Zonisamide for Weight Reduction in Obese Adults

• Sponsor: Duke University (Other)
• Overall Status: Completed
• CT.gov ID: NCT00275834
• Collaborator: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (NIH)
• Enrollment: 225
• Location: 1
• Arms: 3
• Duration (Months): 68
• Patients Per Site Per Month: 3.3

Study Details

Study Description

Brief Summary

The primary aim of this study is to assess long-term weight loss efficacy of zonisamide relative to placebo in obese patients prescribed a dietary intervention.

Condition or Disease	Intervention/Treatment	Phase
Obesity	Drug: Zonisamide	N/A

Detailed Description

This RCT compares two doses of zonisamide and placebo for one year. A total of 225 subjects are randomly assigned to one of the three treatment interventions at Duke University Medical Centre. The primary outcome measure is change in body weight in kilograms. Secondary outcomes include changes in waist circumference, glycaemic and inflammatory markers, lipids, food craving, hunger and satiety, quality of life, blood pressure and heart rate.

Study Design

• Study Type: Interventional
• Actual Enrollment: 225 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Zonisamide for Weight Reduction in Obese Adults
• Study Start Date: Jan 1, 2006
• Actual Primary Completion Date: Sep 1, 2011
• Actual Study Completion Date: Sep 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: A Zonisamide 400 mg	Drug: Zonisamide; zonisamide 400 mg, 200 mg, or placebo
Experimental: B Zonisamide 200 mg	Drug: Zonisamide; zonisamide 400 mg, 200 mg, or placebo
Placebo Comparator: C matching placebo	Drug: Zonisamide; zonisamide 400 mg, 200 mg, or placebo

Outcome Measures

Primary Outcome Measures

1. Change in Body Weight [1 year]

   The primary endpoint was weight loss at 1-year, Month-12 weight minus baseline weight, in kilograms.

Secondary Outcome Measures

1. Proportions of Patients With 5% Weight Loss [1 year]

   These were the proportions of patients losing 5% or more weight at 1-year relative to baseline. The measures were modeled with logistic regressions that included the three-level group proxy and a baseline weight covariate.

2. Proportions of Patients With 10% Weight Loss [1 year]

   This outcomes measure followed the same principles at measurement of proportions of patients with 5% weight loss described elsewhere.

3. Waist Circumference [1 year]

   Analyses was based on intent-to-treat ANCOVA. Difference scores from baseline to endpoint (Month-12) for each measure were regressed on the three-level proxy denoting group while controlling for the baseline value of the same measure. Contrasts were subsequently estimated in models, which had a significant overall treatment effect.

4. Inflammatory Markers (CRP) [1 year]

   C reactive Protein (CRP)

5. Change in Lipids [baseline, 1 year]

6. Quality of Life as Measured by HADS_D [1 year]

   Hospital Anxiety and Depression Scale - Depression (HADS-D) The HADS is a 14-item self-administered questionnaire that consists of 2 scales, one measuring anxiety (HADS-A), and the other measuring depression (HADS-D). Each subscale consists of 7 statements and the participant responds as to how each item applies to him/her over the past week on 4-point response scale. Separate scores are calculated for anxiety and depression and a score (ranging from 0 to 21) is obtained for each subscale. The higher the score, the more severe the anxiety or depression.

7. Change in Blood Pressure [Baseline, 1 year]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria: Age 18-65 years; BMI 30-50

Exclusion Criteria:

Secondary obesity; Significant cardiovascular disease; Stroke, seizure disorder or other significant neurological disease; Significant liver or gallbladder disease; Significant renal disease or history of kidney stones; HIV positive status; Diabetes mellitus; Untreated or unstable hypothyroidism Malignancy in the past 5 years; Concomitant medications that cause significant weight gain or weight loss; Concomitant use of prescription or OTC weight loss medications; Had bariatric surgery or planning surgery in the next 1 year; Weight change of more than 4 kg in the past 3 months; Suicidal subjects; Major depression in the past 6 months; History of psychosis, bipolar disorder, or severe personality disorders; Subjects taking antipsychotics or mood stabilisers; Alcohol or substance abuse in the past 6 months; Currently taking zonisamide or other antiepileptic drugs; History of hypersensitivity to zonisamide or sulfonamides; Pregnant or planning pregnancy in the next year, or breastfeeding; Severe physical disability; Current participation in a commercial weight loss program or planning to participate; Currently following low-carbohydrate, high protein, high fat diet; Use of investigational medications or devices (current or past 4 weeks)

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Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Duke University Medical Centre	Durham	North Carolina	United States	27710

Sponsors and Collaborators

• Duke University
• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Investigators

• Principal Investigator: Kishore M Gadde, MD, Duke University

Study Documents (Full-Text)

None provided.

More Information

Publications

• Gadde KM, Kopping MF, Wagner HR 2nd, Yonish GM, Allison DB, Bray GA. Zonisamide for weight reduction in obese adults: a 1-year randomized controlled trial. Arch Intern Med. 2012 Nov 12;172(20):1557-64. doi: 10.1001/2013.jamainternmed.99.

• Responsible Party: Duke University
• ClinicalTrials.gov Identifier: NCT00275834
• Other Study ID Numbers: Pro00005514; R01DK067352; 1R01DK067352
• First Posted: Jan 12, 2006
• Last Update Posted: Jan 12, 2017
• Last Verified: Nov 1, 2016

• Keywords provided by Duke University: obesity treatment; weight loss; antiobesity drugs; zonisamide
• Additional relevant MeSH terms: Weight Loss; Zonisamide

Study Results

Participant Flow

Recruitment Details	The study was conducted at Duke University Medical Center between 2006 and 2011.
Pre-assignment Detail	Participants are considered to have completed the study if they returned for final study visit. The number completed represents participants who stayed on study drug during the trial plus participants who discontinued study drug during the trial but continued to be followed by study team and completed the final visit assessments.

Arm/Group Title	Placebo	Zonisamide 200 mg	Zonisamide 400 mg
Arm/Group Description	Zonisamide 100 mg and placebo capsules were prepared in accordance with Good Manufacturing Practice (GMP) guidelines in Duke Compounding Facility with active pharmaceutical ingredient (Sochinaz SA, Switzerland, distributed by Bachem Americas, King of Prussia, Pennsylvania) plus dextrose as an inactive ingredient. Identical-looking placebo capsules contained dextrose. Each capsule contained zonisamide 100 mg or placebo, with patients and study staff blinded to contents. Dose was gradually titrated upward as follows: 1 capsule for 15 days, 2 during days 16-30, 3 capsules during days 31-45, and 4 from day 46 onward. The entire dose was taken at night. Blinded dose reduction was allowed and dose increase could be withheld. Patients had the option to discontinue the drug and remain in the study receiving only diet and lifestyle counseling.	Dosing of matching placebo was identical.
Period Title: Overall Study
STARTED	74	76	75
Completed Study While on Study Drug	54	51	62
COMPLETED	71	73	74
NOT COMPLETED	3	3	1

Baseline Characteristics

Arm/Group Title	Placebo	Zonisamide 200 mg	Zonisamide 400 mg	Total
Arm/Group Description	Total of all reporting groups
Overall Participants	74	76	75	225
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	74 100%	76 100%	75 100%	225 100%
>=65 years	0 0%	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	43.5 (10.3)	44.2 (10.1)	42.3 (10.0)	43.4 (10.1)
Gender (Count of Participants)
Female	44 59.5%	45 59.2%	45 60%	134 59.6%
Male	30 40.5%	31 40.8%	30 40%	91 40.4%
Region of Enrollment (participants) [Number]
United States	74 100%	76 100%	75 100%	225 100%

Outcome Measures

1. Primary Outcome

Title	Change in Body Weight
Description	The primary endpoint was weight loss at 1-year, Month-12 weight minus baseline weight, in kilograms.
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

intent-to-treat

Arm/Group Title	Placebo	Zonisamide 200 mg	Zonisamide 400 mg
Arm/Group Description
Measure Participants	74	76	75
Mean (95% Confidence Interval) [kg]	-4.0	-4.4	-7.3

2. Secondary Outcome

Title	Proportions of Patients With 5% Weight Loss
Description	These were the proportions of patients losing 5% or more weight at 1-year relative to baseline. The measures were modeled with logistic regressions that included the three-level group proxy and a baseline weight covariate.
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Zonisamide 200 mg	Zonisamide 400 mg
Arm/Group Description
Measure Participants	74	76	75
Number [participants]	23 31.1%	26 34.2%	41 54.7%

3. Secondary Outcome

Title	Proportions of Patients With 10% Weight Loss
Description	This outcomes measure followed the same principles at measurement of proportions of patients with 5% weight loss described elsewhere.
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Zonisamide 200 mg	Zonisamide 400 mg
Arm/Group Description
Measure Participants	74	76	75
Number [participants]	6 8.1%	17 22.4%	24 32%

4. Secondary Outcome

Title	Waist Circumference
Description	Analyses was based on intent-to-treat ANCOVA. Difference scores from baseline to endpoint (Month-12) for each measure were regressed on the three-level proxy denoting group while controlling for the baseline value of the same measure. Contrasts were subsequently estimated in models, which had a significant overall treatment effect.
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

intent-to-treat

Arm/Group Title	Placebo	Zonisamide 200 mg	Zonisamide 400 mg
Arm/Group Description
Measure Participants	74	76	75
Mean (95% Confidence Interval) [cm]	-4.8	-6.1	-8.5

5. Secondary Outcome

Title	Inflammatory Markers (CRP)
Description	C reactive Protein (CRP)
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

Participants who had CRP testing completed

Arm/Group Title	Placebo	Zonisamide 200 mg	Zonisamide 400 mg
Arm/Group Description
Measure Participants	73	75	75
Mean (Standard Error) [mg/L]	0.523 (0.064)	0.536 (0.06)	0.443 (0.044)

6. Secondary Outcome

Title	Change in Lipids
Time Frame	baseline, 1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Zonisamide 200 mg	Zonisamide 400 mg
Arm/Group Description	Zonisamide 100 mg and placebo capsules were prepared in accordance with Good Manufacturing Practice (GMP) guidelines in Duke Compounding Facility with active pharmaceutical ingredient (Sochinaz SA, Switzerland, distributed by Bachem Americas, King of Prussia, Pennsylvania) plus dextrose as an inactive ingredient. Identical-looking placebo capsules contained dextrose. Each capsule contained zonisamide 100 mg or placebo, with patients and study staff blinded to contents. Dose was gradually titrated upward as follows: 1 capsule for 15 days, 2 during days 16-30, 3 capsules during days 31-45, and 4 from day 46 onward. The entire dose was taken at night. Blinded dose reduction was allowed and dose increase could be withheld. Patients had the option to discontinue the drug and remain in the study receiving only diet and lifestyle counseling.	Dosing of matching placebo was identical.
Measure Participants	74	76	75
Total Cholesterol	-1.9	4.1	-0.1
LDL Cholesterol	-2.0	1.7	-0.3
HDL Cholesterol	2.5	1.5	3.4
Triglycerides	-11.3	0.7	-11.7

7. Secondary Outcome

Title	Quality of Life as Measured by HADS_D
Description	Hospital Anxiety and Depression Scale - Depression (HADS-D) The HADS is a 14-item self-administered questionnaire that consists of 2 scales, one measuring anxiety (HADS-A), and the other measuring depression (HADS-D). Each subscale consists of 7 statements and the participant responds as to how each item applies to him/her over the past week on 4-point response scale. Separate scores are calculated for anxiety and depression and a score (ranging from 0 to 21) is obtained for each subscale. The higher the score, the more severe the anxiety or depression.
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Zonisamide 200 mg	Zonisamide 400 mg
Arm/Group Description
Measure Participants	74	76	75
Least Squares Mean (95% Confidence Interval) [units on a scale]	2.12	2.76	1.95

8. Secondary Outcome

Title	Change in Blood Pressure
Time Frame	Baseline, 1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Zonisamide 200 mg	Zonisamide 400 mg
Arm/Group Description	Zonisamide 100 mg and placebo capsules were prepared in accordance with Good Manufacturing Practice (GMP) guidelines in Duke Compounding Facility with active pharmaceutical ingredient (Sochinaz SA, Switzerland, distributed by Bachem Americas, King of Prussia, Pennsylvania) plus dextrose as an inactive ingredient. Identical-looking placebo capsules contained dextrose. Each capsule contained zonisamide 100 mg or placebo, with patients and study staff blinded to contents. Dose was gradually titrated upward as follows: 1 capsule for 15 days, 2 during days 16-30, 3 capsules during days 31-45, and 4 from day 46 onward. The entire dose was taken at night. Blinded dose reduction was allowed and dose increase could be withheld. Patients had the option to discontinue the drug and remain in the study receiving only diet and lifestyle counseling.	Dosing of matching placebo was identical.
Measure Participants	74	76	75
Systolic	-0.6	-4.4	-1.9
Diastolic	-1.5	-3.6	-3.9

Adverse Events

Time Frame	1-year
Arm/Group Title	Placebo		Zonisamide 200 mg		Zonisamide 400 mg
Arm/Group Description
All Cause Mortality
	Placebo		Zonisamide 200 mg		Zonisamide 400 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		Zonisamide 200 mg		Zonisamide 400 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/74 (0%)		0/76 (0%)		0/75 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		Zonisamide 200 mg		Zonisamide 400 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	30/74 (40.5%)		37/76 (48.7%)		39/75 (52%)
Gastrointestinal disorders
Altered taste	0/74 (0%)		4/76 (5.3%)		4/75 (5.3%)
Dry mouth	3/74 (4.1%)		5/76 (6.6%)		1/75 (1.3%)
Nausea/vomiting	4/74 (5.4%)		4/76 (5.3%)		10/75 (13.3%)
Musculoskeletal and connective tissue disorders
Musculoskeletal problems	9/74 (12.2%)		11/76 (14.5%)		8/75 (10.7%)
Nervous system disorders
Impaired concentration	1/74 (1.4%)		1/76 (1.3%)		4/75 (5.3%)
Impaired memory	1/74 (1.4%)		5/76 (6.6%)		8/75 (10.7%)
Headache	5/74 (6.8%)		8/76 (10.5%)		14/75 (18.7%)
Fatigue	2/74 (2.7%)		4/76 (5.3%)		7/75 (9.3%)
Somnolence	3/74 (4.1%)		9/76 (11.8%)		6/75 (8%)
Psychiatric disorders
Anxiety related	2/74 (2.7%)		5/76 (6.6%)		7/75 (9.3%)
Depression related	3/74 (4.1%)		3/76 (3.9%)		5/75 (6.7%)

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.