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Controlling anal incontinence in women by performing anal exercises with biofeedback or loperamide (capable) trial: design and methods
Contents lists available at Contemporary Clinical Trials Controlling anal incontinence in women by performing anal exerciseswith biofeedback or loperamide (CAPABLe) trial: Design and metho J. Eric Jelovsek ,, Alayne D. Markland , William E. Whitehead Matthew D. Barber , Diane K. Newman ,Rebecca G. Rogers , Keisha Dyer Anthony Visco , Vivian W. Sung , Gary Sutkin Susan F. Meikle ,Marie G. Gantz , on behalf of the Pelvic Floor Disorders Network a Obstetrics, Gynecology & Women's Health Institute, Cleveland Clinic, Cleveland, OH, United Statesb Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, United Statesc Department of Gastroenterology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United Statesd Division of Urology, Department of Surgery, University of Pennsylvania, Philadelphia, PA, United Statese Departments of Obstetrics and Gynecology and Surgery, University of New Mexico Health Sciences Center, Albuquerque, NM, United Statesf Department of Obstetrics and Gynecology Kaiser Permanente, San Diego, CA, United Statesg Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC, United Statesh Department of Obstetrics and Gynecology, Alpert Medical School of Brown University, Providence, RI, United Statesi Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh Medical Center, Pittsburgh, PA, United Statesj The Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, United Statesk RTI International, Research Triangle Park, NC, United States The goals of this trial are to determine the efﬁcacy and safety of two treatments for women experiencing fecal Received 28 May 2015 incontinence. First, we aim to compare the use of loperamide to placebo and second, to compare the use of Received in revised form 10 August 2015 anal sphincter exercises with biofeedback to usual care. The primary outcome is the change from baseline in Accepted 12 August 2015 the St. Mark's (Vaizey) Score 24 weeks after treatment initiation. As a Pelvic Floor Disorders Network (PFDN) Available online 18 August 2015 trial, subjects are enrolling from eight PFDN clinical centers across the United States. A centralized data coordinat-ing center supervises data collection and analysis. These two ﬁrst-line treatments for fecal incontinence are being investigated simultaneously using a two-by-two randomized factorial design: a medication intervention Randomized placebo controlled trial (loperamide versus placebo) and a pelvic ﬂoor strength and sensory training intervention (anal sphincter exercises with manometry-assisted biofeedback versus usual care using an educational pamphlet). Intervention- ists providing the anal sphincter exercise training with biofeedback have received standardized training and Anal sphincter exercises assessment. Symptom severity, diary, standardized anorectal manometry and health-related quality of life out- comes are assessed using validated instruments administered by researchers masked to randomized interven-tions. Cost effectiveness analyses will be performed using prospectively collected data on care costs andresource utilization. This article describes the rationale and design of this randomized trial, focusing on speciﬁcresearch concepts of interest to researchers in the ﬁeld of female pelvic ﬂoor disorders and all other providerswho care for patients with fecal incontinence.
2015 Elsevier Inc. All rights reserved.
in non-institutionalized U.S. adults is 8.3% and consists of liquid stoolin 6.2%, solid stool in 1.6% and mucus in 3.1% Fecal incontinence (FI) is a common problem with a prevalence Treatments for FI may be conservative including dietary manipula- ranging from 2–15% in community settings and up to 19% in women tion, drug therapy, or behavioral treatments such as anal sphincter presenting to specialty clinics The age-adjusted prevalence of FI exercises/pelvic ﬂoor muscle training with or without biofeedback .
Surgical interventions include sphincter repair, rectocele repair, sacralneuromodulation, neosphincter, bulking injections and diversion .
☆ Supported by grants from the Eunice Kennedy Shriver National Institute of Child Health Restoring normal bowel consistency is the ﬁrst-line approach to therapy and Human Development (U10 HD054215, U10 HD041261, U10 HD041261, U10 in patients with extremes of stool consistency (i.e. watery stools or hard HD054214, U10 HD041267, U10 HD069025, U10 HD069010, U10 HD069006, U01 and lumpy stools). This is usually accomplished using anti-diarrheal HD069031) and the National Institutes of Health Ofﬁce of Research on Women's Health.
medications for patients with loose stools and laxatives or enemas for ⁎ Corresponding author at: Cleveland Clinic, 9500 Euclid Ave. A81, Cleveland, OH 44195, patients with constipation or incomplete emptying of the rectum.
E-mail address: (J. Eric Jelovsek).
Since a signiﬁcant proportion of women with FI will complain of leaking 1551-7144/ 2015 Elsevier Inc. All rights reserved.
J. Eric Jelovsek et al. / Contemporary Clinical Trials 44 (2015) 164–174 only with loose stool, an anti-diarrhea medication such as loperamide is to reduce the volume of stool in the rectum Anal sphincter often used as a ﬁrst-line treatment. However, clinical evidence suggests exercises with biofeedback increase the squeeze strength of the that loperamide may have properties that could improve FI in patients anal sphincter through strength training, and when combined with sen- with normal stool consistency A second conservative approach to sory training, may reduce sensory thresholds for patients with rectal treatment of women with FI is using anal sphincter exercises (pelvic hyposensitivity leading to passive fecal incontinence, and increase ﬂoor muscle training) that may or may not include biofeedback sensory thresholds for urgency in patients with urge-related fecal in- assistance. Biofeedback therapy is often combined with additional continence (hypersensitivity) behavioral interventions, such as bowel control strategies with sensorycomponents. Multiple uncontrolled studies have suggested a beneﬁt ofbehavioral interventions that include anal sphincter exercises with bio- 2.2. Design overview feedback for mixed liquid and solid stool consistency types of FI Since medical and behavioral approaches are often recommended as The CAPABLe study design is shown in Eligible participants are ﬁrst-line treatments, there is clinical value in determining the efﬁca- randomized to one of four groups in a two-by-two factorial design: cy of these two conservative treatment options compared to placebo 1) usual care with oral placebo, 2) oral loperamide at a minimum and basic educational information that are considered to be usual care dose of 2 mg taken orally every other day to a maximum of 8 mg daily for FI. Additionally, it is important to know if combined therapy offers with usual care, 3) anal sphincter exercise training with anorectal any beneﬁt over loperamide or anal sphincter exercises alone. The manometry-assisted biofeedback with usual care plus oral placebo primary aims of the Controlling Anal incontinence by Performing Anal and 4) combination oral loperamide with anal sphincter exercise train- Exercises with Biofeedback or Loperamide (CAPABLe) trial are to com- ing with manometry-assisted biofeedback with usual care. All partici- pare the change from baseline in patient-reported scores of FI severity pants receive an educational pamphlet developed by expert consensus using the St. Mark's (Vaizey) Score at 24 weeks after treatment initi- which is publicly available from the National Institute of Diabetes and ation among: 1) women randomized to loperamide versus oral placebo Digestive and Kidney Diseases (NIDDK) for the treatment of FI; 2) women randomized to anal sphincter ). This pamphlet includes basic information about FI and available treat- exercises with biofeedback versus women randomized to usual care ments such as behavioral techniques and medications. For this trial, the using a standardized educational pamphlet; and 3) women receiving pamphlet was modiﬁed by removing a single reference in the document the 2 active treatments together versus either active treatment alone.
