Pregabalin in the Treatment of Essential Tremor

• Sponsor: Baylor College of Medicine (Other)
• Overall Status: Completed
• CT.gov ID: NCT00646451
• Collaborator: Pfizer (Industry)
• Enrollment: 20
• Location: 1
• Arms: 2
• Duration (Months): 30
• Patients Per Site Per Month: 0.7

Study Details

Study Description

Brief Summary

Pregabalin is approved for the treatment of nerve pain as well as an additional therapy in the treatment of seizures. In December 2004, Pfizer gained Food and Drug Administration (FDA) approval for use of pregabalin in nerve pain associated with diabetes and shingles; making it the first FDA-approved treatment for both of these nerve pain states.

Tremor is uncontrolled trembling in part of the body. Essential tremor (ET) is associated with purposeful movement(e.g., holding a glass to drink, shaving, writing and buttoning a shirt). It occurs most often in the hands and head and also may affect the arms, voice box (larynx), trunk, and legs. ET is caused by abnormalities in areas of the brain that control movement. It usually does not result in serious complications.

ET affects approximately 5 million people in the United States. Incidence is highest in people over the age of 60.

ET usually develops gradually during middle age or later in life. Symptoms may remain mild or become more severe over time. Stress, fatigue, anxiety, and hot or cold weather can worsen the disorder. Severe tremor may cause difficulty doing activities of daily living, such as:

• Brushing hair and teeth

• Holding a glass without spilling

• Performing self-care (e.g., getting dressed, shaving, putting on makeup)

• Using eating utensils

• Writing and drawing

The purpose of this pilot/feasibility study is to examine the tolerability and efficacy of Pregabalin in patients with ET.

In other words, can patients diagnosed with ET tolerate high dose of pregabalin? Will the pregabalin be considered as an efficient medicine in the treatment of ET?

Condition or Disease	Intervention/Treatment	Phase
Essential Tremor	Drug: pregabalin (Lyrica); Drug: placebo	Early Phase 1

Detailed Description

Overview We propose a single site, double-blind, placebo-controlled, cross-over design. Drug will be administered in 75mg capsules with a target dose of 300 mg/day. Pregabalin will be titrated upward as described in the "Summary of Schedule" table with flexibility. During weeks 3-5 and 12-14, the investigator will have the option of increasing the study drug from 2 capsules per day (150 mg vs. placebo) to 3 or 4 capsules per day if no benefit is noted. If the dose is increased, it must be done so at a rate of 150mg/day/week. Patients who can not tolerate a higher dose will be allowed to drop back to a previously tolerated dose but must be on that dose for one week prior to evaluation. After treatment and clinical assessment, study drug will be decreased by 150mg/day every 2 days until discontinuation. This pertains to both the wash out phase and at the end of the study. Both adverse events and need for drug titration will be conducted during the safety call.

Identical assessments will be done at baseline and at the end of the treatment period for both drug and placebo. Half of the subjects (group A) will initiate with placebo and then crossover to drug. The other half (group B) will start treatment with pregabalin and then crossover to placebo.

The primary endpoint will be the change in Fahn-Tolosa-Marin Tremor Rating Scale (TRS) from baseline. Scale has Parts A= (severity of rest, action & postural tremor in upper and lower extremities, face, voice, tongue, head & trunk), B= (severity of tremor writing, drawing & pouring), C= (functional disability while speaking, eating, drinking, maintaining hygiene, dressing & working) and the total summed.

Other clinical assessments will include Clinical Global Impression of Change (CGI-C), Quality of Life in Essential Tremor Questionnaire (QUEST) maximum score =100, Hamilton Anxiety Scale (HAM-A) score 0-17 = mild, 18-24 = moderate, and 25-30 moderate to severe, and a sleep hygiene questionnaire rating across 5 domains- physical symptoms, energy & motivation, concentration, interpersonal relations, and psychological symptoms (HD-16). For the TRS, HAM-A, QUEST, and HD-16 higher scores represent increased symptom severity or diminished quality of life and the CGI-C is scored as follows: 1=very much improved, 2=much improved, 3= mildly improved, 4=no change, 5= mildly worse, 6= much worse, and 7=very much worse.

