Trial Outcomes & Findings for Milnacipran in the Treatment of Widespread, Non-Joint Pain in Rheumatoid Arthritis (NCT NCT01207453)

NCT ID: NCT01207453

Last Updated: 2014-11-17

Results Overview

A measure of change in scores on the BPI short form, a "24-hr average pain" item, from baseline to 6 weeks, The BPI short form scores ranges from 0-10, with 10 being the worst pain.

• Recruitment status: COMPLETED
• Study phase: PHASE4
• Target enrollment: 49 participants
• Primary outcome timeframe: Baseline to 6 weeks
• Results posted on: 2014-11-17

Participant Flow

49 patients signed the informed consent document. 8 patients did not meet inclusion criteria and failed screening. 41 patients were randomized and received >= 1 dose of the study drug/placebo. Seven patients stopped participation due to adverse events, and 2 were lost to follow-up. 32 patients completed the study and were analyzed.

Participant milestones

Measure	Milnacipran and Then Placebo Participants first received 6 weeks of milnacipran (titrated up to full dose of 50 mg twice daily). This was followed by a 3-week wash-out. Participants then received 6 weeks of placebo.	Placebo and Then Milnacipran Participants first received 6 weeks of placebo. This was followed by a 3-week wash-out. After the wash-out period, participants then received 6 weeks of milnacipran (titrated up to full dose of 50 mg twice daily).
First Intervention STARTED	23	18
First Intervention COMPLETED	21	17
First Intervention NOT COMPLETED	2	1
Washout STARTED	21	17
Washout COMPLETED	19	17
Washout NOT COMPLETED	2	0
2nd Intervention STARTED	19	17
2nd Intervention COMPLETED	17	15
2nd Intervention NOT COMPLETED	2	2

Reasons for withdrawal

Measure	Milnacipran and Then Placebo Participants first received 6 weeks of milnacipran (titrated up to full dose of 50 mg twice daily). This was followed by a 3-week wash-out. Participants then received 6 weeks of placebo.	Placebo and Then Milnacipran Participants first received 6 weeks of placebo. This was followed by a 3-week wash-out. After the wash-out period, participants then received 6 weeks of milnacipran (titrated up to full dose of 50 mg twice daily).
First Intervention Adverse Event	2	1
Washout Adverse Event	1	0
Washout Lost to Follow-up	1	0
2nd Intervention Adverse Event	1	2
2nd Intervention Lost to Follow-up	1	0

Baseline Characteristics

Milnacipran in the Treatment of Widespread, Non-Joint Pain in Rheumatoid Arthritis

Baseline characteristics by cohort

Measure	Milnacipran and Then Placebo n=23 Participants Participants first received 6 weeks of milnacipran (titrated up to full dose of 50 mg twice daily). This was followed by a 3-week wash-out. Participants then received 6 weeks of placebo.	Placebo and Then Milnacipran n=18 Participants Participants first received 6 weeks of placebo. This was followed by a 3-week wash-out. After the wash-out period, participants then received 6 weeks of milnacipran (titrated up to full dose of 50 mg twice daily).	Total n=41 Participants Total of all reporting groups
Age, Continuous Age	56.39 Year STANDARD_DEVIATION 12.35 • n=5 Participants	58.50 Year STANDARD_DEVIATION 14.79 • n=7 Participants	57.32 Year STANDARD_DEVIATION 13.34 • n=5 Participants
Sex: Female, Male Female	19 Participants n=5 Participants	15 Participants n=7 Participants	34 Participants n=5 Participants
Sex: Female, Male Male	4 Participants n=5 Participants	3 Participants n=7 Participants	7 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline to 6 weeks

A measure of change in scores on the BPI short form, a "24-hr average pain" item, from baseline to 6 weeks, The BPI short form scores ranges from 0-10, with 10 being the worst pain.

Outcome measures

Measure	Placebo n=32 Participants Participants who received placebo in either the first or last 6 weeks of the study.	Milnacipran n=32 Participants Participants who received milnacipran in either the first or last 6 weeks of the study. Milnacipran is taken orally. Participants will gradually be increased to a target dose of 50 mg twice daily.
Brief Pain Inventory (BPI) Change Baseline	5.2 units on a scale Standard Deviation 2.1	5.6 units on a scale Standard Deviation 2.0
Brief Pain Inventory (BPI) Change 6 weeks	4.9 units on a scale Standard Deviation 2.1	4.8 units on a scale Standard Deviation 2.2
Brief Pain Inventory (BPI) Change Change	-0.3 units on a scale Standard Deviation 2.0	-0.7 units on a scale Standard Deviation 1.7

