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Intravenous Immunoglobulin for PANDAS

Primary Purpose

Obsessive-Compulsive Disorder, Children, Anxiety Disorder

Status

Completed

Phase

Phase 3

Locations

United States

Study Type

Interventional

Intervention

Gamunex Intravenous Immunoglobulin

Placebo

About this trial

This is an interventional treatment trial for Obsessive-Compulsive Disorder focused on measuring Placebo Controlled, Obsessive-Compulsive Disorder, Children and Adolescents, Intravenous Immunoglobulin, PANDAS

Eligibility Criteria

4 Years - 13 Years (Child)All SexesDoes not accept healthy volunteers

INCLUSION CRITERIA:

Male and female children 4-13 years of age.

Presence of (Diagnostic and Statistical Manual of Mental Disorders Fourth Edition, Text Revision) DSM-IV TR OCD with or without a tic disorder.

Moderate or greater severity of symptoms, with a score of greater than or equal to 20 on the Children s Yale-Brown Obsessive-Compulsive Scale (CY-BOCS) and greater than or equal to 4 on the Clinical Global Impression Severity scale (CGI-S).

The acute onset within the previous six months of symptoms in a child previously well, or the first acute recurrence within the previous six months, after a period of relatively complete remission of symptoms. The acuity of symptom onset/exacerbation is key and must be severe, dramatic in onset, and proceed from no/minimal symptoms to maximum severity within 24-48 hours.

Symptom onset or first exacerbation preceded within four months by a GAS infection, as documented by positive throat culture, exposure to documented GAS infection (in a close contact, such as a sibling sharing a bedroom), and/or documented two-fold rise in one or more anti-GAS antibody titers such as anti-streptolysin O, anti-streptococcal DNAaseB, anti-carbohydrate antibodies and others.

Onset/exacerbation of OCD is accompanied by at least three of the following 7 clinical signs and symptoms. The acuity of the comorbid symptoms must be similar to the OCD symptoms and occur in the same time interval.

Markedly increased level of anxiety, particularly new onset of separation anxiety.
Emotional lability, irritability, aggressive behavior and/or personality change.
Sudden difficulties with concentration or learning.
Developmental regression ("baby-talk," temper tantrums; behaviors atypical for actual chronological age).
Sleep disorder (insomnia, night terrors, refusal to sleep alone).
Handwriting deterioration or other sign of motoric dysfunction (including new onset of motor hyperactivity, or presence of choreiform finger movements).
Urinary frequency or increased urge to urinate; daytime or night-time secondary enuresis.

EXCLUSION CRITERIA:

History of rheumatic fever, including Sydenham chorea (the neurologic manifestation).

Presence of symptoms consistent with autism, schizophrenia, or other psychotic disorder (unless psychotic symptoms have onset coincident with the possible PANDAS and are attributed to OCD).

Presence of a neurological disorder other than a tic disorder.

IQ <70. Child subjects need to be able to contribute meaningfully to baseline and follow-up ratings, to report adverse effects, and to assent to participation.

Presence of serious or unstable medical illness or psychiatric or behavioral symptoms that would make participation unsafe or study procedures too difficult to tolerate.

IgA deficiency (<20mg/dL). Intravenous immunoglobulin may contain trace IgA, which may very rarely lead to life-threatening anaphylaxis in IgA-deficient participants with anti-IgA antibodies (Misbah 1993).

Hyperviscosity syndromes, which can increase risks associated with IVIG administration.

Need for live virus vaccine within six months after receiving IVIG (which may be 7.5 months from randomization) since IVIG can interfere with effectiveness of such vaccines. IVIG should not be administered sooner than two weeks after administration of a live virus vaccine, for the same reason.

Taking nephrotoxic drugs. Every concomitant medication will be subject to scrutiny and possible consultation with pediatric safety monitors before randomization to study drug. See below as well.

Recent (less than eight weeks) initiation of cognitive-behavior therapy (CBT).

Recent (less than eight weeks) initiation or change in dosage of psychotropic medication for OCD or tic disorder (e.g., serotonin reuptake inhibitors for OCD, alpha-2 agonists or antipsychotics for tic disorders).

Sites / Locations

National Institutes of Health Clinical Center, 9000 Rockville Pike

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Group A

Group B

Arm Description

Drug: Gamunex Intravenous Immunoglobulin 2.0 gm/kg total, IV (in the vein), over 2 days

Drug: Placebo Normal saline, IV (in the vein), over 2 day

Outcomes

Primary Outcome Measures

Children's Yale-Brown Obsessive Compulsive Scale Total Score

Active IVIG will be significantly superior to sham IVIG in reducing OC symptoms and providing global relief of neuropsychiatric symptomatology. Total score is reported as the sum of all items and has a range of 0-40. Higher scores indicate more severe symptoms.

Secondary Outcome Measures

Clinical Global Impressions Improvement

1=very much improved, 2=much improved, 3=slightly improved, 4=no change, 5=slightly worse, 6=much worse, 7=very much worse

Clinical Responder to Treatment

Defined as a CGI-I score of 1 or 2 ("much" or "very much" improved) and a decrease in CY-BOCS of at least 30%

The Degree of Treatment Response is Expected to Correlate With the Percentage Reduction in Antinuclear Antibody Titers Following IVIG Administration.

Non-zero values of antinuclear antibodies are considered "positive" and reflective of an ongoing immune response in the individual. First, the number of participants who were classified at baseline as having "positive" antinuclear antibodies was calculated (see outcome measure data table, which states the number (AKA "count") of participants who had "positive" antinuclear antibodies at baseline). We hypothesized that improvement in the ongoing immune response, and therefore a reduction in antinuclear antibody titers, would mediate the effect of IVIG on OCD symptom improvement. However, because very few participants were classified as "positive" at baseline, it was not appropriate to pursue the original question of whether a decline in antinuclear antibodies (i.e., from "positive" to "negative") was related to symptom improvement.

The Degree of Treatment Response is Also Expected to Correlate With Decreased Inflammation in Specific Regions of the Brain, as Demonstrated by Changes on MRI

Full Information

NCT ID

NCT01281969

First Posted

January 21, 2011

Last Updated

March 5, 2020

Sponsor

National Institute of Mental Health (NIMH)

1. Study Identification

Unique Protocol Identification Number

NCT01281969

Brief Title

Intravenous Immunoglobulin for PANDAS

Official Title

A Placebo-Controlled Trial of Intravenous Immunoglobulin (IVIG) for PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders Associated With Streptococcal Infections)

Study Type

Interventional

2. Study Status

Record Verification Date

August 2018

Overall Recruitment Status

Completed

Study Start Date

January 2011 (undefined)

Primary Completion Date

December 2015 (Actual)

Study Completion Date

August 13, 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

National Institute of Mental Health (NIMH)

4. Oversight

5. Study Description

Brief Summary

Background: - Some children experience a sudden onset of symptoms similar to those found in obsessive-compulsive disorder that may be caused by the body s reaction to an infection with streptococcal bacteria, most commonly seen as strep throat or scarlet fever. When the body s immune system reacts against brain cells following a streptococcal infection, the condition is known as PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections). The immune system response can be inactivated by treatment with a drug known as intravenous immunoglobulin (IVIG). Because there is insufficient research on IVIG s effects on the immune system of children with PANDAS, including whether IVIG is helpful in treating obsessive-compulsive symptoms related to PANDAS, researchers are interested in examining whether IVIG is an appropriate treatment for PANDAS and its associated symptoms. Objectives: - To test the safety and effectiveness of intravenous immunoglobulin for the treatment of obsessive-compulsive disorder in children with PANDAS (pediatric autoimmune neuropsychiatric disorder associated with streptococcal infection). Eligibility: - Children between 4 and 12 years of age who have obsessive-compulsive disorder (with or without a tic disorder) with sudden onset of symptoms following Group A streptococcal bacterial infections. Design: Participants will be screened by telephone to obtain medical history and other information, followed by in-person screening at the National Institutes of Health Clinical Center. Participants will be admitted to the hospital to receive 2 days of infusions of either IVIG or a placebo. Frequent blood samples, imaging studies, and other tests will be performed during this visit. Six weeks after the inpatient stay, participants will return for further blood samples and other tests. Participants who did not receive the study drug, or who received the drug but did not respond to the initial IVIG infusion, will have the option to receive IVIG at this time. Followup visits will take place 3 months and 6 months after the first evaluation, followed by yearly follow-ups for 5 additional years.

Detailed Description

Objective: This study is designed to test the safety and efficacy of intravenous immunoglobulin (IVIG) for the treatment of obsessive-compulsive disorder (OCD) symptoms in children with PANDAS (pediatric autoimmune neuropsychiatric disorder associated with streptococcal infection). Study Population: Thirty-two male and female children with severe obsessive-compulsive symptoms related to a new onset or first recurrence of symptoms consistent with the PANDAS subtype of OCD. Design: his is a multi-site double-blind placebo-controlled trial. Potential subjects will be screened in person at NIMH, and there will be remote video corroboration by a team of collaborators at Yale University. Eligible subjects will be admitted to the 1NW pediatrics inpatient unit at the Clinical Center for further assessment, randomization, and study drug administration according to protocol. Subjects who fail to improve 6 weeks after blinded IVIG/placebo administration (1.0 gm/kg/day of IVIG on two consecutive days; total dose 2.0 gm/kg) will be eligible to receive open-label IVIG. Outcome Measures: Primary: Improvement in obsessions, compulsions, and other neuropsychiatric symptoms. Exploratory: Reduction of titers of cross-reactive antibodies (Abs) Resolution of basal ganglia inflammation (as measured by pre-/post-changes in MRI volumetric scans and inflammatory sequences) Normalization of selected serum and CSF cytokines

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Obsessive-Compulsive Disorder, Children, Anxiety Disorder, Autoimmune Disease, PANDAS

Keywords

Placebo Controlled, Obsessive-Compulsive Disorder, Children and Adolescents, Intravenous Immunoglobulin, PANDAS

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 3

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

48 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Group A

Arm Type

Experimental

Arm Description

Drug: Gamunex Intravenous Immunoglobulin 2.0 gm/kg total, IV (in the vein), over 2 days

Arm Title

Group B

Arm Type

Placebo Comparator

Arm Description

Drug: Placebo Normal saline, IV (in the vein), over 2 day

Intervention Type

Drug

Intervention Name(s)

Gamunex Intravenous Immunoglobulin

Intervention Description

2.0 gm/kg total, IV (in the vein), over 2 days

Intervention Type

Drug

Intervention Name(s)

Placebo

Intervention Description

Normal saline, IV (in the vein), over 2 days

Primary Outcome Measure Information:

Title

Children's Yale-Brown Obsessive Compulsive Scale Total Score

Description

Time Frame

6 weeks

Secondary Outcome Measure Information:

Title

Clinical Global Impressions Improvement

Description

1=very much improved, 2=much improved, 3=slightly improved, 4=no change, 5=slightly worse, 6=much worse, 7=very much worse

Time Frame

6 weeks

Title

Clinical Responder to Treatment

Description

Defined as a CGI-I score of 1 or 2 ("much" or "very much" improved) and a decrease in CY-BOCS of at least 30%

Time Frame

6 weeks

Title

The Degree of Treatment Response is Expected to Correlate With the Percentage Reduction in Antinuclear Antibody Titers Following IVIG Administration.

Description

Time Frame

Baseline

Title

The Degree of Treatment Response is Also Expected to Correlate With Decreased Inflammation in Specific Regions of the Brain, as Demonstrated by Changes on MRI

Time Frame

3 Months

10. Eligibility

Sex

All

Minimum Age & Unit of Time

4 Years

Maximum Age & Unit of Time

13 Years

Accepts Healthy Volunteers

Eligibility Criteria

INCLUSION CRITERIA: Male and female children 4-13 years of age. Presence of (Diagnostic and Statistical Manual of Mental Disorders Fourth Edition, Text Revision) DSM-IV TR OCD with or without a tic disorder. Moderate or greater severity of symptoms, with a score of greater than or equal to 20 on the Children s Yale-Brown Obsessive-Compulsive Scale (CY-BOCS) and greater than or equal to 4 on the Clinical Global Impression Severity scale (CGI-S). The acute onset within the previous six months of symptoms in a child previously well, or the first acute recurrence within the previous six months, after a period of relatively complete remission of symptoms. The acuity of symptom onset/exacerbation is key and must be severe, dramatic in onset, and proceed from no/minimal symptoms to maximum severity within 24-48 hours. Symptom onset or first exacerbation preceded within four months by a GAS infection, as documented by positive throat culture, exposure to documented GAS infection (in a close contact, such as a sibling sharing a bedroom), and/or documented two-fold rise in one or more anti-GAS antibody titers such as anti-streptolysin O, anti-streptococcal DNAaseB, anti-carbohydrate antibodies and others. Onset/exacerbation of OCD is accompanied by at least three of the following 7 clinical signs and symptoms. The acuity of the comorbid symptoms must be similar to the OCD symptoms and occur in the same time interval. Markedly increased level of anxiety, particularly new onset of separation anxiety. Emotional lability, irritability, aggressive behavior and/or personality change. Sudden difficulties with concentration or learning. Developmental regression ("baby-talk," temper tantrums; behaviors atypical for actual chronological age). Sleep disorder (insomnia, night terrors, refusal to sleep alone). Handwriting deterioration or other sign of motoric dysfunction (including new onset of motor hyperactivity, or presence of choreiform finger movements). Urinary frequency or increased urge to urinate; daytime or night-time secondary enuresis. EXCLUSION CRITERIA: History of rheumatic fever, including Sydenham chorea (the neurologic manifestation). Presence of symptoms consistent with autism, schizophrenia, or other psychotic disorder (unless psychotic symptoms have onset coincident with the possible PANDAS and are attributed to OCD). Presence of a neurological disorder other than a tic disorder. IQ <70. Child subjects need to be able to contribute meaningfully to baseline and follow-up ratings, to report adverse effects, and to assent to participation. Presence of serious or unstable medical illness or psychiatric or behavioral symptoms that would make participation unsafe or study procedures too difficult to tolerate. IgA deficiency (<20mg/dL). Intravenous immunoglobulin may contain trace IgA, which may very rarely lead to life-threatening anaphylaxis in IgA-deficient participants with anti-IgA antibodies (Misbah 1993). Hyperviscosity syndromes, which can increase risks associated with IVIG administration. Need for live virus vaccine within six months after receiving IVIG (which may be 7.5 months from randomization) since IVIG can interfere with effectiveness of such vaccines. IVIG should not be administered sooner than two weeks after administration of a live virus vaccine, for the same reason. Taking nephrotoxic drugs. Every concomitant medication will be subject to scrutiny and possible consultation with pediatric safety monitors before randomization to study drug. See below as well. Recent (less than eight weeks) initiation of cognitive-behavior therapy (CBT). Recent (less than eight weeks) initiation or change in dosage of psychotropic medication for OCD or tic disorder (e.g., serotonin reuptake inhibitors for OCD, alpha-2 agonists or antipsychotics for tic disorders).

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Susan E Swedo, M.D.

Organizational Affiliation

National Institute of Mental Health (NIMH)

Official's Role

Principal Investigator

Facility Information:

Facility Name

National Institutes of Health Clinical Center, 9000 Rockville Pike

City

Bethesda

State/Province

Maryland

ZIP/Postal Code

20892

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

Citations:

PubMed Identifier

12670369

Citation

Ballow M, Berger M, Bonilla FA, Buckley RH, Cunningham-Rundles CH, Fireman P, Kaliner M, Ochs HD, Skoda-Smith S, Sweetser MT, Taki H, Lathia C. Pharmacokinetics and tolerability of a new intravenous immunoglobulin preparation, IGIV-C, 10% (Gamunex, 10%). Vox Sang. 2003 Apr;84(3):202-10. doi: 10.1046/j.1423-0410.2003.00286.x.

Results Reference

background

PubMed Identifier

14528103

Citation

Benesch M, Kerbl R, Lackner H, Berghold A, Schwinger W, Triebl-Roth K, Urban C. Low-dose versus high-dose immunoglobulin for primary treatment of acute immune thrombocytopenic purpura in children: results of a prospective, randomized single-center trial. J Pediatr Hematol Oncol. 2003 Oct;25(10):797-800. doi: 10.1097/00043426-200310000-00011.

Results Reference

background

PubMed Identifier

3492741

Citation

Berrios X. [Recurrent Sydenham's chorea: a rare manifestation of rheumatic disease]. Rev Med Chil. 1986 Mar;114(3):254-6. No abstract available. Spanish.

Results Reference

background

PubMed Identifier

29233751

Citation

Frick LR, Rapanelli M, Jindachomthong K, Grant P, Leckman JF, Swedo S, Williams K, Pittenger C. Differential binding of antibodies in PANDAS patients to cholinergic interneurons in the striatum. Brain Behav Immun. 2018 Mar;69:304-311. doi: 10.1016/j.bbi.2017.12.004. Epub 2017 Dec 9.

Results Reference

derived

PubMed Identifier

27663941

Citation

Williams KA, Swedo SE, Farmer CA, Grantz H, Grant PJ, D'Souza P, Hommer R, Katsovich L, King RA, Leckman JF. Randomized, Controlled Trial of Intravenous Immunoglobulin for Pediatric Autoimmune Neuropsychiatric Disorders Associated With Streptococcal Infections. J Am Acad Child Adolesc Psychiatry. 2016 Oct;55(10):860-867.e2. doi: 10.1016/j.jaac.2016.06.017. Epub 2016 Aug 3.

Results Reference

derived

PubMed Identifier

27166296

Citation

Gaughan T, Buckley A, Hommer R, Grant P, Williams K, Leckman JF, Swedo SE. Rapid Eye Movement Sleep Abnormalities in Children with Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS). J Clin Sleep Med. 2016 Jul 15;12(7):1027-32. doi: 10.5664/jcsm.5942.

Results Reference

derived

Links:

URL

https://clinicalstudies.info.nih.gov/cgi/detail.cgi?B_2011-M-0058.html

Description

NIH Clinical Center Detailed Web Page

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Intravenous Immunoglobulin for PANDAS

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