European Journal of Oncology Nursing xxx (2014) 1e10

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Nevasic audio program for the prevention of chemotherapy induced nausea and vomiting: A feasibility study using a randomized controlled trial design Saeed Moradian a, *, Catherine Walshe b, Soodabeh Shahidsales c, Mohammad Reza Ghavam Nasiri c, Mark Pilling a, Alexander Molassiotis a, d a

School of Nursing, Midwifery and Social Work, University of Manchester, Manchester, UK International Observatory on End of Life Care, Division of Health Research, Lancaster University, UK Cancer Research Center, Mashhad University of Medical Sciences, Mashhad, Iran d School of Nursing, The Hong Kong Polytechnic University, Hong Kong b c

a b s t r a c t Keywords: Chemotherapy-induced nausea and vomiting Nevasic Music therapy Feasibility

Purpose: Pharmacological therapy is only partially effective in preventing or treating chemotherapy induced nausea and vomiting (CINV). Therefore, exploring the complementary role of nonpharmacological approaches used in addition to pharmacological agents is important. Nevasic uses specially constructed audio signals hypothesized to generate an antiemetic reaction. The aim of this study was to examine the feasibility of conducting a randomized controlled trial (RCT) to evaluate the effectiveness of Nevasic to control CINV. Methods: A mixed methods design incorporating an RCT and focus group interviews. For the RCT, female breast cancer patients were randomized to receive either Nevasic plus usual care, music plus usual care, or usual care only. Data were analysed using descriptive statistics and linear mixed-effects models. Five focus group interviews were conducted to obtain participants' views regarding the acceptability of the interventions in the trial. Results: 99 participants were recruited to the RCT and 15 participated in focus group interviews. Recruitment targets were achieved. Issues of Nevasic acceptability were highlighted as weaknesses of the program. This study did not detect any evidence for the effectiveness of Nevasic; however, the results showed statistically significant less use of anti-emetics (p ¼ 0.003) and borderline non-significant improvement in quality of life (p ¼ 0.06). Conclusions: Conducting a non-pharmacological intervention using such an audio program is feasible, although difficulties and limitations exist with its use. Further studies are required to investigate the effectiveness of Nevasic from perspectives such as anti-emetic use, as well as its overall effect on the levels of nausea and vomiting. © 2014 Elsevier Ltd. All rights reserved.

Introduction Nausea and vomiting are frequently experienced toxicities associated with chemotherapy (Roscoe et al., 2000; Schwartzberg, 2007). These symptoms have a negative effect on nutritional status, physical functioning and quality of life (Farrell et al., 2013). The standard management of chemotherapy induced nausea and vomiting (CINV) involves the use of pharmacological agents.

* Corresponding author. 61 Steeles Ave E. Toronto, Ontario, M2M 3Y3, Canada. Tel.: þ1 647 858 9755; fax: þ1 416 519 9694. E-mail address: [email protected] (S. Moradian).

Despite advances in pharmacological management, approximately 50% of patients receiving chemotherapy still experience (primarily) nausea and/or vomiting (Pirri et al., 2011). Since pharmacological therapy is only partially effective in preventing or treating CINV, there is a need for additional methods to reduce these symptoms (Ezzo et al., 2006). Mind and body medicines are based on interactions among the brain, mind, body, and behaviour, with the intent to use the mind to affect physical functioning and promote health (NCINIH, 2012). Several mind-body techniques, in addition to conventional antiemetics, have been examined over the years for the treatment of CINV. For example, during the last decade several trials examining the efficacy of acupressure/acupuncture for alleviating CINV have 1462-3889/© 2014 Elsevier Ltd. All rights reserved.

