A Study Of Milnacipran In Patients With Fibromyalgia: Effects On 24 Hour Ambulatory Blood Pressure Monitoring
Condition: Fibromyalgia
MeSH terms: Fibromyalgia; Myofascial Pain Syndromes
Intervention: Milnacipran hydrochloride; Placebo
Intervention description: Milnacipran 100 to 200 mg/day tablet (administered in divided doses, twice daily [BID]), oral administration.; Placebo
Intervention MeSH terms: Milnacipran; Levomilnacipran
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 321.0
Sex: All
Minimum age: 18 Years
Maximum age: 70 Years
Healthy volunteers: No
Keywords: NSRI; milnacipran; fibromyalgia; blood pressure; hypertension

Summary:

      The study is designed to accurately assess any changes in blood pressure and pulse at 100 and
      200 mg daily dose of milnacipran in patients with fibromyalgia syndrome.
    

Eligibility criteria:

        Inclusion Criteria:

          -  To be eligible to participate in the study, patients must meet the following criteria:

               1. Patients may be male or female between the ages of 18 and 70 years, inclusive

               2. Patients must have been diagnosed of primary fibromyalgia, as defined by the 1990
                  ACR Criteria for the Classification of Fibromyalgia

               3. Females must be either postmenopausal (no menses for at least 1 year),
                  posthysterectomy, postoophorectomy (bilateral), or, if of childbearing potential,
                  must have a negative urine pregnancy test prior to randomization and be using a
                  medically acceptable form of contraception (eg, hormonal birth control, IUD,
                  double-barrier method [eg, simultaneous use of two of the following: male condom,
                  female condom, diaphragm], or a barrier method plus a spermicidal agent
                  [contraceptive foam, jelly, or cream])

               4. Patients must have the ability to give written informed consent

               5. Patients may have hypertension untreated or treated with a maximum of two
                  antihypertensive medications. (Note: medications contributing to a combination
                  product(s) will each be considered as a separate medication.) If untreated, the
                  patient should be stable, with no expectation of initiating treatment during the
                  study. If treated, the patient must have been on stable doses of antihypertensive
                  medications for at least 2 months, with the expectation that dose adjustments
                  will not be necessary for the duration of the study. A patient will be classified
                  as hypertensive if the patient is taking antihypertensive medication, has a SBP
                  equal to or greater than 130 mm Hg, or has a DBP equal to or greater than 85 mm
                  Hg. A patient will be classified as normotensive if he/she is not on
                  antihypertensive medication and has a SBP less than 130 mm Hg and DBP less than
                  85 mm Hg

               6. Patients must have a mean of two sitting SBP measurements of less than 160 mm Hg
                  and sitting DBP less than 100 mm Hg at Visit 1 (Screening) and Visit 2
                  (Baseline/Randomization) using an automatic office blood pressure monitor

               7. Patients must have normal physical examination findings, clinical laboratory
                  results, and electrocardiogram (ECG) results from Visit 1 (Screening) or abnormal
                  findings judged not clinically significant by the Investigator and documented as
                  such in the eCRF

               8. Patients must be willing to withdraw from CNS-active therapies marketed as
                  antidepressants, including monoamine oxidase inhibitors, tricyclics,
                  tetracyclics, selective-serotonin reuptake inhibitors (SSRIs), noradrenaline
                  reuptake inhibitors (NARIs), noradrenaline-serotonin reuptake inhibitors (NSRI),
                  serotonin-noradrenaline reuptake inhibitors (SNRIs), and St. John's Wort

               9. Patients must be willing to withdraw from pregabalin (Lyrica) or gabapentin
                  (Neurontin).

              10. Patients must be willing to withdraw from stimulant medications such as those
                  used to treat attention deficit disorder/attention deficit hyperactivity disorder
                  (eg, amphetamine/dextroamphetamine [Adderall], methylphenidate,
                  dextroamphetamine) or the fatigue associated with sleep apnea or shift work (eg,
                  modafinil)

              11. Patients must be willing to withdraw from anorectic agents such as diethylpropion
                  , sibutramine (Meridia), and phentermine (Adipex)

              12. Patients must be willing to withhold certain medications for the 24 hours before,
                  as well as during, any ABPM assessment. These medications include
                  phosphodiesterase type 5 inhibitors (eg, Viagra, Levitra, Cialis, Edex, Muse),
                  decongestants (eg, pseudoephedrine, phenylephrine), and antimigraine therapies
                  (eg, triptans such as Imitrex and Maxalt, ergotamines such as Cafergot and
                  Midrin). If, for any reason, the patient takes any of these medications, the ABPM
                  visit should be rescheduled so that at least 24 hours have transpired since the
                  patient's last use

        Exclusion Criteria:

          -  Patients who meet any of the following criteria will not be eligible to participate in
             the study:

          -  Psychological/Psychiatric Criteria

               1. Patients with a significant risk of suicide, according to the Investigator's
                  judgment or based on an answer of 2 or 3 for question 9 of the Beck Depression
                  Inventory (BDI) (regarding suicidal ideation) performed at Visit 1 (Screening) or
                  Visit 2 (Baseline/Randomization)

               2. Patients with a total BDI score greater than 25 at Visit 1 (Screening) or Visit 2
                  (Baseline/Randomization)

               3. Patients testing positive for illegal substances prior to Visit 2
                  (Baseline/Randomization) as demonstrated by positive drug screening or based on
                  the Investigator's judgment

               4. Patients with any history or behavior that would, in the Investigator's judgment,
                  prohibit compliance for the duration of the study

          -  Somatic Criteria

               1. Patients with myocardial infarction and/or stroke within the past 12 months;
                  active cardiac disease (American Heart Association Functional Class 2, 3, or 4);
                  congestive heart failure; hemodynamically significant valvular heart disease
                  (including patients with a prosthetic heart valve); hypertensive cardiovascular
                  disease changes (heart, eyes or kidneys) that in the Investigator's judgment,
                  would preclude patient participation; ischemic changes; and/or clinically
                  significant cardiac rhythm or conduction abnormalities (including atrial
                  fibrillation, left bundle branch block, second- or third-degree heart block)

               2. Patients with a mean of two sitting systolic blood pressure (SBP) readings equal
                  to or greater than 160 mm Hg or sitting diastolic blood pressure (DBP) equal to
                  or greater than 100 mm Hg at Visits 1 (Screening) and 2 (Baseline/Randomization)
                  using an automatic office blood pressure monitor

               3. Patients with pacemakers

               4. Patients with an upper arm circumference less than 24 cm or greater than 42 cm in
                  their nondominant arm

               5. Patients with evidence of active liver disease (levels of aspartate
                  aminotransferase, alanine aminotransferase, and/or alkaline phosphatase > 1.5×
                  the upper limit of the normal range for the clinical laboratory performing the
                  test)

               6. Patients with renal impairment (estimated creatinine clearance < 50 mL/min)

               7. Patients with documented autoimmune disease. Patients diagnosed with Hashimoto or
                  Grave disease that has been stable for 3 months prior to Visit 1 (Screening) will
                  be allowed to enroll

               8. Patients with current systemic infection (eg, human immunodeficiency virus,
                  hepatitis)

               9. Patients with active cancer, except basal cell carcinoma. Patients taking
                  prophylactic tamoxifen (or other antiestrogen agents) because of a family history
                  of breast cancer or patients taking tamoxifen (or other antiestrogen agents) but
                  who are at least 1 year post-active treatment of breast cancer, may be enrolled

              10. Patients with a current life expectancy of less than 1 year

              11. Patients with active peptic ulcer disease or history of inflammatory bowel
                  disease or celiac sprue

              12. Patients with pulmonary dysfunction or severe chronic obstructive pulmonary
                  disease that, in the Investigator's judgment, could interfere with study
                  participation and completion

              13. Patients with unstable endocrine disease, including unstable diabetes or thyroid
                  disease. Disorders that have been stable for the preceding 3 months will be
                  acceptable

              14. Male patients with prostatic enlargement or other genitourinary disorders who
                  might be at significant risk for dysuria and/or urinary retention while taking
                  agents with noradrenaline-reuptake inhibition properties

              15. Pregnant or breastfeeding patients

              16. Any other conditions (such as epilepsy) that, in the Investigator's judgment,
                  would indicate that the patient is unsuitable for the study (eg, might interfere
                  with study conduct, confound the interpretation of study results, endanger the
                  patient)

          -  Treatment-Related Criteria

               1. Patients who have received treatment with an experimental agent within the last
                  30 days prior to Visit 1 (Screening). Patients who have completed previous
                  milnacipran studies (ie, all respective protocol-related study procedures have
                  been completed by the patient) are eligible to participate. Any patients who
                  failed screening in previous milnacipran studies may be re-evaluated, and
                  eligible patients may enroll. Patients currently enrolled in Study MLN-MD-06 are
                  not eligible to participate

               2. Patients who are receiving concomitant therapy with digitalis (digoxin)
                  preparations. (Note: Patients should not undergo washout of digoxin; therefore,
                  patients on digoxin should not be enrolled in the study)

               3. Patients who are receiving concomitant therapy with monoamine oxidase inhibitors,
                  tricyclics, tetracyclics, SSRIs, noradrenaline or noradrenaline-serotonin (NSRI)
                  reuptake inhibitors, SNRIs, St. John's Wort, and/or other agents marketed as
                  antidepressants and are unable to washout or for whom washout is inadvisable*

               4. Patients who are receiving concomitant therapy with pregabalin (Lyrica) or
                  gabapentin (Neurontin) and are unable to washout or for whom washout is
                  inadvisable*

               5. Patients who are receiving concomitant therapy with stimulant medications such as
                  those used to treat attention deficit disorder/attention deficit hyperactivity
                  disorder (eg, amphetamine/dextroamphetamine [Adderall], methylphenidate,
                  dextroamphetamine) or the fatigue associated with sleep apnea or shift work (eg,
                  modafinil) and are unable to washout or for whom washout is inadvisable*

               6. Patients who are receiving concomitant therapy with anorectic agents such as
                  diethylpropion , sibutramine (Meridia), and phentermine (Adipex) and are unable
                  to washout or for whom washout is inadvisable*

               7. Patients who require the use of agents affecting serotonin pharmacology, such as
                  ondansetron (Zofran), granisetron (Kytril), and/or dolasetron (Anzemet)

               8. Patients who require doses of guaifenesin greater than 2400 mg/d (approximately
                  24 teaspoons)

          -  Occupational Criteria

             1. Patients whose occupation requires them to work nocturnal hours (eg, 11 PM to 7 AM)

          -  ABPM Criteria

               1. Patients whose ABPM results at Visit 2 (Baseline/Randomization) do not satisfy
                  ABPM inclusion/exclusion criteria outlined in the ABPM training manual