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Combining Active and Passive DNA Hypomethylation (EVI-3)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03999723
Recruitment Status : Recruiting
First Posted : June 27, 2019
Last Update Posted : September 17, 2019
Sponsor:
Collaborators:
Van Andel Research Institute
Karolinska University Hospital
Skane University Hospital
Sahlgrenska University Hospital, Sweden
Oslo University Hospital
Helsinki University
Royal Sussex County Hospital
University of Southern California
Imperial College London
University of Copenhagen
Zealand University Hospital
Aalborg University Hospital
Odense University Hospital
Technical University of Denmark
The Leeds Teaching Hospitals NHS Trust
Aarhus University Hospital
Information provided by (Responsible Party):
Kirsten Grønbæk, Rigshospitalet, Denmark

Brief Summary:
This is a multicentre, randomized, parallel-group, placebo-controlled, double-blind phase 2 study of the efficacy and safety of oral vitamin C supplement in combination with azacitidine in patients with higher-risk MDS, CMML-2 and low-blast count AML. The primary purpose is to investigate if oral vitamin C supplementation to azacitidine, compared with azacitidine + placebo, can increase the effectiveness of epigenetic therapy in patients with higher-risk myeloid malignancies, who are not candidates for allogeneic hematopoietic stem cell transplantation. Hence hereby, the investigators wish to clarify whether the standard of care in patients being treated with azacitidine should be changed by routinely adding oral vitamin C.

Condition or disease Intervention/treatment Phase
Myelodysplastic Syndromes Acute Myeloid Leukemia Chronic Myelomonocytic Leukemia Dietary Supplement: Vitamin C Dietary Supplement: Placebo Phase 2

Detailed Description:

EVI-3 is a phase 2 international, multicentre, randomized, parallel-group, placebo-controlled, double-blind study of the efficacy and safety of oral vitamin C supplement in combination with azacitidine (AZA) in patients with higher-risk myeloid malignancies with or without mutations in genes recurrently affected in myeloid malignancies. Treatment allocation is in 1:1 ratio by block randomization stratified by clinical site. Study entry is staggered. Patients are randomized to either oral vitamin C 1000 mg daily or placebo from start of AZA treatment until end of study (EOS) or until AZA treatment is discontinued at the discretion of the treating physician, whichever occurs earlier. The accrual time is estimated to 36 months and 6 months follow-up, thus, maximum treatment duration will be approximately 42 months. A total of 182 patients is planned for enrollment.

Study visits are scheduled at baseline, after 1st AZA treatment cycle, after 6 AZA treatment cycles, and, if AZA treatment is continued, at EOS or end of AZA treatment. Evaluations at study visits include bone marrow investigation, peripheral blood tests, patient-reported outcome measures and adverse events. Bone marrow aspirate and peripheral blood will be collected for biobank at each study visit.

All patients will undergo follow-up once yearly from EOS. Follow-up will include information on survival and disease progression from myelodysplastic syndrome (MDS) or chronic myelomonocytic leukemia (CMML) to acute myeloid leukemia (AML), if diagnosed following a clinical indication for a bone marrow test.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 182 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: A multicentre, randomized, parallel-group, placebo-controlled, double-blind phase 2 study
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: Double-blind masking (Participant, Care Provider, Investigator, (some) Outcomes Assessors)
Primary Purpose: Treatment
Official Title: Combining Active and Passive DNA Hypomethylation: A Multicentre, Randomized, Placebo-Controlled Phase II Study of the Efficacy and Safety of Oral Vitamin C in Combination With Azacitidine in Higher-Risk MDS, CMML-2 and Low-Blast Count AML
Actual Study Start Date : September 11, 2019
Estimated Primary Completion Date : March 2023
Estimated Study Completion Date : March 2023


Arm Intervention/treatment
Experimental: Vitamin C
Oral vitamin C (ascorbic acid) will be given in a dose of 1000 mg daily (two capsules of 500 mg once daily) starting day 1 in the 1st azacitidine (AZA) cycle (D1/C1) and continuing until discontinuation of AZA or end of study, whichever occurs earlier.
Dietary Supplement: Vitamin C
Oral vitamin C (ascorbic acid) 1000 mg daily will be administered from day 1 in the 1st AZA cycle (D1/C1) and continued until discontinuation of AZA or EOS as combination treatment.
Other Name: Ascorbic acid

Placebo Comparator: Placebo
Placebo will be administered orally as two capsules once daily that look and taste identical to the capsules containing vitamin C. Treatment will start day 1 in the 1st azacitidine (AZA) cycle (D1/C1) and continuing until discontinuation of AZA or end of study, whichever occurs earlier. The content of the placebo capsules is glucose monohydrate, potato starch, gelatin, magnesium stearate and talc.
Dietary Supplement: Placebo
Placebo capsules (two capsules once daily) will be administered from day 1 in the 1st AZA cycle (D1/C1) and continued until discontinuation of AZA or EOS.