Study Design

• Study Type: Interventional
• Actual Enrollment: 20 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A 17 Week, Investigator-initiated, Single-center, Double-blind, Randomized, Placebo-controlled, Cross-over Trial of Pregabalin in Essential Tremor
• Study Start Date: Jun 1, 2006
• Actual Primary Completion Date: Dec 1, 2008
• Actual Study Completion Date: Dec 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Pregabalin (Lyrica) Pregabalin (Lyrica) 75 mg bid to a maximum dose of 300 mg bid	Drug: pregabalin (Lyrica); 75 mg bid to 300 mg bid based on per subject tolerability; Other Names: pregabalin
Placebo Comparator: Placebo Placebo to 4 capsules bid	Drug: placebo; up to 4 capsules bid as tolerated

Outcome Measures

Primary Outcome Measures

1. Change in Tremor Rating Scale (TRS) Compared With Baseline. [baseline to 6 weeks]

   Change from baseline in the overall TRS score obtained at the final evaluation (end of study). The overall TRS score will be derived from the three TRS subscales. The minimum and maximum score for part A is 0-80, part B is 0-36, and part C is 0-28 giving a maximum score of 144. TRS part A rates the severity of resting, postural and action tremor in upper and lower extremities, face, tongue, voice, head and trunk. Part B rates the severity of upper extremity tremor while writing, drawing, and pouring liquid. Part C rates functional disability of tremor while speaking, eating, drinking, maintaining hygiene, dressing, and working. Higher scores represent increased symptom severity or diminished quality of life. .

Secondary Outcome Measures

1. Secondary Outcome Measures Quality of Life in Essential Tremor (QUEST), Hamilton Anxiety Scale (HAM-A), Hotel Dieu-16 a Sleep Hygiene Questionnaire(HD-16), and Clinical Clobal Impression-Change Scale (CGI-C) [baseline to 6 weeks]

   The Quality of Life in Essential Tremor Questionnaire (QUEST), Hamilton Anxiety scale (HAM-A) and Hotel Dieu-16 (HD-16) were scored as per published guidelines [7], [8] and [9]. The QUEST rates patient perception as influenced by tremor across 5 domains. A QUEST score will be between 0 and 120 with 0 = no essential tremor and 120 = severe essential tremor. The HAM-A rates the severity of anxiety symptomatology across 14 parameters. Scores of 14-17 = mild anxiety, 18-24 = moderate anxiety, and 25-30 = severe anxiety; The HD-16 rates insomnia-related quality of life across five domains. An HD-16 score of 73.1 - 248.5 = severe insomnia, 61-73.1 = mild insomnia, and 0 - 61 = good sleeper. For the scales, HAM-A, QUEST and HD-16, higher scores represent increased symptom severity or diminished quality of life. CGI-C was scored as follows: 1 = very much improved, 2=much improved, 3=mildly improved, 4=no change, 5=mildly worse, 6= much worse, and 7= very much worse.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

1. Subjects must be between the ages of 18 and 80 inclusive.

2. Each subject must have current manifestations of ET symptoms based on the Tremor Investigational Group (TRIG) criteria for definite or probable ET: - Moderate or severe tremor in head or arms for at least 3 years duration. - No present causes of enhanced physiologic tremor. - No recent exposure to tremorogenic drugs or drug withdrawal states. - No direct or indirect trauma to the nervous system within 3 months preceding the onset of tremor. - No historic or clinical evidence of psychogenic tremor origin.

3. Subjects with a history of seizures are eligible.

4. Subjects must be in generally good health as evidenced by previous medical history and clinical examination.

5. Patients will be allowed to take Beta-blockers but will not be allowed to take any other medication for tremor (primidone, topiramate, benzodiazepines, etc.) An evening dose of a benzodiazepine to improve sleep is acceptable. They must have been on a stable dose of any existing beta-blocker for 4 weeks prior to entry into the study and will not be allowed to change the dose of that medication throughout the controlled portion of the study. Any medication discontinued during screening in order to comply with these criteria must be stopped for 5 half-lives prior to study initiation.

6. Subjects must be accessible by telephone.

7. If the subject is a female of childbearing age, she must have had a hysterectomy, tubal ligation, otherwise be incapable of pregnancy, or have practiced one of the following methods of contraception for at least one month prior to study entry (or a negative urine pregnancy test within one week of study entry): - Hormonal contraceptives - Spermicide and barrier - Intrauterine device - Partner sterility

8. Prior to participation in this study, each subject must sign an informed consent.

Exclusion Criteria:

1. Patients do not meet TRIG criteria for probable ET.

2. Subjects who are not able to abstain from alcohol for 24 hours prior to each evaluation.

3. Patients who can not maintain an identical dose of any medicine that may affect tremor during their entire study involvement.

4. Subjects who have exhibited any psychotic symptomatology.

5. Subjects who have known renal deficiencies.

6. Subjects who have been intolerant of pregabalin in the past

7. Prior surgical treatment for tremor.

8. Patients currently taking more than a single drug for ET.

9. Patients taking anti-seizure medications.

10. Breast feeding or pregnant females.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	PDCMDC 6550 Fannin, Suite 1801	Houston	Texas	United States	77030

Sponsors and Collaborators

• Baylor College of Medicine
• Pfizer

Investigators

• Principal Investigator: Joseph Jankovic, MD, Baylor College of Medicine

Study Documents (Full-Text)

None provided.

