Role of Silymarin in Chemotherapy Toxicity and Cognition Improvement in Breast Cancer Patients

NCT05595109 | Unknown Phase 2 FDA Drug

• 1 other identifier: 35945/10/22
• Study Type: interventional
• Target: 56
• Locations: 1 country
• Sites: 1

Brief Summary

Aim of the work This study aims to evaluate the possible beneficial role of silymarin in attenuating both doxorubicin related cardiac and hepatic toxicities and paclitaxel associated peripheral neuropathy and improving cognitive impairment in patients with breast cancer. This study will be a randomized placebo controlled parallel study. The study will be performed in accordance with the ethical standards of Helsinki declaration in 1964 and its later amendments. Group one: (Placebo group; n=28) which will receive four cycles of AC regimen (doxorubicin and cyclophosphamide; each cycle was given every 21 day) followed by 12 cycles of paclitaxel (each cycle was given in a weekly basis) plus placebo tablets once daily. Group two: (Silymarin group; n=28) which will receive the same regimen plus silymarin 140mg once daily

Conditions

Breast Cancer; Peripheral Neuropathy; Cardiac Toxicities; Hepatic Toxicity; Cognitive Impairment

Keywords

Breast Cancer; neuropathy; Cardiac Toxicities; Hepatic Toxicity; Cognitive Impairment; Chemotherapy; Toxicities; Silymarin

Outcome Measures

Primary Outcomes (2)

• change in ejection fraction

  Doxorubicin related cardiotoxicity will be assessed through :Echocardiography at baseline, Before starting the first chemotherapy cycle (baseline), after the last AC cycle (for assessment of N-terminal prohormone of brain naturetic peptide "NT-proBNP" ) and after the last doxorubicin/ cyclophosphamide (AC) cycle.

  6 months

• change in percentage of patients with peripheral sensory neuropathy

  change in percentage of patients with peripheral sensory neuropathy grade ≥ 2 with the variation of both 12-item neurotoxicity questionnaire (Ntx-12) total score and pain rating scale score.

  6 months

Secondary Outcomes (1)

• changes in serum levels of the measured biological markers.

  6 months

Study Arms (2)

Group one: (Placebo group)

PLACEBO COMPARATOR

which will receive four cycles of AC regimen (doxorubicin and cyclophosphamide; each cycle was given every 21 day) followed by 12 cycles of paclitaxel (each cycle was given in a weekly basis) plus placebo tablets once daily.

Drug: Placebo

Group two: (Silymarin group)

ACTIVE COMPARATOR

which will receive the same regimen plus silymarin 140mg once daily.

Drug: Silymarin

Interventions

Silymarin DRUG

Silymarin administration prevent the neuro-degeneration through inhibiting the activation of microglia, silymarin attenuates the activation of glial cell activation in cellular models possibly through inhibition of inducible nitric oxide synthase (iNOS) production, also reported to protect both microglia and astroglia from oxidative insults induced by peroxide in ex vivo system . It also significantly reduces doxorubicin-pro-oxidative activity and decreases histological changes in liver and heart tissue . The hepato-protective and cardio-protective effects of silymarin may be attributed to its antioxidant capacity, its ability to prevent lipid peroxidation and its ability to increase glutathione concentration. silymarin was reported to improve cognitive impairment in mice.

Group two: (Silymarin group)

Placebo DRUG

which will receive four cycles of AC regimen (doxorubicin and cyclophosphamide; each cycle was given every 21 day) followed by 12 cycles of paclitaxel (each cycle was given in a weekly basis) plus placebo tablets once daily.

Group one: (Placebo group)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age ≥ 18 years old.
• Patients with biopsy confirmed diagnosis breast cancer and with stage II and stage III breast cancer according to the American Joint Committee on Cancer (TNM staging system of breast cancer).
• Patients with performance status \<2 according to Eastern Cooperative Oncology Group (ECOG) score.
• Adequate baseline hematologic values (absolute neutrophilic count ≥ 1.5 × 109/L, platelet count ≥ 100 × 109/L and hemoglobin level ≥ 10 g/dl).
• Patients with adequate liver function (serum bilirubin \< 1.2 mg/dl) and adequate renal function (serum creatinine\< 1.5 mg/d).

You may not qualify if:

• Patients with prior exposure to anthracyclines and neurotoxic agents (Cis-platin, vincristine, paclitaxel, docetaxel, foscarnet ,INH, etc..) in the last 6 months.
• Patients with evidence of metastasis at the initial assessment.
• Concomitant use of antioxidant vitamins (vitamin A, C, E),anticonvulsants, tricyclic antidepressants, other medications used for neuropathic pain (gabapentin, lamotrigine, carbamazepine).
• Presence of clinical evidence for severe cardiac illness (angina pectoris, uncontrolled hypertension, arrhythmias and left ventricular ejection fraction \<50%).
• Preexisting peripheral neuropathy resulting from other causes such as diabetes and brain disorders, hypothyroidism, autoimmune diseases, hepatitis C.
• Patients with diabetes.
• Patients with inflammatory diseases (ulcerative colitis, rheumatoid arthritis).
• Patients with conditions associated with oxidative stress (smoking, tuberculosis, obesity).
• Patients with liver disease (fatty liver, hepatitis C, etc..).
• Patients who are candidates for monoclonal antibodies such as Trastuzumab and other targeted therapy (HER2 positive patients).
• Pregnant and breast feeding women.

