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

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ClinicalTrials.gov Identifier: NCT03682029
Recruitment Status : Recruiting
First Posted : September 24, 2018
Last Update Posted : September 28, 2018
Sponsor:
Collaborators:
Van Andel Research Institute
University of Southern California
Imperial College London
University of Copenhagen
Herlev Hospital
Zealand University Hospital
Technical University of Denmark
Information provided by (Responsible Party):
Kirsten Grønbæk, Rigshospitalet, Denmark

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 syndrome (MDS), and chronic myelomonocytic leukemia (CMML)-0/1 by reversing some of 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 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.

Condition or disease Intervention/treatment Phase
Myelodysplastic Syndromes Chronic Myelomonocytic Leukemia-1 Cytopenia Dietary Supplement: Vitamin C (ascorbic acid) Other: Placebo Not Applicable

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 70 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Prospective, randomized, placebo-controlled trial.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: Randomization performed by the independent provider of study medication (Glostrup Pharmacy).
Primary Purpose: Prevention
Official Title: Epigenetics, Vitamin C, and Abnormal Hematopoiesis - Role of Vitamin C in Epigenetic Regulation in Hematopoiesis Sub-Study on CCUS, Low-Risk MDS, and CMML-0/1
Actual Study Start Date : November 21, 2017
Estimated Primary Completion Date : December 1, 2020
Estimated Study Completion Date : May 1, 2021


Arm Intervention/treatment
Experimental: Vitamin C
Vitamin C (ascorbic acid) 500 mg/capsule. Ingestion of 2 capsules (1000 mg) daily for 12 months.
Dietary Supplement: Vitamin C (ascorbic acid)
Monotherapy with oral vitamin C supplementation to elevate plasma vitamin C level to the upper end of the physiological range.

Placebo Comparator: Placebo
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
Placebo




Primary Outcome Measures :
  1. Mean Change from Baseline in 5-hmC/5-mC Level at 12 Months [ Time Frame: At baseline and at 12 months ]
    Mean change from baseline to 12 months in global 5-hmC/5-mC measured in hematopoietic stem cells is compared between the vitamin C group and the placebo group. In addition, the mean change from baseline in 5-hmC/5-mC at 12 months is compared between participants in the vitamin C arm with baseline plasma vitamin C level in the normal range vs. participants in the vitamin C arm with baseline plasma vitamin C level below the normal range.


Secondary Outcome Measures :
  1. Mean Change from Baseline in 5-hmC/5-mC Level at 3 Months [ Time Frame: At baseline and at 3 months ]
    Mean change from baseline to 3 months in global 5-hmC/5-mC measured in hematopoietic stem cells is compared between the vitamin C group and the placebo group. In addition, the mean change from baseline in 5-hmC/5-mC at 12 months is compared between participants in the vitamin C arm with baseline plasma vitamin C level in the normal range vs. participants in the vitamin C arm with baseline plasma vitamin C level below the normal range.

  2. Mean Change from Baseline in 5-mC at Selected Sites at 12 Months [ Time Frame: At baseline and at 12 months ]
    Mean change from baseline to 12 months in 5-mC at promoters/enhancers/long terminal repeats, and other regulatory genomic regions of tumor suppressors/methylated driver genes/genes involved in hematopoietic development.

  3. Mean Change from Baseline in H3K9 Methylation at Selected Sites at 12 Months [ Time Frame: At baseline and at 12 months ]
    Mean change from baseline to 12 months in methylated histone H3 lysine at position 9 at promoters/enhancers/long terminal repeats, and other regulatory regions of tumor suppressors/methylated driver genes/genes involved in hematopoietic development.

  4. Mean Change from Baseline in Variant Allele Frequency at 12 Months [ Time Frame: At baseline and at 12 months ]
    Mean change from baseline to 12 months in mutant allele burden as measured by the variant allele frequency (VAF).

  5. Mean Change from Baseline in Plasma Cytokine Levels at 12 Months [ Time Frame: At baseline and at 12 months ]
    Mean change from baseline to 12 months in plasma cytokine levels (e.g., IL-6, S100A9, etc.).

  6. Mean Change from Baseline in mRNA Levels of Selected Genes at 12 Months [ Time Frame: At baseline and at 12 months ]
    Mean change from baseline to 12 months in mRNA levels of tumor suppressor genes, oncogenes, epigenetic regulators, cytokines, and genes involved in hematopoietic development.