SECONDARY outcome

Timeframe: Baseline to 6 weeks

CPM is defined as the difference between pain threshold A (measured after a conditioning stimulus activates pathways that inhibit pain) and pain threshold B (measured before the conditioning stimulus is applied). The conditioning stimulus was immersion of the hand in a cold water bath. Pressure pain threshold was assessed at the trapezius muscle initially. Subjects were then instructed to immerse their hand in a water bath for 30 seconds. At 20 seconds, pressure pain threshold at the trapezius was assessed again. We defined the magnitude of subjects' CPM as the difference in pressure pain threshold between baseline and 20 seconds after cold water immersion. This difference was compared to that measured at 6 weeks. The scale for the difference in CPM ranged from 0-11 kg/cm^2, with 0 indicating no change in CPM between 6 weeks and baseline and 11 indicating the maximum possible change. A greater change in CPM between baseline and 6 weeks is indicative of improvements in CPM.

Outcome measures

Measure	Placebo n=32 Participants Participants who received placebo in either the first or last 6 weeks of the study.	Milnacipran n=32 Participants Participants who received milnacipran in either the first or last 6 weeks of the study. Milnacipran is taken orally. Participants will gradually be increased to a target dose of 50 mg twice daily.
Change in Conditioned Pain Modulation (CPM) Baseline	0.8 kg/cm^2 Standard Deviation 1.0	0.8 kg/cm^2 Standard Deviation 1.1
Change in Conditioned Pain Modulation (CPM) 6 Weeks	0.9 kg/cm^2 Standard Deviation 1.3	0.9 kg/cm^2 Standard Deviation 1.1
Change in Conditioned Pain Modulation (CPM) Change	0.1 kg/cm^2 Standard Deviation 1.2	0.1 kg/cm^2 Standard Deviation 1.5

SECONDARY outcome

Timeframe: Baseline to 6 weeks

A measure of the change in SIS score from baseline to 6 weeks. The SIS score ranges from 0-9.75, with high scores being worse indicating more widespread pain and fatigue.

Outcome measures

Measure	Placebo n=32 Participants Participants who received placebo in either the first or last 6 weeks of the study.	Milnacipran n=32 Participants Participants who received milnacipran in either the first or last 6 weeks of the study. Milnacipran is taken orally. Participants will gradually be increased to a target dose of 50 mg twice daily.
Symptom Intensity Scale (SIS) Baseline	5.1 units on a scale Standard Deviation 2.1	5.2 units on a scale Standard Deviation 2.0
Symptom Intensity Scale (SIS) 6 weeks	4.3 units on a scale Standard Deviation 2.4	4.5 units on a scale Standard Deviation 8.3
Symptom Intensity Scale (SIS) Change	-0.8 units on a scale Standard Deviation 1.9	-0.7 units on a scale Standard Deviation 1.6

SECONDARY outcome

Timeframe: Baseline to 6 weeks

A measure of the change in thumbnail pain threshold from baseline to 6 weeks. Thumbnail pain threshold was determined by applying pressure to a subjectt's thumbnail until the subject felt pain. The difference between the average thumbnail pain threshold (an average for the right and left thumbs) at baseline was compared to that at 6 months. Pain threshold was measured in kg/cm^2. The difference in threshold could range from 0-11 kg/cm^2. A higher difference between thresholds indicates improved pain sensitivity.

Outcome measures

Measure	Placebo n=32 Participants Participants who received placebo in either the first or last 6 weeks of the study.	Milnacipran n=32 Participants Participants who received milnacipran in either the first or last 6 weeks of the study. Milnacipran is taken orally. Participants will gradually be increased to a target dose of 50 mg twice daily.
Thumbnail Pain Threshold Baseline	5.8 kg/cm^2 Standard Deviation 3.0	5.3 kg/cm^2 Standard Deviation 2.7
Thumbnail Pain Threshold 6 weeks	5.8 kg/cm^2 Standard Deviation 2.8	6.0 kg/cm^2 Standard Deviation 2.8
Thumbnail Pain Threshold Change	-0.02 kg/cm^2 Standard Deviation 1.4	0.7 kg/cm^2 Standard Deviation 1.4

SECONDARY outcome

Timeframe: Baseline to 6 weeks

A measure of the change in trapezius pain threshold from baseline to 6 weeks. Trapezius pain threshold was determined by applying pressure to a subject's trapezius muscle until the subject felt pain. The difference between the average trapezius pain threshold (an average for the right and left trapezii) at baseline was compared to that at 6 months. Pain threshold was measured in kg/cm^2. The difference in threshold could range from 0-11 kg/cm^2. A higher difference between thresholds indicates improved pain sensitivity.

Outcome measures

Measure	Placebo n=32 Participants Participants who received placebo in either the first or last 6 weeks of the study.	Milnacipran n=32 Participants Participants who received milnacipran in either the first or last 6 weeks of the study. Milnacipran is taken orally. Participants will gradually be increased to a target dose of 50 mg twice daily.
Trapezius Pain Threshold Baseline	4.9 kg/cm^2 Standard Deviation 2.8	5.1 kg/cm^2 Standard Deviation 3.1
Trapezius Pain Threshold 6 Weeks	5.5 kg/cm^2 Standard Deviation 3.1	5.5 kg/cm^2 Standard Deviation 3.1
Trapezius Pain Threshold Change	0.6 kg/cm^2 Standard Deviation 1.5	0.4 kg/cm^2 Standard Deviation 1.3

SECONDARY outcome

Timeframe: Baseline to 6 weeks

A measure of the change in wrist pain threshold from baseline to 6 weeks. Wrist pain threshold was determined by applying pressure to a subject's wrist until the subject felt pain. The difference between the average wrist pain threshold (an average for the right and left wrists) at baseline was compared to that at 6 months. Pain threshold was measured in kg/cm^2. The difference in threshold could range from 0-11 kg/cm^2. A higher difference between thresholds indicates improved pain sensitivity.

Outcome measures

Measure	Placebo n=32 Participants Participants who received placebo in either the first or last 6 weeks of the study.	Milnacipran n=32 Participants Participants who received milnacipran in either the first or last 6 weeks of the study. Milnacipran is taken orally. Participants will gradually be increased to a target dose of 50 mg twice daily.
Wrist Pain Threshold Baseline	5.3 kg/cm^2 Standard Deviation 2.7	5.0 kg/cm^2 Standard Deviation 2.4
Wrist Pain Threshold 6 weeks	5.9 kg/cm^2 Standard Deviation 3.0	5.9 kg/cm^2 Standard Deviation 2.9
Wrist Pain Threshold Change	0.6 kg/cm^2 Standard Deviation 1.6	0.9 kg/cm^2 Standard Deviation 1.5

SECONDARY outcome

Timeframe: Baseline to 6 weeks

A measure of the change in knee pain threshold from baseline to 6 weeks. Knee pain threshold was determined by applying pressure to a subject's knee until the subject felt pain. The difference between the average knee pain threshold (an average for the right and left knees) at baseline was compared to that at 6 months. Pain threshold was measured in kg/cm^2. The difference in threshold could range from 0-11 kg/cm^2. A higher difference between thresholds indicates improved pain sensitivity.

Outcome measures

Measure	Placebo n=32 Participants Participants who received placebo in either the first or last 6 weeks of the study.	Milnacipran n=32 Participants Participants who received milnacipran in either the first or last 6 weeks of the study. Milnacipran is taken orally. Participants will gradually be increased to a target dose of 50 mg twice daily.
Knee Pain Threshold Baseline	7.0 kg/cm^2 Standard Deviation 3.1	6.9 kg/cm^2 Standard Deviation 3.2
Knee Pain Threshold 6 weeks	7.3 kg/cm^2 Standard Deviation 3.1	7.3 kg/cm^2 Standard Deviation 3.2
Knee Pain Threshold Change	0.3 kg/cm^2 Standard Deviation 1.8	0.3 kg/cm^2 Standard Deviation 1.4

Adverse Events

Milnacipran

Serious events: 0 serious events

Other events: 17 other events

Deaths: 0 deaths

Placebo

Serious events: 1 serious events

Other events: 8 other events

Deaths: 0 deaths

Washout Period

Serious events: 0 serious events

Other events: 1 other events

Deaths: 0 deaths

Serious adverse events

Measure	Milnacipran n=41 participants at risk Participants received milnacipran for 6 weeks. The dose was titrated according to the following schedule: 1) Days 1-3: milnacipran 12.5 mg twice daily, 2) Days 4-6: milnacipran 25 mg twice daily, 3) Days 7-42: milnacipran 50 mg twice daily. If participants could not tolerate the full dose, the dose was decreased to the highest tolerated dose.	Placebo n=41 participants at risk Participants received placebo tablets for 6 weeks. The tablets were identical in appearance to the milnacipran tablets.	Washout Period n=41 participants at risk This 3-week period occurred after the first 6 weeks (when participants either received milnacipran or placebo). During the washout period, participants down titrated from the full dosage of milnacipran/placebo to nothing.
Gastrointestinal disorders Colon Abscess	0.00% 0/41 • 6 weeks for intervention with a period of 3 weeks of washout between each intervention period.	2.4% 1/41 • Number of events 1 • 6 weeks for intervention with a period of 3 weeks of washout between each intervention period.	0.00% 0/41 • 6 weeks for intervention with a period of 3 weeks of washout between each intervention period.

Other adverse events

Measure	Milnacipran n=41 participants at risk Participants received milnacipran for 6 weeks. The dose was titrated according to the following schedule: 1) Days 1-3: milnacipran 12.5 mg twice daily, 2) Days 4-6: milnacipran 25 mg twice daily, 3) Days 7-42: milnacipran 50 mg twice daily. If participants could not tolerate the full dose, the dose was decreased to the highest tolerated dose.	Placebo n=41 participants at risk Participants received placebo tablets for 6 weeks. The tablets were identical in appearance to the milnacipran tablets.	Washout Period n=41 participants at risk This 3-week period occurred after the first 6 weeks (when participants either received milnacipran or placebo). During the washout period, participants down titrated from the full dosage of milnacipran/placebo to nothing.
General disorders Headache	4.9% 2/41 • Number of events 2 • 6 weeks for intervention with a period of 3 weeks of washout between each intervention period.	4.9% 2/41 • Number of events 2 • 6 weeks for intervention with a period of 3 weeks of washout between each intervention period.	0.00% 0/41 • 6 weeks for intervention with a period of 3 weeks of washout between each intervention period.
Gastrointestinal disorders Nausea	26.8% 11/41 • Number of events 12 • 6 weeks for intervention with a period of 3 weeks of washout between each intervention period.	7.3% 3/41 • Number of events 4 • 6 weeks for intervention with a period of 3 weeks of washout between each intervention period.	2.4% 1/41 • Number of events 1 • 6 weeks for intervention with a period of 3 weeks of washout between each intervention period.
General disorders Dizziness	4.9% 2/41 • Number of events 2 • 6 weeks for intervention with a period of 3 weeks of washout between each intervention period.	2.4% 1/41 • Number of events 2 • 6 weeks for intervention with a period of 3 weeks of washout between each intervention period.	2.4% 1/41 • Number of events 1 • 6 weeks for intervention with a period of 3 weeks of washout between each intervention period.
General disorders Sleep Problems	7.3% 3/41 • Number of events 3 • 6 weeks for intervention with a period of 3 weeks of washout between each intervention period.	4.9% 2/41 • Number of events 2 • 6 weeks for intervention with a period of 3 weeks of washout between each intervention period.	0.00% 0/41 • 6 weeks for intervention with a period of 3 weeks of washout between each intervention period.
Gastrointestinal disorders Loss of appetite	9.8% 4/41 • Number of events 4 • 6 weeks for intervention with a period of 3 weeks of washout between each intervention period.	0.00% 0/41 • 6 weeks for intervention with a period of 3 weeks of washout between each intervention period.	0.00% 0/41 • 6 weeks for intervention with a period of 3 weeks of washout between each intervention period.
Gastrointestinal disorders Vomiting	7.3% 3/41 • Number of events 3 • 6 weeks for intervention with a period of 3 weeks of washout between each intervention period.	0.00% 0/41 • 6 weeks for intervention with a period of 3 weeks of washout between each intervention period.	0.00% 0/41 • 6 weeks for intervention with a period of 3 weeks of washout between each intervention period.
General disorders Fatigue	4.9% 2/41 • Number of events 2 • 6 weeks for intervention with a period of 3 weeks of washout between each intervention period.	0.00% 0/41 • 6 weeks for intervention with a period of 3 weeks of washout between each intervention period.	0.00% 0/41 • 6 weeks for intervention with a period of 3 weeks of washout between each intervention period.
Gastrointestinal disorders Constipation	4.9% 2/41 • Number of events 2 • 6 weeks for intervention with a period of 3 weeks of washout between each intervention period.	2.4% 1/41 • Number of events 1 • 6 weeks for intervention with a period of 3 weeks of washout between each intervention period.	0.00% 0/41 • 6 weeks for intervention with a period of 3 weeks of washout between each intervention period.
Renal and urinary disorders Urinary Hesitation	4.9% 2/41 • Number of events 2 • 6 weeks for intervention with a period of 3 weeks of washout between each intervention period.	0.00% 0/41 • 6 weeks for intervention with a period of 3 weeks of washout between each intervention period.	0.00% 0/41 • 6 weeks for intervention with a period of 3 weeks of washout between each intervention period.
Nervous system disorders Parathesthesias	0.00% 0/41 • 6 weeks for intervention with a period of 3 weeks of washout between each intervention period.	4.9% 2/41 • Number of events 2 • 6 weeks for intervention with a period of 3 weeks of washout between each intervention period.	0.00% 0/41 • 6 weeks for intervention with a period of 3 weeks of washout between each intervention period.

Additional Information

Yvonne C Lee, MD, MMSc

Brigham and Women's Hospital

Phone: 617-732-8736

Email: ylee9@partners.org

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place