Clinical trial NCT01829425
Conditions: Urinary Incontinence, Urge
Keywords: Hypnosis Mind-Body Therapy Anticholinergics Female Urogenital Diseases
Sponsor: University of New Mexico
Start date: 2013-04-22; Completion date: 2017-10-27
Enrollment: 165 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is randomized controlled trial in which urgency incontinent women (approximately 150-160) will be randomized to hypnotherapy or pharmacotherapy and evaluated at months 2, 6 \&12 Hypotheses: Among patients with urgency urinary incontinence (UUI), hypnotherapy will be non-inferior pharmacotherapy in diminishing UUI episodes. Hypnotherapy may be superior or may not differ from pharmacotherapy in diminishing symptoms or quality of life based on validated questionnaires and/or other diary parameters.

Detailed description:
Study Objectives Primary: To compare change in Urgency Urinary Incontinence (UUI) episodes at 2 month follow-up on voiding diaries between hypnotherapy and pharmacotherapy groups (to determine whether hypnotherapy is at least as effective and durable in treating UUI as pharmacotherapy)

Secondary Analyses:

* To determine whether hypnotherapy is at least as effective in treating UUI as pharmacotherapy comparing change in UUI episodes on voiding diary at 6 and 12 month follow-up
* To determine whether hypnotherapy differs from pharmacotherapy in treating UUI comparing change in questionnaire results and urinary frequency
* enrolled following administration of the Overactive Bladder (OAB) Awareness tool. Participants will keep voiding diaries then be randomized to either pharmacotherapy and conventional behavioral therapy or hypnotherapy and conventional behavioral therapy. Approximately 150-160 women will be randomized.

Randomization will occur using a computer-generated randomization scheme in varying permuted block sizes. Study personnel performing data entry will be masked to participants' treatment. Masking participants to treatment is not feasible. Participants will be followed at 2,6 \& 12 months. Measurements will be performed before treatment, following completion of treatment visits (approximately 8 weeks), and at 6 and 12 months. Primary analysis will be intention to treat. Exploratory analyses of secondary outcomes will also be performed.

Study Visits: UUI participant screening: Study information given. Screening questionnaire given. Visit 1 Enrollment: Formal screening for eligibility, voiding diary reviewed, if eligible, written consent obtained with administration of study questionnaires, demographic and past medical history administration forms, Pelvic Organ Prolapse Quantitation (POP-Q) exam \& hypnotic susceptibility testing scheduled. Pariticipants undergo hypnotic susceptibility testing prior to randomization. Participants randomized to treatment and contacted, treatments arranged. Hypnotherapy group: undergo weekly treatments over 8 weeks. Pharmacotherapy group: weekly counseling sessions over 8 week: Following hypnotherapy or medication counseling completion, f/u voiding diaries collected \& study questionnaires administered. One of two long acting anti-cholinergic medications offered (Long acting Tolterodine or Extended Release Oxybutynin or equivalent generic substitutes).

6 \& 12 month follow-up: Pharmacotherapy subjects receive medications for 1 year and Hypnotherapy subjects encouraged to continue self-hypnosis for 1 year with assistance of audio-recordings, with 1 optional hypnotherapy session between 6-12 months..

Participants informed pharmacotherapy \& hypnotherapy sessions are audio-recorded and reviewed ensuring manual of procedures are followed.

Arms: arm 1: Either of two standard, long acting anti-cholinergic medications (Long acting Tolterodine or Extended Release Oxybutynin)will be given. Subjects receive 8 weeks of medication counseling in conjunction with the medications. Medications will be continued for 1 year. arm 2: Subjects will receive approximately weekly hypnotherapy sessions over 8 weeks and will receive/download digital recordings for home practice. Subjects will be encouraged to practice self-hypnosis +/or listen to their recordings for 1 year.
Interventions: intervention 1: Anticholinergic medications intervention 2: Hypnotherapy
Intervention descriptions: intervention 1: The study will use either of two standard, long acting anti-cholinergic medications and dosages. Pharmacotherapy counseling sessions will also be administered over 8 weeks by trained research personnel. Pharmacotherapy counseling sessions will be audio-recorded and one or more sessions will be reviewed by study personnel to ensure that the medication counselor administers the sessions in a standardized fashion. Pill counts will be performed at the conclusion of the 8 weeks of pharmacotherapy counseling. Subjects will be provided the medication for 1 year. intervention 2: Hypnotherapy will be administered approximately weekly over 8 weeks by certified, trained clinical hypnotherapists. Sessions will be audio-recorded and one or more sessions will be reviewed by study personnel to ensure that the hypnotherapist administers the hypnotherapy session in a standardized fashion.Subjects will receive or download a digital recording specially prepared for them to for home practice of hypnotherapy sessions.Following the 8 weeks of therapy, subjects will be encouraged to continue to practice self-hypnosis and/or listen to their home practice digital recording and this practice will be tracked for the 1 year duration of the study.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
1 
 
 
Protocol for Brain-Centered Therapy versus Medication for Urgency 
Urinary Incontinence An RCT: Hypnotherapy Or Pharmacotherapy 
 
Acronym: Hyp-hOP 
Co-Principal Investigators: 
Loren H. Ketai MD 
Professor Radiology 
University of New Mexico Health Sciences Center 
Yuko M. Komesu MD 
Associate Professor Obstetrics & Gynecology 
University of New Mexico Health Sciences Center 
 
Supported by: 
The National Center of Complementary and Alternative Medicine 
 
Tool Revision History 
Version Number: 1 
Version Date: 10-6-2012 
 
Version Number: 2 
Version Date: 11-30-2012 
 
Version Number: 3 
Version Date: 2-22-2013 
 
Version Number: 4 
Version Date: 5-11-2013 
 
Version Number: 5 
Version Date: 12-12-2013 
 
Version Number: 6 
Version Date: 3-12-2014 
 
Version Number: 7 
Version Date: 10-31-2014 
 
Version Number: 8 
Version Date: 9-4-2015 
 
Version Number 9 
Version Date: 3-25-2016 
 
Version Number 10 
Version Date: 5-11-2016  
 
Version Number 11 
Version Date: 12-16-2016 


 
 
 
 
2 
 
 
Abbreviations 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ACC 
Anterior Cingulate Cortex 
AE 
Adverse Event 
AHRQ 
Agency for Healthcare Research and Quality 
AI 
Anterior Insula 
ANCOVA 
Analysis of covariance 
BOLD 
Brain oxygen level dependent 
Botox 
Onabotulinum toxinA 
BPIC-SS 
Bladder Pain/ Interstitial Cystitis Symptom 
Score 
CD 
Compact Disc 
CTSC 
Clinical Translational Science Center 
Co-I 
Co-Investigator 
Co-PIs 
Co-Primary Investigators 
CRADI-8 
Colorectal Anal Distress Inventory-8 
CRF 
Case report form 
CTSC 
Clinical Translational Science Center 
Cystom. 
Cystometrics 
DSMB 
Data Safety Monitoring Board 
DSMP 
Data Safety Monitoring Plan 
e.g. 
example 
Etc. 
etcetera 
fMRI 
Functional Magnetic Resonance Imaging 
FOV 
Field of view 
f/u 
Follow-up 
H0 
Null hypothesis 
HIPAA 
Health Insurance Portability and 
Accountability Act 
HRPO 
Human Research and Protections Office 
Hyp-hOP 
Hypnotherapy Or Pharmacotherapy: Acronym 
for Protocol for Brain-Centered Therapy 
versus Medication for Urgency Urinary 
Incontinence An RCT: Hypnotherapy Or 
Pharmacotherapy 
Hz 
hertz 
IBS 
Irritable bowel syndrome 
IC 
Interstitial Cystitis 
ICI 
International Consultation on Incontinence 
ISI 
Incontinence Severity Index 
ID 
Identifier/identification 
i.e.  
Id est=in other words 
info 
information 
IRB 
Institutional Review Board 
ITT 
Intention to treat 
LA 
Long Acting 
MD 
Medical doctor 
mo 
month 
MOP 
Manual of Procedures/ Manual of Operations 
MPH 
Master of Public Health 
N 
number 
NA 
Not applicable 
NCCAM 
National Center for Complementary and 
Alternative Medicine 
NEX 
Number of excitations 
OAB 
Overactive Bladder 
OABq-SF 
Overactive Bladder Questionnaire-Short 
Form 
OFC 
Orbital Frontal Cortex 
PI 
Primary Investigator 
PISQ-12 
Pelvic Organ Prolapse Incontinence Sexual 
Questionnaire-12 (Short form) 
POP-Q 
Pelvic Organ Prolapse Quantitation 
PPBC 
Patient Perception Bladder Condition 
RCT 
Randomized controlled trial 
SAE 
Serious Adverse Event 
T1 
Spin lattice relaxation time 
T2 
Spin spin relaxation time 
TE 
Echo time 
TR 
Repetition time 
UNM 
University of New Mexico 
UNMH 
University of New Mexico Hospitals 
UTI 
Urinary Tract Infection 
UUI 
Urgency Urinary Incontinence 
VAS 
Visual Analogue Scale 
XR 
Extended Release 
yo 
Years old 
ZIP 
Zero inflated poissons 
µ 
Mu; used in the text as ‘mean’ 
µh 
Mean of hypnotherapy 
µm 
Mean of medication 


 
 
 
 
3 
 
 
TABLE OF CONTENTS 
Table of Contents 
 
 
 
 
 
 
 
 
 
      Page 
 
 
 
 
 
 
 
 
 
 
 
Study Team roster...............................................................................................................6 
 
Participating Study Sites…………………………………………………………………………7 
 
 
Précis………………………………………………………………………………………………8 
 
1. Study Objectives……………………………………………………………………………………...9 
 
1.1 Primary Objective…………………………………………………………………………….9 
 
1.2 Secondary Objectives………………………………………………………………………..9 
 
2. Background and Rationale…………………………………………………………………………10 
 
 
2.1 Background on Condition…………………………………………………………………..10 
 
 
2.2 Study Rationale………………………………………………………………………………11 
 
3. Study Design…………………………………………………………………………………………. 13 
 
 
 
Flow Diagrams 1 & 2…………………………………………………………………………….17-18 
 
4. Selection and Enrollment of Participants………………………………………………………...19 
 
 
4.1 Inclusion Criteria……………………………………………………………………………..19 
 
 
4.2 Exclusion Criteria…………………………………………………………………………….19 
 
 
4.3 Study Enrollment Procedures………………………………………………………………20 
 
5. Study Interventions…………………………………………………………………………………..21 
 
 
5.1 Interventions, Administration and Duration……………………………………………….21 
 
 
5.2 Handling of Study Interventions…………………………………………………………....24 
 
 
5.3 Concomitant Interventions………………………………………………………………….25 
 
 
 
5.3.1 Allowed Interventions……………………………………………………………25 
 
 
5.3.2 Required Interventions…………………………………………………………. 25 
 
 
5.3.3 Prohibited Interventions…………………………………………………………25 
 
 
5.4 Adherence Assessment……………………………………………………………………26 
 
6. Study Procedures……………………………………………………………………………………27 
 
 
6.1 Schedule of Evaluations: Table 1…………………………………………………………27-28 
 
 
6.2 Description of Evaluations…………………………………………………………………29 
 
6.2.1 Screening Evaluation…………………………………………………………………….29 
 
 
 


 
 
 
 
4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
        
        Page 
 
6.2.2 Enrollment, Baseline and/or Randomization…………………………………………………….29-31 
 
 
 
 
 
 
 
 
 
 
 
 
 
            
6.2.3. Blinding……………………………………………………………………………………..31 
6.2.4 Treatment Visits…………………………………………………………………………….31 
6.2.5 Follow-up Assessments……………………………………………………………………31 
 
 
6.2.6 Completion/Final Evaluation……………………………………………………………....32 
 
7. Safety Assessments…………………………………………………………………………………………..32 
 
 
7.1 Specification of Safety Parameters…………………………………………………………………34 
 
 
7.2 Methods and Timing for Assessing, Recording and Analyzing Safety Parameters…………...35 
 
 
7.3 Adverse events and Serious Adverse Events……………………………………………………..35 
 
 
7.4 Reporting Procedures………………………………………………………………………………..35 
 
 
7.5 Follow-up for Adverse Events………………………………………………………………………36 
 
 
7.6 Safety Monitoring…………………………………………………………………………………….36 
 
8. Intervention Discontinuation..............................................................................................................37 
 
9. Statistical Considerations…………………………………………………………………………………..38 
 
 
9.1 General Design Issues………………………………………………………………………………38 
 
 
9.2 Sample Size and Randomization…………………………………………………………………..40 
                  Treatment Assignment Procedures………………………………………………………………..40 
 
 
9.3 Definition of Populations…………………………………………………………………………….41 
 
 
9.4 Interim Analyses and Stopping Rules……………………………………………………………..43 
 
 
9.5 Outcomes…………………………………………………………………………………………….44 
 
 
    
9.5.1 Primary Outcome…………………………………………………………………………44 
 
 
9.5.2 Secondary Outcomes…………………………………………………………………….44 
 
 
9.6 Data Analyses………………………………………………………………………………………..45 
 
10. Data Collection and Quality Assurance………………………………………………………………...47 
 
 
10.1 Data Collection Forms…………………………………………………………………………….47 
 
 
10.2 Data Management…………………………………………………………………………………47 
 
 
10.3 Quality Assurance…………………………………………………………………………………48 
 
 
 
10.3.1 Training………………………………………………………………………………….48 
 
 
10.3.2 Quality Control Committee…………………………………………………………….48 
 
 
10.3.3 Metrics…………………………………………………………………………………...48 
 
 
10.3.4 Protocol Deviations……………………………………………………………………..49 
 
 
10.3.5 Monitoring………………………………………………………………………………..49 


 
 
 
 
5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page  
11. Participant Rights and Confidentiality………………………………………………………………50 
 
11.1 Institutional Review Board (IRB) Review…………………………………………………… 50 
11.2 Informed Consent Forms………………………………………………………………………50 
 
11.3 Participant Confidentiality……………………………………………………………………...51 
 
11.4 Study Discontinuation…………………………………………………………………………..51 
 
12. Committees……………………………………………………………………………………………….51 
 
13. Publication of Research Findings…………………………………………………………………… 51 
 
14. References………………………………………………………………………………………………..52 
 
15. Appendix of CRFs/Questionnaires attached 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
6 
 
 
Study Team Roster 
 
Co-PIs: 
 
Loren H. Ketai, MD 
MSC10 5530 
1 University of New Mexico 
Albuquerque NM 87131 -0001 
Tel: (505) 272-2269 
Fax: (505) 272-5821 
Email: lketai@salud.unm.edu 
 
Yuko M. Komesu MD 
MSC 10-5580 
1 University of New Mexico 
Albuquerque NM 87131-0001 
Tel: (505)272-9702 
Fax: (505) 272-1336 
Email: ykomesu@salud.unm.edu 
 
Co-Investigators: 
 
Robert Sapien MD 
Department of Emergency Medicine 
MSC10 5560 
1 University of New Mexico 
Albuquerque, NM  87131-0001 
Phone: (505) 272-6349 
Fax: (505) 272-6503 
Email:  rsapien@salud.unm.edu 
 
Andrew Mayer PhD 
The Mind Research Network 
1101 Yale Blvd. NE 
Albuquerque, NM 87106 
Phone: (505) 272-5028 
Fax: (505) 272-8002 
Email:  amayer@mrn.org 
 
Ronald Schrader, PhD 
CTSC Biostatistics Department 
Albuquerque, New Mexico 
Phone: (505) 272-2997 
Email: rschrader@salud.unm.edu 
 
Rebecca Rogers MD 
Department of Obstetrics and Gynecology  
MSC 10 5580 
1 University of New Mexico 
Albuquerque, NM 87131-0001 
Phone: (505) 272-9712 
Fax (505) 272-1336 
Email:  rrogers@salud.unm.edu 
 
 


 
 
 
 
7 
 
 
Other Study Personnel: 
Elizabeth Hervey and Kathy Hopkins 
Program Specialist and Study Research Coordinator 
Department of Obstetrics and Gynecology  
MSC 10 5580 
1 University of New Mexico 
Albuquerque, NM 87131-0001 
Phone: (505) 272-9702 and (505) 272-8900 
Fax: (505) 272-1336 
Email: echervey@salud.unm.edu and kehopkins@salud.unm.edu 
 
 
Urogynecology Research Division 
Department of Obstetrics and Gynecology  
MSC 10 5580 
1 University of New Mexico 
Albuquerque, NM 87131-0001 
Mobile: (505) 967-8428 
Fax: (505) 272-1336 
Email: UROGYN-Research@salud.unm.edu 
 
 
 
Participating Study Sites 
 
 
University of New Mexico Health Sciences Center 
Departments of Radiology and Obstetrics & Gynecology 
MSC 10 5530 (Radiology) and MSC 10 5580 (Obstetrics & Gynecology) 
1 University of New Mexico 
Albuquerque, New Mexico 87131-0001 
 
 
The Mind Research Network 
1101 Yale Blvd. NE 
Albuquerque, NM 87106 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
8 
 
 
Précis 
 
Brain-Centered Therapy versus Medication for Urgency Urinary Incontinence--An RCT: Hypnotherapy 
or Pharmacotherapy 
 
Study Goals & Brief Description: 
Goals/Objectives: 
Specific Aim  (1) Determine whether a mind/body therapy (hypnotherapy) is at least as effective and durable in 
treating urgency urinary incontinence (UUI) as a non-mind/body treatment (pharmacotherapy) 
Hypothesis: Among patients with urgency urinary incontinence, hypnotherapy ameliorates abnormal perception 
of bladder distension outside the hypnotic state and thereby is at least as effective as pharmacotherapy in 
diminishing the symptoms of urgency and severity of incontinence  
Specific Aim (2) Determine whether hypnotherapy treatment of UUI (urgency urinary incontinence) is associated 
with greater modification of brain activation and connectivity on functional MRI than that which occurs following 
pharmacotherapy.  
Hypothesis 2.1. Patients with urgency urinary incontinence will exhibit increased activation within portions of the 
limbic cortex (anterior cingulate cortex and insula) during bladder distension relative to healthy controls. Patients 
will also exhibit an abnormal pattern of functional connectivity within the limbic system.  
Hypothesis 2.2.  Among patients with urgency incontinence, hypnotherapy will decrease hyper-activation of the 
limbic cortex in response to bladder distension and/or modulate functional connectivity within the limbic system.  
Moreover, normalization of hyper-activation and connectivity will be greater in hypnotherapy compared to 
pharmacotherapy. 
 
Brief Description: Design, Outcome, Interventions, Duration, Sample Size and Population: 
This study includes  
1. A single-blinded, randomized controlled trial (RCT) based on a non-inferiority design which compares 
hypnotherapy to pharmacotherapy in treating UUI  
 
Urge incontinent women (N=152) will be randomized to hypnotherapy or pharmacotherapy and 
evaluated at months 2, 6 &12; study duration is thus 1 year. UUI subjects will be stratified for UUI 
severity and fMRI performance. 
 
The primary objective will be to compare group change in UUI episodes at 2 month follow-up.  
 
Secondary objectives will be to compare group change in UUI episodes at 6 & 12 months, other 
voiding diary parameters (urinary frequency, pad counts, cure and “durable cure”), and change 
in the OAB-qSF and other questionnaires (see 1.2) at 2, 6 & 12 months.  
2. Both a cross sectional study and RCT which will compare pre-treatment brain function in subjects with 
UUI to controls and compare the effect of hypnotherapy and pharmacotherapy on brain function in 
patients with UUI.  
 
Up to eighty women (of the planned 152) with UUI will be recruited in order to obtain up to sixty 
analyzable fMRI datasets. Up to 30-35 normative controls will be recruited in order to achieve 
25-30 analyzable fMRI datasets from normative controls. fMRI datasets from UUI patients will be 
compared to fMRI datasets from normative controls. The normative controls will be involved in 
the study for a month or less. 
 
In addition, the same, up to 80, UUI subjects will also undergo fMRI analysis after receiving 
treatment (hypnotherapy or pharmacotherapy) for two months. Post treatment fMRI results from 
UUI subjects will be compared to their baseline images.  These UUI subjects will complete the 
fMRI portion of the trial after being “on study” for 2 months but will continue to have follow up for 
the RCT analysis for one year  (See #1 above) 
 
Measured outcomes will be differences in baseline brain activation and connectivity in UUI 
subjects compared to controls as well as differences  in treatment effect on brain activation and 
connectivity in subjects receiving pharmacotherapy compared to those receiving hypnotherapy  
 
 
 
 
 


 
 
 
 
9 
 
 
 
 
1. Study Objectives 
 
1.1 Primary Objective: 
1.1.1. To determine whether a mind/body therapy (hypnotherapy) is at least as effective and 
durable in treating urgency urinary incontinence (UUI) as a non-mind/body treatment 
(pharmacotherapy), comparing between group changes in UUI episodes recorded on 
voiding diaries at 2 months based on a non-inferiority design. 
 
1.1.2. To determine whether hypnotherapy treatment of UUI (urgency urinary incontinence) is 
associated with greater modification of brain activation and connectivity on functional MRI 
than that which occurs following pharmacotherapy 
 
1.2 Secondary Objectives:  
1.2.1 To determine whether a mind/body therapy (hypnotherapy) is at least as effective and 
durable, in treating urgency urinary incontinence (UUI) as a non-mind/body treatment 
(pharmacotherapy).  
1.2.1.1.1 We will compare differences in UUI “cure” (defined as complete resolution of UUI 
on voiding diaries) separately evaluating 2, 6 and 12 month results (i.e. “cure” at 
2, 6 and 12 months).  
1.2.1.1.2 We will also compare between group differences in “durable cure” (defined as 
complete resolution of UUI on all voiding diaries collected at 2, 6 & 12 months).  
1.2.1.1.3 We will compare change in UUI episodes at 2, 6 & 12 months evaluating change 
in urinary frequency and pad counts recorded on voiding diaries.  
1.2.1.1.4 We will compare between group differences in change in questionnaire scores 
(OAB-q SF, ISI, Global questionnaires and PISQ-12 scores) and between group 
differences in the post-treatment Expectation question at 2, 6 & 12 months.  
 
