Contemporary Clinical Trials 41 (2015) 219–226
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Contemporary Clinical Trials journal homepage: www.elsevier.com/locate/conclintrial
Effectiveness of nasal irrigation for chronic rhinosinusitis and fatigue in patients with Gulf War illness: Protocol for a randomized controlled trial☆,☆☆ Supriya D. Hayer a, David P. Rabago a,⁎, Iliya P. Amaza a, Tony Kille b, Christopher L. Coe e, Aleksandra Zgierska a, Larissa Zakletskaia a, Marlon P. Mundt a, Dean Krahn c,d, Chidi N. Obasi a, Rachel C. Molander c,d a
1100 Delaplaine Court, Madison, WI 53715, Department of Family Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, United States 600 Highland Avenue, Madison, WI 53792, Department of Surgery, Division of Otolaryngology, School of Medicine and Public Health, University of Wisconsin-Madison, United States Department of Psychiatry, Veterans Administration Hospital, 2500 Overlook Terrace, Madison, WI 53705, United States d Department of Psychiatry, School of Medicine and Public Health, University of Wisconsin-Madison, United States e Department of Psychology, University of Wisconsin-Madison, United States b c
a r t i c l e
i n f o
Article history: Received 15 October 2014 Received in revised form 15 January 2015 Accepted 17 January 2015 Available online 24 January 2015 Keywords: Gulf War Illness Chronic rhinosinusitis Fatigue Veterans Xylitol Nasal irrigation
a b s t r a c t Introduction: Gulf War Illness (GWI) affects 1 in 7 returned Persian Gulf War veterans. Quality-oflife impact is large; there is no cure. Chronic sinus symptoms and fatigue are common. Nasal irrigation with saline (NI-S) or xylitol (NI-X) improve sinus symptoms and fatigue in the general population. This trial will assess the effect of NI-S and NI-X on sinus and fatigue symptoms, economic outcomes and pro-inflammatory milieu among participants with GWI. Methods: 75 participants (age 35 to 65 years, 25 in each of three arms) with GWI will be recruited from the Veteran's Administration and the community. They will use routine care for sinus symptoms and fatigue and be randomized to continued usual care alone or additional therapy with NI-S or NI-X. Participants will be able to adjust specific elements of the NI procedure. The primary outcome (Sinonasal Outcome Test, SNOT-20) and other self-reported assessments will occur at baseline, 8 and 26 weeks; lab assessment of pro-inflammatory cellular and cytokine profiles will occur at baseline and 26 weeks. Other outcomes will include fatigue-specific and overall health-related quality of life, pro-inflammatory cellular and cytokine profiles, costeffectiveness and participant satisfaction. Results: Baseline demographic and clinical data from the first 10 participants show effective participant recruitment, enrollment, randomization, retention and data collection. Conclusion: Early study conduct suggests that our participant-oriented approach will yield high rates of participant adherence and data capture, facilitating robust analysis. Results of this study will clarify the value of NI for chronic sinus symptoms and fatigue among patients with GWI. Clinical trial registration: clinicaltrials.gov identifier NCT01700725. Published by Elsevier Inc.
☆ Funding: This study is funded by a grant from the U.S. Department of Defense (W81XWH-11-1-0390). ☆☆ Individual co-authors, materials, and participant-related research services are funded in part by: National Research Service Award (T32AT006956) from the National Center for Complementary and Alternative Medicine (NCCAM) at the National Institutes of Health (NIH) to the University of Wisconsin Department of Family Medicine (Hayer);National Institutes of Health: National Institute on Alcohol Abuse and Alcoholism: K23 AA017508 (Zgierska);Material support was provided by Dupont-Danisco (xylitol saches) and Med-Systems (salt saches and nasal irrigation (neti) pots);Participant-related research services were supported by the Clinical and Translational Science Award (CTSA) program, through the NIH National Center for Advancing Translational Sciences (NCATS), grant UL1TR000427. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. ⁎ Corresponding author at: Department of Family Medicine, University of Wisconsin-Madison, 1100 Delaplaine Court, Madison, WI 53715, United States. Tel.: +1 608 265 2487. E-mail address: [emailprotected] (D.P. Rabago).
http://dx.doi.org/10.1016/j.cct.2015.01.008 1551-7144/Published by Elsevier Inc.
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1. Introduction
2. Materials and methods
Of the 700,000 veterans who returned from the Persian Gulf conflict of 1990–91 (Desert Shield/Desert Storm), up to 100,000 are affected by Gulf War Illness (GWI) [1,2]. Symptoms and co-morbidities span multiple organ systems; the first and third most common complaints have been reported to be chronic upper respiratory complaints (with nasal congestion reported by 47% of patients) and fatigue (41%) [3,4]. The etiology of chronic upper respiratory complaints and fatigue among patients with GWI is unclear. In the general population, chronic upper respiratory symptoms are primarily caused by infectious, irritant and allergic agents. Chronic symptoms change the nasal mucosa, predisposing it to further insult. Fatigue is often concomitant with URI symptoms [5]. Change in the concentration of pro-inflammatory biomarkers in serum and nasal mucosa has been associated with both fatigue [6] and chronic upper respiratory infection [7] in the general population. In spite of substantial research [8], and conflict about the status and relevance of that research [9], the cause and optimal treatment of GWI remain poorly understood. Therapy has focused on symptomatic treatment. The US Department of Defense (DoD) Gulf War Illness Research Program (GWIRP) has called for investigation of therapy to treat GWI [8]. Nasal irrigation (NI) is an adjunctive treatment for chronic upper respiratory symptoms for a variety of conditions that bathes the nasal cavity with liquid [10,11]. Two solutions have been assessed, saline (NI-S) and xylitol (NI-X). NI-S originated in the Ayurvedic medical tradition. Chronic rhinosinusitis (CRS) is the most common indication for NI-S [10]. The Cochrane Collaboration concluded that NI-S is appropriate adjunctive therapy for the symptoms of chronic rhinosinusitis [12]. An element of successful clinical use of NI-S has been patientcentered control of some elements of the irrigation protocol, including the frequency of irrigations and salinity, and has led to improved patient self-management of symptoms and QoL, and decreased side effects [13]. NI-X has a shorter clinical and cultural history, with medical use spanning only a few decades [14]. Xylitol is a naturally occurring, non-absorbed, five-carbon sugar reported to increase the effectiveness of resident natural killer cells in the nasal mucosa when used topically [15]. Xylitol has been reported to prevent dental caries [16] and acute otitis media [17]. It has been assessed for chronic upper respiratory symptoms in limited trials [12]. Neither NI-S nor NI-X has been assessed for GWI, and neither has been studied using assessment of pro-inflammatory biomarkers. The primary aim of this study is to determine whether nasal irrigation using a participant controlled protocol improves upper respiratory and fatigue symptoms among participants with GWI. We hypothesize that routine care plus either form of NI will be more effective than routine care alone. Our secondary aims are:
2.1. Study design The study is a 26-week, three-arm randomized controlled trial (RCT) to assess the comparative effectiveness of three therapeutic approaches in patients with GWI affected by CRS and fatigue. All groups will utilize routine care for their symptoms of CRS and fatigue. Group 1 will add NI with saline (NI-S) twice daily and Group 2 will add NI with xylitol (NI-X) twice daily to their usual care regimen. Group 3 will continue to use routine care only. 2.2. Eligibility Eligibility is based on self-report. Potential participants will be initially screened by phone and then in person at a later date. Inclusion criteria include (1) deployment to the Persian Gulf for the purpose of Operation Desert Shield or Operation Desert Storm during the first Gulf War (1990–1991); and (2) a diagnosis of GWI as based on a modified application of the “Kansas” GWI case definition [4]. The modification to this case definition involves making some of the exclusionary diagnoses relative, rather than absolute, if persons are stable with respect to the condition, and symptoms are well controlled/in remission, and have not resulted in hospitalizations within five years prior to enrollment. These diagnoses include diabetes, heart disease, stroke, melanoma, alcohol or drug dependence, depression, cancer, liver disease, posttraumatic stress and bipolar disorders: (personal communication with content expert Lea Steele, 8-2612) [4]; (3) Eligible participants must also have a diagnosis of CRS which is defined by the presence for more than 12 weeks of 2 or more major factors (facial pain, nasal obstruction/purulence, hypo/anosmia, purulence in the nasal cavity) or one major and two minor factors (fever, headache, cough, fatigue, ear pain, dental pain, ear pain/fullness); and (4) self-reported average daily sinus and fatigue ratings of moderate to severe grades over the past month [22] as indicated by at least 3 points on a 0–10 ordinal response symptom severity scale [22] (Table 1). Exclusion criteria include self-reported pregnancy; current use of NI, neurological or musculoskeletal conditions that could facilitate aspiration, or patients who otherwise cannot physically perform the NI procedure; anatomical abnormalities detected on CT or nasal endoscopy concerning for neoplasm perforations; and unstable psychiatric illness and competency as determined by psychiatric evaluation prior to enrollment. “Kansas definition” exclusions of lupus, multiple sclerosis, schizophrenia, active cancer treatment and presence of cognitive or physical impairments following a stroke remain absolute exclusionary criteria. 2.3. Recruitment and consent
a) To explore whether use of NI is associated with changes in the inflammatory marker concentration nasal in mucus and serum. b) To explore whether use of NI is cost-effective and satisfying to participants. c) To explore the ability of pretreatment psychosocial and clinical characteristics to predict which patients will benefit most from the two forms of NI.
Veterans will be recruited from the Madison and surrounding area. Recruitment from VA hospitals is based on an active duty screen which identifies veterans who were in the first Gulf War, and on an ICD-9 billing record screen to identify those diagnosed with CRS (473.*) and fatigue (780.7), or multiple episodes of acute rhinosinusitis (461.9) in the past two years. Potentially eligible participants receive a letter with an ‘opt-in/
S.D. Hayer et al. / Contemporary Clinical Trials 41 (2015) 219–226 Table 1 Inclusion/exclusion criteria. Inclusion criteria • 35–65 years • Deployment to the Persian Gulf for the purpose of Operation Desert Shield/Storm during the first Gulf War (1990–1991) • Diagnosis of GWI as based on the “Kansas” GWI case definition [4] • Diagnosis of CRS • Moderate-to-severe sinus symptom impact (≥3 points on a 0–10 ordinal response scale) [22] as assessed by the single item: “What has been the average level of your sinus symptoms daily over the past month on a 0–10 scale” • Moderate-to-severe fatigue severity (≥3 points on a 0–10 ordinal response scale) as assessed by the single item: “What has been the average level of your daily fatigue over the past month on a 0–10 scale” Exclusion criteria • Self-reported pregnancy • Current use of NI or nasal spray • Self-reported neurological or musculoskeletal conditions that could facilitate aspiration, or patients who otherwise cannot physically perform the NI procedure • Self-reported borderline personality disorder • Severe or unstable mental health problems • Concern for neoplasm on computed tomography scan and/or endoscopy GWI, Gulf War Illness; CRS, chronic rhinosinusitis; NI, Nasal Irrigation.
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opt-out’ card inviting them to participate in an initial phone screen or declining further contact. Community outreach efforts will include local advertisements and collaboration with local veterans' service organizations to access Gulf War veterans who may not use VA health services. Informed consent process will be obtained in a two-stage process. Verbal informed consent will be obtained prior to the initial telephone screening, and written informed consent will be administered in person at the in-person screening visit (Fig. 1).
2.4. Participant assessment procedures After phone-based screening, interested eligible persons will be invited to a private, in-person meeting at the UW Clinical Research Unit (CRU) lasting approximately 3 h. The CRU is a state-of the-art clinical research facility located within the University of Wisconsin Hospital and Clinics, and is funded by an NIH Clinical And Translational Science Award (CTSA). The session is divided into 2 parts. The first part will take approximately 20 min during which the research coordinator describes the study goals, procedures, activities and possible alternatives, and answers all questions. Education about the
ICD-9, Internation Classification of Diseases-9 Code; NI-X, Nasal Irrigation-Xylitol; NI-S, Nasal Irrigation-Saline Fig. 1. Recruitment/randomization flowchart. ICD-9, International Classification of Diseases-9 Code; NI-X, Nasal Irrigation-Xylitol; and NI-S, Nasal Irrigation-Saline.
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study will be assisted by the use of a Power Point slide presentation and a 30-second film about NI. Following this, interested prospective candidates will provide written consent for part 2 of the screening and study participation, and sign Health Insurance Portability and Accountability Act (HIPAA) forms, prior to further screenings. Interested eligible persons will then be enrolled, receive a study identification number and undergo baseline data collection. They will then be randomized toNI-S, NI-X or routine care alone using a computer generated block design with blocks of three. Participants will learn of group assignment after completion of eligibility determination, completion of baseline questionnaires and enrollment; they will open an opaque envelope containing a card containing group designation. 2.5. Measurement To meaningfully understand GWI and the potential effectiveness of nasal irrigation on CRS and fatigue, we will assess baseline and ongoing participant status using a multidimensional suite of assessments including sinus computed tomography (CT) scan (baseline only), validated questionnaire instruments for overall quality of life, sinus and fatigue symptoms, and serum and nasal biomarkers. Data will be collected on costs related to sinus and fatigue during the study period, including self-reported physician visits, related tests and medications (Table 2). Allocation will be concealed from assessors at baseline and follow-up time points and blinding will be assessed using a short questionnaire. 2.6. Baseline participant characteristics A sinus CT scan, the gold standard imaging modality to evaluate CRS severity [19], will be used to assess the baseline radiologic severity of CRS. CT findings indicative of CRS include mucosal thickening, bone changes, air-fluid levels, obstruction of the sinus ostia, and polyposis. CT imaging correlates to the presence or absence of paranasal sinus disease in those patients with suggestive symptoms. The CT images will be evaluated by an ENT (TK) surgeon using the Lund–McKay staging system, a validated and reproducible tool well-suited for use in clinical research [20]. We will also assess baseline status using nasal endoscopy (TK). Endoscopic findings will be scored based on a modified grading system based on that described by Lund and Mackay [20]. Polyps are graded as absent (0), present in the middle meatus (1), or present beyond the middle meatus (2). Discharge is graded as not present (0), thin (1), or thick and
purulent (2). Edema will be graded as absent (0), mild (1), or severe (2). Mental health status is an important prognosticator of adherence to chronic therapy. The Mini International Neuropsychiatric Interview (MINI) will be used to characterize potential subjects whose mental health precludes their safe and/or reliable study participation. The MINI is a structured neuropsychiatric interview developed specifically to assess major Axis I disorders as based on the DSM-IV criteria. The reliability and validity of the MINI have been confirmed in previous studies [21]. 2.7. Interventions Participants in the nasal irrigation groups will be instructed on the irrigation technique using a slide presentation, short film, and live demonstration. Saline and xylitol irrigant will be delivered to the nasal cavity using a nasal irrigation cup (“neti pot”), a simple hand-held vessel that uses the force of gravity to gently irrigate the user's nasal cavity (http://sinucleanse.org/ company/about.htm). Participants are instructed to irrigate the nasal cavity twice daily. The irrigation procedure has been used in prior studies [24]. Participants will mix the irrigant using salt or xylitol powder provided in individual use saches using room temperature distilled water. The neti pot spout is inserted into one nostril and the head tipped; irrigant solution enters the nasal cavity, proceeds toward the back of the nose, traverses the posterior margin of the nasal septum, washes over the nasal mucosa and structures within the nasal cavity, then proceeds anteriorly and exits the nasal cavity via the contralateral nostril. The procedure is then repeated on the other side. The irrigant volume is 120 mL per nostril per irrigation session. 2.8. Nasal irrigation solutions NI-S solution is made with using a pre-packaged commercial product containing salt and sodium bicarbonate that produces a 2% saline solution using a protocol tested in prior clinical trials (http://sinucleanse.org/company/about.htm) [11]. NI-X solution is made with crystallized xylitol pre-packaged for use in this study by the manufacturer (http://www.danisco. com/food-beverages/). The NI-X is a 5% xylitol solution, and has been used in prior NI safety and clinical trials [15,17]. The individual xylitol saches contain 6.25 g of xylitol powder for dissolution in 120 ml of distilled water.
