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

Официальное название

Safety and Tolerability of Supratherapeutic Vitamin C Supplementation in Class A Glucose-6-Phosphate Dehydrogenase (G6PD A) Deficiency and Pyruvate Kinase Deficiency (PKD)

Обзор

This study is testing whether high-dose Vitamin C is safe and well-tolerated in patients with two inherited red blood cell disorders - Pyruvate Kinase Deficiency (PKD) and Class A Glucose-6-Phosphate Dehydrogenase Deficiency (G6PDA). Both conditions cause red blood cells to break down too quickly, leading to anemia and related complications. Our earlier research showed that a single oral dose of Vitamin C (250 mg, 500 mg, or 750 mg) reduced red blood cell breakdown by approximately 50% within one hour. This study builds on those findings by testing different doses and frequencies of Vitamin C to find the safest and most effective dosing schedule. Participants will take Vitamin C once, twice, or three times daily over a 3-week period, with careful monitoring of blood counts, red blood cell survival, iron levels, and any side effects. The study will first enroll 3 adult patients with PKD at Huntsman Cancer Institute. If the results are safe and promising, the study will be extended to patients with G6PDA deficiency, and eventually to children ages 4 and older at Primary Children's Hospital in Salt Lake City. The goal is to establish a foundation for Vitamin C as a novel therapy to reduce anemia and red blood cell destruction in these rare inherited disorders.

Подробное описание

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.

Вмешательства

• Препарат Vitamin C
  Oral pharmacological grade Vitamin C (Ascorbic Acid) administered at escalating doses and frequencies over a 3-week period. Three dose levels are evaluated: 250 mg, 500 mg, and 750 mg, administered once daily (QD), twice daily (BID), or three times daily (TID) depending on the assigned arm. The maximum daily dose does not exceed 2,000 mg/day, consistent with the NIH-recommended maximum daily dose.

Первичные конечные точки

• Incidence of Dose-Limiting Toxicities (DLTs) [Срок оценки: From first dose of study intervention through the 28-day safety follow-up visit (approximately 7 weeks per participant)]
• Number of Participants With Treatment-Related Adverse Events as Assessed by NCI CTCAE v5.0 [Срок оценки: From first dose of study intervention through the 28-day safety follow-up visit (approximately 7 weeks per participant)]
• Change in Hemoglobin Concentration from Baseline [Срок оценки: Baseline (Day 1) through Week 3 of treatment and 28-day safety follow-up visit]
• Change in Reticulocyte Count from Baseline [Срок оценки: Baseline (Day 1) through Week 3 of treatment and 28-day safety follow-up visit]
• Change in Lactate Dehydrogenase (LDH) from Baseline [Срок оценки: Baseline (Day 1) through Week 3 of treatment and 28-day safety follow-up visit]
• Change in Systolic Blood Pressure from Baseline [Срок оценки: Baseline (Day 1) through Week 3 of treatment and 28-day safety follow-up visit]
• Change in Heart Rate from Baseline [Срок оценки: Baseline (Day 1) through Week 3 of treatment and 28-day safety follow-up visit]

Критерии участия

Критерии включения

• Confirmed diagnosis of Pyruvate Kinase Deficiency (PKD) or Class A glucose-6-phosphate dehydrogenase (G6PD A) as verified by genetic mutation documentation or enzymatic testing
• 18 years of age or older
• Able to take oral medications either by mouth or via gastrostomy tube
• Willing and able to provide written informed consent prior to any study procedures
• Heterozygous female carrier of G6PDA deficiency

Критерии исключения

• Does not have an established diagnosis of Pyruvate Kinase Deficiency (PKD) or Class A Glucose-6-Phosphate Dehydrogenase Deficiency (G6PDA)
• Unable to tolerate oral medications either by mouth or gastrostomy tube
• Currently pregnant or planning to become pregnant during the study period
• Incarcerated individuals
• Unable to provide written informed consent or assent
• Known allergy or hypersensitivity to Vitamin C (ascorbic acid)

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Нерандомизированное

Модель

Последовательный дизайн

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

США · 1 центр

• University of Utah — Salt Lake City

Публикации

• Gammal RS, Pirmohamed M, Somogyi AA, Morris SA, Formea CM, Elchynski AL, Oshikoya KA, McLeod HL, Haidar CE, Whirl-Carrillo M, Klein TE, Caudle KE, Relling MV. Expanded Clinical Pharmacogenetics Implementation Consortium Guideline for Medication Use in the Context of G6PD Genotype. Clin Pharmacol Ther. 2023 May;113(5):973-985. doi: 10.1002/cpt.2735. Epub 2022 Sep 24. PMID 36049896
• Mohammed BM, Fisher BJ, Kraskauskas D, Ward S, Wayne JS, Brophy DF, Fowler AA 3rd, Yager DR, Natarajan R. Vitamin C promotes wound healing through novel pleiotropic mechanisms. Int Wound J. 2016 Aug;13(4):572-84. doi: 10.1111/iwj.12484. Epub 2015 Aug 20. PMID 26290474
• Bechara N, Flood VM, Gunton JE. A Systematic Review on the Role of Vitamin C in Tissue Healing. Antioxidants (Basel). 2022 Aug 19;11(8):1605. doi: 10.3390/antiox11081605. PMID 36009324
• Coffey R, Jung G, Olivera JD, Karin G, Pereira RC, Nemeth E, Ganz T. Erythroid overproduction of erythroferrone causes iron overload and developmental abnormalities in mice. Blood. 2022 Jan 20;139(3):439-451. doi: 10.1182/blood.2021014054. PMID 34614145
• Grootendorst S, de Wilde J, van Dooijeweert B, van Vuren A, van Solinge W, Schutgens R, van Wijk R, Bartels M. The Interplay between Drivers of Erythropoiesis and Iron Homeostasis in Rare Hereditary Anemias: Tipping the Balance. Int J Mol Sci. 2021 Feb 23;22(4):2204. doi: 10.3390/ijms22042204. PMID 33672223
• Lal A, Patterson L, Goldrich A, Marsh A. Point-of-care end-tidal carbon monoxide reflects severity of hemolysis in sickle cell anemia. Pediatr Blood Cancer. 2015 May;62(5):912-4. doi: 10.1002/pbc.25447. Epub 2015 Feb 14. PMID 25683629
• Quinn J, Gerber B, Fouche R, Kenyon K, Blom Z, Muthukanagaraj P. Effect of High-Dose Vitamin C Infusion in a Glucose-6-Phosphate Dehydrogenase-Deficient Patient. Case Rep Med. 2017;2017:5202606. doi: 10.1155/2017/5202606. Epub 2017 Nov 26. PMID 29317868
• Mehta JB, Singhal SB, Mehta BC. Ascorbic-acid-induced haemolysis in G-6-PD deficiency. Lancet. 1990 Oct 13;336(8720):944. doi: 10.1016/0140-6736(90)92317-b. No abstract available. PMID 1976956

Идентификаторы

NCT: NCT07612345 · 00187727

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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