Intravenous Immunoglobulin for PANDAS

• Sponsor: National Institute of Mental Health (NIMH) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT01281969
• Collaborator: (none)
• Enrollment: 48
• Location: 1
• Arms: 2
• Duration (Months): 91.4
• Patients Per Site Per Month: 0.5

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Obsessive-Compulsive Disorder; Children; Anxiety Disorder; Autoimmune Disease; PANDAS	Drug: Gamunex Intravenous Immunoglobulin; Drug: Placebo	Phase 3

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 48 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Placebo-Controlled Trial of Intravenous Immunoglobulin (IVIG) for PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders Associated With Streptococcal Infections)
• Study Start Date: Jan 1, 2011
• Actual Primary Completion Date: Dec 1, 2015
• Actual Study Completion Date: Aug 13, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Group A Drug: Gamunex Intravenous Immunoglobulin 2.0 gm/kg total, IV (in the vein), over 2 days	Drug: Gamunex Intravenous Immunoglobulin; 2.0 gm/kg total, IV (in the vein), over 2 days
Placebo Comparator: Group B Drug: Placebo Normal saline, IV (in the vein), over 2 day	Drug: Placebo; Normal saline, IV (in the vein), over 2 days

Outcome Measures

Primary Outcome Measures

1. Children's Yale-Brown Obsessive Compulsive Scale Total Score [6 weeks]

   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

1. Clinical Global Impressions Improvement [6 weeks]

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

2. Clinical Responder to Treatment [6 weeks]

   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%

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

   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.

4. 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 [3 Months]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 4 Years to 13 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

• 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.

1. Markedly increased level of anxiety, particularly new onset of separation anxiety.

2. Emotional lability, irritability, aggressive behavior and/or personality change.

3. Sudden difficulties with concentration or learning.

4. Developmental regression ("baby-talk," temper tantrums; behaviors atypical for actual chronological age).

5. Sleep disorder (insomnia, night terrors, refusal to sleep alone).

6. Handwriting deterioration or other sign of motoric dysfunction (including new onset of motor hyperactivity, or presence of choreiform finger movements).

7. 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).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	National Institutes of Health Clinical Center, 9000 Rockville Pike	Bethesda	Maryland	United States	20892

Sponsors and Collaborators

• National Institute of Mental Health (NIMH)

Investigators

• Principal Investigator: Susan E Swedo, M.D., National Institute of Mental Health (NIMH)

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• NIH Clinical Center Detailed Web Page

Publications

• 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.
• 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.
• Berríos X. [Recurrent Sydenham's chorea: a rare manifestation of rheumatic disease]. Rev Med Chil. 1986 Mar;114(3):254-6. Spanish.

• Responsible Party: National Institute of Mental Health (NIMH)
• ClinicalTrials.gov Identifier: NCT01281969
• Other Study ID Numbers: 110058; 11-M-0058
• First Posted: Jan 24, 2011
• Last Update Posted: Mar 17, 2020
• Last Verified: Aug 1, 2018

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by National Institute of Mental Health (NIMH): Placebo Controlled; Obsessive-Compulsive Disorder; Children and Adolescents; Intravenous Immunoglobulin; PANDAS
• Additional relevant MeSH terms: Autoimmune Diseases; Disease; Anxiety Disorders; Compulsive Personality Disorder; Obsessive-Compulsive Disorder; Immunoglobulins; Immunoglobulins, Intravenous; Antibodies; gamma-Globulins; Rho(D) Immune Globulin

Study Results

Participant Flow

Arm/Group Title	IVIG	Placebo	Screened But Not Randomized
Arm/Group Description	Gamunex Intravenous Immunoglobulin: 2.0 gm/kg total, IV (in the vein), over 2 days	Placebo: Normal saline, IV (in the vein), over 2 days	Excluded prior to randomization because child did not meet study entry criteria or child refused consent
Period Title: Overall Study
STARTED	18	18	12
COMPLETED	17	18	0
NOT COMPLETED	1	0	12

Baseline Characteristics

Arm/Group Title	IVIG	Placebo	Total
Arm/Group Description	Gamunex Intravenous Immunoglobulin: 2.0 gm/kg total, IV (in the vein), over 2 days	Placebo: Normal saline, IV (in the vein), over 2 days	Total of all reporting groups
Overall Participants	17	18	35
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	8.99 (2.37)	9.61 (2.32)	9.30 (2.32)
Sex: Female, Male (Count of Participants)
Female	5 29.4%	7 38.9%	12 34.3%
Male	12 70.6%	11 61.1%	23 65.7%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 5.9%	1 5.6%	2 5.7%
Not Hispanic or Latino	16 94.1%	17 94.4%	33 94.3%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 5.9%	0 0%	1 2.9%
Asian	1 5.9%	0 0%	1 2.9%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	1 5.9%	0 0%	1 2.9%
White	14 82.4%	16 88.9%	30 85.7%
More than one race	0 0%	2 11.1%	2 5.7%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	17 100%	18 100%	35 100%
Clinical Global Impressions Severity (participants) [Number]
Moderate (4)	2 11.8%	3 16.7%	5 14.3%
Marked (5)	8 47.1%	9 50%	17 48.6%
Severe (6)	7 41.2%	4 22.2%	11 31.4%
Extreme (7)	0 0%	2 11.1%	2 5.7%
Children's Yale-Brown Obsessive Compulsive Scale Total (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	26.47 (5.14)	28.78 (3.98)	27.65 (4.66)

Outcome Measures

1. Primary Outcome

Title	Children's Yale-Brown Obsessive Compulsive Scale Total Score
Description	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.
Time Frame	6 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Group A	Group B
Arm/Group Description	Gamunex Intravenous Immunoglobulin: 2.0 gm/kg total, IV (in the vein), over 2 days	Placebo: Normal saline, IV (in the vein), over 2 days
Measure Participants	17	18
Mean (Standard Deviation) [units on a scale]	20.59 (10.12)	25.67 (8.65)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Group A, Group B
	Comments	Analysis of covariance model controlling for baseline scores. A priori power calculations based on the Perlmutter et al. study (IVIG effect size 1.2) suggested that a sample size of 16 per group would be sufficient to detect an effect size of 1.0 with 80% power.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.44
	Comments	p-value is unadjusted. a priori threshold for statistical significance is .05
	Method	ANCOVA
	Comments	F(1,34)=0.62, p=.44
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.97
	Confidence Interval	(2-Sided) 95%; -7.1 to 3.15
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Group A	Group B
Arm/Group Description	Gamunex Intravenous Immunoglobulin: 2.0 gm/kg total, IV (in the vein), over 2 days	Placebo: Normal saline, IV (in the vein), over 2 days
Measure Participants	17	18
Mean (Standard Deviation) [units on a scale]	2.88 (1.20)	3.53 (1.62)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Group A, Group B
	Comments	The Wilcoxon two-sample test was used to compare CGI-Improvement ratings (an ordinal variable) at week 6. Power calculation was based on CYBOCS as primary outcome.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	.12
	Comments	p-value is not adjusted.
	Method	Wilcoxon (Mann-Whitney)
	Comments	Mean rank sum in the placebo group = 19.92; mean rank sum in the IVIG group = 15.97. Z = -1.18, p=.12

3. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Group A	Group B
Arm/Group Description	Gamunex Intravenous Immunoglobulin: 2.0 gm/kg total, IV (in the vein), over 2 days	Placebo: Normal saline, IV (in the vein), over 2 days
Measure Participants	17	18
Number [participants]	6 35.3%	4 22.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Group A, Group B
	Comments	Chi-squared test was used to compare distribution of responders by randomization group. Power calculation was based on CY-BOCS (primary outcome).
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	.40
	Comments	p-value is not adjusted for multiple comparisons.
	Method	Chi-squared
	Comments	X2 = 0.72, p=.40

4. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	IVIG	Placebo
Arm/Group Description	Gamunex Intravenous Immunoglobulin: 2.0 gm/kg total, IV (in the vein), over 2 days	Placebo: Normal saline, IV (in the vein), over 2 days
Measure Participants	17	18
Count of Participants [Participants]	8 47.1%	5 27.8%

5. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	AE data were collected 1 week post-infusion and at 6 weeks post infusion.
Arm/Group Title	Group A		Group B
Arm/Group Description	Gamunex Intravenous Immunoglobulin: 2.0 gm/kg total, IV (in the vein), over 2 days		Placebo: Normal saline, IV (in the vein), over 2 days
All Cause Mortality
	Group A		Group B
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Group A		Group B
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/17 (0%)		0/18 (0%)
Other (Not Including Serious) Adverse Events
	Group A		Group B
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	17/17 (100%)		5/18 (27.8%)
General disorders
Headache	8/17 (47.1%)		3/18 (16.7%)
Sore throat	1/17 (5.9%)		2/18 (11.1%)
Stomach or abdominal discomfort	3/17 (17.6%)		1/18 (5.6%)
Nausea (vomiting)	4/17 (23.5%)		1/18 (5.6%)
Muscle/bone/joint pain	3/17 (17.6%)		2/18 (11.1%)
Tiredness/fatigue	2/17 (11.8%)		1/18 (5.6%)
Anxiety	2/17 (11.8%)		2/18 (11.1%)

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.