Cymbalta® (duloxetine): Efficacy and Safety in Adolescents With Fibromyalgia

Detailed Information

The safety and effectiveness of duloxetine has been established for treatment of JFM in patients 13 to 17 years of age; however, it has not been established in patients less than 13 years of age.¹

Efficacy and Safety of Duloxetine Vs Placebo in Adolescents With Juvenile Fibromyalgia

Study Design

A 13-week randomized, double-blind, placebo controlled, multi-site study (N=184) evaluated the safety and efficacy of duloxetine 30/60mg daily (N=91) compared to placebo (N=93) in adolescent patients aged 13 to 17 years with JFM.²

Patients randomized to the duloxetine treatment group received 30 mg daily during week 1; then the dose was increased to 60 mg, two 30-mg capsules, daily. Investigators were able to adjust the dose back to 30 mg, if necessary, based on the patient's response. No dose adjustment were permitted after week 7 and the dose was decreased to 30 mg.²

Following the double-blind study, an open-label extension phase [weeks 14-39 (N=106)] was completed to measure the secondary endpoints. During the open-label treatment

• patients who received duloxetine 30 mg daily were increased to 60 mg daily, and

• patients who received duloxetine 60 mg daily were tapered to 30 mg daily.²

Key Inclusion/Exclusion Criteria

The study included patients

• 13 to 17 years old

• diagnosed with JPFS, and

• with pain scores ≥4 on the average pain severity item of the BPI.²

Patients were excluded from the study if they 

• had recently given birth, pregnant, or nursing

• were treated with duloxetine 6 months prior

• experienced duloxetine hypersensitivity

• had evidence of an autoimmune disease or rheumatologic disorder

• experienced a DSM-IV axis I psychiatric disorder within the past year, excluding a few disorders with PI approval

• were diagnosed with and required pharmacologic treatment for a secondary DSM-IV axis I condition

• were diagnosed with any DSM-IV axis II psychiatric disorder, or

• were diagnosed with DSM-IV axis I psychosis, bipolar disorder, or schizoaffective disorder during lifetime.²

Outcome Measures

The study evaluated the mean change in 24-hour BPI average pain severity from baseline to week 13 between duloxetine 30/60 mg daily and placebo.²

The secondary endpoints measured improvements at the end of double-blind treatment period [Week 13 (N=149)] and open-label extension [Weeks 14–39 (N=106)] in

• BPI severity and interference scores

• treatment response (≥30%, ≥50% reductions on BPI average pain severity)

• PPQ

• CGI-S (overall and mental illness)

• FDI: child and parent versions

• CDI

• Multidimensional Anxiety Scale for Children

• safety, and

• tolerability.²

Baseline Characteristics

A total of 184 patients were randomized (Table 1).²

Table 1. Patient Demographics and Baseline Characteristics^a,²

	Placebo n=93	Duloxetine n=91
Age (y)	15.33 (1.42)	15.74 (1.38)
Female, n (%)	65 (69.89)	73 (80.22)
Race, n (%)
Caucasian	70 (75027)	72 (79.12)
African American	8 (8.60)	7 (7.69)
Asian	7 (7.53)	6 (6.59)
American Indian or Alaska	0 (0)	1 (1.10)
Native Hawaiian or others	1 (1.08)	0 (0)
Multiracial	6 (6.45)	4 (4.40)
BMI (kg/m2)	24.10 (5.92)	24.11 (7.09)
Time since diagnosis for fibromyalgia, y, mean (SD)	0.38 (1.24)	0.19 (0.47)

Abbreviation: BMI = body mass index.

^a Intent-to-treat population.

Efficacy

From baseline to week 13, the change in 24-hour average BPI pain severity score was not statistically significant (p=.052) between the duloxetine treatment group and placebo treatment group.²

Duloxetine showed improvement over placebo on the primary endpoint with a p-value of .052 from the prespecified primary analysis,^1,2 and p values ranging from .011 to .020 from sensitivity analyses which assigned baseline values to missing assessments of some patients who did not complete the trial for various reasons.¹

During the open-label extension phase (weeks 14-39), statistical significance was seen at the LS mean change from baseline in BPI average score in patients who switched to duloxetine in open-label trial from placebo during double-blind treatment (p<.001) (Table 2).²

Table 2. Secondary Endpoints at Double-Blind and Open-Label Treatment Period²

	Placebo n=93	Duloxetine n=91		Treatment Difference		P Value		Placebo/Duloxetine n=75	Duloxetine/Duloxetine n=91
	LS Means for Change From Baseline (SE)
	Double-Blind Treatment Period						Open-Label Treatment Period
BPI severity and interference ratings
Worst pain score	-0.96 (0.267)	-1.43 (0.275)		-0.47		0.175		-0.8 (0.256)a	-0.65 (0.262)b
Least pain score	-0.60 (0.242)	-0.96 (0.247)		-0.35		0.255		-0.45 (0.212)b	-0.29 (0.218)
Pain score right now	-1.17 (0.270)	-1.44 (0.276)		-0.26		0.446		-0.29 (0.252)	-0.38 (0.259)
Incidence of treatment response, n (%)c
≥30% reduction	33 (36.26)	47 (52.22)		--		0.032d		27 (37.50)	25 (36.23)
≥50% reduction	22 (24.18)	36 (40.00)		--		0.029d		18 (25.00)	17 (24.64)
PPQ score
Average pain score	-9.41 (2.946)	-11.03 (2.982)		-1.62		0.669		-6.44 (3.296)	-10.65 (3.080)a
Worst pain score	-8.46 (3.322)	-14.36 (3.367)		-5.90		0.169		-8.06 (3.677)b	-4.15 (3.427)
Pain score right now	-7.20 (3.065)	-8.99 (3.092)		-1.79		0.647		-6.34 (3.335	-4.74 (3.075)
CGI-S score
Overall	-0.66 (0.118)	-0.88 (0.121)		-0.22		0.146		-0.67 (0.121)a	-0.67 (0.125)a
Mental illness	-0.15 (0.087)	-0.16 (0.089)		-0.01		0.927		-0.24 (0.101)b	-0.20 (0.104)
FDI total score
Child total score	-5.00 (1.021)	-3.97 (1.038)		1.03		0.431		-1.03 (1.267)	-1.71 (1.202)
Parent total score	-4.17 (1.139)	-3.25 (1.152)		0.92		0.529		-2.27 (1.327)	-3.49 (1.227)a
CDI total score	-2.45 (0.674)	-3.28 (0.682)		-0.83		0.335		-1.41 (0.681)b	-0.42 (0.703)
MASC total score	-4.99 (1.558)	-6.21 (1.575)		-1.21		0.540		-0.78 (1.432)	-0.55 (1.478)

Abbreviations: BPI = Brief Pain Inventory; CDI = Children's Depression Inventory; CGI-S = Clinical Global Impression-Severity; FDI = Functional Disability Inventory; MASC = Multidimensional Anxiety Scale for Children; PPQ = Pediatric Pain Questionnaire.

^a p≤.01.

^b p≤.05.

^c Defined as reduction in BPI average pain for open-label and double-blind + open-label periods, only within group change was tested.

^d From the Cochran-Mantel-Haenszel test controlling for pooled investigator sites.

Safety Results

In this study, duloxetine's observed safety was similar to previous pediatric duloxetine trials used to establish other indications.²

Frequently reported AEs were nausea, headache, vomiting and decreased appetite Table 3.²

Table 3. Overall Safety During Double-blind Treatment Period²

	Placebo n=93 n (%)	Duloxetine n=91 n (%)
TEAEs≥1, total
Mild	58 (62.37)	75 (82.42)
Moderate	29 (26.88)	34 (37.36)
Severe	4 (4.30)	8 (8.79)
Most frequently reported TEAEs (≥10%)
Nausea	14 (15.05)	23 (25.27)
Headache	10 (10.75)	13 (14.29)
Vomiting	5 (5.38)	14 (15.38)
Decreased appetite	3 (3.23)	14 (15.38)
Columbia suicidal-severity rating scale
Suicidal ideation or behavior	3 (3.23)	6 (6.59)
Non-suicidal self-injurious behavior	1 (1.08)	5 (5.49)
Serious adverse events	0	2 (2.2)
Discontinuation due to adverse events, total	1 (1.08)	5 (5.49)
Diarrhea	1 (1.08)	0
Nausea	0	1 (1.1)
Somnolence	0	1 (1.1)
Anxiety	0	1 (1.1)
Depressed mood	0	1 (1.1)
Suicidal behavior	0	1 (1.1)
Death(s)	0	0

Abbreviation: TEAE = treatment-emergent adverse events.

The top frequently reported discontinuation reason during the double-blind treatment period are in Table 4 and during the open-label extension period are in Table 5.²

Table 4. Frequently Reported Reasons for Discontinuation During Double-Blind Treatment Period²

Discontinuations	Duloxetine (N=17)	Placebo (N=18)
Adverse event	5	1
Lack of efficacy	1	3
Parent/caregiver decision	2	4
Lost to follow-up	2	3
Protocol violation	4	3
Withdrawal by patient	3	4

Table 5. Frequently Reported Reasons for Discontinuation During Open-Label Extension Period²

Discontinuations	Duloxetine (N=18)	Placebo (N=25)
Adverse event	5	5
Lack of efficacy	2	4
Parent/guardian decision	2	4
Lost to follow-up	4	3
Sponsor decision	1	5
Physician decision	4	4

Enclosed Prescribing Information

CYMBALTA® (duloxetine) tablets, for oral use, Lilly

References

The published reference below is available by contacting 1-800-LillyRx (1-800-545-5979).

1. Cymbalta [package insert]. Indianapolis, IN: Eli Lilly and Company; 2020.

2. Upadhyaya HP, Arnold LM, Alaka K, et al. Efficacy and safety of duloxetine versus placebo in adolescents with juvenile fibromyalgia: results from a randomized controlled trial. Pediatr Rheumatol Online J. 2019;17(1):27. http://dx.doi.org/10.1186/s12969-019-0325-6.

Glossary

AE = adverse event

BPI = Brief Pain Inventory

CDI = Children's Depression Inventory

CGI-S = Clinical Global Impression-Severity

DSM-IV = Diagnostic and Statistical Manual of Mental Disorders, fourth edition

FDI = Functional Disability Inventory

JFM = juvenile fibromyalgia

JPFS = juvenile primary fibromyalgia syndrome

LS = least squares

PI = Principal Investigator

PPQ = Pediatric Pain Questionnaire