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

NCT ID: NCT01860300

Last Updated: 2016-05-11

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: NA
• Total Enrollment: 46 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-03-31
• Study Completion Date: 2017-05-31

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GAS infection or who otherwise need to be prescribed antibiotics for any clinical reason during the follow-up will be withdrawn from the study and immediately deblinded.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.

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.

Conditions

Tic Disorders

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Antibiotic

Amoxicillin-Potassium Clavulanate Combination

Group Type: EXPERIMENTAL

Amoxicillin-Potassium Clavulanate Combination

Intervention Type: DRUG

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.

Placebo

Placebo

Group Type: PLACEBO_COMPARATOR

placebo

Intervention Type: DRUG

Interventions

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.

Intervention Type: DRUG

placebo

Intervention Type: DRUG

Other Intervention Names

Augmentin

Eligibility 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

• Minimum Eligible Age: 3 Years
• Maximum Eligible Age: 16 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University of Roma La Sapienza

OTHER

Sponsor Role: lead

Responsible Party

Francesco Cardona

Assistant Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Francesco Cardona, MD

Role: PRINCIPAL_INVESTIGATOR

Sapienza Università di Roma

Locations

Department of Pediatrics and Child Neuropsychiatry

Rome, , Italy

Site Status: RECRUITING

Countries

Italy

Central Contacts

Francesco Cardona, MD

Role: CONTACT

francesco.cardona@uniroma1.it

+390644712288

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Other Identifiers

2012-002430-36

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

Sapienza Università di Roma

Identifier Type: -

Identifier Source: org_study_id