Electroacupuncture for the Management of Symptom Clusters in Cancer Patients and Survivors

Study Overview
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Brief Summary
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This is a sham-controlled, patient and assessor-blinded pilot trial to evaluate the feasibility of administering EA as an intervention for symptom clusters in cancer patients and survivors, and to evaluate the degree that EA could reduce symptom clusters and the possible underlying mechanisms through examining its influence on biomarkers that are linked with the symptoms. Participants will be randomized to either the treatment arm (those who will receive EA) or the control arm (those who will receive sham-EA). The treatment period for both groups will be 10 weeks. There will be one study visit a week over the course of the 10-week treatment period, for a total of 10 study treatment visits. Participants in the treatment arm will receive EA at 13 standardized acu-points that have been chosen for their therapeutic effects. Participants in the control arm will receive electrical stimulation at non-disease acu-points. There will be four data collection time points for each participant: (1) baseline, (2) mid-treatment (5 weeks from baseline), (3) end of treatment (10 weeks from baseline), and (4) 4 weeks after end of treatment (14 weeks from baseline). At each of these timepoints, 10mL of peripheral blood will be collected for a biomarker analysis and participants will be asked to complete 4 questionnaires and a computerized cognitive test to evaluate their cognitive function, fatigue level, insomnia, psychological distress, and quality of life. An optional neuroimaging procedure will be available to all eligible participants. In total, study participation will last for 14 weeks.

Detailed Description
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The purpose of this study is to investigate the efficacy, safety, and feasibility of offering electroacupuncture as an intervention to improve cancer-related symptoms (cognitive impairment, fatigue, psychological distress and insomnia) and quality of life among cancer patients and survivors receiving care at UCI Health. In addition, changes in biomarkers (plasma BDNF, pro-inflammatory cytokines and mitochondrial DNA) known to be associated with cancer-related symptoms. We hypothesize that EA is an effective, safe, and feasible intervention for cancer patients and survivors. Our specific aims are as follows: To compare the efficacy of EA versus sham-EA control in reducing cognitive toxicity, fatigue, psychological distress, insomnia, and to improve quality of life. To evaluate the impact of EA versus sham-EA control on biomarkers, including circulating BDNF, pro-inflammatory cytokines (IL-1β, IL-4, IL-6, IL-8, IL-10, TNF-alpha), mitochondrial DNA (oxidative stress indicator). To compare the reduction of structural (brain gray matter) and functional connectivity at the prefrontal, medial temporal, and parietal brain regions pre- and post-EA treatment. To assess the safety and feasibility of administering EA to manage symptom clusters in cancer patients and survivors. As the UCI MINDS C2C registry (UCI IRB Approval #: HS# 2015-2494) will be leveraged to recruit some patients, we will quantify the characteristics associated with non-response to our study advertisement among C2C registrants using C2C-collected data.

Official Title
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Electroacupuncture for the Management of Symptom Clusters in Cancer Patients and Survivors (EAST): A Feasibility Study

Conditions
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Cancer

Intervention / Treatment
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* Other: Electroacupuncture
* Other: Sham-Electroacupuncture


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients diagnosed with cancer that have received anti-cancer treatment 16 years of age or older Life expectancy ≥ 6 months Complaints of one or more of the following symptoms: memory impairment/attention deficit, fatigue, insomnia, depression, or anxiety over the past 7 days Exclusion Criteria: Presence of metastasis Severe needle phobia Severe psychiatric or medical disorders which would affect cognitive assessments Known bleeding disorder (e.g. hemophilia, Von Willebrand's disease, thrombocytopenia) Has pacemaker or other electronic metal implants Epilepsy Already receiving acupuncture therapy or received acupuncture treatment in the past 3 months. Breastfeeding, pregnant or are planning get pregnant during the study period Additional exclusion criteria for optional neuroimaging procedure: - Has any contraindications to fMRI including metal fragments/implants in the body, sever claustrophobia, and non-removable metal orthodontic braces, metallic retainers and oral wires.

