A Double-Blind, Placebo-Controlled Trial of Metformin in Individuals With Fragile X Syndrome (FXS)
概览
- 阶段
- 2 期
- 干预措施
- Placebo Medication
- 疾病 / 适应症
- Fragile X Syndrome
- 发起方
- University of Alberta
- 入组人数
- 125
- 试验地点
- 2
- 主要终点
- Change from baseline in the Expressive Language Sampling (ELS) mean Number of Different Words (NDW) score
- 状态
- 已完成
- 最后更新
- 3个月前
概览
简要总结
This study is a controlled trial of metformin in individuals with fragile X syndrome between the ages of 6 and 35 years. Participants will be randomized in a double-blind design to either drug or placebo and will attend three visits to the study site in a 4-month period for a series of tests. The primary objectives are to assess safety, tolerability, and efficacy of metformin in the treatment of language deficits, behavior problems, and obesity/excessive appetite in individuals with fragile X syndrome.
详细描述
This is a multi-center study at the University of Alberta and CHU Sainte-Justine for fragile X syndrome (FXS) patients aged 6 to 35 years inclusive. It is a randomized, double-blind, placebo-controlled trial of metformin (also known as Glumetza, Glucophage, Fortamet), a type 2 diabetes medication that can also improve obesity and excessive appetite. Metformin has emerged as a candidate drug for the targeted treatment of FXS based on animal studies showing rescue of multiple phenotypes in the FXS model. Metformin may contribute to normalizing signaling pathways in FXS in the central nervous system, which may include activities of mTOR and PI3K, both of which have shown to be pathogenically overactive in FXS. In addition, metformin inhibits phosphodiesterase, which would lead to correction of cAMP levels, and MMP9 production, which is also elevated in FXS. Looking at the potential signaling pathways, metformin appears to be a good candidate for targeting several of the intracellular functions in neurons disrupted in FXS and, therefore, has potential to rescue several types of symptoms in individuals with FXS. Researchers have utilized metformin in the clinical treatment of over 20 individuals with FXS between the ages of 4 and 58 years and have found the medication to be well tolerated and to provide benefits not only in lowering weight gain and normalizing appetite but also in language and behavior. In this controlled trial, the researchers hope to further assess metformin's safety and benefits in the areas of language and cognition, eating and weight loss, and overall behavior. Each participant will be involved in this trial for a period of 4 months. This will include 3 visits to one of the sites and 5 phone calls. At each visit, the researchers will assess behavioral, cognitive, and language development. The researchers will also assess the side effects of the study medication throughout the trial.
研究者
入排标准
入选标准
- •Subject has Fragile X syndrome with a molecular genetic confirmation of the full FMR1 mutation (\>200 CGG repeats) or the other loss of function mutations of the FMR1 gene (SNVs and deletions of the gene).
- •Subject is a male or non-pregnant, non-lactating female age 6 through 35 years, inclusive.
- •Subjects who are capable of becoming pregnant must use an acceptable method of birth control for the duration of the study. Acceptable forms of birth control include abstinence (only for subjects who are not sexually active), intrauterine devices in place for at least 3 months, oral contraceptives, surgical sterilization, or adequate barrier methods.
- •Subject must have a caregiver (parent, guardian, or other legally authorized representative) who is willing to participate in the whole study.
- •Subject and caregiver are able to attend the clinic regularly and reliably.
- •Subject and/or subject's caregiver is able to understand, read, write and speak English or French fluently to complete study-related materials.
- •For subjects who are not their own legal guardian, subject's caregiver is able to understand and sign an informed consent to participate in the study.
- •The use of concomitant medication must be stable, in terms of dose and dosing regimen, for at least 4 weeks prior to Screening and must remain stable during the period between first visit (Screening) and the commencement of the study; every effort should be made to maintain stable regimens of allowed concomitant medications from the time of commencement of double-blind study medication until the last study assessment.
- •Behavioral/educational treatments must be stable for 4 weeks prior to first visit (Screening) and must remain stable during the period between Screening and the commencement of randomized double-blind study medication.
- •10\. Overall age equivalent is not higher than 13 and IQ is not higher than 85, as assessed at Screening on the Leiter-III, and subject must speak at least occasional 3-word phrases.
排除标准
- •Families that are not cooperative and will not follow through with the demands of this study.
- •Subject has a life-threatening medical problem or other major systemic illness that compromises health or safety and/or would interfere with this study.
- •Age younger than 6 or older than 35 years.
- •History of intolerable adverse events with metformin.
- •Current or recent metformin treatment (within the past 4-months).
- •BMI inferior to 2 standard deviations below the mean for age using the World Health Organization scale.
- •Serum creatinine \> 1.4 mg/dl (female) or \> 1.5 mg/dl (male).
- •History of metabolic acidosis or a condition with lactic acidosis.
- •Severe Vitamin B12 deficiency.
- •Pregnancy at screening or unwillingness to use acceptable method of birth control, if applicable.
