A Double-Blind, Placebo-Controlled Trial of Metformin in Individuals With Fragile X Syndrome
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 120
- 试验地点
- 3
- 主要终点
- Change from baseline in the Expressive Language Sampling (ELS) mean Number of Different Words (NDW) score
研究概览
简要总结
This study is a controlled trial of metformin in individuals with fragile X syndrome between the ages of 6 and 25 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-site study for fragile X syndrome (FXS) patients aged 6 to 25 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. The 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 the UC Davis MIND Institute 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.
Study record updated 9/26/2018 to reflect the following IRB-approved protocol modifications: Erroneous references to "digital" books for primary outcome measure were removed, as this measure is administered using print (non-digital) materials. Eligibility criteria were updated to include subjects with IQ of up to and including 79 on the Leiter-III at screening. The Hyperphagia Questionnaire (HQ-CT) was replaced by the Anxiety Depression and Mood Screen (ADAMS) as a secondary outcome measure.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 6 Years 至 25 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Molecular genetic confirmation of the full FMR1 mutation or mosaicism.
- •Males and non-pregnant, non-lactating females age 6 to 25 years, inclusive.
- •Ability of subject and/or caregiver to understand, read, write, and speak English fluently to complete study-related materials.
- •IQ ≤ 79 as measured by the Leiter-III at screening.
- •Participant is able to speak at least occasional 3-word phrases.
- •Participant and parent/caregiver are willing to participate in the protocol and able to attend the clinic regularly and reliably.
- •Stable concomitant medication dose and dosing regimen for at least 4 weeks prior to the screening/baseline visit, and the intention to maintain a stable regimen of allowed concomitant medications for the full duration of the study.
- •Stable behavioral/educational treatments for at least 4 weeks prior to the screening/baseline visit.
- •Sexually active women of childbearing potential must be using a medically acceptable method of birth control for the duration of the study and have a negative urine pregnancy test collected at the initial screening/baseline visit.
- •For participants who are not their own legal guardian, the parent/legal authorized representative is able to understand and sign an informed consent to participate in the study.
排除标准
- •Non-cooperation or inability to follow through with the study protocol.
- •Life-threatening medical problem or other major systemic illness that compromises health or safety and/or would interfere with the study.
- •History of intolerable adverse events with metformin.
- •Current or recent metformin treatment (within the past year).
- •Body mass index (BMI) less than 2 standard deviations for age.
- •Serum creatinine > 1.4 mg/dl (female) or > 1.5 mg/dl (male) at screening.
- •History of metabolic acidosis or a condition with lactic acidosis.
- •Severe 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. Liquid placebo will be provided to any participants unable to swallow the placebo capsules. 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 (Drug)
Active Metformin Medication
The active metformin medication will be dosed in a weight-dependent manner. Liquid metformin (100mg/cc) will be provided to any participants unable to swallow the metformin capsules. 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 (Drug)
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 FXS-normed Aberrant Behavior Checklist - Community Edition (ABC-C)(Baseline, Week 8, 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 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 Anxiety Depression and Mood Screen (ADAMS) 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 Swanson, Nolan and Pelham Questionnaire (SNAP-IV) 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)