Ages Eligible for Study
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Minimum Age: 16 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: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This is a randomized sham-controlled, patient and assessor-blinded pilot trial.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment Arm<br>Each participant will attend a total of 10 treatment visits (one visit per week), over the course of 10 weeks. Each EA session will be approximately 1 hour. Participants in the treatment arm will receive EA at 13 standardized acu-points that were chosen for their therapeutic effects. | Other: Electroacupuncture<br>* EA at 13 standardized acu-points that were chosen for their therapeutic effects: Shenting (GV24), Baihui (DU20), Sinshencong (EX-HN1), Zhongwan (CV12), Guanyuan (CV4), Neiguan (PC6) bilateral, Shenmen (HT7) bilateral, Zusanli (ST36) bilateral, Sanyinjiao (SP6) bilateral, Taixi (KI3) bilateral, Zhaohai (KI6) bilateral, Hegu (LI4) bilateral, Taichong (LIV3) bilateral<br>|
| Sham Comparator: Control Arm<br>Each participant in the control arm will attend a total of 10 treatment visits (one visit per week), over the course of 10 weeks. Participants in the control arm will receive electrical stimulation at non-disease related acu-points for approximately 1 hour per session. | Other: Sham-Electroacupuncture<br>* Non-disease related points with electrical stimulation: Pianli (LI6) bilateral, Wenliu (LI7) bilateral, Fuyang (BL59) bilateral, Kunlun (BL60) bilateral, Sanyangluo (TE8), Sidu (TE9) bilateral, Daheng (SP15) bilateral<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Subjective Cognitive Function (FACT-Cog version 3) | All subjects will complete the FACT-Cog version 3 questionnaire to assess self-perceived subjective cognitive function. FACT-Cog is a validated questionnaire containing 33 items in the domains of concentration, functional interference, mental acuity, memory, multitasking and verbal fluency. Total score is calculated by summing scores from all the items and ranges from 0-148, and higher scores represent better subjective cognitive functioning. | All the mean scores will be compared before acupuncuture and 5, 10 and 14 weeks after baseline for EA and sham-EA control groups. The mean score changes will also be compared between the EA and sham-EA control groups at 5, 10 and 14 weeks after baseline. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Cognitive Function (CANTAB®,) | All subjects will complete Cambridge Neuropsychological Test Automated Battery (CANTAB®), to assess objective cognitive functions. CANTAB® is a computerized cognitive testing software to assess various cognitive domains. Both subjective and objective assessments are recommended by the International Cognition and Cancer Task Force (ICCTF). | All the mean scores will be compared before acupuncuture and 5, 10 and 14 weeks after baseline for EA and sham-EA control groups. The mean score changes will also be compared between the EA and sham-EA control groups at 5, 10 and 14 weeks after baseline. | 
| Fatigue (MFSI-SF) | Multidimensional Fatigue Symptom Inventory- Short Form (MFSI-SF) is a validated questionnaire that comprises of 30 items and contains 5 subscales, each with 6 items: general fatigue, physical fatigue, emotional fatigue, mental fatigue, and vigor. The total score is obtained by subtracting the vigour subscale from the sum of all the dimensions (total score range from 24 to 96), with a higher score indicating higher fatigue level. | All the mean scores will be compared before acupuncuture and 5, 10 and 14 weeks after baseline for EA and sham-EA control groups. The mean score changes will also be compared between the EA and sham-EA control groups at 5, 10 and 14 weeks after baseline. | 
| Psychological Distress and Insomnia (RSCL) | The Rotterdam Symptom Checklist (RSCL) will be used to measure the psychological symptoms (anxiety and depression) and insomnia. Psychological distress is indicated by a score of >16 in the psychological domain (range 7 to 28). Insomnia is measured by a single item in the checklist (not at all, a little, quite a bit, very much). | All the mean scores will be compared before acupuncuture and 5, 10 and 14 weeks after baseline for EA and sham-EA control groups. The mean score changes will also be compared between the EA and sham-EA control groups at 5, 10 and 14 weeks after baseline. | 
| Quality of Life (EORTC QLQ-30) | The European Organization for Research and Treatment of Cancer quality of life questionnaire (EORTC QLQ-30) is a validated questionnaire developed to assess cancer patients' health-related quality of life. It incorporates 5 functional scales (cognitive, emotional, physical, role, and social), symptom scales (e.g. pain, fatigue, insomnia), and a global health scale. Most questions used 4-point scale (1 'Not at All' to 4 'Very Much'); 2 questions used 7-point scale (1 'Very Poor' to 7 'Excellent'). Scores are averaged, and transformed to 0-100 scale. Higher scores represent a better global health status and better degree of functioning while lower symptom scores indicate less severe symptoms. | All the mean scores will be compared before acupuncuture and 5, 10 and 14 weeks after baseline for EA and sham-EA control groups. The mean score changes will also be compared between the EA and sham-EA control groups at 5, 10 and 14 weeks after baseline. | 
| Quality of Life (EQ-5D-5L) | EQ-5D comprises a visual analog scale of general health status ranging from 0 (worst imaginable) to 100 (best imaginable) and a descriptive system based on five dimensions of health status: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. The EQ-5D descriptive index responses were mapped into a single dimension health utility index (UI) ranging from death (0) to full health (1), with health states worse than death being possible (<0), by using utility weights for the US population. | All the mean scores will be compared before acupuncuture and 5, 10 and 14 weeks after baseline for EA and sham-EA control groups. The mean score changes will also be compared between the EA and sham-EA control groups at 5, 10 and 14 weeks after baseline. | 