Table 2 Study measurements. Measures
Baseline
8-week
26-week
• • • • • • • • • •
* * * * * * * * * *
* * *
* * *
* * *
* * *
The Sinonasal Outcomes Test (SNOT-20) [23] Multidimensional Fatigue Inventory (MFI) [25] The Medical Outcomes Survey Short Form-36 (SF-36) [26] Baseline Mini International Neuropsychiatric Interview (MINI) [21] Economic cost-effectiveness Subject treatment satisfaction Nasal irrigation calendar and medication use log Baseline nasal endoscopy Baseline sinus computerized tomography (CT) scan Blood draw and nasal swab/wash to for pro-inflammatory cellular and cytokine profiles
*
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2.9. Primary outcome Sinus disease specific health-related quality of life will be measured using the total score of a validated 20-item SinoNasal Outcome Test (SNOT-20), a recommended tool for clinical trial research involving CRS [22,23]. The SNOT-20 is a reliable and valid outcome measure for patients with CRS (Cronbach's α 0.9, test–retest r = 0.9); it describes the health burden and is sensitive to clinical change [23]. Patients who are more affected by CRS tend to have greater SNOT-20 scores (P b 0.01). The SNOT-20 score is expected to improve in NItreated subjects compared to controls; findings in a prior RCT assessing NI-S in the general population are consistent with the above evidence [18,24]. 2.10. Secondary outcomes Fatigue will be assessed using the Multidimensional Fatigue Inventory (MFI) [25], a validated disease specific outcome measure for fatigue. The instrument has good internal consistency (average Cronbach's alpha 0.84) as well as established construct and convergent validity [25]. Overall health related quality of life will be assessed using the Medical Outcomes Survey Short Form-36 (SF-36), a validated questionnaire designed to assess health status, function and overall health related quality of life [26]. The SF-36 has good internal consistency and discriminant validity. The SF-36 has broad clinical application and has been validated in a variety of clinical and non-clinical samples. GWI and CRS both affect sleep and breathing parameters. Prior studies suggest that both may be improved with NI-S in some subjects. We have therefore augmented the SF-36 with eighteen relevant sleep and breathing related questions from the Wisconsin Sleep Cohort [27] questionnaire and the Asthma Control Test [28] respectively. Economic cost-effectiveness will be derived from selfreport of personal and medical care costs of subjects. The costs of the interventions will be calculated based on comparable charges for patients not enrolled in a research study. Effectiveness of each study intervention will be defined as the proportion of subjects who have at least 50% improvement in sinus-related quality of life as assessed by the SNOT-20 questionnaire at the 26-week follow-up. The cost-effectiveness ratio (CER), reported as the “dollars spent per subject restored to health,” will then be derived by dividing the average cost of the intervention by the average effectiveness. The CER will be compared between the NI groups and a control group [29–31]. Subject treatment satisfaction will be assessed using two single-item questions (7-point Likert scale) evaluating subject treatment satisfaction and a perceived global change [32,33]. In addition, at 26 weeks subjects will also be asked about their treatment experience using a semi-structured 30-minute qualitative exit interview that will be recorded for transcription and evaluation of the study [34]. Very little qualitative work has been done in the field of GWI and NI. Qualitative studies have been used to good effect in the understanding of illnesses such as chronic fatigue syndrome [35]. 2.11. Tertiary outcomes CRS and fatigue symptoms overlap in many patients, with fatigue being a “minor” criterion in the formal diagnosis of CRS
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[22]. Management of CRS symptoms by medical or surgical means [24,36] has been reported to alleviate fatigue. They may therefore be associated at an underlying biological level. The inflammatory response may be both a specific response to infection and injury, and a reflection of the body's integrated reaction to many other challenges to homeostasis, including stress and fatigue [37]. The inflammatory bias may also respond to therapy compared to control. Laboratory assessments of stress- and illness-sensitive biomarkers will therefore include serum-based complete blood count, sedimentation rate, Creactive protein, Interleukin (IL)-6 levels and its soluble receptor. In addition, nasal inflammatory markers such as eosinophils, neutrophils, and cytokines IL 6, IL 10 and IL 12 will also be evaluated and quantified [38]. These will be obtained via an antecubital blood draw and nasal wash conducted at baseline and 26 weeks. Bias will be minimized by a clinical protocol designed to offer maximum possible masking in a study of a physical procedure such as nasal irrigation. Participants in the two irrigation groups will be able to taste salt vs sugar based irritant. They will be told that it is not known whether NI with either solution compared to routine care is effective for treating sinus and fatigue symptoms in GWI. Furthermore, outcomes data will be collected by telephone or in-person interviewers masked to treatment assignment. Because the saline and xylitol irrigants can be tasted, we will make every effort to assess core outcomes including the SNOT-20, MFI and SF-36 prior to side effects, limiting bias. We will also assess blinding of the assessor at 8 and 26 weeks. 