Table 1.
Double-blind, placebo-controlled treatment studies of individuals with fragile X
| FDA register number | Compound | Mechanism | Cohort (years) | Sample size | Outcomes measured (OM) | Phase/sponsor | Results/publications | |
|---|---|---|---|---|---|---|---|---|
| Primary1 | Secondary2 | |||||||
| 14/22, 64% | ||||||||
| NCT00788073 | Arbaclofen (STX209) | GABA-B agonist | 6–50 | 63 | ABC-C_I | ABC-CFX, CGI-S, CGI-I, Vineland-II, SRS, RBANS, SB5, PPVT | II/Seaside | OM:1 not met, 2↓ABC-CFX-SA [112] |
| NCT01282268 | Arbaclofen | GABA-B agonist | 12–50 | 125 | ABC-CFX_SA | CGI-S, CGI-I, Vineland-II, ADHD-RS, SB5, PSI, CSHQ | III/Seaside | OM:1 not met [46] |
| NCT01325220 | Arbaclofen | GABA-B agonist | 5–11 | 172 | ABC-CFX_SA | CGI-S, CGI-I, Vineland-II, ADHD-RS, SB5, PSI, CSHQ | III/Seaside | OM:1 not met, 2↓ABC-CFX-I, ↓PSI [46, 113] |
| NCT01725152 | Ganaxolone | GABA-A agonist | 6–17 | 60 | CGI-I | ABC-CFX, ADAMS, PPI, KiTAP, ERP, ET, SNAP-IV, PARS | II/Marinus | Pending |
| NCT02126995 | Metadoxine | GABA transporter | 14–50 | 62 | ADHD-RS | ABC-CFX, CGI-S, CGI-I, Vineland-II, SRS, KiTAP, ERP, ET, PARS | II/Alcobra | OM:1 not met, 2↑Vineland II DL [44, 64] |
| NCT00718341 | Mavoglurant (AFQ056) | mGluR5 antagonist | 18–35 | 30 | ABC-C_T | ABC-CFX, CGI-S, CGI-I, SRS, KiTAP, ET, VAS, RBANS.. | II/Novartis | OM:1 not met,2 ↓ABC-C_T (n=7 FM) [261] |
| NCT01253629 | Mavoglurant | mGluR5 antagonist | 18–45 | 175 | ABC-C_T | ABC-C, CGI-S, CGI-I, SRS, KiTAP | IIb/Novartis | OM:1 & 2 not met, tolerated well [9] |
| NCT01357239 | Mavoglurant | mGluR5 antagonist | 12–17 | 139 | ABC-C_T | ABC-C, CGI-S, CGI-I, SRS, KiTAP | IIb/Novartis | OM:1 & 2 not met, tolerated well [9] |
| NCT01015430 | Basimglurant (RO4917523) | mGluR5 antagonist | 18–50 | 40 | Safety, PK | ABC-C, ADAMS, CGI-S, CGI-I, KiTAP, ET, VAS, RBANS | IIa/Roche | Not in public domain |
| NCT01517698 | Basimglurant | mGluR5 antagonist | 14–40 | 185 | ADAMS_T | ABC-C, ADAMS, CGI-S, CGI-I, WISC-IV, CBI-M | IIb/Roche | Not in public domain |
| NCT01750957 | Basimglurant | mGluR5 antagonist | 5–13 | 180 | Safety | PK, ABC-C, ADAMS, CGI-S, CGI-I, WISC-IV, CBI-M | IIb/Roche | Not in public domain |
| NCT01911455 | Acamprosate | GABA/Glutamate | 5–23 | 48 | ABC-C_SW | CGI-S, CGI-I, VAS, ABC, PARS, ADAMS, CSQ, ELS, SRS | II/III Cinn Child | Pending |
| NCT01894958 | Trofinetide | IGF-1 analog | 14–40 | 70 | Safety | CGI-S, CGI-I, ABC-CFX, SRS, FXS scale, VAS-P/C, KiTAP | II/Neuren | OM: 1Tolerated well, 2-several improved [63] |
| NCT00054730 | CX516 | Ampakine | 18+ | 49 | Memory | CGI-I, multiple Z scores, SNAP-IV | II/Cortex | OM: 1 Tolerated well,2↑CGI-I in a subset [40] |
| NCT01053156 | Minocycline | MMP-9 | 3–16 | 66 | CGI-I,VAS | VAS-mb, ABC-C, Vineland-II, EVT-2 | II/UC Davis | OM:1 ↑CGI-I, 2↑VAS, ↓MMP-9; [87] |
| NCT01474746 | Sertraline | SSRI | 2–6 | 30 | CGI-I,VAS | Vineland-II, PSI-4, PLS-5, MSEL | II/UC Davis | OM:1↑CGI-I (46%),2 ↑VAS [262] |
| NCT01120626 | Donepezil | Cholinergic drug | 12–29 | 45 | ABC-C_T/CNT | MRS, WM tests, CARS | II/Stanford | Pending |