More Information

Publications

• Ferrara JM, Kenney C, Davidson AL, Shinawi L, Kissel AM, Jankovic J. Efficacy and tolerability of pregabalin in essential tremor: a randomized, double-blind, placebo-controlled, crossover trial. J Neurol Sci. 2009 Oct 15;285(1-2):195-7. doi: 10.1016/j.jns.2009.06.044. Epub 2009 Jul 25.

• Responsible Party: Joseph Jankovic, Principal Investigator, Baylor College of Medicine
• ClinicalTrials.gov Identifier: NCT00646451
• Other Study ID Numbers: H-19086
• First Posted: Mar 28, 2008
• Last Update Posted: Apr 26, 2021
• Last Verified: Apr 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Joseph Jankovic, Principal Investigator, Baylor College of Medicine: Essential tremor; Activities of Daily Living (ADL's)
• Additional relevant MeSH terms: Tremor; Essential Tremor; Pregabalin

Study Results

Participant Flow

Arm/Group Title	Pregabalin First, Then Placebo	Placebo First, Then Pregabalin
Arm/Group Description	Pregabalin: 75 mg bid to 300 mg bid based on per subject tolerability. Study crossover design. Patients were randomized for treatment with PGB or placebo, titrated over 6 weeks.	Placebo capsules: up to 4 capsules bid as tolerated. Study crossover design. Patients were randomized for treatment with PGB or placebo, titrated over 6 weeks.
Period Title: Overall Study
STARTED	10	10
COMPLETED	6	10
NOT COMPLETED	4	0

Baseline Characteristics

Arm/Group Title	All Participants
Arm/Group Description	Demographics and clinical characteristics of participants at study initiation are listed in Table 1 of the paper. Sixteen of 20 patients completed the study and were included in the analysis of drug efficacy (Table 2).
Overall Participants	20
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	62.2 (12.7)
Sex: Female, Male (Count of Participants)
Female	11 55%
Male	9 45%
Tremor Rating Scale (TRS) (units on a scale) [Mean (Standard Deviation) ]
TRS Part A	18.3 (6.0)
TRS Part B	50.8 (16.4)
TRS Part C	43.1 (16.3)
TRS total	37.1 (11.6)

Outcome Measures

1. Primary Outcome

Title	Change in Tremor Rating Scale (TRS) Compared With Baseline.
Description	Change from baseline in the overall TRS score obtained at the final evaluation (end of study). The overall TRS score will be derived from the three TRS subscales. The minimum and maximum score for part A is 0-80, part B is 0-36, and part C is 0-28 giving a maximum score of 144. TRS part A rates the severity of resting, postural and action tremor in upper and lower extremities, face, tongue, voice, head and trunk. Part B rates the severity of upper extremity tremor while writing, drawing, and pouring liquid. Part C rates functional disability of tremor while speaking, eating, drinking, maintaining hygiene, dressing, and working. Higher scores represent increased symptom severity or diminished quality of life. .
Time Frame	baseline to 6 weeks

Outcome Measure Data

Analysis Population Description

Indistinguishable capsules and an identical titration protocol were used for PGB and placebo. Patients received the study drug at an initial dose of 75 mg twice daily, with upward titration to a target dose of 150 mg bid up to 300 mg bid. The study drug was increased at a rate of 150 mg/day/week.

Arm/Group Title	1-Pregabalin	2-Placebo
Arm/Group Description	pregabalin : 75 mg bid to 300 mg bid based on per subject tolerability. Crossover study design and measure change in TRS Pregabalin group versus placebo group.	placebo capsules : up to 4 capsules bid as tolerated. Crossover study design and measure change in TRS Pregabalin group versus placebo group.
Measure Participants	20	16
TRS Part A	2.4 (4.7)	-0.2 (4.1)
TRS Part B	6.7 (12.3)	3.6 (6.6)
TRS Part C	4.5 (13.9)	-1.5 (12.8)
Total TRS	5.1 (9.7)	0.3 (4.6)