to the drug loperamide. We felt that this basic information that is pub- The purpose of this article is to describe the rationale and design of licly available should be provided to all patients seeking care for FI.
this randomized trial, focusing on speciﬁc research concepts of interest Enrollment began April, 2014 and recruitment is anticipated to continue to researchers caring for women with FI, and to inform investigators through March 2016 (clinicaltrial.gov # NCT02008565).
designing randomized trials that combine medical interventions withstandardized methods of behavioral interventions.
2.3. Study population The study population consists of adult women with at least The Pelvic Floor Disorders Network (PFDN) is a clinical trials monthly FI over the last 3 months that is bothersome enough to network composed of eight geographically diverse clinical centers in seek and desire treatment. Since FI may be a secondary symptom of the United States, a Data Coordinating Center (DCC), and a Eunice colorectal malignancy, all women must have negative colon cancer Kennedy Shriver National Institute of Child Health and Human Develop- screening based on one of the 2008 US Preventative Task Force rec- ment NICHD representative. The primary goal of the PFDN is to improve ommended approaches. Women with predominant extremes of the level of knowledge about pelvic ﬂoor disorders and their treatments stool consistency on the Bristol Stool Form are excluded since pa- including pelvic organ prolapse, urinary incontinence and FI in women.
tients with constipation are not candidates for potentially constipat-ing agents such as loperamide and patients with chronic watery 2.1. Rationale for using a factorial design diarrhea may have a variety of causes for their diarrhea that needto be treated such as infectious etiologies . A detailed list of the The value of using a factorial design for the CAPABLe study is that it inclusion and exclusion criteria is in .
allows a comparison of two ﬁrst-line treatment options to placebo/usual care in a single population, thereby improving efﬁciency, reducingtrial cost and allowing a comparison of combination therapy compared 2.4. Randomization and baseline measures to single therapy for FI in women. A factorial design is particularlyvaluable in evaluating a combination of interventions that have separate Participants undergo a single randomization to one of the four mechanisms of action. Our study design directly compares anal sphinc- treatment combinations. Randomization is a 0.5:1:1:1 allocation, to ter exercises with biofeedback versus usual care and drug therapy with minimize the women who are randomized to no active therapy. Ran- loperamide versus placebo, as well as comparing both treatments domization is stratiﬁed by site using randomly permuted blocks; the together compared with either alone.
sizes of the blocks are known only to the DCC.
Anal sphincter exercises with biofeedback and drug therapy for FI After all screening assessments and consent are completed, the coor- have different mechanisms of action that culminate in improving dinator randomizes the participant at the baseline visit. Randomization sphincter strength and anorectal sensation. The most well accepted is accomplished through the web-based data management system that properties of loperamide are that it affects gastrointestinal smooth mus- assigns a randomization number that links to the biofeedback/usual cle by inhibiting intestinal peristalsis increasing oral-cecal transit care intervention assignment and loperamide/placebo treatment time and increasing the mucosal exposure to intestinal efﬂuent and assignment. Women randomized to usual care undergo anal manome- decreasing stool weight Less known properties of loperamide are try measurements at baseline, 12 and 24 weeks. Women randomized that it increases sensitivity of the recto-anal inhibitory reﬂex, in- to the anal manometry plus anal sphincter exercises with biofeedback creases rectal perception and ﬁrst incontinence volume and intervention receive intervention at the baseline visit (following ran- increases anal sphincter squeeze duration These properties, along domization) as well as at, 2, 4, 6, 9, 12 and 24 weeks. The loperamide/ with decreasing fecal urgency, promote quicker restroom-seeking placebo is stored in and dispensed from the investigational pharmacy behavior. Combined, this may serve as a barrier to stool leakage, and at each clinical site.
J. Eric Jelovsek et al. / Contemporary Clinical Trials 44 (2015) 164–174 Fig. 1. Consort diagram for the study.
Overencapsulation, bottling and labeling were done by a qualiﬁed con-tract manufacturing organization and drug supply provided to each site demonstrates a summary of masking for the trial. For the by the DCC. A two-part label was used such that an unmasked portion of anal sphincter exercises with biofeedback/usual care intervention, the the label can be removed and retained by the site pharmacist, and a physician, telephone interviewers, and the outcome evaluators are masked label will remain on the bottle for distribution to the masked to the treatment assignment for the entire study duration. Be- havioral interventionists are not masked to the anal sphincter exercises The protocol allows for dose adjustment during the trial ranging with biofeedback/usual care assignments, but are masked to the from 2 mg loperamide/placebo (one capsule) orally every other day to loperamide/placebo assignment. For the loperamide/placebo interven- a max of 8 mg loperamide/placebo (4 capsules) daily. Dose adjustments tion, the physician, participant, study coordinator(s) and telephone are not performed by staff that collects outcome data since dose escala- interviewers are masked to the assignment for the duration of the tion or reduction may lead to unmasking; it was hypothesized that study, and only the research pharmacist is unmasked. A placebo more placebo participants may dose escalate and more loperamide tablet was manufactured to match the loperamide tablet as closely as participants may dose reduce. Investigators felt it was important to possible in appearance and weight. Loperamide and placebo tablets allow for dose ranging due to efﬁcacy and side-effects rather than are over-encapsulation by standard DB Capsules (Capsugel, Greenwood, limit participants to one or two escalation options. This allows for SC) which are backﬁlled with a standard inert excipient (Avicel).
more accurate determination of an appropriate dose of loperamide for J. Eric Jelovsek et al. / Contemporary Clinical Trials 44 (2015) 164–174 Protocol inclusion and exclusion criteria.
Inclusion criteria: Masked to anal sphincter exercises with loperamide/placebo biofeedback/usual care intervention 1. Age ≥18 years 2. Fecal incontinence deﬁned as any uncontrolled loss of liquid or solid fecal material that occurs at least monthly over the last 3 months that is bothersome enough to desire treatment 3. If a patient is 50–75 years old they should have current negative colon cancer screening based on the US Preventative Task Force recommendation (2008) • Primary outcome that includes either: • Most secondary outcomes a. Annual screening with high-sensitivity fecal occult blood testing or b. Sigmoidoscopy every 5 years, with high-sensitivity fecal occult blood testing c. Screening colonoscopy every 10 years • Anal sphincter exercises with biofeedback/usual care treatment Patients who are ≥76 years old do not need routine colon cancer screening since the likelihood that detection and early intervention will yield a mortality beneﬁt • Adverse events that declines after age 75 because of the long average time between adenoma • Medical follow-up development and cancer diagnosis. Patients 50–75 years old without a current negative colon cancer screening may elect to undergo one of these screening • Productivity data collection options and if results are normal, they may continue to screen for eligibility in the Exclusion criteria: 1. Stool consistency over the last 3 months that includes items 1 or 7 based on the Bristol Stool form scale 2. Current bloody diarrhea (loose, watery stools 3 or more times a day with ⁎ Telephone interviewer: individual from the Quality of Life Call Center.
⁎⁎ Evaluator: the individual(s) at the clinical sites performing outcome assessments.
3. Current or past diagnosis of colorectal or anal malignancy # Interventionist: the individual(s) at the clinical sites providing the anal 4. Diagnosis of inﬂammatory bowel disease sphincter exercises with biofeedback/ intervention and conducting rectal manometry 5. Current or history of rectovaginal ﬁstula or cloacal defect 6. Rectal prolapse (mucosal or full thickness)7. Prior removal or diversion of any portion of colon or rectum8. Prior pelvic ﬂoor or abdominal radiation9. Refusal or inability to provide written consent 10. Inability to conduct telephone interviews conducted in English or Spanish controlled, after which, the dosage should be titrated to meet individual 11. Fecal impaction by rectal and abdominal exam requirements, up to 8 mg/day. For this study, participants are seen in 12. Untreated pelvic organ prolapse beyond the hymen; patients with prolapse person at their ﬁrst treatment visit, 12 weeks, and 24 weeks. Study beyond the hymen who are currently using a pessary are eligible coordinators also call the participants at the 2, 6, 16 and 20 week inter- 13. Incontinence only to ﬂatus14. Has taken any loperamide (Imodium®) or diphenoxylate plus atropine vals to administer global instruments to assess efﬁcacy and tolerability (Lomotil®) in the last 30 days of loperamide/placebo and manage dose adjustments accordingly. For 15. Previously received and failed treatment of fecal incontinence using evaluation of patient perceived efﬁcacy, the Patient Global Symptom loperamide (Imodium®) or diphenoxylate plus atropine (Lomotil®) over Control rating scale (PGSC) is used Dose escalation is based exclu- the last 3 months sively on the result of the PGSC as shown in the ranging from 1 16. Current supervised anal sphincter exercise/pelvic ﬂoor muscle training with (strongly disagree) to 5 (strongly agree). The participant is instructed to 17. Previously received and failed treatment of fecal incontinence using either maintain the current drug/dose if PGSC is 4 or 5 (agree/strongly supervised anal sphincter exercise/pelvic ﬂoor muscle training with agree that their treatment is giving adequate control of stool leakage), or dose escalate if PGSC is 1–3 (disagree/strongly disagree that their 18. Previous allergy or intolerance to loperamide treatment is giving adequate control) in the absence of bothersome 19. Pregnant, nursing, or planning to become pregnant before the end of thestudy follow-up period.
side effects. Participants who report inadequate control of stool leakage 20. Childbirth within the last 3 months on the PGSC are instructed to increase the daily dose of study medica- 21. Neurological disorders known to affect continence, including spinal cord tion by one capsule (2 mg loperamide or placebo) up to a maximum injury, advanced multiple sclerosis or Parkinson's disease and debilitating stroke of 4 capsules (8 mg loperamide or placebo) per day. Participants are 22. Known diagnosis of hepatic impairment23. Chronic abdominal pain in the absence of diarrhea not required to take the entire daily dose at one time.
24. Acquired Immunodeﬁciency Syndrome (AIDS) Bothersome side effects are monitored using a patient global tolera- 25. Currently taking anti-retroviral drugs bility scale (PGTS) which is modiﬁed from the PGSC Dose reductionis based on the participants' responses to the PGTS. The participant isinstructed to reduce the current drug/dose if PGTS is 4 or 5 (agree/strongly agree that the treatment is giving them bothersome side patients with FI. To accommodate this dose adjustment and minimize effects) as shown in the Participants who report bothersome the possibility of the coordinator inﬂuencing dose, adjustments are side effects of the medication are instructed to decrease the daily dose standardized using a dose escalation/reduction matrix driven by the of study medication by one capsule to a minimum of one capsule participant's rating of global symptom control and tolerability; this (2 mg loperamide or placebo) every other day. They are instructed to matrix is outlined in discontinue the study medication if they have a PGSC score of 1–3(inadequate control of stool leakage) combined with a PGTS score of 2.6. Medical intervention with loperamide versus placebo 4–5 (bothersome side effects). If bothersome side effects are reportedat any time during the study, the participant is instructed to contact Participants randomized to the loperamide treatment group begin the clinical site and the site investigators may choose to discontinue or with 2 mg of loperamide per day. The FDA approved initial dose in temporarily hold the study drug. In addition, dose reduction or medica- adults with acute or chronic diarrhea is 4 mg (two capsules) followed tion discontinuation can occur at any time if a patient reports bother- by 2 mg (one capsule) after each unformed stool until diarrhea is some side effects.
J. Eric Jelovsek et al. / Contemporary Clinical Trials 44 (2015) 164–174 Table 3Dose Escalation/change in study medication and management of adverse events between medication steps, based on efﬁcacy and tolerability.
No change in medication Patients are instructed to discontinue medication The Patient Global Symptom Control rating (PGSC) scale is:My current treatment is giving me adequate control of my stool leakage.
Disagree The Patient Global Tolerability rating Scale (PGTS) is:My current medication is giving me bothersome side effectsDisagree ⁎ Max dose of 4 capsules (8 mg loperamide or placebo) per day.
⁎⁎ Minimum dose of 1 capsule (2 mg loperamide or placebo) every other day.
