Clinical trial NCT00618956: A Study Of Milnacipran In Patients With Fibromyalgia: Effects On 24 Hour Ambulatory Blood Pressure Monitoring
Official title: A Randomized, Double-Blind, Placebo-Controlled, Dose Escalation Study of Milnacipran 100 And 200 MG Daily in Patients With Fibromyalgia: Effects On 24 Hour Ambulatory Blood Pressure
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Fibromyalgia
Keywords: NSRI
milnacipran
fibromyalgia
blood pressure
hypertension
Lead sponsor: Forest Laboratories
Sponsor class: INDUSTRY
Collaborators: name: Cypress Bioscience, Inc.
First posted: 2008-02-20
Enrollment: 321
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Detailed description: This study is double blind (neither you nor the physician will know if you are receiving active study drug or placebo, an inactive compound such as a sugar pill) and it is being conducted at various research centers in the United States.

If the study staff determines that you are eligible and you decide to participate, there will be approximately 11 study visits in about 3 months. During these visits, you will undergo routine health exams and complete different kinds of questionnaires.

This study requires that you wear a blood pressure cuff continuously for 24 hours on three separate occasions. You will also be required to make multiple same-day visits to the study site on three separate occasions for blood draws.

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

Primary outcomes:
measure: Change From Baseline in Mean Systolic Blood Pressure Following 12-hour Period Post-AM Dose at Visit 4
timeFrame: 4 weeks (1 week of dose-escalation, 3 weeks of 100 mg/d)
measure: Change From Baseline in Mean Systolic Blood Pressure Following 12-hour Period Post-AM Dose at Visit 6
timeFrame: 7 weeks (1 week of dose-escalation, 3 weeks of 100 mg/d, followed by 1 week at 150 mg/d and 2 weeks of 200 mg/d)
Secondary outcomes:
measure: Change From Baseline in Mean Systolic Blood Pressure /Diastolic Blood Pressure for 12-hour Period Post-AM Dose at Visit 4
timeFrame: 4 weeks (1 week of dose-escalation, 3 weeks of 100 mg/d)
measure: Change From Baseline in Mean SBP/DBP Following 12-hour Period Post-AM Dose at Visit 6
timeFrame: 7 weeks (1 week of dose-escalation, 3 weeks of 100 mg/d, followed by 1 week at 150 mg/d and 2 weeks of 200 mg/d)
measure: Change From Baseline in Mean Heart Rate (HR) Following 24-hour Treatment at Visit 4
timeFrame: 4 weeks (1 week of dose-escalation, 3 weeks of 100 mg/d)
measure: Change From Baseline in Mean HR Following 24-hour Treatment at Visit 6
timeFrame: 7 weeks (1 week of dose-escalation, 3 weeks of 100 mg/d, followed by 1 week at 150 mg/d and 2 weeks of 200 mg/d)
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Site #032
state: Alabama
city: Birmingham
country: United States
facility: Site #035
state: Alabama
city: Phoenix
country: United States
facility: Site #038
state: Arizona
city: Pismo Beach
country: United States
facility: Site #019
state: California
city: San Diego
country: United States
facility: Site #016
state: California
city: Walnut Creek
country: United States
facility: Site #008
state: California
city: Delray Beach
country: United States
facility: Site #037
state: Florida
city: Jacksonville
country: United States
facility: Site #025
state: Florida
city: Ocala
country: United States
facility: Site #009
state: Florida
city: Orlando
country: United States
facility: Site #011
state: Florida
city: Tampa
country: United States
facility: Site #036
state: Florida
city: Atlanta
country: United States
facility: Site #006
state: Georgia
city: Libertyville
country: United States
facility: Site #030
state: Illinois
city: Evansville
country: United States
facility: Site #018
state: Indiana
city: Indianapolis
country: United States
facility: Site #034
state: Indiana
city: Worchester
country: United States
facility: Site #004
state: Massachusetts
city: Springfield
country: United States
facility: Site #013
state: Missouri
city: Albuquerque
country: United States
facility: Site #021
state: New Mexico
city: East Syracuse
country: United States
facility: Site #005
state: New York
city: Rochester
country: United States
facility: Site #010
state: New York
city: Charlotte
country: United States
facility: Site #029
state: North Carolina
city: Winston-Salem
country: United States
facility: Site #022
state: North Carolina
city: Cleveland
country: United States
facility: Site #002
state: Ohio
city: Toledo
country: United States
facility: Site #017
state: Ohio
city: Eugene
country: United States
facility: Site #023
state: Oregon
city: Eugene
country: United States
facility: Site #007
state: Oregon
city: Medford
country: United States
facility: Site #001
state: Oregon
city: Mechanicsburg
country: United States
facility: Site #026
state: Pennsylvania
city: Greer
country: United States
facility: Site #014
state: South Carolina
city: Bristol
country: United States
facility: Site #027
state: Tennessee
city: Memphis
country: United States
facility: Site #024
state: Tennessee
city: Nashville
country: United States
facility: Site #031
state: Tennessee
city: Sugarland
country: United States
facility: Site #028
state: Texas
city: Salt Lake City
country: United States
facility: Site #003
state: Utah
city: Woodstock
country: United States
facility: Site #012
state: Vermont
city: Richmond
country: United States
facility: Site #020
state: Virginia
city: Bellingham
country: United States
facility: Site #015
state: Washington
city: Racine
country: United States
facility: Site #033
state: Wisconsin
Study officials:
affiliation: Forest Laboratories
name: Allan Spera
role: STUDY_DIRECTOR
References:
citation: Trugman JM, Palmer RH, Ma Y. Milnacipran effects on 24-hour ambulatory blood pressure and heart rate in fibromyalgia patients: a randomized, placebo-controlled, dose-escalation study. Curr Med Res Opin. 2014 Apr;30(4):589-97. doi: 10.1185/03007995.2013.861812. Epub 2013 Nov 20.