Three Way Interaction Between Gabapentin, Duloxetine, and Donepezil in Patients With Diabetic Neuropathy

• Sponsor: Wake Forest University (Other)
• Overall Status: Terminated
• CT.gov ID: NCT00619983
• Collaborator: National Institute of Neurological Disorders and Stroke (NINDS) (NIH)
• Enrollment: 22
• Locations: 2
• Arms: 4
• Duration (Months): 62.9
• Patients Per Site: 11
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The purpose of the study is to determine whether the combination of the the three drugs gabapentin, duloxetine, and donepezil are effective in treating pain in people with diabetic neuropathy or patients with failed low back syndrome (chronic back pain).

Condition or Disease	Intervention/Treatment	Phase
Diabetic Neuropathic Pain; Chronic Low Back Pain	Drug: donepezil; Drug: duloxetine; Drug: donepezil 2.5 mg and duloxetine 30mg; Drug: placebo; Drug: gabapentin	Phase 4

Detailed Description

Neuropathic pain is a complex and likely heterogeneous disorder, and we recognize that clinically useful agents such as opioids, gabapentin, and antidepressants may be effective precisely because they have multiple mechanisms of action at multiple sites. This study, however, will not only provide important mechanistic information regarding one cascade which can be manipulated for analgesia, but will also provide much needed systematic and practical guidance for multi-drug therapy in patients with neuropathic pain.

This study in patients with diabetic neuropathic pain and patients with failed low back syndrome, culminate in a quantitative description of interactions between activators of descending noradrenergic activity, norepinephrine transporter inhibitors, and cholinesterase inhibitors to exploit the plasticity of analgesia in chronic pain states. We will focus on practical applications, using clinically approved drugs, including gabapentin (Neurontin®) to activate noradrenergic activity, duloxetine (Cymbalta®) to inhibit the norepinephrine transporter, and donepezil (Aricept®), approved for the treatment of Alzheimer's dementia, but not previously tested to treat neuropathic pain, to inhibit cholinesterase.

After the baseline measurements and physical examination patients will be trained to use a Personal Digital Assistant (PDA) to answer questions about their diabetic neuropathic pain or their chronic back pain. Upon successful completion of these tasks the patients will be randomized to receive one of the drug choices or placebo (inactive pill).

The study will last for a total of 16 weeks and includes 5 visits to the research center with each visit lasting approximately 2 hours.

Study Design

• Study Type: Interventional
• Actual Enrollment: 22 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Three Way Interaction Between Gabapentin, Duloxetine, and Donepezil in Patients With Diabetic Neuropathy
• Study Start Date: Feb 1, 2008
• Actual Primary Completion Date: May 1, 2013
• Actual Study Completion Date: May 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Donepezil Donepezil 5 mg once per day for 12 weeks. Gabapentin will be titrated in all groups beginning at week 8.	Drug: donepezil; Group 1: Will receive donepezil 5mg once a day; Other Names: Aricept® ; Drug: gabapentin; Week 8: all subjects will have open label gabapentin added to their randomized study medication; Other Names: neurontin
Active Comparator: Duloxetine Group 2: Will receive duloxetine 30 mg twice a day for 12 weeks. Gabapentin will be titrated in all groups beginning at week 8.	Drug: duloxetine; Group 2: Will receive duloxetine 30 mg twice a day; Other Names: Cymbalta® ; Drug: gabapentin; Week 8: all subjects will have open label gabapentin added to their randomized study medication; Other Names: neurontin
Active Comparator: Donepezil + Duloxetine Group 3: Will receive a combination of donepezil 2.5 mg and duloxetine 30mg for 12 weeks. Gabapentin will be titrated in all groups beginning at week 8.	Drug: donepezil 2.5 mg and duloxetine 30mg; Group 3: Will receive a combination of donepezil 2.5 mg and duloxetine 30mg; Other Names: Cymbalta® Aricept® ; Drug: gabapentin; Week 8: all subjects will have open label gabapentin added to their randomized study medication; Other Names: neurontin
Placebo Comparator: Placebo Group 4:Will receive placebo pills. Gabapentin will be titrated in all groups beginning at week 8.	Drug: placebo; Group 4: Will receive placebo pills; Drug: gabapentin; Week 8: all subjects will have open label gabapentin added to their randomized study medication; Other Names: neurontin

Outcome Measures

Primary Outcome Measures

1. Visual Analog Scale for Pain [Study completion (16 weeks)]

   The primary outcome measure is the visual analog scale (VAS) for pain, a 10 cm line upon which the subject marks their intensity of pain. The line is anchored on the left as "No pain at all" and on the right as "The worst pain imaginable". The score is the number of millimeters from the left origin of the line. The primary outcome measure for each period was the average value of all assessments for that period (2 weeks of measures for baseline, 6 weeks of measures for test drug alone, 6 weeks of measures for test drug plus gabapentin, and 2 weeks of measures for gabapentin alone).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Diagnosis of diabetic neuropathy

• Age 18-80

• Willing to temporarily discontinue gabapentin or monoamine reuptake inhibitors upon entry into the study

Exclusion Criteria:

• Pregnancy

• Allergy to study medications

• Uncontrolled narrow-angle glaucoma

• Currently being treatment with thioridazine (Mellaril)

• Unstable medical conditions including cardiac, pulmonary, renal or hepatic diseases

• Treatment with a monoamine oxidase inhibitor (MAOI) within 14 days of randomization

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Wake Forest University Baptist Medical Center	Winston-Salem	North Carolina	United States	27157
2	Cleveland Clinic	Cleveland	Ohio	United States	44195

Sponsors and Collaborators

• Wake Forest University
• National Institute of Neurological Disorders and Stroke (NINDS)

Investigators

• Principal Investigator: James C Eisenach, MD, Wake Forest University Health Sciences

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Oct 19, 2010
• Informed Consent Form - Apr 16, 2010

More Information

Publications

None provided.

• Responsible Party: Wake Forest University
• ClinicalTrials.gov Identifier: NCT00619983
• Other Study ID Numbers: IRB00003943; 5R01NS057594
• First Posted: Feb 21, 2008
• Last Update Posted: Sep 11, 2018
• Last Verified: Aug 1, 2018

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Wake Forest University: Asymmetric Diabetic Proximal Motor Neuropathy; Diabetic Autonomic Neuropathy; Diabetic Neuralgia; Diabetic Neuropathy, Painful; Neuralgia, Diabetic; Low back pain, chronic
• Additional relevant MeSH terms: Neuralgia; Diabetic Neuropathies; Back Pain; Low Back Pain; Gabapentin; Duloxetine Hydrochloride; Donepezil

Study Results

Participant Flow

Arm/Group Title	Donepezil	Duloxetine	Donepezil + Duloxetine	Placebo
Arm/Group Description	Donepezil 5 mg /day from 2-14 weeks with gabapentin titrated beginning at week 8 and maintained until week 15.	Duloxetine 30 mg twice per day from 2-14 weeks with gabapentin titrated beginning at week 8 and maintained until week 15.	Donepezil 2.5 mg /day and duloxetine 30 mg / day from 2-14 weeks with gabapentin titrated beginning at week 8 and maintained until week 15.	Placebo from 2-14 weeks with gabapentin titrated beginning at week 8 and maintained until week 15.
Period Title: Test Drug Alone
STARTED	5	5	6	6
COMPLETED	3	4	4	3
NOT COMPLETED	2	1	2	3
Period Title: Test Drug Alone
STARTED	3	4	4	3
COMPLETED	3	4	4	3
NOT COMPLETED	0	0	0	0
Period Title: Test Drug Alone
STARTED	3	4	4	3
COMPLETED	3	4	4	3
NOT COMPLETED	0	0	0	0

Baseline Characteristics

Arm/Group Title	Donepezil	Duloxetine	Donepezil + Duloxetine	Placebo	Total
Arm/Group Description	Donepezil 5 mg /day from 2-14 weeks with gabapentin titrated beginning at week 8 and maintained until week 15.	Duloxetine 30 mg twice per day from 2-14 weeks with gabapentin titrated beginning at week 8 and maintained until week 15.	Donepezil 2.5 mg /day and duloxetine 30 mg / day from 2-14 weeks with gabapentin titrated beginning at week 8 and maintained until week 15.	Placebo from 2-14 weeks with gabapentin titrated beginning at week 8 and maintained until week 15.	Total of all reporting groups
Overall Participants	5	5	6	6	22
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	62	56	59	70	60
Sex: Female, Male (Count of Participants)
Female	4 80%	0 0%	1 16.7%	3 50%	8 36.4%
Male	1 20%	5 100%	5 83.3%	3 50%	14 63.6%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	2 40%	2 40%	2 33.3%	1 16.7%	7 31.8%
White	3 60%	3 60%	4 66.7%	5 83.3%	15 68.2%
More than one race	0 0%	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	5 100%	5 100%	6 100%	6 100%	22 100%

Outcome Measures

1. Primary Outcome

Title	Visual Analog Scale for Pain
Description	The primary outcome measure is the visual analog scale (VAS) for pain, a 10 cm line upon which the subject marks their intensity of pain. The line is anchored on the left as "No pain at all" and on the right as "The worst pain imaginable". The score is the number of millimeters from the left origin of the line. The primary outcome measure for each period was the average value of all assessments for that period (2 weeks of measures for baseline, 6 weeks of measures for test drug alone, 6 weeks of measures for test drug plus gabapentin, and 2 weeks of measures for gabapentin alone).
Time Frame	Study completion (16 weeks)

Outcome Measure Data

Analysis Population Description

As noted in patient flow, data are available for only 14 of 22 subjects due to failure of the electronic daily diaries used to assess pain during the study and to study discontinuation in some cases

Arm/Group Title	Donepezil	Duloxetine	Donepezil + Duloxetine	Placebo
Arm/Group Description	Donepezil 5 mg /day from 2-14 weeks with gabapentin titrated beginning at week 8 and maintained until week 15.	Duloxetine 30 mg twice per day from 2-14 weeks with gabapentin titrated beginning at week 8 and maintained until week 15.	Donepezil 2.5 mg /day and duloxetine 30 mg / day from 2-14 weeks with gabapentin titrated beginning at week 8 and maintained until week 15.	Placebo from 2-14 weeks with gabapentin titrated beginning at week 8 and maintained until week 15.
Measure Participants	3	4	4	3
Baseilne ( weeks)	3.3	6.4	5.8	4.9
Test drug alone (6 weeks)	4.1	2.9	5.2	3.9
Drug plus gabapentin (6 weeks)	2.9	2.7	3.9	4.1
Gabapentin alone (2 weeks)	2.2	3.0	4.3	4.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Donepezil, Duloxetine, Donepezil + Duloxetine, Placebo
	Comments	Due to failure of daily electronic diaries and exhaustion of funds, we were only able to recruit < 30% of the number of subjects required in our power analysis.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.69
	Comments
	Method	ANOVA
	Comments	Repeated measures ANOVA

Adverse Events

Time Frame	During the 16 week study
Arm/Group Title	Donepezil		Duloxetine		Donepezil + Duloxetine		Placebo
Arm/Group Description	Donepezil 5 mg /day from 2-14 weeks with gabapentin titrated beginning at week 8 and maintained until week 15.		Duloxetine 30 mg twice per day from 2-14 weeks with gabapentin titrated beginning at week 8 and maintained until week 15.		Donepezil 2.5 mg /day and duloxetine 30 mg / day from 2-14 weeks with gabapentin titrated beginning at week 8 and maintained until week 15.		Placebo from 2-14 weeks with gabapentin titrated beginning at week 8 and maintained until week 15.
All Cause Mortality
	Donepezil		Duloxetine		Donepezil + Duloxetine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/5 (0%)		0/5 (0%)		0/6 (0%)		0/6 (0%)
Serious Adverse Events
	Donepezil		Duloxetine		Donepezil + Duloxetine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/5 (0%)		0/5 (0%)		0/6 (0%)		1/6 (16.7%)
Cardiac disorders
Angina	0/5 (0%)	0	0/5 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1
Other (Not Including Serious) Adverse Events
	Donepezil		Duloxetine		Donepezil + Duloxetine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/5 (20%)		0/5 (0%)		0/6 (0%)		1/6 (16.7%)
Gastrointestinal disorders
nausea	0/5 (0%)	0	0/5 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1
Infections and infestations
osteomyelitis	1/5 (20%)	1	0/5 (0%)	0	0/6 (0%)	0	0/6 (0%)	0

Limitations/Caveats

We recruited only a small proportion of the planned enrollment in the period of grant funding, leading to early termination of the study. Also, the failure of the electronic diaries and loss of primary outcome data prevented the planned analysis.

More Information

Certain Agreements

Principal Investigators are NOT 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.