Clinical trial NCT06406127: Effect of Alpha Lipoic Acid on Chemotherapy Induced Neurological Changes in Breast Cancer Patients
Official title: Effect of Alpha Lipoic Acid on Chemotherapy Induced Neurological Changes in Breast Cancer Patients
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Breast Cancer
Alpha Lipoic Acid
Paclitaxel
Neurologic Disorder
Chemotherapy
Lead sponsor: Ain Shams University
Sponsor class: OTHER
Collaborators: name: Dar EL Salam Cancer Hospital
First posted: 2024-05-09
Enrollment: 92
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: 92 female cancer patients, aged from 18 to 75 years old (with a first diagnosis of breast cancer) who will receive Paclitaxel-based chemotherapy (12 weeks) as first line therapy, will be enrolled in the study and will be randomly assigned to either:

* Group I: will receive the chemotherapy protocol or
* Group II: will receive the chemotherapy protocol plus 600 mg daily dose of Alpha Lipoic Acid for 14 weeks (one week before the start of paclitaxel and continue till one week after the end of paclitaxel).

  \* Blood samples will be withdrawn 2 times (week 1 and week 12) to measure the following: (Stored in -80 C till the end of the study)
* Tumor Necrotizing Factor- alpha (TNF-α) by ELISA.
* Brain-Derived Neurotrophic Factor (BDNF) by ELISA.

  \* All patients will be subjected to 6 tests/questionnaires (week 1 - week 12 - week 24) to predict the functionality of the brain:
* Functional Assessment of Cancer Therapy-Cognitive (FACT-Cog) version 3
* Mini-Cog Test
* Mini Mental State Examination (MMSE)
* Controlled Oral Word Association Test (COWAT)
* Hopkins Verbal Learning Test (HVLT)
* Trail Making Test (TMT)

Detailed description: 92 Female Cancer patients will be randomized to 2 groups, the first group will receive the alpha lipoic acid beside their chemotherapy regimen and the other group will only receive the chemotherapy regimen. Both groups will be watched for any changes in their neurological behaviors by asking and receiving answers on the questionnaires that were mentioned before. This will be done in 3 different time margins:

* Before starting the chemotherapeutic regimen
* after ending the chemotherapeutic regimen
* after 6 months of receiving the chemotherapeutic regimen this will show even the late symptoms and effects of the chemotherapy. Also serum biomarkers will be measured (TNF alpha and BDNF) 2 times; one before starting the chemotherapeutic regimen and the other after ending the treatment.

Throughout the treatment process, both groups will be monitored for any side effects concerning the alpha lipoic acid or the chemotherapeutic regimen.

Eligibility criteria: Inclusion Criteria:

* Female breast cancer patients aged 18 to 75 years old.
* Patients with a first diagnosis of cancer and indication for first-line therapy with Paclitaxel-based chemotherapy.
* Patients are those who are diagnosed with Stage 1 to 3 non-metastatic breast cancer.
* Patients are intended to receive 12 weeks of paclitaxel (75 - 80 mg/m2) according to the TC protocol.
* No previous neurological conditions (including dementia, Alzheimer's disease, Parkinson's disease) and taking no neurological-related drugs.
* Normal hepatic and renal function (bilirubin ≤1.5 mg/dL, creatinine ≤2.0 mg/dL).
* Eastern Cooperative Oncology Group (ECOG) performance status from 0 - 2.
* Patient Health Questionnaire (PHQ) score from 0 - 9.

Exclusion Criteria:

* Hypersensitivity / Allergy to Alpha Lipoic Acid.
* Any condition that contraindicates chemotherapy (i.e., pregnancy, lactation).
* New-onset neurological symptoms or presence of any neurological disorder.
* Patients with known history or current treatment with neurological agents.
* Alcohol abuse.
* Current participation in any other clinical investigation.

