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Add-on Pilot Trial of Minocycline to Treat Fragile X Syndrome

Primary Purpose

Fragile X Syndrome

Status

Completed

Phase

Not Applicable

Locations

Canada

Study Type

Interventional

Intervention

Minocycline

About this trial

This is an interventional treatment trial for Fragile X Syndrome focused on measuring Clinical Drug Trial

Eligibility Criteria

13 Years - 35 Years (Child, Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria:

Diagnosis of FXS by clinical evaluation and confirmed by FMR1-DNA testing with presence of full mutation or mosaicism for the full mutation. Prior DNA testing reports will be accepted, when available.
Age between 13 to 35 years inclusive at the time of informed consent.
Male or female
CGI-Severity Score of 4 or greater, indicative of moderate or greater severity of behavioural problems. This is a 7-point scale of clinical global impression of severity that the clinician fills out after considering all the available information on the patient, including the parent history, the examination in clinic, reports from the school and other sources.
Score of 9 or greater on the Aberrant Behaviour Checklist - Irritability Scale (top 50th %-tile). The ABC is a global behaviour checklist implemented for the measurement of drug and other treatment effects in mentally impaired individuals. It is made up of 5 empirically derived dimensions including irritability, lethargy/withdrawal, inappropriate speech, hyperactivity, and stereotypic behaviour based on 58 items that describe various behavioural problems.
Availability of parent and/or caregiver for all clinic visits and assessments.
English language fluency and reading level of 6th grade or greater in one caregiver.

Exclusion Criteria:

Allergy to minocycline.
Kidney disease or elevated renal function tests.
Liver disease or elevated liver function tests.
Participants with neutropenia, anemia, or thrombocytopenia.
History of systemic lupus erythematosus or screening anti-nuclear antibody (ANA) titre of >1:40, as minocycline may cause a lupus-like reaction.
Individuals who do not have a mother or caregiver who is willing to participate in the clinic visits.
Individuals who are pregnant or at risk to become pregnant, specifically sexually active females will be excluded.
Presence of persistent psychotic symptoms
Subjects with symptom severity likely judged to endanger personal safety or safety of others.
History of systemic lupus erythematosus or screening anti-nuclear antibody (ANA) titre of >1:40, as minocycline may cause a lupus-like reaction.

Sites / Locations

Surrey Place Centre

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

minocyline 50 mg or 100 mg PO BID

Arm Description

open label treatment with minocycline low or high dose, 50 mg or 100 mg PO (by mouth) BID (twice a day), added to existing medication regimen for 8 weeks

Outcomes

Primary Outcome Measures

Change From Baseline of ABC Irritability Subtest Score at 8 Weeks

The 15-item Irritability Scale includes questions about aggression, self-injury, tantrums, agitation, and unstable mood on a scale of 0 to 45 with higher scores indicating greater severity. This scale has been successfully used in previous medication studies in children with autism and in patients with FXS and in a controlled trial of ampakine CX516 in FXS. All ABC subscales showed good reliability when used by parents and caregivers of individuals with FXS to assess behavior in the CX516 study NCT00054730, and yielded intraclass correlation coefficient (ICC) values of 0.7-0.9.

ABC Irritability Subtest Score

ABC Irritability subtest score was used

ABC Irritability Subtest Score

ABC (Aberrant behavior checklist) Irritability subtest score was used

Secondary Outcome Measures

Parent Defined Target Symptoms Scale-Visual

Clinical Global Impression Scale

Stanford Binet 5 (SB5)

The Peabody Picture Vocabulary Test Third Edition (PPVT-III)

The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS)

Non-Verbal Associative Learning Task (NVALT)

Vineland Adaptive Behaviour Scales (VABS)

Parent Defined Target Symptoms Scale-Visual

Clinical Global Impression Scale

Stanford Binet 5 (SB5)

The Peabody Picture Vocabulary Test Third Edition (PPVT-III)

The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS)

Non-Verbal Associative Learning Task (NVALT)

Vineland Adaptive Behaviour Scales (VABS)

Full Information

NCT ID

NCT00858689

First Posted

March 9, 2009

Last Updated

February 16, 2016

Sponsor

FRAXA Research Foundation

Collaborators

Fragile X Research Foundation of Canada

1. Study Identification

Unique Protocol Identification Number

NCT00858689

Brief Title

Add-on Pilot Trial of Minocycline to Treat Fragile X Syndrome

Official Title

Add-on Pilot Trial of Minocycline in Fragile X Syndrome

Study Type

Interventional

2. Study Status

Record Verification Date

February 2016

Overall Recruitment Status

Completed

Study Start Date

October 2007 (undefined)