Please cite this article in press as: Moradian, S., et al., Nevasic audio program for the prevention of chemotherapy induced nausea and vomiting: A feasibility study using a randomized controlled trial design, European Journal of Oncology Nursing (2014), j.ejon.2014.10.016


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been a focus of research (Ezzo et al., 2006; Taspinar and Sirin, 2010; Suh, 2012). In addition, the impact of psychological factors on nausea and vomiting has been widely acknowledged, and the efficacy of inducing these psychosomatic aspects, e.g. by relaxation training, coping preparations, imagery, music therapy, distraction techniques or hypnosis, has been demonstrated in a number of studies (Schneider and Hood, 2007; Tipton et al., 2007; Gimeno, 2010). Nevertheless, many patients still experience nausea and vomiting in relation to chemotherapy. The need to evaluate additional ways to reduce these symptoms is still, therefore, a priority. Nevasic, which is an audio program, is a technical innovation that proposes using specially constructed audio signals to generate an antiemetic reaction. Nevasic was originally developed as an audio tape over a decade ago (branded as TravelWell and MorningWell for motion and pregnancy sickness), and is now available in a number of formats including as a CD and App. Nevasic has been registered as a Medical Device in the UK, the USA, and in Australia (as an exempt product under the Therapeutic Goods Act) (http:// The process of emesis is complex, believed to involve different organs such as the brain, intestines and vestibular labyrinths. Nevasic is theorized to work by emitting specific constructed tones, frequencies and pulses which disrupt the normal auditory signal chain at the vestibular level, and thus having an effect on the experience of nausea and vomiting. No studies have examined the Nevasic effect(s) on chemotherapy-related nausea and vomiting. Only one study was conducted to compare the effectiveness of controlling breathing and listening to the Nevasic on increasing tolerance to nauseogenic motion. The results showed that mean (±SD) motion exposure time in minutes tolerated before the onset of moderate nausea was significantly longer (p < 0.01) for controlling breathing (10.7 ± 5.6 min) and longer (p < 0.01) for the music audiotape (10.4 ± 5.6 min) compared with control (9.2 ± 5.9 min) (Yen Pik Sang et al., 2003). The objectives of this study were to examine the feasibility of implementing and conducting a randomized controlled trial (RCT) using the Nevasic program. We sought to determine feasibility of recruitment and randomization, acceptability of the interventions, adherence to the trial and to evaluate potential effect of Nevasic on cancer patients undergoing chemotherapy. Methods Study design We conducted a pilot, multicenter, randomized controlled trial with three parallel arms (intervention, attention, and control) in Mashhad, Iran. The attention arm was used to assess the feasibility of using the three arms and include one (control) group that mimics the intervention as closely as possible to determine the “true” effects of the intervention over the placebo effects (Dowrick and Bhandari, 2012) and also to control for the potentially therapeutic effects of the placebo (Noll et al., 2004), as it has been stated that placebos may improve outcomes in up to 30e40% of patients with a wide range of clinical conditions (Wilcox, 2008). Participants' perspectives regarding the burden of completing this study and the acceptability of the intervention and attention arms of the trial were obtained by conducting semi-structured focus groups.

(Levin et al., 2009). Eligibility criteria for participants were: diagnosed with breast cancer, chemotherapy naïve, scheduled to receive moderately high emetogenic chemotherapy, aged over 18 years, and able to read and write in Persian. Patients, who had any other disease, were undertaking any concomitant treatment which might affect the severity of their nausea and vomiting, had any condition resulting in them not being able to listen to Nevasic or relaxation music, were excluded. Ethical considerations Ethical approval of the study was obtained from the ethics committees in Mashhad University of Medical Sciences (MUMS) and University of Manchester. The participants gave informed verbal and written consent. Sample size A sample size for a pilot study is usually based on pragmatic issues and the necessity of examining feasibility (Leon et al., 2011). For this pilot feasibility study, therefore, no formal sample size calculation was conducted. Lancaster et al. (2004) suggest that 30 participants per group is an adequate sample size for a feasibility RCT. Hertzog (2008) suggests that 30 per group may be required for a good estimation of the recruitment and attrition rate. For this study, 30 participants seemed feasible in terms of time and resources. Assuming a 20% attrition rate, it was planned to randomize 114 participants equally to one of three groups, with 38 per group. Recommendations for both the number of focus groups and sample size vary. It is emphasized that both too few and too many groups can affect the quality of focus group studies; therefore, quantity must be balanced against quality (Bryant and Charmaz, 2007). For this study, 4e8 participants per group and 3e4 focus groups was planned to allow us to examine themes common across groups. Randomization and allocation The participants were randomly assigned to one of the three treatment groups using a list (generated by nQuery Advisor program), done by a Statistician who was independent of this study. Trial participants were invited to participate in the focus groups based on the criteria that they had something to state on the mentioned topics and were comfortable talking to the interviewers and each other and prepared to engage in the discussion. Limited the number of specific questions (6e8 questions regarding issues with questionnaires, listening to music or Nevasic, practical ability to use them and adherence to the study and ended with any suggestions or questions) were designed and asked participants to freely talk about them. The sessions were run by the researcher and an oncologist from cancer research center affiliated to MUMS. Study settings Participants were recruited from three cancer centers in Mashhad, Iran from March 2011 to February 2012. Two of these centers were affiliated to MUMS and the third center was a radiation and oncology center run by a charity. These centers are among Iran's leading cancer centers and serve a population of 7 million across Khorasan province.