2. Secondary Outcome

Title	Secondary Outcome Measures Quality of Life in Essential Tremor (QUEST), Hamilton Anxiety Scale (HAM-A), Hotel Dieu-16 a Sleep Hygiene Questionnaire(HD-16), and Clinical Clobal Impression-Change Scale (CGI-C)
Description	The Quality of Life in Essential Tremor Questionnaire (QUEST), Hamilton Anxiety scale (HAM-A) and Hotel Dieu-16 (HD-16) were scored as per published guidelines [7], [8] and [9]. The QUEST rates patient perception as influenced by tremor across 5 domains. A QUEST score will be between 0 and 120 with 0 = no essential tremor and 120 = severe essential tremor. The HAM-A rates the severity of anxiety symptomatology across 14 parameters. Scores of 14-17 = mild anxiety, 18-24 = moderate anxiety, and 25-30 = severe anxiety; The HD-16 rates insomnia-related quality of life across five domains. An HD-16 score of 73.1 - 248.5 = severe insomnia, 61-73.1 = mild insomnia, and 0 - 61 = good sleeper. For the scales, HAM-A, QUEST and HD-16, higher scores represent increased symptom severity or diminished quality of life. CGI-C was scored as follows: 1 = very much improved, 2=much improved, 3=mildly improved, 4=no change, 5=mildly worse, 6= much worse, and 7= very much worse.
Time Frame	baseline to 6 weeks

Outcome Measure Data

Analysis Population Description

Change in secondary measures of efficacy compared with baseline.

Arm/Group Title	Pregabalin	Placebo
Arm/Group Description	Patients received the study drug at an initial dose of 75 mg twice daily, with upward titration to a target dose of 150 mg twice daily. Patients were given the option to increase the study drug to as high as 300 mg twice daily if inadequate benefit was perceived after 3 weeks of treatment. The study drug was increased at a rate of 150 mg/day/week. All patients in both periods were contacted by phone after two weeks of treatment to facilitate drug titration and address any adverse events. Patients were permitted to return to a lower dose if side effects occurred during drug titration. After assessment protocols were completed, patients were titrated off the study drug at a rate of 150 mg every 2 days until discontinuation.	Patients received the study drug/matching placebo at an initial dose of 75 mg twice daily, with upward titration to a target dose of 150 mg twice daily. Patients were given the option to increase the study drug to as high as 300 mg twice daily if inadequate benefit was perceived after 3 weeks of treatment. The study drug was increased at a rate of 150 mg/day/week. All patients in both periods were contacted by phone after two weeks of treatment to facilitate drug titration and address any adverse events. Patients were permitted to return to a lower dose if side effects occurred during drug titration. After assessment protocols were completed, patients were titrated off the study drug at a rate of 150 mg every 2 days until discontinuation.
Measure Participants	20	16
QUEST	8.0 (20.3)	-9.7 (14.5)
HAM-A	1.1 (5.2)	4.1 (5.4)
HD-16	32.2 (146.8)	-38.6 (99.3)
CGI-C	3.9 (1.3)	3.8 (0.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	1-Pregabalin, 2-Placebo
	Comments	Outcome on study completers was assessed via ANOVA models using a 2 × 2 Latin-square crossover design including sequence, period, and treatment effects. A significant carryover effect was excluded. Analyses were performed using Stata IC version 10.0 for Windows. Unfortunately the small sample size of our study limits the possibility of a meaningful post-hoc analysis targeted to these variables.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.162
	Comments
	Method	ANOVA
	Comments
Other Statistical Analysis		The Quest rates patient perception of health status as influenced by tremor across 5 domains, physical, psychosocial, communication, hobbies/leisure, and work/finance. HAM-A rates severity of anxiety symptomatology across 14 parameters. Scores of 14-17 correspond to mild anxiety, scores of 18-24 is moderate anxiety and 25-30 severe anxiety. HD-16 rates insomnia-related QoL across 5 domains: physical symptoms, energy & motivation, concentration, interpersonal relations and psychological symptoms. These scales were scored per published guidelines.

Adverse Events

Time Frame	14 weeks of study duration
Arm/Group Title	Pregabalin		Placebo
Arm/Group Description	pregabalin: 75 mg bid to 300 mg bid based on per subject tolerability		placebo capsules: up to 4 capsules bid as tolerated
All Cause Mortality
	Pregabalin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Pregabalin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/20 (0%)		0/18 (0%)
Other (Not Including Serious) Adverse Events
	Pregabalin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	14/20 (70%)		9/18 (50%)
General disorders
drowsiness	5/20 (25%)	5	3/18 (16.7%)	3
dizziness	4/20 (20%)	4	1/18 (5.6%)	1
fatigue	3/20 (15%)	3	0/18 (0%)	0
instability	3/20 (15%)	3	1/18 (5.6%)	1
insomnia	0/20 (0%)	0	2/18 (11.1%)	2
headache	0/20 (0%)	0	2/18 (11.1%)	2

Limitations/Caveats

This is a investigator initiated trial that was completed in 2008 under 42 CFR 11.22 (b) and does not meet criteria. The study was a pilot and did not lead to registration nor to indication so this level of reporting is not be warranted.

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.