Iloperidone in Mixed States of Bipolar Disorder

• Sponsor: The University of Texas Health Science Center at San Antonio (Other)
• Overall Status: Completed
• CT.gov ID: NCT02413918
• Collaborator: Novartis Pharmaceuticals (Industry), Vanda Pharmaceuticals (Industry)
• Enrollment: 41
• Location: 1
• Arm: 1
• Duration (Months): 36
• Patients Per Site Per Month: 1.1

Study Details

Study Description

Brief Summary

1. To assess the acute and long-term bimodal efficacy of iloperidone (IL), as an adjunct to ongoing treatment with lithium (Li) or divalproex (DIV) or lamotrigine (LAM) or any combination of the three thereof, in a group of patients with an index episode of a mixed state in BD.

2. To assess background, baseline features, and behavioral components which characterize treatment response/non-response in the acute and long term management of MS

Condition or Disease	Intervention/Treatment	Phase
Bipolar Disorder	Drug: iloperidone	Phase 4

Detailed Description

This is a prospective 20-week, open-label study of iloperidone added to ongoing treatment regimen with mood stabilizers (Li or DIV or LAM or any combination of these) in the acute and maintenance treatment of MS- Total number of subjects: 40.

Severity of the illness and psychopathological features will be measured by the following rating scales: YMRS, MADRS, CGI-S and GAS, and the BISS .

The study will monitor the safety and tolerability of the combination iloperidone plus mood stabilizers.

Efficacy Measures: Primary efficacy measures include 1) Mixed effects repeat measure of change from baseline in BISS total score and, secondarily, manic and depression subscale scores.

Secondary Efficacy Measures: 1) response defined as 50% reduction in YMRS and MADRS and 2) Time to intervention or discontinuation for any mood episode.

Iloperidone will be initiated at 2 mg at hs on day 1 with increase to 4mg at hs on day 2, 8 mg at hs on day 3. All patients will have iloperidone titrated to receive a dosage of at least 12 mg a day. Dosages can be titrated up to 24 mg a day based on tolerability and clinical indication. Dosage of iloperidone can be reduced to 6 mg a day if patients develop side effects necessitating a reduction in the dosage

Study Design

• Study Type: Interventional
• Actual Enrollment: 41 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Open Label Study of Iloperidone (IL) as Adjunctive Treatment in Mixed States (MS) of Bipolar Disorder (BD)
• Study Start Date: Apr 1, 2012
• Actual Primary Completion Date: Apr 1, 2015
• Actual Study Completion Date: Apr 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Open Label iloperidone open label iloperidone (oral tablet, 6mg-24mg, QD, 20 weeks) as adjunct to current lithium, divalproex, or lamotrigine.	Drug: iloperidone; Qualifying subjects will take iloperidone starting at 2mg and up to a minimum of 12mg, maximum of 24mg, for 20 weeks in conjunction to the subjects current lithium, and or divalproex, and or lamotrigine.; Other Names: Fanapt

Outcome Measures

Primary Outcome Measures

1. Measure of Response by Change From Baseline to End of Study in BISS Depression and Mania Scale Scores [Baseline and 20 weeks]

   The Bipolar Inventory of Symptoms Scale is a reliable and valid measure which assesses Depression and Mania symptoms of bipolar disorder. There are 42 items; each item is rated on a 0-4 scale. The BISS is a clinician-rated instrument. The Scale is rated as follows: 0 Not at all Slight Mild Moderate Severe Each of the 42 items is rated separately, with a score, based on the most recent 7 day period. For Depression: Items 1-21 items of the assessment are summed up and multiplied by 4 to give a cumulative score out of 84. The higher the score, the more severe the depression. For Mania: Items 22-42 are summed up and multiplied by 4 to give a cumulative score out of 84. The higher the score, the more severe the mania. The mean is calculated from the change in score between baseline and week 20.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Male or female;

2. Age 18 years and older

3. Patients on:

• Li at a stable dose for 2 weeks or longer, and a serum level at screening of greater than or equal to 0.5 mEq/l OR

• DIV dose for 2 weeks or longer, and a serum level at screening of greater than or equal to 45 ug/ml OR

• LAM (dosage/day ≥100mg) at a stable dose for 2 weeks or longer OR

• Any combination 3a, 3b, or 3c

1. Patients meeting DSM-IV TR diagnosis of bipolar disorder, I or II, as assessed using the MINI, (Sheehan et al., 1998) PLUS any ONE of criteria 5 or 6 or 7