Health system in Iran

Female breast cancer patients were the target population for the study, as they are likely to experience the symptom of interest

Iran's health care system is managed primarily by the government. Health care and public health services are provided through a

Please cite this article in press as: Moradian, S., et al., Nevasic audio program for the prevention of chemotherapy induced nausea and vomiting: A feasibility study using a randomized controlled trial design, European Journal of Oncology Nursing (2014), j.ejon.2014.10.016

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nation-wide network. This network consists of a referral system, starting at primary care centers in the periphery going through secondary level hospitals in the provincial capital and tertiary hospitals in major cities (Mehrdad, 2009). Health care is financed via a mixture of public expenditure, consumer co-payments and revenue that is raised from special contracts between health insurance organizations and medical universities. Cancer services in Iran are mainly organized through the medical universities and delivered by multidisciplinary teams within specialized cancer centers. Patients are likely to visit a wide range of specialist consultants and other professionals, first for tests and then for surgical and other treatment/services (Mehrdad, 2009). Outcome measures Feasibility studies can help to reveal whether outcome measures are most appropriate; and whether changes occur in the intended domains (Bennett and Closs, 2011). The frequency and duration of nausea and amount of vomiting was measured using the translated version of Rhodes Index of Nausea, Vomiting and Retching (INVR) (Rhodes and McDaniel, 1999). The Rhodes INVR can conceivably cover anticipatory, acute and delayed phases (Brearley et al., 2008). The INVR was developed from the INV-1 and INV-2 (Chou et al., 2005), both of which showed good levels of reliability (Zhou et al., 1999), (Cronbach's a ¼ 0.89e0.97 and 0.98, respectively) and good concurrent validity, with a correlation coefficient of 0.87 (Chou et al., 2005). The psychometric properties of the Persian version of the Rhodes INVR were assessed in our previous study and demonstrated good evidence of reliability (Cronbach's a ¼ 0.88) and content validity (Moradian et al., 2014). Participants were instructed to complete the INVR questionnaire daily [first every 12 h (in the morning and evening) and then changed it to once daily (in the evening)] from the day of chemotherapy administration to day 5 post chemotherapy. We covered both acute CINV (within the first 24 h after chemotherapy administration) and delayed CINV (begins after the first 24 h of chemotherapy administration and it may last for 5 days). Although it is acknowledged that delayed CINV can last for longer in some patients, the first 3e4 days are the most crucial, as shown in many studies in the literature. Health-related quality of life (HR-QOL) was measured by the validated Iranian version of European Organization Research and Treatment of Cancer-Quality of Life (EORTC QLQ-C30) and EORTC QLQ e BR23 (Safaee and Dehkordi, 2007). Breast cancer module (EORTC QLQ e BR23) is a supplementary questionnaire module employed in conjunction with the QLQ-C30. It can provide more detailed information relevant to evaluating the quality of life (QOL) in specific patient populations (breast cancer). The module comprises 23 questions assessing disease symptoms, side effects of treatment (surgery, chemotherapy, radiotherapy and hormonal treatment), body image, sexual functioning and future perspective. The participants were requested to fill out the QOL-C30 (plus BR23) questionnaires at baseline, and on day 6 following chemotherapy (the primary time-point was day 6 post chemotherapy) in order to assess the effect of the two interventions on patients' follow-up HRQOL scores and to control for the baseline score differences among the three groups. Self-administered questionnaires were designed and divided, based on the time when they were to be completed, into the baseline data and treatment progression questionnaires (Table 1). The baseline data consisted of questions related to sociodemographic variables which might influence participants' experience of nausea and vomiting after chemotherapy. These variables included age, history of nausea and vomiting (nausea with past pregnancy, history of labyrinthitis, nausea and vomiting when


