Milnacipran (Savella) in Irritable Bowel Syndrome (IBS)

A Randomized, Double-Blind, Placebo-Controlled Study to Assess the Efficacy of Milnacipran in the Treatment of Irritable Bowel Syndrome

Purpose: The investigators are proposing to examine the use of Savella® (Milnacipran) for treating irritable bowel syndrome (IBS) in women.

Participants: Eligible participants will meet the Rome III diagnostic criteria for IBS.

Procedures: This study will observe patients treated with Savella® as well as patients treated with a placebo (pill with no active drug). The investigators will monitor and compare several patient and symptom related outcomes, as well as evaluate health related quality of life, psychological distress and related psychosocial measures to determine if the addition of Savella® improves clinical pain response as well as secondary outcomes including quality of life.

Study Overview

• Status: Terminated
• Conditions: Irritable Bowel Syndrome
• Intervention / Treatment: Drug: Milnacipran; Drug: Milnacipran; Drug: Milnacipran; Drug: Placebo

Detailed Description

Irritable bowel syndrome (IBS) is a common functional gastrointestinal disorder characterized primarily by abdominal pain associated with bowel dysfunction. Like many other painful functional somatic syndromes (e.g. fibromyalgia) the pathophysiology of IBS includes abnormal responses to pain and dysregulation of brain-body pain pathways. IBS affects up to 10% of the population, is a leading reason for visits to gastroenterologists and primary care doctors, and, in the United States, annually accrues health care costs over $20 billion.

In their practice the investigators use centrally acting agents to treat IBS. Historically, the investigators have used tricyclic antidepressants based on results of clinical trials, including our NIH funded trial on desipramine. Nonetheless, these agents can produce side effects that limit their full application. More recently the investigators have begun to use SNRIs because they have been shown to benefit for various pain syndromes like diabetic neuropathy, fibromyalgia. The initial impression is that Milnacipran helps improve IBS symptoms and global well being. There is now a need to systematically determine Milnacipran's value for IBS.

• Study Type: Interventional
• Enrollment (Actual): 2
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • UNC Center for Functional GI and Motility Disorders

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 79 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• Meet Rome III criteria for IBS and have no red flags.
• Must have had a colonoscopy within the previous 5 years to exclude inflammatory or other bowel disease
• Be fluent and literate in English
• Must either be of non-childbearing potential or agree to utilize approved birth control for the duration of the study

Exclusion Criteria:

• Diagnosis or treatment of any clinically symptomatic biochemical or structural abnormality of the GI tract within 6 months prior to screening, or active disease within 6 months prior to screening.
• Any other diagnosis to explain the abdominal pain,
• Clinical evidence of significant cardiovascular, respiratory, renal, hepatic, gastrointestinal, hematologic, neurologic, psychiatric or any disease that may interfere with the subject successfully completing the trial
• Hepatic dysfunction (ALT [SGPT] or AST [SGOT] >3 times the upper limit of normal) or renal impairment (serum creatinine > 2mg/dL)
• Has disease affecting electrolytes balance, such as SIADH with serum Sodium less than 130mmol/L
• Any evidence of or treatment of malignancy (other than localized basal cell, squamous cell skin cancer or cancer in situ that has been resected) within the previous year
• Any surgery on the stomach, small intestine or colon, excluding appendectomy
• A major psychiatric disorder (DSM-III-R or DSM-IV) including major depression or other psychoses that has required hospitalization in the last 1 year.
• History of attempted suicide or uncontrolled bipolar disorder.
• Currently using antidepressants for psychiatric conditions like major depression. Use of TCA or SSRI class antidepressant acceptable if being used specifically for treatment of bowel symptoms and patient is willing to taper off the medication
• Previous use of Milnacipran or other SNRI antidepressant (duloxetine, venlafaxine, desvenlafaxine)
• A diagnosis of seizure disorder
• A diagnosis of glaucoma
• Currently taking heparin or warfarin

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Group A (50mg - 100mg); Group A will begin treatment with Milnacipran 50mg BID (n=20) during Phase I and will be increased to 100mg BID during Phase II	Drug: Milnacipran; 50mg Milnacipran PO, BID, for 6 weeks.; Other Names: Savella; Drug: Milnacipran; Milnacipran, 100mg PO, BID, for six weeks; Other Names: Savella; Drug: Milnacipran; Milnacipran, 50mg PO BID for 12 weeks; Other Names: Savella
Active Comparator: Group B (50mg x12); Subjects in this arm will be maintained at Milnacipran 50mg BID for the entirety of the 12 weeks of the study.	Drug: Milnacipran; 50mg Milnacipran PO, BID, for 6 weeks.; Other Names: Savella; Drug: Milnacipran; Milnacipran, 100mg PO, BID, for six weeks; Other Names: Savella; Drug: Milnacipran; Milnacipran, 50mg PO BID for 12 weeks; Other Names: Savella
Placebo Comparator: Group C (Placebo - 50mg); Group C will begin treatment with Placebo BID (n=20) during Phase I and will be given 50mg BID during Phase II	Drug: Milnacipran; 50mg Milnacipran PO, BID, for 6 weeks.; Other Names: Savella; Drug: Milnacipran; Milnacipran, 100mg PO, BID, for six weeks; Other Names: Savella; Drug: Milnacipran; Milnacipran, 50mg PO BID for 12 weeks; Other Names: Savella; Drug: Placebo; Inactive pill, identical in shape, size, and appearance to active drug, PO, BID.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Pain Response	Visual Analog Scale (VAS) scores (range 0-100 mm; 0 = none, 100 = worst pain) were recorded for pain before the beginning of the study, at 6 weeks of treatment and at the end visit i.e. 10 weeks. Ideally, VAS would have been administered at the 12th week; however, subject was terminated at the 10th week visit. A positive pain response (ie pain relief) was defined as >30% decrease in the VAS score between baseline and the final study visit.	Twelve Weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Quality of Life ( IBS-QOL)	After six weeks of treatment with Milnacipran, treatment groups were compared with placebo for clinically significant improvement in IBS-QOL. 11 point reduction in IBS-QOL compared to baseline was considered as clinically significant improvement.	Six Weeks
Subject Self Reported Adequate Relief of Pain	The study sought to determine if the Milnacipran arms had a greater proportion of adequate relief over the placebo group. Subjects were asked to answer 'yes' or 'no' as to whether or not they had adequate relief of pain due to irritable bowel syndrome.	Twelve Weeks
Treatment Efficacy Questionnaire (TEQ)	Treatment Efficacy Questionnaire is a measure of treatment effectiveness. The score ranges from 1 to 48, 1 is minimum score and 48 is the maximum score. The investigators was looking to see if the Milnacipran treatment groups have a higher proportion of subjects with significant improvement in efficacy, judged as a TEQ score of >28, compared to placebo group.	Twelve Weeks
Dose Related Incremental Benefit in Pain Reduction Based on VAS	The investigator was looking to see if, for group A, when increased from 50 mg BID to 100 mg BID there is significant improvement of pain scores i.e. 30% pain reduction, and for group C, if there was significant improvement of pain scores when switched from placebo to 50 mg BID of Milnacipran	12 Weeks

Collaborators and Investigators

• Sponsor: Spencer Dorn, MD, MPH
• Collaborators: Forest Laboratories
• Investigators: Principal Investigator: Spencer D Dorn, MD, MPH, University of North Carolina, Chapel Hill

Study record dates

Study Major Dates

• Study Start: April 1, 2012
• Primary Completion (Actual): February 1, 2013
• Study Completion (Actual): February 1, 2013

Study Registration Dates

• First Submitted: November 10, 2011
• First Submitted That Met QC Criteria: November 14, 2011
• First Posted (Estimate): November 16, 2011

Study Record Updates

• Last Update Posted (Actual): April 13, 2017
• Last Update Submitted That Met QC Criteria: March 15, 2017
• Last Verified: March 1, 2017

More Information

Terms related to this study

• Keywords: Irritable Bowel Syndrome; Abdominal Pain; IBS; Savella; Milnacipran
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Disease; Gastrointestinal Diseases; Colonic Diseases, Functional; Colonic Diseases; Intestinal Diseases; Syndrome; Irritable Bowel Syndrome; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Analgesics, Non-Narcotic; Psychotropic Drugs; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Antidepressive Agents; Serotonin and Noradrenaline Reuptake Inhibitors; Milnacipran; Levomilnacipran
• Other Study ID Numbers: 11-1105a

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No