3. Data collection and management We will collect outcomes information at all stages of recruitment, randomization, and treatment processes; the trial will be reportable according to CONSORT guidelines. We will record the number of potentially recruitable patients, invitation letters sent, responses received and their resolution and the number of assessment sessions attended. Follow-up data will include the number at each follow-up, the number of participants completing the trial, and the number of withdrawals due to all causes. Handling procedures for data transfer, entry and subsequent maintenance will be performed by a data manager (LZ). For our study we have developed a Research Electronic Data Capture (REDCap) [39] database to track data on each stage of recruitment, randomization, treatment, and treatment outcomes and will be able to report each in an integrated fashion. REDCap database provides data management, functionality, and support for study data capture. REDCap offers: 1) an interface with data validation for data captured on forms and surveys; 2) audit trails for tracking data manipulation and export procedures; 3) automated export procedures for seamless data downloads to SAS statistical package; 4) reporting capabilities; 5) procedures for importing data from external sources and 6) capabilities to grant user access rights to study data. REDCap uses MySQL databases via a secure web interface with data checks during data entry to ensure data quality. REDCap includes a complete suite of features to support HIPAA compliance, including a full audit trail, user-based privileges, and integration with the institutional LDAP server. The MySQL databases and the web server are both housed on secure
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servers operated by the UW Department of Family Medicine (DFM). The servers are in a physically secure location and are backed up nightly, with the backups stored in accordance with the DFM-ITS retention schedule of daily, weekly, and monthly tapes retained for 1 month, 3 months, and 6 months, respectively. Weekly backup tapes are stored offsite. The DFM servers provide a stable, secure, well-maintained, and high-capacity data storage environment, and both REDCap and MySQL are widely-used, powerful, reliable, well-supported systems. Access to study data in REDCap is restricted to IRB approved members of the study research team by username and password. We will use electronic methods to routinely transfer data from the UW secured servers including the Online Collaborative Research Environment (Oncore); and REDCap [39] databases prior to study analyses. Data handling processes were tested prior to the start of recruitment. The data manager wrote a detailed code book to facilitate analysis and data sharing. Requests for data will be reviewed by the senior author (DR) and our primary statistician. Representatives from the US AMRMC are eligible to review study records per research funding announcement guidelines. 4. Protection of human subjects The study was approved by: 1) University of WisconsinMadison Institutional Review Board, 2) United States Army Human Research Protection Office, 3) William S. Middleton Memorial Veterans Hospital Research and Development Committee and 4) Dupont Human Studies Committee (manufacturer of xylitol). 5. Data safety monitoring body Standardized forms will be used for monitoring and reporting of side effects and adverse events. The principal investigator or a designated study physician will be present in case of a significant adverse event. The research staff will assess each subject monthly during the study with the following question: ‘Do you think that you have had any side effects or problems with your sinus symptom therapy?’ [If ‘Yes’] ‘Please tell me more about that.’ Information regarding side effects and adverse events will be made available to the PI who will decide if the subject requires further medical care. The PI will report serious adverse events to the UW Research Subjects Advocate, the UW IRB and the project officer of the funding agency within 48 h. Reports will be made using the subject's ID number without other identifying information. Annual reports summarizing adverse events will be submitted to the Department of Defense under its guidelines. In addition, in accordance with Department of Defense guidelines, we have assigned a medical monitor, a person otherwise unassociated with the study. The medical monitor will review all unanticipated problems involving risk to subjects or other serious adverse events, and all subject deaths regardless of their association with the protocol, and provide an unbiased written report of the event within 10 calendar days. He will comment on the outcomes of the adverse event and the relationship of the event to the protocol. The monitor will also indicate whether s/he concurs with the details of the report provided by the PI. Reports of significant events related or