2.7. Manometric biofeedback intervention versus usual care alone these techniques for home use. A manual of procedures describes guide-lines in an algorithm approach to determine the correct sensory sub- To address the limitations of most FI biofeedback intervention protocol to use based on pre-determined criteria. We collaborated studies, investigators for this study developed 3 separate anal sphincter with the device manufacturer to develop on-screen prompts to guide exercises with biofeedback sub-protocols: (1) strength training with the interventionists through these protocols. To help ensure adherence home anal sphincter exercises, (2) sensory training for hyposensitive with this standardized regimen and treatment ﬁdelity, audiotapes are rectal distention, and (3) sensory training for urge-resistance rectal dis- obtained from select biofeedback sessions and members of the study tention. Anorectal manometry (ARM) data were also standardized for team audit the tapes using standardized procedure checklists.
this trial, and include measurements of strength, squeeze duration, The software and catheter from the mcompass (Medspira, Minneap- and sensation. All participants have ARM performed at baseline, 12 olis, MN) manometry device was redesigned speciﬁcally for this proto- weeks, and 24 weeks. Among participants randomized to anal sphincter col. Building on existing software available for ARM, the research team exercises with biofeedback, the ARM data are key measures for deter- partnered with staff from Medspira to create novel biofeedback soft- mining which of the sensory sub-protocols to use along when combined ware speciﬁcally tailored for the 3 biofeedback subprotocols in the with data from the patient-reported bowel diaries.
trial. The mcompass system uses a tablet computer which wirelessly As provider experience is a major factor in performing anal sphincter connects to the catheter. This system allows for equipment mobility exercises with biofeedback for FI, all study interventionists participating and visual feedback to the participant for the strength and sensory in the CAPABLe trial were required to review standardized online training. The system's manometric catheter simultaneously measures content, undergo hands-on training conducted with live models, and pressures in the rectum and the anal canal to help participants isolate assessment by experienced providers trained using protocol-speciﬁc sphincter contractions while avoiding inappropriate contractions of performance checklists. All interventionists were required to review abdominal wall muscles during strength training. The catheter contains online learning modules including instructional videos prior to a balloon that is positioned in the rectum and used to simulate rectal ﬁll- attending the training sessions. Training included e-learning content ing for the sensory protocols. All participants randomized to the anal provided using slides, problem-oriented patient case discussions, and sphincter exercises with biofeedback protocol are also prescribed a hands-on practice with live models. Each interventionist completed a home exercise program based on their individual performance during 75 minute certiﬁcation exam in the conduct of patient visits that includ- the intervention visits. Participants record their home exercises in an ed performing ARM diagnostic testing, manometric biofeedback with exercise record and complete a seven-day bowel diary before the next strength and sensory training and education on when to use each senso- anal sphincter exercise with biofeedback visit.
ry protocol. Trained interventionists include certiﬁed registered nurse Subjects randomized to usual care are scheduled for visits with the practitioners, physician assistants and physical therapists. A minimum interventionist at baseline, 12, and 24 weeks. ARM data are collected of two certiﬁed interventionists are available at each clinical site.
at these visits. The usual care subjects complete a 7-day bowel diary Subjects randomized to the anal sphincter exercises with biofeed- prior to these visits. At the baseline visit, the interventionists give the back receive a structured individualized program during the ﬁrst 12- same structured education using the NIDDK bowel control handout weeks of the 24-week study including visits at baseline, 2, 4, 6, 9, and that the anal sphincter exercises with biofeedback group receives.
12 weeks for a total of 6 biofeedback intervention visits. DiagnosticARM evaluation is performed at each visit in order to guide the 2.8. Data collection and follow up manometric biofeedback protocols and home anal sphincter exercises.
All participants receive the strength training sub-protocol focusing on A timeline of visits, events and data collection is listed in .
correct anal sphincter muscle isolation, anal sphincter contraction After initial screening, eligible patients will be given a 7-day bowel strength, and the duration of the contraction beginning at the ﬁrst diary and receive a Quality of Life (QOL) telephone interview. Random- visit and continuing on subsequent visits as needed. The visits at, 2, 4, ization, review of bowel diary, and baseline ARM are performed at the 6 and 9 weeks include a sensory protocol for participants who have par- baseline visit scheduled 2 to 4 weeks after the screening visit.
tially lost the ability to detect the presence of stool in the rectum (called We attempted, when possible, to keep the study visits similar hyposensitivity) or a urge resistance protocol for those participants who between groups. However, the group randomized to receive anal experience strong sensations of urgency to defecate which are difﬁcult sphincter exercises with biofeedback has more intervention visits by to suppress (called hypersensitivity). At each visit, interventionists the nature of the treatment. Participants randomized to usual care provide feedback using standardized handouts given that reinforce have in-person visits at baseline, 12 and 24 weeks. Conversely, those J. Eric Jelovsek et al. / Contemporary Clinical Trials 44 (2015) 164–174 randomized to anal sphincter exercises with biofeedback have in- 2.9. Considerations in the selection of primary outcome person visits at baseline, 2, 4, 6, 9, 12 and 24 weeks. In our judgment,if we had kept the number of visits the same between the anal sphincter To meet recommendations of the NIH consensus statement and the exercise with biofeedback group and the usual care group, this Cochrane review, the protocol committee focused on using a primary would have been perceived as artiﬁcial and burdensome to the outcome measure that could incorporate the patient perspective as usual care participants and may have inﬂuenced patient retention in well as FI frequency, severity, bother, fecal urgency and patient desire for treatment. Furthermore, the team also desired an instrument that A supply of study drug (loperamide) or placebo is dispensed at the had published evidence supporting its validity and data to guide the in- baseline and 12 week visits. At 12 and 24 weeks, the participants are terpretation and clinical relevance of improvement in scores from the asked to bring their recently completed bowel diary to the clinic, to patient perspective. The protocol committee considered a variety of complete QOL interviews by telephone, and to undergo repeat ARM patient-centered outcome measures including severity scales, FI epi- evaluation. Participants receive a telephone call from the research coor- sodes, quality of life scales, global satisfaction scales, overall treatment dinator at weeks 2, 6, 16 and 20 to assess updates in medical history, satisfaction as well as using multiple primary endpoints. Unfortunately, medications, efﬁcacy and tolerability of medications. Adverse events no single primary outcome available for trials in FI that is broadly are collected on all participants at the 2, 6, 12, 16, 20, and 24 week accepted was available. A variety of measures that more or less met calls or visits and at any time in between when self-reported bother- recommended requirements were reviewed, and the committee some symptoms are noted.
elected to use change from baseline to 24 weeks in the St. Mark's Participants in the anal sphincter exercises with biofeedback group (Vaizey) FI severity scale as the primary outcome because the scale are instructed to record in a diary the use of exercises at home. Compli- meets as many of the desired attributes as possible while maintain- ance with loperamide/placebo is monitored using pill counts, a single ing participant acceptability. Data exist that correlate improvement question provider-reported adherence , and the modiﬁed Medica- in the frequency of FI episodes with improvement in the St. Mark's tion Adherence Self-Report Inventory (MASRI) at the 12 and (Vaizey) Score (r = 0.79, P b .001) , as well as moderate correla- 24 week in-person visits. These three methods of "triangulation" are tion with changes in maximum incremental squeeze pressure consistent with recommendations by Osterberg to use several methods (r = − 0.30, P b 0.05) .
in order to improve accuracy in assessing medication adherence The St. Mark's Score is also proved responsive to change. When Cost data and resource utilization are collected at the screening visit assessing the correlation between the St. Mark's Score and global and at the 12 and 24 week visits. The primary outcome is assessed at impression of improvement after treatment, data demonstrate that the 24 week in-person visit by a masked coordinator. At this ﬁnal visit, average St. Mark's Score severity scores are 1 point lower than baseline participants are asked if they know whether they received loperamide for patients who rate their situation as "worse or equal", 4 points lower or placebo (i.e., whether they became unmasked).
for patients who reported their situation to be "better", and 9 points Table 4Timeline of visits, events and data collection.
