A Study to Evaluate the Safety and the Effects of Risperidone Compared With Other Atypical Antipsychotic Drugs on the Growth and Sexual Maturation in Children

• Sponsor: Johnson & Johnson Pharmaceutical Research & Development, L.L.C. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01050582
• Collaborator: (none)
• Enrollment: 244
• Locations: 29
• Arms: 2
• Duration (Months): 21
• Patients Per Site: 8.4
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the effects of risperidone compared with other atypical antipsychotic drugs on the physical maturity, growth and development of children, and the risk of prolactin-related adverse events (side effects) associated to these drugs.

Condition or Disease	Intervention/Treatment	Phase
Schizophrenia; Bipolar Disorder; Autistic Disorder; Conduct and Other Disruptive Behavior Disorders	Drug: Risperidone; Drug: Other atypical antipsychotic drugs	Phase 4

Detailed Description

This is a study to find out what the effects are of long-term use of atypical antipsychotics (drugs used to treat mental health and some behavior disorders) in children and adolescents on their growth and physical maturity. Atypical antipsychotics are used in the treatment of a wide range of disorders in children and adolescents, such as; schizophrenia, bipolar mania, autistic disorder or other disruptive behavior disorders. This study does not involve using any new medication, but to look into some of the side effects that children and adolescents may experience from taking an atypical antipsychotic. One of the side effects of some atypical antipsychotics is an increased level of "prolactin", a hormone that occurs naturally in the body which can lead to "hyperprolactinemia" a condition in which the pituitary gland produces too much prolactin. In order to further investigate these possible side effects, two groups of children and adolescents (aged 8 to 16) with a diagnosis of schizophrenia, bipolar mania, autistic disorder, or conduct and other disruptive behavior disorders who are or have been recently treated with an atypical antipsychotic will be enrolled; 1 group of children and adolescents will either be currently taking or have recently been treated with risperidone and the second group of children and adolescents will either be currently taking or have recently been treated with an a similar type of atypical antipsychotic therapy. The results will then be compared to see if the age of physical maturation, growth and development differs between the two groups, using data collected during an office visit and previous information available from existing medical records. The patient's growth will be assessed using information on height and weight taken from the medical records at different time points before (up to one year previous) and since they started treatment with antipsychotic therapy. In addition, there will also be one visit to the clinic where the growth and stage of sexual maturity of the patient will be reviewed by both the study doctor and through the patient's own assessment, using a questionnaire and pictures developed specially to assess stages of physical development (so called - Tanner stage). In addition, one blood sample will be taken from each patient to check the levels of prolactin hormone in the blood to see if this differs between treatment groups. Potential patients will be identified through automated databases and/or medical chart review. If, after fully understanding the purpose of this study, the parent, legal guardian and their child agree to participate by signing an informed consent (children to sign an assent form), information (specified below) related to your child's treatment and development will be collected directly from central medical records or from notes kept by your child's doctor for evaluation. The following data will be collected from available medical records: information about the patient's use of antipsychotic drug and prescriptions; previous records of the patient's height, weight, and growth; physical and sexual development (so called, Tanner stage [developmental stage]) if available; results of previous blood tests taken to evaluate the level of the hormone prolactin if available; and, history of any side effects that could be related to increased levels of the hormone prolactin. All the above information will be collected within 1 year before the patient started antipsychotic therapy. The same information (if available) will also be collected following the time that the patient starting taking their atypical antipsychotic medication until the present time. As much information as possible will be collected for this period of time so that a determination of how taking antipsychotic drugs may have influenced the patient's growth can be made. The study doctor will see each patient for a single study visit. This visit will take place at a convenient time approximately one week after informed consent/assent has been obtained. At the clinic visit, the study doctor will do some examinations to check the patient's general health and assess their growth and physical development. These will include: a physical examination (including developmental stage assessment [Tanner stage]), weight and height, vital signs (pulse, respiration rate, temperature and blood pressure), medical history, and the collection of information regarding the occurrence of any side effects thought to be related to the use of atypical antipsychotic medication or related to the hormone prolactin. In addition to being assessed by the study doctor, the patient will be asked to complete the Tanner Stage questionnaire. This will involve the patient reviewing both pictures and written descriptions of children at different stages of physical development. The patient will have to decide which picture/description is most representative of their body. The study doctor will also look at the patient's current use of any other medications. Each patient will participate in the study for about one week. The outcome measures of the study will be to compare Z-scores for height, age at current Tanner stage, and prolactin-related adverse events between patients exposed to risperidone and patients exposed to other atypical antipsychotic drugs. Outcome measures will be collected during the study visit and retrospectively during the time of exposure for up to 2 years prior to the study visit.

Study Design

• Study Type: Interventional
• Actual Enrollment: 244 participants
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Evaluation of Growth, Sexual Maturation, and Prolactin-Related Adverse Events in the Pediatric Population Exposed to Atypical Antipsychotic Drugs
• Study Start Date: Oct 1, 2009
• Actual Primary Completion Date: Jul 1, 2011
• Actual Study Completion Date: Jul 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Risperidone Risperidone as per local prescribing practices	Drug: Risperidone; As per local prescribing practices
Experimental: Other atypical antipsychotic drugs Other atypical antipsychotic drugs as per local prescribing practices	Drug: Other atypical antipsychotic drugs; As per local prescribing practices

Outcome Measures

Primary Outcome Measures

1. Height (cm) Z-score at Study Visit [One single study visit, approximately one week after informed consent has been obtained]

   Height (cm) measured at the study visit was converted to a Z-score based on the US Center for Disease Control 2000 growth charts for US subjects and European growth charts for ex-US subjects. A z-score indicates how many standard deviations a subject is away from the expected height for the subject's age and gender.

Secondary Outcome Measures

1. Age (Years) at Current Tanner Stage [One single study visit, approximately one week after informed consent has been obtained]

   Tanner stage is an evaluation of pubertal development with values ranging from 1 (pre-pubertal) to 5 (adult). A standardized, validated tool containing standardized pictures and written descriptions of the stages of pubic hair development, breast development for girls, and genital development for boys was used by physicians to make their assessment.

2. Number of Participants With Retrospectively Reported Potentially Prolactin-Related Adverse Events [Retrospectively during the time of exposure for up to 2 years prior to the study visit]

   Previous potentially prolactin-related adverse events, including hyperprolactinemia, were reviewed and abstracted from participants' medical records. Potentially prolactin-related adverse events include breast symptoms, menstrual disorders, hyperprolactinemia, and prolactinoma.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 8 Years to 16 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• One or both parents (according to local regulations) or a guardian must have signed an informed consent document indicating that they understand the purpose of and procedures required for the study and are willing to participate in the study (If appropriate according to local regulations, the patient must also assent)

• Treated for schizophrenia, bipolar mania, autistic disorder, or conduct and other disruptive behavior disorders

• Had at least 6 months of exposure for an atypical antipsychotic drug within 24 months before the study visit (patients may or may not be taking the atypical antipsychotics at the time of actual enrollment, eligible patients can have exposure to multiple atypical antipsychotics, however, they cannot concomitantly be exposed to more than 1 atypical antipsychotic for a period of greater than 30 days)

• Had medical records or automated data available for at least 1 year prior to the start of exposure

• Height and weight were recorded at least once within 1 year before the start of exposure, and if available at any time points after the start of exposure in the medical records or electronic databases (not mandatory)

Exclusion Criteria:

• Have at least 1 medical record, at any time before the start of exposure, consistent with malignancy (other than non-melanoma skin cancer), pregnancy, or a developmental delay or abnormality associated with growth or sexual maturation delays not related to the specified indications

• Had exposure to prolactin elevating medications other than atypical antipsychotics and selective serotonin reuptake inhibitors (SSRIs)

• Had exposure to Paliperidone

• Cannot comply with study procedures

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		San Francisco	California	United States
2		Aurora	Colorado	United States
3		Altamonte Springs	Florida	United States
4		Gainesville	Florida	United States
5		Smyrna	Georgia	United States
6		Naperville	Illinois	United States
7		Indianapolis	Indiana	United States
8		Valparaiso	Indiana	United States
9		Boston	Massachusetts	United States
10		Cambridge	Massachusetts	United States
11		Glen Oaks	New York	United States
12		Cleveland	Ohio	United States
13		Columbus	Ohio	United States
14		Antwerpen		Belgium
15		Freiburg		Germany
16		Jena		Germany
17		Mannheim		Germany
18		München		Germany
19		Tübingen		Germany
20		Ulm		Germany
21		Würzburg		Germany
22		Athens		Greece
23		Nijmegen		Netherlands
24		Gdansk		Poland
25		Kielce		Poland
26		Lódź		Poland
27		Sosnowiec		Poland
28		Warszawa N/A		Poland
29		Warszawa		Poland

Sponsors and Collaborators

• Johnson & Johnson Pharmaceutical Research & Development, L.L.C.

Investigators

• Study Director: Johnson & Johnson Pharmaceutical Research & Development, L.L. C. Clinical Trial, Johnson & Johnson Pharmaceutical Research & Development, L.L.C.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Johnson & Johnson Pharmaceutical Research & Development, L.L.C.
• ClinicalTrials.gov Identifier: NCT01050582
• Other Study ID Numbers: CR016687; RISNAP4022
• First Posted: Jan 15, 2010
• Last Update Posted: Nov 27, 2012
• Last Verified: Oct 1, 2012

• Keywords provided by Johnson & Johnson Pharmaceutical Research & Development, L.L.C.: Schizophrenia; Bipolar Disorder; Autistic Disorder; Conduct and Other Disruptive Behavior Disorders; Risperidone; RISPERDAL; Antipsychotic Agents; Prolactin; Pediatrics
• Additional relevant MeSH terms: Disease; Schizophrenia; Bipolar Disorder; Autistic Disorder; Mental Disorders; Problem Behavior; Attention Deficit and Disruptive Behavior Disorders; Risperidone; Antipsychotic Agents

Study Results

Participant Flow

Recruitment Details	A total of 244 subjects were assessed for eligibility of whom 230 signed informed consent. Of the 230, 43 were found not to meet inclusion or exclusion criteria, 2 withdrew consent, and 1 was not kept in the study due to a site decision. A total of 184 subjects were included in the analysis.

Arm/Group Title	Risperidone	Other Atypical Antipsychotics
Arm/Group Description	Subjects with at least 6 months exposure to risperidone within 24 months prior to enrollment	No risperidone exposure within 24 months of enrollment, no more than 30 days lifetime exposure to risperidone, and at least 6 months exposure to another atypical antipsychotic within 24 months prior to enrollment
Period Title: Overall Study
STARTED	133	51
COMPLETED	133	51
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Risperidone	Other Atypical Antipsychotics	Total
Arm/Group Description	Subjects with at least 6 months exposure to risperidone within 24 months prior to enrollment	No risperidone exposure within 24 months of enrollment, no more than 30 days lifetime exposure to risperidone, and at least 6 months exposure to another atypical antipsychotic within 24 months prior to enrollment	Total of all reporting groups
Overall Participants	133	51	184
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	12 (2.5)	12 (2.5)	12 (2.5)
Sex: Female, Male (Count of Participants)
Female	16 12%	18 35.3%	34 18.5%
Male	117 88%	33 64.7%	150 81.5%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	1 0.8%	1 2%	2 1.1%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	12 9%	6 11.8%	18 9.8%
White	110 82.7%	36 70.6%	146 79.3%
More than one race	3 2.3%	1 2%	4 2.2%
Unknown or Not Reported	7 5.3%	7 13.7%	14 7.6%
Region of Enrollment (participants) [Number]
United States	59 44.4%	40 78.4%	99 53.8%
Germany	41 30.8%	6 11.8%	47 25.5%
Poland	19 14.3%	3 5.9%	22 12%
Netherlands	8 6%	0 0%	8 4.3%
Greece	3 2.3%	2 3.9%	5 2.7%
Belgium	3 2.3%	0 0%	3 1.6%

Outcome Measures

1. Primary Outcome

Title	Height (cm) Z-score at Study Visit
Description	Height (cm) measured at the study visit was converted to a Z-score based on the US Center for Disease Control 2000 growth charts for US subjects and European growth charts for ex-US subjects. A z-score indicates how many standard deviations a subject is away from the expected height for the subject's age and gender.
Time Frame	One single study visit, approximately one week after informed consent has been obtained

Outcome Measure Data

Analysis Population Description

All participants with a height assessment available at the study visit.

Arm/Group Title	Risperidone	Other Atypical Antipsychotics
Arm/Group Description	Subjects with at least 6 months exposure to risperidone within 24 months prior to enrollment	No risperidone exposure within 24 months of enrollment, no more than 30 days lifetime exposure to risperidone, and at least 6 months exposure to another atypical antipsychotic within 24 months prior to enrollment
Measure Participants	132	50
Mean (Standard Deviation) [z-score]	0.40 (1.189)	0.09 (1.079)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Risperidone, Other Atypical Antipsychotics
	Comments	Null hypothesis is that there is no difference between the risperidone and other atypical antipsychotics groups in current height z-score.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Regression, Linear
	Comments	Covariates: weight (wt) divided expected wt for age and height (ht), age, use of concomitant medication with growth effects, preexposure ht z-score.
Method of Estimation	Estimation Parameter	Slope
	Estimated Value	0.447
	Confidence Interval	(2-Sided) 95%; 0.220 to 0.674
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.116
	Estimation Comments	Slope associated with treatment dummy variable with 1 indicating risperidone and 0 indicating other atypical antipychotics.

2. Secondary Outcome

Title	Age (Years) at Current Tanner Stage
Description	Tanner stage is an evaluation of pubertal development with values ranging from 1 (pre-pubertal) to 5 (adult). A standardized, validated tool containing standardized pictures and written descriptions of the stages of pubic hair development, breast development for girls, and genital development for boys was used by physicians to make their assessment.
Time Frame	One single study visit, approximately one week after informed consent has been obtained

Outcome Measure Data

Analysis Population Description

Participants with a physician assessed Tanner stage value.

Arm/Group Title	Risperidone	Other Atypical Antipsychotics
Arm/Group Description	Subjects with at least 6 months exposure to risperidone within 24 months prior to enrollment	No risperidone exposure within 24 months of enrollment, no more than 30 days lifetime exposure to risperidone, and at least 6 months exposure to another atypical antipsychotic within 24 months prior to enrollment
Measure Participants	124	49
Tanner Stage 1	10.2 (1.31)	10.3 (1.78)
Tanner Stage 2	11.3 (1.68)	11.2 (1.73)
Tanner Stage 3	13.1 (2.18)	12.2 (1.21)
Tanner Stage 4	14.9 (1.27)	15.0 (1.46)
Tanner Stage 5	15.1 (0.69)	15.0 (1.82)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Risperidone, Other Atypical Antipsychotics
	Comments	The null hypothesis is that there is no difference between the risperidone and other atypical antipsychotics groups in age (years) at current Tanner stage.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.378
	Comments
	Method	Regression, Linear
	Comments	Covariates: Tanner stage and gender
Method of Estimation	Estimation Parameter	Slope
	Estimated Value	-0.221
	Confidence Interval	(2-Sided) 95%; -0.711 to 0.269
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.250
	Estimation Comments	Slope associated with treatment dummy variable with 1 indicating risperidone and 0 indicating other atypical antipsychotics.

3. Secondary Outcome

Title	Number of Participants With Retrospectively Reported Potentially Prolactin-Related Adverse Events
Description	Previous potentially prolactin-related adverse events, including hyperprolactinemia, were reviewed and abstracted from participants' medical records. Potentially prolactin-related adverse events include breast symptoms, menstrual disorders, hyperprolactinemia, and prolactinoma.
Time Frame	Retrospectively during the time of exposure for up to 2 years prior to the study visit

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Risperidone	Other Atypical Antipsychotics
Arm/Group Description	Subjects with at least 6 months exposure to risperidone within 24 months prior to enrollment	No risperidone exposure within 24 months of enrollment, no more than 30 days lifetime exposure to risperidone, and at least 6 months exposure to another atypical antipsychotic within 24 months prior to enrollment
Measure Participants	133	51
Number [participants]	7 5.3%	3 5.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Risperidone, Other Atypical Antipsychotics
	Comments	Null hypothesis is that there is no difference between the risperidone and other atypical antipsychotics groups in frequency of retrospectively reported potentially prolactin-related adverse events
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	>0.999
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.865
	Confidence Interval	() 95%; 0.189 to 3.963
	Parameter Dispersion	Type: Value:
	Estimation Comments	Estimated OR is from a logistic regression model including factors for treatment arm, age, indication, and use of concomitant medication with growth effects.

Adverse Events

Time Frame	Days from signing of informed consent to study visit
Adverse Event Reporting Description	Adverse events prospectively reported from the time of signing informed consent to the study visit are summarized.
Arm/Group Title	Risperidone		Other Atypical Antipsychotics
Arm/Group Description	Subjects with at least 6 months exposure to risperidone within 24 months prior to enrollment		No risperidone exposure within 24 months of enrollment, no more than 30 days lifetime exposure to risperidone, and at least 6 months exposure to another atypical antipsychotic within 24 months prior to enrollment
All Cause Mortality
	Risperidone		Other Atypical Antipsychotics
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Risperidone		Other Atypical Antipsychotics
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/133 (0%)		0/51 (0%)
Other (Not Including Serious) Adverse Events
	Risperidone		Other Atypical Antipsychotics
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/133 (6%)		3/51 (5.9%)
Gastrointestinal disorders
Nausea	1/133 (0.8%)		0/51 (0%)
General disorders
Fatigue	1/133 (0.8%)		1/51 (2%)
Drug ineffective	1/133 (0.8%)		0/51 (0%)
Oedema	1/133 (0.8%)		0/51 (0%)
Infections and infestations
Eye infection	1/133 (0.8%)		0/51 (0%)
Lower respiratory tract infection	0/133 (0%)		1/51 (2%)
Nasopharyngitis	0/133 (0%)		1/51 (2%)
Investigations
Blood prolactin increased	1/133 (0.8%)		0/51 (0%)
Weight increased	1/133 (0.8%)		0/51 (0%)
Metabolism and nutrition disorders
Obesity	1/133 (0.8%)		0/51 (0%)
Nervous system disorders
Sedation	1/133 (0.8%)		0/51 (0%)
Headache	1/133 (0.8%)		0/51 (0%)
Psychiatric disorders
Middle insomnia	1/133 (0.8%)		0/51 (0%)
Reproductive system and breast disorders
Breast pain	0/133 (0%)		1/51 (2%)

Limitations/Caveats

A total of 350 subjects in a 1:1 ratio between the two arms was planned. Recruitment difficulties led to an imbalance in the number of subjects per arm and to early termination of the study. The results should be interpreted within this context.

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.