A Trial of Gabapentin in Vulvodynia: Biological Correlates of Response

• Sponsor: University of Tennessee (Other)
• Overall Status: Completed
• CT.gov ID: NCT01301001
• Collaborator: University of Tennessee Health Science Center (Other)
• Enrollment: 230
• Locations: 3
• Arms: 2
• Duration (Months): 41
• Patients Per Site: 76.7
• Patients Per Site Per Month: 1.9

Study Details

Study Description

Brief Summary

The Specific aims of this project are to (1) test the prediction that pain from tampon insertion (primary outcome measure) is lower in PVD patients when treated with gabapentin compared to when treated with placebo. Secondary outcome measures include intercourse pain and 24-hour pain and (2)perform a mechanism-based analysis of gabapentin effectiveness, and to gain insight into the underlying pathophysiology of subtypes of PVD that may lead to more specific treatment options.

Condition or Disease	Intervention/Treatment	Phase
Vulvodynia	Drug: Placebo oral capsule; Drug: Gabapentin	N/A

Detailed Description

This is a 18-week, randomized, double-blind, placebo-controlled, two-treatment, two-period crossover design, where 120 women between 18 of age and older who report insertional dyspareunia, pain with tampon insertion, and tenderness localized to the vulvar vestibule will be enrolled in the study. Electronically entered daily diaries will be used to determine if pain is lower in PVD subjects when treated with gabapentin (up to 3600 mg/d) compared to when treated with placebo. Biological measurements will include assessment of allodynia and hyperalgesia from capsaicin administration, muscle tension using a vaginal pressure algometer, number of tender points by clinical examination, and changes in blood pressure, pulse and heart rate variability. . The Long-range goals of this project are to explicate the underlying pathophysiologic mechanisms of PVD, and to use this knowledge to create evidence-based differential diagnoses of subtypes of PVD and to individualize treatments for each subtype. The immediate goal is to conduct a multicenter, randomized controlled trial (RCT) of gabapentin treatment for PVD, and which will also provide critical data on a new PVD-testing and response paradigm, as well as on characteristics that may define subtypes of PVD. Gabapentin, an anticonvulsant with analgesic, anxiolytic, and antispasmotic effects, was selected because of its efficacy in treating other neuropathic pain conditions.

Study Design

• Study Type: Interventional
• Actual Enrollment: 230 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: A Controlled Trial of Gabapentin in Vulvodynia: Biological Correlates of Response
• Study Start Date: Aug 1, 2012
• Actual Primary Completion Date: Jan 1, 2016
• Actual Study Completion Date: Jan 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo oral capsule Placebo capsule daily in first intervention period and Gabapentin capsule 3000 mg daily in in second intervention (after washout period)	Drug: Placebo oral capsule; Placebo 2 capsules am and 3 capsules pm; Other Names: Sugar pill ; Drug: Gabapentin; Gabapentin 1200 mg am and 1800 mg pm; Other Names: Gralise 600 mg capsule
Active Comparator: Gabapentin Gabapentin capsule 3000 mg daily in first intervention period and Placebo capsule in second intervention (after washout period)	Drug: Placebo oral capsule; Placebo 2 capsules am and 3 capsules pm; Other Names: Sugar pill ; Drug: Gabapentin; Gabapentin 1200 mg am and 1800 mg pm; Other Names: Gralise 600 mg capsule

Outcome Measures

Primary Outcome Measures

1. Tampon Test Pain Intensity [Week 6 for each treatment arm]

   Tampon pain on a 11-point Numeric Rating Scale (0 = no pain at all; 10 = worse pain ever). One tampon was inserted each week. Tampon pain was assessed during last week of maintenance phase (7 days).

Secondary Outcome Measures

1. Coital Pain [Week 6 of each treatment arm]

   Coital pain on an 11-point Numeric Rating Scale (0 = no pain at all; 10 = worse pain ever), assessed after each sexual intercourse event. The number of sexual intercourse events was averaged during final week of each treatment arm.

2. Vulvodynia Pain [Week 6 for each treatment arm]

   Overall vulvodynia pain on an 11-point Numeric Rating Scale (0 = no pain at all; 10 = worse pain ever). Pain was assessed daily during the last week of treatment. Daily scores were averaged.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

1. Women who are 18 years of age and older, as long as no vaginal atrophy is present. If vaginal atrophy is present, then topical hormone replacement can be provided for a minimum of 6 weeks and then she must be re-screened to be eligible,

2. Greater than 3 continuous months of insertional (entryway) dyspareunia, pain to touch, or both with tampon insertion (modified 'Friedrich's Criteria', and

3. an average pain level of "4" or greater on the 11-point tampon test (0 = no pain at all; 10 = worse pain ever) during the 2-week screening period must be exhibited.

(One tampon will be inserted each week). 4.) Must report pain with the "Tampon Insertion Pain" Test at visit 1

Exclusion Criteria:

1. Other vulvar conditions, including dermatoses, vulvitis, vulvar papillomatosis, or atrophic vaginitis (presence of a maturation index)

2. previous vestibulotomy

3. active vaginal infection (positive Affirm ™ VPIII microbial identification test)

4. pregnancy or at risk for pregnancy and not using a reliable birth control method for at least 3 months prior to entering the study

5. any unstable medical condition, including renal impairment (creatinine clearance of ≤60 mL/min, BUN > 30mg/dL, serum creatinine > 2 mg/dL), significant hematological disease (leukopenia [WBC < 3.0 x 10-3µl, leukocytosis [WBC >20.0 x 10-3μl], neutropenia [ABS < 1.50 x 10-3 μl, <20%]), (thrombocytopenia [platelets < 100,000 μl], anemia [HCT < 27%, HBG <8 g/dL, RBC <3 x 10-6]), cardiovascular disease (cardiac conduction disturbance, CHF, hypertension [140/90]), hepatic insufficiency (serum AST, ALT, or ALP ≥ 3 times upper limit of normal), neurological disorder (seizures, syncopal episodes, peripheral neuropathy, severe pain other than that caused by vulvodynia), autoimmune disease, or respiratory illness

6. psychiatric disorder, including history of major depressive disorder or substance abuse disorder within the past 6 months, a score of > 12 on the depression subscale of the Hospital Anxiety and Depression Scale (HADS), indicting a major depressive episode (35,36), a serious risk of suicide, or lifetime history of psychosis, hypomania or mania

7. multiple allergies

8. use of benzodiazepines, opiates, muscle relaxants, tricyclic antidepressants (TCAs), serotonin-norepinephrine reuptake inhibitors (SNRIs) or CNS stimulants (including methylphenidate, amphetamine dextroamphetamine) within 2 weeks of randomization and during the study

9. use of certain herbal agents within 2 weeks of randomization and during the study, including ginkgo biloba, evening primrose, St. John's Wort, Valerian, kava kava)

10. topical lidocaine use

11. Subjects, who are diagnosed with coexisting vaginismus, fibromyalgia and/or interstitial cystitis, must have greater vulvar pain than their coexisting conditions or they will not be eligible for study participation

12. Subject who have previously taken gabapentin or Lyrica but discontinued the medication due to side effects are not eligible

13. Subjects with active infections (Candida, BV, trichomonas, chlamydia, GC and HSV via Affirm/culture) must be treated and re-screened to eligible for participation

14. Subjects with 10% or greater parabasal cells and/or vaginal atrophy can be provided with topical hormone replacement for a minimum of 6 weeks and then must be re-screened to be eligible

15. Subjects who have had gastric bypass surgery are ineligible for study participation due to drug absorption problems

16. HPV/abnormal Pap is not exclusionary

17. Ongoing counseling and/or physical therapy is not exclusionary

18. Subjects who report signs of mixed Vulvodynia (spontaneous/provoked, localized, generalized) during prescreening will not be excluded

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Rutgers - Robert Wood Johnson Medical School	New Brunswick	New Jersey	United States	08901-1962
2	University of Rochester School of Medicine and Dentistry	Rochester	New York	United States	14642-0002
3	Clinical Research Center	Memphis	Tennessee	United States	38104

Sponsors and Collaborators

• University of Tennessee
• University of Tennessee Health Science Center

Investigators

• Principal Investigator: Candace S Brown, MSN, PharmD, University of Tennessee Health Science Center
• Principal Investigator: David C Foster, M.D., University of Rochester
• Principal Investigator: Gloria A Bachmann, M.D., Rutgers Robert Wood Johnson Medical School

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Web link for study information and Pre-screening questionnaire

Publications

None provided.

• Responsible Party: University of Tennessee
• ClinicalTrials.gov Identifier: NCT01301001
• Other Study ID Numbers: 10-00985-FB CSBrown Vulvodynia
• First Posted: Feb 23, 2011
• Last Update Posted: Nov 8, 2017
• Last Verified: Apr 1, 2016

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Keywords provided by University of Tennessee: Vulvodynia
• Additional relevant MeSH terms: Vulvodynia; Gabapentin

Study Results

Participant Flow

Recruitment Details	Participants were recruited between August 8, 2012 and January 19, 2016 from three academic centers.
Pre-assignment Detail	230 women were screened, 89 met entry criteria and 66 completed the trial. Of the 141 patients who were excluded prior to randomization, 16 decided not to participate in the trial,101 did not meet inclusion criteria, and 24 did not return for randomization.

Arm/Group Title	Placebo First, Then Gabepentin	Gabapentin First, Then Placebo
Arm/Group Description	Placebo capsule daily in first intervention period and Gabapentin capsule 3000 mg daily in in second intervention (after washout period) Placebo oral capsule: Placebo 2 capsules am and 3 capsules pm Gabapentin: Gabapentin 1200 mg am and 1800 mg pm	Gabapentin capsule 3000 mg daily in first intervention period and Placebo capsule in second intervention (after washout period) Placebo oral capsule: Placebo 2 capsules am and 3 capsules pm Gabapentin: Gabapentin 1200 mg am and 1800 mg pm
Period Title: First Intervention
STARTED	44	45
COMPLETED	34	36
NOT COMPLETED	10	9
Period Title: First Intervention
STARTED	34	36
COMPLETED	34	36
NOT COMPLETED	0	0
Period Title: First Intervention
STARTED	34	36
COMPLETED	30	36
NOT COMPLETED	4	0

Baseline Characteristics

Arm/Group Title	All Study Participants
Arm/Group Description	44 subjects were randomized to Placebo First and 45 subjects were randomized to Gabapentin First
Overall Participants	89
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	36.54 (2.30)
Sex/Gender, Customized (Count of Participants)
Female	89 100%
Male	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	58 65.2%
White	30 33.7%
More than one race	1 1.1%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	89 100%

Outcome Measures

1. Primary Outcome

Title	Tampon Test Pain Intensity
Description	Tampon pain on a 11-point Numeric Rating Scale (0 = no pain at all; 10 = worse pain ever). One tampon was inserted each week. Tampon pain was assessed during last week of maintenance phase (7 days).
Time Frame	Week 6 for each treatment arm

Outcome Measure Data

Analysis Population Description

Intention to Treat

Arm/Group Title	Placebo	Gabapentin
Arm/Group Description	2 capsules am and 3 capsules pm	2 capsules (1200 mg) am and 3 capsules (1800 mg) pm
Measure Participants	89	89
Mean (95% Confidence Interval) [units on a scale]	4.29	3.96

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Gabapentin
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.07
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.3
	Confidence Interval	(2-Sided) 95%; -0.7 to 0.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Coital Pain
Description	Coital pain on an 11-point Numeric Rating Scale (0 = no pain at all; 10 = worse pain ever), assessed after each sexual intercourse event. The number of sexual intercourse events was averaged during final week of each treatment arm.
Time Frame	Week 6 of each treatment arm

Outcome Measure Data

Analysis Population Description

Intent to treat

Arm/Group Title	Placebo	Gabapentin
Arm/Group Description	2 capsules am and 3 capsules pm	1200 mg am and 1800 mg pm
Measure Participants	89	89
Mean (95% Confidence Interval) [units on a scale]	3.97	3.85

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Gabapentin
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.76
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.1
	Confidence Interval	(2-Sided) 95%; -0.9 to 0.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Vulvodynia Pain
Description	Overall vulvodynia pain on an 11-point Numeric Rating Scale (0 = no pain at all; 10 = worse pain ever). Pain was assessed daily during the last week of treatment. Daily scores were averaged.
Time Frame	Week 6 for each treatment arm

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Gabapentin
Arm/Group Description	2 capsules am and 3 capsules pm	1200 mg am and 1800 mg pm
Measure Participants	89	89
Mean (95% Confidence Interval) [units on a scale]	2.88	2.71

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Gabapentin
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.36
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.2
	Confidence Interval	(2-Sided) 95%; -0.5 to 0.2
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	16 weeks
Adverse Event Reporting Description	Definition of adverse events is the same as clinicaltrials.gov
Arm/Group Title	Placebo		Gabapentin
Arm/Group Description	2 capsules am and 3 capsules pm		2 capsules (1200 mg) am and 3 capsules (1800) mg pm
All Cause Mortality
	Placebo		Gabapentin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/89 (0%)		0/89 (0%)
Serious Adverse Events
	Placebo		Gabapentin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/89 (1.1%)		0/89 (0%)
Cardiac disorders
unstable angina and malignant hypertension	1/89 (1.1%)	1	0/89 (0%)	0
Nervous system disorders
cluster headache	1/89 (1.1%)	1	0/89 (0%)	0
Respiratory, thoracic and mediastinal disorders
asthma with acute exacerbation	1/89 (1.1%)	1	0/89 (0%)	0
Other (Not Including Serious) Adverse Events
	Placebo		Gabapentin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	20/89 (22.5%)		31/89 (34.8%)
Gastrointestinal disorders
Nausea	3/89 (3.4%)	4	8/89 (9%)	13
Infections and infestations
Rhinitis	4/89 (4.5%)	4	10/89 (11.2%)	14
Bacterial Vaginosis	4/89 (4.5%)	4	7/89 (7.9%)	7
Nervous system disorders
Dizziness	3/89 (3.4%)	3	9/89 (10.1%)	17
Fatigue	1/89 (1.1%)	1	5/89 (5.6%)	7
Headache	5/89 (5.6%)	7	7/89 (7.9%)	15
Somnolence	4/89 (4.5%)	4	7/89 (7.9%)	7

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.