This project is an extension of the CDC-funded FORWARD (Fragile X Online Registry With Accessible Research Database) study. From its inception in 2010, the goal of the FORWARD study has been to characterize the natural history of fragile X syndrome (FXS). This current extension project is known as FORWARD-MARCH (Multiple Assessments for Research CHaracterization) because it will include multiple assessments to characterize behavioral, adaptive, and cognitive function in greater depth and thereby further improve understanding of the natural history of FXS. FORWARD-MARCH continues the mission of FORWARD to better understand the natural history of FXS in order to improve the lives of children and adolescents with FXS and the lives of their families. FORWARD-MARCH will also better define trajectories of development in FXS that will be useful in understanding the long-term effects of an intervention relative to the natural history of FXS.
FORWARD-MARCH builds upon the foundation of the FORWARD study. The FORWARD study included 24 participating FXS specialty clinics throughout the US that are members of the FXCRC (Fragile X Clinical & Research Consortium). The FORWARD study worked closely with the Centers for Disease Control and Prevention (CDC), the National Fragile X Foundation (NFXF), and other stakeholders in the FXS community. FORWARD-MARCH will also involve a contractor, Chickasaw Nation Industries (CNI), funded through a contract with the CDC. CNI will assist in data collection and management.
Between September 2022 and August 2026, FORWARD-MARCH expects to enroll at least 600 individuals with fragile X syndrome who were born between 2003-2017. The majority of these individuals will already be FORWARD study participants, enabling researchers to conduct longitudinal analyses incorporating previously collected data. Cognitive, behavioral, and adaptive function will be assessed using parent or caregiver-completed surveys and in-person clinical assessments. After completion of data collection, deidentified data will be securely maintained at CDC and will be an important long-term resource for analyses of the natural history of FXS.
Previous phases of the FORWARD study, conducted between 2012 and 2022, have received IRB review and approval by the institutions of each participating clinic. These previous phases of the study did not require review by a CDC IRB, as CDC had no participant contact and did not have access to personal identifying information (PII). The extension of the FORWARD study covered in this protocol (FORWARD-MARCH, 2022-2026) will continue to be reviewed and approved by the institutions of each participating clinic conducting data collection. However, review and approval are also being sought from the CDC IRB because PII will be maintained on CDC servers and because CDC's contractor, CNI, will regularly have access to PII and interact directly with study participants. A reliance agreement allowing CNI to rely on CDC's IRB is being developed and will be executed before data collection is begun. To clarify which aspects of the protocol involve CDC and CNI staff (rather than just clinic staff), sections 3,4 and 5 of this protocol document each end with a subsection that specifically focuses on the role of CDC and CNI staff.
This is a 3-part study, with each part having a unique set of objectives for male
adolescents aged 12 to < 18 years with fragile X syndrome (FXS). Part 1 is an openlabel,
single-dose, pharmacokinetics (PK) assessment of BPN14770 25 mg and
50 mg; Part 2 is double-blind (DB) and randomized; and Part 3 is an open-label
extension (OLE) for patients who complete Part 2.
The Drug Product ZYN002 is a transdermal CBD gel. CBD is the primary non-euphoric cannabinoid contained in the Cannabis sativa L. plant. The CBD contained within ZYN002 is a pharmaceutically produced Active Pharmaceutical Ingredient (API) that is chemically identical to the CBD present in Cannabis. ZYN002 is currently being evaluated in clinical trials in children and adolescents with Fragile X Syndrome (FXS), autism spectrum disorder, 22q11.2 deletion syndrome, and developmental and epileptic encephalopathies. The present protocol for ZYN2-CL-031 (INSPIRE) is designed to evaluate the safety and tolerability of ZYN002 in the treatment of 11q11.2 Deletion Syndrome. Enrolled participants will be treated for a 1-14 week period and then further evaluated for continuation. Those eligible will be able to continue in the open-label study for an additional 24 weeks of treatment.
The Drug Product ZYN002 is a transdermal CBD gel. CBD is the primary non-euphoric cannabinoid contained in the Cannabis sativa L. plant. The CBD contained within ZYN002 is a pharmaceutically produced Active Pharmaceutical Ingredient (API) that is chemically identical to the CBD present in Cannabis. ZYN002 is currently being evaluated in clinical trials in children and adolescents with Fragile X Syndrome (FXS), autism spectrum disorder, 22q11.2 deletion syndrome, and developmental and epileptic encephalopathies. The safety and efficacy of ZYN002 in the treatment of behavioral symptoms in children and adolescents with FXS has been evaluated in three studies: Study ZYN2-CL-009, a completed open-label, multiple-center, multiple-dose study (n=20); Study ZYN2-CL-016, a completed randomized, double-blind, placebo-controlled, multiple-center study (n=212 randomized); and Study ZYN2-CL-017, an ongoing open-label extension and expanded access study to assess the long-term safety and tolerability of ZYN002 (n=240). The present protocol for ZYN2-CL-033 (RECONNECT) is designed to evaluate the efficacy and safety of ZYN002 for the treatment and behavioral symptoms in children and adolescents with genetic evidence of full mutation FXS. Qualified subjects that complete ZYN2-CL-033 will have the opportunity to roll over to the open label ZYN2-CL-017 study.