Primary outcomes:
measure: Tumor Necrotizing Factor Alpha Serum Levels
timeFrame: At baseline of treatment and After 12 weeks of the paclitaxel-based therapy (at the end of therapy)
Secondary outcomes:
measure: Response assessment by questionnaire - FACT-COG Test
timeFrame: For 3 times during the study: - At baseline - After 12 weeks of the paclitaxel-based therapy. - After 6 months from the start of the paclitaxel-based therapy.
measure: Response assessment by questionnaire - Mini-Cog Test
timeFrame: For 3 times during the study: - At baseline - After 12 weeks of the paclitaxel-based therapy. - After 6 months from the start of the paclitaxel-based therapy.
measure: Response assessment by questionnaire - Mini Mental State Examination (MMSE)
timeFrame: For 3 times during the study: - At baseline - After 12 weeks of the paclitaxel-based therapy. - After 6 months from the start of the paclitaxel-based therapy.
measure: Response assessment by questionnaire - Controlled Oral Word Association Test (COWAT)
timeFrame: For 3 times during the study: - At baseline - After 12 weeks of the paclitaxel-based therapy. - After 6 months from the start of the paclitaxel-based therapy.
measure: Response assessment by questionnaire - The Verbal Memory Arabic Test (VMAT)
timeFrame: For 3 times during the study: - At baseline - After 12 weeks of the paclitaxel-based therapy. - After 6 months from the start of the paclitaxel-based therapy.
measure: Response assessment by questionnaire - Trail Making Test (TMT)
timeFrame: For 3 times during the study: - At baseline - After 12 weeks of the paclitaxel-based therapy. - After 6 months from the start of the paclitaxel-based therapy.
measure: Brain Derived Neurotrophic Factor Serum Levels
timeFrame: At baseline and After 12 weeks of the paclitaxel-based therapy (at the end of therapy)
Other outcomes:
measure: Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]
timeFrame: through study completion, an average of 1 year.
measure: Monitoring the chemotherapy toxicity and side effects.
timeFrame: through study completion, an average of 1 year.
measure: Monitoring Drug-Drug interactions.
timeFrame: through study completion, an average of 1 year.
Locations:
city: Cairo
country: Egypt
facility: Dar El Salam Cancer Hospital (Harmel Hospital)
state: El Malek El Saleh
Study officials:
affiliation: Ain Shams University - Faculty of Pharmacy
name: Manal H El Hamamsy, Doctorate
role: PRINCIPAL_INVESTIGATOR
References:
citation: NCD Countdown 2030 collaborators. NCD Countdown 2030: worldwide trends in non-communicable disease mortality and progress towards Sustainable Development Goal target 3.4. Lancet. 2018 Sep 22;392(10152):1072-1088. doi: 10.1016/S0140-6736(18)31992-5. Epub 2018 Sep 20.
citation: Rostom Y, Abdelmoneim SE, Shaker M, Mahmoud N. Presentation and management of female breast cancer in Egypt. East Mediterr Health J. 2022 Oct 30;28(10):725-732. doi: 10.26719/emhj.22.076.
citation: Brown T, McElroy T, Simmons P, Walters H, Ntagwabira F, Wang J, Byrum SD, Allen AR. Cognitive impairment resulting from treatment with docetaxel, doxorubicin, and cyclophosphamide. Brain Res. 2021 Jun 1;1760:147397. doi: 10.1016/j.brainres.2021.147397. Epub 2021 Mar 8.
citation: Bellens A, Roelant E, Sabbe B, Peeters M, van Dam PA. A video-game based cognitive training for breast cancer survivors with cognitive impairment: A prospective randomized pilot trial. Breast. 2020 Oct;53:23-32. doi: 10.1016/j.breast.2020.06.003. Epub 2020 Jun 12.
citation: Janelsins MC, Kohli S, Mohile SG, Usuki K, Ahles TA, Morrow GR. An update on cancer- and chemotherapy-related cognitive dysfunction: current status. Semin Oncol. 2011 Jun;38(3):431-8. doi: 10.1053/j.seminoncol.2011.03.014.