possibly related to the protocol will be forwarded to the Department of Defense. Unanticipated problems will also be reported to the IRB. In addition, any adverse events or problems will be reported to the VA in accordance with their reporting requirements. In the event of a suspected or actual data breach, the VA project officer and information security officer will be notified within 1 h of the event. 6. Stopping rules The trial will be stopped only if the UW patient advocate and the medical monitor determine continuation poses an unacceptable risk due to serious adverse events in one or more of the treatment arms. They could decide to terminate one of the arms of the trial or the entire trial. We have not proposed an interim analysis for efficacy and therefore have established no formal stopping rules. The trial is of modest sample size and even if one or both of the irrigation treatments reduce sinus symptoms more than usual care, we do not consider this an important enough reason to end the trial early. Previous trials of nasal irrigation have been of modest quality; we believe that this study is of sufficient duration and methodological rigor to more clearly evaluate the effectiveness of nasal irrigation for GWI. 7. Statistical issues 7.1. Sample size calculation The sample size for this study was calculated based upon detection of a significant overall F-test in a 3-arm trial, with a power of 80% and a type I error of 5% (α = 0.05). Based on prior research [24], we assume that the two active treatment arms will report a 35% reduction in SNOT-20 symptom scores compared to baseline. The control group is expected to report no significant changes in the SNOT-20 scores from baseline. Assuming a 35% improvement in the active treatment arms, an effective sample size of 20 subjects per study arm would provide 80% power (1-Beta = 0.81) to detect a significant overall F-test of difference in treatment effects between the groups. Assuming 20% loss to follow-up or missing data, 25 subjects per study arm (3 N = 75) will be enrolled. 7.2. Data analysis Descriptive analysis will be conducted on all data before formal testing of hypotheses. Baseline self-reported subject characteristics of the 3 groups will be assessed to determine the randomization success. If significant baseline differences are found between the groups, they will be assessed as covariates. All questionnaires, including the primary outcome measure, will yield continuous variables. Repeated measures analysis of variance [40–42] will be used to test the hypotheses within each group at baseline and follow-up points. Differences between the study groups will be analyzed at each time point in the repeated measures model, and comprehensively for the entire timeframe of the study. Statistical significance will first be assessed using the global F-test; specific pair-wise contrasts between groups will be performed if the overall F-test is significant. Distributional assumptions will be tested, and
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variable transformations will be applied if necessary. Missing data will be analyzed for the degree and possible reasons for missingness. Where appropriate, imputation methods will be applied. Cost-effectiveness will be analyzed using an econometric approach. We will compute the cost-effectiveness ratios (CER) of the 3 study interventions. Subject's personal and medical care costs will be assessed through questionnaire and administrative data. The CER will be evaluated for each treatment arm to determine the most cost-effective treatment. Because the distributions of ratios do not conform to standard statistical testing, bootstrap analysis will be applied to determine standard errors and statistical tests of significance in pairwise comparisons of the CERs [31]. The bootstrap analysis will be conducted by sampling equal sample sizes (N = 25) with replacement from the three study groups, calculating cost effectiveness ratios from the bootstrap iteration samples, and constructing CERs comparing pairs of treatment arms. Bootstrap samples will be repeated 1000 times. The median bootstrap sample will be used as the CER outcome, with confidence intervals from the 2.5th percentile to the 97.5th percentile iteration. A qualitative interview will be analyzed using the qualitative study method of transcribed in-depth long interview [34]. The interview which will be audio-taped, then stripped of all identifiers except a code number and transcribed. Transcripts will be reviewed and discussed by the study team and major themes will be identified using a consensus approach consistent with prior SNI studies [43]. The statistical analysis of cytokine, eosinophil counts and neutrophil counts is