Table 1 Study instruments and timing of administration. Time


D-1 or D1 (prior to chemotherapy administration)

QoL C30 (Plus BR23) questionnaires Socio-demographic data questionnaire (baseline data questionnaire) Daily diary of sickness's questionnaire (treatment progression questionnaire) Daily diary of sickness's questionnaire Daily diary of sickness's questionnaire QoL C30 (Plus BR23) questionnaires Questionnaire about experience of study

D1 (evening of chemotherapy administration) D2 e D5 (daily in the evening) D6 (in evening) D6 (evening or later)

eating certain foods and history of motion sickness) and psychological problems (participants were asked if they experienced anxiety and/or depression through two questions, one from the EORTC QLQ-C30 and the other in the baseline data questionnaire). It has already been proven that these variables influence the risk of developing CINV (Molassiotis et al., 2002; Roscoe et al., 2010). This questionnaire was administered at baseline (before starting the chemotherapy), prior to randomization. The treatment progression questionnaire served as a daily diary of the patients' nausea and vomiting experience over the study period. The questionnaire collected data about how often participants used Nevasic in the intervention group, or listened to music in the attention group. The total daily intake of the prescribed antiemetic medication, the regular intake, and the pro re nata (PRN e as necessary doses) were measured by this structured diary. In addition, the frequency, duration and effectiveness of listening to Nevasic or music were also assessed by the diary. Patient satisfaction with using Nevasic (intervention group) or listening to music (attention group) and perceived effectiveness were determined by completing two 6-point Likert scales. A free text response to a questionnaire was available to ensure participants had an opportunity to report unanticipated issues, and provide more feedback on their thoughts and feelings. Medical information such as cancer diagnosis, stage of disease, chemotherapy protocol used and dosage was obtained from the patients' medical records. Data collection procedure Potential eligible patients were referred by the oncologists to the researcher. The invitation letter and information sheet were given to potential patients by the researcher at that time. Patients were given detailed information about the study and the research process. They then had the opportunity to ask questions. On the day of the patients' chemotherapy, or one day before, having been given all the information, which was confirmed by the researcher as being fully understood, the potential participants were asked to sign a consent form. The participants were then randomized to one of the three groups using a computer-generated list. After randomization, all the participants were given the treatment progression questionnaire. Those in the intervention and attention groups were also issued with a CD player and headphones with the Nevasic program or music files downloaded onto them as appropriate, and could keep the equipment at the end of the study. The procedure for the intervention and attention groups were identical, except that those in the Nevasic intervention group listened to the ‘active’ intervention of Nevasic, and those in the attention group listened to pre-selected music. They were given clear instructions on the use of the Nevasic program or music which included: only listening through the headphones provided; listening to Nevasic or music immediately once they started to feel

Please cite this article in press as: Moradian, S., et al., Nevasic audio program for the prevention of chemotherapy induced nausea and vomiting: A feasibility study using a randomized controlled trial design, European Journal of Oncology Nursing (2014), j.ejon.2014.10.016


