Age: 0+
Healthy Volunteers: Not accepted
Inclusion Criteria:
1. Diagnosis of CLIFAHDD (confirmed by clinical and genetic report per best practices)
2. NALCN variant with predicted NALCN gain-of-function in established functional assays and/or computational assessments
3. Age >6 months at the time of initial consent/assent
4. Weight >6kg at the time of initial consent/assent
5. Ability of participant or Legally Authorized Representative (LAR) to understand and the willingness to sign a written informed consent document.
6. For children (<18y at time of consent/assent), informed assent (if developmentally appropriate) and parental informed consent to participate in the study
7. Willingness to comply with all study-related requirements, including Aprepitant regimen and travel to San Antonio, TX for specified visits
8. Has adequate organ functions as defined by the following laboratory parameters at baseline (laboratory parameters outside of these ranges that are deemed clinically insignificant should be discussed with the Independent Safety Monitor):
1. Absolute neutrophil count ≥1000 cells/uL;
2. hemoglobin ≥8.5 g/dL;
3. platelet count ≥100,000/mm3;
4. aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 x upper limit of normal (ULN);
5. total bilirubin ≤ 1.5 x institutional ULN (exception: subjects with known Gilbert's syndrome and total bilirubin ≤2 x institutional ULN at screening or anytime during the prior 6 months are eligible);
6. adequate renal function defined as calculated creatinine clearance >60 mL/min using the Cockcroft Gault Method;
7. acceptable coagulation parameters including international normalized ratio (INR) <1.4 and partial thromboplastin time (PTT) ≤ 1.5 x institutional ULN;
8. serum albumin ≥3.0 g/dL
9. Women of child-bearing age participants must use highly effective forms of birth control defined as those with a failure rate of < 1% per year. Acceptable methods include: complete sexual abstinence (anticipated given severity of neurodevelopmental symptoms in CLIFAHDD), combined hormonal contraceptives, progestogen-only hormonal contraceptives, intrauterine devices (IUDs), intrauterine hormone-releasing systems (IUS), bilateral tubal occlusion, or vasectomized partner (provided the partner is the sole sexual partner).
Exclusion Criteria:
1. Known hypersensitivity to any component of the study treatment formulation(s)
2. Concomitant use of pimozide, terfenadine, astemizole, cisapride, flibanserin, lomitapide (contraindicated CYP3A4 substrate)
3. Concomitant use of strong (Clarithromycin, telithromycin, nefazodone, itraconazole, ketoconazole, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, tipranavir) or moderate (amiodarone, erythromycin, fluconazole, miconazole, diltiazem, verapamil, delavirdine, amprenavir, fosamprenavir, conivaptan, danazol, ketoconazole) CYP3A4 inhibitors and strong CYP3A4 inducers (apalutamide, carbamazepine, dexamethasone, enzalutamide, fosphenytoin, lumacaftor, midostaurin, mitotane, pentobarbital, phenobarbital, rifampin, phenytoin) or CYP3A4 substrates (Docetaxel, paclitaxel, etoposide, irinotecan, ifosfamide, imatinib, vinorelbine, vinblastine, vincristine, colchicine, axitinib). Participants on one of these medications but unable to discontinue for the trial and considered otherwise low risk should be discussed with the Independent Safety Monitor but may be considered for enrollment.
4. Concomitant use of high-risk cytochrome P450 family 2 subfamily C member 9 (CYP2C9) substrates (e.g., warfarin or phenytoin or tolbutamide)
5. Patients who are medically unstable or have been hospitalized for an acute medical condition in the 3 months prior to the first active drug visit
6. Patients who are acutely ill in the hospital or intensive care unit (ICU)
7. Any other history of clinically significant acute or chronic neurologic disease, respiratory disease, cardiovascular disease, gastrointestinal disease, liver disease, renal disease, endocrine disorder, infectious disease, or any other medical or psychiatric condition that in the opinion of the investigator or study clinician will significantly increase the safety risk for the subject or confound the interpretation of the study data.
8. Currently receiving any other investigational agents or has received study treatment or used an investigational device within 30 days of the first dose of treatment
9. Caregivers unwilling to follow study procedures or follow protocol as outlined.
10. Pregnancy