Sponsors & Collaborators

• Tanta University: lead

Study Sites (1)

Tanta university

Tanta, 35945/10/2022, Egypt

Location

Related Publications (10)

• Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021 May;71(3):209-249. doi: 10.3322/caac.21660. Epub 2021 Feb 4.

  PMID: 33538338 BACKGROUND

• Ibrahim AS, Khaled HM, Mikhail NN, Baraka H, Kamel H. Cancer incidence in egypt: results of the national population-based cancer registry program. J Cancer Epidemiol. 2014;2014:437971. doi: 10.1155/2014/437971. Epub 2014 Sep 21.

  PMID: 25328522 BACKGROUND

• Klein I, Lehmann HC. Pathomechanisms of Paclitaxel-Induced Peripheral Neuropathy. Toxics. 2021 Sep 22;9(10):229. doi: 10.3390/toxics9100229.

  PMID: 34678925 BACKGROUND

• Rawat PS, Jaiswal A, Khurana A, Bhatti JS, Navik U. Doxorubicin-induced cardiotoxicity: An update on the molecular mechanism and novel therapeutic strategies for effective management. Biomed Pharmacother. 2021 Jul;139:111708. doi: 10.1016/j.biopha.2021.111708. Epub 2021 May 13.

  PMID: 34243633 BACKGROUND

• Huehnchen P, Muenzfeld H, Boehmerle W, Endres M. Blockade of IL-6 signaling prevents paclitaxel-induced neuropathy in C57Bl/6 mice. Cell Death Dis. 2020 Jan 22;11(1):45. doi: 10.1038/s41419-020-2239-0.

  PMID: 31969555 BACKGROUND

• Cardinale D, Iacopo F, Cipolla CM. Cardiotoxicity of Anthracyclines. Front Cardiovasc Med. 2020 Mar 18;7:26. doi: 10.3389/fcvm.2020.00026. eCollection 2020.

  PMID: 32258060 BACKGROUND

• Prasanna PL, Renu K, Valsala Gopalakrishnan A. New molecular and biochemical insights of doxorubicin-induced hepatotoxicity. Life Sci. 2020 Jun 1;250:117599. doi: 10.1016/j.lfs.2020.117599. Epub 2020 Mar 29.

  PMID: 32234491 BACKGROUND

• Aboelwafa HR, El-Kott AF, Abd-Ella EM, Yousef HN. The Possible Neuroprotective Effect of Silymarin against Aluminum Chloride-Prompted Alzheimer's-Like Disease in Rats. Brain Sci. 2020 Sep 11;10(9):628. doi: 10.3390/brainsci10090628.

  PMID: 32932753 BACKGROUND

• Abd Eldaim MA, Barakat ER, Alkafafy M, Elaziz SAA. Antioxidant and anti-apoptotic prophylactic effect of silymarin against lead-induced hepatorenal toxicity in rats. Environ Sci Pollut Res Int. 2021 Nov;28(41):57997-58006. doi: 10.1007/s11356-021-14722-8. Epub 2021 Jun 8.

  PMID: 34100211 BACKGROUND

• Shokouhi G, Kosari-Nasab M, Salari AA. Silymarin sex-dependently improves cognitive functions and alters TNF-alpha, BDNF, and glutamate in the hippocampus of mice with mild traumatic brain injury. Life Sci. 2020 Sep 15;257:118049. doi: 10.1016/j.lfs.2020.118049. Epub 2020 Jul 4.

  PMID: 32634430 BACKGROUND

MeSH Terms

Conditions

Breast Neoplasms; Peripheral Nervous System Diseases; Cardiotoxicity; Cognitive Dysfunction

Interventions

Silymarin

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases; Neuromuscular Diseases; Nervous System Diseases; Heart Diseases; Cardiovascular Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Drug-Related Side Effects and Adverse Reactions; Chemically-Induced Disorders; Radiation Injuries; Wounds and Injuries; Cognition Disorders; Neurocognitive Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Flavonolignans; Flavonoids; Chromones; Benzopyrans; Pyrans; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: principal investigator

Study Record Dates

• First Submitted: October 22, 2022
• First Posted: October 26, 2022
• Study Start: October 28, 2022
• Primary Completion: April 28, 2023
• Study Completion: October 28, 2024
• Last Updated: October 26, 2022

Record last verified: 2022-10

Data Sharing

• IPD Sharing: Will not share

Locations

EG (1)