Epigenetics, Vitamin C, and Abnormal Blood Cell Formation - Vitamin C in Patients With Low-Risk Myeloid Malignancies

NCT03682029 | Active Not Recruiting

• 1 other identifier: H-16022249 low-risk cohort
• Study Type: interventional
• Target: 109
• Locations: 2 countries
• Sites: 5

Brief Summary

The primary purpose of this multi-centre, randomized, placebo-controlled, double-blind phase II study is to investigate if oral vitamin C may change the biology of low-risk myeloid malignancies; i.e., clonal cytopenia of undetermined significance (CCUS), low-risk myelodysplastic syndromes (MDS), and chronic myelomonocytic leukemia (CMML)-0/1 by reversing the epigenetic changes characteristic of these disease entities. The epigenetic regulator TET2 is the gene most often affected in CCUS. Preclinical studies have shown that active demethylation by the TET enzymes is dependent on vitamin C, and the investigators and collaborators have shown that plasma vitamin C levels are exceedingly low in hematological cancer patients but are easily corrected by oral vitamin C. This study is part of an array of EVITA studies aimed at clarifying whether the standard of care of patients with myeloid malignancies should be changed and oral vitamin C supplement added to the treatment recommendations.

Conditions

Myelodysplastic Syndromes; Chronic Myelomonocytic Leukemia-1; Cytopenia

Keywords

Clonal Cytopenia of Undetermined Significance; Myelodysplastic Syndromes; Chronic Myelomonocytic Leukemia; Low-Risk Myeloid Malignancies; Vitamin C; Epigenetics; TET2; Randomized, Placebo-Controlled Trial; Clinical Study

Outcome Measures

Primary Outcomes (1)

• Median Change from Baseline in Variant Allele Frequency at 12 Months

  Median change from baseline to 12 months in mutant allele burden as measured by the variant allele frequency (VAF) and number of mutations in the vitC group vs. the placebo group.

  At baseline and at 12 months

Secondary Outcomes (9)

• Mean Change from Baseline in 5-hmC/5-mC Level at 3 Months and 12 months

  At baseline and at 3 months and 12 months

• Mean Change from Baseline in 5-mC at Selected Sites at 12 Months

  At baseline and at 12 months

• Mean Change from Baseline in H3K9 Methylation at Selected Sites at 12 Months

  At baseline and at 12 months

• Mean Change from Baseline in Plasma Cytokine Levels at 12 Months

  At baseline and at 12 months

• Mean Change from Baseline in mRNA Levels of Selected Genes at 12 Months

  At baseline and at 12 months

Study Arms (2)

Vitamin C

EXPERIMENTAL

Vitamin C (ascorbic acid) 500 mg/capsule. Ingestion of 2 capsules (1000 mg) daily for 12 months.

Dietary Supplement: Vitamin C (ascorbic acid)

Placebo

PLACEBO COMPARATOR

Placebo capsule. Ingestion of 2 capsules daily for 12 months. Placebo will be prepared as capsules that look and taste identical to the vitamin C supplement capsules. The content of the placebo is lactose, potato starch, gelatin, magnesium stearate, and talc.

Other: Placebo

Interventions

Vitamin C (ascorbic acid) DIETARY_SUPPLEMENT

Monotherapy with oral vitamin C supplementation to elevate plasma vitamin C level to the upper end of the physiological range.

Vitamin C

Placebo OTHER

Placebo

Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• A diagnosis of CCUS:
• Persistent cytopenia for \> 6 months defined as hgb \< 11.3 g/dL (7 mmol/L) in women and hgb \< 12.9 g/dL (8 mmol/L) in men, thrombocyte count \< 150 x 10\^9/L or neutrophil count \< 1.8 x 10\^9/L
• Normal cytogenetics (with the exception of deletion of the Y chromosome which can be accepted)
• A bone marrow morphology that is not diagnostic of MDS or any other malignancy
• Other common causes of cytopenia (vitamin or other deficiencies, virus infection, etc.) have been ruled out
• Hematolytic conditions have been ruled out
• The presence of a detectable mutation in genes recurrently affected in myeloid malignancy representing a clonal marker (excluding germline mutations)
• A diagnosis of MDS as according to World Health Organization (WHO) 2016 diagnostic criteria
• Revised international prognostic scoring system (IPSS-R) risk score ≤ 3 AND bone marrow blast percentage \< 5 defining low-risk
• A diagnosis of CMML-0 or -1 as according to WHO 2016 diagnostic criteria
• AND
• (All diagnostic categories) The presence of a detectable mutation in genes recurrently affected in myeloid malignancy representing a clonal marker (excluding germline mutations)

You may not qualify if:

• Unwillingness to discontinue any and all use of vitamin C medication/supplementation including multivitamin at least 24 hours prior to Baseline investigations and sampling
• Lack of ability to understand the information given, or lack of willingness to sign a written informed consent document
• Treatment with chemotherapy within the past 6 months
• Patients receiving active treatment for their myeloid malignancy, including investigational agents, with the exception of granulocyte colony-stimulating factor (G-CSF) and erythropoietin
• History of allergic reactions to ascorbic acid
• Unwillingness to comply with all aspects of the protocol

Sponsors & Collaborators

• Rigshospitalet, Denmark: lead
• Van Andel Institute - Stand Up To Cancer Epigenetics Dream Team: collaborator
• University of Southern California: collaborator
• Imperial College London: collaborator
• University of Copenhagen: collaborator
• Odense University Hospital: collaborator
• Technical University of Denmark: collaborator
• Aalborg University Hospital: collaborator

Study Sites (5)

Keck Hospital of University of Southern California

Los Angeles, California, 90033, United States

Location

Rigshospitalet

Copenhagen, N/A = Not Applicable, 2100, Denmark

Location

Aalborg University Hospital

Aalborg, Denmark

Location

Herlev University Hospital

Copenhagen, 2730, Denmark

Location

Odense University Hospital

Odense, Denmark

Location

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MeSH Terms

Conditions

Myelodysplastic Syndromes; Cytopenia; Leukemia, Myelomonocytic, Chronic

Interventions

Ascorbic Acid

Condition Hierarchy (Ancestors)

Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases; Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Myelodysplastic-Myeloproliferative Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Sugar Acids; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Hydroxy Acids; Carbohydrates

Study Officials

• Kirsten Grønbæk, Professor

  Rigshospitalet, Denmark

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Randomization performed by the independent provider of study medication (Glostrup Pharmacy).
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor, MD, DMSc

Model Details: Prospective, randomized, placebo-controlled trial.

Study Record Dates

• First Submitted: September 20, 2018
• First Posted: September 24, 2018
• Study Start: November 21, 2017
• Primary Completion: September 27, 2023
• Study Completion: September 27, 2025
• Last Updated: April 17, 2024

Record last verified: 2024-04

Data Sharing

• IPD Sharing: Will not share

Locations

DK (4); US (1)