citation: Lee JH, Nan A. Combination drug delivery approaches in metastatic breast cancer. J Drug Deliv. 2012;2012:915375. doi: 10.1155/2012/915375. Epub 2012 Apr 26.
citation: Emadi A, Jones RJ, Brodsky RA. Cyclophosphamide and cancer: golden anniversary. Nat Rev Clin Oncol. 2009 Nov;6(11):638-47. doi: 10.1038/nrclinonc.2009.146. Epub 2009 Sep 29.
citation: Inagaki M, Yoshikawa E, Matsuoka Y, Sugawara Y, Nakano T, Akechi T, Wada N, Imoto S, Murakami K, Uchitomi Y. Smaller regional volumes of brain gray and white matter demonstrated in breast cancer survivors exposed to adjuvant chemotherapy. Cancer. 2007 Jan 1;109(1):146-56. doi: 10.1002/cncr.22368.
citation: Schultz C, Engelhardt M. Anatomy of the hippocampal formation. Front Neurol Neurosci. 2014;34:6-17. doi: 10.1159/000360925. Epub 2014 Apr 16.
citation: Anderson JE, Trujillo M, McElroy T, Groves T, Alexander T, Kiffer F, Allen AR. Early Effects of Cyclophosphamide, Methotrexate, and 5-Fluorouracil on Neuronal Morphology and Hippocampal-Dependent Behavior in a Murine Model. Toxicol Sci. 2020 Jan 1;173(1):156-170. doi: 10.1093/toxsci/kfz213.
citation: Yap NY, Toh YL, Tan CJ, Acharya MM, Chan A. Relationship between cytokines and brain-derived neurotrophic factor (BDNF) in trajectories of cancer-related cognitive impairment. Cytokine. 2021 Aug;144:155556. doi: 10.1016/j.cyto.2021.155556. Epub 2021 May 10.
citation: Sommer C, Kress M. Recent findings on how proinflammatory cytokines cause pain: peripheral mechanisms in inflammatory and neuropathic hyperalgesia. Neurosci Lett. 2004 May 6;361(1-3):184-7. doi: 10.1016/j.neulet.2003.12.007.
citation: Werida RH, Elshafiey RA, Ghoneim A, Elzawawy S, Mostafa TM. Role of alpha-lipoic acid in counteracting paclitaxel- and doxorubicin-induced toxicities: a randomized controlled trial in breast cancer patients. Support Care Cancer. 2022 Sep;30(9):7281-7292. doi: 10.1007/s00520-022-07124-0. Epub 2022 May 21.
citation: Odabasoglu F, Halici Z, Aygun H, Halici M, Atalay F, Cakir A, Cadirci E, Bayir Y, Suleyman H. alpha-Lipoic acid has anti-inflammatory and anti-oxidative properties: an experimental study in rats with carrageenan-induced acute and cotton pellet-induced chronic inflammations. Br J Nutr. 2011 Jan;105(1):31-43. doi: 10.1017/S0007114510003107. Epub 2010 Nov 15.
citation: Biewenga GP, Haenen GR, Bast A. The pharmacology of the antioxidant lipoic acid. Gen Pharmacol. 1997 Sep;29(3):315-31. doi: 10.1016/s0306-3623(96)00474-0.
citation: Haghighatdoost F, Hariri M. The effect of alpha-lipoic acid on inflammatory mediators: a systematic review and meta-analysis on randomized clinical trials. Eur J Pharmacol. 2019 Apr 15;849:115-123. doi: 10.1016/j.ejphar.2019.01.065. Epub 2019 Feb 2.
citation: Al-Majed AA, Gdo AM, Al-Shabanah OA, Mansour MA. Alpha-lipoic acid ameliorates myocardial toxicity induced by doxorubicin. Pharmacol Res. 2002 Dec;46(6):499-503. doi: 10.1016/s1043661802002311.
citation: Aliomrani M, Mesripour A, Mehrjardi AS. Creatine and Alpha-Lipoic Acid Antidepressant-Like Effect Following Cyclosporine A Administration. Turk J Pharm Sci. 2022 Apr 29;19(2):196-201. doi: 10.4274/tjps.galenos.2021.27217.
citation: Costa DSJ, Loh V, Birney DP, Dhillon HM, Fardell JE, Gessler D, Vardy JL. The Structure of the FACT-Cog v3 in Cancer Patients, Students, and Older Adults. J Pain Symptom Manage. 2018 Apr;55(4):1173-1178. doi: 10.1016/j.jpainsymman.2017.12.486. Epub 2017 Dec 30.
citation: Limpawattana P, Manjavong M. The Mini-Cog, Clock Drawing Test, and Three-Item Recall Test: Rapid Cognitive Screening Tools with Comparable Performance in Detecting Mild NCD in Older Patients. Geriatrics (Basel). 2021 Sep 16;6(3):91. doi: 10.3390/geriatrics6030091.