Clinical trial NCT04418115: Fatigue As a Late Effect in Breast Cancer Survivors - is Acupuncture a Treatment Option?
Official title: Acupuncture for Fatigue in Breast Cancer Survivors: a Study Protocol for a Pragmatic, Mixed-method, Randomised Controlled Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Fatigue
Depression, Anxiety
Insomnia
Hot Flashes
Quality of Life
Lead sponsor: Kristiania University College
Sponsor class: OTHER
Collaborators: name: Norwegian Cancer Society
name: University of Bergen
name: Memorial Sloan Kettering Cancer Center
name: Dana-Farber Cancer Institute
name: University Hospital, Akershus
name: University of York
name: University of Tromso
First posted: 2020-06-05
Enrollment: 223
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: The study is a pragmatic, mixed-method, randomized controlled trial
Primary purpose: TREATMENT

Brief summary: The success of treatment of breast cancer has improved, hence the prevalence of survivors have increased. However, experienced late effects from the cancer itself or from cancer treatment is substantial. Anti-cancer treatment can have a number of side effects including nausea, fatigue, vomiting, anorexia and alopecia. Late effects such as cancer related fatigue (CRF) are very persistent. CRF is a common side effect of cancer therapy, and affects the quality of life of patients and their families. It is important to point out that CRF is a form of fatigue that are different from normal fatigue which everyone can experience every now and then. Acupuncture is increasingly used in cancer centers both in the US and Europe, and that patients are positive to using acupuncture. Albeit the emerging evidence for acupuncture and CRF, acupuncture has neither been offered as a treatment for CRF within a Norwegian hospital nor in general practice. Hence the investigators think there is a need for a large randomized controlled trial (RCT) in a Norwegian health care setting.

Detailed description: Introduction Breast cancer is the most common tumour type in women worldwide. The success of the treatment of breast cancer have improved hence the prevalence of survivors have increased (American Cancer Society). However, experienced side effects from the cancer itself or from cancer treatments is substantial. Anti-cancer treatment can have a number of side-effects including nausea, fatigue, vomiting, anorexia and alopecia (1 - 3). However, some side effects such as cancer-related fatigue (CRF) are very persistent. CRF is a common adverse effect of cancer and cancer therapy, and effects the quality of life of the patients (4). The definition of CRF from the National Comprehensive Cancer Network (NCCN) is that it is "a distressing, persistent, subjective sense of physical, emotional and/or cognitive tiredness, related to cancer or cancer treatment, that is not proportional to recent activity and interferes with usual functioning" (5). It is important to point out that CRF is a form of fatigue that are different from normal fatigue which everyone can experience every now and then. The symptoms of CRF is under-reported by patients and underestimated and undertreated by clinicians, despite the prevalence and negative impact of CRF (6). It is recommended to patients that they are screened for CRF after completion of primary treatment and that they are offered specific information and strategies for management of the fatigue (7). Getting CRF as a side-effect after cancer treatment can have a major impact in their life.

In Norway on average 3090 women are diagnosed with breast cancer each year, giving a incidence rate per 100 000 persons of 121,0. In 2014, 3348 patients were diagnosed with breast cancer. The prevalence of fatigue is high in breast cancer survivors (BCS), with some studies reporting as many as 50% of the patients experiencing this (8). In a meta-analysis involving 12327 BCS, concluded that approximately one in four BCS suffers from severe fatigue (9). Several different treatments have been recommended for CRF such as exercise, psychosocial intervention, pharmacological interventions and mind-body interventions (4). From several randomized trials mind-body interventions such as yoga and acupuncture has been shown to relieve fatigue in cancer survivors (7). These studies, have however not focused solely on BCS but included other cancer types as well (10). Acupuncture has been shown to have an effect on CRF (10,11). A recent meta-analysis on CRF and acupuncture is positive (12) In Norway BCS are offered treatment such as cognitive behaviour therapy, exercise, relaxation techniques, yoga and nutritional coaching for their CRF. The use of acupuncture in the treatment of chemotherapeutic induced nausea is well established in Norway (13), also a Norwegian study on acupuncture on hot flashes in breast cancer patients has been published (14). The patients are found to be positive to acupuncture (15,16). In US acupuncture seems to have found its place in several hospitals which offers integrative medicine care to cancer patients (10).

