High-Dose Vitamin C in G6PDA and Pyruvate Kinase Deficiency: A Safety Study (G6PDA PKD)

Pyruvate kinase deficiency (PKD) and Class A Glucose-6-Phosphate Dehydrogenase deficiency (G6PDA) are inherited red blood cell enzyme disorders characterized by chronic hemolytic anemia. Current treatment options are limited and do not fully address the underlying mechanisms of red blood cell destruction, iron overload, and oxidative stress.

Our preliminary studies demonstrated that oral Vitamin C administration at doses of 250 mg, 500 mg, and 750 mg reduced the rate of hemolysis by approximately 50% within one hour of administration, as measured by end-tidal carbon monoxide corrected for ambient CO (ETCOc) - a validated marker of red blood cell breakdown. These findings provide a strong rationale for evaluating the safety and optimal dosing frequency of Vitamin C supplementation in these patient populations.

Study Design:

This is a Phase I, single-site, sequential within-patient dose escalation study. Three adult PKD patients will be enrolled in the initial cohort, each assigned to a different starting dose:

Patient 1: 250 mg daily → 250 mg twice daily → 250 mg three times daily Patient 2: 500 mg daily → 500 mg twice daily → 500 mg three times daily Patient 3: 750 mg daily → 750 mg twice daily → 750 mg twice daily + 500 mg once daily (to reach the NIH-recommended maximum daily dose of 2,000 mg/day)

Each dosing frequency will be maintained for one week, for a total active treatment period of 3 weeks per participant. Safety and hematologic assessments will be performed at baseline and at each dose adjustment visit (9 assessments per participant).

Assessments:

At each visit, participants will undergo:

ETCOc measurement to assess real-time hemolysis Complete blood count and reticulocyte count Metabolic panel including bilirubin and LDH Iron studies including serum iron, transferrin, ferritin, hepcidin, and erythroferrone Vital signs and adverse event assessment

Study Extension:

Following successful completion of the PKD cohort, the study will be extended to G6PDA patients, including 5 G6PDA males and 5 G6PDA heterozygous females from a well-characterized family. A subsequent extension to pediatric patients ages 4 and older is planned at Primary Children's Hospital in Salt Lake City, pending safety and preliminary efficacy data from the adult cohort.