberts A, Lynch B. Safety evaluation of alpha-lipoic acid (ALA). Regul Toxicol Pharmacol. 2006 Oct;46(1):29-41. doi: 10.1016/j.yrtph.2006.06.004. Epub 2006 Aug 14. |
| 1815532 | Background | Segermann J, Hotze A, Ulrich H, Rao GS. Effect of alpha-lipoic acid on the peripheral conversion of thyroxine to triiodothyronine and on serum lipid-, protein- and glucose levels. Arzneimittelforschung. 1991 Dec;41(12):1294-8. |
| 13825981 | Background | GAL EM, RAZEVSKA DE. Studies on the in vivo metabolism of lipoic acid. 1. The fate of DL-lipoic acid-S35 in normal and thiamine-deficient rats. Arch Biochem Biophys. 1960 Aug;89:253-61. doi: 10.1016/0003-9861(60)90051-5. No abstract available. |
| 16899332 | Background | Cremer DR, Rabeler R, Roberts A, Lynch B. Long-term safety of alpha-lipoic acid (ALA) consumption: A 2-year study. Regul Toxicol Pharmacol. 2006 Dec;46(3):193-201. doi: 10.1016/j.yrtph.2006.06.003. Epub 2006 Aug 8. |
| 8786016 | Background | Ziegler D, Hanefeld M, Ruhnau KJ, Meissner HP, Lobisch M, Schutte K, Gries FA. Treatment of symptomatic diabetic peripheral neuropathy with the anti-oxidant alpha-lipoic acid. A 3-week multicentre randomized controlled trial (ALADIN Study). Diabetologia. 1995 Dec;38(12):1425-33. doi: 10.1007/BF00400603. |
| 10499773 | Background | Reljanovic M, Reichel G, Rett K, Lobisch M, Schuette K, Moller W, Tritschler HJ, Mehnert H. Treatment of diabetic polyneuropathy with the antioxidant thioctic acid (alpha-lipoic acid): a two year multicenter randomized double-blind placebo-controlled trial (ALADIN II). Alpha Lipoic Acid in Diabetic Neuropathy. Free Radic Res. 1999 Sep;31(3):171-9. doi: 10.1080/10715769900300721. |
| 10480774 | Background | Ziegler D, Hanefeld M, Ruhnau KJ, Hasche H, Lobisch M, Schutte K, Kerum G, Malessa R. Treatment of symptomatic diabetic polyneuropathy with the antioxidant alpha-lipoic acid: a 7-month multicenter randomized controlled trial (ALADIN III Study). ALADIN III Study Group. Alpha-Lipoic Acid in Diabetic Neuropathy. Diabetes Care. 1999 Aug;22(8):1296-301. doi: 10.2337/diacare.22.8.1296. |
| 10656234 | Background | Ruhnau KJ, Meissner HP, Finn JR, Reljanovic M, Lobisch M, Schutte K, Nehrdich D, Tritschler HJ, Mehnert H, Ziegler D. Effects of 3-week oral treatment with the antioxidant thioctic acid (alpha-lipoic acid) in symptomatic diabetic polyneuropathy. Diabet Med. 1999 Dec;16(12):1040-3. doi: 10.1046/j.1464-5491.1999.00190.x. |
| 12610036 | Background | Ametov AS, Barinov A, Dyck PJ, Hermann R, Kozlova N, Litchy WJ, Low PA, Nehrdich D, Novosadova M, O'Brien PC, Reljanovic M, Samigullin R, Schuette K, Strokov I, Tritschler HJ, Wessel K, Yakhno N, Ziegler D; SYDNEY Trial Study Group. The sensory symptoms of diabetic polyneuropathy are improved with alpha-lipoic acid: the SYDNEY trial. Diabetes Care. 2003 Mar;26(3):770-6. doi: 10.2337/diacare.26.3.770. |
|
|
| years |
|
| Age, Categorical | Count of Participants | Participants |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| Units | Counts |
|---|---|
| Participants |
|
|
| Secondary | Proportion of Patients Who Complete the Proposed Regimen of Daily ALA | Number | participants | 4 months |
|
|
|
| Secondary | Cumulative Rate of Adverse Events | Number | participants | 4 months |
|
|
|
| Secondary | Total Neuropathy Score (TNS) | The Total Neuropathy score (TNS) is a validated score that combines signs, symptoms, and very limited nerve conduction studies (NCS). It was designed to assess peripheral nerve function and has been used as an endpoint in clinical trials of toxic neuropathy. The TNS is a composite scale with a range of values from 0 (normal) to 28 (severely affected). It includes data from 7 different categories. Patients are asked to assess the severity of sensory symptoms on a scale of 0 (no symptoms) to 4 (symptoms above knees or elbows, or functionally disabling). Next, 4 examination categories are assessed. These include pin sensation, vibration sensation, deep tendon reflexes, and strength. Signs are scored from 0 to 4 depending on severity. The nerve conduction portion of the scale consists of measurements of a motor (peroneal) and sensory (sural) nerve. Motor and sensory responses are graded on a scale of 0 to 4 depending on the severity of an abnormality. | Failure to reach the MTD precluded our ability to perform any meaningful analysis of the TNS. | 4 months |
|
|
| 0 |
| 9 |
| 9 |
| 9 |
|
| Rash | Skin and subcutaneous tissue disorders | Systematic Assessment | Mild - not related to study drug Moderate - possibly related to study drug |
|
| Indigestion | Gastrointestinal disorders | Systematic Assessment | Mild - probably related to study drug |
|
| Constipation | Gastrointestinal disorders | Systematic Assessment | Moderate - possibly related to study drug |
|
| Pain | Gastrointestinal disorders | Systematic Assessment |
|
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| D001941 |
| Breast Diseases |
| D012871 | Skin Diseases |
| D017437 | Skin and Connective Tissue Diseases |
| D003067 |
| Coenzymes |
| D045762 | Enzymes and Coenzymes |
| D005227 | Fatty Acids |
| D008055 | Lipids |