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Efficacy of Amoxicilline/Clavulanic Acid in Patients Affected by Tic Disorder Colonized by Group A Streptococcus (AntibioTICS)

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ClinicalTrials.gov Identifier: NCT01860300
Recruitment Status : Unknown
Verified May 2016 by Francesco Cardona, University of Roma La Sapienza.
Recruitment status was:  Recruiting
First Posted : May 22, 2013
Last Update Posted : May 11, 2016
Sponsor:
Information provided by (Responsible Party):
Francesco Cardona, University of Roma La Sapienza

Brief Summary:

This study is an extension of the European Multicentre Tics In Children Studies (EMTICS) COURSE study for which a separate study protocol exists; Aim of this clinical trial is to study the efficacy of treatment with antibiotics in reducing severity of tics and associated neuropsychiatric symptoms in patients with a tic disorder colonised by GAS.

Primary Objective: Test the hypothesis that antibiotic treatment of GAS colonisation compared to placebo is associated with a larger reduction of tic and associated neuropsychiatric symptoms in the short-term (1 month) in patients with a tic disorder colonised by GAS.

Secondary Objective: Test the hypothesis that antibiotic treatment of GAS colonisation is superior to placebo in the long-term (1 year) reduction of tic and associated neuropsychiatric symptoms in patients with a tic disorder colonized by GAS.

Patients affected by a chronic tic disorder followed in the EMTICS- Longitudinal Course Study that show a positive culture for GAS at any microbiological examination during their follow-up will be considered eligible for the treatment trial.

Patients showing GAS positivity will be invited to participate in the clinical trial.

The patients enrolled will be randomly assigned to antibiotic or placebo in a 1:1 ratio.

All participating patients will undergo a microbiological, serological and clinical assessment 1 month after the date of entering in the treatment trial (i.e. around 20 days after the end of treatment). Then, the patients will be followed with clinical, laboratory and microbiological assessments every four months for 1 year.

Patients will be deblinded at the end of the treatment trial follow-up (1 year after the recruitment).

Patients who will develop a true GAS infection or who otherwise need to be prescribed antibiotics for any clinical reason during the follow-up will be withdrawn from the study and immediately deblinded. Data of such patients would, however, remain part of the study analyses, following the intention-to-treat principle.


Condition or disease Intervention/treatment Phase
Tic Disorders Drug: Amoxicillin-Potassium Clavulanate Combination Drug: placebo Not Applicable

Detailed Description:

Following the few studies performed on this topic, children affected by tic disorder show a rate of Group A Streptococcus (GAS) colonization similar or slightly higher than that reported in the normal population.

However, several studies have documented high rates of elevated anti-streptolysin O titers (ASOT) in children affected by tic disorders. One study reported a significantly higher ASOT in 150 children with tics compared to 150 healthy children, documenting a direct relationship between ASOT and tic severity. In this study, however, throat swab culture analyses on a subsample of patients failed to detect a predominant GAS serotype associated with tics. An American cohort of 81 patients with TS also exhibited higher ASOT than age-matched healthy volunteers and a mixed group of patients with autoimmune diseases. Increased ASOT, anti-deoxyribonuclease B (DNAse B), anti- streptococcal M12 and M19 titres were also observed in a smaller German sample of patients with TS. In a British cohort of 100 patients with TS (50% children), ASOT was raised in 64% of children and in 68% of adults with TS; this was significantly higher than in neurological disease and healthy control subjects. Two other reports from British and Italian cohorts confirmed these findings. However, a subsequent study failed to find a significant association with ASOT and anti-DNAse B titres using the same cross-sectional approach. More recently, a study on a large service-based cohort of TS patients confirmed the significant elevated rate of the high ASOT, but evidenced also that, on prospective analysis, ASOT were persistently elevated in 57% of patients with TS. Moreover, in tic patients the enhanced immune response is not limited to ASOT but it involves a broad range of GAS antigens.

Taken together, these observations lead to hypothesize that TS patients colonized by GAS are not merely carriers and that this colonization may promote a sustained anti-streptococcal immune response contributing to the persistence of tic symptoms.

If this hypothesis is true, the antibiotic treatment of GAS colonization in patients affected by a chronic tic disorder could modify their symptoms in term of severity and number of exacerbations.

Up to now, only tic patients diagnosed as Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infection (PANDAS) underwent a controlled antibiotic treatment: two trials, aimed to study the efficacy of different preventive regimens on number of tic exacerbations, obtained however mixed results, mainly due to poor compliance.