Interventions and outcomes visit First visit All participants:and informed consent St. Mark's (Vaizey) Score Loperamide/ placebo dispensing Anal sphincter tone 7-day bowel diary review Efﬁcacy (PGSC) Tolerability (PGTS) Adherence measures Quality of life measures Usual care group:Diagnostic manometry Bowel diary review Anal exercises with manometry-assisted biofeedback groupDiagnostic manometry Anal exercises with manometry-assisted biofeedback Bowel diary review Note: Baseline visit is 3 weeks after screening visit. All timelines have a window of +/−1 week.
† All screening activities may be done by either the masked or unmasked coordinator.
⁎ Eligibility includes provider's physical exam to assess applicable exclusion criteria.
⁎⁎ All participants will be instructed by the masked coordinator to collect data in the bowel diary for one week prior to the baseline, 12 week, and 24 week visits.
⁎⁎⁎ Other measures include: Bristol Stool Form scale , ABLe Measure, PISQ-IR extended version Body Image Scale Dietary Fruit/Veggie/Fiber Screener .
⁎⁎⁎⁎ Quality of Life measures are conducted by telephone interview any time between Screening and Baseline visits and again at 12 and 24 weeks and include Rome III IBS Criteria ScalePelvic Floor Distress Inventory (Short PFDI) , Modiﬁed Manchester with FISI , Fecal Incontinence Adaptation Index, QOL Measures (Short PFIQ, SF-12) PAC-SYM ,and Modiﬁed PGI-I J. Eric Jelovsek et al. / Contemporary Clinical Trials 44 (2015) 164–174 lower in patients who rate their situation "much better" (P b .05). This procedure manual are measures that address the degree of adherence also supports the assertion that the St. Mark's Score is consistent with with study interventions. The questionnaire to assess whether partici- patients' subjective perception of relief from FI . For all of these pants were unmasked to whether they received loperamide or placebo reasons, the team felt that the St. Mark's Score is the best existing assesses the integrity of masking in the drug treatment arm.
measure that captures a meaningful outcome of FI treatment.
2.12. Mediators of treatment effects 2.10. Secondary outcome measures The ARM test at baseline, 12 and 24 weeks is a process measure that The secondary outcome measures listed in are alternative assesses whether the anal sphincter exercises and biofeedback are measures of treatment efﬁcacy. The key secondary outcomes are having the expected impact on anal canal squeeze pressure, rectal the frequency of FI episodes on a 7-day bowel diary, and validated qual- pressure during squeezing, and sensory thresholds for ﬁrst sensation ity of life measures, which are measured at baseline, 12 weeks, and and strong urge. These are hypothesized to mediate the impact of pelvic 24 weeks in all treatment groups. Additional secondary outcome mea- ﬂoor exercises and biofeedback on the St. Mark's Score of FI severity.
sures are tallies of adverse events and estimates of the cost of delivering The ARM test is performed at baseline, 12, and 24 weeks. Socio- the interventions. Secondary safety outcomes include monitoring of demographic variables measured at baseline will also be examined as adverse events. Comparisons of adverse events and serious adverse possible moderators of treatment efﬁcacy.
events between treatment groups will be reported at the end of thestudy. All adverse events and serious adverse events reported by partic- 2.13. Sample size and power ipants are compared between treatment groups on a quarterly basis andreviewed by the Data Safety Monitoring Board. Possible adverse events describes the hypothesized value of the primary outcome in include abdominal distension, abdominal pain or discomfort, allergic re- each of the treatment groups. A difference in change from baseline in St.
actions, constipation, nausea, vomiting, tiredness, dizziness, and drows- Mark's (Vaizey) Score at 24 weeks of at least 5 is hypothesized between iness. Bothersome adverse events will be classiﬁed using the PGTS.
each of the groups assigned to receive a single active treatment and Study drug dose reduction will be based exclusively on the result of those randomized to usual care (placebo and educational pamphlet), and a modest negative interaction is assumed in the combined therapyarm (loperamide and anal sphincter exercise + biofeedback). This is 2.11. Measures of compliance with study interventions consistent with the minimally important difference (MID) of −5 forthe St. Mark's (Vaizey) Score derived using three different methods of Adherence to taking the study medication, the exercise log, number detecting a clinically important difference . In the study conducted of anal sphincter exercises and biofeedback visits completed, and audits by Bols et al., various methods were used to estimate the MID and the of tape recordings to assess whether the interventionists adhered to the authors concluded that an MID of −5 seemed preferable and yieldedthe lowest misclassiﬁcation rate We also requested from Bolset al. a reanalysis of the MID of the St. Mark's (Vaizey) Score without the medication item in the questionnaire, and it appears that an MID Secondary outcomes in CAPABLe.
of −5 is still appropriate for the modiﬁed St. Mark's (Vaizey) Score Medication and Medical History Review without medication.
Previous and interval treatment for pelvic ﬂoor disorders or bowel disorders Randomization will be unequal, with fewer patients randomized to 7-day bowel diary the combination of placebo drug and usual care (0.5:1:1:1 allocation).