1.2.2 Additionally, we will evaluate the baseline occurrence of concomitant syndromes such as 
irritable bowel and painful bladder syndrome in this population of women with UUI based on 
the medical history, CRADI-8, IBS Module, and IC and VAS pain questionnaires. We will 
explore whether there are differences in bowel or IC symptoms following treatment if there 
are sufficient numbers of women with bowel or IC problems at baseline. 
 
1.2.3 To confirm differences in brain activation and connectivity on functional MRI in UUI subjects 
compared to normative controls.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
10 
 
 
2. Background and Rationale 
2.1 Background 
Urgency urinary incontinence (urgency associated with involuntary urine loss, or UUI)38 affects millions of women 
daily and can impair quality of life more than diabetes. Twice as common in women, urgency incontinence 
increases with age and afflicts 24% of women ≥ 40 years old.16 It is associated with nursing home placement in 
the elderly and its stigma results in social isolation, depression and decreased work productivity in younger 
women.16,41,52,59,69 Urgency incontinence burden will increase as the U.S. population ages and will consume 76 
billion dollars in 2015 and 86 billion dollars by 2020.32 Despite the magnitude of this problem, medications, a 
cornerstone of treatment, are only 15% more effective than placebo with little evidence of durability beyond 12 
weeks.38,54 Medications are poorly tolerated, with compliance as low as 45% at 1 month and 13% at 1 year.21 
Patients who continue medications are unlikely to be cured and must bear the cost of chronic drug therapy.54 In 
2000, the U.S. spent $1.2 billion for these medications.38 The cost will continue to rise as the number of 
Americans most at risk for incontinence, those older than 65, increases an additional 21% by 2015.  
 
While pharmacotherapy of urgency incontinence has focused the diminishing motor innervation of the bladder 
by blockade of the peripheral parasympathetic system, new paradigms point to the alternative of focusing 
treatment on the brain. Treatment based on recognition of urgency incontinence as a functional disorder provides 
an alternative to continued costly reliance on pharmacotherapy. Current knowledge suggests UUI pathogenesis 
is similar to other functional disorders such as irritable bowel syndrome (IBS) and fibromyalgia. Advances in 
brain imaging suggest that increased perceptual awareness, or hyper-vigilance, is likely the cause of functional 
disorders.6,45,74 Specifically, magnetic resonance imaging (MRI) of the brain has shown that women with urgency 
incontinence manifest abnormal activation of the limbic cortex, the portion of the brain that integrates emotional 
context with stimuli arising within the body (interoception).20,27,33.36,71 Connectivity between the limbic cortex and 
other portions of the brain may also be altered in patients with urgency incontinence. No urgency incontinence 
treatment has specifically targeted brain activation and connectivity as a means of controlling symptoms nor has 
any attempt been made to assess changes in abnormal brain activation or connectivity following treatment. The 
effects of mind/body therapies on brain function have only been studied during or immediately after treatment.48 
This proposal will be the first work to assess whether mind/body therapy of a functional disorder is accompanied 
by persistent changes in brain function. Hypnotherapy, a mind/body therapy that can be administered in a 
standardized and reproducible fashion, is the best candidate for assessing these changes.  
 
Hypnosis can profoundly alter sensory awareness and cognitive processing in response to external stimuli.24 It 
promotes “dissociation from painful experience and distress via hypnotic induction” and modulates activation of 
the limbic cortex in response to pain and conflict resolution.28 Hypnotherapy has been used to successfully treat 
other functional disorders, with subjects experiencing lasting decrease in symptoms outside the hypnotic 
state.60,42 These successes are best characterized in the treatment of irritable bowel syndrome (IBS), a functional 
gastrointestinal disorder closely analogous to urgency incontinence.34,47 No work has yet addressed whether 
persistent change in brain activity or connectivity underlies this post-hypnotic clinical improvement. 
 
Our long term goal is to shift the focus of UUI treatment towards the brain and away from the peripheral nervous 
system. The objective here, in pursuit of that goal, is to determine whether hypnotherapy can be at least as 
effective in treating UUI as current pharmacologic therapy. Our central hypothesis is that hypnotherapy can be 
used to modulate neurologic interactions between the brain and bladder, providing effective UUI treatment. 
Recent work using functional magnetic resonance imaging (MRI) of the brain has better delineated the abnormal 
neurologic interactions that could be targeted for treatment of UUI, specifically, the accentuated neural responses 
to afferent signals from visceral organs that are the basis for hyper-vigilance.6,12,23 Mind/body, specifically 
hypnotherapy, treatment of UUI offers the hope of targeting this hyper-vigilance and redirecting focus of UUI 
treatment to the brain. Hypnotherapy has successfully treated other functional disorders.6 One case series and 
our own pilot randomized controlled trial indicate that hypnotherapy can be a well-tolerated, effective treatment 
for UUI.29  Neurophysiologic models link the effects of hypnotherapy to altered activation of the limbic (emotional) 
brain and its connections with the executive control portions of the brain.25,26 This process modulates subject 
attention and offers the means to counterbalance the effects of hyper-vigilance.26  The rationale for our proposal 
is based on this prior work which has shown that brain activation is abnormal in subjects with UUI, that UUI may 
respond to hypnotherapy, and that hypnotherapy targets these sites of abnormal brain activation. Proof that 
hypnotherapy provides durable relief from UUI would change the focus of UUI treatment and would demonstrate 


 
 
 
 
11 
 
 
the physiologic basis for the use of a mind/body therapy to treat UUI, a functional disorder that affects a large 
segment of the population. We will test our central hypothesis with the study goals described previously. 
 
 
2.2 Rationale 
For the RCT: Specific Aim 1) Pharmacotherapy for urgency incontinence targets bladder receptors. It has had 
uneven therapeutic success due to side effects that have deterred long term use.24,66,38 The objective of this aim 
is to change the target of urgency incontinence therapy to the brain using hypnotherapy to provide a treatment 
which is as effective and durable as the standard treatment, pharmacotherapy. To attain this objective, we will 
test our working hypothesis that the central abnormality in urgency incontinence is an altered perception of 
bladder distension and that hypnotherapy more directly affects this abnormality than medications, resulting in 
greater improvement in urinary urgency and incontinence. Our approach randomizes women to active 
interventions for 8 weeks; 8 weeks of hypnotherapy sessions vs. 8 weeks of pharmacotherapy with counseling 
sessions. Pharmacotherapy treatments will utilize standard anticholinergic medications, long-acting Tolterodine 
or Oxybutynin. Regarding the choice of anti-cholinergics, meta-analyses conclude that no one drug has proven 
superior in treating urgency incontinence but that, extended release formulations of medications are more 
effective than immediate release.38  We will compare change in improvement in voiding diaries and validated 
questionnaires following both treatments. We will follow subjects at 2 months, then at 6 and 12 months. The 8 
weeks of active interventions will be followed by recommendations for self-hypnosis and/or hypnosis audiofile 
use or continued medication use for 12 months. The rationale for this aim is to demonstrate that hypnotherapy 
targeting hyper-vigilance improves urinary continence as well as does pharmacotherapy.  When the studies 
proposed in Aim #1 have been completed, we expect that the results will redirect the focus of incontinence 
treatment towards mind-based therapy and foster additional trials of this therapy for other functional disorders. 
For the fMRI; Specific Aim 2): Current knowledge suggests urgency incontinence pathogenesis is similar to other 
functional disorders such as IBS, representing a manifestation of 
“hyper-vigilance” to normal body 
sensations.6,55,75 The objective of this aim is to demonstrate that hypnotherapy results in sustained post-therapy 
amelioration of abnormal limbic cortical function  that is the physiologic correlate of this abnormal perceptual 
state present in patients with urgency incontinence on fMRI.  Among patients with functional disorders abnormal 
activity within the limbic cortex involves the insula and anterior cingulate cortex.6,23,40,61 Conceptually, the insula 
can be considered the sensory cortex for physiologic conditions and the anterior cingulate cortex the limbic 
behavioral motor cortex.27 As the latter, anterior cingulate cortex activation is associated with the emotional 
response to discomfort and is activated during expectation of unpleasant events.75 Patients with functional 
disorders manifest both abnormal activation of the limbic cortex and abnormal connectivity between these 
structures and other sites in the brain.62,68 This connectivity is complex and analyses of its structure have varied 
between investigators and between specific functional disorders.56,12,70 In most studies controls and subjects with 
functional disorders have displayed differences in connectivity between the limbic cortex and sites in the central 
executive network (e.g. prefrontal cortex).45,56,72   
 
Hypnotherapy offers a mechanism to sustain that effect in order to provide clinically useful therapy. The hypnotic 
state results in functional changes in the limbic cortex. It has been shown to decrease anterior cingulate cortex 
activation in response to acute pain and in response to conflict monitoring.63,73 The interaction between the 
anterior cingulate cortex and the other portions of the brain during hypnosis, however, is not constant across all 
settings. Connectivity with the prefrontal and frontal cortex may increase when pain is suppressed by hypnosis 
and diminish when conflict monitoring is suppressed by hypnosis.24,25,53,60 Furthermore, the anterior cingulate 
cortex is not the sole target in the limbic cortex for mind/body therapies. It appears to be an important nexus for 
acute stimuli but chronic symptoms may be mediated elsewhere.31 Treatment of chronic pain with both hypnosis 
and acupuncture is associated more strongly with decreased activation of the insula and alterations of its 
connectivity to other sites including the central executive network.2,5,48  Modulation of activity in these sites has 
been associated with  acute amelioration of chronic pain.69 Alteration of insula connectivity persists for the first 
hour following therapy and may be important in achieving a sustained treatment effect.  
 
Our working hypothesis is that among patients with urgency incontinence hypnotherapy causes sustained 
decreases in abnormal evoked activation of the limbic cortex in response to bladder distension and/or 
modulates abnormal intrinsic activity (functional connectivity) in these same areas. We also predict that this 
normalization of evoked activation and functional connectivity will be greater than that seen with 


 
 
 
 
12 
 
 
pharmacotherapy. Our approach will be to evaluate evoked brain activation and functional brain connectivity on 
fMRI in normative subjects and in urge incontinent subjects, the latter pre and post treatment after 
randomization to drug or hypnotherapy. The rationale for this approach is to demonstrate that hypnotherapy 
treatment of urgency incontinence ameliorates limbic system activity and abnormal resting connectivity 
associated hyper-vigilance. Demonstration that this therapeutic effect is sustained outside the hypnotic state 
would be the initial exploration of brain plasticity in response to mind/body therapy. The expected outcome of 
this innovative proposal would be the first demonstration of the physiologic correlate of successful mind/body 
treatment of a functional disorder. 
 
 
3. Study Design 
Brief Description: 
 
This study includes  
1. A single-blinded, randomized controlled trial (RCT) based on a non-inferiority design which compares 
hypnotherapy to pharmacotherapy in treating UUI. 
 
Urge incontinent women (N=152) will be randomized to hypnotherapy or pharmacotherapy and 
evaluated at months 2, 6 &12    
2.  Both a cross sectional study and RCT which will evaluate up to 80 of these women with UUI.  
 
These women will undergo fMRI before treatment and their baseline imaging results will be 
compared to  normative controls.  
 
In addition, the  UUI subjects participating in the fMRI will undergo imaging after treatment. The 
images of UUI subjects following treatment will be compared to their baseline images. 
 
Outcomes: 
 
Primary Outcomes: 
1. Between group differences in change in UUI episodes for Specific Aim 1 at 2 month follow-up 
based on 3 day voiding diaries 
2. Between group differences in change in activation of limbic cortex and brain connectivity following 
treatment  for Specific Aim 2  
Secondary Outcomes: 
1. Between group differences in change in UUI episodes for Specific Aim 1 from baseline to follow-up 
at both 6 and 12 months based on 3 day voiding diaries. 
2. Between group differences in change in pad counts, voiding frequency and cure (resolution) of UUI 
on voiding diary for Specific Aim 1 at 2, 6 and 12 month follow-up as well as “durable cure” 
(resolution of UUI on all follow-up diaries at 2, 6 & 12 months) 
3. Between group differences in the post-treatment expectation question and between group 
differences  in questionnaire change scores (the OAB-qSF, ISI,  PISQ-12, Global questionnaire, 
CRADI-8, IBS Module, IC questionnaire) for Specific Aim 1 at 2, 6 and 12 month follow-up 
4. Baseline differences in activation of the limbic cortex and brain connectivity in women with UUI 
compared to normative controls for Specific Aim 2 
 
Overview: 
 
Women with UUI who meet inclusion criteria and who choose to participate in the study will be enrolled at the 
University of New Mexico Urogynecology Clinic. We will screen subjects for study entry as we always do 
clinically, based on voiding diaries to ensure that subjects have UUI (and not other types of incontinence) and 
with a screening questionnaire, the OAB Awareness tool. Subjects will be randomized to treatment with either: 
1) Pharmacotherapy (a standard therapy for UUI) and conventional behavioral therapy or 2) Hypnotherapy and 
conventional behavioral therapy. All subjects will give signed informed consent prior to study treatment. 
Approximately 152 women will be randomized to hypnotherapy or to pharmacotherapy with approximately half 
in each group. UUI subjects will be informed that study participation will be approximately 1 year; Measurements 
will be performed prior to treatment, following completion of treatment visits (treatment visits are performed over 
8 weeks), and again at 6 and 12 months. The latter visits at 6 and 12 months do not necessarily require in-person 


 
 
 
 
13 
 
 
study visits and may be performed via phone and mail. The primary analysis of the RCT will be performed as an 
intention to treat analysis. A secondary analysis will be performed as a per protocol analysis. 
 
A subset of subjects with UUI (up to 80) in both treatment groups will have brain fMRIs performed at baseline 
and follow-up at the Mind Research Network. In addition, 30-35 normative controls will also undergo an fMRI at 
the Mind Research Network to compare fMRI in affected women versus controls. Subjects will give signed 
informed consent prior to study participation 
 
 
Randomization to treatment for RCT: 
A. Randomization to treatment 
Study participants will be randomized to either pharmacotherapy or hypnotherapy groups using a computer-
generated randomization scheme in varying permuted block sizes of 4-8 which will be stratified for fMRI 
performance and UUI severity (< 4 UUI episodes vs. ≥ 4 UUI episodes on 3 day voiding diaries) to ensure 
relatively equal numbers in both treatment groups. Group assignments will be placed in opaque, sealed 
envelopes by an individual otherwise unassociated with the study. The envelopes will be opened and subjects 
will be randomized only after subjects have signed informed consent and answered baseline questions and 
questionnaires. Investigators involved in analyzing fMRIs, investigators participating in the RCT, study personnel 
performing data entry and the study statistician will be blinded to knowledge of subjects’ treatment groups. 
Investigator blinding will only be breached if a subject suffers an unexpected clinical event and investigator 
knowledge of the subject’s treatment is essential to providing standard of care. Subjects cannot be blinded to 
treatment interventions as it will be obvious to them whether or not they are undergoing hypnotherapy or taking 
medications. 
 
Visits for Study: (Refer to Flow Diagrams at end of this section) 
 
A. UUI STUDY SUBJECTS: 
Screening: Subjects in the UNMH Urogynecology clinics with UUI who qualify for study entry will be asked 
whether they are interested in study participation. These subjects will be assured that declining study 
participation will not affect their clinical care. In addition, women with UUI who contact the UNMH Ob-Gyn 
research division expressing interest in study participation will have the study explained to them and follow the 
same procedures as UNMH subjects (see following). Potential subjects will be given a copy of the study consent 
for their review. Those who are interested will be administered the OAB Awareness tool,18 a validated measure 
which screens for presence of OAB, to screen whether or not they are candidates for the study. They will also 
be instructed how to keep a voiding diary. If they ultimately choose to participate in the study, they will be asked 
to bring the diary with them for Visit 1 (below). The patient will be given the option to schedule Study Visit 1 or 
given the option to contact the study coordinator to schedule Study Visit 1 at a later date if they are uncertain 
regarding study participation. 
 
Visit 1 (At study entry): All subjects; (1) Will return voiding diaries (which will be reviewed by the study coordinator 
for completeness and UUI frequency) & instruction regarding voiding diaries will be reiterated & arrangements 
made for return of future voiding diaries (2) Will be administered the OABq-SF questionnaire,15  the Incontinence 
Severity Index (ISI), and the Patient Perception of Bladder Condition (PPBC).85 (see questionnaires attached). 
The OABq-SF questionnaire is a condition specific validated questionnaire developed to quantitate OAB 
symptoms and the PPBC is a validated global questionnaire regarding subjects’ impression of the severity of 
their urinary condition.84 The ISI is a commonly used, validated 2 item questionnaire which adds another 
dimension to the outcomes, a description of UUI severity and is an accepted outcome measure in the 2012 
AHRQ summary of nonsurgical treatments of urinary incontinence.84 If subjects are willing, they will also answer 
a condition-specific validated measure of sexual function, the PISQ-12..64,65,66 Urinary incontinence has been 
found to adversely affect sexual function and many studies have reported upon its improvement following 
therapy.67,68,16 (3) Answer demographic questions and questions about their past medical history. Subjects will 
also be administered the Colorectal Anal Distress Inventory 8 (CRADI-8) subscale of the PFDI-20 (which has 
been validated in women with bowel symptoms and pelvic floor disorders),87 the Rome III IBS Module, and the 
Painful Bladder Interstitial Cystitis Symptom Score (PBIC-SS)86  and Pain Visual Analogue Scale,37 as irritable 
bowel (IBS) and painful bladder (Interstitial Cystitis)  syndromes are associated with UUI. IBS and IC may be 


 
 
 
 
14 
 
 
important covariates in treatment success and have responded to other UUI treatments  (4) Will have already 
undergone a pelvic examination which includes the Pelvic Organ Prolapse Quantitation (POP-Q) Exam during 
their routine clinical evaluation within the last year; if they have not, however, they will undergo a POP-Q exam. 
The POP-Q is a validated examination recommended by the International Continence Society to standardize 
quantitation of subjects’ prolapse9 (5) Subjects will have cystometry scheduled as this is part of clinical care to 
help distinguish between the different types of incontinence. This is a test where subjects have a catheter placed 
in the bladder, the bladder is filled with sterile fluid and bladder volumes at which sensations of urgency and 
desire to void occur are recorded. Subjects who have undergone formal UDS and whose UDS results are 
available, do not have to have cystometry repeated unless they choose to participate in the fMRI study. (6) 
Subjects who are willing to undergo fMRI and are free from MRI contraindications will be informed of the 
date/time of the fMRI visit or their contact information will be obtained. They will be contacted regarding the fMRI 
date/time before Visit 3 (7) Behavioral interventions, a standard treatment for urgency incontinence, will be 
discussed with all subjects and a hand-out will be given to all subjects and arrangements for future contact with 
subjects will be made. 
 
Visit 2: Cystometry will be performed (see #5 above, Visit 1) Cystometry is a test where subjects have a catheter 
placed in their bladder, the bladder is filled with sterile fluid and bladder volumes at which sensations of 
increasing urge to void are recorded. It is part of clinical care to help distinguish between the different types of 
incontinence. Subjects will be treated with prophylactic antibiotics the day of cystometric testing after 
documenting absence of allergies to the antibiotics prescribed. Prior to cystometry the subjects will have a urine 
pregnancy test (if they are premenopausal and have not had a hysterectomy or permanent sterilization) and 
urine dipstick performed to rule out a urinary tract infection. While the bladder catheter is still in place, subjects 
may have urine and vaginal swab samples collected and stored for possible future analysis (For example, urine 
may be analyzed for biomarkers and microbiome analysis). Those who will undergo fMRI will also undergo a 
brief simulation of the procedure to be performed in the fMRI; their bladders will be filled and emptied and they 
will rate their urge to void (from 0-10) while this occurs. This will be done in order to decrease anxiety regarding 
the procedure while in the fMRI scanner.  Subjects may undergo hypnotic susceptibility testing (using the 
validated Stanford C Hypnotic Susceptibility Test) at this time or any time before their 1st intervention treatment. 
 
Visit 3 for fMRI subjects: Up to eighty of the UUI subjects (approximately half from the hypnotherapy group and 
half from the pharmacotherapy group) willing to have an fMRI and without contraindications to fMRI will 
participate in the fMRI portion of the study and will return for their baseline fMRI. Urine dipstick testing and 
pregnancy testing (in women who are premenopausal and without a history of a hysterectomy or permanent 
sterilization) will be performed: subjects who are pregnant or who have a urinary tract infection may not undergo 
fMRI testing. FMRI subjects will be pretreated with prophylactic antibiotics, will have a bladder catheter placed 
and will be asked to a) concentrate on a picture placed before them while they have the MRI performed b) they 
will next have their bladders filled with sterile fluid and be asked to rate the degree of bladder discomfort or “urge 
to void” experienced during bladder filling c) they will then have the catheters removed, the amount of urine 
voided will be measured and subjects will be discharged to home and given instructions to contact the study 
personnel if questions or problems arise.   
 
The subjects will be randomized to treatment interventions and contacted by the study personnel and 
arrangements made for their interventions, which must begin within one month. Subjects will be administered 
the Patient Expectation question. 
 
Visits Overview: Hypnotherapy subjects will have a total of 8 hypnotherapy sessions scheduled over 8 weeks 
and Conventional pharmacotherapy subjects will have a total of 8 visits scheduled over 8 weeks with the 
medication counselor (see the following) 
 
Visit for Hypnotherapy Subjects: Visit 3 (for subjects who did not undergo fMRI) Visit 4 (for subjects who did 
undergo fMRI): Hypnotherapy Subject Visits 3-10 for those who did not undergo fMRI, Visits 4-11 for those who 
did undergo fMRI-- 8 hypnotherapy sessions over 8 weeks-- Hypnotherapy sessions: Subjects assigned to 
hypnotherapy will be scheduled for these visits which will be performed by a certified clinical hypnotherapist, 
other than Dr. Robert Sapien. The hypnotherapists will be supervised by Dr. Robert Sapien, a certified 
hypnotherapist and Board Certified Pediatric Emergency Medicine physician and UNMH faculty member. The 


 
 
 
 
15 
 
 
subjects will be informed that the sessions will be audio-recorded and one or more sessions will be reviewed by 
study personnel to ensure that the hypnotherapist administers the hypnotherapy session in a standardized 
fashion. Recordings will be stored on the research computer and access to these recordings will be available to 
assigned research personnel only. All recordings will be stored for approximately 7 years, in the same fashion 
as other data, and then will be destroyed. The hypnotherapists have been instructed to not use the patients’ 
name or any other identifiers during the recorded session.  The subjects will undergo 8 hypnotherapy sessions 
over 8 weeks. Sessions will last approximately 60 minutes.  Session #1: The hypnotherapist will explain 
hypnotherapeutic principles; subjects will inform the hypnotherapist regarding any phobias or fears (so that these 
triggers will be avoided). Subjects will undergo their 1st hypnotherapy session and hypnosis will then be 
terminated. Session #2: address emotions around UUI and life impact, visualize pelvic floor exercise mechanics, 
and undergo their 2nd hypnotherapy session followed by termination of hypnosis. Subjects will receive a CD or 
be instructed how to download a digital recording (for use on a digital device) specially prepared for them to for 
home practice of hypnotherapy sessions. This will occur at either their 2nd or 3rd hypnotherapy session; they will 
be instructed NOT to listen to the hypnotherapy CD/digital recording while driving and encouraged to listen to 
the CD/digital recording daily and record the home use of their CD/digital recording. Session #3,4,5,6,7; same 
as session 3. Session #8: same as previous sessions. In addition, the subjects will be counseled to expect 
occasional and temporary setbacks in their bladder symptoms and the hypnotherapist and subject will discuss 
how to cope with these setbacks.  
 
Pharmacotherapy Visit 3-10 for subjects who did not undergo fMRI, Visits 4-11 for those who did undergo fMRI 
---8 medication counseling sessions over 8 weeks-- Medication Counseling Session: Subjects assigned to 
pharmacotherapy (medications) will be scheduled for these visits which will be performed by trained personnel. 
The subjects will be informed that several or all sessions will be audio-recorded and one or more sessions will 
be reviewed by study personnel to ensure that the medication counselor administers the sessions in a 
standardized fashion. Recordings will be stored on the research computer and access to these recordings will 
be available to assigned research personnel only. All recordings will be stored for approximately 7 years, in the 
same fashion as other data, and then will be destroyed. The medication counselors have been instructed to not 
use the patients’ name or any other identifiers during the recorded session.  Subjects will be scheduled for in 
person visits with the medication counselor who will review medications and their side effects. However, if 
subjects state these in person visits are overly burdensome, these visits may occur via phone as long as the 
patient comes in for at least 2 of the subsequent visits for pill dispensation which should occur midway and at 
the end of the 8 sessions. These sessions will take as long as required/desired for subjects to feel that they have 
received adequate instruction/counseling. Discussion of strategies to cope with their bladder symptoms will 
occur. The expected side effects of medications (such as dry mouth, constipation) will be discussed and 
strategies to cope with side effects will also occur.  It is expected that these sessions will take approximately 20-
60 minutes, depending on the subjects’ needs. The medication may be changed if the patient complains of side-
effects from the initial anti-cholinergic or perceives that her response in UUI treatment is inadequate; a different 
anti-cholinergic may be given to the patient if she requests a different UUI medication. The study will use either 
of two standard, long acting anti-cholinergic medications and dosages (Long acting Tolterodine 4mg/day or 
Extended Release Oxybutynin 10 mg/day). Initial medication use will usually be Oxybutynin 10 mg/day but will 
depend on the patient history (for example those who have used Oxybutynin unsuccessfully will be given 
Tolterodine and vice versa). A recent AHRQ meta-analysis found that there was no difference in effectiveness 
or side-effects between the available anti-cholinergics used to treat UUI as long as the medications were 
extended release formulations, such as those used in this study.38 
 
Visit 12—follow-up fMRI testing (for the fMRI group):  Follow-up fMRI will be performed on the subjects who had 
baseline fMRIs performed. These will be performed in the same fashion as described in Visit #3. In addition, 
patients may have urine and vaginal swab samples collected and stored for possible future analysis (For 
example, urine may be analyzed for biomarkers). 
 
Final visit 11 (for those who did not undergo fMRIs) and Final visit 13 (for those who did undergo fMRI):  The 
final study visit will be scheduled at the end of the hypnotherapy or medication counseling sessions, 
approximately 8-12 weeks after study entry. Those who are in the subgroup who have undergone prior fMRI 
testing will have it performed at this session.  At the final study visit, subjects will 1) be administered the OABq-
SF, ISI, the PPBC, CRADI-8, IBS Module and IC questionnaires, PISQ-12 and answer the question regarding 


 
 
 
 
16 
 
 
how well the therapy met their expectations for treatment. Their compliance with medications or home practice 
of hypnotherapy will be documented 2) They will return their follow-up voiding diary 3) receive patient incentives 
for the time and inconvenience they have experienced from study participation. In addition, patients may have 
urine and vaginal swab samples collected and stored for possible future analysis (For example, urine may be 
analyzed for biomarkers).  
 
Length of visits: Each hypnotherapy session will last approximately 60 minutes, each pharmacotherapy visit will 
take approximately 20-60 minutes, and each Brain fMRI visit will last approximately 60-120 minutes. The 6 and 
12 month visits may be conducted via phone or mail, if the subject desires, in order to decrease subject 
inconvenience. 
 
B. NORMATIVE CONTROLS PARTICIPATING IN ONLY THE FMRI STUDY: 
In addition to the UUI study subjects described previously, we will also enroll a group of women without UUI and 
OAB symptoms (and with OAB Awareness Tool screening questionnaire scores < 8). This normative group 
(approximately 30-35 subjects) will keep voiding diaries, answer questionnaires, and undergo urine pregnancy 
and dipstick testing and cystometric testing and receive prophylactic antibiotics (as described previously) 
followed by performance of a Brain MRI in order to compare baseline fMRIs in women with and without UUI.  
 
Screening: FMRI portion of the study explained to subject, including the cystometry and fMRI procedures. 
Subject administered OAB Awareness tool and fMRI eligibility assessed. Subject given voiding diary instructions. 
Subject given copy of consent and either has visit scheduled to sign consent after subject has time to consider 
whether she wants to participate in the study. If subject states she is certain that she wants to participate, she 
has the option of signing the consent at this time. If the consent is signed, then the subject is administered the 
medical history and demographic forms. If subject states at this visit that she would like to participate in the study, 
appointments are scheduled for the cystometry and fMRI and arrangements are made for the patient to receive 
prophylactic antibiotics prior to the bladder catheterizations. If patient is uncertain whether she wants to 
participate, the research coordinator’s contact information is given to the subject. 
 
Visit 1: Subjects return for the visit with the voiding diary and study eligibility is re-confirmed. The consent is 
signed, if this has not happened previously. The medical history and demographics forms are administered. 
POP-Q exam is performed if it has not been performed in the last year. Cystometry is explained to the subject 
once more. Urine pregnancy test is performed (if patient is premenopausal and has not had a hysterectomy or 
permanent sterilization procedure) and urine screen for UTI performed. Cystometry is performed as previously 
described in Visit #2 for the UUI subjects. The subjects will also have simulation of the procedure to be performed 
in the fMRI. Patients will have urine and vaginal swab samples collected and stored for possible future analysis 
(For example, urine may be analyzed for biomarkers and microbiome analysis). Future fMRI appointment is 
confirmed. 
 
Visit 2: Urine pregnancy test performed (if patient is premenopausal and has not had hysterectomy or permanent 
sterilization procedure) and urine screen for UTI performed. FMRI procedures again explained to subjects. FMRI 
performed as described previously in visit 3 for fMRI UUI subjects. Subjects are given instructions and contact 
numbers to call in the event questions or problems arise. Subjects thanked and subject incentives given or 
arrangements made to give incentives. 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
17 
 
 
Flow Diagram 1--- for UUI Subjects: 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Flow Diagram 2--- Normative Controls for FMRI study 
Study Visit #1: Pt returns for study visit with her voiding diary and voiding diary reviewed for study eligibility/UUI frequency. 
Consent Signed. fMRI eligibility assessed. Past medical history & Demographics sheet & baseline questionnaires (OAB-qSF, 
ISI,PBBC, PISQ-12, IBS Module, CRADI-8, BPIC and vas pain questionnaire administered).  POP-Q exam performed if not 
performed in last 12 months. Cystometrics scheduled. FMRI may be scheduled (for fMRI eligible & willing subjects) @ this visit 
or arrangements made to contact subjects regarding fMRI. Arrangements made to contact pts for scheduling future appts. and 
for patients to receive prophylactic antibiotics for catheterization(s). Behavioral Therapy reviewed & handouts given 
Study Visit #3: FMRI (up to 80) Urine screen for UTI and 
pregnancy test performed.  FMRI procedures again 
explained to subjects. FMRI performed. Subject incentives 
given or arrangements made to give incentives. 
Study Visits #3-10 (or #4-11): 8 hypnotherapy sessions 
over 2 months. CD logs documenting home practice 
gathered weekly/sent to coordinator. Session(s) taped 
for quality assurance and randomly audited.  
Study Visit #2: Cystometry explained to subject. Urine 
pregnancy test and urine screen for UTI performed. 
Cystometry performed. FMRI patients will undergo 
fMRI task simulation and have urine and vaginal swab 
samples collected and stored for possible future 
analysis. Subjects may undergo hypnotic susceptibility 
testing at this time or any time prior to initiating 
study treatment. 
Study Visit #12: (for pts who had a 
baseline fMRI & same procedure 
as Visit #3): F/U fMRI performed 
and have urine and vaginal swab 
samples collected and stored for 
possible future analysis. 
Study Visits #3-10 (or #4-11): 8 Pharmacotherapy sessions 
over 2 months. Medication logs gathered weekly and sent 
to study coordinator. Session(s) taped for quality 
assurance and randomly audited. 
Study Visit #11  (or #13): Final Research Coordinator Meeting with patients after treatment finished (approx. 2-3 months 
after randomization); f/u questionnaires administered (OABq-SF,ISI, PBBC, PISQ-12, CRADI-8,IBS Module, BPIC  
questionnaire, Post-treatment Expectation question), voiding diary and treatment compliance information collected. Urine 
may be collected and stored for possible future analysis. Plans for f/u explained & Contact information re-confirmed. Pt 
incentives given 
Study Visit #12: (for pts who had a 
baseline fMRI & same procedure as 
Visit #3) F/U fMRI performed and 
have urine and vaginal swab samples 
collected and stored for possible 
future analysis. 
6 mo. f/u with patients after treatment finished (approx. 6 months after treatment & may be phone/mail f/u): f/u 
questionnaires administered (OABq-SF, ISI,PPBC, PISQ-12, CRADI-8, IBS Module, BPIC, Post-treatment Expectation), voiding 
diary  and treatment compliance information collected. Plans for f/u explained & Pt incentives given/mailed. Arrangements 
made for hypnotherapy patients who choose optional additional hypnotherapy session prior to 12-mo follow-up. 
12 mo. f/u with patients after tx finished (approx. 12 months after tx & may be phone f/u): f/u questionnaires administered 
(OABq-SF, ISI,PPBC, PISQ-12, CRADI-8,IBS Module, BPIC, Post treatment Expectation question), voiding diary and treatment 
compliance information collected. Pts thanked and Pt incentives given/mailed 
Patients Randomized (N=152). Patients notified of randomization and of pending appointment times and dates 
Pretreatment Expectation question administered 
Screening Visit: Study explained to patient. Pt. administered OAB Awareness Tool & given voiding diary instructions.  Pt. given 
copy of consent and either has visit scheduled to sign consent or pt. given research coordinator’s info. for future contact 


 
 
 
 
18 
 
 
Flow Diagram 2--- for fMRI Normative Controls: 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Visit #1 Cystometrics: Subjects (up to 30-35) return for study visit with voiding diary and study eligibility (for FMRI as a 
normal control) confirmed. Consent signed if this has not happened previously and past medical history/Demographics sheet 
administered if consent signed at this visit.  POP-Q exam performed if not performed in last year. Cystometry explained to 
subject. Urine pregnancy test and urine screen for UTI performed and have urine and vaginal swab samples collected and 
stored for future analysis. Cystometry and fMRI task performed. fMRI appointment confirmed.  
Study Visit #2 fMRI:  Urine screen for UTI and pregnancy test repeated.  FMRI procedures again explained to subjects. 
FMRI performed. Subjects are given instructions and contact numbers to call in the event questions or problems arise.  
Subjects thanked and subject incentives given or arrangements made to give incentives. 
Screening Visit (subject may also sign consent at this visit if desired): FMRI Study explained to subject. Subject administered 
OAB Awareness Tool and fMRI eligibility assessed.  Subject given voiding diary instructions.  Subject given copy of consent and 
either has visit scheduled to sign consent or if subject wishes, may sign consent at this time. If consent has been signed at this 
visit, the Past Medical History and Demographic forms will be administered at this time. Cystometry and fMRI procedures will 
be explained to the subject. Appointments for subject to undergo cystometry (see visit 1) & fMRI may be scheduled at this 
time or subject may be given research coordinator’s info. for future contact.  Arrangements made for patient to receive 
prophylactic antibiotics prior to bladder catheterizations. 


 
 
 
 
19 
 
 
4. Selection and Enrollment of Participants 
4.1 Inclusion Criteria & 4.2 Exclusion Criteria:  
All study participants must meet all the inclusion criteria as noted below to participate in the study. Additionally, 
if subjects have any of the exclusion criteria as specified below, they will be excluded from the respective 
portion of the study. 
 
For the RCT: 
Inclusion Criteria for the RCT: Women with Urgency Urinary Incontinence (UUI) who meet inclusion criteria and 
who choose to participate in the study will be enrolled. They must be able to understand the study procedures 
and agree to comply with them for the duration of the study. Inclusion criteria: 
 
Non-pregnant English-speaking women 
 
> 18 yo  
 
OAB Awareness scores ≥ 8  
 
 ≥ 3 UUI episodes/week for ≥ 3 months 
 
 
Exclusion Criteria for the RCT:  Women who have any of the exclusion criteria as specified below will be 
excluded from study participation 
 
 
Women with a history of neurologic diseases such as Multiple Sclerosis, Parkinson’s disease, stroke, 
or dementia 
 
History of schizophrenia or untreated bipolar disorder or current drug or alcohol dependence  
 
Women who have taken anticholinergic medications for UUI within the last 3 weeks (women who have 
taken anti-cholinergics for UUI but discontinued them > than 3 weeks ago may participate in the study) 
or have a sacral neuromodulator in place to treat UUI or have received Onabotulinum toxin A in the 
last 12 months to treat UUI 
 
Contraindications to anticholinergic medications (untreated narrow angle glaucoma, significant urinary 
retention or gastric retention) 
 
Pregnant women or lactating women, women who plan to become pregnant in the next year, or pre-
menopausal women unwilling to use contraception if engaging in sexual relations during the year of 
study participation (hysterectomy is considered to be a form of contraception) 
 
Untreated urinary tract infection  
 
Prolapse which extends past the hymen (POP-Q points of ≥ 1+) which may be responsible for UUI 
symptoms 
 
Women who cannot keep the majority of the study therapy appointments or those without reliable 
contact phone numbers or methods of communication with the study personnel. 
 
For the fMRI: 
 
Inclusion Criteria for UUI subjects participating in the fMRI portion of the study: Women with UUI who 
meet criteria for the RCT and who are willing to participate in the fMRI portion of the study. They must 
be able to understand the study procedures and agree to comply with them. 
 
Exclusion Criteria for UUI subjects participating in the fMRI portion of the study: Women who have any of the 
exclusion criteria as specified below will be excluded from participation in the fMRI portion of the study 
 
Women with a history of severe claustrophobia or ferro-magnetic implants such as cochlear 
implants, cardiac pacemakers or aneurysm clips. 
 
Inclusion Criteria for normative controls participating in the fMRI study: These women must be able to 
understand the study procedures and agree to comply with them. Other criteria:  
 
Women 46-80 years old* 
 
Absence of  UUI/OAB symptoms or treatment  
 
OAB Awareness Tools Scores <8  
 
Willingness to undergo fMRI 


 
 
 
 
20 
 
 
*Explanation of age range for the above: In an attempt to assure comparable age ranges of controls to affected 
UUI subjects, we initially pooled data from both our pilot hypnotherapy and pilot fMRI studies and have found that 
the median patient age was 54 with the second quartile=46-54, and third quartile=55-62. We initially chose these 
quartiles as the age range for the normative control group but subsequently found that the age range was overly 
restrictive in the upper age ranges. We expanded the upper limit to 80 years in order to have flexibility in age 
adjustment of controls. 
 
Exclusion Criteria for normative controls participating in the fMRI study: Women who have any of the 
exclusion criteria as specified below will be excluded from participation in the fMRI portion of the study  
 
 
Women with UUI/OAB 
 
Women with a history of neurologic diseases such as Multiple Sclerosis, Parkinson’s disease, stroke, or 
dementia 
 
History of schizophrenia or untreated bipolar disorder or current drug or alcohol dependence   
 
Pregnant women or lactating women, women who plan to become pregnant in the next year, or pre-
menopausal women unwilling to use contraception if engaging in sexual relations during the year of 
study participation (hysterectomy is considered to be a form of contraception) 
 
Untreated urinary tract infection  
 
Women with a history of severe claustrophobia or women with ferro-magnetic implants such as 
cochlear implants, cardiac pacemakers or aneurysm clips 
 
4.3 Study Enrollment Procedures 
 
Identifying and recruiting candidates  
Candidates will be identified and recruited based on eligibility criteria.  Potential candidates will be identified by 
UNMH Urogynecology personnel. Subjects will be recruited using a variety of means including phone calls to 
potential participants and personal contact in clinic. Subjects must be willing and able to give informed consent 
themselves. 
   
Screening log  
A screening log of potential participants will be kept with the following information recorded:  date of screening, 
date of informed consent, whether or not subject was enrolled, participant identification number, reason for 
termination, and whether or not a study termination visit was conducted. 
 
Consent procedures 
Subjects will be recruited in a private setting (a patient consult or exam room) by a member of the research team. 
Subjects will be asked if they are interested in study participation in a private setting, and if they verbalize interest, 
they will be given a copy of the consent forms to read. The patient will be given ample time to consider 
participation.  They will have questions answered by study investigators and be given the opportunity to take the 
consent home and discuss the study with family and friends or to sign the consent at that time. If they choose to 
participate after taking the consent home, subjects will be offered arrangements for subjects to return to the 
study site and sign the consent in the presence of a study investigator, and they will sign the consent in a private 
setting (consult or exam room or office).  Subjects with UUI will be randomized to treatment with either: 1) 
Pharmacotherapy (a standard therapy for UUI) and conventional behavioral therapy or 2) Hypnotherapy and 
conventional behavioral therapy. Approximately 152 women will be randomized to hypnotherapy or to 
pharmacotherapy with approximately half in each group. Up to eighty UUI subjects willing and able to undergo 
fMRI (who meet inclusion & exclusion criteria) will also participate in the fMRI portion of the study. All subjects 
will give signed informed consent prior to study treatment. Approximately 30-35 normative control subjects will 
be recruited and consented in the same fashion as the UUI subjects but will only participate in the fMRI portion 
of the study as described previously. A total of up to approximately 200 subjects will be enrolled in the study.  
 
 
 
 
 


 
 
 
 
21 
 
 
5. Study Interventions 
 
5.1 Interventions, Administration and Duration 
UUI subjects will be randomized to hypnotherapy or pharmacotherapy. At their baseline study visit all subjects 
will receive information regarding standard behavioral therapy (see the “Lifestyle Modification, Behavioral 
Therapy and Physical Floor Therapy Handout”) 
 
Hypnotherapy: Hypnotherapy will be administered over 8 weeks in 8 sessions by certified, trained clinical 
hypnotherapists in their outpatient offices. The subjects will be informed that several or all sessions will be audio-
recorded and one or more sessions will be reviewed by study personnel to ensure that the hypnotherapist 
administers the hypnotherapy session in a standardized fashion. Recordings will be stored on the research 
computer and access to these recordings will be available to assigned research personnel only. All recordings 
will be stored for approximately 7 years, in the same fashion as other data, and then will be destroyed. The 
hypnotherapists have been instructed to not use the patients’ name or any other identifiers during the recorded 
session.  Sessions will last approximately 1 hour with a brief outline of these sessions as follows; Session #1: 
The hypnotherapist will explain hypnotherapeutic principles; subjects will inform the hypnotherapist regarding 
any phobias or fears (so that these triggers will be avoided). Subjects will undergo their 1st hypnotherapy session 
and hypnosis will then be terminated. Session #2: address emotions around OAB and life impact, visualize pelvic 
floor exercise mechanics, and undergo their 2nd hypnotherapy session followed by termination of hypnosis. 
Subjects may choose to either receive a CD or to download a digital recording (for use on a digital device) 
specially prepared for them to for home practice of hypnotherapy sessions. This will occur at either their 2nd or 
3rd hypnotherapy session; they will be instructed NOT to listen to the hypnotherapy CD/digital recording while 
driving and encouraged to listen to the CD/digital recording daily and record the home use of their CD/digital 
recording. Session #3,4,5,6,7; same as session 3. Session #8: same as previous sessions. In addition, the 
subjects will be counseled to expect occasional and temporary setbacks in their bladder symptoms and the 
hypnotherapist and subject will discuss how to cope with these setbacks. The details of these sessions are 
detailed in the “Hypnotherapy Session Guidelines” (see Attached MOP). Following the 8 weeks of therapy, 
subjects will be encouraged to continue to practice self-hypnosis and/or listen to their home practice CD/digital 
recording given to them and this practice will be tracked for the 1 year duration of the study. Hypnotherapy 
patients will also have the opportunity to have one additional hypnotherapy session prior to their 12-month follow-
up visit: arrangements for the session can be initiated at their 6-month follow-up visit. 
 
