sodium ({(2S)-1,4-bis[2-(4-chloro-3-fluorophenoxy)acetamido]bicyclo[2.2.2]octan-2-yl}oxy)methyl hydrogen phosphate-2-amino-2-(hydroxymethyl)propane-1,3-diol (1/1/1) for Vanishing white matter disease

Inclusion criteria

• {"criterion_text":"- Males and females ≥18 y of age (Cohort 1 and Cohort 1b), ≥12 y and <18 y of age (Cohort 2), and ≥6 y and <12 y of age (children Cohort 3), and ≥6 mos and <6 y of age (Cohort 4-children [≥1 y and <6 y of age] and infants [≥6 mos and <1 y of age])\n- Have VWM disease defined as: a. A clinical diagnosis by a physician experienced in the assessment of VWM disease; AND b. A molecular diagnosis of VWM disease (Note: Subjects can provide a verified report of molecular diagnosis including the specific mutation(s), will not be required to reconfirm diagnosis), AND c. An MRI presentation consistent with VWM disease, as assessed by a neuroradiologist or by a physician experienced in the assessment of VWM disease except for presymptomatic homozygous carriers of Cree leukoencephalopathy (EIF2B5 R195H) or other mutation with known imminent risk of significant clinical decline or death (requires approval from Sponsor).\n- Subject must have a designated caregiver who is able to complete the respective caregiver-centered assessments. The caregiver must be consistently present at visits, including telehealth visits, to report on symptoms and comply with the protocol. The caregiver must be willing to provide informed consent.\n- Subject is willing and able to give informed consent. Where local regulations permit inclusion of participants deemed not able to provide informed consent, a legally authorized representative (LAR) must provide informed consent on the subject’s behalf, and the subject must provide assent, in accordance with the local regulations, guidelines, and Institutional Review Board (IRB), or Independent Ethics Committee (IEC). If the subject becomes cognitively impaired (diminished capacities) during the study and is unable to provide informed consent, the subject should be discontinued from the study unless local regulations permit inclusion of participants deemed not able to provide informed consent. In such case, a LAR must provide informed consent on behalf of the subject and the subject must provide assent as per local regulations, guidelines, and IRB or IEC. Careful consideration will be given to ensure that cognitive impairment/diminished capacity does not limit the subject’s right to withdraw from the study. The LAR and the caregiver can be the same person.\n- Subjects in Cohorts 1, 1b, 2, and 3 must meet criteria a and at least 1 of the other criteria listed below (ab or bc): a.\tMedical history of at least 1 neurological symptom that is assessed by the investigator as having a reasonable possibility of being related to VWM disease b.\tMotor criteria as defined below: i. All age groups: (1) Inability to walk 10 or more steps with or without light support of 2 hands c.\tCognitive criteria as defined below (Note: Subjects are not required to complete testing if they meet the motor criteria or if they are able to provide source documentation of prior cognitive testing performed by a qualified psychologist and meeting eligibility criteria obtained in the past 12 months): i.\tAdults and adolescents ≥16 y of age must have: (1) A perceptual reasoning index <50 (Wechsler Adult Intelligence Scale, fourth edition [WAIS-IV]) ii.\tAdolescents and children ≥6 y and <16 y of age must have: (1)\tA visuospatial reasoning index <50 (block design, visual puzzles, Wechsler Intelligence Scale for Children performance, fifth edition [WISC-V]) AND (2)\tA fluid reasoning index <50 (matrix reasoning, figure weights, WISC-V). Note: At the Sponsor’s discretion, pediatric subjects <16 y of age who are unable to complete the subtests for calculating BOTH indices of the WISC-V due to functional impairment (eg,e.g., due to fine motor or visual impairment) may meet inclusion criteria by a score <50 on either the visuospatial reasoning index OR the fluid reasoning index of the WISC-V. Pediatric subjects in Cohort 4 must meet both criteria a and b below, or criterion c: a.\tMedical history of at least 1 neurological symptom that is assessed by the investigator as having a reasonable possibility of being related to VWM disease b.\tMotor criteria as defined below: i.\tMore than minimal head control as demonstrated by: (1) While in prone position, the subject can lift his/her head and sustain the position for 10 seconds and bring his/her arms actively to weight bearing in that position c.\tPresymptomatic and homozygous for Cree Leukoencephalopathy (EIF2B5 R195H) or other mutation with known imminent risk of significant clinical decline or death (sponsor must be notified and provide approval prior to screening and enrolling a patient that meets eligibility with only this criterion).\n- All male subjects who are sexually active and not surgically sterilized must agree to use an acceptable contraceptive method. Additionally, male subjects must agree to not donate sperm during the study until 30 days after the final dose of study drug.\n- All female subjects who are sexually active and of childbearing potential must agree to use a contraceptive method. Additionally, female subjects must agree to not donate eggs during the study and for 30 days after the final dose of study drug."}

Exclusion criteria

• {"criterion_text":"- Pediatric subjects ≥6 mos and <6 y of age must not be on any form of respiratory support at the time of Screening.\n- Treatment with any other investigational treatment within 30 days or 5 half-lives (whichever is longer) prior to Study Day 1 and during the study. Current participation in another trial is not permitted unless it is a non-interventional study and the sole purpose of this study is for long term follow-up describing clinical features or survival data (registry). Non interventional studies that include biomarker assessments (including, but not limited to, sampling of blood, urine, CSF, or neuroimaging) are not allowed.\n- Because metallic orthodontic devices may generate image artifacts during MRI scans, subjects with such devices will undergo further evaluation by the Sponsor to determine their inclusion or exclusion from the study.\n- Subject who has any clinically significant electrocardiogram (ECG) abnormalities, including QT interval corrected for heart rate using Fridericia’s correction formula (QTcF) of >450 msec for adult males, >470 msec for adult females, or >450 msec for adolescents ≥12 y and <18 y of age (Cohort 2) and children ≥6 y and <12 y of age (Cohort 3)), or >414 msec for infants and children ≥0.5 y and <6 y of age (Cohort 4).\n- Current Subject with current or history of abnormal screening laboratory or imaging results that, in the opinion of the Investigator, are indicative of any significant cardiac, endocrinologic, hematologic, hepatic, immunologic, infectious, metabolic, urologic, pulmonary, gastrointestinal, dermatologic, psychiatric, renal, neurologic, and/or other major disease (other than VWM disease) that would preclude administration of FGT or safe participation in the study\n- Subject who has suicidal ideation at the Screening Visit (V1). Prior medical history and/or C SSRS may be used to inform the Investigator’s decision\n- Changes in medication use for the management of VWM disease symptoms within the 4 weeks preceding Screening\n- Seizure disorder not considered adequately controlled by the Investigator within the 6 months preceding Screening\n- Subjects who, in the opinion of the Investigator, is incapable of completing study-required visits and procedures to assess primary and secondary endpoints (eg, due to severe comorbid conditions or severity of VWM disease)\n- Adult female subjects who are pregnant, breastfeeding, or providing breast milk."}

Primary endpoints

• {"endpoint_text":"- AEs and SAEs during the Safety Evaluation Period","definition_or_measurement_approach":"Adverse events (AEs) and serious adverse events (SAEs) monitored and recorded during the Safety Evaluation Period."}
• {"endpoint_text":"- Vital signs, ECGs, clinical laboratory tests, and suicidality assessments during the Safety Evaluation Period","definition_or_measurement_approach":"Serial measurement of vital signs, ECGs, clinical labs and suicidality assessments during the Safety Evaluation Period as safety outcome measures."}
• {"endpoint_text":"- Plasma concentrations of A-1684909 at pre-specified visits from Baseline up to Week 96 for all cohorts","definition_or_measurement_approach":"Plasma pharmacokinetic sampling at pre-specified visits from baseline through Week 96 to measure concentrations of A-1684909."}
• {"endpoint_text":"- CSF concentrations of A-1684909 at Week 12, Week 48, and Week 96 for all cohorts","definition_or_measurement_approach":"CSF sampling at Weeks 12, 48 and 96 to quantify A-1684909 concentrations in cerebrospinal fluid."}
• {"endpoint_text":"- Plasma PK parameters of A-1684909 following dosing at V4 (Study Day 14) for Cohorts 1 and 1b: Cmax; Tmax; AUC0-24h; Ctrough; and t1/2, functional","definition_or_measurement_approach":"Derivation of PK parameters (Cmax, Tmax, AUC0-24h, Ctrough, t1/2) from plasma concentration-time data following dosing at V4 (Study Day 14) for Cohorts 1 and 1b."}

Secondary endpoints

• {"endpoint_text":"- AEs and SAEs at last visit (Week 197)","definition_or_measurement_approach":"Recording of AEs and SAEs up to and including the last visit (Week 197)."}
• {"endpoint_text":"- Vital signs, ECGs, clinical laboratory tests and suicudality up to last vist (Week 197)","definition_or_measurement_approach":"Assessment of vital signs, ECGs, labs and suicidality through to the last visit (Week 197)."}

Methods

• Subject recruitment via call center provided by The Patient Recruiting Agency™ (sponsor duty: "Subject recruitment - call center") — contact lance@tpra.com (US)
• Telephone-based recruitment and telephone scripts (document: K2_Recruitment material_TelephoneScript_Public) and email reply scripts (document: K2_Recruitment material_Email_Reply_Script) — indicates recruitment by phone and email channels
• Site-based recruitment at Amsterdam UMC (contact registerVWM@amsterdamumc.nl) — site registry/contact used for identification and recruitment

Netherlands

Earliest CTIS Part Ii Submission Date

19-01-2024

Latest Decision Or Authorization Date

03-04-2026

Processing Time Days

805

Number Of Sites

1

Number Of Participants

16

Primary sponsor

Full Name

Calico Life Sciences LLC

Organisation Type

Pharmaceutical company

Country Of Registered Address

United States

Contract research organisations

Name

Worldwide Clinical Trials

Responsibilities

Vendor management and Rater qualification & certification management, Medical monitoring

Name

Clario

Responsibilities

ECG machines reading

Third parties

• {"country":"United States","full_name":"Clario","duties_or_roles":"ECG machines reading","organisation_type":"Industry"}
• {"country":"Croatia","full_name":"Worldwide Clinical Trials","duties_or_roles":"Vendor management and Rater qualification & certification management, Medical monitoring","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Abbvie Inc.","duties_or_roles":"","organisation_type":"Pharmaceutical company"}
• {"country":"Germany","full_name":"AbbVie Deutschland GmbH & Co. KG","duties_or_roles":"","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Clinical Ink Inc.","duties_or_roles":"","organisation_type":"Pharmaceutical company"}
• {"country":"Ireland","full_name":"Millmount Healthcare Limited","duties_or_roles":"","organisation_type":"Pharmaceutical company"}
• {"country":"Switzerland","full_name":"Labcorp Central Laboratory Services S.a.r.l.","duties_or_roles":"","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"The Patient Recruiting Agency™","duties_or_roles":"Subject recruitment - call center","organisation_type":"Health care"}