Anal sphincter tone on physical examination using the Digital Rectal Examination Power calculations were based on the hypothesized changes from base- Manometry measures including: distance (cm) of catheter insertion to locate high line in St. Mark's (Vaizey) Score at 24 weeks shown in . If we pressure zone (HPZ) of anal canal, resting anal canal pressures (mm of Hg) at 2 assume a follow up rate of 100% at 24 weeks, then a sample size of cm, 1 cm, and 0 cm insertion, resting rectal pressures (mm Hg) with anal sensor 245, with 35 participants in the placebo/usual care group and 70 in at 2 cm, 1 cm, and 0 cm insertion, maximum anal and rectal pressures during each of the other three groups, will provide 90% power to detect a differ- squeeze with the catheter at the HPZ, volume of air (mL) at ﬁrst sensation for ence in each treatment arm (loperamide vs. placebo averaged over the perception of rectal distention, volume of air (mL) at urge to defecate, maximumtolerable rectal volume of air (mL), volume of air (mL) at sensation of strong two exercise treatments and exercise + biofeedback vs. usual care aver- urge and rectal balloon pressure at sensation of strong urge aged over the two drug treatments) at a 0.025 level of signiﬁcance. It Dietary ﬁber intake using the Fruits/Vegetables/Fiber Screener questionnaire will also provide 80% power to detect a difference in drug alone or Pelvic Symptoms: Pelvic Floor Distress Inventory Short Form (PFDI-Short) exercise alone vs. the placebo/usual care combination, and 55% power including all subscales, Pelvic organ prolapse/urinary incontinence sexual to detect a difference in combined drug and exercise vs. either interven- function questionnaire — IUGA Revised (PISQ-IR) and an additional analintercourse question Modiﬁed Manchester Health Questionnaire that includes tion alone, at a 0.05 level of signiﬁcance. The power to detect an interac- the 4-item Fecal Incontinence Severity Index (FISI) tion that is signiﬁcant at the 0.05 or 0.10 levels will be approximately Modiﬁed Patient Global Impression of Improvement (PGI-I) for bowel function, 14% and 23%, respectively. Despite having only 55% power, we chose Adaptation using the Fecal Incontinence Adaptation Index, Defecatory symptoms to include the third aim as primary rather than secondary, because we as measured by Patient Assessment of Constipation Symptoms questionnaire(PAC-SYM) think it is important to compare combination therapy to each treatment Quality of life — Medical Outcome Study Short-Form-12 (SF-12) including all alone. It may be particularly important if the magnitude of the interac- subscales, Pelvic Floor Impact Questionnaire Short Form including all subscales tion between the treatment arms is greater than we anticipate, in (PFIQ-Short), Body Image Scale Efﬁcacy and Tolerability using the Patient Global Symptom Control rating scale (PGSC) and Patient Global Tolerability Scale (PGTS) modiﬁed from the PGSC Compliance with treatment using pill counts, a single question provider-reported Hypothesized change from baseline in St. Mark's (Vaizey) Score at 24 weeks in each treat- adherence and the modiﬁed Medication Adherence Self-Report Inventory Productivity loss including: days of missed work, missed household chores, Anal sphincter exercise + caregiver costs, travel time, transportation costs, out of pocket appointment (educational pamphlet) costs, incontinence products costs and laundry costs.
Rome III IBS criteria Bowel leakage as measured by the Accidental Bowel Leakage (ABLe) instrument J. Eric Jelovsek et al. / Contemporary Clinical Trials 44 (2015) 164–174 which case our power to detect the differences would also be higher individual treatment. Patient satisfaction with treatment modality at than our estimates indicate. If we assume a conservative follow up 12 and 24 weeks, deﬁned as "much better" or "very much better" on rate of 85% at 24 weeks, and we use analysis methods that are consistent the PGI-I, will be assessed using generalized linear modeling based on with an assumption that missing outcomes will be missing at random, the predictors described in the model for the primary aims.
then power calculations yield a sample size estimate of 294 patients We will conduct exploratory analyses to evaluate whether a number (42 in the usual care (educational pamphlet)/placebo group and 84 in of factors act as confounders (mediators) of any treatment effects for ei- each of the other treatment combinations) to obtain the power levels ther drug/placebo or biofeedback/usual care treatments, whether these described above.
factors potentially act as effect modiﬁers for these treatments, or wheth-er the factors act as independent predictors of changes in FI. This analy- 2.14. Data analysis plan sis will use similar models to those described for the primary outcometo model change from baseline to 12 and 24 weeks in St. Mark's (Vaizey) The primary outcome, change from baseline in St. Mark's (Vaizey) Score as a function of both categorical measures (presence of IBS, stool Score at 24 weeks, will be compared among treatment groups using consistency, a three-level measure of treatment adherence for both linear regression. Because the St. Mark's (Vaizey) Score is assessed at treatment modalities, and adverse events) and continuous measures both 12 and 24 weeks, the primary analysis will be based on a longitu- (bowel diary measures, constipation symptoms, digital rectal tone, dinal model, with changes from baseline in St. Mark's (Vaizey) Score at anal manometry measures, and dietary ﬁber intake). To evaluate both 12 and 24 weeks as the dependent variable, and the independent whether the factor acts as a confounder (mediator) of the treatment ef- variables including treatment assignment (both drug and exercise), fect, the model will include the same terms as the primary outcome interaction between drug and exercise treatment assignments, week models with the factor added to determine whether the addition of (12 or 24), 2- and 3-way interactions between week and treatment as- the factor results in a change in the estimated treatment effect. To assess signments, Rome III irritable bowel syndrome (IBS) clinical trial status, whether each factor acts as a treatment effect modiﬁer, terms for the interaction between Rome III IBS clinical trial status and treatment, factor, the factor by treatment interaction and for the treatment by and clinical site. If the interactions between treatment arms and/or time by factor interaction will be added to the model.
between treatment and Rome III IBS status are not statistically signiﬁ- A decision-analytic model will be constructed to evaluate the cost- cant, then the statistical test comparing the treatment groups will be effectiveness of loperamide, anal sphincter exercises with biofeedback, averaged over the other variable involved in the interaction. If there is and combined therapy. The analysis will be conducted from a patient a statistically signiﬁcant interaction, then the treatment groups will be and societal perspective and the model will include costs for the inter- compared within each level of the other variable involved in the vention, as well as for the management of adverse events, productivity interaction. The interactions between time and treatment arms will loss and use of FI products (e.g., pad use) during the six-month period allow for statistical tests to compare the treatments at the 24 week following initiation of treatment. The intervention cost will be estimat- time point for the primary outcome, since the model will include change ed based on the amount of medication and number of exercise/biofeed- from baseline at both 12 and 24 weeks. Patients with IBS may be back sessions that the participants used/attended during the trial. The included in the trial as IBS remains an important risk factor for fecal probability of adverse events, amount of productivity loss, and FI prod- incontinence. However, the analysis will control for this using the inter- uct use will also be based on results from the CAPABLe trial. Effective- actions described. Under the assumption that any missing outcome data ness will be measured using quality adjusted life years (QALY). A will be missing at random (thus, missing St. Mark's (Vaizey) Scores at validated algorithm developed by Brazier and Roberts (2002) will be 24 weeks may be related to both 12-week outcomes and covariates), used to generate a preference-based index score and hence QALYs this model will produce more accurate estimates in the presence of based on patients' responses to the SF-12 questionnaire collected during missing data than one that models only outcomes at 24 weeks. The the CAPABLe trial . Compared to other utility elicitation methods model will account for the dependence between repeated measure- (e.g., standard gamble, time trade-off), this approach helps minimize ments on the same subject. Two-sided tests of the effect of drug treat- subject burden. Cost-effectiveness will be assessed by the incremental ment assignment (loperamide vs. placebo) and exercise treatment cost effectiveness ratio (ICER), which reﬂects the incremental cost assignment (anal sphincter exercises with biofeedback vs. usual care associated with each additional QALY. In addition, we will perform sen- (educational pamphlet)) on change from baseline in St. Mark's (Vaizey) sitivity analyses to assess how the cost-effectiveness of each interven- Score at 24 weeks will be performed at a type I error level of 0.025. The tion may change when varying the value of key input parameters in same model will be used to test whether there is a difference in combi- nation treatment compared to loperamide and combination treatment Validity of anal manometry will be assessed by measuring the asso- compared to anal sphincter exercises with biofeedback in change from ciation between manometry measures and digital squeeze strength, baseline in St. Mark's (Vaizey) Score at 24 weeks with type I error of incontinence severity (St. Mark's Score), global impression of improve- 0.05. We will also test for differences in the change in score over time ment, and impact on quality of life as measured by the CRADI subscale among the 4 individual treatment groups. Missing data mechanisms on the PFDI, CRAIQ subscale on the PFIQ, Modiﬁed Manchester, and FI will be explored, and sensitivity analyses will be conducted to assess adaptation index. Chi-square tests will be used to compare drug treat- the robustness of the previously described analyses. Methods employed ment groups with respect to the percent of participants/coordinators for sensitivity analyses may include multiple imputation or inverse who responded that they thought the participant was assigned the probability weighting methodology .