Primary Completion Date

November 2008 (Actual)

Study Completion Date

January 2009 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

FRAXA Research Foundation

Collaborators

Fragile X Research Foundation of Canada

4. Oversight

Data Monitoring Committee

5. Study Description

Brief Summary

Fragile X Syndrome (FXS) is the most common known inherited form of mental impairment, developmental disability and autism. Minocycline is an antibiotic that has recently been used to treat the mouse model for Fragile X, and was found to reverse the structural abnormalities that are seen their brain cells. The purpose of this research study is to determine if minocycline is an effective treatment for patients with fragile X syndrome (FXS).

Detailed Description

Fragile X Syndrome (FXS) is the most common known inherited form of mental impairment and is also associated with a range of learning disabilities, neurological problems, such as seizures, and behavioural difficulties. For many individuals with FXS, behavioral difficulties result in severe problems within the family and community, particularly in the form of agitation, temper outbursts, hyperactivity, and aggression. These problems often require a variety of psychopharmacological and behavioural approaches. Although a variety of medications can be helpful in FXS there are no targeted interventions based on molecular abnormalities that have been studied. Defects in dendritic spine formation have been found in the brains of patients with Fragile X, suggesting these structures may represent an anatomical and physiological basis for the cognitive deficits associated with this disorder. Recent research has suggested that minocycline may have a specific benefit in the treatment of FXS. Minocycline is an antibiotic that has been found to inhibit the activity of matrix metallo-proteinase-9 (MMP-9), which is up-regulated in the hippocampus of FMR1 KO (Fragile X Mental Retardation-1 Knockout) mice and may be responsible for the immature dendritic spine profile of hippocampal neurons. Minocycline has recently been used to treat the FXS KO mouse model for Fragile X, and was found to rescue this abnormal phenotype by inducing the formation of mature dendritic spines in FMR1 KO hippocampal neurons, both in vitro and in vivo. Minocycline treated FXS KO mice also performed significantly better in the elevated maze, a cognitive performance test that measures activity and anxiety. Exciting preclinical effects of minocycline with regard to the FXS disease model have led to this pilot proposal, which is designed to generate preliminary data that could be used to support a larger clinical trial. The overall hypothesis is that minocycline is a specific molecular targeted treatment for FXS that will display beneficial effects on disruptive behaviour and possibly other associated features of FXS via a reduction in MMP-9 activity.

6. Conditions and Keywords

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

Fragile X Syndrome

Keywords

Clinical Drug Trial

7. Study Design

Primary Purpose

Treatment

Study Phase

Not Applicable

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

20 (Actual)

8. Arms, Groups, and Interventions

Arm Title

minocyline 50 mg or 100 mg PO BID

Arm Type

Experimental

Arm Description

open label treatment with minocycline low or high dose, 50 mg or 100 mg PO (by mouth) BID (twice a day), added to existing medication regimen for 8 weeks

Intervention Type

Drug

Intervention Name(s)

Minocycline

Other Intervention Name(s)

Solodyn, Dynacin, Arestin, Minocin

Intervention Description

50-100 mg PO BID for 8 weeks with an option for a 1 year extension.

Primary Outcome Measure Information:

Title

Change From Baseline of ABC Irritability Subtest Score at 8 Weeks

Description

Time Frame

Baseline and 8 weeks

Title

ABC Irritability Subtest Score

Description

ABC Irritability subtest score was used

Time Frame

8 weeks

Title

ABC Irritability Subtest Score

Description

ABC (Aberrant behavior checklist) Irritability subtest score was used

Time Frame

1 year

Secondary Outcome Measure Information:

Title

Parent Defined Target Symptoms Scale-Visual

Time Frame

Baseline

Title

Clinical Global Impression Scale

Time Frame

Baseline

Title

Stanford Binet 5 (SB5)

Time Frame

Baseline

Title

The Peabody Picture Vocabulary Test Third Edition (PPVT-III)

Time Frame

Baseline

Title

The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS)

Time Frame

Baseline

Title

Non-Verbal Associative Learning Task (NVALT)

