Epigenetics, Vitamin C and Abnormal Hematopoiesis - Pilot Study (EVITA-Pilot)

Restoring Physiological Vitamin C Levels to the Normal Range: Influence on Epigenetic Regulation in Normal and Malignant Hematopoiesis

This study evaluates whether vitamin C improves responses to epigenetic therapy with DNMTis. Half of the patients will receive vitamin C and DNMTi while the other half will receive placebo and DNMTi.

Study Overview

• Status: Completed
• Conditions: Acute Myeloid Leukemia; Myelodysplastic Syndrome
• Intervention / Treatment: Dietary supplement: Vitamin C; Dietary supplement: Placebo

Detailed Description

Recently, it was documented that hematological cancer patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) exhibited severe vitamin C deficiency. Vitamin C is an essential co-factor for ten-eleven translocation (TET) enzymes, which initiate DNA demethylation through oxidation of 5-methylcytosine (mC) to 5-hydroxy-methylcytosine (hmC). In-vitro studies show that vitamin C at physiological doses added to DNA methyltransferase inhibitors (DNMTis), induce a synergistic inhibition of cell proliferation and enhanced apoptosis. These effects are mediated via a viral mimicry response recently associated with cancer stem-like cell death and enhanced immune signals including increased expression of bi-directionally transcribed endogenous retrovirus (ERV) transcripts, increased presence of cytosolic double stranded RNAs, and activation of an interferon inducing cellular response to these transcripts. Data suggest that correction of vitamin C deficiency may improve responses to epigenetic therapy with DNMTis. In the EVITA pilot study, the investigators include MDS/AML patients and explore the potential role of restoring vitamin C within the normal physiological range in treatment of hematological cancer with DNMTis.

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Denmark
  • København Ø, Denmark, 2100
    • Rigshospitalet

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• MDS/AML patient in treatment with DNMTi

Exclusion Criteria:

• Intake of vitamin C as a dietary supplement including multivitamin
• Non-compliance

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Vitamin C; Oral intake of vitamin C tablet (500 mg) daily for 56 days	Dietary supplement: Vitamin C; Oral intake of vitamin C tablet (500 mg) daily for 56 days
PLACEBO_COMPARATOR: Placebo; Oral intake of placebo tablet daily for 56 days	Dietary supplement: Placebo; Oral intake of placebo tablet daily for 56 days

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Overall 5-hmC/5-mC ratio	Change from baseline to day 84
Overall lysine methylation levels	Change from baseline to day 84
5-hmC/5-mC ratio at regulatory genomic regions of genes involved in hematopoietic development	Change from baseline to day 84
Accumulation of 5-hmC/5-mC at regulatory regions of ERVs	Change from baseline to day 84
Aberrant histone methylation associated with hematopoietic development	Change from baseline to day 84
Aberrant histone methylation associated with ERVs	Change from baseline to day 84
Expression levels of ERVs	Change from baseline to day 84
Activity of the viral defense pathway measured by RNA and protein expression	Change from baseline to day 84
ERV specific T-cell recognition in vivo	Change from baseline to day 84

Collaborators and Investigators

• Sponsor: Rigshospitalet, Denmark
• Collaborators: Van Andel Research Institute

Publications and helpful links

General Publications

• Gillberg L, Orskov AD, Nasif A, Ohtani H, Madaj Z, Hansen JW, Rapin N, Mogensen JB, Liu M, Dufva IH, Lykkesfeldt J, Hajkova P, Jones PA, Gronbaek K. Oral vitamin C supplementation to patients with myeloid cancer on azacitidine treatment: Normalization of plasma vitamin C induces epigenetic changes. Clin Epigenetics. 2019 Oct 17;11(1):143. doi: 10.1186/s13148-019-0739-5.

Study record dates

Study Major Dates

• Study Start (ACTUAL): August 8, 2016
• Primary Completion (ACTUAL): May 29, 2017
• Study Completion (ACTUAL): May 29, 2017

Study Registration Dates

• First Submitted: August 9, 2016
• First Submitted That Met QC Criteria: August 18, 2016
• First Posted (ESTIMATE): August 24, 2016

Study Record Updates

• Last Update Posted (ACTUAL): September 24, 2018
• Last Update Submitted That Met QC Criteria: September 20, 2018
• Last Verified: September 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Bone Marrow Diseases; Hematologic Diseases; Myelodysplastic Syndromes; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Protective Agents; Micronutrients; Vitamins; Antioxidants; Ascorbic Acid
• Other Study ID Numbers: H-16022249

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO