AFQ056 for Language Learning in Children With FXS

NCT02920892 | Completed Phase 2 Results DMC FDA Drug

• 2 other identifiers: ORA 150609031U01NS096767-01
• Study Type: interventional
• Target: 110
• Locations: 1 country
• Sites: 14

Brief Summary

The purpose of this clinical trial is to investigate the impact of AFQ056 on language learning in 3-6 year old children with Fragile X Syndrome (FXS).

Conditions

Fragile X Syndrome

Outcome Measures

Primary Outcomes (1)

• Change in Weighted Child Intentional Communication Score

  The Weighted Child Intentional Communication Score is derived from a 22 minute semi-structured examiner/child play session. Structured and unstructured component scores are found by multiplying each intentional communication act by the following weights: nonverbal = 1; single symbol = 2; and multiple symbols = 3. The two scores are summed together to obtain the total. Higher scores indicate more child-initiated communication. There is no maximum score. The scale was administered at Baseline, Month 2, Month 4, Month 6, and Month 8. A composite score representing the average of the estimated change scores calculated at months 2, 4, 6, and 8 was recorded. A higher least squares mean value indicates a greater increase in WCS score from baseline.

  Baseline through Month 8

Secondary Outcomes (7)

• Change in Mullen Scales of Early Learning (MSEL) Developmental Quotient (DQ)

  Baseline through Month 8

• Change in Mullen Scales of Early Learning (MSEL) Expressive Language Subscore

  Baseline through Month 8

• Change in Vineland Adaptive Behavior Scale (Vineland-3) Composite Score

  Baseline through Month 8

• Change in Vineland Adaptive Behavior Scale (Vineland-3) Communication Subscore

  Baseline and Month 8

• Change in Preschool Language Scale (PLS-5) Expressive Communication Score

  Baseline and Month 8

Study Arms (3)

Double-Blind AFQ056 with language intervention

EXPERIMENTAL

After a 4-month single-blind placebo lead-in period, subjects with FXS were randomized to receive AFQ056 suspension by mouth twice per day in an 8 month double-blind treatment period. During the double-blind treatment period, subjects in the AFQ056 treatment group began with a dose of 25 mg AFQ056 twice per day and titrated to their maximum tolerated dose over the course of 7 weeks. After 7 weeks the dose was fixed, and at the 2 month visit, the intensive language intervention was initiated. Subjects continued the language intervention while remaining on a stable dose of AFQ056 (ranging from 12.5 mg BID to 100 mg BID), for the next 6 months. Safety and efficacy assessments were performed throughout.

Drug: AFQ056; Other: Language Intervention

Double-Blind Placebo with language intervention

PLACEBO COMPARATOR

After a 4-month single-blind placebo lead-in period, subjects with FXS were randomized to receive a placebo suspension by mouth twice per day in an 8 month double-blind treatment period. During the double-blind treatment period, dose titration to maximum tolerated dose of matching placebo occurred over 7 weeks. After 7 weeks, the dose was fixed, and at the 2 month visit, the intensive language intervention was initiated. Subjects continued the language intervention while remaining on placebo for the next 6 months. Safety and efficacy assessments were performed throughout.

Drug: Placebo; Other: Language Intervention

Open-Label AFQ056 with language intervention

EXPERIMENTAL

After 8 months of treatment in the placebo-controlled phase, all subjects had assessments completed and were given the opportunity to enter the open-label extension (OLE) in which all subjects received AFQ056. The OLE began with 2 months of flexible dose titration to each subject's maximum tolerated dose followed by a period of stable treatment. Subjects also continued the language intervention through the extension phase. The duration of the stable treatment depended on when the subject was enrolled into the study. Those enrolled prior to June 15-30, 2019 received a 6-month period of stable treatment. Those enrolled after June 15, 2019 had their period of stable treatment shortened on a sliding scale, such that their treatment including weaning, if necessary, ended before August 31, 2021 (study drug expiration).

Drug: AFQ056; Other: Language Intervention

Interventions

AFQ056 DRUG

12.5 mg - 100 mg oral suspension (liquid)

Also known as: Mavoglurant

Double-Blind AFQ056 with language intervention; Open-Label AFQ056 with language intervention

Placebo DRUG

Placebo oral suspension (liquid)

Double-Blind Placebo with language intervention

Language Intervention OTHER

All subjects will begin an intensive language intervention 2 months after starting treatment with AFQ056 or placebo and will continue the intervention through the end of the study. The language intervention will be administered by a trained language specialist through a combination of in clinic visits and at home synchronous video conferencing sessions. The intervention will subsequently be delivered to the parent by a speech-language clinician through weekly clinician coaching, homework, and feedback sessions. The language intervention is designed to help parents learn and use verbally responsive interactional strategies more frequently and effectively throughout the course of their daily interactions with their children.

Double-Blind AFQ056 with language intervention; Double-Blind Placebo with language intervention; Open-Label AFQ056 with language intervention

Eligibility Criteria

• Age: 32 Months - 6 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• Age 32 months to 6 years inclusive at Screening (visit 1).
• Has an FMR1 full mutation.
• \*\*Note Presence of mosaicism is allowed
• DQ\<75 calculated from the Mullen Scales of Early Learning at time of screening.
• Parent or legal guardian is available and able to communicate well with the investigator, comply with study requirements and provide written informed consent.
• \*\*Note\*\*The Parent or legal guardian who will be signing consent form, should be the individual administering the language intervention
• English is the primary language spoken in the home and the subject's first language is English.
• Meet criteria indicating evidence of intentional communication based on parent interview via a communication eligibility screening tool.
• \*\*Note\*\* On the Eligibility Screening Tool - Communication, the child must have at time of screening:
• Section 1: Answer of YES; the child uses at least 5 spoken words to label items on a daily basis.
• Section 2: At least 3 YES answers to items 1-10 if child does not have at least 5 spoken words.
• Produces 3 or more intentional acts of communication on the structured portion of the Weighted Communication play sample at time of screening.
• \*\*Note: subjects are permitted to use augmentative communication devices throughout the study if the device is the subject's primary form of communication and the device has been prescribed for the subject by an SLP.
• Stable behavioral and other therapy regimen for 30 days prior to screening.
• \*\*Note: Patients will be allowed to continue their standard of care therapies throughout the trial but these will not be changed during the placebo lead in or placebo controlled portion of the trial, outside of the standard changes occurring from school schedules.

You may not qualify if:

• Use of medications impacting GABA, glutamate and/or mGluR5 pathway receptors or transmission.
• Note\*\* Lithium taken as a dietary supplement is permitted if the dose is less than 5mg/day. A 5mg/day dose is the recommended dietary intake level, and therefore is not considered to be therapeutic. Lithium dosage must remain the same throughout the duration of the trial and documented in the concomitant medication log.
• Unstable seizure disorder as defined by any seizure in the 6 months prior to the screening visit, and/or any change in anti-convulsant drug dosing in the 60 days prior to screening.
• \*\*Note\*\* Use of levetiracetam and oxcarbazepine are among permitted anticonvulsants.
• Use of any other investigational drug at the time of enrollment or within 30 days or 5 half-lives (whichever is longer) of the investigational drug prior to screening until end of study visits (or longer if required by local regulations).
• History of hypersensitivity to AFQ056 or any mGluR antagonist.
• History or presence of any clinically significant disease of any major system organ class, within the past 2 years prior to screening including but not limited to neurological, cardiovascular, endocrine, metabolic, renal, or gastrointestinal disorders. This does not include typical features of FXS such as psychological symptoms or history of epileptic seizures.
• Significant acute illness that did not completely resolve at least four weeks prior to the Screening visit.
• Abnormal laboratory values at screening that are in the opinion of the investigator are clinically significant and may jeopardize the safety of the study subject.
• Use of (or use within at least 5 half-lives before dosing) concomitant medications that are strong/moderate inhibitors or inducers of CYP1A1/2, CYP2C9/19 or CYP3A4 (see Appendix B).
• Subjects who are, in the opinion of the investigator, unable to comply with the requirements of the study.
• Presence of immunodeficiency diseases at the time of screening, based on medical history, including a positive HIV test result.
• History of a positive Hepatitis B surface antigen (HBsAg) or Hepatitis C result at time of screening.
• History or presence of suicidal thoughts and/or suicide attempts.