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nauseous/vomiting either during or after chemotherapy administration; listening to the Nevasic/music program all the way through 27 min or until they feel symptoms diminished; not skipping any part of the Nevasic/music program. They were instructed that they could repeat these stages if their symptoms returned. The duration of the intervention/attention was 6 days. Participants in all three (intervention, attention, control) groups were told to take their anti-emetics post chemotherapy as prescribed. The participants were instructed in the completion of the measures and follow-up questionnaire. The participants were asked to return the measures and questionnaires using pre-paid self-addressed envelopes. Participants' views regarding the burden (negative impacts) of completing this study, and the acceptability of using Nevasic or music were obtained by conducting five focus group interviews. Since focus group data were analysed one focus group at a time, the researcher could use the multiple groups to assess if the themes that emerged from one group also emerged from other groups (Charmaz, 2000). Data were analysed using constant comparison method which is particularly used when there are multiple focus groups within the same study and allows the researcher to assess saturation in general and across-group saturation in particular (Onwuegbuzie et al., 2009). The researcher attempted to create an environment in which the participants felt relaxed and encouraged to engage and exchange feelings, views and ideas about the matters that came up for discussion. In addition, exchanges of views and the general content of discussion were documented. Observational notes were written immediately after each focus-group interview. Each group interview lasted approximately one and half hour and was taperecorded with participants' consent. Statistical methods and data analysis The main study outcomes in terms of the feasibility issues were assessed through process evaluation using a logic model of change (Oakley et al., 2006). Intention to treat (ITT) analysis was used as a strategy for analysis of the results to avoid various potentially misleading artifacts such as non-random attrition of participants from the study (Hollis and Campbell, 1999). The data were analysed using different methods according to the types of variables and the number of participants in the study groups. Descriptive statistics were used to summarize the sample characteristics and demographics. The baseline values were compared between the groups and centers. By looking at the profiles over time for individuals, it was established that the mean values at each time-point were representative. Moreover the baseline (Day 0) values for two groups of patients (those who completed all assessments, and those who dropped out before Day 6) were examined. Based on a clinically relevant difference in nausea score of 10% (¼ 12  0.1 ¼ 1.2), it was observed that differences occurred at baseline between these two groups, which meant that attrition had not occurred at random. It is known that standard analysis techniques require complete data from patients; consequently when drop-outs are not random, this can lead to bias in the analysis. Therefore, a mixed model approach was chosen which utilizes all the data, estimates values based on the correlation structure between time-points, and is less susceptible to bias due to non-random attrition. In addition, the score data was positively skewed. An assumption of linear models is that the model residuals are approximately normally distributed (Gaussian), which can occur with ill-fitting models or non-normal data. However, attempts to transform this endpoint did not improve its properties. After model fitting, the residuals were approximately Normally distributed, and the main results were confirmed with simple non-parametric tests (i.e. KruskaleWallis

test between each group at the time-points, and Friedman's test between the time-points). In order to assess the effect of Nevasic (intervention group) and music (attention group) on patients' follow-up HR-QOL scores, and to control for baseline score differences between the control and the other two groups, the nonparametric Wilcoxon signed rank test (change scores did not have a Normal distribution) was used. Data from focus groups were analysed using thematic content analysis. After each session recorded data were transcribed, read repeatedly and extra and irrelevant information was removed. Taken notes were compared and key points were discussed. Then data were categorized and tabulated and an agreed list of themes was formulated in order to address the initial goal of the study. A process of constant comparison and contrast of themes was employed to write a description and interpretation of the patients' perceptions. Frequencies of themes were used to assist in determining their importance in the interpretations of the participant's answers to the interview questions. Results Patient enrolment, allocations and demographics During the recruitment period, 392 breast cancer patients were scheduled to receive moderately high emetogenic chemotherapy regimens within the three centers. Of these patients, 99 patients gave consent to participate in the study, 46 (46.5%) from the first site, 21 (21.2%) from the second and 32 (32.3%) from the third (Fig. 1). Chi-square tests indicated there were similar proportions from the 3 centers in the groups (X2 ¼ 0.64, df ¼ 2, p ¼ 0.72). In addition, Chi-square tests indicated that there were no differences between the participants and the non-participants regarding demographic characteristics (age, marital status, occupation, education). Socio-demographic and clinical characteristics of the sample Socio-demographic and clinical characteristic of participants are shown in Table 2. There was no significant difference between the three groups for any demographic and treatment characteristics. Feasibility of patient recruitment In this study, the recruitment rate was 84.6% and only 15.4% refused to participate. The results from focus group interviews show that an important factor facilitating recruitment in this study was patients' attitudes to trial participation, as all participants stated that one of the main reasons for participating was a belief that their participation would benefit future patients with the same condition. Patients signified a wish to recognize any possibility that could contribute to helping prevent chemotherapy side effects such as nausea and vomiting. The inconvenience related to the trial was considered relatively minor. Feasibility of randomization A standard randomization procedure was utilized; however, failing to adequately control for patients' past history in relation to nausea and vomiting affected the homogeneity of the sample. It has been shown that younger patients (

Nevasic audio program for the prevention of chemotherapy induced nausea and vomiting: A feasibility study using a randomized controlled trial design.

Pharmacological therapy is only partially effective in preventing or treating chemotherapy induced nausea and vomiting (CINV). Therefore, exploring th...
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