Abstract
Background: Limited success of previous clinical trials for Fragile X syndrome (FXS) has led researchers to consider combining different drugs to correct the pleiotropic consequences caused by the absence of the Fragile X mental retardation protein (FMRP). Here, we report the results of the LovaMiX clinical trial, the first trial for FXS combining two disease-modifying drugs, lovastatin, and minocycline, which have both shown positive effects when used independently.Aim: The main goals of the study were to assess the safety and efficacy of a treatment combining lovastatin and minocycline for patients with FXS.Design: Pilot Phase II open-label clinical trial. Patients with a molecular diagnostic of FXS were first randomized to receive, in two-step titration either lovastatin or minocycline for 8 weeks, followed by dual treatment with lovastatin 40 mg and minocycline 100 mg for 2 weeks. Clinical assessments were performed at the beginning, after 8 weeks of monotherapy, and at week 20 (12 weeks of combined therapy).Outcome Measures: The primary outcome measure was the Aberrant Behavior Checklist-Community (ABC-C) global score. Secondary outcome measures included subscales of the FXS specific ABC-C (ABC-CFX), the Anxiety, Depression, and Mood Scale (ADAMS), the Social Responsiveness Scale (SRS), the Behavior Rating Inventory of Executive Functions (BRIEF), and the Vineland Adaptive Behavior Scale second edition (VABS-II).Results: Twenty-one individuals out of 22 completed the trial. There were no serious adverse events related to the use of either drugs alone or in combination, suggesting good tolerability and safety profile of the combined therapy. Significant improvement was noted on the primary outcome measure with a 40% decrease on ABC-C global score with the combined therapy. Several outcome measures also showed significance.Conclusion: The combination of lovastatin and minocycline is safe in patients for FXS individuals and appears to improve several elements of the behavior. These results set the stage for a larger, placebo-controlled double-blind clinical trial to confirm the beneficial effects of the combined therapy.
Highlights
Fragile X syndrome (FXS) is an X-linked neurodevelopmental disorder caused by a CGG trinucleotide repeat expansion at the 5′ untranslated region of the FMR1 gene leading to its methylation and its consequent silencing
Since dual therapy brings cumulated risk of adverse effects that could arise from either lovastatin, minocycline alone or in combination, direct exposition to both treatment at the beginning of the trial was avoided in accordance with Ethics Board recommendations, in the context of a substitute consent
Prior exposition to either drugs as monotherapy for 8 weeks before 12 weeks with dual therapy was chosen to reassure participants and caregivers while facilitating monitoring of arising adverse effect’s origin. This unique design allowed the direct comparison between lovastatin and minocycline during the monotherapy period
Summary
FXS is an X-linked neurodevelopmental disorder caused by a CGG trinucleotide repeat expansion at the 5′ untranslated region of the FMR1 gene leading to its methylation and its consequent silencing. This results in reduced or absent expression of the FMRP, which is essential for proper brain development and synaptic functioning [1, 2]. Current treatments are mostly symptomatic with limited efficacy The latter includes antidepressants, stimulants, alpha2-agonists, and antipsychotics [3]. Limited success of previous clinical trials for Fragile X syndrome (FXS) has led researchers to consider combining different drugs to correct the pleiotropic consequences caused by the absence of the Fragile X mental retardation protein (FMRP). We report the results of the LovaMiX clinical trial, the first trial for FXS combining two disease-modifying drugs, lovastatin, and minocycline, which have both shown positive effects when used independently
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