Sponsors & Collaborators

• Elizabeth Berry-Kravis: lead
• National Institute of Neurological Disorders and Stroke (NINDS): collaborator
• Novartis Pharmaceuticals: collaborator

Study Sites (14)

Univeristy of California - Davis

Davis, California, 95817, United States

Location

Children's Hospital of Colorado

Denver, Colorado, 80045, United States

Location

Yale University

New Haven, Connecticut, 06520, United States

Location

Children's National Medical Center

Washington D.C., District of Columbia, 20010, United States

Location

Emory University

Atlanta, Georgia, 30033, United States

Location

Rush University Medical Center

Chicago, Illinois, 60612, United States

Location

Boston Children's Hospital

Boston, Massachusetts, 02115, United States

Location

St Louis Children's Hospital (Washington University School of Medicine)

St Louis, Missouri, 63110, United States

Location

Columbia University - New York Presbyterian

New York, New York, 10605, United States

Location

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, 45229, United States

Location

Nationwide Children's Hospital

Columbus, Ohio, 43205, United States

Location

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, 19104, United States

Location

Children's Hospital of Pittsburgh

Pittsburgh, Pennsylvania, 15213, United States

Location

Vanderbilt University Medical Center

Nashville, Tennessee, 37232, United States

Location

Related Publications (1)

• Protic D, Breeze E, Mendoza G, Zafarullah M, Abbeduto L, Hagerman R, Coffey C, Cudkowicz M, Durbin-Johnson B, Ashwood P, Berry-Kravis E, Erickson CA, Filipink R, Gropman A, Lehwald L, Maxwell-Horn A, Morris S, Bennett AP, Prock L, Talboy A, Tartaglia N, Veenstra-VanderWeele J, Tassone F. Negative effect of treatment with mGluR5 negative allosteric modulator AFQ056 on blood biomarkers in young individuals with Fragile X syndrome. SAGE Open Med. 2024 Sep 29;12:20503121241282401. doi: 10.1177/20503121241282401. eCollection 2024.

  PMID: 39483619 DERIVED

MeSH Terms

Conditions

Fragile X Syndrome

Interventions

mavoglurant

Condition Hierarchy (Ancestors)

X-Linked Intellectual Disability; Intellectual Disability; Neurobehavioral Manifestations; Neurologic Manifestations; Nervous System Diseases; Sex Chromosome Disorders; Chromosome Disorders; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; Heredodegenerative Disorders, Nervous System

Results Point of Contact

• Title: Elizabeth Berry-Kravis, MD PhD
• Organization: Rush University Medical Center

Elizabeth_Berry-Kravis@rush.edu

312-942-4036

Study Officials

• Elizabeth Berry-Kravis, MD, PhD

  Rush University Medical Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Masking Details: After screening assessments, participants who met entry criteria and agreed to participate entered a single-blind 4-month placebo lead-in during which study participants had therapy treatments as usual to control for the effects of the language intervention. The 4-month placebo lead-in allowed for placebo effects to stabilize. At the end of the 4-month placebo lead-in, all participants will enter a double blind placebo controlled phase in which they will have a repeat battery of AFQ056 baseline assessments and will be randomized 1:1 to AFQ056 or placebo. Both treatment groups received an intensive language intervention for 6 months after 2 months of flexible dose titration to establish their maximum tolerated dose (MTD). After 8 months of treatment in the placebo-controlled phase (including 6 months of language intervention), all participants had final assessments and entered the open label extension (OLE) of about 8 months.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor of Pediatrics, Neurological Sciences, Biochemistry

Model Details: The trial will use a double-blind placebo-controlled parallel-group flexible-dose forced titration design. 100 eligible subjects with Fragile X Syndrome age 32 months to 6 years will enter a 4-month single-blind placebo lead-in period, followed by an 8-month double-blind treatment period during which subjects will randomized 1:1 to AFQ056 or placebo and will receive 6 months of language intervention. Subjects will then be invited to participate in an open-label extension phase during which all participants will receive treatment with active drug and continue language intervention for up to 8 months.

Study Record Dates

• First Submitted: September 28, 2016
• First Posted: September 30, 2016
• Study Start: August 17, 2017
• Primary Completion: May 17, 2022
• Study Completion: May 17, 2022
• Last Updated: October 10, 2023
• Results First Posted: October 10, 2023

Record last verified: 2023-09

Locations

US (14)