| NCT01254945 | Oxytocin | Brain peptide | 13–28 | 8 | Eye gaze | HR, RSA, HRV, cortisol | Ib/Stanford | OM:1↑Eye gaze, 2↓cortisol [77, 263] |
| NCT01329770 | Vitamins C & E | Antioxidants | 6–18 | 30 | DBC, WISC | Tolerability | II/Imabis | Pending [264] |
| N/A | Melatonin | Hormone | 2–15 | 15 | Sleep times | Actiwatch | II/UC Davis | OM:1↑sleep; [265] |
| N/A | L-AcCarnitine | Brain energy | 6–13 | 63 | ConnersGI-P | Vineland-Survey, WISC-R | II/TELETHON | OM:1↓HI/I, 2↑Vineland [266] |
| N/A | MPH/DAMP | Stimulants | 3–11 | 15 | ConnersAbb | ACTeRS, IQ measures | II/Denver Child | OM:1MPH:↓I, 2↓ACTeRS; [267] |
Modified from Table 1, Budimirovic and Phan [268] with permission
Abbreviations: FDA Federal Drug Administration, GABA gamma-aminobutyric acid, ABC-C_I Aberrant Behavior Checklist-Community Edition (ABC-C), Irritability subscale, CGI-S Clinician Global Impression-Severity, CGI-I CGI improvement, VABS-II Vineland Adaptive Behavior Scale, Second Edition, SRS Social Responsiveness Scale, RBANS Repeatable Battery for the Assessment of Neurological Status, SB5 Stanford-Binet Version 5, ABC-C FX _SA ABC-CFX, Social Avoidance subscale, PSI Parenting Stress Index, CSHQ Children’s Sleep Habits Questionnaire, PPVT Peabody Picture Vocabulary Test, ADHD-RS Attention-Deficit Hyperactivity Disorder Rating Scale, ABC-C FX ABC-C, FXS-specific, ADAMS Anxiety Depression and Mood Scale, PPI prepulse inhibition, KiTAP Tests of Attentional Performance for Children, ERP evoked response potentials, ET eye tracking, SNAP-IV Swanson, Nolan and Pelhram Rating Scale, PARS Pediatric Anxiety Rating Scale, ABC-C_T ABC-C total score, ADAMS_T ADAMS total score, WISC-IV Wechsler Intelligence Scale for Children, 4th ed, CBI-M Caregiver Burden Inventory-Modified, MMP9 matrix metallopeptidase 9, VAS visual analog scale (VAS-C, clinician rated; VAS-mb, multiple behaviors; VAS-P, parent rated), mGluR5antagonist metabotropic glutamate receptor 1/5 antagonist, GABA/Glutamate GABA/glutamate normalizer, ABC-C_SW ABC-C, Lethargy/Social Withdrawal subscale, CSQ Caregiver Strain Questionnaire, ELS Expressive Language Sampling, Trofinetide Neu-2566-FXS-001 study, IGF-1 insulin-like growth factor, PLS-5 Preschool Language Scale-Version 5, MSEL Mullen Scales of Early Learning, CNT Contingency Naming Task, MRS magnetic resonance spectroscopy, WM working memory tests, CARS Childhood Autism Rating Scale, HR heart rate, RSA respiratory sinus arrhythmia, HRV heart rate variability, SSRI selective serotonin reuptake inhibitor, DBC Developmental Behavior Checklist, EVT-2 Expressive Vocabulary Test, 2nd ed, PK pharmacokinetics, ConnersGI-P Conners General Index-Parent Version, WISC-R WISC-Revised, MPH methylphenidate, DAMP dextroamphetamine, Conners Abb Conners Abbreviated Version, ACTeRS ADD-H Comprehensive Teacher’s Rating Scales, IQ intellectual quotient
1reflects a primary outcome measure (OM)
2reflects a secondary outcome measure (OM)
Italized under Mechanism are clinical trials targeting excitatory-inhibitory imbalance in FXS