CAST: Chronic Kidney Disease Antidepressant Sertraline Trial

• Sponsor: VA Office of Research and Development (U.S. Fed)
• Overall Status: Completed
• CT.gov ID: NCT00946998
• Collaborator: University of Texas Southwestern Medical Center (Other), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (NIH)
• Enrollment: 201
• Locations: 2
• Arms: 2
• Actual Duration (Months): 92.7
• Patients Per Site: 100.5
• Patients Per Site Per Month: 1.1

Study Details

Study Description

Brief Summary

This is a randomized double-blinded placebo-controlled trial to see if treatment with sertraline as compared with placebo tablets will improve depression symptoms in patients with chronic kidney disease who have not yet started dialysis or received a kidney transplant. The investigators will also investigate whether sertraline treatment will improve quality of life and whether it is safe to use in patients with kidney disease. The study subject will be randomly assigned to take either sertraline or a placebo tablet for 12 weeks.

Condition or Disease	Intervention/Treatment	Phase
Chronic Kidney Disease; Depression	Drug: Sertraline; Drug: placebo	Phase 3

Detailed Description

This is a randomized double-blinded placebo-controlled trial of adults with predialysis stages 3-5 Chronic Kidney Disease and Major Depressive Episode. Subjects will be randomized in a double-blind fashion to placebo or sertraline (beginning at 50 mg/d and escalated by 50 mg increments every 2 weeks to a maximum of 200 mg/d) and followed for 12 weeks. The primary outcome is to investigate if treatment with sertraline, as compared with placebo, results in an improvement in depression symptom severity as measured by the Quick Inventory of Depressive Symptomatology Clinician Rated (QIDS-C-16) score. Secondary outcomes include whether sertraline, as compared with placebo, improves overall function and quality of life and whether it will result in more serious adverse events.

Study Design

• Study Type: Interventional
• Actual Enrollment: 201 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Randomized Trial of Sertraline Treatment of Depression in Chronic Kidney Disease
• Actual Study Start Date: Feb 8, 2010
• Actual Primary Completion Date: Nov 23, 2016
• Actual Study Completion Date: Nov 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Sertraline Patients with predialysis Chronic Kidney Disease stages 3-5 and with major depressive episode	Drug: Sertraline; Sertraline is a serotonin-selective reuptake inhibitor (SSRI) used to treat major depression. Dosage will begin at 50 mg/d and will be escalated by 50 mg increments every 2 weeks to a maximum of 200 mg/d
Placebo Comparator: Placebo Patients with predialysis Chronic Kidney Disease stages 3-5 and with major depressive episode	Drug: placebo; Placebo tablet will be identical and matched to sertraline tablet.

Outcome Measures

Primary Outcome Measures

1. Change From Baseline to Exit in Depression Symptom Severity as Measured by the QIDS-C-16 Score. [baseline to 12 weeks]

   The score range is 0 to 27; higher scores indicate more severe depression; a score of 0 to 5 corresponds to a normal affect; 6 to 10 to a mild affect; 11 to 15 to a moderate affect; 16 to 20 to a severe affect; and 21 or greater to very severe depression.

Secondary Outcome Measures

1. Response to Treatment Defined as a Decline of 50% in the Baseline QIDS-C-16 Score and Remission of Depression Defined as a QIDS-C-16 Score of 5 [baseline to 12 weeks]

   The score range is 0 to 27; higher scores indicate more severe depression; a score of 0 to 5 corresponds to a normal affect; 6 to 10 to a mild affect; 11 to 15 to a moderate affect; 16 to 20 to a severe affect; and 21 or greater to very severe depression.

2. Change From Baseline to Exit in Overall Function as Assessed by the Work and Social Adjustment Scale [baseline to 12 weeks]

   Each item is rated on a 0 to 8 Likert scale with 0 indicating no impairment and 8 indicating severe impairment and a total score range of 0 to 40.

3. Change in Quality of Life From Baseline to Exit in the Kidney Disease Quality of Life -Short Form, Version 1.3, Patient-reported Overall Health. [baseline to 12 weeks]

   Raw scores from version 1.3 were transformed to a scale from 0 to 100, in which higher numbers signify more favorable quality of life.

4. Serious Adverse Events During the 12 Week Study Duration. [during 12 week study duration]

   death, dialysis initiation, hospitalizations, or bleeding requiring transfusion

Eligibility Criteria

Criteria

• Ages Eligible for Study: 21 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Male or female adults aged greater than 21 years.

• Predialysis stages 3, 4 or 5 CKD.

• Current Major Depressive Episode.

• QID-C-16 score of 11.

• Able to understand and sign informed consent.

Exclusion Criteria:

• No healthcare power of attorney to sign informed consent.

• Unwilling or unable to participate.

• Kidney transplant recipient.

• Initiated on maintenance dialysis

• Significant hepatic dysfunction or liver enzyme abnormalities 3 times the upper limits of normal.

• Terminal chronic obstructive pulmonary disease or cancer.

• Recent history of active bleeding, such as gastrointestinal bleeding requiring hospitalization 3 months prior

• Current use of class I anti-arrhythmic medications.

• Use of pimozide, MAO inhibitors, reserpine, guanethidine, cimetidine or methyldopa; tri-cyclic anti-depressants, neuroleptics or anti-convulsants, excluding gabapentin

• Use of other serotonergic drugs or supplements such as triptans, tramadol, linezolid, tryptophan, and St. John's Wort.

• Ongoing use of anti-depressants

• Past treatment failure on Sertraline

• Initiation of psychotherapy for depression in the 3 months prior to study entry

• Alcohol or substance abuse or dependence that requires acute detoxification at study entry

• Present or past psychosis or Bipolar I or II disorder

• Dementia or a Mini-Mental State Examination score of <23

• Suicidal ideation

• Pregnancy, lactation and women of childbearing potential not using adequate contraception

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	VA North Texas Health Care System Dallas VA Medical Center, Dallas, TX	Dallas	Texas	United States	75216
2	University of Texas Southwestern Medical Center at Dallas	Dallas	Texas	United States	75390

Sponsors and Collaborators

• VA Office of Research and Development
• University of Texas Southwestern Medical Center
• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Investigators

• Principal Investigator: Susan S Hedayati, MD MHS, University of Texas Southwestern Medical Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: VA Office of Research and Development
• ClinicalTrials.gov Identifier: NCT00946998
• Other Study ID Numbers: CLIN-008-09S; 1I01CX000217-01; 1R01DK085512-01A1
• First Posted: Jul 27, 2009
• Last Update Posted: Mar 9, 2018
• Last Verified: Feb 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
• Product Manufactured in and Exported from the U.S.: No
• Keywords provided by VA Office of Research and Development: Chronic Kidney Disease; Depression; Antidepressants; randomized controlled trial; treatment; Sertraline
• Additional relevant MeSH terms: Kidney Diseases; Renal Insufficiency, Chronic; Depression; Depressive Disorder; Sertraline

Study Results

Participant Flow

Arm/Group Title	Sertraline	Placebo
Arm/Group Description	Patients with predialysis Chronic Kidney Disease stages 3-5 and with major depressive episode Sertraline: Sertraline is a serotonin-selective reuptake inhibitor (SSRI) used to treat major depression. Dosage will begin at 50 mg/d and will be escalated by 50 mg increments every 2 weeks to a maximum of 200 mg/d	Patients with predialysis Chronic Kidney Disease stages 3-5 and with major depressive episode placebo: Placebo tablet will be identical and matched to sertraline tablet.
Period Title: Overall Study
STARTED	102	99
Received Treatment as Randomized	102	99
COMPLETED	97	96
NOT COMPLETED	5	3

Baseline Characteristics

Arm/Group Title	Sertraline	Placebo	Total
Arm/Group Description	Patients with predialysis Chronic Kidney Disease stages 3-5 and with major depressive episode Sertraline: Sertraline is a serotonin-selective reuptake inhibitor (SSRI) used to treat major depression. Dosage will begin at 50 mg/d and will be escalated by 50 mg increments every 2 weeks to a maximum of 200 mg/d	Patients with predialysis Chronic Kidney Disease stages 3-5 and with major depressive episode placebo: Placebo tablet will be identical and matched to sertraline tablet.	Total of all reporting groups
Overall Participants	97	96	193
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	57.7 (14.5)	59.1 (12.2)	58.4 (13.4)
Sex: Female, Male (Count of Participants)
Female	23 23.7%	29 30.2%	52 26.9%
Male	74 76.3%	67 69.8%	141 73.1%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	21 21.6%	14 14.6%	35 18.1%
Not Hispanic or Latino	76 78.4%	82 85.4%	158 81.9%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	1 1%	1 0.5%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	56 57.7%	55 57.3%	111 57.5%
White	41 42.3%	40 41.7%	81 42%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	97 100%	96 100%	193 100%
Chronic Kidney Disease Stage (Count of Participants)
CKD Stage 3	46 47.4%	44 45.8%	90 46.6%
CKD Stage 4	34 35.1%	36 37.5%	70 36.3%
CKD Stage 5	17 17.5%	16 16.7%	33 17.1%
Diabetes Mellitus (Count of Participants)
Count of Participants [Participants]	58 59.8%	55 57.3%	113 58.5%
Estimated glomerular filtration rate (mL/min/1.73 m^2) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [mL/min/1.73 m^2]	27.0	27.5	27.5
16-item Quick Inventory of Depression Symptomatology Clinician-rated Score (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	14.0 (2.4)	14.1 (2.4)	14.0 (2.4)

Outcome Measures

1. Primary Outcome

Title	Change From Baseline to Exit in Depression Symptom Severity as Measured by the QIDS-C-16 Score.
Description	The score range is 0 to 27; higher scores indicate more severe depression; a score of 0 to 5 corresponds to a normal affect; 6 to 10 to a mild affect; 11 to 15 to a moderate affect; 16 to 20 to a severe affect; and 21 or greater to very severe depression.
Time Frame	baseline to 12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sertraline	Placebo
Arm/Group Description	Patients with predialysis Chronic Kidney Disease stages 3-5 and with major depressive episode Sertraline: Sertraline is a serotonin-selective reuptake inhibitor (SSRI) used to treat major depression. Dosage will begin at 50 mg/d and will be escalated by 50 mg increments every 2 weeks to a maximum of 200 mg/d	Patients with predialysis Chronic Kidney Disease stages 3-5 and with major depressive episode placebo: Placebo tablet will be identical and matched to sertraline tablet.
Measure Participants	97	96
Mean (95% Confidence Interval) [units on a scale]	-4.1	-4.2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sertraline, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.82
	Comments
	Method	Mixed Models Analysis
	Comments

2. Secondary Outcome

Title	Response to Treatment Defined as a Decline of 50% in the Baseline QIDS-C-16 Score and Remission of Depression Defined as a QIDS-C-16 Score of 5
Description	The score range is 0 to 27; higher scores indicate more severe depression; a score of 0 to 5 corresponds to a normal affect; 6 to 10 to a mild affect; 11 to 15 to a moderate affect; 16 to 20 to a severe affect; and 21 or greater to very severe depression.
Time Frame	baseline to 12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sertraline	Placebo
Arm/Group Description	Patients with predialysis Chronic Kidney Disease stages 3-5 and with major depressive episode Sertraline: Sertraline is a serotonin-selective reuptake inhibitor (SSRI) used to treat major depression. Dosage will begin at 50 mg/d and will be escalated by 50 mg increments every 2 weeks to a maximum of 200 mg/d	Patients with predialysis Chronic Kidney Disease stages 3-5 and with major depressive episode placebo: Placebo tablet will be identical and matched to sertraline tablet.
Measure Participants	97	96
Response (>/=50% decline in score)	31 32%	24 25%
Remission (score =/<5)	15 15.5%	14 14.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sertraline, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.28
	Comments	Represents the response outcome.
	Method	Mixed Models Analysis
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Sertraline, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.86
	Comments	Represents remission outcome.
	Method	Mixed Models Analysis
	Comments

3. Secondary Outcome

Title	Change From Baseline to Exit in Overall Function as Assessed by the Work and Social Adjustment Scale
Description	Each item is rated on a 0 to 8 Likert scale with 0 indicating no impairment and 8 indicating severe impairment and a total score range of 0 to 40.
Time Frame	baseline to 12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sertraline	Placebo
Arm/Group Description	Patients with predialysis Chronic Kidney Disease stages 3-5 and with major depressive episode Sertraline: Sertraline is a serotonin-selective reuptake inhibitor (SSRI) used to treat major depression. Dosage will begin at 50 mg/d and will be escalated by 50 mg increments every 2 weeks to a maximum of 200 mg/d	Patients with predialysis Chronic Kidney Disease stages 3-5 and with major depressive episode placebo: Placebo tablet will be identical and matched to sertraline tablet.
Measure Participants	97	96
Mean (95% Confidence Interval) [units on a scale]	-5.0	-3.2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sertraline, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.32
	Comments
	Method	Mixed Models Analysis
	Comments

4. Secondary Outcome

Title	Change in Quality of Life From Baseline to Exit in the Kidney Disease Quality of Life -Short Form, Version 1.3, Patient-reported Overall Health.
Description	Raw scores from version 1.3 were transformed to a scale from 0 to 100, in which higher numbers signify more favorable quality of life.
Time Frame	baseline to 12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sertraline	Placebo
Arm/Group Description	Patients with predialysis Chronic Kidney Disease stages 3-5 and with major depressive episode Sertraline: Sertraline is a serotonin-selective reuptake inhibitor (SSRI) used to treat major depression. Dosage will begin at 50 mg/d and will be escalated by 50 mg increments every 2 weeks to a maximum of 200 mg/d	Patients with predialysis Chronic Kidney Disease stages 3-5 and with major depressive episode placebo: Placebo tablet will be identical and matched to sertraline tablet.
Measure Participants	97	96
Median (Inter-Quartile Range) [units on a scale]	0.0	0.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sertraline, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.61
	Comments
	Method	Mixed Models Analysis
	Comments

5. Secondary Outcome

Title	Serious Adverse Events During the 12 Week Study Duration.
Description	death, dialysis initiation, hospitalizations, or bleeding requiring transfusion
Time Frame	during 12 week study duration

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sertraline	Placebo
Arm/Group Description	Patients with predialysis Chronic Kidney Disease stages 3-5 and with major depressive episode Sertraline: Sertraline is a serotonin-selective reuptake inhibitor (SSRI) used to treat major depression. Dosage will begin at 50 mg/d and will be escalated by 50 mg increments every 2 weeks to a maximum of 200 mg/d	Patients with predialysis Chronic Kidney Disease stages 3-5 and with major depressive episode placebo: Placebo tablet will be identical and matched to sertraline tablet.
Measure Participants	97	96
Death	0 0%	0 0%
Dialysis initiation	7 7.2%	5 5.2%
Hospitalization other than dialysis initiation	8 8.2%	7 7.3%
acute suicidal intent	0 0%	1 1%
bleed with transfusion or hospitalization	2 2.1%	2 2.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sertraline, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	>.99
	Comments	For death
	Method	Chi-squared
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Sertraline, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.77
	Comments	For comparison of dialysis initiation between groups.
	Method	Chi-squared
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Sertraline, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	>0.99
	Comments	Hospitalization other than dialysis initiation
	Method	Chi-squared
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Sertraline, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5
	Comments	For comparison of acute suicidal intent.
	Method	Chi-squared
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Sertraline, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	>0.99
	Comments	For comparison of bleeding requiring blood transfusion or hospitalization.
	Method	Chi-squared
	Comments

Adverse Events

Time Frame	12 weeks of randomized study duration.
Arm/Group Title	Sertraline		Placebo
Arm/Group Description	Patients with predialysis Chronic Kidney Disease stages 3-5 and with major depressive episode Sertraline: Sertraline is a serotonin-selective reuptake inhibitor (SSRI) used to treat major depression. Dosage will begin at 50 mg/d and will be escalated by 50 mg increments every 2 weeks to a maximum of 200 mg/d		Patients with predialysis Chronic Kidney Disease stages 3-5 and with major depressive episode placebo: Placebo tablet will be identical and matched to sertraline tablet.
All Cause Mortality
	Sertraline		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/97 (0%)		0/96 (0%)
Serious Adverse Events
	Sertraline		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	13/97 (13.4%)		13/96 (13.5%)
Blood and lymphatic system disorders
Bleeding requiring a blood transfusion or hospitalization	2/97 (2.1%)		2/96 (2.1%)
Cardiac disorders
Acute myocardial infarction	0/97 (0%)		1/96 (1%)
General disorders
Hospitalization other than for dialysis initiation	8/97 (8.2%)		7/96 (7.3%)
Nervous system disorders
stroke	1/97 (1%)		1/96 (1%)
Psychiatric disorders
acute suicidal intent	0/97 (0%)		1/96 (1%)
Renal and urinary disorders
Dialysis initiation	7/97 (7.2%)		5/96 (5.2%)
Other (Not Including Serious) Adverse Events
	Sertraline		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	55/97 (56.7%)		35/96 (36.5%)
Gastrointestinal disorders
Nausea, indigestion, or vomiting	22/97 (22.7%)		10/96 (10.4%)
Diarrhea	13/97 (13.4%)		3/96 (3.1%)
anorexia	1/97 (1%)		1/96 (1%)
Increased appetite	1/97 (1%)		2/96 (2.1%)
General disorders
Insomnia	7/97 (7.2%)		10/96 (10.4%)
Somnolence	9/97 (9.3%)		5/96 (5.2%)
Dizziness, syncope, or fall	8/97 (8.2%)		4/96 (4.2%)
Headache	6/97 (6.2%)		4/96 (4.2%)
Dry mouth	4/97 (4.1%)		4/96 (4.2%)
Nervous system disorders
Decreased memory or confusion	2/97 (2.1%)		3/96 (3.1%)
Tremor	3/97 (3.1%)		1/96 (1%)
Psychiatric disorders
Anxiety, irritability, or agitation	7/97 (7.2%)		4/96 (4.2%)
Reproductive system and breast disorders
Decrease libido or erectile dysfunction	3/97 (3.1%)		2/96 (2.1%)
Skin and subcutaneous tissue disorders
Rash	3/97 (3.1%)		1/96 (1%)

Limitations/Caveats

[Not Specified]

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.