active or placebo treatment or did not know which treatment had We will evaluate secondary outcomes evaluated at 12 and 24 weeks, been assigned. Conﬁdence intervals for the number of unmasked partic- including efﬁcacy outcomes, additional treatments for FI, adherence to ipants/coordinators in each treatment group will be estimated. Open- study treatment and adverse events, comparing loperamide vs. placebo, ended responses regarding the reason for thinking the patient was in anal sphincter exercises with biofeedback vs. usual care (educational either the active or placebo group will be categorized and reported pamphlet), and combination therapy vs. each individual treatment.
For categorical outcomes, generalized linear modeling will be used in-stead of linear regression. We will evaluate changes from baseline 2.15. Discussion (1122/1500 words) to 12 and 24 weeks in condition-speciﬁc and generalized qualityof life, sexual function, and adaptation comparing loperamide vs.
This large multisite study tests two conservative treatments of FI, the placebo, and anal sphincter exercises with biofeedback vs. usual care antidiarrheal medication loperamide and anal sphincter exercises with (educational pamphlet), and combination therapy versus each biofeedback. These two treatments are recommended by clinical J. Eric Jelovsek et al. / Contemporary Clinical Trials 44 (2015) 164–174 practice guidelines as ﬁrst-line treatments for FI, but the evidence for One challenge in designing this study was deciding on what the their efﬁcacy is insufﬁcient. Studies supporting the use of loperamide control group would be to compare to the anal sphincter exercises for FI were small, uncontrolled studies published more than 10 years with biofeedback group. We decided to compare 6 sessions of anal ago, and limited to patients with diarrhea-associated FI . Most stud- sphincter exercises with biofeedback to a standard educational inter- ies of pelvic ﬂoor biofeedback for the treatment of FI were single-site vention in the form of an educational brochure delivered only at the studies and have yielded inconsistent results, raising concerns that the initial visit. It could be argued that these two treatments are not outcomes are highly dependent on the skills and experience of the balanced for nonspeciﬁc treatment components such as expectation of interventionist Thus, a well-controlled, multisite study to assess beneﬁt or contact time with an interventionist. We decided to use a the efﬁcacy of each of these treatment approaches is needed. The CAPA- standard care educational control for the following reasons: (1) Biofeed- BLe trial is the ﬁrst adequately powered multi-center clinical trial to back training is a complex, multicomponent treatment, and it remains evaluate both of these primary interventions for FI, and the results difﬁcult to identify the key mechanism(s) mediating treatment efﬁcacy.
will ﬁll important voids in our knowledge of the treatment of this trou- Parallel group treatment trials often aim to isolate the key mediator bling condition.
of treatment efﬁcacy, but that is not possible with biofeedback.
A strength of this study is that these two treatments are being tested (2) The use of a complex control condition such as 6 sessions of anal simultaneously in a factorial design; each active treatment, loperamide sphincter exercises taught without biofeedback devices would intro- and biofeedback, is paired with an appropriate control, with loperamide duce additional non-speciﬁc treatment components, such as targeted being compared to placebo tablets and biofeedback compared to a counseling from the interventionist that would make it difﬁcult to inter- standard-care educational intervention. This is an efﬁcient study design pret the loperamide vs. placebo arm of the study in the context of this that makes it possible to evaluate efﬁcacy of these two independent factorial design. For these reasons, we concluded that we should ﬁrst es- treatments simultaneously without the cost and effort that would be tablish that anal sphincter exercises with biofeedback are superior to required for two independent, parallel group studies. Another advan- minimum standard care (e.g. education) in an adequately controlled tage of this design is that it will allow us to test whether combining multisite study.
the two active treatments is more effective than either treatment used Two challenges in evaluating behavioral interventions such as alone. However, our target sample size provides only 55% power to biofeedback are (1) that the intervention protocol is not standardized detect the hypothesized 3-point difference in change from baseline in so there are variations in how it is implemented in different clinics, St. Mark's (Vaizey) score at 24 weeks between those randomized to and (2) the outcomes seem to depend on the skill and experience of both versus only one active treatment.
the interventionists. To address the ﬁrst problem, a group of experts Loperamide is a logical choice for ﬁrst-line treatment of FI because on the biofeedback treatment of FI worked to disaggregate biofeedback (a) diarrhea is consistently found to be the strongest risk factor for FI training for FI into three key procedures: strength training, sensory in population-based surveys and (b) incontinence for liquid stools discrimination training to improve the detection of rectal ﬁlling, and de- is 4 times more common than incontinence for solid stools . Howev- sensitization to the sensation of urgency to defecate. We then collabo- er, constipation is an adverse event that affects an estimated 2.4% of rated with a device manufacturer to develop separate software patients who are treated with loperamide for diarrhea and/or diarrhea programs for each of these biofeedback procedures. To address the sec- related FI, and currently loperamide is only approved by the FDA ond problem, the protocol was standardized in the manual of opera- for the treatment of diarrhea. In this study, we decided not to limit tions, required in person training and certiﬁcation, and monitored enrollment to patients with diarrhea-associated FI but to include through audiotapes.
patients with normal Bristol Stool consistency ratings of 2–6 .