研究组 & 干预措施
Placebo Medication
The placebo will be dosed in a weight-dependent manner. For participants under 50kg at baseline, the initial dose will be 250mg once per day, and if this dose is well tolerated, they will increase each week by 250mg until a maximum dose of 1000mg daily is reached. For participants at and above 50kg at baseline, the initial dose will be 500mg once per day, and if this dose is well tolerated, they will increase each week by 500mg until a maximum dose of 2000mg daily is reached. After the 4-week titration period, each participant will continue dosing at his or her maximum tolerated dose daily for the remaining 12 weeks of the study.
干预措施: Placebo Medication
Active Metformin Medication
The active metformin medication will be dosed in a weight-dependent manner. For participants under 50kg at baseline, the initial dose will be 250mg once per day, and if this dose is well tolerated, they will increase each week by 250mg until a maximum dose of 1000mg daily is reached. For participants at and above 50kg at baseline, the initial dose will be 500mg once per day, and if this dose is well tolerated, they will increase each week by 500mg until a maximum dose of 2000mg daily is reached. After the 4-week titration period, each participant will continue dosing at his or her maximum tolerated dose daily for the remaining 12 weeks of the study.
干预措施: Metformin
结局指标
主要结局
Change from baseline in the Expressive Language Sampling (ELS) mean Number of Different Words (NDW) score
时间窗: Baseline, End of Treatment/Week 16
The ELS is collected from shared interactions around a wordless picture book involving the participant and the examiner. The primary outcome measure will be Number of Different Words (NDW) derived from transcripts of audiorecorded samples of spoken language taken from two sampling contexts (conversation and narration), according to procedures described by Abbeduto and colleagues (Abbeduto et al., 1995; Kover et al., 2012). Samples are collected pre- and post- treatment using different books on each occasion. The mean of NDW in conversation and NDW in narration will be computed, and statistically adjusted through analysis of covariance for differences in talkativeness as outlined in Conners et al., 2018. The mean NDW score ranges from 1 to infinite/unspecified. An increase (positive change) in score from baseline to follow-up indicates improvement. The greater the increase, the greater the improvement.
次要结局
- Change from baseline in the Anxiety Depression and Mood Screen (ADAMS) overall score(Baseline, Week 8, End of Treatment/Week 16)
- Change from baseline in the Pediatric Quality of Life Questionnaire (PedsQL) Parent Proxy overall score(Baseline, Week 8, End of Treatment/Week 16)
- Change from baseline in the Child Sleep Habits Questionnaire (CSHQ) overall score(Baseline, Week 8, End of Treatment/Week 16)
- Change from baseline in the FXS-normed Aberrant Behavior Checklist - Community Edition (ABC-C)(Baseline, Week 8, End of Treatment/Week 16)
- Change from baseline in the Visual Analog Scale (VAS)(Baseline, Week 8, End of Treatment/Week 16)
- Change from baseline in the Vineland Adaptive Behavior Scales-Third Edition (VABS-III) Adaptive Behavior Composite Score(Baseline, End of Treatment/Week 16)
- Change from baseline in the Care Related Quality of Life (CarerQoL) overall score(Baseline, Week 8, End of Treatment/Week 16)
- Change from baseline in The Memory Game(Baseline, End of Treatment/Week 16)
- Change from baseline in the NIH Toolbox Picture Sequence Memory Test(Baseline, End of Treatment/Week 16)
- Change from baseline in the NIH Toolbox Flanker Inhibitory Control and Attention Test(Baseline, End of Treatment/Week 16)
- Improvement of symptoms in FXS using the Clinical Impression - Improvement (CGI-I) scale(Baseline, Week 8, End of Treatment/Week 16)
- Change from baseline in the Swanson, Nolan and Pelham Questionnaire (SNAP-IV) overall score(Baseline, Week 8, End of Treatment/Week 16)
- Change from baseline in the EuroQol-5D (EQ-5D) overall score(Baseline, Week 8, End of Treatment/Week 16)
- Change from baseline in the NIH Toolbox Oral Reading Recognition Test(Baseline, End of Treatment/Week 16)
- Change from baseline in the Sensory Profile-2 or Sensory Profile Adolescents/Adults(Baseline, Week 8, End of Treatment/Week 16)
- Change from baseline in the NIH Toolbox List Sorting Working Memory Test(Baseline, End of Treatment/Week 16)
- Change from baseline in the NIH Toolbox Dimensional Change Card Sort Test(Baseline, End of Treatment/Week 16)
- Change from baseline in the NIH Toolbox Pattern Comparison Processing Speed Test(Baseline, End of Treatment/Week 16)
- Change from baseline in the NIH Toolbox Speeded Matching Test(Baseline, End of Treatment/Week 16)
- Change from baseline in Event Related Potentials during the Auditory Oddball Paradigm and Pseudoword Paradigm(Baseline, End of Treatment/Week 16)
- Change from baseline in the NIH Toolbox Picture Vocabulary Test(Baseline, End of Treatment/Week 16)
- Change from baseline in Eye Tracking(Baseline, End of Treatment/Week 16)