2. Patients meeting DSM-IV TR diagnostic criteria for a mixed manic episode with Young Mania Rating Scale (YMRS) score>/=14 and Montgomery Asberg Depression Rating Scale (MADRS) score>/=14

3. Patients meeting the criteria for a manic/hypomanic episode for at least 2 days with the simultaneous presence of Young Mania Rating Scale (YMRS) score>/=14 PLUS Montgomery Asberg Depression Rating Scale (MADRS) score>/=14 ;

4. Patients meeting DSM-IV TR diagnostic criteria for a major depressive episode with the simultaneous presence of MADRS score>/=14 PLUS meeting the criteria for a manic/hypomanic episode for at least 2 days with the simultaneous presence of Young Mania Rating Scale (YMRS) score>/=14

Exclusion Criteria:

1. Patients with a current Axis I diagnosis of schizophrenia, schizophreniform disorder, schizotypal disorder, bipolar disorder with psychotic sub-type that requires hospitalization, drug induced mania or AIDS induced mania

2. Women with a positive pregnancy test or who are lactating

3. Women of child-bearing potential who are not practicing a clinically accepted method of contraception

4. Patients with general medical conditions that contraindicate psychoactive medications or uncontrolled medical disorder or central nervous system diseases.

5. Patients whose clinical status requires inpatient or day hospital treatment

6. History of severe side effects associated with therapeutic doses of Li, DIV, LAM

7. Alcohol or drug dependent at time of enrollment

8. Suicidal at time of enrollment.

9. Current or previous exposure to iloperidone

10. Patients taking medication that cause QTC prolongation

11. Patients with serious cardiac disease

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UT Health Science Center San Antonio	San Antonio	Texas	United States	78229

Sponsors and Collaborators

• The University of Texas Health Science Center at San Antonio
• Novartis Pharmaceuticals
• Vanda Pharmaceuticals

Investigators

• Principal Investigator: Charles Bowden, MD, UT Health Science Center San Antonio

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: The University of Texas Health Science Center at San Antonio
• ClinicalTrials.gov Identifier: NCT02413918
• Other Study ID Numbers: HSC20120137
• First Posted: Apr 10, 2015
• Last Update Posted: Feb 8, 2018
• Last Verified: May 1, 2017

• Keywords provided by The University of Texas Health Science Center at San Antonio: mixed episode
• Additional relevant MeSH terms: Bipolar Disorder; Iloperidone

Study Results

Participant Flow

Recruitment Details	Recruitment occurred April 2013 to April 2015 from patients in the clinic or from responders to t.v. advertisements.
Pre-assignment Detail	Subjects who met inclusion criteria at screening visit were started on study medication at visit 2.

Arm/Group Title	Open Label Iloperidone
Arm/Group Description	open label iloperidone (oral tablet, 6mg-24mg, QD, 20 weeks) as adjunct to current lithium, divalproex, or lamotrigine. iloperidone: Qualifying subjects will take iloperidone starting at 2mg and up to a minimum of 12mg, maximum of 24mg, for 20 weeks in conjunction to the subjects current lithium, and or divalproex, and or lamotrigine.
Period Title: Overall Study
STARTED	41
COMPLETED	16
NOT COMPLETED	25

Baseline Characteristics

Arm/Group Title	Open Label Iloperidone
Arm/Group Description	open label iloperidone (oral tablet, 6mg-24mg, QD, 20 weeks) as adjunct to current lithium, divalproex, or lamotrigine. iloperidone: Qualifying subjects will take iloperidone starting at 2mg and up to a minimum of 12mg, maximum of 24mg, for 20 weeks in conjunction to the subjects current lithium, and or divalproex, and or lamotrigine.
Overall Participants	31
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	30 96.8%
>=65 years	1 3.2%
Sex: Female, Male (Count of Participants)
Female	26 83.9%
Male	5 16.1%

Outcome Measures

1. Primary Outcome

Title	Measure of Response by Change From Baseline to End of Study in BISS Depression and Mania Scale Scores
Description	The Bipolar Inventory of Symptoms Scale is a reliable and valid measure which assesses Depression and Mania symptoms of bipolar disorder. There are 42 items; each item is rated on a 0-4 scale. The BISS is a clinician-rated instrument. The Scale is rated as follows: 0 Not at all Slight Mild Moderate Severe Each of the 42 items is rated separately, with a score, based on the most recent 7 day period. For Depression: Items 1-21 items of the assessment are summed up and multiplied by 4 to give a cumulative score out of 84. The higher the score, the more severe the depression. For Mania: Items 22-42 are summed up and multiplied by 4 to give a cumulative score out of 84. The higher the score, the more severe the mania. The mean is calculated from the change in score between baseline and week 20.
Time Frame	Baseline and 20 weeks

Outcome Measure Data

Analysis Population Description

Subjects who are currently treated with mood stabilizers (Lithium, Divalproex or Lamotrigine), with a diagnosis of Bipolar Disorder I or II.

Arm/Group Title	Mean Change in Depression for Study Completers	Mean Change in Mania for Study Completers	Mean Change in Depression for All Study Participants	Mean Change in Mania for All Study Participants
Arm/Group Description	Measurement of mean change in depression for all subjects who entered study and completed 20 weeks	Measurement of mean change in mania for all study participants who completed 20 weeks.	Mean change in depression for all study participants, including early terminators.	Mean change in mania for all study participants, including early terminators
Measure Participants	16	16	41	41
Number [percentage change in score on BISS scale]	35.7	61.8	25	48

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Mean Change in Depression for Study Completers
	Comments	BISS Outcomes: Mean changes in depression and mania for study completers were measured. The a priori hypothesis was a mean change of 50%.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0094
	Comments	p value is not adjusted for multiple comparisons (see above). A priori threshold for significance was p<0.05.
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-14.9
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Deviation; Value: 20.0
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Mean Change in Mania for Study Completers
	Comments	BISS Outcomes: Mean changes in mania for study completers were measured. The a priori hypothesis was a mean change of 50%.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-15.4
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Deviation; Value: 10.1
	Estimation Comments

Adverse Events

Time Frame	3 years
Arm/Group Title	Open Label Iloperidone
Arm/Group Description	open label iloperidone (oral tablet, 6mg-24mg, QD, 20 weeks) as adjunct to current lithium, divalproex, or lamotrigine. iloperidone: Qualifying subjects will take iloperidone starting at 2mg and up to a minimum of 12mg, maximum of 24mg, for 20 weeks in conjunction to the subjects current lithium, and or divalproex, and or lamotrigine.
All Cause Mortality
	Open Label Iloperidone
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Open Label Iloperidone
	Affected / at Risk (%)	# Events
Total	0/31 (0%)
Other (Not Including Serious) Adverse Events
	Open Label Iloperidone
	Affected / at Risk (%)	# Events
Total	31/31 (100%)
Blood and lymphatic system disorders
Edema of the legs	2/31 (6.5%)	2
Cardiac disorders
Heart palpitations	9/31 (29%)	9
Atrial fibrilation	2/31 (6.5%)	2
Endocrine disorders
Increased Thirst	11/31 (35.5%)	14
Eye disorders
Blurry vision	2/31 (6.5%)	2
Dry Eyes	2/31 (6.5%)	2
Gastrointestinal disorders
dry mouth	12/31 (38.7%)	12
Diarrhea/Loose stool	4/31 (12.9%)	4
Abdominal Bloating	2/31 (6.5%)	2
General disorders
Drowsiness	5/31 (16.1%)	5
Immune system disorders
Flu symptoms/muscle weakness/fatigue	6/31 (19.4%)	8
Nasal Congestion	5/31 (16.1%)	5
Metabolism and nutrition disorders
weight gain	8/31 (25.8%)	8
Musculoskeletal and connective tissue disorders
Tremors	5/31 (16.1%)	5
worsening of Fibromyalgia	2/31 (6.5%)	2
Nervous system disorders
dizzy/lightheaded	8/31 (25.8%)	10
Migraine headache	3/31 (9.7%)	3
Psychiatric disorders
Anxiety	4/31 (12.9%)	4
Decreased concertration	5/31 (16.1%)	5
Renal and urinary disorders
Urinary tract infection	2/31 (6.5%)	2
Urinary Incontinence	8/31 (25.8%)	8
Respiratory, thoracic and mediastinal disorders
Shortness of breath	2/31 (6.5%)	2
Vascular disorders
Hypertension(high blood pressure)	2/31 (6.5%)	2

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.