Herbal Treatment to Improve Chemotherapy Delivery

Study Overview
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Brief Summary
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This study is designed to:(1) determine the efficacy of Traditional Chinese Medicine (TCM) 'Tonifying Spleen and Kidney Sequential Regimen' (TSKSR) in improving the completion rate of 8-cycle CapeOX chemotherapy in patients with stage II (high-risk)& III colon cancer;(2) evaluate the efficacy of the TCM-TSKSR on adverse events of CapeOX chemotherapy and it's impact on patients' quality of life (QoL).A randomized,double-blinded,placebo-controlled clinical trial including seven centers will be conducted in Mainland China.The study will enroll patients with stage II (high-risk)& III colon cancer who have completed radical surgery and are going to receive CapeOX chemotherapy.All participants will receive chemotherapy as prescribed by their treating physicians and be randomly assigned to either concurrent use of TCM-TSKSR or placebo.

Detailed Description
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CapeOX chemotherapy is a combination therapy of Oxaliplatin 130mg/m^2 IV on 1st day and Capecitabine 1000mg/m^2 PO twice daily from 1th day to 14th day,21 days for each course of treatment.Adverse effects of chemotherapy,such as myelosuppression and gastrointestinal reactions,may lead to dose reductions,treatment delays or even discontinuation among cancer patients. According to IDEA study,the completion rate of 8-cycle CapeOX chemotherapy in colorectal cancer patients is 64%,which means that nearly 4 in 10 patients could not complete adjuvant chemotherapy as planned,which may negatively impact patients' survival outcomes.Some prior studies have shown that TCM can improve patients' symptom control and QoL during adjuvant chemotherapy,which may further improve the completion of adjuvant chemotherapy. However,there is a lack of definitive evidence to evaluate the effects of TCM in stage II(high-risk)& III colon cancer patients who receive adjuvant chemotherapy after radical surgery.The study will be conducted between 2018 and 2021.Four hundred participants will be enrolled and randomly assigned to either the experimental group or the control group.

Official Title
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Effect of TCM-TSKSR on Completion Rates of Chemotherapy in Patients With Stage II & III Colon Cancer: A Randomized Placebo-Controlled Clinical Trial

Conditions
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Colon Cancer

Intervention / Treatment
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* Drug: Tonifying Spleen and Kidney Sequential Regimen
* Drug: Placebo of 'Tonifying Spleen and Kidney Sequential Regimen


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient with pathological diagnosis of colon cancer; no residual tumor at the resection margin. tumor-node-metastasis(TNM)Stage II (high-risk)or III colon cancer according to 8th edition of American Joint Committee on Cancer(AJCC)Staging Manual. High-risk stage II disease is characterized by at least one of the following: T4 tumor, inadequately sampled nodes (<12 lymph nodes), clinical presentation with bowel obstruction or perforation, poorly differentiated histology ,exclusive of those cancers that are High degree of microsatellite instability(MSI-H), lymphovascular invasion,perineural invasion(PNI). Underwent radical surgery no more than six weeks ago and plan to start chemotherapy. Have not been enrolled in other therapeutic clinical trials within the near 30 days. Age between 18 to 75 years; All genders; Eastern Cooperative Oncology Group - performance status(ECOG-PS)from 0 to 2; Women who are pregnant, lactating or of reproductive age are not eligible, while those of reproductive age using secure contraceptives are eligible. No history of previous malignancy other than adequately treated in situ carcinoma of the uterine cervix or basal or squamous cell carcinoma of the skin, unless there has been a disease-free interval of at least 5 years. Laboratory testing: blood routine examination: WBC≥3.5×109/L，NEUT≥1.5×109/L,PLT≥100×109/L,HGB≥90g/L;biochemical tests:TBIL≤1.5×ULN,AST(SGOT),ALT(SGPT)≤2.5×ULN,Scr≤1.5×ULN;CEA after surgery was normal. Consented. Agree not to be enrolled in other interventional studies during the research. Exclusion Criteria: Patients not suitable for chemotherapy of CapeOX ,which will be determined by the investigator or the attending physician. Clinically relevant cardiovascular and/or cerebrovascular disease,active hepatitis,severe abnormalities in liver/ renal function tests. Known allergy to any of the components of study drug. Those who cannot take the study drug orally because of bowel obstruction and/or require for peripheral vein nutrition. Malabsorption or diseases that affect the absorption. Unstable situations or situations that may endanger the safety of patients and their compliance, such as severe mental illness,schizophrenia. Colostomy

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TCM group<br>Tonifying Spleen and Kidney Sequential Regimen(TSKSR) will be prescribed to the participants in each course of chemotherapy. | Drug: Tonifying Spleen and Kidney Sequential Regimen<br>* TSKSR will be given to the participants as follows:Liu-jun-an-wei Granule,1 pack each time,twice a day,PO,from 0 to 6th day of chemotherapy and Qi-tu-er-zhi Granule,1 pack each time,twice a day,PO,from 7th to 20th day of chemotherapy.<br>* Other names: TSKSR;|
| Placebo Comparator: Placebo group<br>Placebo of Tonifying Spleen and Kidney Sequential Regimen(TSKSR)similar in color,smell and texture with TSKSR will be prescribed to participants in each course of chemotherapy. | Drug: Placebo of 'Tonifying Spleen and Kidney Sequential Regimen<br>* Placebo of TCM-TSKSR will be given to the participants as follows:placebo of Liu-jun-an-wei Granule,1 pack each time,twice a day,PO,from 0 to 6th day of chemotherapy and placebo of Qi-tu-er-zhi Granule,1 pack each time,twice a day,from 7th to 20th day of chemotherapy.<br>* Other names: Placebo of TSKSR;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Completion Rate of 8-cycle Adjuvant Chemotherapy | Completion Rate of 8-cycle Adjuvant Chemotherapy=number of participants completing 8-cycle adjuvant chemotherapy/number of participants randomized to each group*100% | 6months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Completion Rate of Adjuvant Chemotherapy of Each Participant | Completion Rate of Adjuvant Chemotherapy of Each Participant=number of the last courses of chemotherapy/8*100% | 6months | 
| Completion Rate of 4-cycle Adjuvant Chemotherapy | Completion Rate of 4-cycle Adjuvant Chemotherapy=number of participants completing 4-cycle adjuvant chemotherapy/number of participants randomized to each group*100% | 3months | 
| Time to Treatment Failure,TTF | TTF is the period from randomization to the earliest day of an event such as withdrawal from protocol treatment for any reasons, patients refusal and loss to follow-up. | 6months | 
| Relative Dose Intensity (RDI) of Adjuvant Chemotherapy | Relative dose intensity (RDI) (%) = (actual dose/ initial dose of adjuvant chemotherapy) × 100% | 6months | 
| Proportion of Modifications of Time | Proportion of Modifications of Time=number of participants delaying chemotherapy /number of participants randomized to each group*100%.Delay is defined as ≥7days because of adverse event,such as weakness, myelosuppression, gastrointestinal reactions and other toxicity,except for administrative issues related to hospitalization. | 6months | 
| Time of Dose Reductions of Adjuvant Chemotherapy for the First Time | It is the period from randomization to when a chemo-induced grade 3-4 granulocytopenia and/or a chemo-induced grade 2 thrombocytopenia is observed in participants for the first time,in which case,the dose of both Oxaliplatin and Capecitabine will be reduced by 25% of planned dosage. | 6months | 
| Time of Dose Reductions of Adjuvant Chemotherapy for the Second Time | It is the period from randomization to when a chemo-induced grade 3-4 granulocytopenia and/or a chemo-induced grade 2 thrombocytopenia is observed in participants for the second time,in which case,the dose of both Oxaliplatin and Capecitabine will be reduced by 50% of planned dosage. | 6months | 
| Proportion of Salvage Treatment | Proportion of Salvage Treatment=Number of participants receiving salvage treatment/Number of participants randomized to each group*100%. | 6months | 
| Incidence of a Chemo-induced Grade 3-4 Nausea/Vomiting |  | 6 months | 
| Incidence of a Chemo-induced Grade 2 Diarrhea |  | 6 months | 
| Changes of Participants' ESAS Score | Edmonton Symptom Assessment Scale(ESAS) score will be used to evaluate the change of participants' QoL during adjuvant chemotherapy.ESAS has 9 items designed to assess the severity of commonly reported symptoms experienced by cancer patients,including pain, fatigue, drowsiness, nausea, dyspnea, depression, anxiety, well-being, and loss of appetite.Each items ranges from 0 to 10. | 6 months | 
| Changes of Participants' FACT-C Score | Functional Assessment of Cancer Therapy-Colorectal (FACT-C) score will be used to evaluate the change of participants' QoL during adjuvant chemotherapy.The FACT-C consists of 36 items,in four domains of well-being (physical,emotional,social,and functional),on a scale of 0 to 4. | 6months | 
| Changes of TCM Symptoms Score | Based on a prior expert consensus,11 TCM symptoms were considered to be the most common symptoms during CapeOX chemotherapy,including vomiting, numbness, diarrhea, constipation, sensation of chill, nocturia, forgetfulness, spontaneous sweating, night sweats, dry mouth and canker sores, each of which ranges from 0 to 10. | 6months | 
| Changes of Spleen Deficiency Scale Score | Based on prior researches,the investigator designed Spleen Deficiency Scale,which includes 8 items involving appetite,abdominal distension and so on.Each question ranges from 1 to 5. | 6months | 
| Changes of Kidney Deficiency Scale Score | Based on prior researches,the investigator designed Kidney Deficiency Scale, which includes 8 items involving soreness of waist, tinnitus, and so on. Each question ranged from 1 to 5. | 6months | 
| Incidence of AEs | Adverse effects(AEs) includes abnormal results of blood/urine/stool routine examination, liver/renal function test and electrocardiograms. | 6months | 
| Incidence of SAEs | Serious Adverse effects(SAEs) includes abnormal results of blood/urine/stool routine examination, liver/renal function test and electrocardiograms. | 6months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Colon Cancer, Traditional Chinese Medicine, Adverse Effect of Chemotherapy, Chemotherapy