Time Frame

Baseline

Title

Vineland Adaptive Behaviour Scales (VABS)

Time Frame

Baseline

Title

Parent Defined Target Symptoms Scale-Visual

Time Frame

8 weeks

Title

Parent Defined Target Symptoms Scale-Visual

Time Frame

1 year

Title

Clinical Global Impression Scale

Time Frame

8 weeks

Title

Clinical Global Impression Scale

Time Frame

1 year

Title

Stanford Binet 5 (SB5)

Time Frame

1 year

Title

The Peabody Picture Vocabulary Test Third Edition (PPVT-III)

Time Frame

8 weeks

Title

The Peabody Picture Vocabulary Test Third Edition (PPVT-III)

Time Frame

1 year

Title

The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS)

Time Frame

8 weeks

Title

The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS)

Time Frame

1 year

Title

Non-Verbal Associative Learning Task (NVALT)

Time Frame

8 weeks

Title

Non-Verbal Associative Learning Task (NVALT)

Time Frame

1 year

Title

Vineland Adaptive Behaviour Scales (VABS)

Time Frame

8 weeks

Title

Vineland Adaptive Behaviour Scales (VABS)

Time Frame

1 year

10. Eligibility

Sex

All

Minimum Age & Unit of Time

13 Years

Maximum Age & Unit of Time

35 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Diagnosis of FXS by clinical evaluation and confirmed by FMR1-DNA testing with presence of full mutation or mosaicism for the full mutation. Prior DNA testing reports will be accepted, when available. Age between 13 to 35 years inclusive at the time of informed consent. Male or female CGI-Severity Score of 4 or greater, indicative of moderate or greater severity of behavioural problems. This is a 7-point scale of clinical global impression of severity that the clinician fills out after considering all the available information on the patient, including the parent history, the examination in clinic, reports from the school and other sources. Score of 9 or greater on the Aberrant Behaviour Checklist - Irritability Scale (top 50th %-tile). The ABC is a global behaviour checklist implemented for the measurement of drug and other treatment effects in mentally impaired individuals. It is made up of 5 empirically derived dimensions including irritability, lethargy/withdrawal, inappropriate speech, hyperactivity, and stereotypic behaviour based on 58 items that describe various behavioural problems. Availability of parent and/or caregiver for all clinic visits and assessments. English language fluency and reading level of 6th grade or greater in one caregiver. Exclusion Criteria: Allergy to minocycline. Kidney disease or elevated renal function tests. Liver disease or elevated liver function tests. Participants with neutropenia, anemia, or thrombocytopenia. History of systemic lupus erythematosus or screening anti-nuclear antibody (ANA) titre of >1:40, as minocycline may cause a lupus-like reaction. Individuals who do not have a mother or caregiver who is willing to participate in the clinic visits. Individuals who are pregnant or at risk to become pregnant, specifically sexually active females will be excluded. Presence of persistent psychotic symptoms Subjects with symptom severity likely judged to endanger personal safety or safety of others. History of systemic lupus erythematosus or screening anti-nuclear antibody (ANA) titre of >1:40, as minocycline may cause a lupus-like reaction.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Carlo Paribello, M.D.

Organizational Affiliation

Fragile X Research Foundation of Canada

Official's Role

Principal Investigator

Facility Information:

Facility Name

Surrey Place Centre

City

Toronto

State/Province

Ontario

ZIP/Postal Code

M5S 2C2

Country

Canada

12. IPD Sharing Statement

Citations:

PubMed Identifier

20937127

Citation

Paribello C, Tao L, Folino A, Berry-Kravis E, Tranfaglia M, Ethell IM, Ethell DW. Open-label add-on treatment trial of minocycline in fragile X syndrome. BMC Neurol. 2010 Oct 11;10:91. doi: 10.1186/1471-2377-10-91.

Results Reference

result

Links:

URL

http://www.fragile-x.ca

Description

The Fragile X Research Foundation of Canada is a non-profit organization which is dedicated to funding biomedical research for improved treatment and, ultimately, a cure for fragile X.

URL

http://www.fraxa.org

Description

FRAXA is a non-profit organization whose mission is to accelerate progress toward effective treatments and a cure for Fragile X, by funding the most promising research.

Learn more about this trial

Add-on Pilot Trial of Minocycline to Treat Fragile X Syndrome

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