complex; [6,7] there is no consensus about how to analyze multiple cytokines and cellular biomarkers. However, our analysis will be hypothesis-driven. Consistent with our hypotheses, we are most interested in whether subjects show a pro-inflammatory bias at baseline and whether that bias decreases in response to therapy. Therefore we will construct our analyses to address specific cytokines that in isolation or in combination have been identified as proinflammatory. Examples include eosinophil count alone, and the combinations of IL-8 and neutrophils, and IL-1ß, IL-6 and TNF-alpha. These concentrations or cell counts are continuous variables and will be statistically handled in the manner as described above for questionnaire based outcomes. Compliance to twice daily NI therapy, and use of medical resources, will be assessed using daily calendar logs and submitted monthly. We will assess other variables as covariates, primarily focusing on gender, age and smoking status. Other variables include use of antibiotics, antihistamines, nasal steroids and decongestants, results of the baseline psychiatric, endoscopic and CT scores. For those covariates that are measured before treatment, tests of the assumption of independence of treatment and covariate will be conducted [44]. Propensity scores will be estimated and used as a single confounding covariate structure [45,46]. 8. Results This study is currently enrolling participants. Baseline demographic and clinical data on the first 10 participants suggest that balanced allocation through effective randomization of middle age adults (52.6 ± 7.03 years, 5 female); NI-S, NI-X and control groups contain 3, 3, and 4 participants respectively.
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SNOT-20 and MFI scores of 45.9 ± 6.3 and 11.5 ± 2.3 suggest moderate symptom severity and that essential eligibility criterion are being met. Effective recruitment, enrollment, and followup rates among initial participants suggest high project feasibility and robust data collection. Anecdotal evidence suggests that participants are satisfied with study procedures and adherence to NI in both intervention groups is high. Follow up data are pending.
9. Discussion Effective therapy for the many symptoms of GWI continue to plague the estimated 100,000 affected returned veterans of the first Gulf War. Several studies have evaluated the effect of liquid NI-S and NI-X on chronic sinus symptoms in the general population and in the context of workplace-related airborne irritants and allergies [47,48,13,14,18]. In one NI-S study, fatigue among NI-S compared to routine care improved but not by a significant margin [24]. The current study is designed to determine whether participants can effectively manage or mitigate respiratory and fatigue based symptoms using daily NI-S or NI-X with a patient oriented irrigation protocol. Statistically and clinically positive outcomes on the SNOT-20 proposed study would suggest that NI is an effective adjunctive treatment for CRS and fatigue in patients with GWI. This would provide immediate, practical benefits to individual patients and society at-large through improved quality-of-life and decreased work-related expenses associated with GWI, and medical resource use, including topical agents and antibiotics [24]. The study is also designed to investigate the mechanism of action of NI through the assessment of inflammatory serum and nasal mucosa biomarkers, the first study to do so. Inflammatory processes may contribute to the development and perpetuation of initially infectious illness and to resultant generalized fatigue. Evaluation of biomarkers may contribute to the understanding of GWI, and suggest research in more targeted therapy. Given the overlap between sinus symptoms and fatigue, positive findings in this study may also suggest that NI could be an effective, patient controlled safe and inexpensive therapy for returned military personnel and members of the general population. A complete understanding of GWI and NI continues to elude the research community. This study will address aspects of both through a flexible NI use protocol that allows participants to optimize the therapy in a several intervention parameters. Positive results on the primary and secondary outcome measures carry the potential of high patient and societal impact for both GWI veterans and society in general.
References [1] CDC. Current estimates from the national health interview survey. US Dept of Health and Human Services: Vital Health Statistics; 1994 96–1521[PHS]. [2] Conboy L, St John M, Schnyer R. The effectiveness of acupuncture in the treatment of Gulf War illness. Contemp Clin Trials May 2012;33(3): 557–62. [3] Fukada K, Nisenbaum R, Stewart G, Thompson WW. Chronic multisystem illness affecting air force verterans of the Gulf War. JAMA 1998;280:981–8. [4] Steele L. Prevalence and patterns of Gulf War illness in Kansas veterans: association of symptoms with characteristics of person, place and time of military service. Am J Epidemiol 2000;10(152):992–1002.
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