  7. Mean Change from Baseline in mRNA Levels of Selected Genes at 3 Months [ Time Frame: At baseline and at 3 months ]
    Mean change from baseline to 3 months in mRNA levels of tumor suppressor genes, oncogenes, epigenetic regulators, cytokines, and genes involved in hematopoietic development.

  8. Number of Participants with Serious Adverse Events and Treatment-Related Adverse Events as Assessed by CTCAE v5.0 [ Time Frame: Through study completion, 12 months ]
    Number of serious adverse events and treatment-related adverse events as assessed by CTCAE v5.0. Adverse events, that are not considered serious or related to vitamin C intake, will not be recorded.

  9. Percentage of Participants with Vitamin C Deficiency [ Time Frame: Day 1 ]
    Percentage of participants with baseline plasma vitamin C level below the normal physiological range.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

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)

OR

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

OR

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)

Exclusion Criteria:

  • 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03682029


Contacts
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Contact: Kirsten Grønbæk, Professor +4535456060 Kirsten.Groenbaek@regionh.dk
Contact: Stine Ulrik Mikkelsen, MD +4535456071 stine.ulrik.mikkelsen@regionh.dk

Locations
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United States, California
University of Southern California Not yet recruiting
Los Angeles, California, United States, 90033
Contact: Casey O'Connell, MD, FACP    323-865-3105    oconnell_c@med.usc.edu   
Contact: Ibrahim Syed    +1 323 226 4182    isyed@med.usc.edu   
Principal Investigator: Casey O'Connell, MD         
Denmark
Rigshospitalet Recruiting
Copenhagen, N/A = Not Applicable, Denmark, 2100
Contact: Kirsten Grønbæk, Professor    +4535456060    Kirsten.Groenbaek@regionh.dk   
Contact: Stine Ulrik Mikkelsen, MD    +4535456071    stine.ulrik.mikkelsen@regionh.dk   
Sub-Investigator: Stine Ulrik Mikkelsen, MD         
Principal Investigator: Kirsten Grønbæk, Professor         
Sub-Investigator: Linn Gillberg, PhD         
Sub-Investigator: Andreas Due Ørskov, MD         
Sub-Investigator: Jakob Werner Hansen, MD, PhD         
Herlev Hospital Not yet recruiting
Copenhagen, Denmark, 2730
Contact: Bo Mortensen, MD, PhD    +4538686483    bo.kok.mortensen@regionh.dk   
Principal Investigator: Bo Mortensen, MD, PhD         
Sponsors and Collaborators
Rigshospitalet, Denmark
Van Andel Research Institute
University of Southern California
Imperial College London
University of Copenhagen
Herlev Hospital
Zealand University Hospital
Technical University of Denmark
Investigators
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Principal Investigator: Kirsten Grønbæk, Professor Rigshospitalet, Denmark

Publications:

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Responsible Party: Kirsten Grønbæk, Professor, MD, DMSc, Rigshospitalet, Denmark
ClinicalTrials.gov Identifier: NCT03682029     History of Changes
Other Study ID Numbers: H-16022249 low-risk cohort
First Posted: September 24, 2018    Key Record Dates
Last Update Posted: September 28, 2018
Last Verified: September 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Kirsten Grønbæk, Rigshospitalet, Denmark:
Clonal Cytopenia of Undetermined Significance
Myelodysplastic Syndromes
Chronic Myelomonocytic Leukemia
Low-Risk Myeloid Malignancies
Vitamin C
Epigenetics
TET2
Randomized, Placebo-Controlled Trial
Clinical Study
Additional relevant MeSH terms:
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Preleukemia
Leukemia, Myelomonocytic, Chronic
Leukemia, Myelomonocytic, Juvenile
Myelodysplastic Syndromes
Leukemia
Neoplasms by Histologic Type
Neoplasms
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Leukemia, Myeloid
Myelodysplastic-Myeloproliferative Diseases
Vitamins
Ascorbic Acid
Micronutrients
Nutrients
Growth Substances
Physiological Effects of Drugs
Antioxidants
Molecular Mechanisms of Pharmacological Action
Protective Agents