Potential adverse effects of hypnotherapy include: a) “False Memory Syndrome”: Although, in the 1980s ‘false 
memory syndrome’ was described with the use of hypnotherapy in child abuse survivors, the current practice of 
hypnotherapy uses a much different approach to this therapeutic application. Current practice includes open-
ended lines of questioning as opposed to suggestive or leading lines of questioning utilized in the 1980s with 
these victims. Transformation of hypnotherapy practices has greatly decreased occurrence of false memory 
syndrome, indeed calling into question its true existence. Recently, the hypermnesia attributed to the hypnotic 
state has been rejected based on more rigorous research.22 Last, the use of hypnotherapy in this study is for 
UUI treatment and recall of emotionally traumatic events will not be part of the protocol. Thus, serious risk to 
subjects undergoing hypnotherapy for UUI is negligible. b) Possibility that hypnotherapy is ineffective adjunctive 
treatment for urgency urinary incontinence & potential risks regarding home practice hypnotherapy CD/digital 
recording: Hypnotherapy subjects will be clearly instructed to use their home practice CD/digital recording only 
when and where they are can pay full attention to the CD/digital recording. Specifically they will be instructed 
NOT to drive and listen to the hypnotherapy home practice CD/digital recording. It is possible that hypnotherapy 
is ineffective in urgency urinary incontinence treatment. In this case, the subjects will have been inconvenienced 
because of the time devoted to the hypnotherapy sessions.  
 
Pharmacotherapy: Pharmacotherapy counseling sessions will be administered over 8 weeks in 8 sessions by 
trained personnel in private settings either at UNMH or UNM CTSC outpatient clinic rooms or administrative 
offices. The subjects will be informed that several or all sessions will be audio-recorded and one or more sessions 
will be reviewed by study personnel to ensure that the medication counselor administers the hypnotherapy 
session in a standardized fashion. Recordings will be stored on the research computer and access to these 
recordings will be available to assigned research personnel only. All recordings will be stored for approximately 
7 years, in the same fashion as other data, and then will be destroyed. The medication counselors have been 


 
 
 
 
22 
 
 
instructed to not use the patients’ name or any other identifiers during the recorded session.  Subjects will be 
scheduled for in person visits with the medication counselor who will review medications and their side effects. 
However, if subjects state these in person visits are overly burdensome, these visits may occur via phone as 
long as the patient comes in for at least 2 of the subsequent visits for pill dispensation which should occur midway 
and at the end of the 8 sessions. These sessions will take as long as required/desired for subjects to feel that 
they have received adequate instruction/counseling. Discussion of strategies to cope with their bladder 
symptoms will occur. The expected side effects of medications (such as dry mouth, constipation) will be 
discussed and strategies to cope with side effects will also occur.  It is expected that these sessions will take 
approximately 20-60 minutes, depending on the subjects’ needs. The medication may be modified if the patient 
complains of side-effects from the initial anti-cholinergic or perceives that her response in UUI treatment is 
inadequate; a different anti-cholinergic may be given to the patient if she requests a different UUI medication. 
The study will use either of two standard, long acting anti-cholinergic medications and dosages (Long acting 
Tolterodine 4mg/day or Extended Release Oxybutynin 10 mg/day or their equivalent generic substitutes). Initial 
medication use will usually be Oxybutynin 10 mg/day but will depend on the patient history (for example those 
who have used Oxybutynin unsuccessfully will be given Tolterodine and vice versa). A recent AHRQ meta-
analysis found that there was no difference in effectiveness or side-effects between the available anti-
cholinergics used to treat UUI as long as the medications were extended release formulations, such as those 
used in this study.38 The details of these sessions are in the “Pharmacotherapy Session Guidelines” (see 
Attached MOP). Following the 8 weeks of therapy as described previously, subjects will continue to take their 
anti-cholinergic medications and continued use of medication will be tracked for the 1 year duration of the study. 
 
Potential adverse effects of pharmacotherapy: Subjects randomized to pharmacotherapy will be instructed take 
a standard anticholinergic extended release dose (see above) for urgency incontinence. Subjects with major 
contraindications to anticholinergic medications will be excluded from study participation (see exclusion criteria). 
Serious adverse events related to anticholinergic medications are rare, however mild side-effects are relatively 
common; these include dry mouth, constipation, dyspepsia or mild nausea, dry eyes, and change in urination 
such as urinary hesitancy.38,54 Subjects in this proposal will be informed regarding potential side effects of 
medications, will keep medication logs and will regularly meet with a medication counselor to review these side 
effects. Minor side effects may include symptoms such as dry mouth, dry eyes or constipation. The original anti-
cholinergic may be changed to a different long acting anti-cholinergic for UUI if the patient finds the minor side 
effects to be bothersome and wishes to change medications. Serious medication related adverse events occur 
the medication will be discontinued (see protection against risks below). If subjects report urinary retention or 
other symptoms of concern to the medication counselor, subjects will be instructed to stop the medication. 
Simultaneously a clinic visit to the UNM Urogynecology Clinic will be arranged so that subjects may be 
appropriately evaluated. These measures will decrease the risk of harm from study participation. 
 
Functional MRI: The UUI subjects (approximately half from the hypnotherapy group and half from the 
pharmacotherapy group) willing to have an fMRI and without contraindications to fMRI will participate in the fMRI 
portion of the study and will undergo a baseline fMRI and a follow-up fMRI at the conclusion of their 8 weeks of 
treatment (as described above). Approximately 30-35 normative controls will also undergo one fMRI. All subjects 
will have urine dipstick testing and pregnancy testing (in women who are premenopausal and without a history 
of a hysterectomy or permanent sterilization) performed prior to fMRI: subjects who are pregnant or who have a 
urinary tract infection may not undergo fMRI testing. The fMRI protocol is below. In brief, FMRI subjects will have 
a bladder catheter placed and will be asked to a) concentrate on a picture placed before them while they have 
the MRI performed b) they will next have their bladders filled with sterile fluid and be asked to rate the degree of 
bladder discomfort or “urge to void” experienced during bladder filling c) they will then have the catheters 
removed, the amount of urine voided will be measured and subjects will be discharged to home and given 
instructions to contact the study personnel if questions or problems arise.  The time required for each fMRI 
session is approximately 1-2 hours.  
 
 
 
 
 
 


 
 
 
 
23 
 
 
FMRI PROTOCOL: 
FMRI Data Acquisition:  
High resolution T1 [TE (echo time) = 1.64 ms, TR (repetition time) = 2.53 s, 7° flip angle, number of excitations 
(NEX) = 1, slice thickness = 1 mm, FOV (field of view) = 256 mm, resolution = 256 x 256] anatomic images will 
be collected on a 3 Tesla Siemens Trio scanner at the beginning of each experiment. For each of the FMRI 
tasks, echo-planar images will be collected using a single-shot, gradient-echo Introduction: The fMRI portion of 
this study will be performed at the Mind Research Network (MRN). The study investigator at the MRN has 
extensive experience evaluating the role of the ACC and anterior insula in error monitoring, cognitive control and 
the perception of pain.  His team has investigated the role of the ACC and anterior insula in the subjective 
experience of pain. Specifically, participants were requested to continuously rate their subjective experience of 
pain on a Likert scale from 0-10, with the scale being updated at a 10 Hz frequency. Functional results indicated 
that this subjective regressor captured unique variance related to the experience of pain in the ACC and anterior 
insula compared to traditional modeling techniques.  
FMRI Subject and Task:  
Study participants will complete two tasks while undergoing FMRI. Presentation software will be programmed to 
control stimulus presentation, synchronize stimulus events with the scanner and collect response data for offline 
analyses. A non-ferrous key-press device will be positioned directly under the subject’s right hand to continuously 
(10 Hz sampling frequency) record current voiding urge levels on an 11-point Likert scale (0 = “no urge” to 10 = 
“worst urge imaginable”). To minimize neuronal activation associated with eye movements, subjects will be 
instructed to maintain visual fixation throughout all trials on the centrally presented cross. An eye-tracking device 
will be used to record saccades during the experiment.                       
Task A:  For this task, participants will be asked to continuously rate their urge levels to void while maintaining 
centrally presented cross. During this time, participants’ bladders will be filled following the methods described 
by Griffiths et al.35 A urethral catheter will be placed into the bladder for bladder filling/emptying.  A small volume 
of saline solution (usually 50-100 ml depending on individual subject’s urge sensations noted on cystometry) will 
be introduced into the empty bladder following which the solution will be repeatedly infused into and withdrawn 
from the bladder while functional brain imaging is performed. The infusion/withdrawal cycle will be performed, 
more liquid being infused than withdrawn. The bladder will then be filled further until the subject signals strong 
bladder sensation. The volume at which this sensation occurs will be recorded and beginning at this bladder 
volume infusion/withdrawal cycles will be repeated during fMRI scanning. Two to 4 blocks will be performed, 
depending on the level of subject discomfort.  
Task B: All participants will be asked to maintain fixation on a centrally presented cross. This data will be used 
in conjunction with the results from Task A to perform functional connectivity analyses. All participants will 
complete two FMRI runs of this task totaling 10 minutes of acquisition time. Both of these tasks will initially be 
performed by control subjects without symptoms of OAB as confirmed by the OAB-q questionnaire. Control 
subjects will be imaged to provide normative values for ACC, AI and OFC activation in our imaging facility and 
confirm that we are able to replicate the differences between control and UUI subjects demonstrated in prior 
work. The same tasks will be performed twice on UUI subjects entering the study. Subjects with UUI will undergo 
fMRI scanning during performance of both tasks before therapy and following therapy. Volumes of saline solution 
instilled in the second phase of Task A during the pre-therapy fMRI will be recorded. Identical volumes will be 
instilled during the post therapy scanning of subjects with UUI. For the fMRI tasks, echo-planar images will be 
collected using single-shot, gradient-echo planar pulse sequences. The first image of each run will be eliminated 
to account for T1 equilibrium effects in addition to the two dummy scans that are part of the Siemens sequence. 
FMRI Image Processing: The methods used to analyze FMRI data will be similar to those employed by our team 
in previous studies. Specifically, the current analyses will closely parallel a recent experiment that was conducted 
by the research team in which subjective ratings of pain were recorded. In that study data were generated in a 
task which required participants to subjectively rate their pain to a cold pressor stimulus. We modeled the 
regressors corresponding to the application of the stimulus (cold temps) as well as the individual subject's pain 
ratings separately. Preprocessing steps of fMRI data obtained during both tasks will include slice correction, 
temporal auto-correlations correction and motion correction. For task A, a voxel-wise multiple regression analysis 
will be used to estimate the beta weights corresponding to the functional activation resulting from each of the 
separate conditions. The multiple regression will contain one individually tailored demeaned regressor 
corresponding to each individual subject’s urge to void (urge regressor). The urge regressor will resemble a step 
function, with each button press signaling the onset of either increasing or decreasing subjective levels of urge 
to void. The resulting step functions will then be convolved with a gamma variate function derived from known 


 
 
 
 
24 
 
 
parameters of the hemodynamic response. In addition, a regressor corresponding to the inflation and the 
deflation of the bladder will be created by convolving the experimental time-course with a gamma variate function 
 
Potential adverse effects of fMRI and bladder catheterization: a) fMRI: These risks are small as MRIs are 
commonly performed clinical procedures without significant risk and without radiation exposure. Subjects will be 
screened to rule out the presence of metallic objects prior to the MRI scan as an MRI machine is essentially a 
large magnet capable of moving iron containing objects. Absolute caution will be implemented to ensure that 
only non-ferrous objects are present during all of the MRI sessions. Participants will be asked to change into 
hospital scrubs prior to being placed in the scanner to ensure that they do not introduce any metallic objects into 
the imaging environment. Participants will also be screened for the presence of a pacemaker or any other metallic 
objects in their body, such as an aneurysm clip, ear implant, or nerve stimulator. Participants with these or other 
metallic devices will not be allowed to participate in the study. As the effects of MR on pregnancy have not been 
fully studied, subjects are pregnant will be excluded from the study. The MRI may also cause claustrophobia and 
anxiety from loud noises made by the machine. A two-way intercom system and a video monitoring system will 
provide continual monitoring of the subject’s condition. If discomfort or concern is expressed or detected, the 
experiment will be stopped and the subject will be given the option to discontinue at any time. Ambient scanner 
noise will be below current recommended guidelines.  
b) Bladder catheterization: In addition to bladder catheter placement for cystometric evaluation those subjects 
who participate in the fMRI portion of the study will also be catheterized at the time of fMRI in order to fill the 
bladder (see fMRI above).The risks of bladder catheterization, although unlikely, include dysuria, hematuria and 
urinary tract infection.  A meta-analysis concluded that prophylactic antibiotics for complex bladder testing 
decreased significant bactiuria with few side-effects, with a reported range of bactiuria of 1-8% in the groups 
treated with antibiotic prophylaxis.46 To decrease infection risks of bladder catheterization during this study, 
prophylactic antibiotics will be given to all subjects prior to and for the day of catheterization. Nitrofurantoin or 
Trimethoprim/Sulfamethoxazole will be administered prior to and for the day of catheterization. Subjects allergic 
to these medications will be given appropriate alternate antibiotic prophylaxis. Prior to the procedure, the patient 
will be informed regarding the procedure protocol and potential discomforts and side-effects.  Participants will 
be clearly informed of their right to withdraw from the study at any time. Catheterization will be performed using 
sterile technique by nursing staff whose standard practice is to perform this procedure. Additionally, subjects will 
have urine dipsticks checked at study entry and prior to bladder catheterization to ensure absence of urinary 
tract infections. Subjects noting persistent urinary tract infection symptoms following the tasks will have urine 
dipstick testing and a urine culture performed. Subjects with evidence of a urinary tract infection will be treated 
and urinary infection occurrence will be tracked.  
 
5.2 Handling of Study Interventions 
 
This study involves the use of long-acting Oxybutynin (Ditropan XR 10 mg) and long acting Tolterodine (Detrol 
LA 4 mg), or their equivalent generic substitutions, as pharmacologic therapy for urgency urinary incontinence.  
These medications will be ordered in bulk by the research pharmacist and stored with the research pharmacy.  
The medications will be signed out from the research pharmacist to the research coordinator for the study 
participant.  The Investigators will request that subjects to return unused medications to the research coordinator 
who will in turn return the unused medications to the pharmacy.  A research pharmacy accounting log tracks 
medications issued to subjects and records information including date, dose number, amount received, patient 
ID, initials of recorder, and initials of person dispensing drug as well as medications returned. Please refer to the 
MOP Chapter—Pharmacotherapy Handling Chapter and Accountability Log. 
 
For behavioral interventions, pharmacotherapy counseling and hypnotherapy interventions, please refer to 
previous section 5.1. None of these interventions will be masked. 
 
 
 
 
 
 
 


 
 
 
 
25 
 
 
5.3 Concomitant Interventions 
 
5.3.1 Allowed Interventions   
 
Behavioral Interventions and Pelvic Floor Exercise (see 5.1) 
 
IF subjects are already engaging in the following activities, they will be allowed. Subjects will be requested 
to inform the study coordinator if they initiate these activities during the12 months that they participate in 
the study.  
o Meditation 
o Yoga 
o Acupuncture for non-UUI indications 
o Tai Chi 
 
 
5.3.2 Required Interventions 
 
Hypnotherapy (if randomized to hypnotherapy group) 
 
Medication Counseling and Ditropan XR or Detrol LA or their generic substitutions (if randomized to 
pharmacotherapy group) 
 
5.3.3 Prohibited Interventions 
 
No other anticholinergic medications (such as Toviaz®/Fesoterodine or Sanctura®/Trospium or 
Vesicare®/Solifenacin or Enablex®/Darifenacin) or beta 3 agonists (such as Myrbetriq®/Mirabegron)  
for UUI should be taken by research subjects for the year they participate in the study  
 
Sacral Neuromodulation for UUI treatment (neuromodulators programmed for other indications are 
allowed) 
 
Onabotulinum toxin (“Botox”) injected intravesically for UUI treatment in the last 12 months 
 
Acupuncture specifically administered to treat UUI 
 
Herbal remedies specifically designed to treat UUI 
 
5.4 Adherence Assessment 
Non-adherence/Non-Compliance to treatment or use of off-protocol therapies will be defined as follows— 
 
Non-adherence/Non-Compliance to treatment protocol at 2 month follow-up of the study: 
Definition Non-adherence/Non-Compliance: 
 
 Medication group: Subjects state ‘no’ on the Pharmacotherapy Compliance form (question 
#1) that they are no longer taking their medications at 2 month follow-up 
 
Hypnotherapy group: Attendance of < 60% of hypnotherapy appointments  
 
Measures of adherence and compliance and steps taken to improve non-adherence during 1st 12 weeks of the 
study: Data on adherence to the treatment protocol will be collected weekly during the treatment phase of the 
study by research staff and reviewed monthly by the PI. Pharmacotherapy adherence/compliance will be tracked 
with the compliance questionnaires at 2, 6 and 12 months. Hypnotherapy adherence/compliance will be tracked 
by hypnotherapy session compliance and with compliance questionnaires at 2, 6, and 12 months. Off-protocol 
treatments used will also be tracked based on the compliance questionnaires administered at 2, 6 and 12 
months.  Data on adherence will be reviewed at each of the DSMB meetings (described subsequently). Available 
data on the use of anti-cholinergics for urgency urinary incontinence suggests an overall non-compliance or 
withdrawal rate of 30% in randomized controlled trials.54 In clinical practice discontinuation rates have been 
reported to be even higher with continuation rates less 45% at 1 month and 13% at 1 year.21 If average adherence 
falls below the suggested rate of 60%, a conference call will occur for study investigators to discuss methods for 
improving adherence without affecting the integrity of the study. However, given the data regarding anti-
cholinergic side effects, it is quite possible that this non-adherence rate is not changeable. Protocol adherence 
in subjects randomized to hypnotherapy will be measured by monitoring compliance in keeping hypnotherapy 


 
 
 
 
26 
 
 
appointments. If adherence of hypnotherapy subjects falls below a suggested rate of less than 60%, a conference 
call for study personnel to discuss methods for improving treatment adherence will occur.   
 
Non-adherence/Non-Compliance or use of off-protocol therapies at 6, 12 month follow-up visits 
Definition of Non-adherence/Non-Compliance at 6 & 12 month follow-up:  
 
Medication group: Subjects state ‘no’ on the Pharmacotherapy Compliance form (question #1) that they 
are no longer taking their medications at 6 or 12 month follow-up 
 
Hypnotherapy group: Subjects who state ‘no’ on the Hypnotherapy Compliance form (question #1) that 
they are not  listening to their hypnotherapy CD/digital recording or practicing self-hypnosis at 6 or 12 
month follow-up  
 
Definition of use of off-protocol treatments 
 
Subjects use other treatments for UUI such as sacral neuromodulation, intravesical botox in the last 12 
months or other UUI medications (such as Toviaz®/Fesoterodine or Sanctura®/Trospium or 
Vesicare®/Solifenacin or Enablex®/Darifenacin or Myrbetriq®/Mirabegron) 
 
Subjects use acupuncture to specifically to treat UUI  
 
Subjects use herbal remedies specifically to treat UUI 
 
For Analysis of non-compliance or use of off-protocol treatments: See Section 9.5.Subjects who are non-
compliant or use off-protocol therapies will still be analyzed in their assigned treatment groups in the ITT 
analysis. When subjects implement off-protocol therapies, we will examine the sensitivity of the per protocol 
analyses in two ways.  First, we will modify the models to incorporate a time-varying treatment parameter that 
can be used to examine the effect of received treatment. Second, we will censor all measurements after they 
receive alternative treatment, and then impute all censored measurements based on information collected from 
those who do not switch. Non-Compliance will be analyzed in the per-protocol analysis first as a categorical 
variable (yes/no) in its relationship to the outcome(s) and will then be evaluated as continuous variables (i.e. nu 
times self-hypnosis practiced or CD/digital recording used) and its relationship to the outcome(s). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
27 
 
 
6. Study Procedures: 6.1 Schedule of Evaluations—Table 1. 
 
 
 
Assessment & 
Evaluation 
Tools 
Screening 
Visit  
Day 
  
Enroll 
V 1 
Day 
-60 --1 
Cystom. 
V2 
Day  
-60- -1 
fMRI 
V3 
Day  
-60--1 
Randomize 
Treatment 
 
Day 0 
Treat1 
V3orV4 
 
Week 1 
Treat2 
V4orV5 
 
Week2  
Treat3 
V5orV6 
 
Week 3 
Inclusion/ 
Exclusion 
x 
x 
 
 
 
 
 
 
Informed 
Consent 
 
x 
 
 
 
 
 
 
Eligibility 
Form/ OAB 
Awareness  
Tool 
x 
x 
 
 
 
 
 
 
Eligibility Form fMRI 
x 
x 
 
x 
 
 
 
 
Demographic 
 & Medical Hx 
Forms & POP-Q  (if 
without in last yr) 
 
x 
 
 
 
 
 
 
Voiding  
Diary 
 
x 
 
 
 
 
 
 
OABq-SF,ISI, PPBC, 
PISQ-12,CRADI-8, 
IBS module, BPIC 
+VAS 
 
x 
 
 
 
 
 
 
Expectation 
Question-baseline 
 
 
 
 
x 
 
 
 
Expectation 
Question- 
Follow-up 
 
 
 
 
 
 
 
 
Stanford  
Susceptibility 
Test (choices of 
times=x) 
 
x 
x 
x 
 
 
 
 
Pregnancy Test 
 
 
x 
x 
 
 
 
 
Urine Dipstick 
 
 
x 
x 
 
 
 
 
Cystometry  
procedure  
Checklist & 
Cystometry Data 
Form 
 
 
x 
 
 
 
 
 
fMRI procedure 
Checklist 
 
 
 
x 
 
 
 
 
fMRI Task 
sheet and urine and 
vaginal swab sample 
collected and stored 
for possible future 
analysis. 
 
 
x 
x 
 
 
 
 
Incontinence Log & 
Med or Hypnotx CD 
logs 
 
 
 
 
 
x 
x 
x 
Adverse Events 
 
 
x 
x 
 
x 
x 
x 


 
 
 
 
28 
 
 
 
Assessment & 
Evaluation 
Tools 
Treat4 
V6orV7 
 
Week 4 
Treat5 
V7orV8 
 
Week 5 
Treat6 
V8orV9 
 
Week  
6 
Treat7 
V9or 
V10 
Week  
7 
Treat8 
V10or 
V11 
Week  
8 
fMRI 
V12 
 
Week 
 9 
Followup 
End Tx 
V11or13 
Week 8-10 
Followup 
6 mo 
 
Mo 6 
Followup 
12 mo 
 
Mo 12 
Voiding  
Diary 
 
 
 
 
 
 
x 
x 
x 
OABq-SF, 
ISI,PPBC, PISQ-
12, IBS module, 
CRADI-8,BPIC  
 
 
 
 
 
 
x 
x 
x 
Expectation 
Question-
baseline 
 
 
 
 
 
 
 
 
 
Expectation 
Question- 
Follow-up 
 
 
 
 
 
 
x 
x 
x 
Urine and 
vaginal swab 
sample 
collected and 
stored for 
possible future 
analysis 
 
 
 
 
 
 
x 
 
 
Incontinence 
Log & Med or 
Hypnotx CD 
logs 
x 
x 
x 
x 
x 
 
 
 
 
Medication or 
Hypnotx 
Compliance 
Questionnaire 
 
 
 
 
 
 
x 
x 
x 
Adverse Events 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Pregnancy Test 
 
 
 
 
 
x 
 
 
 
Urine Dipstick 
 
 
 
 
 
x 
 
 
 
fMRI 
procedure 
Checklist 
 
 
 
 
 
x 
 
 
 
fMRI Task 
sheet filled and 
urine and 
vaginal swab 
sample 
collected and 
stored for 
possible future 
analysis. 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
29 
 
 
6.2 Description of Evaluations 
6.2.1 Screening Evaluation 
Screening visit – Potential participants will be screened by the coordinator/Study personnel before enrollment 
to determine eligibility for the RCT portion of the study based on inclusion/exclusion criteria. Subjects will also 
be screened for fMRI eligibility; however if the subject is ineligible for the fMRI, they may still participate in the 
RCT portion of the study. In general, the consent will be obtained within 4-6 weeks of the screening visit but 
subjects will be given all the time necessary to decide whether or not they want to participate in the study.  
 
Subjects in the UNMH Urogynecology clinics with UUI who qualify for study entry will be asked whether they are 
interested in study participation. These subjects will be assured that declining study participation will not affect 
their clinical care. In addition, women with UUI who contact the UNMH Ob-Gyn research division expressing 
interest in study participation will have the study explained to them and follow the same procedures as UNMH 
subjects (see following). Potential subjects will be given a copy of the study consent for their review. Those who 
are interested will be administered the OAB Awareness tool, a validated measure which screens for presence of 
OAB, to screen whether or not they are candidates for the study. They will also be instructed how to keep a 
voiding diary, if this has not already been done, as it is the standard of clinical care for all subjects with UUI. If 
they ultimately choose to participate in the study, they will be asked to bring the diary with them for Visit 1 (below). 
The patient will be given the option to schedule Study Visit 1 or given the option to contact the study coordinator 
to schedule Study Visit 1 at a later date if they are uncertain regarding study participation. 
 
6.2.2 Enrollment, Baseline Visit/Evaluation and Randomization 
Enrollment/Consent & Baseline Visit for women in RCT (Day -60 to -1):  
Informed Consent Process: Written informed consent will be obtained from each subject at study entry. And will 
be obtained by the following process: 
1) Subjects will be asked if they are interested in study participation in a private setting, and if they verbalize 
interest, a copy of the consent forms will be explained and given to them to review so that they may 
discuss the study with family and friends.  
2) The PI or Co-Is will meet with subjects to review the consent form and confirm the subject’s understanding 
of the study and to answer their questions. Subjects will answer screening questions to ensure they are 
appropriate candidates for the study.  
3) If subjects state that they are interested in study participation after explanation of the study as noted 
previously, an appointment will be made for subjects to return to sign the consent and fill out the baseline 
information and questionnaires.  
4) If they state that they are not certain, they will be given the study coordinator’s contact information so that 
they can call study personnel if they decide to participate in the study; a study appointment will be made 
for subjects to return to sign the consent after they contact study personnel.  
5) At the enrollment appointment, which occurs in a private setting, subjects sign the consent after study 
personnel are certain that subjects have had appropriate counseling and understanding regarding the 
study and that the study and consent have been explained to them in a fashion congruent with their 
medical literacy. Consent will be obtained after screening is performed and will be re-reviewed in the 
future in the event changes are required. In general, consent will be obtained at the baseline visit. The 
PI or Co-Is, Study Coordinator(s) or Study Nurse(s) will obtain verbal and written informed consent on 
one IRB approved consent after explaining study and before collecting any data. Human subject’s 
protection will follow local and national regulations at all times. 
 
Baseline assessments include: 
 
Questionnaires – OABq-SF, ISI, PPBC, PISQ-12, CRADI-8, IBS Module, IC & VAS pain 
questionnaire 
 
Voiding Diary 
 
Demographics form 
 
Medical history form 
 
POP-Q examination if one has not been performed during their routine clinical examination 


 
 
 
 
30 
 
 
within the last year (Pelvic Organ Prolapse Quantitation Exam, a validated examination 
recommended by the International Continence Society to standardize quantitation of 
patients’ prolapse) 
 
Arrangements will be made for cystometric testing, Stanford hypnotic susceptibility testing, and fMRI testing (if 
the subject is willing and without contraindications to fMRI). The expectation question will also be explained to 
subjects but will not be formally administered until the subject has been randomized to treatment. Adverse events 
will be tracked and followed up appropriately as noted in the DSMP. Subjects willing to participate in the fMRI 
study will be screened regarding whether or not they meet criteria for entry into the fMRI study. Subjects who 
meet criteria and who are willing to participate in the fMRI portion of the study will be scheduled for their fMRI or 
arrangements will be made to contact the subject to inform them of the date/time of their fMRI. The subjects will 
be randomized within a month of obtaining the consent. 
 
Enrollment/Consent & Baseline Visit for Normative Controls ONLY participating in fMRI study (Day 0): In 
addition to the UUI study subjects described previously, a group of women without UUI and without OAB 
symptoms (also determined by the OAB Awareness Tool screening questionnaire) will be enrolled. This 
normative group (approximately 30-35 subjects) will keep voiding diaries, answer questionnaires, and undergo 
urine pregnancy and dipstick testing and cystometric testing followed by performance of an fMRI in order to 
compare baseline fMRIs in women with and without UUI. The consenting process will be the same as described 
for the UUI subjects.  For this group of women, cystometrics may be performed the same day they are enrolled 
and fMRI will be scheduled for the following week (if this is not possible, the fMRI should be scheduled within 2 
weeks). The procedures will be performed as outlined previously and subsequently in 6.4.3 and 6.4.4.  
 
Baseline Cystometrics 
Cystometrics (Day -60 to -1) Cystometric testing (a bladder filling test during which patient sensations are 
recorded at various volumes and evidence of stress or urgency incontinence recorded) will be performed. Testing 
includes a urine pregnancy test and urine dipstick. See MOP Chapter “Study Procedures” regarding forms to be 
filled. If subject chooses to undergo an fMRI, they will have simulation of their fMRI task performed and may 
have urine and vaginal swab samples collected and stored for possible future analysis (For example, urine may 
be analyzed for biomarkers and microbiome analysis. See MOP Chapter “Study Procedures” regarding forms to 
be filled as noted in Section 5.1. 
Baseline FMRI 
FMRI (Day -60 to -1 for baseline and week 9 for follow-up) will be performed on women willing and able to 
have fMRI at baseline and follow-up. Testing includes a urine pregnancy test and urine dipstick. Forms to be 
completed include the fMRI procedure are noted in the “Study Procedures” MOP and has been described in the 
Protocol Section 5.1. 
 Other Baseline Tests/Questionnaires 
Stanford Hypnotic Susceptibility Testing (Day -60 to week 1) this validated test may be administered by the 
hypnotherapist any time before the subject receives either their pharmacotherapy or hypnotherapy intervention. 
Its administration depends primarily on scheduling issues between the subject and hypnotherapist; attempts will 
be made to couple this testing with any of the subjects’ pre-treatment visits (enrollment, cystometrics, fMRI) 
though the subject may have to come for a separate visit if this is not possible. 
Patient Expectation Question (Day 0 and prior to treatment) the subject will be administered this question 
after randomization and prior to treatment. The question will be explained to the patient at enrollment, but will 
not be administered until the patient is notified regarding her group assignment by the Research Coordinator or 
her designee. 
 
 
 
 


 
 
 
 
31 
 
 
 
Randomization  
Randomization to Treatment (Day 0) Subjects will be informed of their randomization to treatment by the 
Research Coordinator (or her designee if she is absent). Please refer to Statistics Section 9.  Randomization will 
occur within 2-months of Enrollment. Treatment visits will be initiated within one month following randomization 
with a goal of initiating treatment within 1 week. However, subjects will be given the necessary time to prepare 
for their upcoming weekly treatment sessions. 
6.2.3 Blinding 
This study is a single blinded trial. Every effort will be made to maintain masking until the study’s completion of 
treatment of the 152 subjects in the RCT. Investigators involved in analyzing fMRIs, Co-Is, other than Dr. Sapien, 
participating in the RCT, study personnel performing data entry and the study statistician will be blinded to 
knowledge of subjects’ treatment groups. Investigator blinding will only be breached if a subject suffers an 
unexpected clinical event and investigator knowledge of the subject’s treatment is essential to providing standard 
of care. Subjects cannot be blinded to treatment interventions as it will be obvious to them whether or not they 
are undergoing hypnotherapy or taking medications. 
6.2.4 Treatment Visits 
Treatment Visits (weeks 1-8) Depending on randomization, participants will either undergo medication 
counseling sessions or hypnotherapy sessions. These visits are expected to be initiated within one month 
following randomization with the goal of initiating treatment within 1 week of randomization. However, subjects 
will be given the necessary time to prepare for their upcoming weekly treatment sessions. These visits are 
expected to be completed within 8 weeks of initiation of the first treatment.  
 
The number of sessions attended by subjects will be recorded. The Medication side effects/incontinence log and 
the Hypnotherapy CD-digital recording use/incontinence logs will be collected at the visits. Please refer to section 
5 for details.  
 
6.2.5 Follow-up Assessments 
All subjects will have follow-up assessments irrespective whether they discontinue study interventions or are 
non-compliant with interventions or use off-protocol treatments.  
 
Follow-up Assessment at End of Treatment (weeks 8-10 depending on whether subject had fMRI): A 
subject visit will be arranged by study personnel for the post-treatment (end of counseling/hypnotherapy session) 
assessments which should occur within 2 weeks of finishing the treatment sessions for those subjects not 
undergoing fMRI or within 3 weeks of finishing treatment for those who will also undergo a follow-up fMRI. 
Subjects may have urine and vaginal swab samples collected and stored for possible future analysis (For 
example, urine may be analyzed for biomarkers). 
The assessments and visit will include 
 
Questionnaires; OABq-SF, ISI, PPBC, PISQ-12, CRADI-8, IBS Module, and IC questionnaire. Follow-up 
Expectation Question and Compliance Questionnaire 
 
Voiding Diary 
 
Subject feedback regarding study participation 
 
Confirm subject contact information (patient email address, mailing address, cell and landline phone 
numbers, name/address/phone number of friend or relative in event of difficulty contacting patient) 
 
Confirm arrangements for patient incentive payments and for follow-up in 6 months  
 
6 month Follow-up (month 6) the Study Coordinator or her designee will arrange 6 month follow-up assessment 
visits for subjects. Although it is preferable to have an in-person visit, it is possible to have the visit performed 
via phone and mail. Patient reimbursements will be paid at the in-person visit. If the subject has a phone/mail 
visit arrangements for reimbursement will be made following completion of this visit. The follow-up assessment 
should be completed within 5-7 months of completion of hypnotherapy or pharmacotherapy sessions.  
Final assessments & follow-up include 


 
 
 
 
32 
 
 
 
Questionnaires; OABq-SF, ISI, PPBC, PISQ-12, CRADI-8, IBS Module and IC questionnaire. Follow-up 
Expectation Question and Compliance Questionnaire 
 
Voiding Diary 
 
Subject feedback regarding study participation 
 
Confirm subject contact information (patient email address, mailing address, cell and landline phone 
numbers, name/address/phone number of friend or relative in event of difficulty contacting patient) 
 
Confirm arrangements for patient reimbursement and for follow-up at 12 months 
 
6.2.6 Completion/Final Evaluation 
12 month Follow-up (month 12) The Study Coordinator or her designee will arrange 12 month follow-up 
assessment visits for subjects. Although it is preferable to have an in-person visit, it is possible to have the visit 
performed via phone and mail. Patient reimbursements will be paid at the in-person visit. If the subject has a 
phone/mail visit arrangements for reimbursement will be made following completion of this visit. The follow-up 
assessment should be completed within 10-14 months of completion of hypnotherapy or pharmacotherapy 
sessions. These same evaluations will be needed for subjects who discontinue study interventions early. 
Potential reasons for early termination include events which results in distress to the subjects as a result of study 
participation (See Chapter 7 Safety and Chapter 8 Intervention Discontinuation) and follow-up for all subjects 
who discontinue interventions but are willing to continue to participate in the study will be the same as though 
who continue the interventions (12 months). 
Final assessments & follow-up include 
 
Questionnaires; OABq-SF, ISI, PPBC, PISQ-12, CRADI-8, IBS Module and IC questionnaire. Follow-up 
Expectation Question and Compliance Questionnaire 
 
Voiding Diary 
 
Subject feedback regarding study participation 
 
Thank subjects for study participation 
 
7. Safety Assessments 
Potential complications of the study interventions will be tracked (as described subsequently) and include the 
following; 
 
Hypnotherapy 
 
Severe emotional upset  
 
CD/digital recording use while performing activities requiring intense concentration (driving) 
‘False Memory Syndrome’ and severe emotional upset--- Relevant background, management and modification 
of intervention or participant assessments: Although, in the 1980s ‘false memory syndrome’ was described with 
the use of hypnotherapy in child abuse survivors, the current practice of hypnotherapy uses a much different 
approach to this therapeutic application. Current practice includes open-ended lines of questioning as opposed 
to suggestive or leading lines of questioning utilized in the 1980s with these victims. Transformation of 
hypnotherapy practices has greatly decreased occurrence of false memory syndrome. Recently, the 
hypermnesia attributed to the hypnotic state has been rejected based on more rigorous research.22 Last, the 
use of hypnotherapy in this study is for UUI treatment and recall of emotionally traumatic events will not be part 
of the hypnotherapy protocol. Thus, serious risk to subjects undergoing hypnotherapy for UUI is negligible. If a 
subject reports severe emotional upset attributed to the sessions, her sessions will be terminated. In the 
unlikely event that >33% of study subjects report that they experience serious emotional upset from study 
participation the study will be suspended and a review will occur. If these events are found to be attributable to 
hypnotherapy, the study will continue to be suspended until the hypnotherapy protocol is re-evaluated and 
revised (see below). Serious emotional upset includes inability to work or events that would necessitate 
evaluation by a physician or care provider. It is highly unlikely that hypnotherapy would unmask or de-repress 
significant emotional upset (e.g. hysteria, uncontrollable anger or hostility) in subjects. The potential for this 
occurring will be minimized by excluding subjects with a history of schizophrenia or untreated bipolar disorder 
and by having the hypnotherapist guide the sessions and terminate sessions if subjects are beginning to show 
signs of undue duress during hypnotherapy. Although other hypnotherapy studies have not reported significant 


 
 
 
 
33 
 
 
emotional upset as a complication, we believe that it is prudent to prepare for this unlikely possibility. A report 
of a subject experiencing serious emotional upset from study participation will result in a meeting of the PIs and 
review of the issues surrounding its occurrence. The PIs and Study Coordinator will generate a report, assess 
whether it was preventable, and develop an action plan to prevent recurrence including protocol revision and 
this report will be given the DSMB.  While this occurrence is very unlikely, we recognize that sporadic 
occurrence of emotional upset is possible in any setting. In the very unlikely event that a third of subjects 
complain of significant emotional upset, the study should be halted until the circumstances surrounding its 
occurrence are investigated in depth.  
 
Use of CD/digital recording while performing activities requiring intense concentration (driving)--Management 
and modification of intervention or participant assessments: Hypnotherapy subjects will be clearly instructed to 
ONLY use their hypnotherapy home practice CD/digital recording when and where they are can pay full attention 
to the recording. They will clearly be instructed NOT to listen to the hypnotherapy CD/digital recording during 
activities which require their full attention; specifically the will be instructed NOT to drive and listen to the home 
hypnotherapy practice CD/digital recording. If it is found that subjects listen to the CD/digital recording while they 
are driving, the PIs and Study Coordinator will generate a report and develop an action plan including protocol 
revision which will be given to the DSMB. 
 
Pharmacotherapy:  
 
Constipation 
 
Dry Eyes 
 
Dry mouth 
 
Dyspepsia or Nausea 
 
Urinary Hesitancy or Retention 
Relevant background, management and modification of intervention or participant assessment for the above: 
Serious adverse events related to anticholinergic medications are rare, however mild side-effects are relatively 
common; these include dry mouth, constipation, dyspepsia or mild nausea, dry eyes, and change in urination 
such as urinary hesitancy, as reported in an AHRQ and Cochrane meta-analysis.38,54 Subjects in this proposal 
will be informed regarding potential side effects of medications, will keep medication logs and will regularly meet 
with a medication counselor to review these side effects. If symptoms such as dry mouth, dry eyes, dyspepsia 
or constipation occur, if the patient finds the minor side effects to be bothersome and wishes to change 
medications the original anti-cholinergic may be changed to the alternate long acting anti-cholinergic. If there is 
a greater degree of symptom severity (e.g. obstipation, nausea and vomiting, urinary retention) the medication 
will be discontinued. A clinic visit to the UNM Urogynecology Clinic will be arranged so that the subjects may be 
appropriately evaluated. If subjects report symptoms of concern to the medication counselor or other study 
personnel, subjects will be instructed to stop the medication and a clinic visit to the UNM Urogynecology Clinic 
will be arranged so that subjects may be appropriately evaluated. These measures will decrease the risk of harm 
from study participation. It is unlikely that these FDA approved, routinely prescribed medications will result in 
serious harm, but if significant events are reported, subjects will be evaluated and the PIs and Study Coordinator 
will generate a report and which will be distributed to the DSMB, HRPO (if meets HRPO reporting guidelines see 
7.4) and NCCAM consistent with NCCAM policies (see 7.4). If the events are attributable to the medications, an 
action plan will be developed which may include protocol modification. 
 
Bladder Catheterization 
 
Dysuria 
 
Hematuria 
 
Urinary Tract Infection 
Relevant background, management and modification of intervention or participant assessment for the above: 
Subjects will have bladder catheters placed for their cystometric evaluation and those who participate in the fMRI 
portion of the study will also be catheterized to undergo bladder filling for the fMRI task. Cystometric evaluation 
is considered a routine standard of care procedure for women with urgency urinary incontinence. The risks of 
bladder catheterization, although unlikely, include dysuria, hematuria and urinary tract infection.  A recent meta-
analysis concluded that prophylactic antibiotics for complex bladder testing decreased significant bactiuria with 
few side-effects, with a reported range of bactiuria of 1-8% in the groups treated with antibiotic prophylaxis.46To 


 
 
 
 
34 
 
 
decrease infection risks of bladder catheterization during this study, prophylactic antibiotics will be given to all 
subjects prior to and the day of catheterization. Nitrofurantoin or Trimethoprim/Sulfamethoxazole will be 
administered prior to and the day of catheterization. Subjects allergic to these medications will be given 
appropriate alternate antibiotic prophylaxis. Prior to the procedure, the patient will be informed regarding the 
procedure protocol and potential discomforts and side-effects.  Participants will be clearly informed of their right 
to withdraw from the study at any time. Catheterization will be performed using sterile technique by nursing staff 
whose standard practice is to perform this procedure. Additionally, subjects will have urine dipsticks checked at 
study entry and prior to bladder catheterization to ensure absence of urinary tract infections. Subjects noting 
persistent urinary tract infection symptoms following the tasks will have urine dipstick testing and a urine culture 
performed. Subjects with evidence of a urinary tract infection will be treated. UTI, hematuria and dysuria 
occurrence will be tracked and AEs reported to the DSMB. If these events occur in 10% or more subjects, the 
protocol will be reviewed and revised.  
 
FMRI 
 
Claustrophobia and Anxiety 
 
Dysuria, Hematuria and Urinary Tract Infection due to catheterization 
 
Unexpected Abnormality on MRI 
Relevant background, management and modification of intervention or participant assessment for the above: 
These risks are small as MRIs are commonly performed clinical procedures without significant risk and without 
radiation exposure. To avoid the claustrophobia and anxiety which may occur with fMRI performance, subjects 
will be screened to rule out a history of claustrophobia prior to the MRI. Since the MRI may cause claustrophobia 
and anxiety from loud noises made by the machine (despite the fact that the MRN ambient scanner noise is 
below the current recommended guidelines), a two-way intercom system and a video monitoring system will 
provide continual monitoring of the subject’s condition. If discomfort or concern is expressed or detected, the 
experiment will be stopped and the subject will be given the option to discontinue at any time. This event will be 
recorded. Please refer to evaluation and approach to events which may be associated with bladder 
catheterization described above. If an unexpected significant brain abnormality is found on fMRI the subject will 
be referred to her primary physician or other appropriate physician to evaluate the abnormality/finding.  
 
Any of the following 
 
Possible breach of confidentiality, stress, emotional distress and inconvenience:  
 
Relevant background, management and modification of intervention or participant assessment for the above: 
These risks are possible with participation in any research study and will be minimized. In the unlikely 
circumstance that confidentiality is breeched potential embarrassment associated with the diagnosis of urgency 
urinary incontinence may occur. This risk will be minimized by assigning a study number to each participant upon 
entry into the study and with the other measures described previously under Section III: Confidentiality in the 
DSMP. The stress, emotional distress and inconvenience will be minimized by recruiting, enrolling, evaluating 
and treating subjects in a private setting (private clinic exam rooms and private consultative, administrative, 
research and practitioners offices). The patient will reassured that declining study participation will have no effect 
on their current or future clinical care. HIPAA consent will be signed in accordance with the UNMH HRPO (IRB) 
and the patient informed of the protections that HIPAA guarantees to the privacy of their health information. To 
further ensure the security of personal health information all data will be de-identified as described above. The 
database will be password protected and accessible only to research personnel.   Only coded information will 
be entered into the database. All paper-based study subject folders will be kept in a locked cabinet in the 
Urogynecology research division administrative area. Therapies will be administered in a one on one setting. 
Appointments for therapy will be scheduled with efforts made to minimize inconvenience to the subject while 
maintaining study fidelity and completing counseling therapies within a two month window. 
 
7.1 Specification of Safety Parameters 
Events will be captured by research staff as described in the DSMB with particular attention to the following 
noted in the Frequency of Specific Events Table and are also explained in Section 7.4 and include; 
1) potential breach of confidentiality 2) lack of adherence to functional MRI screening for metallic objects near 
MRI scanner or potential lack of adherence to pregnancy and UTI screening 3) request for MRI termination due 
to anxiety, claustrophobia while in the scanner 4) symptoms of dysuria, hematuria or urinary tract infections 


 
 
 
 
35 
 
 
associated with bladder catheterization 5) potential symptoms related to anticholinergic use such as severe 
nausea/vomiting or constipation, or inability to void 6) potential symptoms related to hypnotherapy sessions such 
severe emotional upset which interferes with subject functioning 7) failure of subjects to comply with 
hypnotherapy CD/audio-recording  instructions regarding prohibition of driving while listening to the recordings 
 
7.2 Methods and Timing for Assessing, Recording, and Analyzing Safety Parameters 
See section 7.0 above. As noted previously, the Frequency of Specific Events Table will be used to record the 
more significant potential symptoms/side effects of the interventions noted above and are further explained in 
Section 7.4 as well. 
 
7.3 Adverse Events and Serious Adverse Events 
 
Definitions 
An adverse event (AE) is any untoward medical occurrence in a subject during participation in the clinical study 
or with the use of the interventions being studied. An adverse finding can include a sign, symptom, abnormal 
assessment (laboratory test value, vital signs, electrocardiogram findings, etc.) or any combination of these. 
AEs will be recorded regardless of their relationship to the study intervention. 
 
A Serious Adverse Event (SAE) is any untoward medical occurrence that results in death, is life threatening 
requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant 
disability/incapacity or congenital anomaly. Generally, an SAE can result in one or more of the following 
outcomes: 
• 
Death 
• 
A life-threatening event 
• 
Inpatient hospitalization or prolongation of existing hospitalization  
• 
A persistent or significant disability/incapacity 
• 
A congenital anomaly or birth defect 
• 
Important medical event based upon appropriate medical judgment 
Classification of AE Severity 
AEs will be labeled according to severity, which is based on their impact on the patient. An AE will be termed 
“mild” if it does not have a major impact on the patient, “moderate” if it causes the patient some minor 
inconvenience and “severe” if it causes a substantial disruption to the patient’s well-being. 
 
AE Attribution Scale 
AEs will be categorized according to the likelihood that they are related to the study intervention. Specifically, 
they will be labeled definitely unrelated, possibly related, probably related or definitely related to the study 
intervention. 
 
AE Guidelines Adverse events will be reported in a manner consistent with the UNM HRPO (Human Research 
Protections Office) and NCCAM policies (See below). 
 
7.4 Reporting Procedures 
Monitoring of Adverse Events & Frequency of Periodic Observations & Reporting & Follow-up: Adverse events 
will be monitored by spontaneous subject report and subject interviews and data review. At each clinic visit or 
follow-up telephone call, subjects will be asked to recall any adverse events since the time of their last contact 
(either via phone call, in-person clinic or study visit). The Study Coordinator (or her surrogate in her absence) 
will record the information using a standardized format and report the data to the PI’s. If the AE is a reportable 
event as defined by the UNM HRPO (i.e. meets all the following criteria; it was unanticipated, caused harm or 
placed a person at increased risk of harm, and was more likely than not to have been related to the research) it 
will also be reported to the UNM HRPO (see UNM HRPO “Event form” attached which must be signed by the PI 
or a designee in his/her absence and supporting documentation including the current consent) and the DSMB. 
The UNM HRPO will be notified of reportable events as soon as possible and within 5 days of the event date or 


 
 
 
 
36 
 
 
the “site awareness” date. AEs will be followed until they are resolved or considered stable, typically for one 
month, although this time will be extended to up to 4-6 months, depending on the instability of the event.  
 
SAEs will be immediately (i.e. as soon as the Investigators or Study personnel are made aware that an SAE 
occurred) reported to the UNM IRB (HRPO) as per IRB guidelines and the NIH Project Officer and addressed 
by the DSMB if determined to be attributable to study participation (see SAEs below). 
 
 A Data Safety and Monitoring Board has been identified for this study. AE reports will be generated using 
standard forms, including the Adverse Event Case Report Form and Serious Adverse Event Case Report Form 
(see attached). The DSMB will meet quarterly for the first year and the DSMB will reassess and determine 
whether observations can be reviewed semi-annually thereafter. During the DSMP formal meetings the events 
will be reviewed. The severity of the event will be determined and an action plan to avoid recurrence of events 
(if found to be attributable to study participation) will be formulated and implemented. Research related adverse 
events will be reviewed and annual reports which include AE reports, subject enrollment/withdrawals and 
protocol violations will be generated for the University of New Mexico Health Sciences Center Human Research 
Protections Office (HRPO), Data Safety Monitoring Board and NCCAM/NCCAM Project Officer.  
 
 
SAE Reporting 
SAEs that are unanticipated, serious, and possibly related to the study intervention will be reported to the Data 
Safety Monitoring Board, the Human Research Protections Office (HRPO), and NCCAM in accordance with 
requirements. 
 
• 
Unexpected fatal or life-threatening SAEs related to the interventions will be reported to the NCCAM 
Program Officer within 7 days (and will result in emergency convening of the Data Safety Monitoring Board). We 
will observe all UNM HRPO SAE reporting policies (see prior section). Other serious and unexpected AEs related 
to the intervention will be reported to the NCCAM Program Official within 15 days. 
 
• 
Anticipated or unrelated SAEs will be handled in a less urgent manner but will be reported to the Data 
Safety Monitoring Board, the UNM HRPO, NCCAM and other oversight organizations in accordance with their 
requirements. In the annual AE summary, the Independent Monitor Report (Data Safety Monitoring Board) will 
state that they have reviewed all AE reports. 
 
7.5 Follow-up for Adverse Events 
AEs will be followed by the research team until they are resolved or considered stable, typically for one month, 
although this time will be extended to up to 4-6 months, depending on the instability of the event and will be 
tracked on the Adverse Event or SAE CRFs and the AE and SAE Tables by the PI and Research Coordinator. 
 
7.6 Safety Monitoring 
The Co-PIs and NCCAM advisors have designated a Data Safety and Monitoring Board to perform an 
independent review of ongoing study progress and safety. The Data Safety and Monitoring Board for this study 
is comprised of Drs. Charles North, Cheryl Aine, Darren Braude, and Clifford Qualls who are not associated with 
this research project and thus work independently of the PIs, Drs Loren Ketai and Yuko Komesu, the Co-Principal 
Investigators. The DSMB members are not part of the key personnel involved in this grant. They are qualified to 
review the patient safety data generated by this study because of their unique expertise in the areas of radiology, 
statistics, urgency urinary incontinence, hypnotherapy and ethics. The CVs of all members of the Data Safety 
Monitoring Board are attached to the DSMP. 
 
Data Safety Monitoring Board: This DSMB will consist of: 
 
1.Charles North, MD 
University of New Mexico Health Sciences Center 
Professor of Family Medicine  
Dr. North has experience in treating women with UUI as well as experience in ethical decision-making as 
Former Acting Head of U.S. Indian Health Services. 


 
 
 
 
37 
 
 
 
2.Cheryl J. Aine, PhD 
University of New Mexico Health Sciences Center 
Research Professor, Department of Radiology 
Dr. Aine has extensive experience in NIH-sponsored imaging studies with particular interest in neuro-imaging 
and would be appropriate for this proposal which includes brain imaging.  
 
3.Darren Braude, MD, MPH, EMT-P 
University of New Mexico Health Sciences Center 
Professor, Department of Emergency Medicine & Anesthesiology 
Dr. Braude is a Clinical Hypnotherapist and his expertise in hypnosis makes him an appropriate DSMB 
member. 
 
4.Clifford Qualls, PhD 
University of New Mexico Health Sciences Center 
Professor Emeritus, Mathematics Statistics 
Dr. Qualls is a PhD statistician for the UNMH CTSC 
 
8. Intervention Discontinuation 
Interventions will be discontinued if they result in substantial disruption to the subject’s well-being with potential 
events listed in section 7. 
 
Hypnotherapy will be discontinued for the individual subject if the subject complains of severe emotional upset 
attributed to hypnotherapy. Serious emotional upset includes inability to work or events that would necessitate 
evaluation by a physician or care provider. It is unlikely that this will occur. The potential for this occurring will be 
minimized by excluding subjects with a history of schizophrenia or untreated bipolar disorder and by having the 
hypnotherapist guide the sessions and terminate sessions if subjects are beginning to show signs of undue 
duress during hypnotherapy. However, though it is highly unlikely that hypnotherapy could potentially unmask or 
de-repress significant emotional upset (see Section 7) if a subject reports serious emotional upset from 
hypnotherapy, the intervention will be terminated and reported. The subject will continue to be followed clinically 
by the investigators until the symptoms resolve. If necessary, a Behavioral Health Consultation will be generated 
and will result in a meeting of the PIs and review of the issues surrounding its occurrence. The subject will be 
followed after intervention discontinuation (if it is found to be directly attributable to the intervention) until it 
resolves, typically within a month but potentially longer. The PIs and Study coordinator will generate a report, 
assess whether it was preventable, and develop an action plan to prevent recurrence including potential protocol 
revision and this will be reported immediately to the DSMB.  
 
If serious medication related adverse events occur (significant urinary retention, debilitating constipation or 
nausea and vomiting) the medication will be discontinued. A clinic visit to the UNM Urogynecology Clinic will be 
arranged so that the subjects may be appropriately evaluated. If subjects report urinary retention or symptoms 
of a urinary tract infection or other symptoms of concern to the medication counselor or other study personnel, 
subjects will be instructed to stop the medication and a clinic visit to the UNM Urogynecology Clinic will be 
arranged so that subjects may be appropriately evaluated. Urinary retention will be evaluated by bladder 
catheterization or bladder scanning. These measures will decrease the risk of harm from study participation. It 
is unlikely that these routinely prescribed medications will result in serious harm, but if serious complications are 
reported, subjects will be evaluated and the PIs and Study Coordinator will generate a report and which will be 
given to the DSMB. If the events, such urinary retention or persistent urinary tract infections are directly 
attributable to the medications, an action plan will be developed which may include discontinuation of the 
treatment, potential protocol revision. The subject will be followed until the problem resolves, typically within a 
month but potentially longer. 
 
Participants will continue to be followed with their permission if a study intervention is discontinued for the 
duration of the study (if the participant is willing). All data will continue to be collected (with the participant’s 
permission) including questionnaires and voiding diaries. 
 


 
 
 
 
38 
 
 
 
9. Statistical Considerations 
 
9.1 General Design Issues 
This study includes  
1. A single-blinded, randomized controlled trial (RCT) based on a non-inferiority design which compares 
hypnotherapy to pharmacotherapy in treating UUI. 
 
Urge incontinent women (N=152) will be randomized to hypnotherapy or pharmacotherapy and 
evaluated at months 2, 6 &12    
2.  Both a cross sectional study and RCT which will evaluate up to 80 of these women with UUI.  
 
These women will undergo fMRI before treatment and their baseline imaging results will be 
compared to  normative controls.  
 
In addition, the  UUI subjects participating in the fMRI will undergo imaging after treatment. The 
images of UUI subjects following treatment will be compared to their baseline images. 
 
Specific Aims, Hypotheses and Outcomes; 
 
Primary Outcomes: 
1. Between group differences in change in UUI episodes for Specific Aim 1 at 2 month follow-up based 
on 3 day voiding diaries 
2. Between group differences in change in activation of limbic cortex and brain connectivity following 
treatment  for Specific Aim 2  
Secondary Outcomes: 
1. Between group differences in change in UUI episodes for Specific Aim 1 from baseline to follow-up 
at both 6 and 12 months based on 3 day voiding diaries. 
2. Between group differences in change in pad counts, voiding frequency and cure (resolution) of UUI 
on voiding diary for Specific Aim 1 at 2, 6 and 12 month follow-up as well as “durable cure” 
(resolution of UUI on all follow-up diaries at 2, 6 & 12 months) 
3. Between group differences in the follow-up expectation question and between group differences  in 
questionnaire change scores (the OAB-qSF, ISI,  PISQ-12, Global questionnaire, CRADI-8, IBS 
Module, IC questionnaire) for Specific Aim 1 at 2, 6 and 12 month follow-up 
4. Baseline differences in activation of the limbic cortex and brain connectivity in women with UUI 
compared to normative controls for Specific Aim 2 
 
 
1. Specific Aim 1: Determine whether a mind/body therapy (hypnotherapy) is as, or is more effective and 
durable, in treating urgency urinary incontinence (UUI) than a non-mind/body treatment (pharmacotherapy) 
Hypothesis: Among patients with urgency urinary incontinence, hypnotherapy ameliorates abnormal perception 
of bladder distension outside the hypnotic state and thereby diminishes symptoms of urgency and decreases 
incontinence as effectively as (or more effectively than) pharmacotherapy 
 
Clinical response of UUI subjects to Hypnotherapy compared to Pharmacotherapy Outcomes: 
The primary outcome for the analysis of Objective 1 will be change in UUI episodes for the hypnotherapy group 
compared to the pharmacotherapy group at 2 months based on 3 day voiding diaries.  
 
Secondary outcome measures of Objective 1 will include differences between the hypnotherapy and 
pharmacotherapy groups regarding change in UUI episodes at 6 and 12 months, and change in urinary 
frequency, pad counts and cure (defined as zero UUI episodes) on voiding diaries at 2, 6 and 12 month follow-
up, and “Durable Cure” of UUI (defined as zero UUI episodes on all voiding diaries which include the 2, 6 and 
12 month diaries). Secondary outcomes will also compare group differences in expectation attainment (i.e. 
differences in answers to follow-up Expectation question) and between group differences in questionnaire 
change scores [OAB-qSF, ISI, Global (PPBC) questionnaires and Sexual function scores (PISQ-12) in those 
women willing to answer the PISQ-12]  while accounting for covariates such as medical history and demographic 
variables as well as pain/interstitial cystitis (based on VAS pain scale and PBIC-SS) or bowel abnormalities 


 
 
 
 
39 
 
 
(based on the CRADI-8 questionnaire and IBS Module) and evaluating change in the CRADI-8, IBS Module or 
PBIC-SS questionnaires if adequate numbers of subjects are found to have bowel or IC abnormalities. 
 
A randomized, single-blinded, parallel group active controlled trial using a non-inferiority design was chosen. 
The non-inferiority design was chosen as the control group will be taking an intervention, anti-cholinergics, which 
is the standard of standard of care for  women with UUI; we wished to evaluate whether a novel mind-body 
treatment, hypnotherapy, was at least as successful in treating UUI as the standard therapy. Both the primary 
and secondary outcome measures are validated and reliable measures which accurately reflect UUI severity. 
The International Consultation on Incontinence (ICI) recommends that all incontinence research include 
validated questionnaires and voiding diaries.1 The voiding diary adheres to ICI recommended parameters with 
an intra-class correlation coefficient=.76 and moderate-excellent convergent validity with patient recall as 
measured by Spearman’s rank correlation=.7.8 The most commonly used primary outcome measure in 
randomized controlled trials, as noted in a recent AHRQ Review, is the 3-7day voiding diary.84 As 3 day voiding 
diaries are as valid as 7 day diaries and are far less burdensome to patients, 3 day diaries will be used in this 
study.8 The OABq-SF, validated for overactive bladder, discriminates between patients who are continent and 
incontinent.15 Internal consistency of its symptom bother subscale (.86) and its quality of life subscale (.89-.96) 
are high. It received a Grade A recommendation from the ICI as it met content and construct validity, internal 
consistency, test-retest reliability, and responsiveness standards.14 The Global scale, the PPBC, has 
demonstrated good construct and discriminant validity and responsiveness measured against UUI episodes 
(Spearman correlation co-efficients .21-.37, P<.0001) and is more specific for use in patients with Urgency 
Urinary Incontinence compared to many other global indices.84,85  This scale is important as Global ratings may 
provide the single best disease-related measure of change from the individual’s perspective.19 
 
 
2. Specific Aim 2: Determine whether hypnotherapy treatment of UUI (urgency urinary incontinence) is 
associated with greater modification of brain activation and connectivity on functional MRI than that which 
occurs following pharmacotherapy.  
Hypothesis 2.1. Patients with urgency urinary incontinence will exhibit increased activation within portions of the 
limbic cortex (anterior cingulate cortex and insula) during bladder distension relative to healthy controls. Patients 
will also exhibit an abnormal pattern of functional connectivity within the limbic system.  
Hypothesis 2.2.  Among patients with urgency incontinence, hypnotherapy will decrease hyper-activation of the 
limbic cortex in response to bladder distension and/or modulate functional connectivity within the limbic system.  
Moreover, normalization of hyper-activation and connectivity will be greater in hypnotherapy compared to 
pharmacotherapy 
 
Baseline (pre-treatment) differences between subjects with UUI and healthy controls with respect to task related 
limbic system activity and resting connectivity in subjects:  
Primary outcome measures for Objective 2.1 will be UUI subject versus normal control differences in task related 
activation of the insula and anterior cingulate cortex and differences in resting functional connectivity between 
these groups. Task related fMRI signals have been used extensively in the investigation of both motor and 
cognitive tasks and have been found to correlate well with other indices of neuronal function and neuronal spatial 
location within the brain.7 More recently fMRI measurement of resting functional connectivity has been shown to 
be powerful tool for the investigator of neuronal function and localization. By using spontaneous rather than event 
related signal this technique results in a threefold increase in signal to noise. Resting functional activity has 
successfully demonstrated group differences between controls and numerous disease states, including 
differences between patients with chronic pain and healthy controls.28  
 
Post-treatment 
differences 
between 
subjects 
receiving 
hypnotherapy 
versus 
subjects 
receiving 
pharmacotherapy with respect to task related limbic system activity and resting connectivity:  
Primary outcome measures for Objective 2.2 will be pharmacotherapy treated subject versus hypnotherapy 
treated subject change in task related activation of the insula and anterior cingulate cortex and change in resting 
functional connectivity between these groups. The test-retest reliability of fMRI results have been evaluated in 
multiple settings including within multicenter research consortiums.82 Assessment of the reliability of brain 
activation within regions of interest has shown intra-class correlation coefficients frequently greater than 0.8.30 
Test-retest reliability has also been shown to be preserved over a one year time span.3  


 
 
 
 
40 
 
 
 
9.2 Sample Size and Randomization 
Power Analysis/ Sample Size Calculation  for Clinical RCT Specific Aim 1: We performed sample size 
calculations for change in UUI episodes and change in OABq-SF scores based on our pilot data & urgency 
incontinence literature.11,16,52 The study design will use a non-inferiority design to compare the primary outcome 
(change in UUI episodes in the hypnotherapy versus pharmacotherapy groups). With respect to the outcome 
variable of percent reduction in UUI episodes as determined by bladder diaries, we will use a one-sided non-
inferiority test at level alpha = 0.25 and a non-inferiority margin of 5%.  If 𝜇ℎis the population mean percent 
reduction in incontinent episodes for the hypnotherapy group, and 𝜇𝑚 is the population mean percent reduction 
in incontinent episodes for the medications group, we will then test H0: 𝜇ℎ−𝜇𝑚≤−5 against the one-sided 
alternative H𝐴: 𝜇ℎ−𝜇𝑚> −5 using significance level 0.025.  If the null hypothesis is rejected then we may 
conclude hypnotherapy is not inferior to medication therapy, on average, by more than 5%, and in fact may be 
superior to medication therapy, with respect to percent reduction in incontinent episodes. The test may be 
performed by computing the lower 97.5% one-sided confidence bound for 𝜇ℎ−𝜇𝑚. If the lower confidence bound 
exceeds -5% we will conclude non-inferiority of hypnotherapy.  Should that lower bound exceed zero we will 
conclude superiority.  Assuming a subject drop-out, withdrawal and missing data rate as high as 33%, 52 subjects 
will be available for analysis in both hypnotherapy and medications groups. If 𝜇ℎ−𝜇𝑚 ≥ 9%, this sample size 
would provide power ≥ 80% for the non-inferiority test. Rigorous efforts will be made to reach an achieved attrition 
rate of 20-25%, such that approximately 60 subjects would be available for analysis in each group. This would 
allow for detecting non-inferiority if the actual 𝜇ℎ−𝜇𝑚 ≥ 8 %. If the attrition rate at 1 year follow-up is < 20%, 
randomization of 152 subjects will allow us to detect even smaller inter-group differences than quoted previously.  
 
Power Analysis/ Sample size Calculation for fMRI for Hypothesis 2.1 (Normative controls vs. urgency 
incontinence subjects): Regions of interest containing the insula and anterior cingulate cortex will be analyzed 
in keeping with our a priori hypothesis using two way ANCOVA with group as the between subject’s factor and 
age as a covariate. Pre-treatment β weights for both bladder filling and urgency regressor effect on anterior 
cingulate cortex and insula signal among normative subjects will be compared to the effect on signal in urgency 
incontinence subjects. The planned study size allows detection of differences between groups with an effect size 
>0.8 with power of 0.8, smaller than the observed effect size in our pilot study.43 The effect size observed in our 
pilot study (Cohen’s d ranged from 0.8 to 1.5) suggests that the study will be adequately powered (greater than 
0.8) to reject the null hypothesis at an alpha=0.05. In addition to analysis of prior regions of interest, group wise 
whole brain contrast will also be performed using an identical statistical model. False positives will be corrected 
at a significance threshold corresponding to p <.005 applied in combination with a minimum cluster size threshold 
of 32 native voxels (p < 0.05), parameters derived from 10,000 Monte Carlo simulations.80 Analysis of between 
group differences in functional connectivity will be performed in a similar fashion to that used to analyze brain 
activation evoked by bladder filling and emptying. The large observed effect size in our preliminary data (>3) 
suggests that the sample size used for proposed analysis of evoked potentials will be more than adequate. 
Although the principal purpose of this analysis is to further explore the pathophysiologic underpinnings of UUI 
within the brain, we will also explore the use of evoked potentials and functional connectivity as a biomarker for 
UUI. Towards that end we will construct receiver operator curves (ROCs) based on fMRI output from controls 
and patients with UUI. 
 
Statistical Analysis 2.2 Pre- and Post-Treatment measurements in patients with UUI:  Prior functional MRI 
analysis during the hypnotic state has shown complete suppression of anterior cingulate cortex activation in 
response to pain.55 However, the magnitude of suppression of anterior cingulate cortex or insula signal outside 
the hypnotic state has not been studied. Current study size will be able to detect differences between pre and 
post treatment signal within a treatment group with an effect size of approximately 0.5 and a power of 0.8. Minimal 
effect size would be approximately equivalent to a 60% decrease in the excess (above normative control) anterior 
cingulate cortex and insula signal. We predict a main effect of time, suggesting that both treatments are effective 
in reducing activity within the anterior cingulate cortex and insula. However, we also predict a significant Group 
x Time interaction, indicating that that change in activity will be greater for the hypnotherapy relative to the 
pharmacotherapy group. Minimum detectable effect size for the Group X Time interaction is 0.7 with power of 
0.8 and alpha of 0.05. Similar to brain activation, no prior data is available in the literature regarding the expected 
change in waking state connectivity following hypnotherapy. Current study size will be able to detect within-group 
differences between pre and post treatment signal with a minimal effect size of approximately 0.5 and a power 


 
 
 
 
41 
 
 
of 0.8, much lower than the observed effect size of >3 in our pilot study. The minimum effect size would be 
reached with a 15% decrement in anterior cingulate cortex to insula connectivity. As for evoked activity we predict 
both a main effect of time, and predict a significant Group x Time interaction, indicating that change in functional 
connectivity will be greater for the hypnotherapy relative to the pharmacotherapy group. Minimum detectable 
effect size for the Group X Time interaction is 0.7 with power of 0.8 and alpha of 0.05.This minimum effect size 
will be reached when between group differences in anterior cingulate cortex to insula connectivity are ≥ 30%.  
        
The principal purpose of this analysis will be to explore the mechanism of action of hypnotherapy when used to 
treat UUI, using pharmacotherapy as a control treatment that is not expected to exert its therapeutic effect via 
the brain. In addition we will explore the utilization of evoked activity and functional connectivity as biomarkers 
by correlating changes in these fMRI parameters with physiologic outcome measures, specifically UUI episodes. 
We understand that there is currently insufficient literature to determine the optimal method of assessing this 
correlation in the setting of a non-inferiority study design, and will look towards OCRA guidance on this aspect 
of the analytic plan in the future. 
 
Treatment Assignment Procedures 
Randomization to treatment 
Study participants will be randomized to either pharmacotherapy or hypnotherapy groups using a computer-
generated randomization scheme in varying permuted block sizes of 4-8.  SAS 9.3® Proc-Plan software will 
create a randomization scheme of varying permuted block sizes of 4-8 to avoid severe inequality of group sizes 
for this 2 arm study. Subjects will be stratified based on fMRI performance and UUI severity (< 4 UUI episodes 
vs. ≥ 4 UUI episodes on 3 day voiding diaries). UUI severity should be comparable in both groups because it is 
a potential risk factor for treatment failure. UUI severity will be defined by UUI frequency. Burgio83 identified risk 
factors for unsuccessful behavioral treatment of UUI. Women with > 10 UUI episodes on baseline voiding diaries 
were much less likely to be completely continent after behavioral treatment. For purposes of this study, on a 3 
day diary approximately 4 UUI episodes would be a potential risk factor for treatment failure and stratification will 
be performed in order to avoid UUI severity imbalances between the treatment groups. FMRI stratification will 
be performed to ensure appropriate representation of both treatment groups in the fMRI study. 
 
The UNMH CTSC biostatistics core will generate the computer randomization scheme for the study. Dr. Ronald 
Schrader will generate the scheme before enrollment begins and will be blinded to subject allocation after the 
RCT is initiated; he will have no patient contact, research personnel will not disclose unique patient identifiers to 
him, and he will remain blinded to patient randomization until study completion. Trial randomization codes will 
be maintained by the CTSC and Dr. Clifford Qualls (who is uninvolved with study analysis) will have the ability 
to break the blind. Breaking blinding is planned when all subjects in the RCT (N=152) have completed 12 month 
follow-up and when data collection and data quality checking have been completed. In the extremely unlikely 
event that the study is terminated or discontinued early due to excessive numbers of unanticipated and severe 
AEs determined to be warranted by the DSMB, the blind will be broken earlier than planned. The latter will occur 
after agreement by NCCAM and the DSMB, in which case the CTSC biostatistics office will be notified and the 
blind will be broken.  
 
Group assignments will be placed in opaque, sealed envelopes by an individual otherwise unassociated with 
the study. The envelopes will be opened and subjects will be randomized only after subjects have signed 
informed consent and completed baseline evaluations. Investigators involved in interpreting fMRIs, 
investigators participating in the RCT, study personnel performing data entry and the study statistician will be 
blinded to knowledge of subjects’ treatment groups. Investigator blinding will only be breached if a subject 
suffers an unexpected clinical event and investigator knowledge of the subject’s treatment is essential to 
providing standard of care. Subjects cannot be blinded to treatment interventions as it will be obvious to them 
whether or not they are undergoing hypnotherapy or taking medications. 
 
 
 
 
9.3 Definition of Populations (ITT versus Per Protocol) 
Intention to Treat: 


 
 
 
 
42 
 
 
The primary analysis for the RCT will be an Intention to Treat Analysis. Outcomes for the RCT will be performed 
comparing subjects randomized to hypnotherapy compared to pharmacotherapy who have at least baseline 
efficacy assessments. Subjects who are missing, non-compliant or who use off-protocol therapies will still be 
analyzed in their assigned treatment groups in the ITT. For the primary analysis, any missing observations will 
be treated as missing at random.  We will also use both parametric mixed models and longitudinal semi-
parametric regression model to explore and compare differences over time of urinary incontinent episodes in the 
two arms 
 
Per Protocol Analysis: 
A secondary analysis for the RCT will be a per protocol analysis, evaluating outcomes for subjects based on  
therapy compliance and use of off-protocol therapies as well as performing sensitivity analysis for missing values 
 
Non-adherence/Non-Compliance to treatment protocol at 2 month follow-up of the study: 
Definition Non-adherence/Non-Compliance: 
 Medication group: Subjects state ‘no’ on the Pharmacotherapy Compliance form (question 
#1) that they are no longer taking their medications at 2 month follow-up 
 
Attendance of < 60% of hypnotherapy appointments  
Measures taken to improve non-adherence during 1st 12 weeks of the study: Data on adherence to the treatment 
protocol will be collected weekly during the treatment phase of the study by research staff and reviewed monthly 
by the PI. Data on adherence will be reviewed at each of the DSMB meetings (described above). Adherence of 
participants randomized to medications will be evaluated by assessing their answer to question #1 on the 
Pharmacotherapy Compliance form (see above). Available data on the use of anti-cholinergics for urgency 
urinary incontinence suggests an overall non-compliance or withdrawal rate of 30% in randomized controlled 
trials and rates below 45% at 1 month and 13% at 1 year in clinical practice. If average adherence falls below 
the suggested rate of 60% a conference call will occur for study investigators to discuss methods for improving 
adherence without affecting the integrity of the study. However, given the data regarding anti-cholinergic side 
effects, it is quite possible that this non-adherence rate is not changeable. Protocol adherence in subjects 
randomized to hypnotherapy will be measured by monitoring compliance in keeping hypnotherapy appointments. 
If adherence of hypnotherapy subjects falls below a suggested rate of less than 60%, a conference call for study 
personnel to discuss methods for improving treatment adherence will occur.   
 
Non-compliance/Non-Compliance or use of off-protocol therapies at 6, 12 month follow-up visits 
Definition of Non-adherence/Non-Compliance at 6 & 12 month follow-up:  
 
Medication group: Subjects state ‘no’ on the Pharmacotherapy Compliance (question #1) form that they 
are no longer taking their medications at 6 or 12 month follow-up 
 
Hypnotherapy group: Subjects who state ‘no’ on the Hypnotherapy Compliance form (question #1) that 
they are not  listening to their hypnotherapy CDs or practicing self-hypnosis at 6 or 12 month follow-up  
 
Definition of use of off-protocol treatments 
 
Subjects use other treatments for UUI such as sacral neuromodulation, intravesical botox in the last 12 
months or other UUI medications (such as Toviaz®/Fesoterodine or Sanctura®/Trospium or 
Vesicare®/Solifenacin or Enablex®/Darifenacin or Myrbetriq®/Mirabegron) 
 
Subjects use acupuncture to specifically to treat UUI  
 
Subjects use herbal remedies specifically to treat UUI 
 
Analysis of non-compliance or use of off-protocol treatments:  
Subjects who are non-compliant or use off-protocol therapies will still be analyzed in their assigned treatment 
groups in the ITT analysis. When subjects implement off-protocol therapies, we will examine the sensitivity of 
the per protocol analyses in two ways.  First, we will modify the models to incorporate a time-varying treatment 
parameter that can be used to examine the effect of received treatment. Second, we will censor all 
measurements after they receive alternative treatment, and then impute all censored measurements using 
multiple imputations based on information collected from those who do not switch. Non-Compliance will be 
analyzed in the per-protocol analysis first as a categorical variable (yes/no) in its relationship to the outcome(s) 


 
 
 
 
43 
 
 
and will then be evaluated as a continuous variable (i.e. times self-hypnosis practiced or CD/digital recording 
used) in its relationship to the outcome. 
 
Missing Data: 
 
Standard procedures will be used to ensure that data are as complete and accurate as possible. In order to 
decrease missing data, data collection forms will be designed for recording measurements and the Redcap 
(Research Electronic Data Capture) System, as recommended by the UNMH CTSC, will be used by the research 
staff for data management. Study personnel will check the data collection forms for completeness before study 
participants leave the clinic so that missing clinical information may be addressed while study participants are 
still in the clinic. Downloads will be performed to check for missing values and skipped entries using SAS®  
programming and will be designed to avoid skipped entries and allow flagging of missing data. Our goal is to 
maintain a loss to follow-up rate less than 10% though we will conservatively plan on a loss to follow-up rate of 
20%. Our goal is to maintain a missing data rate of less than 10% overall. 
 
We anticipate that missing data will be generated in two primary ways; 1) Small numbers of subjects may 
withdraw consent or be lost to follow-up and will not have any measurements after their withdrawal. In this case, 
the study will be missing all data and these will be censored observations. The missing data may fall across the 
spectrum from missing completely at random to missing not at random 2) Subjects may fail to provide data at a 
specific follow-up time due to unforeseen life-events (illness, family emergencies) that do not allow them to 
provide assessments within the allowable window.  The missing data from this second group will follow an 
intermittent pattern. Again, the missing data may fall across the spectrum from missing completely at random to 
missing not at random   
 
We will use two general strategies for assessing the sensitivity of both primary and secondary analyses to 
missing at random and missing completely at random assumptions.  First, for individuals that withdraw from the 
study or have missing visits, we will collect information on the reasons for those missed visits.  That information, 
coupled with data collected from earlier visits will be used to develop comparisons of the two treatment arms 
using pattern mixture models. For the second approach, we will use multiple imputation based on a model 
conditional on baseline covariates, treatment group, and all previous measures. Separate imputation models will 
be used for the two groups.  
 
9.4 Interim Analyses and Stopping Rules 
 
Stopping Rules 
This is a low risk study as both interventions are low risk; pharmacotherapy is a standard, accepted treatment of 
UUI and hypnotherapy is considered a low risk intervention as hypnosis can only occur in subjects who allow 
themselves to be hypnotized (i.e. the hypnotic state cannot be forced upon individual). Nonetheless, in the 
unlikely event that the following situations occur, the study will be stopped prior to completion if: (1) any of the 
interventions are associated with SAEs attributable to the interventions that call into question the safety of the 
interventions (likelihood is extremely low) (2) difficulty in study recruitment or retention will significantly impact 
the ability to evaluate the study endpoints (likelihood is extremely low)  (3) any new information becomes 
available during the trial that necessitates stopping the trial (likelihood is extraordinarily low). 
 
In the unlikely event that >33% of study subjects report that they experience serious emotional upset from study 
participation the study will be suspended and a review will occur. Serious emotional upset includes inability to 
work or events that would necessitate evaluation by a physician or care provider. It is unlikely that this will occur 
as we have had 0/17 subjects in our pilot study evaluating hypnotherapy treatments in OAB subjects report 
physical or emotional upset from study participation. However, it is highly unlikely that hypnotherapy could 
potentially unmask or de-repress significant emotional upset (e.g. hysteria, uncontrollable anger or hostility) in 
subjects. The potential for this occurring will be minimized by excluding subjects with a history of schizophrenia 
or untreated bipolar disorder and by having the hypnotherapist guide the sessions and terminate sessions if 
subjects are beginning to show signs of undue duress during hypnotherapy. A report of a subject experiencing 
serious emotional upset from study participation will result in a meeting of the PIs and review of the issues 
surrounding its occurrence. The PIs and Study coordinator will generate a report, assess whether it was 


 
 
 
 
44 
 
 
preventable, and develop an action plan to prevent recurrence including potential protocol revision and this report 
will be given the DSMB. The likelihood of this occurring is very small. Sporadic occurrence of emotional upset is 
always possible in any setting, and if an individual treated with hypnotherapy notes this occurrence which she 
attributes to hypnotherapy, the intervention will be terminated. However, we believe that if a third of subjects 
complain of this issue, the study should be halted until the circumstances surrounding its occurrence are 
investigated. Other hypnotherapy studies have not reported this occurring; however, we believe that it is prudent 
to consider this as a possibility and to prepare for it as a possibility, although highly unlikely. The study would 
also be stopped if there were statistically significant differences in SAEs (as defined in section 7.3) definitely 
attributable to the interventions (hypnotherapy or pharmacotherapy). The medications in the pharmacotherapy 
arm, considered standard of care treatments, have undergone rigorous FDA approval, and it would be highly 
unlikely that these events would occur. 
 
9.5 Outcomes 
Outcomes documentation will not be reviewed and adjudicated by a committee. Outcomes will be analyzed by 
the Investigators and Study Statistician, Dr. Ronald Schrader, after the study is completed and the blind is broken 
using standard SAS® software on the Redcap® database maintained in a fashion consistent with UNM HRPO 
policy. 
 
9.51 Primary Outcome 
Specific Aim 1: Determine whether a mind/body therapy (hypnotherapy) is as, or is more effective and durable, 
in treating urgency urinary incontinence (UUI) than a non-mind/body treatment (pharmacotherapy) 
 
The primary outcome for the analysis of Objective 1 will be change in UUI episodes based on 3 day voiding 
diaries for the hypnotherapy group compared to the pharmacotherapy group at 2 month follow-up (See flow 
Diagrams Section 5. “Study Interventions”) 
 
Specific Aim 2: Determine whether hypnotherapy treatment of UUI (urgency urinary incontinence) is associated 
with greater modification of brain activation and connectivity on functional MRI than that which occurs following 
pharmacotherapy. 
Hypothesis 2.2.  Among patients with urgency incontinence, hypnotherapy will decrease hyper-activation of the 
limbic cortex in response to bladder distension and/or modulate functional connectivity within the limbic system.  
Moreover, normalization of hyper-activation and connectivity will be greater in hypnotherapy compared to 
pharmacotherapy 
 
The primary outcome is to evaluate whether UUI subjects treated with hypnotherapy have decreased hyper-
activation of the limbic cortex (ACC and insula) in response to bladder distention and/or modulation in functional 
connectivity within the limbic cortex in response to bladder distension compared to subjects treated with 
pharmacotherapy. This will be obtained after the subjects finish their 8 weeks of either pharmacotherapy or 
hypnotherapy (Visit 12; see flow Diagrams Section 5. “Study Interventions’) 
 
9.5.2 Secondary Outcomes 
Specific Aim 1: Determine whether a mind/body therapy (hypnotherapy) is as, or is more effective and durable, 
in treating urgency urinary incontinence (UUI) than a non-mind/body treatment (pharmacotherapy) 
 
This Aim’s primary outcome: will be to compare between group difference in change in UUI episodes at 2 months. 
Secondary outcomes  will be to; determine whether a mind/body therapy (hypnotherapy) is as, or is more 
effective and durable, in treating urgency urinary incontinence (UUI) than a non-mind/body treatment 
(pharmacotherapy) comparing change in UUI episodes at 6 and 12 months as well as comparing between group 
changes in urinary frequency and pad counts recorded on 3 day voiding diaries at 2,6 and 12 months, difference 
in “cure” in UUI episodes (defined as complete resolution of UUI, i.e. 0 UUI episodes, on voiding diaries at 2,6 
and 12 months) and “durable cure” (defined as complete resolution of UUI on all follow-up voiding diaries at 2, 6 
and 12 months), differences in expectation attainment (i.e. between group differences in follow-up Expectation 
question) and differences in questionnaire change scores [OAB-q SF, ISI, Global (PPBC) questionnaire scores 
and change in sexual function based on PISQ-12 scores].  Additionally, we will evaluate the baseline occurrence 
of concomitant syndromes such as irritable bowel syndrome and painful bladder syndrome in this population of 


 
 
 
 
45 
 
 
women with UUI based on the medical history and CRADI-8 and IBS Module and IC questionnaires. We will 
explore whether there is a difference in pain and IC symptoms following treatment if there are sufficient numbers 
of women with  bowel abnormalities and IC at baseline. 
 
Specific Aim 2: Determine whether hypnotherapy treatment of UUI (urgency urinary incontinence) is associated 
with greater modification of brain activation and connectivity on functional MRI than that which occurs following 
pharmacotherapy. 
Hypothesis 2.1. Patients with urgency urinary incontinence will exhibit increased activation within portions of the 
limbic cortex (anterior cingulate cortex and insula) during bladder distension relative to healthy controls. Patients 
will also exhibit an abnormal pattern of functional connectivity within the limbic system.  
 
This Aims’ secondary outcome will be to evaluate differences in brain activation of the limbic cortex and brain 
connectivity at baseline between women with UUI and normative controls. 
 
9.6 Data Analyses 
 
Specific Aim 1: Determine whether a mind/body therapy (hypnotherapy) is as, or is more effective and durable, 
in treating urgency urinary incontinence (UUI) than a non-mind/body treatment (pharmacotherapy) 
 
Statistical Analysis: Improvement between hypnotherapy and controls will be compared at baseline and follow-
up at 2, 6, 12 months. Because of the possibility that a number of subjects may be cured (i.e. report “0” urgency 
incontinence episodes) at follow-up on voiding diary, we will use a zero inflated Poisson (ZIP) generalized linear 
mixed model for the analysis and compare groups’ urgency incontinence episodes. The ZIP model analysis is 
proposed because the data are expected to be relatively low counts with the potential of a large numbers of 
zeroes, particularly at 2 and 6 months, in excess of those allowed by the Poisson.  Simple conversion to percent 
change will not correct the discrete nature of the data (“cures” become 100 percent change rather than 0 UUI 
count at 2 months), and standard least squares methods will not be appropriate.  If there is no inflation at 0, i.e. 
standard Poisson regression is appropriate, then the associated log-linear model yields percent change as a 
natural parameter (by exponentiating the group effect).  If there is significant inflation at 0, the confidence interval 
for percent change in the mean will be constructed by combining the two portions of the model with standard 
error estimated by the delta method, and checked via bootstrap methods. We will be able to derive mean UUI 
episodes as well as mean % change in UUI episodes following ZIP model analyses. All other parameters, which 
are normally distributed or continuous variables, will be compared using a linear mixed model analysis. It is 
unlikely that there will baseline differences between groups, given that this is a randomized controlled trial. If 
baseline differences between groups are found (e.g. incontinence duration, coexisting illnesses, prior treatment), 
appropriate variables will be added to the analysis as covariates. We will include pre-treatment patient 
expectations and hypnotic susceptibility as covariates in the analysis and determine if they are independent 
predictors of treatment response. We will not exclude subjects based on hypnotic susceptibility to increase the 
generalizability of our findings. We anticipate subjects’ pre-treatment expectations will be an independent 
predictor of improvement in urgency incontinence & questionnaire scores (the previously determined sample 
size is adequately powered to find a relatively small partial R2 of .0513 between expectations and outcomes). The 
primary outcome measure will be change in UUI episodes from baseline to follow-up with a between group 
comparison, and not “cure”. However, the term “cure” may be used for secondary analyses. As such, our 
definition of “cure” will be: absence of UUI episodes recorded on voiding diaries at 2, 6 and 12 month follow-up.  
Primary analyses will be performed using intention to treat. A per protocol analysis will also be performed; those 
who did not comply with the study interventions, extensively used other concomitant treatments known to 
improve UUI (e.g. used other UUI medications, underwent sacral neuro-modulation), or missed multiple 
treatment sessions will be considered to have been off protocol subjects. Similar analyses will be performed 
comparing group differences in change in questionnaire scores while accounting for covariates such as 
pain/interstitial cystitis (based on VAS pain scale and IC questionnaire) or bowel abnormalities (based on the 
CRADI-8), medical history and demographic variables (based on the medical history and demographic sheets) 
on the outcomes.  
 


 
 
 
 
46 
 
 
Specific Aim 2: Determine whether hypnotherapy treatment of UUI (urgency urinary incontinence) is associated 
with greater modification of brain activation and connectivity on functional MRI than that which occurs following 
pharmacotherapy.  
Hypothesis 2.1. Patients with urgency urinary incontinence will exhibit increased activation within portions of the 
limbic cortex (anterior cingulate cortex and insula) during bladder distension relative to healthy controls. Patients 
will also exhibit an abnormal pattern of functional connectivity within the limbic system.  
Hypothesis 2.2.  Among patients with urgency incontinence, hypnotherapy will decrease hyper-activation of the 
limbic cortex in response to bladder distension and/or modulate functional connectivity within the limbic system.  
Moreover, normalization of hyper-activation and connectivity will be greater in hypnotherapy compared to 
pharmacotherapy. 
 
Statistical Analysis of 2.1 Normative controls vs. urgency incontinence subjects: Regions of interest containing 
the insula and anterior cingulate cortex will be analyzed in keeping with our a priori hypothesis using two way 
ANCOVA with group as the between subject’s factor and age as a covariate. Pre-treatment β weights for both 
bladder filling and urgency regressor effect on anterior cingulate cortex and insula signal among normative 
subjects will be compared to the effect on signal in urgency incontinence subjects. The planned study size allows 
detection of differences between groups with an effect size >0.8 with power of 0.8, smaller than the observed 
effect size in our pilot study.43 The effect size observed in our pilot study (Cohen’s d ranged from 0.8 to 1.5) 
suggests that the study will be adequately powered (greater than 0.8) to reject the null hypothesis at an 
alpha=0.05. In addition to analysis of prior regions of interest, group wise whole brain contrast will also be 
performed using an identical statistical model. False positives will be corrected at a significance threshold 
corresponding to p <.005 applied in combination with a minimum cluster size threshold of 32 native voxels (p < 
0.05), parameters derived from 10,000 Monte Carlo simulations.80 Analysis of between group differences in 
functional connectivity will be performed in a similar fashion to that used to analyze brain activation evoked by 
bladder filling and emptying. The large observed effect size in our preliminary data (>3) suggests that the sample 
size used for proposed analysis of evoked potentials will be more than adequate. 
Although the principal purpose of this analysis is to further explore the pathophysiologic underpinnings of UUI 
within the brain, we will also explore the use of evoked potentials and functional connectivity as a biomarker for 
UUI. Towards that end we will construct receiver operator curves (ROCs) based on fMRI output from controls 
and patients with UUI. 
 
Statistical Analysis 2.2 Pre- and Post-Treatment measurements in patients with UUI: Efficacy of hypnotherapy 
and pharmacotherapy on anterior cingulate cortex and right insula activation will be compared using a 2x2 (Group 
x Time) mixed model ANCOVA to correct for potential differences in group characteristics (e.g. age). Analysis of 
treatment effect will be focused on the anterior cingulate cortex and insula based on preliminary data that 
suggests the effect size for change in activation will be highest in these regions. Prior functional MRI analysis 
during the hypnotic state has shown complete suppression of anterior cingulate cortex activation in response to 
pain.55 However, the magnitude of suppression of anterior cingulate cortex or insula signal outside the hypnotic 
state has not been studied. Current study size will be able to detect differences between pre and post treatment 
signal within a treatment group with an effect size of approximately 0.5 and a power of 0.8. Minimal effect size 
would be approximately equivalent to a 60% decrease in the excess (above normative control) anterior cingulate 
cortex and insula signal. We predict a main effect of time, suggesting that both treatments are effective in 
reducing activity within the anterior cingulate cortex and insula. However, we also predict a significant Group x 
Time interaction, indicating that that change in activity will be greater for the hypnotherapy relative to the 
pharmacotherapy group. Minimum detectable effect size for the Group X Time interaction is 0.7 with power of 
0.8 and alpha of 0.05. Simple effects tests will also be conducted to ensure that randomization to treatment arm 
was successful (i.e. no differences in baseline activity across the two groups).  
Similar analyses will be conducted to evaluate the effect of treatment on functional connectivity. No prior data is 
available in the literature regarding the expected change in waking state connectivity following hypnotherapy. 
Current study size will be able to detect within-group differences between pre and post treatment signal with a 
minimal effect size of approximately 0.5 and a power of 0.8, much lower than the observed effect size of >3 in 
our pilot study. The minimum effect size would be reached with a 15% decrement in anterior cingulate cortex to 
insula connectivity. As for evoked activity we predict both a main effect of time, and predict a significant Group x 
Time interaction, indicating that change in functional connectivity will be greater for the hypnotherapy relative to 
the pharmacotherapy group. Minimum detectable effect size for the Group X Time interaction is 0.7 with power 


 
 
 
 
47 
 
 
of 0.8 and alpha of 0.05.This minimum effect size will be reached when between group differences in anterior 
cingulate cortex to insula connectivity are ≥ 30%.  
The principal purpose of this analysis will be to explore the mechanism of action of hypnotherapy when used to 
treat UUI, using pharmacotherapy as a control treatment that is not expected to exert its therapeutic effect via 
the brain. In addition we will explore the utilization of evoked activity and functional connectivity as biomarkers 
by correlating changes in these fMRI parameters with physiologic outcome measures, specifically UUI episodes. 
We understand that there is currently insufficient literature to determine the optimal method of assessing this 
correlation in the setting of a non-inferiority study design, and will look towards OCRA guidance on this aspect 
of the analytic plan in the future. 
 
Anticipated/Expected Outcomes: Results from this study should confirm the differences between normative and 
urgency incontinence subjects with respect to limbic system evoked activation and functional connectivity. 
Confirmation of abnormal functional connectivity in urgency incontinence subjects during the resting state would 
be a particularly important contribution to the study of functional disorders in general. Abnormal resting 
connectivity data does not require that data be acquired and temporally linked to a performance of a task while 
in the MRI scanner making data acquisition less technically demanding. Abnormal resting connectivity has thus 
far only been observed in fibromyalgia but if shown to be more widely present among functional disorders could 
prove a diagnostic tool and/or target of new therapies. Demonstration that hypnotherapy’s impact on brain 
activation and connectivity extends past the hypnotic state and persists during wakefulness would allow 
treatment effects of hypnotherapy, and perhaps other mind/body therapies, to be assessed temporally distant 
from the time of therapy. The delayed assessment should give much better insight into the likelihood of a durable 
clinical benefit for the patient. Demonstration that hypnotherapy has greater impact on functional MRI  
findings than pharmacotherapy would argue that resultant brain plasticity is related to mind-body therapy rather 
than due to altered sensory input (from the bladder).  
 
10. Data Collection and Quality Assurance 
 
10.1 Data Collection Forms 
The Study Coordinator and her designee (neither of whom will perform data entry) will collect baseline 
information from subjects including Past medical history & Demographics sheet & baseline questionnaires (OAB-
qSF, ISI, PBBC, PISQ-12, CRADI-8, IBS Module, BPIC, Expectation questionnaires administered) and 2, 6 and 
12 month follow-up questionnaires and compliance information on CRFs. The questionnaires are standardized, 
validated questionnaires presented in their suggested paper formats. Unique patient identifiers are not included 
on the CRFs as the CRFs only include the research subject numbers, date and HRPO study # and CRF version 
numbers. The research staff responsible for data entry into the database will be blinded to subject randomization. 
The research nurse performing Cystometrics and fMRI tasks will not be involved in the fMRI interpretation. Drs. 
Mayer and Ketai, who will perform fMRI interpretation, will be blinded to subject randomization.  
 
During this study all medical history , physical exam information, testing results and questionnaires obtained at 
baseline and follow-up will be for research purposes only and data will be kept in strict confidence and will be 
identified with a study code number unique to the subject without other patient identifiers. The database will be 
secured with password protection. The database will be built using the web-based platform, REDCap®, as 
recommended by the UNM CTSC. The study’s data entry personnel will receive only coded information that is 
entered into the database under those identification numbers. Only coded information without unique patient 
identifiers will be entered into the study database. Only study personnel will have access to individually 
identifiable private information and data. Confidentiality will be maintained by keeping paper-based study subject 
folders for all enrolled subjects in a locked cabinet in the Urogynecology research area (this folder will include 
case report forms, laboratory reports, questionnaires, voiding diaries, intake forms). A separate log linking patient 
codes and unique patient identifiers will be kept on password protected computer available to study personnel.   
 
 
 
 
 
 


 
 
 
 
48 
 
 
10.2 Data Management 
Data will be collected on CRFs approved by the UNMH HRPO including demographic and patient history forms, 
eligibility forms, questionnaires, Cystometrics and fMRI task data sheets, pharmacotherapy side effect and 
hypnotherapy practice logs, treatment compliance logs as well as forms related to AE tracking. These data will 
be maintained as noted above by the Investigators and Research personnel. The database used by the UNM 
Urogynecology research team will be password protected. The database will be built using the web-based 
platform, REDCap®, as recommended by the UNM CTSC. The study’s data entry personnel will receive only 
coded information that is entered into the database under those identification numbers. Only coded information 
without unique patient identifiers will be entered into the study database. Only study personnel will have access 
to individually identifiable private information and data. Confidentiality will be maintained by keeping paper-based 
study subject folders for all enrolled subjects in a locked cabinet in the Urogynecology research area (this folder 
will include case report forms, laboratory reports, questionnaires, voiding diaries, intake forms). Consents will be 
kept separate from these research folders and will be kept in a separate locked cabinet in the UNM Research 
Administrative area. A separate log linking patient codes and unique patient identifiers will be kept on password 
protected computer available only to study personnel.  CRFs will include forms used to collect subject information 
including demographic, medical history forms, questionnaires, compliance forms, fMRI screening forms, 
inclusion and exclusion criteria forms as well as patient behavioral therapy instruction handouts. 
 
Data collected at the Mind Research Network using standardized paper forms or digitally will only be identified 
with the study’s unique identifier (ID) for the participant. The link between the name of the participant and the 
study ID will be kept confidential by the MRN on a secure portal. All data storage devices at the Mind Research 
Network are encrypted devices. Personally identifying information will not be stored in files on networked 
computers and paper forms. Such information will be kept in separate locked file cabinets. Electronic data are 
doubly protected against computer catastrophe. Data will be backed up daily. The backup system will be used 
only by a designated administrator, preventing accidental deletion even by project staff. 
 
10.3 Quality Assurance 
10.3.1 Training 
Research Study Staff all complete training as required by the UNM (these include; Research University workshop 
for Human Research Protections Office submissions, Human Research Protections training certification, UNM 
Financial Conflicts of Interest training, UNM Health Sciences Center Culture of Compliance, UNM Health 
Sciences Center Code of Conduct and Compliance, HIPAA and Breach Notification,  HIPAA Training, HIPAA 
and Accounting of Disclosure, Cash Management Trainings and Ethics training (Ethics: A Framework for Ethical 
Decision Making). In completing these training classes, research staff acknowledge the rules and regulations 
regarding human subjects protection, HIPAA regulations compliance, and all University-related policies and 
procedures governing research.  These classes provide each coordinator with the tools to effectively and 
efficiently execute research protocols and maintain compliance with federal, state, and university regulations. In 
addition, the Research Information Specialist has completed the following training: Certified Clinical Research 
Coordinator (for certification), Essentials of Leadership’, Patient Scheduling and the 2011 NIH Regional Grants 
Seminar. Each employee's training profile is reviewed annually with the Research Information Specialist to 
assure compliance with federal, state, and university guidelines.   
 
Training for the medication counselor(s) will include 2-3 one hour training sessions, similar to the amount of 
training given in our hypnotherapy pilot study. Acceptability of counselor performance will be checked with the 
pharmacotherapy counseling fidelity checklist used by research staff to audit random sessions. Training for the 
hypnotherapists will include three 1-2 hour training sessions. Acceptability of hypnotherapist performance will be 
checked with the hypnotherapy fidelity checklist used by research staff to audit random sessions.  
 
10.3.2 Quality Control Committee NA 
10.3.3 Metrics 
Outcome measures will have the following quality control metrics: 
RCT outcomes: 
1. Research study members who distribute and evaluate the voiding diary(s) will complete a training and 
certification process and random audits will be performed by research members one another’s 
interpretations. See MOP “Voiding Diary Guidelines” 


 
 
 
 
49 
 
 
2. Research study members who distribute the treatment compliance and expectation questions will be 
trained and certified on their administration and interpretation and random audits will be performed by 
research members one another’s interpretations.  
3. The OAB-qSF15, ISI, the global questionnaire (PPBC),10,81 PISQ-1264,65,66, CRADI-887, IBS Module and 
BPIC questionnaire86 are validated measures which will be administered in their recommended, standard 
format.  
FMRI outcomes: BOLD-related evoked activity and functional connectivity maps will both undergo extensive QA 
procedure 
1.  The transformation matrix registering each subject's functional data to structural space will be visualized 
for accuracy (for both the evoked and resting state data) 
2. Raw images will be examined for excessive motion as well as artifacts. In addition, the degree of motion 
will also be quantified for each individual based on the first two statistical moments from the cohort using 
previously published algorithms at the end of the study 50  
3. We will examine the fit of different modeling parameters on a per-subject basis.  
 
10.3.4 Protocol Deviations 
Data on adherence to the treatment protocol will be collected weekly during the treatment phase of the study by 
research staff and reviewed monthly by the PI. Data on adherence will be reviewed at each of the DSMB 
meetings (described above). Adherence of participants randomized to medications will be evaluated by 
performing review of the compliance to treatment forms collected at 2,  6 and 12 months for the pharmacotherapy 
group. Available data on the use of anti-cholinergics for urgency urinary incontinence suggests an overall non-
compliance or withdrawal rate of 30% in randomized controlled trials and rates below 45% at 1 month and 13% 
at 1 year in clinical practice.54,21 If average adherence falls below the suggested rate of 60%, a conference call 
will occur for study investigators to discuss methods for improving adherence without affecting the integrity of 
the study. However, given the data regarding anti-cholinergic side effects, it is quite possible that this non-
adherence rate is not changeable. Protocol adherence in subjects randomized to hypnotherapy will be measured 
by monitoring compliance in keeping hypnotherapy appointments during the active intervention phase of the 
study, then review of compliance will be followed at 2, 6, and 12 months based on the compliance to 
hypnotherapy treatment forms. If adherence of hypnotherapy subjects falls below a suggested rate of less than 
60% in the active treatment phase of the study, a conference call for study personnel to discuss methods for 
improving treatment adherence will occur.   
A protocol deviation form will be completed by the study coordinator or her surrogate in her absence, for any 
event which occurs or is performed outside the study protocol. Protocol deviations include missed visits, 
incomplete visit assessments, informed consent-randomization deviations, errors in eligibility assessments, and 
study treatments. Treatment protocol deviations (e.g. off-protocol treatments) will be captured and documented 
on the Hypnotherapy Compliance and Pharmacotherapy Compliance forms that will be administered to subjects 
at their 2, 6 and 12 month follow-up. These will be reviewed by the Investigators (in the aggregate without 
individual identifiers to identify the frequency of occurrence) and will be reported to the DSMB at all their regularly 
scheduled meetings. Reporting of protocol deviations will follow UNM HRPO guidelines. 
 
10.3.5 Monitoring 
Description of Plan for Data Quality and Management and Data Collection Forms―The study staff under the 
over site of the PIs will review all data collection forms on an ongoing basis for data completeness and accuracy 
as well as protocol compliance. Data verification will be performed by personnel other than the individual 
performing data entry onto the database on 10% of data collected. Data quality control metrics will be reviewed 
by the research team. The results of the data review will be incorporated into the reports for each DSMB meeting 
and in the Annual Report. The research team will be responsible for data collection and management for the 
project. Only the research team will have access to the data. Information will be collected by Investigators and 
research staff and recorded on the CRF’s which will be considered source data. Data collection forms which 
have been developed prior to study initiation will be maintained as part of Good Clinical Practice (GCP). 
Research coordinator will review data collection forms for completeness. Data will be de-identified after the data 
is labeled with a participant code number. Study folders will be kept in a locked cabinet (see Database Protection 
above) only available to the study personnel. The study folders with data collection forms will be de-identified. 
Direct patient identifiers will be linked to the patient’s code number log (or ‘data link’) kept separately from the 
study folders; the link is necessary in the event that the subject needs to be contacted in the future (see Database 


 
 
 
 
50 
 
 
Protection).Information with patient identifiers such as informed consent forms and HIPAA authorizations will be 
kept separate from the study folders in a secured area. 
Frequency of Data Review for this Study― The frequency of data review for this study differs according to the 
type of data and is summarized in the following Table. The Reviewers will include the PIs, Study Coordinator 
and the Data Safety Monitoring Board. 
 
11. Participant rights and Confidentiality 
11.1 Institutional Review Board (IRB) Review 
This protocol and the informed consent document and any subsequent modifications will be reviewed and 
approved by the UNMH Human Research Protections Office (HRPO).  
 
11. 2 Informed Consent Forms 
Written informed consent will be obtained from each subject at study entry. Informed consent will be obtained by 
the following process: 
1) Subjects will be asked if they are interested in study participation in a private setting, and if they verbalize 
interest, a copy of the consent forms will be explained and given to them to review so that they may 
discuss the study with family and friends.  
2) The PI or Co-Is will meet with subjects to review the form and confirm the subject’s understanding of the 
study and to answer their questions. Subjects will answer screening questions to ensure they are 
appropriate candidates for the study.  
3) If subjects state that they are interested in study participation after explanation of the study as noted 
previously, an appointment will be made for subjects to return to sign the consent and fill out the baseline 
information and questionnaires.  
4) If they state that they are not certain, they will be given the study coordinator’s contact information so that 
they can call study personnel if they decide to participate in the study; a study appointment will be made 
for subjects to return to sign the consent after they contact study personnel.  
5) At the enrollment appointment, which occurs in a private setting, subjects sign the consent after study 
personnel are certain that subjects have had appropriate counseling and understanding regarding the 
study and that the study and consent have been explained to them in a fashion congruent with their 
medical literacy. Consent will be obtained after screening is performed and will be re-reviewed in the 
future in the event changes are required. In general, consent will be obtained at the baseline visit. The 
PI or Co-Is, Study Coordinator(s) or Study Nurse(s) will obtain verbal and written informed consent on an 
IRB approved consent after explaining study and before collecting any data. Human subject’s protection 
will follow local and national regulations at all times. 
 
This study will not recruit Non-English speakers as the hypnotherapists are primarily English-speaking. Although 
we are not targeting vulnerable populations including students, Native American women or economically 
Data type 
Frequency of review 
Reviewer 
Subject accrual (including 
compliance with protocol enrollment 
criteria) 
Quarterly 
 
PI, Study Coordinator, DSMB 
Status of all enrolled subjects, as of 
date of reporting  
Quarterly 
 
PI, Study Coordinator,  DSMB 
Adherence & Compliance data 
regarding study visits and 
interventions & Data Quality Review 
Quarterly 
 
PI, Study Coordinator,  DSMB 
AEs and rates 
Per occurrence 
PI,  Study Coordinator, DSMB 
SAEs 
Per occurrence (see SAE 
reporting above) 
PI, Study Coordinator.  DSMB, 
NCCAM 


 
 
 
 
51 
 
 
disadvantaged women, we are drawing from the UNMH patient population which includes these groups of 
women. We will carefully proceed with informed consent. These subjects like all our subjects, will have protective 
measures taken to ensure that individuals understand the study and their roles as study subjects, and all subjects 
will be given appropriate time to decide whether or not they want to participate in the study. Subjects unable to 
give their own informed consent will not be enrolled in the study. The consent form describes the purpose of the 
study, the procedures to be followed, and the risks and benefits of participation. A copy will be given to each 
study participant and this will be documented in the participant’s record. In order to be comply with UNMHSC 
IRB regulations regarding potential future studies and analyses of findings and NIH directives regarding public 
access to NIH-funded databases, participants will be asked to sign an optional consent addendum for storage 
and use of data for future studies as this study has now completed enrollment. Data will be stored as outlined in 
section 10.2, and as stated in that section information in the database is de-identified with only research numbers 
used.  
 
 
11.3 Participant Confidentiality 
The plan to ensure protection of subjects’ privacy includes the following elements:  
Subjects will be asked if they are interested in study participation in a private setting, and if they verbalize interest, 
they will be given a copy of the consent forms to read. If they choose to participate, arrangements will be made 
for subjects to sign the consent in the presence of a study investigator in a private setting. All subjects will be 
reassured that declining study participation will have no effect on the clinical care that they receive. Researchers 
will ask subjects’ permission to review their medical records and record study findings (e.g. answers to the 
questionnaires, the standardized pelvic exam, cystometric results, voiding diary results, functional MRI results). 
No information will be given to anyone without the subject’s permission; a Health Insurance Portability and 
Accountability Act (HIPAA) Authorization Consent will be obtained from the patient as required by the University 
of New Mexico IRB (HRPO). The investigators and the consents guarantee subject confidentiality, as required 
and substantiated in the University of New Mexico HRPO (IRB) study consents which further requires that all 
data will be identified with an identification code unique to the subject. During this study all evaluations, medical 
history and physical exams and questionnaires and imaging results performed at baseline and follow-up will be 
for research purposes only and data will be kept in strict confidence. All data, whether generated in the laboratory 
or on examinations will be identified with an identification code, a Participant ID (PID) otherwise referred to as a 
study number, unique to the subject. All records will be kept in a locked file cabinet. Information will not be 
released without written permission of the participant, except as necessary for monitoring by the UNM HRPO or 
NCCAM.  (Please also refer as well to the above sections; section 10.1 Data Collection forms and 10.2 Data 
Management). 
 
11.4 Study Discontinuation 
The study may be discontinued at any time by the UNM HRPO (IRB), the NCCAM or other government agencies 
as part of their duties to ensure that research participants are protected. 
 
12. Committees 
Data Safety Monitoring Board (see section 7.6 and DSMP) 
 
13. Publication of Research Findings 
Publications of the results of this study will be determined by the PIs and Co-Is of this study. Authorship will 
follow the guidelines of the International Committee of Medical Journal Editors and require authorship credit 
based on 1) substantial contributions to conception and design and acquisition of data, or analysis and 
interpretation of data; 2) drafting the article or revising it critically for important intellectual content; and 3) final 
approval of the version to be published. Authors will meet condition 1, 2, and 3. 
Final research data will be shared via abstract submission, presentation at appropriate research meetings and 
publications in peer reviewed journals. Manuscripts arising from this funding will be submitted to PubMed Central 
upon acceptance for publications. Our project will register at Clinical trials.gov and the project design will be 
publically available. Any presentation, abstract or manuscript will be made available for review by NCCAM if 
desired prior to submission. 
 
 


 
 
 
 
52 
 
 
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