| Safety Monitoring | Participants will be monitored for adverse events such as bruising, pain or discomfort, bleeding and possible infections. Severity are graded according to the Common Terminology Criteria for Adverse Events V5. | Through study completion, an average of 14 weeks per participant. | 
| Biomarkers - Plasma BDNF (pg/ml) | Plasma brain-derived neurotropic factor (BDNF) levels at each time point, and changes from baseline | BDNF levels will be compared before acupuncuture and 5, 10 and 14 weeks after baseline for EA and sham-EA control groups. The changes will also be compared between the EA and sham-EA control groups at 5, 10 and 14 weeks after baseline. | 
| Biomarkers - Plasma cytokines (IL-1β, IL-4, IL-6, IL-8, IL-10, TNF-alpha, pg/mL) | Plasma cytokine levels at each time point, and changes from baseline | Cytokine levels will be compared before acupuncuture and 5, 10 and 14 weeks after baseline for EA and sham-EA control groups. The changes will also be compared between the EA and sham-EA control groups at 5, 10 and 14 weeks after baseline. | 
| Biomarkers - Mitochondrial DNA content | Mitochondrial DNA (mtDNA) content at each time point, and changes from baseline | mtDNA content will be compared before acupuncuture and 5, 10 and 14 weeks after baseline for EA and sham-EA control groups. The changes will also be compared between the EA and sham-EA control groups at 5, 10 and 14 weeks after baseline. | 
| Biomarkers - Gray matter volume | Neuroimaging scans (rsfMRI, FLAIR, diffusion weighed, T1-weighted and T2-weighted sequences) | Neuroimaging measures will be compared before acupuncuture and 10 weeks after baseline for EA and sham-EA control groups. The changes will also be compared between the EA and sham-EA control groups at 10 weeks after baseline. | 
| Biomarkers - White matter volume | Neuroimaging scans (rsfMRI, FLAIR, diffusion weighed, T1-weighted and T2-weighted sequences) | Neuroimaging measures will be compared before acupuncuture and 10 weeks after baseline for EA and sham-EA control groups. The changes will also be compared between the EA and sham-EA control groups at 10 weeks after baseline. | 
| Biomarkers - Mean diffusivity | Neuroimaging scans (rsfMRI, FLAIR, diffusion weighed, T1-weighted and T2-weighted sequences) | Neuroimaging measures will be compared before acupuncuture and 10 weeks after baseline for EA and sham-EA control groups. The changes will also be compared between the EA and sham-EA control groups at 10 weeks after baseline. | 
| Biomarkers - Fractional anisotropy | Neuroimaging scans (rsfMRI, FLAIR, diffusion weighed, T1-weighted and T2-weighted sequences) | Neuroimaging measures will be compared before acupuncuture and 10 weeks after baseline for EA and sham-EA control groups. The changes will also be compared between the EA and sham-EA control groups at 10 weeks after baseline. | 
| Biomarkers - Radial diffusivities | Neuroimaging scans (rsfMRI, FLAIR, diffusion weighed, T1-weighted and T2-weighted sequences) | Neuroimaging measures will be compared before acupuncuture and 10 weeks after baseline for EA and sham-EA control groups. The changes will also be compared between the EA and sham-EA control groups at 10 weeks after baseline. | 
| Biomarkers - Axial diffusivities | Neuroimaging scans (rsfMRI, FLAIR, diffusion weighed, T1-weighted and T2-weighted sequences) | Neuroimaging measures will be compared before acupuncuture and 10 weeks after baseline for EA and sham-EA control groups. The changes will also be compared between the EA and sham-EA control groups at 10 weeks after baseline. | 
| Biomarkers - Resting state functional connectivities | Neuroimaging scans (rsfMRI, FLAIR, diffusion weighed, T1-weighted and T2-weighted sequences) | Neuroimaging measures will be compared before acupuncuture and 10 weeks after baseline for EA and sham-EA control groups. The changes will also be compared between the EA and sham-EA control groups at 10 weeks after baseline. | 
| Feasibility - Recruitment (number of participants recruited) | The number of participants recruited (% of target recruitment) | Through study completion, approximately 2 years. | 
| Feasibility - Recruitment (rate of recruitment) | Number of patients recruited per month | Through study completion, approximately 2 years. | 
| Feasibility - Recruitment (reasons for declining participation) | Reasons for declining participation will be documented. | Through study completion, approximately 2 years. | 
| Feasibility - Recruitment (time spent on recruitment) | Time spent on recruitment, in minutes, wil be documented to assess recruitment productivity. | Through study completion, approximately 2 years. | 
| Feasibility - Compliance (number of acupuncture sessions successfully completed) | Number of acupuncture sessions successfully completed in total | Through study completion, approximately 2 years. | 
| Feasibility - Compliance (proportion of participants completing the scheduled acupuncture sessions) | Proportion of participants completing all the scheduled acupuncture sessions | Through study completion, approximately 2 years. | 
| Feasibility - Acceptability | Study participants will complete a questionnaire evaluating their perceptions towards the EA treatment at the end of treatment. | Upon completion of treatment, at 10 weeks from baseline. | 
| Feasibility - Satisfaction | Participants will be asked if they are satisfied and benefited from the treatment, and whether they would consider undergoing treatment again outside of a trial setting. | Upon completion of treatment, at 10 weeks from baseline. | 
| Feasibility - Blinding assessment | Participants will be asked whether they believe that they have received EA or sham-EA at the end of treatment. | Upon completion of treatment, at 10 weeks from baseline. |