Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
L-citrulline · 5 trials · 8 indications
This outcome measures the change in self-reported pain using either the Numeric Rating Scale (NRS) or the Faces Pain Scale. Participants will rate their pain at baseline (prior to study treatment) and again at the time of hospital discharge. The pain scale used depends on the participant's age and cognitive ability. A clinically meaningful improvement is defined as a reduction of ≥2 points or ≥30% from baseline.
Time (in hours) from administration of the initial bolus dose of study drug (L-citrulline or placebo) to the end of the last IV opioid dose required during the hospitalization. This endpoint reflects how quickly the participant's vaso-occlusive crisis resolves to a degree that no longer requires intravenous opioid pain medication.
Mechanical ventilation (MV) = invasive or noninvasive MV incl. bilevel (biphasic) positive airway pressure or continuous positive airway pressure. Inotrope use = medications considered within the derivation of total inotrope score (dopamine, dobutamine, milrinone, epinephrine, phenylephrine, norepinephrine). Both measures recorded until earliest of subject hospital discharge or Day 28.
Time in hours from the initiation of the treatment until mechanical ventilation is required, whether non-invasive (e.g., high flow nasal cannula, bilevel positive airway pressure, oxygen therapy) or invasive (i.e., requiring intubation).
Time in hours from the initiation of the treatment until non-invasive mechanical ventilation is required (e.g., high flow nasal cannula, bilevel positive airway pressure, oxygen therapy) .
Time in hours from the initiation of the treatment until intubation for invasive mechanical ventilation is required.
Systolic blood pressure measured in mmHg
Diastolic blood pressure measured in mmHg
Mean arterial pressure measured in mmHg
Citrulline Blood Levels: 1. Baseline sample in OR prior to Cardiopulmonary Bypass prior to administration of first bolus of Citrulline or Placebo 2. Immediately after Bolus 1 administered in Operating Room. 3. 30 minutes after separation from Cardiopulmonary Bypass; immediately prior to administration of Bolus 2 and start of continuous infusion of Citrulline or Placebo. 4. Six hours after after start of infusion. 5. 12 hours after start of infusion. 6. 24 hours after start of infusion. 7. 48 hours after start of infusion; or whenever infusion is discontinued if prior to 48 hours.
| Arm | Type | Description |
|---|---|---|
| Placebo | PLACEBO_COMPARATOR | Participants randomized to this arm will receive a placebo intravenous (IV) treatment designed to match the appearance and administration schedule of L-citrulline. The placebo will be given as a single bolus dose followed by a continuous infusion for up to 12 hours. All participants will continue to receive standard of care pain management for sickle cell disease, consistent with the treating site's protocol and adjusted as needed based on the patient's clinical condition. |
| L-citrulline Intravenous Treatment Arm | EXPERIMENTAL | Participants randomized to this arm will receive intravenous (IV) L-citrulline, a naturally occurring amino acid being investigated for its potential to treat vaso-occlusive crises (VOCs) in sickle cell disease. The study drug will be administered as a 50 mg/kg IV bolus, followed by a continuous infusion at 9 mg/kg/hour for up to 12 hours. The investigational product is provided as an isotonic solution in vials containing L-citrulline 50 mg/mL. Treatment will begin within 120 minutes of informed consent/assent and following the initial dose of opioid or ketamine, but prior to any subsequent doses. All participants will continue to receive standard-of-care (SoC) pain management per site protocol, which may be adjusted based on clinical response to study treatment. |
| L-citrulline | EXPERIMENTAL | * Bolus of 150 mg/kg at the initiation of cardiopulmonary bypass, but after removal of any crystalloid base; * Addition of study medication at a concentration of 200 μmol/L given as a bolus during bypass. This may be administered as a one-time bolus or multiple administrations to compensate for fluids containing L-citrulline that may be removed from the patient during the course of the operation and thus to maintain the concentration of 200 μmol/L; * Bolus of 20 mg/kg 30 minutes after decannulation from cardiopulmonary bypass; * 9 mg/kg/hr continuous infusion for up to 48 hours. |
| 1 | EXPERIMENTAL | Intravenous L-citrulline |
| 2 | PLACEBO_COMPARATOR | Placebo of intravenous L-citrulline |
| IV L-Citrulline (Turnobi) Arm | ACTIVE_COMPARATOR | Patients randomized to citrulline will receive an initial intravenous bolus of 20 mg/kg (to a maximum of 1500 mg) L-citrulline over 10 minutes. The study solution will be prepared as a 5% isotonic solution (50 mg/mL) in 5% dextrose water. Immediately after the initial bolus, a continuous intravenous infusion of L-citrulline at 9 mg/kg (max 700 mg) per hour will be administered through a dedicated intravenous line or port of a multi-lumen catheter. |
| Placebo Arm | PLACEBO_COMPARATOR | Patients randomized to placebo arm will receive an infusion of 5% dextrose water matched for volume and color to the citrulline infusion. The placebo infusion will consist of an initial iv bolus (up to 30 mL) over 10 minutes followed by a continuous infusion of 5% dextrose water (about 15 mL/hr). The initial bolus and subsequent infusion will be administered through a dedicated intravenous line or port of a multi-lumen catheter. |
| Intravenous L-Citrulline | EXPERIMENTAL | IV bolus of 150 mg/kg L-citrulline at the initiation of bypass, followed by L-citrulline (200 μmol/L) addition to the filtration or hemoconcentration replacement fluid used during bypass. Plus L-citrulline (20 mg/kg) bolus 30 minutes after decannulation from bypass, immediately followed by 9 mg/kg/h continuous L-citrulline infusion for 48 hours. |
| Placebo of Intravenous L-Citrulline | PLACEBO_COMPARATOR | Placebo administered according to the same schedule as L-citrulline |
| Name | Type | Description |
|---|---|---|
| L-citrulline | DRUG | This intervention uses intravenous L-citrulline as an acute treatment for vaso-occlusive crisis (VOC) in sickle cell disease, administered as a 50 mg/kg IV bolus followed by a 9 mg/kg/hr continuous infusion. Unlike other studies that evaluate oral citrulline or chronic VOC prevention, this study focuses on real-time symptom resolution in the emergency department setting by targeting impaired nitric oxide production and vasoconstriction. The selected dosing regimen was optimized in prior studies to achieve a therapeutic plasma concentration associated with improved pain scores and reduced opioid use, distinguishing it mechanistically and clinically from other interventions. |
| Placebo | OTHER | Placebo intravenous (IV) treatment designed to match the appearance and administration schedule of L-citrulline |
| Placebo of intravenous L-citrulline | DRUG | Placebo of intravenous L-citrulline |
| Intravenous L-Citrulline | DRUG | - |
Inclusion Criteria: * SCD (all genotypes) * Children, adolescents and young adults between ages 6 to 21 years * In a steady disease state and not in the midst of any acute complication other than VOC due to SCD at study entry * Baseline NRS score \>5 or Faces Pain Scale score ≥6 * For females of ch...
| Company | Ticker | Trials | Lead Phase | Drugs |
|---|---|---|---|---|
| Fresenius Medical Care AG Sponsored ADR | FMS | 2 | PHASE3 | Dialysis |
| AstraZeneca PLC | AZN | 1 | PHASE2 | AZD4144 |
| CalciMedica, Inc. | CALC | 1 | PHASE2 | Auxora |
| Talphera, Inc. | TLPH | 1 | N/A | Undisclosed |
| SeaStar Medical Holding Corporation | ICU | 2 | - | Undisclosed |
| Collegium Pharmaceutical, Inc. | COLL | 1 | - | Flozin |
L-Citrulline is an investigational small molecule being studied for several conditions, including atrial septal defect, acute lung injury, acute hypoxemic respiratory failure, congenital heart defects, and sickle cell disease. It is being developed by Travere Therapeutics, Inc. (NASDAQ: TVTX) and is currently in Phase 2 clinical development.
L-Citrulline is an amino acid that serves as a precursor to L-arginine, which is involved in nitric oxide production. By increasing L-arginine availability, it may enhance nitric oxide synthesis, potentially improving blood flow and oxygenation. However, no specific molecular target has been identified for this drug.
L-Citrulline is being developed by Travere Therapeutics, Inc., a biopharmaceutical company traded on NASDAQ under the ticker symbol TVTX. The company is conducting clinical trials to evaluate the drug's safety and efficacy in various patient populations.
L-Citrulline is currently in Phase 2 clinical development. It is an investigational drug and has not been approved by the FDA. The company has completed several earlier-stage trials and is continuing to study the drug in additional indications.
L-Citrulline has been studied in several clinical trials, including NCT00335244 and NCT01120964 for children undergoing heart bypass surgery, NCT04570384 for acute hypoxemic respiratory failure in COVID-19 patients, and NCT06989567 for sickle cell disease. The most recent trial, NCT06989567, is not yet recruiting.
L-Citrulline is the L-isomer of the amino acid citrulline, which is the biologically active form found in the body. It is sometimes referred to simply as citrulline, but the drug being developed by Travere Therapeutics is specifically the L-form administered intravenously.