DrugLib.com — Drug Information Portal

Rx drug information, pharmaceutical research, clinical trials, news, and more

Brain-Centered Therapy Versus Medication for Urgency Urinary Incontinence : Hypnotherapy Or Pharmacotherapy

Information source: University of New Mexico
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Urinary Incontinence, Urge

Intervention: Anticholinergic medications (Drug); Hypnotherapy (Behavioral)

Phase: N/A

Status: Recruiting

Sponsored by: University of New Mexico

Official(s) and/or principal investigator(s):
Yuko Komesu, MD, Principal Investigator, Affiliation: University of New Mexcio Health Science Center

Overall contact:
Yuko Komesu, MD, Phone: 505-272-9702, Email: ykomesu@salud.unm.edu


This study includes: 1. A trial in which urge incontinent women (N=152) will be randomized to hypnotherapy or pharmacotherapy and evaluated at months 2, 6 &12.

- The primary objective will be change in Urgency Urinary Incontinence (UUI)


- Secondary objectives will; be change in subjects' responses in questionnaires that

measure the severity of overactive bladder (OAB) symptoms and incontinence severity (Overactive Bladder Questionnaire-Short Form, Incontinence Severity Index and the Patient Perception of Bladder Condition), the impact of those symptoms on quality of life (Pelvic Organ Prolapse Incontinence Sexual Questionnaire-12), change in pad counts and urinary frequency, differences in subjects' attainment of expectations for treatment following therapy. Baseline occurrence of irritable bowel and painful bladder syndrome will be recorded and their potential change in severity following treatment will be explored. 1. a. The Hypothesis: Among patients with urgency urinary incontinence, hypnotherapy decreases abnormal perception of bladder distension outside the hypnotic state and is at least as effective as pharmacotherapy in diminishing the symptoms of urgency and severity of incontinence 2. A comparison of pre-treatment brain function in a subgroup of subjects with UUI to normal controls and an evaluation of post-treatment effect of hypnotherapy and pharmacotherapy on brain function in UUI subjects.

- Approximately sixty women with UUI will undergo functional magnetic resonance

imaging (fMRI) before treatment and these baseline results will be compared to approximately 20-30 normal controls.

- The same 60 UUI subjects will also undergo fMRI analysis after receiving

hypnotherapy or pharmacotherapy for two months. Post treatment fMRI results from UUI subjects will be compared to their baseline results.

- Measured outcomes will be differences in baseline brain function in UUI subjects

compared to normal controls as well as differences in treatment effect on brain function in subjects receiving pharmacotherapy compared to those receiving hypnotherapy 2a. The Hypotheses: 1) Patients with UUI will exhibit increased activation within portions of the brain, the limbic cortex (anterior cingulate cortex& insula), during bladder distension relative to controls. Patients will also exhibit an abnormal pattern of functional connectivity within these parts of the brain. 2) Among patients with UUI, hypnotherapy will decrease hyper-activation of portions of the brain in response to bladder distension and/or modulate functional connectivity within these portions of the brain. Moreover, normalization of hyper-activation and connectivity will be greater in hypnotherapy compared to pharmacotherapy.

Clinical Details

Official title: Protocol for Brain-Centered Therapy Versus Medication for Urgency Urinary Incontinence An RCT: Hypnotherapy Or Pharmacotherapy

Study design: Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Single Blind (Investigator), Primary Purpose: Treatment

Primary outcome:

Urgency Urinary Incontinence episodes recorded on voiding diaries

Evoked brain activation and resting connectivity on functional MRI

Secondary outcome:

Urinary urge incontinence cure

Questionnaire scores

urinary frequency and pad counts

Irritable bowel syndrome and bowel symptoms and/or Painful Bladder/Interstitial Cystitis in this population

Evoked brain activation and resting connectivity on functional MRI

Detailed description: Detailed Description: Study Objectives 1. Primary Objective: 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) by comparing change in urinary incontinence episodes recorded on voiding diaries between groups using a non-inferiority design. 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 2. Secondary Objectives: 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 change in questionnaire results as well as urinary frequency and pad counts recorded on voiding diaries 2. To determine the baseline occurrence of concomitant syndromes such as irritable bowel syndrome or other bowel symptoms such as constipation or anal incontinence or painful bladder syndrome in this population of women with UUI based on the medical history and questionnaires. We will explore whether there is a difference in irritable bowel and other bowel symptoms and IC symptoms following treatment if there are sufficient numbers of women with pain and IC at baseline. 3. To confirm differences in brain activation and connectivity on functional MRI in UUI subjects compared to normative controls. Overview: 1. Women with UUI who meet inclusion criteria and who choose to participate in the study will be enrolled by the University of New Mexico Urogynecology Division. Investigators will screen subjects for study entry based on voiding diaries to ensure that subjects have UUI 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. One hundred fifty-two women will be randomized to hypnotherapy or to pharmacotherapy. Study participation for these UUI subjects will be approximately 1 year; Measurements will be performed prior to treatment, following completion of treatment visits (treatment visits are performed over approximately 8 weeks), and again at 6 and 12 months. 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. 2. A subset of approximately 60 subjects with UUI (drawn from both treatment groups) will have brain fMRIs performed at baseline and follow-up. Approximately 20-30 normative controls will also undergo an fMRI to compare fMRI in affected women versus unaffected controls. Measured outcomes will be differences in baseline brain activation during bladder filling and in resting brain 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. Study participants will be randomized to either pharmacotherapy or hypnotherapy groups using a computer-generated randomization scheme in varying permuted block sizes. Investigators involved in analyzing fMRI results, investigators analyzing the RCT results and study personnel performing data entry will be blinded to knowledge of subjects' treatment groups. Blinding of subjects to treatment is not feasible. Visits for Study: 1)UUI study subjects Screening: Subjects who are interested in study participation will be given information about the study and administered a screening questionnaire and be given the opportunity to consider carefully whether they would like to participate in the study Visit 1: Enrollment-- All subjects; Will be formally screened for eligibility prior to signing the consent. (1) If eligible, written consent to participate will be obtained (2) Will be administered the study questionnaires (3) Answer demographic questions and questions about their past medical history(4) Undergo a Pelvic Organ Prolapse Quantitation (POP-Q) exam if they have not had one performed in the last year. Subjects will have cystometry scheduled (5) Voiding diary will be reviewed (6) Subjects who are willing and able to undergo fMRI will be screened and scheduled for that study (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 Visit 1). Subjects who will undergo fMRI will also undergo a brief simulation of the fMRI tasks at this time, filling and emptying the bladder. Subjects will undergo hypnotic susceptibility testing at this visit if at all feasible (if not feasible, this will be performed at a separate visit prior to randomization). Visit 3 for fMRI Subjects: The baseline fMRI will be performed Randomization: The subjects will be randomized to treatment interventions and contacted by the study personnel and arrangements made for their interventions Visits 3-10 for Hypnotherapy Treatments for those who did not undergo fMRI, Visits 4-11 for those who did undergo fMRI: Hypnotherapy sessions--Subjects assigned to hypnotherapy will be scheduled for these visits which will be performed by a certified clinical hypnotherapist. The subjects will have hypnotherapy sessions scheduled approximately weekly over 8 weeks. Visits 3-10 for Pharmacotherapy Treatments for those who did not undergo fMRI, Visits 4-11 for those who did undergo fMRI--Medication Counseling Session: Subjects assigned to pharmacotherapy will be scheduled for these visits which will be performed by trained research personnel. The subjects will have pharmacotherapy counseling sessions scheduled approximately weekly over 8 weeks. Visit 12—follow-up fMRI testing (for the fMRI group): Follow-up fMRI will be performed on subjects who had baseline fMRIs performed. Post Therapy visit--Visit 11 (for those who did not undergo fMRIs) or Visit 13 (for those who did undergo fMRI): This study visit will be scheduled at the end of the hypnotherapy or medication counseling sessions. Those who are in the subgroup who have undergone prior fMRI testing will have it performed following completion of their active interventions. At the final study visit, subjects will 1) be administered study questionnaires 2) They will return their follow-up voiding diary 6 and 12 month follow-up visits may be conducted via phone, in person, or mail. Pharmacotherapy subjects will continue to receive their medications for 1 year and Hypnotherapy subjects will be encouraged to continue self-hypnosis with the aid of hypnotherapy recordings for 1 year. 2)Normative Controls participating in only the FMRI study: will be screened to ensure they do not suffer from OAB and will give written informed consent. They will undergo a Pelvic Organ Quantitation Exam, answer demographic questions and undergo cystometric testing and a brief simulation of the fMRI tasks; filling and emptying the bladder. They will then have their fMRI performed at a separate visit. Description of Interventions: 1. Hypnotherapy: Hypnotherapy will be administered over approximately 8 weeks by certified, trained clinical hypnotherapists. The subjects will be informed that 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. They will be encouraged to listen to the CD/digital recording daily for one year. 2. Pharmacotherapy: Pharmacotherapy counseling sessions will be administered over approximately 8 weeks by trained research personnel. Subjects will be scheduled for visits with the medication counselor who will review medications and their side effects. Subjects will be informed that sessions will be audio-recorded and one or more sessions will be reviewed by study personnel to ensure that the counseling is delivered in a standardized fashion. If subjects state that in person visits are burdensome, these visits may occur via phone. The study will use either of two standard, long acting anti-cholinergic medications and dosages (Long acting Tolterodine or Extended Release Oxybutynin or their equivalent generic substitutes). Following the 8 weeks of therapy as described previously, subjects will continue to take their anti-cholinergic medications or one year. Description of Functional MRI: 1. 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 at the beginning of each experiment. For each of the FMRI tasks, echo-planar images will be collected using a single-shot, gradient-echo 2. 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. 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. Subjects will be scanned while undergoing bladder filling and emptying. 3. FMRI Image Processing: 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 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. Connectivity analysis will be performed. Functional connectivity will be measured between specific points and the remainder of the brain (i. e. whole brain analysis) as in our pilot study. Averaged individual residualized time-courses from these spheres will be the primary regressor in whole-brain BOLD connectivity analyses. Resultant Pearson's correlation coefficients will then be converted to z-scores using Fisher's method and blurred using a 10 mm Gaussian kernel & contrasted across the two groups using independent sample T-tests Statistical Analysis 1. Specific Aim 1: Investigators performed sample size calculations for change in UUI episodes and change in OABq-SF scores based on investigators' pilot data & urgency incontinence literature. 6,7 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,investigators will use a one-sided non-inferiority test at level alpha = 0. 25 and a non-inferiority margin of 5%. If μ_h is the population mean percent reduction in incontinent episodes for the hypnotherapy group, and μ_m is the population mean percent reduction in incontinent episodes for the medications group,investigators will then test H_0: μ_h-μ_m≤-5 against the one-sided alternative H_0: μ_h-μ_m>-5 using significance level 0. 025. If the null hypothesis is rejected then investigators 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 μ_h-μ_m. If the lower confidence

bound exceeds - 5% investigators will conclude non-inferiority of hypnotherapy.

Should that lower bound exceed zero investigators 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 μ_h-μ_m≥9%, this sample size would provide power ≥ 80% for the non-inferiority test. Improvement between hypnotherapy and controls will be compared at baseline and follow-up at 2, 6, 12 months. Parameters will be compared using a generalized linear mixed model analysis. If baseline differences between groups are found (e. g. incontinence severity, coexisting illnesses, prior treatment), appropriate variables will be added to the analysis as covariates. Primary analyses will be performed using intention to treat. A per protocol analysis will also be performed. Similar analyses will be performed comparing group differences in change in questionnaire scores while accounting for other covariates such as pain/interstitial cystitis or bowel abnormalities 2. Specific Aim 2. 1 (Normative controls vs. urgency incontinence subjects): Regions of interest containing the insula and anterior cingulate cortex will be analyzed in keeping with the 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 the pilot study. 43 The effect size observed in the 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 the preliminary data (>3) suggests that the sample size used for proposed analysis of evoked potentials will be more than adequate. 3. Specific Aim 2. 2 Efficacy of hypnotherapy and pharmacotherapy on anterior cingulate cortex and 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. 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. Investigators predict a main effect of time, suggesting that both treatments are effective in reducing activity within the anterior cingulate cortex and insula. However, investigators 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. 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 the pilot study. The minimum effect size would be reached with a 15% decrement in anterior cingulate cortex to insula connectivity. As for evoked activity investigators 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%. 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 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. Investigators will use multiple imputation based on a model conditional on baseline covariates, treatment group, and the previous measures. Separate imputation models will be used for the two groups. 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 adverse event tracking. As noted above data base has been constructed using the web-based platform, REDCap® The study's data entry personnel will receive only coded information that is entered into the database under those identification numbers. 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. The Mind Research Network (MRN) investigators (investigators responsible for performing the fMRIs) will collect data using standardized paper forms or digitally. Data 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. Quality Control 1. RCT outcomes: a) Research study members who distribute and evaluate the voiding diary(s) will complete a training and certification process b) Research study members who distribute the treatment compliance and expectation questions will be trained and certified on their administration and interpretation 2. FMRI outcomes: BOLD-related evoked activity and functional connectivity maps will both undergo extensive QA procedures. 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 3. Investigators will examine the fit of different modeling parameters on a per-subject basis. 3. Description of Plan for Data Quality and Management and Data Collection Forms: The study staff under the over site of the PIs will review 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. The results of the data review will be incorporated into the reports for each DSMB meeting and in the Annual Report. Data collection forms will be maintained as part of Good Clinical Practice (GCP). Research coordinator will review data collection forms for completeness.


Minimum age: 18 Years. Maximum age: N/A. Gender(s): Female.


Inclusion Criteria:(For RCT) 1. Non-pregnant English-speaking women 2. 18 yo or older 3. OAB Awareness scores ≥ 8 4. 3 UUI episodes/week for ≥ 3 months Exclusion Criteria: (For RCT) 1. Women with a history of neurologic diseases such as Multiple Sclerosis, Parkinson's disease, stroke, or dementia 2. History of schizophrenia or untreated bipolar disorder or current drug or alcohol dependence 3. 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 4. Contraindications to anticholinergic medications (untreated narrow angle glaucoma, significant urinary retention or gastric retention) 5. 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) 6. Untreated urinary tract infection 7. Prolapse which extends past the hymen (POP-Q points of ≥ 1+) which may be responsible for UUI symptoms 8. 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.

Locations and Contacts

Yuko Komesu, MD, Phone: 505-272-9702, Email: ykomesu@salud.unm.edu

University of New Mexico Health Science Center, Albuquerque, New Mexico 87131, United States; Recruiting
Yuko Komesu, MD, Phone: 505-272-9712, Email: ykomesu@salud.unm.edu
Loren Ketai, MD, Phone: 505-272-2269, Email: lketai@salud.unm.edu
Yuko Komesu, MD, Principal Investigator
Additional Information

Related publications:

Komesu YM, Ketai LH, Mayer AR, Teshiba TM, Rogers RG. Functional MRI of the Brain in Women with Overactive Bladder: Brain Activation During Urinary Urgency. Female Pelvic Med Reconstr Surg. 2011;17(1):50-54.

Komesu YM, Sapien RE, Rogers RG, Ketai LH. Hypnotherapy for treatment of overactive bladder: a randomized controlled trial pilot study. Female Pelvic Med Reconstr Surg. 2011 Nov;17(6):308-13. doi: 10.1097/SPV.0b013e31823a08d9.

Coyne K, Revicki D, Hunt T, Corey R, Stewart W, Bentkover J, Kurth H, Abrams P. Psychometric validation of an overactive bladder symptom and health-related quality of life questionnaire: the OAB-q. Qual Life Res. 2002 Sep;11(6):563-74.

Sandvik H, Seim A, Vanvik A, Hunskaar S. A severity index for epidemiological surveys of female urinary incontinence: comparison with 48-hour pad-weighing tests. Neurourol Urodyn. 2000;19(2):137-45.

Coyne KS, Matza LS, Kopp Z, Abrams P. The validation of the patient perception of bladder condition (PPBC): a single-item global measure for patients with overactive bladder. Eur Urol. 2006 Jun;49(6):1079-86. Epub 2006 Jan 24.

Coyne KS, Zyczynski T, Margolis MK, Elinoff V, Roberts RG. Validation of an overactive bladder awareness tool for use in primary care settings. Adv Ther. 2005 Jul-Aug;22(4):381-94.

Burgio KL, Locher JL, Goode PS, Hardin JM, McDowell BJ, Dombrowski M, Candib D. Behavioral vs drug treatment for urge urinary incontinence in older women: a randomized controlled trial. JAMA. 1998 Dec 16;280(23):1995-2000.

Starting date: March 2013
Last updated: June 25, 2015

Page last updated: August 23, 2015

-- advertisement -- The American Red Cross
Home | About Us | Contact Us | Site usage policy | Privacy policy

All Rights reserved - Copyright DrugLib.com, 2006-2017