The design, interventions and outcome measures of the CAPABLe We believe the decision to include patients with a range of stool consis- trial have been carefully considered in order to provide valid, reliable tency provides the best opportunity to assess the generalizability of estimates of the efﬁcacy, safety and cost-effectiveness of two commonly loperamide as a ﬁrst-line treatment for FI. We will be able to investigate used primary conservative therapies for women with FI with a focus on whether Bristol Stool Scale scores at enrollment predict the response to patient-centered outcomes. This study will provide important founda- loperamide treatment in secondary analyses.
tional evidence for the treatment of this common and burdensome It can be challenging to recruit patients to participate in a study of the efﬁcacy of drugs that are already available to the patient throughprescription or as an over-the-counter medication; they may have a Appendix A. Pelvic ﬂoor disorders network contributors negative expectation of beneﬁt based on their prior experience withthe drug, or they may opt to try the drug without the burden of partic- ipating in the trial. The use of a factorial design may mitigate this prob- J. Eric Jelovsek, Principal Investigator lem because each patient is offered two treatments and has the Mathew D. Barber, Co-investigator possibility of experiencing two effective treatments in combination. In Marie Fidela R. Paraiso, Co-investigator this study, we will exclude participants who have taken loperamide in Mark D. Walters, Co-investigator the previous 30 days or who have failed a treatment trial of loperamide Beri Ridgeway, Co-investigator or diphenoxylate within the last 3 months. However, we will not Brooke Gurland, Co-investigator eliminate all patients who have taken loperamide in the past because Massarat Zutshi, Co-investigator patients who have never taken this popular treatment for FI would like- Geetha Krishnan, Research Nurse ly represent a biased subset of patients who have milder symptoms of FI Ly Pung, Research Nurse and/or who have constipation-related FI.
Annette Graham, Research Nurse Subjects vary in their response to any investigational drug and Alpert Medical School of Brown University—Women & Infant's their tolerance for its side-effects. Investigators frequently want to Hospital of Rhode Island take this variability into account by titrating the dose of the investiga- Vivian W. Sung, Principal Investigator tional drug treatment (and the placebo) for each subject; however Deborah L. Myers, Co-investigator drug titration creates opportunities for (1) unmasking the trial and Charles R. Rardin, Co-investigator (2) introducing experimenter bias. In this study, we eliminate these Cassandra Carberry, Co-investigator threats by titrating the drug dose based on subject-ratings of improve- B. Star Hampton, Co-investigator ment in FI frequency and subject-ratings of side-effects in a standard- Kyle Wohlrab, Co-investigator ized fashion.
Ann S. Meers, RN, Research Nurse J. Eric Jelovsek et al. / Contemporary Clinical Trials 44 (2015) 164–174 Jutta Thornberry, Program Manager Anthony Visco, Principal Investigator Kristin Zaterka-Baxter, Clinical Study Specialist Cindy Amundsen, Co-investigator Lindsay Morris, Research Coordinator Alison Weidner, Co-investigator Amanda Honeycutt, Economist Nazema Siddiqui, Co-investigator University of Pennsylvania Amie Kawasaski, Co-investigator Lily Arya, Principal Investigator Shantae McLean, Clinical Site Coordinator Ariana Smith, Co-investigator Nicole Longoria, Clinical Research Coordinator Heidi Harve, Co-investigator Jessica Carrington, Clinical Research Coordinator Uduak Umoh Andy, Co-investigator Niti Mehta, Clinical Research Specialist Pamela Levin, Co-investigator Ingrid Harm-Ernandes, Interventionist Diane K. Newman, Co-investigator Jennifer Maddocks, Interventionist Mary Wang, Interventionist Amy Pannullo, Interventionist Donna Thompson, Interventionist University of Alabama at Birmingham Teresa Carney, Interventionist Alayne Markland, Primary Investigator Michelle Kingslee, Research Coordinator Holly Richter, Co-investigator Lorraine Flick, Research Nurse R. Edward Varner, Co-investigator University of Pittsburgh Robert Holley, Co-investigator Halina Zyczynski, Principle Investigator L. Keith Lloyd, Co-investigator Pam Moalli, Co-investigator Tracy S. Wilson, Co-investigator Gary Sutkin, Co-investigator Alicia Ballard, Co-investigator Jonathan Shepherd, Co-investigator Jeannine McCormick, Research Nurse Michael Bonidie, Co-investigator Velria Willis, Research Nurse Steven Abo, Co-investigator Nancy Saxon, Research Nurse Janet Harrison, Co-investigator Kathy Carter, Research Nurse Lori Geraci, Research Coordinator Julie Burge, Research Coordinator Judy Gruss, Research Coordinator NIH Project Scientist Karen Mislanovich, Research Coordinator Susan Meikle, Co-investigator Ellen Eline, Interventionist University of California, San Diego Beth Klump, Interventionist Charles Nager, Principal Investigator University of North Carolina at Chapel Hill Michael Albo, Co-investigator William E. Whitehead Ph.D., Co-investigator Emily Lukacz, Co-investigatorCindy Furey, InterventionistPatricia Riley, Interventionist JoAnn Columbo, Research Coordinator Sherella Johnson, Research Coordinator Kaiser Permanente — San Diego Shawn Menefee, Co-investigator Karl Luber, Co-investigator Keisha Dyer, Co-investigator Gouri Diwadkar, Co-investigator Jasmine Tan-Kim, Co-investigator University of New Mexico Rebecca G. Rogers, Primary Investigator Yuko Komesu, Co-investigator Gena Dunivan, Co-investigator Peter Jeppson, Co-investigator Sara Cichowski, Co-investigator Christy Miller, Interventionist Erin Yane, Interventionist Julia Middendorf, Research Nurse Risela Nava, Research Coordinator Dennis Wallace, Principal Investigator Marie G. Gantz, Alternate Principal Investigator Amanda Youmans-Weisbuch, Clinical Study Specialist Poonam Pande, Chemistry, Manufacturing, and Controls Project Kelly Roney, Regulatory Project Leader Ryan E. Whitworth, Statistician Lauren Klein Warren, Statistician Kevin A. Wilson, Clinical Research Informatics Project Leader Daryl Matthews, Data Manager James W. Pickett, II, Programmer Yan Tang, Programmer Tamara L. Terry, Research Manager J. Eric Jelovsek et al. / Contemporary Clinical Trials 44 (2015) 164–174
EP 1 613 598 B1 EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention of the grant of the patent: C07D 215/22 (2006.01) 19.10.2011 Bulletin 2011/42 (86) International application number: (21) Application number: 04815093.2 (22) Date of filing: 16.12.2004 (87) International publication number: