Health-related Quality of Life-intervention in Survivors of Breast and Other Cancers Experiencing Cancer-related Fatigue Using Traditional Chinese Medicine: The HERBAL Trial

Study Overview
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Brief Summary
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This study is a phase 2, randomized, double-blinded, placebo-controlled trial to evaluate the efficacy and safety of a Traditional Chinese Medicine decoction, the modified Xiang Bei Yang Rong Tang, in alleviating cancer related fatigue in cancer survivors.

Detailed Description
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Cancer-related fatigue (CRF) is a distressing, persistent and subjective sense of physical, emotional, or cognitive tiredness related to cancer or its treatment. Currently there is a lack of effective conventional pharmacological intervention for treating this condition. Traditional Chinese Medicine (TCM) could be alternative therapy for managing CRF. This study is a phase 2, randomized, double-blinded, placebo-controlled trial to examine the efficacy and safety of a TCM decoction, the modified Xiang Bei Yang Rong Tang (XBYRT) in alleviating CRF in cancer survivors. Study participants recruited from National Cancer Centre Singapore (NCCS) will be randomized to receive either the XBYRT or placebo decoction. Participants will take their assigned decoction daily for a duration of 8 weeks and will be assessed using patient reported outcome (PRO) questionnaires. PROs used are the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ 30) for QOL, the Multidimensional Fatigue Symptom Inventory Short Form (MFSI-SF) for fatigue and Functional Assessment of Cancer Therapy-Cognitive Function (FACT-Cog) Version 3 for cognitive abilities. The changes in scores measured by these assessment tools will be compared between the XBYRT intervention and placebo groups. Blood biomarkers such as inflammatory cytokines, mitochondrial DNA and oxidative stress markers will also be evaluated in the study participants. Additionally, adverse events or serious adverse events in participants will be monitored for safety. Results from this study will provide a better understanding on the role of TCM in managing CRF.

Official Title
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HEalth-Related Quality of Life-intervention in Survivors of Breast and Other Cancers Experiencing Cancer-related Fatigue Using TraditionAL Chinese Medicine: The HERBAL Trial

Conditions
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Cancer, Fatigue, Cognitive Impairment

Intervention / Treatment
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* Other: Modified Xiang Bei Yang Rong Tang
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥21 years Clinically diagnosed cancer (Stages I-III) Completed surgery/chemotherapy/radiotherapy for at least 1 month At least one month after starting on aromatase inhibitors or ovarian suppression for breast cancer survivors Not expected to receive surgery/chemotherapy/radiotherapy next 10 weeks Fatigue screening score ≥4 for past 7 days Life expectancy ≥3 months Patients satisfy TCM syndrome differentiation as qi and blood deficiency Experience 2 major symptoms coupled with typical tongue and pulse conditions; 2 major symptoms and 1 possible symptom coupled with tongue and pulse conditions; 1 major symptom and at least 2 possible symptoms coupled with tongue and pulse conditions Able to read and understand English or Mandarin Exclusion Criteria: Cancer recurrence and/or metastasis Untreated co-morbidities causing fatigue (e.g. Severe anaemia, thyroid disorder) On medications that cause fatigue (e.g. beta blockers) Patients on warfarin Cancer survivors receiving adjuvant therapy during the study period. Aromatase inhibitors and anti-HER2 monoclonal antibodies are acceptable. Receiving or planning to receive treatment from other TCM practitioners during the study period Breast feeding or intending to conceive/get pregnant during the study treatment period Patients who present with yin deficiency and deficiency syndromes (e.g. phlegm-dampness, blood stasis, toxic-heat and qi stagnation)

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 80 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: XBYRT decoction<br>Participants assigned to receive the modifed Xiang Bei Yang Rong Tang granules | Other: Modified Xiang Bei Yang Rong Tang<br>* Modified Xiang Bei Yang Rong Tang is a combination of 15 herbal components and it is available in granules form to be dissolved in hot water for consumption<br>|
| Placebo Comparator: Placebo<br>Participants assigned to receive placebo (contains 5% of XBYRT) granules | Other: Placebo<br>* Placebo granules contain 5% XBYRT, colourant, bitterant and 95% starch filler<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Difference in Global Health Status (GHS) score | Difference in Global Health Status (GHS) score from the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) between XBYRT interventional and placebo arms from baseline to 8 weeks after baseline. The GHS scale ranges in score from 0-100. A higher score represents a better quality of life | 8 weeks from baseline | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Difference in Multidimensional Fatigue Symptom Inventory-Short Form (MFSI-SF) scores | Difference in MFSI-SF scores between XBYRT interventional and placebo arms. THE MFSI-SF consists of 30 items and has 5 subscales, each with 6 items: general fatigue, physical fatigue, emotional fatigue, mental fatigue, and vigour. The MFSI-SF measures different dimensions of fatigue, which can be combined to obtain an overall score. A higher score represents worse fatigue (total score ranges from -24 to 96) | 4, 8 and 10 weeks from baseline | 
| Difference in Functional Assessment of Cancer Therapy-Cognitive (FACT-Cog) version 3 scores | Difference in FACT-Cog V3 scores between XBYRT interventional and placebo arms. FACT-Cog v.3 will be used to assess subjective cognitive disturbances. These disturbances are assessed via 33 items in the domains of concentration, functional interference, mental acuity, memory, multitasking and verbal fluency (total score ranges from 0-148). A lower score represents worse cognitive function. | 4, 8 and 10 weeks from baseline | 
| Incidence of adverse events | Adverse events reported according to the Adverse events Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 | baseline, and 4, 8 and 10 weeks from baseline | 
| Difference in EORTC QLQ-C30 version 3.0 Functional and Symptom scale scores | Difference in EORTC QLQ-C30 scores between XBYRT interventional and placebo arms. The EORTC QLQ-C30 consists of 30 items across functional domains, symptoms domains and a global health status domain. All of the scales and single-item measures range in score from 0 to 100. A high score for a functional scale represents a high level of functioning. A high score for a symptom scale represents a high level of problems. | 4, 8 and 10 weeks from baseline | 
| Mitochondrial DNA (mtDNA) content | Mitochondrial DNA (mtDNA) content reduction in XBYRT interventional and placebo arms | baseline, 4, 8 and 10 weeks from baseline | 
| Inflammatory cytokines : C reactive protein (CRP) and cytokines TNF-α, IL-1β, IL-6, and IL-8 | Plasma inflammatory cytokine levels in XBYRT interventional and placebo arms | baseline, 4, 8 and 10 weeks from baseline | 
| Oxidative stress markers : malondialdehyde (MDA), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) | Plasma oxidative stress markers levels in XBYRT interventional and placebo arms | baseline, 4, 8 and 10 weeks from baseline | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cancer, Cancer Related Fatigue, Cognitive Impairment, Survivorship, Traditional Chinese Medicine