Methodological approach A pragmatic, randomised controlled trial At the moment the study group, behind this present application, is running a pilot study on fatigue in breast cancer survivors with acupuncture as the intervention. This pilot study has been approved by the Regional Committee for Medical and Health Research Ethics (REK sør-øst A; reference 2017/2197). The purpose of conducting this pilot study is to examine the feasibility of our approach that is intended to be used in the planned larger randomised controlled study. Hence the design and methodological approach of the study in question wil be equal to the ongoing pilot study. By doing this the investigators can evaluate the feasibility of recruitment, randomization, collaboration, assessment procedures, and implementation of acupuncture. This will help us also to identify, revisions, if any, needed in the design of the larger, pragmatic randomised trial.

The intention with the pragmatic, RCT is to test acupuncture as a complete treatment package, i.e. including the therapeutic relationship and expectation, and address the important question of the overall effect of acupuncture-care, which is highly relevant to breast cancer survivors experiencing CRF. This question concerning the overall effect of acupuncture is also of importance for their health care providers and health authorities in general. As such a pragmatic trial will help users choose between options for care, and ''explanatory'' to describe trials that test causal research hypotheses (i.e., that a given intervention causes a particular benefit).Further, a pragmatic trials are primarily designed to determine the effects of an intervention under the usual conditions in which it will be applied, whereas explanatory trials are primarily designed to determine the effects of an intervention under ideal circumstances.

Baseline assessment includes sociodemographic data, medical and gynaecological history, previous experience with acupuncture, which other self-provided and therapist-provided interventions they have used earlier to relieve fatigue, current use of drugs and dietary supplements, level of physical activity, smoking status and level of alcohol consumption.

At each treatment session the acupuncturists ask specifically about, and record, any adverse events that have occurred during or after the last treatment, and adverse event forms are filled in at 4, 8 and 12 weeks.

Fatigue, and the severity of it, will be measured at inclusion/baseline, just after acupuncture treatment. This will be measured after 12 weeks after the inclusion in the control group; thereafter in both groups at 6 months after baseline evaluation. All secondary measurements will be measured at the same time intervals.

Participants and recruitment Women between 18-60 yrs who are defined as breast cancer survivors by their respective cancer hospital will be invited to take part in the study.To achieve a homogenues group of participants an important inclusion criteria be that they are treated with Tamoxifen. The potential participants will be given written information about the study - no further information will be given by the health personnell at the hospital. If they want to participate, after reading the information, the participants have to sign the paper and send it to Kristiania University College/AcuBreast study by a pre addressed and stamped envelope. Thereafter the research team will contact the potential participants. Women who are interested in participating, will than register their fatigue on a Visual Analog Pain Scale (VAS); women scoring ≥4 will be eligible. Participants will be excluded if they have needle phobia; low platelet count (\<50 000); co-morbidity with a bleeding disorder; co-morbidity with thyroid dysfunction; planned to be pregnant during the study period or present pregnant; haemoglobin levels \<10 g/dl and haematocrit \<30; anaemia on active pharmacological treatment or receiving blood transfusion or steroids, and life expectancy \<6 months. In addition, lymphoedematous limbs are excluded from needling.

Randomization Our collaborating statistician from the University of Bergen, will prepare the randomisation database and acts as a central randomisation service.

Acupuncture group The women randomized to acupuncture treatment will receive 12 acupuncture treatments during 8-12 weeks. The participating acupuncturists must have finished their Bachelor degree in acupuncture at least 5 years ago and they will be members of the "The Norwegian Acupuncture Association". The form of acupuncture used in this trial will be based upon theories from Traditional Chinese Medicine (TCM). The diagnostic process in TCM is complex and unique. It is a procedure that guides the practitioners to establish for themselves a correct treatment according to their theoretical knowledge and clinical experience within Chinese medicine. Taking a medical history according to TCM theories, match somehow the experience of a ''lived body.'' Hence added to the acupuncture treatment, there could be given relevant advices in relation to diet, exercise, rest and sex. Such advices are common within TCM; all advices given would be registered within the study in question.

Control group Our control group will do "business as usual". Hence they will continue with their usual care for their CRF. By inclusion in the pilot study and by the end of it, the participants in the control group will fill in the requested and similar instruments as the participants in the acupuncture group.

Safety of acupuncture and special procedures for our patient group. Acupuncture in general has been reported to be safe in the hands of well-educated acupuncturists (17-19). Special precautions have been described for treating cancer patients with acupuncture (20). Avoid needling the arm of patients who have undergone axillary dissection, the same applies for any lymphedematous limbs. Possible participants with low platelet count; comorbidity with a bleeding disorder or are planning pregnancy within the study period will be excluded.