Investigators here designed a placebo-controlled trial with amoxicilline/clavulanic acid in tic patients showing GAS colonization. This drug is the first line therapy for streptococcal pharyngo-tonsillitis. Some previous studies have shown a superiority of amoxicillin versus penicillin in the treatment of GAS infections. A 10-day course of amoxicillin is considered sufficient and efficient in the treatment of GAS tonsillo-pharyngitis. Moreover, oral amoxicillin/clavulanic acid and oral clindamycin for 10 days achieved comparable rates of bacteriologic eradication at 12 days and 3 months. Furthermore, amoxicilline/clavulanic acid has been demonstrated to be efficacious in the treatment of GAS colonization. A few antibiotic regimens - evaluated prospectively in randomized, controlled trials- have demonstrated efficacy for termination of GAS carriage: among these, a regimen of 10 days of amoxicillin/ clavulanic acid was more effective than repeat penicillin in patients with treatment failure. Thus, the 10-days regimen of amoxicilline/clavulanic acid should be efficient in GAS eradication and, on the other hand, the shortness of the treatment should avert problems in patient's compliance.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 46 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Multicentre, Randomised, Double-blinded, Placebo-controlled Trial of Efficacy of Amoxicilline/Clavulanic Acid in Patients Affected by Tic Disorder Colonized by Group A Streptococcus
Study Start Date : March 2013
Estimated Primary Completion Date : April 2017
Estimated Study Completion Date : May 2017


Arm Intervention/treatment
Experimental: Antibiotic
Amoxicillin-Potassium Clavulanate Combination
Drug: Amoxicillin-Potassium Clavulanate Combination
Amoxicillin-Potassium Clavulanate Combination will be prescribed at the dose of 25/3.6 mg/kg/day for 10 days, 2 times/day, as oral suspension.
Other Name: Augmentin

Placebo Comparator: Placebo
Placebo
Drug: placebo



Primary Outcome Measures :
  1. Severity of tic disorder [ Time Frame: one month ]
    YGTSS scores


Secondary Outcome Measures :
  1. Severity of tic disorder [ Time Frame: one year ]
    YGTSS scores


Other Outcome Measures:
  1. Severity of associated neuropsychiatric symptoms [ Time Frame: one month - one year ]
    CYBOCS - PUTS - SCQ - SNAP-IV -SDQ



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Ages Eligible for Study:   3 Years to 16 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Diagnosis of Tourette Syndrome or another chronic tic disorder according to DSM IV-TR criteria.
  • Evidence of GAS colonization at any visit of EMTICS Longitudinal Course Study.
  • Either no current psychotropic medication or on stable anti-tic medication for at least 2 months before the enrolment in the trial.
  • Able (in the Investigators opinion) and willing to comply with all study requirements.

Exclusion Criteria:

  • Children and/or parents are unable to understand and comply with protocol
  • Any antibiotic treatment for any reason during the last month before enrolment in the trial.
  • Clinical manifestations of pharyngitis or other streptococcal infections at moment of enrolment in the trial.
  • Known or suspected hypersensitivity to penicillin or other β-lactam antibacterials, a history of amoxicillin-clavulanate-associated cholestatic jaundice or hepatic dysfunction.
  • Known and/or suspected renal or hepatic impairment (due to the potential for drug-related toxicity in patients with such a condition).
  • Scheduled elective surgery or other procedures requiring general anaesthesia during the study.
  • Any other significant disease or disorder which, in the opinion of the Investigator, may either put the participants at risk because of participation in the study, or may influence the result of the study, or the participant's ability to participate in the study.
  • Participants who have participated in another research study involving an investigational product in the past 12 weeks

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01860300


Contacts
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Contact: Francesco Cardona, MD +390644712288 francesco.cardona@uniroma1.it

Locations
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Italy
Department of Pediatrics and Child Neuropsychiatry Recruiting
Rome, Italy, 00185
Sub-Investigator: Valeria Neri, MD         
Sponsors and Collaborators
University of Roma La Sapienza
Investigators
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Principal Investigator: Francesco Cardona, MD Sapienza Università di Roma
Additional Information:
Publications:

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Responsible Party: Francesco Cardona, Assistant Professor, University of Roma La Sapienza
ClinicalTrials.gov Identifier: NCT01860300    
Other Study ID Numbers: Sapienza Università di Roma
2012-002430-36 ( EudraCT Number )
First Posted: May 22, 2013    Key Record Dates
Last Update Posted: May 11, 2016
Last Verified: May 2016
Keywords provided by Francesco Cardona, University of Roma La Sapienza:
Tic Disorders
Tourette Syndrome
Additional relevant MeSH terms:
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Tics
Tic Disorders
Disease
Pathologic Processes
Dyskinesias
Neurologic Manifestations
Nervous System Diseases
Movement Disorders
Central Nervous System Diseases
Neurodevelopmental Disorders
Mental Disorders
Amoxicillin
Clavulanic Acid
Clavulanic Acids
Amoxicillin-Potassium Clavulanate Combination
Anti-Bacterial Agents
Anti-Infective Agents
beta-Lactamase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action