Study of Orofacial Pain and PropRANOlol

Temporomandibular Disorders Clinical Trial

— SOPPRANO  

Official title:

Effect of COMT (Catecholamine-O-methyltransferase) Genetic Polymorphisms on Response to Propranolol Therapy in Temporomandibular Disorder

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02437383
• Other study ID #: 14-2526
• Secondary ID: 1U01DE024169-011
• Status: Completed
• Phase: Phase 2
• Start date: August 20, 2015
• Est. completion date: April 25, 2018

Study information

• Verified date: April 2018
• Source: University of North Carolina, Chapel Hill
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Purpose:

Primary: To evaluate the efficacy of extended-release (ER) propranolol compared to placebo in the reduction of a pain index in patients with temporomandibular disorder (TMD).

Secondary: To determine if extended-release propranolol efficacy varies according to participants' catechol-O-methyltransferase (COMT) genetic polymorphisms and to investigate the efficacy of extended-release propranolol compared with placebo using secondary endpoints.

Exploratory: To investigate whether the efficacy of extended-release propranolol in the reduction of the pain index varies according to participants' polymorphisms in 3 other genetic regions and according to various phenotypic characteristics.

Participants:

200 patients with chronic TMD will be randomly assigned, in a 1:1 parallel, double-blind fashion, to receive either extended-release propranolol or placebo at one of three study sites: University of North Carolina-Chapel Hill School of Dentistry; University of Florida-Gainesville College of Dentistry; and the State University of New York at Buffalo School of Dental Medicine.

Procedures (methods):

Randomization will be to either propranolol or placebo. The 10-week study treatment period is divided into: 1 week of drug titration, 8 weeks of drug maintenance, and 1 week of drug tapering. The titration and tapering doses are 60 mg (capsules) once per day orally; the maintenance dose is 60 mg twice per day orally. Participants will attend 6 clinic visits over 12-15 weeks as follows: screening and baseline visit (Visit [V] 0, 7-21 days prior to V1); randomization and start of treatment (titration) (V1, study day 0); maintenance visit 2 (V2, 1 week post-randomization, study day 7+3); maintenance visit 3 (V3, 5 weeks post-randomization, study day 35 +/- 7); tapering visit (V4, 9 weeks post-randomization, study day 63 +/- 7); and tapering visit 5 (V5, 11 weeks post-randomization and 1 week after drug tapering ends, study day 77 +/- 7). Depending on the visit, procedures will include: reviews of medical history, weekly alcohol consumption, concomitant therapies and medications, adverse events, compliance, and eligibility; administration/review of questionnaires; blood draw; pregnancy test in women of childbearing potential; and dispensing of study drug.

Description:

"Temporomandibular disorder" (TMD) encompasses all musculoskeletal disorders of the masticatory system and includes myalgia, arthralgia, temporomandibular joint (TMJ) disc displacements, and TMJ degenerative joint diseases. The prevalence of TMD ranges from 6% to 12% in the general population, with muscle dysfunction the most prevalent TMD diagnostic group. TMD is associated with substantial disability and suffering and negatively impacts quality of life. Jaw pain is the most common symptom that compels treatment seeking. In addition to facial pain, TMD patients frequently report comorbid pain conditions such as headache, low back pain, and fibromyalgia. New approaches to TMD therapy are urgently needed to improve clinical outcomes and reduce economic impact of this disorder.

There is currently no FDA-approved product labeled specifically to manage/treat TMD; however, classes of drugs are used to relieve TMD-associated pain, such as non-steroidal anti-inflammatory drugs (NSAIDs), anti-inflammatory drugs, corticosteroids, benzodiazepines, sedative hypnotics, muscle relaxants, opioids, antidepressants, and anticonvulsants - although evidence to establish their efficacy and safety in this population is scarce. Practitioners' justification for their use may be based on poorly controlled clinical trials or clinical trials in other pain disorders such as acute postsurgical dental pain, arthritic pain, chronic lower back pain, and neuropathic pain. Thus, there is a need for controlled clinical trials to better understand the physiological mechanisms responsible for TMD symptoms.

Evidence suggests that enhanced β-adrenergic drive contributes to the pathogenesis of TMD and other complex persistent pain conditions. For example, individuals with myofascial pain conditions have elevated catecholamine levels and augmented sympathetic responses to stressors. While increased β-adrenergic drive appears to heighten pain, β-adrenergic antagonists can reduce clinical pain and/or nociceptive sensitivity. A recent study of a single infusion of propranolol in TMD and fibromyalgia patients revealed short-term improvement in clinical pain ratings. The antagonist pindolol was similarly efficacious in alleviating cardinal symptoms of fibromyalgia pain. In addition, intramuscular injections of low-dose propranolol in rats reduced inflammatory pain associated with carrageen-induced inflammation of the gastrocnemius muscle.

The study hypothesis is that therapy with the nonselective β-adrenergic receptor antagonist propranolol extended-release capsules (FDA approved to treat many cardiac conditions, tremor, migraine, and pheochromocytoma) will provide efficacious and safe treatment for painful TMD. It has well-studied pharmacodynamic, pharmacokinetic, and side-effect profiles. Peak blood level occurs at approximately 6 hrs, and the plasma half-life is approximately 10 hrs. The primary objective is to investigate the efficacy of propranolol compared with placebo over 9 weeks to reduce pain in patients with TMD. Secondary objectives are to: investigate by treatment group whether reduction in pain varies according to polymorphisms in the COMT gene coding region; and investigate the effect of propranolol compared with placebo to affect pain sensitivity, physical and emotional function, adverse effects, and use of rescue medications. Exploratory objectives are to: investigate gene-by-treatment group interaction to determine the effect of propranolol on reduction in the pain index according to polymorphisms in the COMT, beta-2 adrenergic receptor (ADRβ2), and beta-3 adrenergic receptor (ADRβ3) genetic coding regions.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 200
• Est. completion date: April 25, 2018
• Est. primary completion date: April 4, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

Inclusion:

• Diagnostic criteria for TMD: Group II, Masticatory Muscle Disorders, Myalgia

• Facial pain for at least 3 months (and at least 10 of the last 30 days at Visit 0)

• Average pain intensity rating =30 (0-100 numeric rating scale) over the past week or average daily pain intensity rating =30 on the same scale on at least 3 days over the past week

• Agrees to terms for continuing/discontinuing certain prescription/over-the-counter pain medications throughout participation

• Agrees to not commence new prescription medication, injection therapy, occlusal splint therapy or certain other pain management techniques throughout participation

• Agrees to limit consumption of alcohol to no more than 7 drinks/week (females) and no more than 14 drinks/week (males) throughout participation

• If a female of childbearing potential, agrees to use of contraception (licensed hormonal method, intrauterine device, condoms with contraceptive foam, abstinence, or partner vasectomy) throughout participation

• Able to understand and comply with study procedures and provide written informed consent

Exclusion:

• History of congestive heart failure or certain cardiac conditions including coronary artery disease, uncontrolled hypertension, or hypotension

• Bronchial asthma, nonallergic bronchospasm, renal failure or dialysis, diabetes mellitus, hyperthyroidism, fibromyalgia, or uncontrolled seizures

• Currently taking a ß-blocker or certain other medications including haloperidol, intravenous verapamil, or reserpine

• Currently taking an opioid medication

• Daily prescription medication, occlusal splint therapy, or an investigational drug or treatment for pain management within past 30 days

• Injection therapy or certain other pain management techniques within last 2 weeks

• Facial trauma or orofacial surgery within past 6 weeks

• Active orthodontic treatment

• History of major depression or other psychiatric disorder requiring hospitalization within past 6 months

• Treatment for drug or alcohol abuse within the last year

• Smokes 25 or more cigarettes/day

• Currently receiving chemotherapy or radiation therapy

• Pregnant or breastfeeding

Related Conditions & MeSH terms

• Temporomandibular Disorders
• Temporomandibular Joint Disorders
• Temporomandibular Joint Dysfunction Syndrome

Intervention

Drug:
• Propranolol ER
Capsules given orally according to schedule at Visit 1, Visit 2, Visit 3, and Visit 4.
• Placebo
Gelatin capsules with a microcrystalline cellulose filler manufactured to mimic propranolol ER 60 mg capsules

Locations

Country	Name	City	State
United States	University at Buffalo School of Dental Medicine	Buffalo	New York
United States	University of North Carolina at Chapel Hill School of Dentistry	Chapel Hill	North Carolina
United States	University of Florida-Gainesville College of Dentistry	Gainesville	Florida

Sponsors (6)

Lead Sponsor	Collaborator
University of North Carolina, Chapel Hill	National Institute of Dental and Craniofacial Research (NIDCR), National Institutes of Health (NIH), Rho, Inc., State University of New York at Buffalo, University of Florida

Country where clinical trial is conducted

United States, 

References & Publications (3)

Diatchenko L, Slade GD, Nackley AG, Bhalang K, Sigurdsson A, Belfer I, Goldman D, Xu K, Shabalina SA, Shagin D, Max MB, Makarov SS, Maixner W. Genetic basis for individual variations in pain perception and the development of a chronic pain condition. Hum Mol Genet. 2005 Jan 1;14(1):135-43. Epub 2004 Nov 10. — View Citation

Gürsoy S, Erdal E, Herken H, Madenci E, Alasehirli B, Erdal N. Significance of catechol-O-methyltransferase gene polymorphism in fibromyalgia syndrome. Rheumatol Int. 2003 May;23(3):104-7. Epub 2002 Oct 22. — View Citation

Tchivileva IE, Lim PF, Smith SB, Slade GD, Diatchenko L, McLean SA, Maixner W. Effect of catechol-O-methyltransferase polymorphism on response to propranolol therapy in chronic musculoskeletal pain: a randomized, double-blind, placebo-controlled, crossover pilot study. Pharmacogenet Genomics. 2010 Apr;20(4):239-48. doi: 10.1097/FPC.0b013e328337f9ab. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Change in the Weekly Mean Pain Index After 9 Weeks of Treatment Stratified Per Number of COMT LPS Haplotypes	Weekly mean pain index computed as the arithmetic mean of daily pain index values during the week prior to randomization and prior to each study visit. Daily pain index is computed as pain intensity (0-100 numeric rating scale where 0 = "no pain" and 100 = "the most intense pain imaginable") multiplied by pain duration (0-100 percentage scale where percent = "percent of waking day you had facial pain") as reported in the Daily Symptom Diary, divided by 100. The pain index range is from 0 to 100. A higher score means a worse outcome. The pain index was stratified per number of catechol-O-methyltransferase (COMT) Low Pain Sensitive (LPS) haplotypes.	Visit 1 (study day 0) and Visit 4 (study day 63 +/-7)
Other	Change in the Weekly Mean Pain Index After 9 Weeks of Treatment Stratified Per Number of COMT Valine Alleles at rs4680	Weekly mean pain index computed as the arithmetic mean of daily pain index values during the week prior to randomization and prior to each study visit. Daily pain index is computed as pain intensity (0-100 numeric rating scale where 0 = "no pain" and 100 = "the most intense pain imaginable") multiplied by pain duration (0-100 percentage scale where percent = "percent of waking day you had facial pain") as reported in the Daily Symptom Diary, divided by 100. The pain index range is from 0 to 100. A higher score means a worse outcome. The pain index was stratified per number of catechol-O-methyltransferase (COMT) valine alleles at single nucleotide polymorphism (SNP) rs4680.	Visit 1 (study day 0) and Visit 4 (study day 63 +/-7)
Primary	Change in the Weekly Mean Pain Index After 9 Weeks of Treatment	Weekly mean pain index computed as the arithmetic mean of daily pain index values during the week prior to randomization and prior to each study visit. Daily pain index is computed as pain intensity (0-100 numeric rating scale where 0 = "no pain" and 100 = "the most intense pain imaginable") multiplied by pain duration (0-100 percentage scale where percent = "percent of waking day you had facial pain") as reported in the Daily Symptom Diary and divided by 100. The pain index range is from 0 to 100. A higher score means a worse outcome.	Visit 1 (study day 0) and Visit 4 (study day 63 +/-7)
Secondary	Change in the Weekly Mean Pain Intensity After 9 Weeks of Treatment	Weekly mean pain intensity computed as the arithmetic mean of daily pain intensity values during the week prior to randomization and prior to each study visit. Daily pain intensity is measured on 0-100 numeric rating scale where 0 = "no pain" and 100 = "the most intense pain imaginable") as reported in the Daily Symptom Diary. A higher score means a worse outcome.	Visit 1 (study day 0) and Visit 4 (study day 63 +/-7)
Secondary	Change in the Weekly Mean Pain Duration After 9 Weeks of Treatment	Weekly mean pain duration computed as the arithmetic mean of daily pain duration values during the week prior to randomization and prior to each study visit. Daily pain duration is measured on 0-100 percentage scale where percent = "percent of waking day you had facial pain" as reported in the Daily Symptom Diary. A higher score means a worse outcome.	Visit 1 (study day 0) and Visit 4 (study day 63 +/-7)
Secondary	Change in the SF-McGill Pain Questionnaire Affective Component After 9 Weeks of Treatment	The SF-McGill Pain Questionnaire contains 4 affective descriptors rated on a 0-3 scale where 0 = "none," 1 = "mild," 2 = "moderate," and 3 = "severe." The item scores are summed to yield a total score ranging from 0 to 12. A higher score means a worse outcome.	Visit 1 (study day 0) and Visit 4 (study day 63 +/-7)
Secondary	Change in the SF-McGill Pain Questionnaire Sensory Component After 9 Weeks of Treatment	The SF-McGill Pain Questionnaire contains 11 sensory descriptors rated on a 0-3 scale where 0 = "none," 1 = "mild," 2 = "moderate," and 3 = "severe." The item scores are summed to yield a total score ranging from 0 to 33. A higher score means a worse outcome.	Visit 1 (study day 0) and Visit 4 (study day 63 +/-7)
Secondary	Change in the SF-McGill Pain Questionnaire Present Facial Pain Intensity After 9 Weeks of Treatment	Self-reported present intensity of facial pain at the moment of assessment scored on a descriptive scale where 1 = "no pain' and 6 = "excruciating pain." A higher score means worse outcome.	Visit 1 (study day 0) and Visit 4 (study day 63 +/-7)
Secondary	Change in the SF-McGill Pain Questionnaire Weekly Average Facial Pain Intensity After 9 Weeks of Treatment	Self-reported average facial pain intensity for the last week scored on 0-100 numerical rating scale where 0 = "no pain" and 100 = "the most intense pain imaginable". A higher score means a worse outcome.	Visit 1 (study day 0) and Visit 4 (study day 63 +/-7)
Secondary	Change in the SF-McGill Pain Questionnaire Weekly Average Facial Pain Duration After 9 Weeks of Treatment	Self-reported average facial pain duration for the last week scored on 0-100 percentage scale where percent = "percent of waking day you had facial pain". A higher score means a worse outcome.	Visit 1 (study day 0) and Visit 4 (study day 63 +/-7)
Secondary	Change in the SF-McGill Pain Questionnaire Weekly Fatigue After 9 Weeks of Treatment	Self-reported average fatigue for the last week scored on 0-100 numerical rating scale where 0 = "no fatigue" and 100 = "the greatest imaginable." A higher score means a worse outcome.	Visit 1 (study day 0) and Visit 4 (study day 63 +/-7)
Secondary	Number of Participants Stratified Per Graded Chronic Pain Scale (GCPS) Grade After 9 Weeks of Treatment	Individuals were classified into 6 chronic pain grades: 0 = no pain; I = low pain intensity and low pain-related disability; IIa = high pain intensity and low pain-related disability; IIb = high pain intensity and high activity interference; III = moderate pain-related disability; and IV = severe pain-related disability. For analyses, this variable was dichotomized: grades 0-IIa were combined in one category and all higher grades in another. A higher grade means a worse outcome.	Visit 4 (study day 63 +/-7)
Secondary	Change in the Jaw Functional Limitation Scale (JFLS) Global Score After 9 Weeks of Treatment	The JFLS contains 20 items that measure limitations across mastication, vertical jaw mobility, and verbal/emotional expression rated on a 0-10 scale where 0 = "no limitation" and 10 = "severe limitation." The Global Score is computed as the mean response for all items and ranges from 0 to 10. A higher score means a worse outcome.	Visit 1 (study day 0) and Visit 4 (study day 63 +/-7)
Secondary	Change in the Headache Impact Test (HIT-6) Global Score After 9 Weeks of Treatment	The HIT-6 contains 6 items and assesses headache-related disability by the frequency of daily activity limitations ranging from "never" to "always." The 6 item scores are summed to yield a global score ranging from 36 to 78. A higher score means a worse outcome.	Visit 1 (study day 0) and Visit 4 (study day 63 +/-7)
Secondary	Change in the Pittsburgh Sleep Quality Index (PSQI) Global Score After 9 Weeks of Treatment	The PSQI has 19 items grouped into 7 component scores, each weighted equally on a 0-3 scale, The 7 component scores are summed to yield a global PSQI score, which has a range of 0-21. A higher score means a worse outcome.	Visit 1 (study day 0) and Visit 4 (study day 63 +/-7)
Secondary	Number of Participants Stratified Per Dichotomized Score From the Patient Global Impression of Change (PGIC) Scale After 9 Weeks of Treatment	The PGIC scale assesses patient overall change in the severity of illness following treatment. Participants rate how they feel now compared with how they felt before receiving study drug on a 7-point scale where 0 = "No change or condition has got worse" and 6 = "A great deal better." A higher score means a better outcome. For analyses, this variable was dichotomized: scores from 0 to 3 were combined in one category of "No" (no significant improvement) and scores from 4 to 6 were combined in another category of "Yes" (significant improvement with the study treatment).	Visit 4 (study day 63 +/-7)
Secondary	Change in the Perceived Stress Scale (PSS) Global Score After 9 Weeks of Treatment	The PSS assesses the frequency of 14 sources of stress on a scale from 0 = "never" to 4 = "very often." The item scores are summed to yield a global score ranging from 0 to 56. A higher score means a worse outcome.	Visit 1 (study day 0) and Visit 4 (study day 63 +/-7)
Secondary	Change in the Hospital Anxiety and Depression Scale (HADS) Depression Score After 9 Weeks of Treatment	The HADS is a 14-item assessment of anxiety (7 items) and depression (7 items) using the relative frequency of symptoms over the past week, rated on a 4-point scale ranging from 0 = "not at all" to 3 = "very often indeed". Responses are summed to provide separate scores for anxiety and depression with a range from 0 to 21. A higher score means a worse outcome.	Visit 1 (study day 0) and Visit 4 (study day 63 +/-7)
Secondary	Change in the Hospital Anxiety and Depression Scale (HADS) Anxiety Score After 9 Weeks of Treatment	The HADS is a 14-item assessment of anxiety (7 items) and depression (7 items) using the relative frequency of symptoms over the past week, rated on a 4-point scale ranging from 0 = "not at all" to 3 = "very often indeed". Responses are summed to provide separate scores for anxiety and depression with a range from 0 to 21. A higher score means a worse outcome.	Visit 1 (study day 0) and Visit 4 (study day 63 +/-7)
Secondary	Change in the Symptom Checklist 90-Revised (SCL-90R) Somatization Scale Score After 9 Weeks of Treatment	The SCL-90R Somatization Scale is a 12-item assessment of somatic symptom distress over the past 7 days rated from 0 = "not at all" to 4 = "extremely." The scale score is computed as the mean for all items. The score range is from 0 to 4. A higher score means a worse outcome.	Visit 1 (study day 0) and Visit 4 (study day 63 +/-7)
Secondary	Change in the SF-12 Health Survey v2 (SF-12v2) Physical Component Summary (PCS) After 9 Weeks of Treatment	The SF-12v2 contains 7 questions assessing 8 domains of functioning and well-being rated from: "excellent" to "poor" (for general health); "yes, limited a lot" to "no, not limited at all" (for functional level); and "all of the time" to "none of the time" (for emotional state). These 8 domains can be further summarized into a physical component summary (PCS) and a mental component summary (MCS). summary (MCS). The range for each component is 0-100 and a higher score means a better outcome.	Visit 1 (study day 0) and Visit 4 (study day 63 +/-7)
Secondary	Change in the SF-12 Health Survey v2 (SF-12v2) Mental Component Summary (MCS) After 9 Weeks of Treatment	The SF-12v2 contains 7 questions assessing 8 domains of functioning and well-being rated from: "excellent" to "poor" (for general health); "yes, limited a lot" to "no, not limited at all" (for functional level); and "all of the time" to "none of the time" (for emotional state). These 8 domains can be further summarized into a physical component summary (PCS) and a mental component summary (MCS). The range for each component is 0-100 and a higher score means a better outcome.	Visit 1 (study day 0) and Visit 4 (study day 63 +/-7)
Secondary	Change in Thermal Pain Threshold After 9 Weeks of Treatment	Temperature values, measured in degrees Celsius, from 4 examiner-applied contact heat stimuli will be averaged to measure the experimental thermal pain threshold (temperature at which pain is first perceived). The range was 32-50 degrees Celsius and a higher value means a better outcome.	Visit 1 (study day 0) and Visit 4 (study day 63 +/-7)
Secondary	Change in Thermal Pain Tolerance After 9 Weeks of Treatment	Temperature values, measured in degrees Celsius, from 4 examiner-applied contact heat stimuli will be averaged to measure the experimental thermal pain tolerance (temperature at which pain can no longer be tolerated). The range was 32-50 degrees Celsius and a higher value means a better outcome.	Visit 1 (study day 0) and Visit 4 (study day 63 +/-7)
Secondary	Change in Pressure Pain Threshold at Temporalis Muscle After 9 Weeks of Treatment	Pressure values, measured in kilopascals (kPa), from up to 5 experimental pressure stimuli, bilaterally applied to the area of temporalis muscle, are averaged to obtain a single pressure pain threshold value per anatomical site. The range is 0-500 kPa and a higher value means a better outcome.	Visit 1 (study day 0) and Visit 4 (study day 63 +/-7)
Secondary	Change in Pressure Pain Threshold at Masseter Muscle After 9 Weeks of Treatment	Pressure values, measured in kilopascals, from up to 5 experimental pressure stimuli, bilaterally applied to the area of masseter muscle, will be averaged to obtain a single pressure pain threshold value per anatomical site.	Visit 1 (study day 0) and Visit 4 (study day 63 +/- 7)
Secondary	Change in Pressure Pain Threshold at Temporomandibular Joint After 9 Weeks of Treatment	Pressure values, measured in kilopascals, from up to 5 experimental pressure stimuli, bilaterally applied to the area of temporomandibular joint, will be averaged to obtain a single pressure pain threshold value per anatomical site.	Visit 1 (study day 0) and Visit 4 (study day 63 +/-7)
Secondary	Change in Pressure Pain Threshold at Trapezius Muscle After 9 Weeks of Treatment	Pressure values, measured in kilopascals, from up to 5 experimental pressure stimuli, bilaterally applied to the area of trapezius muscle, will be averaged to obtain a single pressure pain threshold value per anatomical site.	Visit 1 (study day 0) and Visit 4 (study day 63 +/-7)
Secondary	Change in Pressure Pain Threshold at Lateral Epicondyle After 9 Weeks of Treatment	Pressure values, measured in kilopascals, from up to 5 experimental pressure stimuli, bilaterally applied to the area of lateral epicondyle, will be averaged to obtain a single pressure pain threshold value per anatomical site.	Visit 1 (study day 0) and Visit 4 (study day 63 +/-7)
Secondary	Change in Pain-free Jaw Opening After 9 Weeks of Treatment	Measured at TMD exam. A higher value means a better outcome.	Visit 1 (study day 0) and Visit 4 (study day 63 +/-7)
Secondary	Change in Maximum Unassisted Jaw Opening After 9 Weeks of Treatment	Measured at TMD exam. A higher value means a better outcome.	Visit 1 (study day 0) and Visit 4 (study day 63 +/-7)
Secondary	Change in Maximum Assisted Jaw Opening After 9 Weeks of Treatment	Measured at TMD exam. A higher value means a better outcome.	Visit 1 (study day 0) and Visit 4 (study day 63 +/-7)
Secondary	Change in Systolic Blood Pressure After 9 Weeks of Treatment	Average of 3 repeated measures taken with a 2-minute interval.	Visit 1 (study day 0) and Visit 4 (study day 63 +/-7)
Secondary	Change in Diastolic Blood Pressure After 9 Weeks of Treatment	Average of 3 repeated measures taken with a 2-minute interval.	Visit 1 (study day 0) and Visit 4 (study day 63 +/-7)
Secondary	Change in Heart Rate After 9 Weeks of Treatment	Average of 3 repeated measures taken with a 2-minute interval.	Visit 1 (study day 0) and Visit 4 (study day 63 +/-7)