Data analysis All analyses will be conducted blinded to group allocation. The primary analysis is intention-to-treat, comparing mean changes from baseline to end of treatment after 12 weeks in the two groups, using a two-sample t-test. In the presence of meaningful baseline differences, analysis of covariance will be employed. It is anticipated that the data will be somewhat right-skewed, therefore analyses will be checked after appropriate data conversion, and also checked using non-parametric methods. Secondary analyses will compare the changes at different time points. Secondary measures will be analyzed using appropriate parametric or non-parametric methods. Subgroup analyses include per-protocol analyses to assess efficacy of acupuncture care, and comparison of changes in fatigue scores among women grouped by TCM syndromes.

Data and safety monitoring The study is performed according to the Helsinki declaration and Good Clinical Practice requirements. Application for approval of the studies will be sent to the Regional Committee for Medical and Health Research Ethics (REK sør-øst).

Dissemination and communications strategy The investigators will utilize dissemination and public outreach to boost the impact of the work in the research project. Scientific results will be published in high-impact journals, and results will be presented on national and international scientific meetings.

Project management Professor Terje Alraek, at Kristiania University College, Institute of Health Sciences, has worked within the field of acupuncture for more than 30 years. First and still as a clinician and from 1994 has he been involved in research on acupuncture. He has during his research initiated, been invited to and developed several international groups of researcher with interest in acupuncture. Alraek and the foreign members of the established research group have published a substantial amount of scientific papers and they have also published many books in relation to all the problems of doing research on such a complex intervention as acupuncture.

The research team are happy to have managed to have one national- and two important international cancer centers as collaborating partners on this project. Our collaborating partners in US besides being researchers, are also experienced clinicians in treating breastcancer survivors with acupuncture for fatigue at their respective centers.

User involvement The user representative has a special responsibility for ensuring that the research is in line with the preferences, values and needs of breast cancer patients suffering from CRF.

Qualitative studies Participants from, the acupuncture- and control groups, will be asked to write about their experiences. The former with acupuncture treatment and the latter one of being in the control group.

Biomarkers and Cancer related fatigue Nested within this RCT, is one sub-study measuring biomarkers (CRP, IL1, IL6, TNF-α, CRP, aPL in addition to the current genotype genes TNF-308 and IL-6-174) from blood samples (n=80). Such biomarkers can potentially address changes of cancer related fatigue.

Eligibility criteria: Inclusion Criteria:

1. Breast cancer survivors, aged 18 or older, not receiving any curative cancer treatment
2. Fatigue score on a VAS scale ≥4 will be eligible
3. Sufficient knowledge of Norwegian is necessary for communicating with the acupuncturist and for filling in and understanding all the Norwegian questionnaires within the study.
4. Participants who have freely agreed to take part in the study and have signed an informed consent form.

Exclusion Criteria:

1. Any causal pathology related to fatigue or receiving ongoing acupuncture treatment for fatigue.
2. Participants who are pregnant at baseline or planning to get pregnant within the treatment period will be excluded. Reason is that several acupuncture points should be avoided during pregnancy and several of those are related to the treatment of fatigue.
3. Potential participants who are unable to understand, speak, or who find it difficult to communicate in Norwegian will be excluded from the study.
4. Individuals presenting with clinically diagnosed conditions or pathologies known to contribute to fatigue and persons whose fatigue could be attributed to pre-existing conditions

Primary outcomes:
measure: Fatigue
timeFrame: 12 weeks (treatment completion), Change from baseline registration at 3 and 6 month
measure: Fatigue 2
timeFrame: Change from baseline registration at 3 and 6 month
Secondary outcomes:
measure: Anxiety and depression
timeFrame: 12 weeks (treatment completion), Change from baseline registration at 3 and 6 months
measure: Bergen Insomnia Scale
timeFrame: 12 weeks (treatment completion), Change from baseline registration
measure: The Epworth Sleepiness Scale
timeFrame: 12 weeks (treatment completion), Change from baseline registration
measure: Hot flashes
timeFrame: 12 weeks (treatment completion), Change from baseline registration
measure: Quality of Life (QLQ) questionnaire
timeFrame: 12 weeks (treatment completion), Change from baseline registration
measure: Quality-adjusted life year - QALY questionnaire
timeFrame: Baseline and 6 months
Other outcomes:
Locations:
city: Oslo
country: Norway
facility: Kristiania University College
Study officials:
affiliation: School of Health Sciences, Kristiania University College
name: Terje Alraek, PhD
role: PRINCIPAL_INVESTIGATOR
References: