Antibiotic Treatment and Intravenous Immunoglobulin Trial for PANDAS (ATIVPANDAS)

February 17, 2023 updated by: Stefano Pallanti, CNS Onlus

Antibiotic Treatment and Intravenous Immunoglobulin Double-blind, Randomized, Placebo-controlled Trial for PANDAS

An increasing body of evidence indicates that an immune basis might underline a number of pediatric neuropsychiatric disorders. Research studies found a subgroup of children who had Obsessive compulsive (OCD) and/or tic disorders following a Group A beta-hemolytic streptococcal (GAS) infection. The subgroup is identified by the acronym, PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections. More recently, several PANDAS variants have been described, including adult-onset variant. There are many evidences that OCD/tic symptoms could be due to an immunologic reaction against brain tissues following a streptococcal infection.

The purpose of this study is to know if sertraline (one of the SSRI approved by FDA to improve OCD/tic symptoms in these patients) plus antibiotic (benzathine penicillin G or azithromycin in case of penicillin allergy) is more effective than SSRI only.

Patients who will not respond to antibiotic will be treated with intravenous immunoglobulin (IVIG) in order to inactivate the immune reaction versus brain tissues.(No treatment response is based on the lack of a Y-BOCS score improvement of at least 35%).

Objectives:

  • To determine the safety and efficacy of SSRI+AB compared to SSRI only.
  • To test the safety and additional beneficial effects of high dose of IVIG on antibiotic prophylaxis for the treatment of OCD symptoms in non-responders patients with PANDAS.

Study methodology:

  • Participants will be screened to obtain medical history and other information at Neurologic and Psychiatric Sciences Department of Florence University Hospital and at Paris-est University.
  • Participants will receive a treatment of either SSRI+AB or SSRI+placebo for 12 weeks (double-blind randomized trial)
  • Patients who will not respond to AB will be admitted to the hospital to receive IVIG for 5 days, for 5 consecutive months.
  • Follow-up visits will take place 3 and 6 months after the first evaluation, followed by 6 months follow-ups for 3 additional years.

Blood samples (including blood cytokine determination), ECG, Doppler and 2-dimensional echocardiogram EEG, imaging studies (2 tesla MRI), and other tests will be performed both before and after the treatment with SSRI+AB or SSRI+placebo and in case also after IVIG treatment.

Study Overview

Detailed Description

Inclusion criteria for PANDAS subjects are:

  • Ages 4 -40 years
  • Presence of DSM-IV-R obsessive compulsive disorder or tic disorder and at least two of the following:

    1. Anxieties e.g. new onset separation anxiety
    2. Sensory abnormalities (tactile/auditory/visual defensiveness or visual misperceptions)
    3. Behavioral Regression (e.g. new onset impulsivity, hyperactivity, meltdowns)
    4. Deterioration in school performance or in handwriting
    5. Emotional lability and/or depression
    6. Urinary symptoms (frequent urination or enuresis)
    7. Sleep disturbances
    8. Anorexia
  • Sudden onset of symptoms or episodic course of symptom severity following infections.
  • Symptoms are of moderate severity with Yale-Brown Obsessive Compulsive Scale (Y-BOCS) (or with the children's version for subjects below 16 years of age) of more or equal to 16 and/or Yale Global Tic Severity Scale (YGTSS) of more or equal to 21 and with significant impairment (CGI of moderate or worse).
  • Laboratory documentation of infection as documented by at least two of these: positive throat culture, documented rise in one or more anti-GAS antibody titers such as anti-streptolysin O, anti-streptococcal DNAaseB.

Exclusion criteria for all subjects are: non-tic neurologic disorder, presence of immunologic disorder, presence of serious medical illness, IgA deficiency (< 20mg/dL), hyperviscosity syndromes, psychotropic therapy.

Interventions:

All patients will be treated with sertraline (to a maximum of 200 mg/day. This study will involve a 12 week double-blind, placebo-controlled, randomized trial with benzathine penicillin G (1.200.000 U every 3 weeks) or azithromycin (500 mg/week) in case of penicillin allergy. Non-responders patients will be treated with IVIG (2 g/kg of body weight over 5 days, for 5 consecutive months)

Outcomes:

Primary Outcome Measures:

  • Significant reduction of OC/tic symptoms severity, as assessed by YBOCS/YGTSS, compared to placebo, after antibiotic prophylaxis. [ Time Frame: 6 months ]
  • Significant reduction of OC/tic symptoms severity, as assessed by YBOCS/YGTSS, compared to placebo, after IVIG treatment. [ Time Frame: 6 months ]

Secondary Outcome Measures:

  • The degree of treatment response is expected to correlate with the percentage reduction in antibodies titers following IVIG administration. [ Time Frame: 6 months]
  • The degree of treatment response is also expected to correlate with decreased inflammation in specific regions of the brain, as demonstrated by macroscopic changes and microstructural alterations on MRI and serum and CSF cytokines and chemokines [ Time Frame: 6 months ]

Expected impact:

  • To clarify the utility of antibiotic and IVIG therapy in PANDAS and how the IVIG produce their effects.
  • To individualize the treatment.
  • To disseminate new data for the treatment of PANDAS.

Study Type

Interventional

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

4 years to 40 years (Child, Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Ages 4 -40 years
  • Presence of DSM-IV-R obsessive compulsive disorder or tic disorder and at least two of the following:

    1. Anxieties e.g. new onset separation anxiety
    2. Sensory abnormalities (tactile/auditory/visual defensiveness or visual misperceptions)
    3. Behavioral Regression (e.g. new onset impulsivity, hyperactivity, meltdowns)
    4. Deterioration in school performance or in handwriting
    5. Emotional lability and/or depression
    6. Urinary symptoms (frequent urination or enuresis)
    7. Sleep disturbances
    8. Anorexia
  • Sudden onset of symptoms or episodic course of symptom severity following infections
  • Laboratory documentation of infection

Exclusion Criteria:

  • Exclusion criteria for all subjects are: non-tic neurologic disorder, presence of immunologic disorder, presence of serious medical illness, IgA deficiency (< 20mg/dL), hyperviscosity syndromes, psychotropic therapy.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: SSRI+AB
Intervention: sertraline+antibiotic (penicillin/azithromycin) 12 weeks treatment with a combination of sertraline (to a maximum of 200 mg/day)and one antibiotic ( benzathine penicillin G 1.200.000 U every 3 weeks or, in case of allergy, azithromycin 500 mg/week ). Patients who will not respond to SSRI+antibiotic (penicillin/azithromycin) will be treated with IVIG (2g/kg over 5 days for 5 consecutive months)

12 weeks treatment with a combination of Sertraline (to a maximum of 200 mg/day) and an antibiotic (benzathine penicillin G 1.200.000 U every 3 weeks or, in case of allergy, azithromycin 500 mg/week.

Non-responder patients will be treated with IVIG (2g/kg over 5 days for 5 consecutive months)

Other Names:
  • Zoloft
  • Lustral
  • Bicillin L-A
  • Permapen
  • Zythromax
Patients who will not respond to SSRI+antibiotic (penicillin/azithromycin) will be treated with IVIG (2g/kg over 5 days for 5 consecutive months)
Other Names:
  • Gammagard
  • Gamimune N
Placebo Comparator: SSRI+placebo
Intervention: Sertraline+placebo 12 weeks treatment with a combination of sertraline (to a maximum of 200 mg/day) and a placebo
12 weeks treatment with a combination of sertraline (to a maximum of 200 mg/day) and placebo
Other Names:
  • Zoloft
  • Lustral

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
The improvement of OC/tic symptoms will be superior in patients treated with SSRI+AB and in case with IVIG, compared with those treated with SSRI+placebo, as assessed by the YBOCS/YGTSS
Time Frame: 6 months
6 months

Secondary Outcome Measures

Outcome Measure
Time Frame
The degree of treatment response is expected to correlate with the percentage reduction in antibodies titers following IVIG administration
Time Frame: 6 months
6 months
The degree of treatment response is also expected to correlate with decreased inflammation in specific regions of the brain, as demonstrated by macroscopic changes and microstructural alterations on MRI and serum and CSF cytokines and chemokines
Time Frame: 6 months
6 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Collaborators

Investigators

  • Principal Investigator: Stefano Pallanti, MD; PhD

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

June 1, 2013

Primary Completion (Actual)

December 1, 2013

Study Completion (Actual)

June 1, 2016

Study Registration Dates

First Submitted

December 14, 2012

First Submitted That Met QC Criteria

January 14, 2013

First Posted (Estimate)

January 16, 2013

Study Record Updates

Last Update Posted (Estimate)

February 20, 2023

Last Update Submitted That Met QC Criteria

February 17, 2023

Last Verified

February 1, 2023

More Information

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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