Primary Outcome Measures :
  1. Duration of azacitidine (AZA) therapy [ Time Frame: 0-42 months ]
    Duration of AZA therapy in patients randomized to AZA + oral vitamin C (arm A) compared to patients randomized to AZA + placebo (arm B) assessed at end of study (EOS)


Secondary Outcome Measures :
  1. Adverse events and serious adverse events [ Time Frame: 0-42 months ]
    Number and ratio of patients with a (serious) adverse event in arm A vs. arm B assessed from the time of administration of intervention (day 1, AZA cycle 1 = D1/C1) to EOS. Total number of adverse events and serious adverse events and the number per year from D1/C1 to EOS in arm A vs. arm B. Number of patients discontinuing the intervention and discontinuation rate in arm A vs. arm B from D1/C1 to EOS

  2. Overall survival [ Time Frame: 0-42 months ]
    Overall survival in months in arm A vs. arm B calculated from the time of randomization to EOS

  3. Overall response rate [ Time Frame: 0-42 months ]
    Rate of overall response and rates of individual responses (as according to international consensus criteria), including best response, in arm A vs. arm B after 6 AZA cycles and at EOS

  4. Patient-reported outcome (PRO) measures [ Time Frame: 0-42 months ]
    Change in PRO measures including health-related quality of life scores (EORTC QLQ-C30 and Hematological Malignancy (HM)-PRO) from baseline to end of 1st AZA cycle, after 6 AZA cycles and EOS, if AZA treatment ongoing, respectively, in arm A vs. arm B. Numerical PRO scores after the 1st AZA cycle and after 6 AZA cycles (and EOS), respectively, in arm A vs. arm B

  5. Variant allele frequency (VAF) of mutated clones [ Time Frame: 0-42 months ]
    Change in VAF of mutated clones (in percentage points and in percentage) in bone marrow mononuclear cells from baseline to end of 6th AZA cycle and to end of treatment (if occurring before EOS) in arm A vs. arm B. Number and ratio of patients with appearance of new mutations between baseline and end of 6th AZA cycle (and end of treatment) in arm A vs. arm B. Total number of new mutations in arm A vs. arm B from baseline to end of 6th AZA cycle (and end of treatment)

  6. Global 5-hydroxymethylcytosine (5-hmC)/5-methylcytosine (5-mC) [ Time Frame: 0-42 months ]
    Change in global 5-hmC/5-mC in bone marrow CD34+ cells from baseline to end of 1st AZA cycle, end of 6th AZA cycle and end of treatment (if occurring before EOS), respectively, in arm A vs. arm B. Global 5-hmC/5-mC in bone marrow CD34+ cells at end of 1st AZA cycle and end of 6th AZA cycle (and end of treatment), respectively, in arm A vs. arm B

  7. Site specific 5-hmC/5-mC [ Time Frame: 0-42 months ]
    Change in 5-hmC/5-mC at specific loci at promoters/enhancers/long terminal repeats (LTRs) or at other regulatory genomic regions of tumor suppressors, oncogenes, genes involved in hematopoietic development or human endogenous retrovirus (HERV) in bone marrow CD34+ cells from baseline to end of 1st AZA cycle, end of 6th AZA cycle and end of treatment (if occurring before EOS), respectively, in arm A vs. arm B. Site specific 5-hmC/5-mC in bone marrow CD34+ cells at end of 1st AZA cycle and end of 6th AZA cycle (and end of treatment), respectively, in arm A vs. arm B

  8. Gene expression [ Time Frame: 0-42 months ]
    Change in expression of genes involved in viral defense pathways, cell differentiation and tumor suppression in bone marrow CD34+ cells from baseline end of 1st AZA cycle, end of 6th AZA cycle and end of treatment (if occurring before EOS), respectively, in arm A vs. arm B. Expression of genes involved in viral defense pathways, cell differentiation and tumor suppression in bone marrow CD34+ cells at end of 1st AZA cycle and end of 6th AZA cycle (and end of treatment), respectively, in arm A vs. arm B

  9. mRNA expression of HERV and HERV specific T-cell responses [ Time Frame: 0-42 months ]
    Change in levels of mRNA expression of HERV in bone marrow CD34+ cells and HERV specific T-cell responses from baseline to end of 1st AZA cycle, end of 6th AZA cycle and end of treatment (if occurring before EOS), respectively, in arm A vs. arm B. Levels of HERV mRNA in bone marrow CD34+ cells and HERV specific T-cell responses at end of 1st AZA cycle and end of 6th AZA cycle (and end of treatment), respectively, in arm A vs. arm B.



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:

• Patients eligible for treatment with azacitidine with one of the following diagnoses according to World Health Organization 2016:

  • MDS Higher-risk MDS according to the IPSS-R, i.e., intermediate- to very high-risk (IPSS-R score > 3)
  • CMML CMML with 10-29 percent marrow blasts without myeloproliferative disorder
  • AML AML with 20-30 percent blasts (low-blast count AML)

Note: Patients with therapy-related MDS are eligible if they have not received radiation or chemotherapy for six months.

Exclusion Criteria:

  • Patients eligible for allogeneic stem cell transplantation
  • Prior therapy with hypomethylating agents
  • Any matter constituting an exclusion criterion for treatment with azacitidine
  • Patients receiving other active cancer treatment, including investigational agents, with the exception of hydroxyurea for white blood cell control and granulocyte colony-stimulating factor
  • History of allergic reactions to ascorbic acid
  • History of kidney or urinary tract stones requiring intervention within the past year
  • Lack of ability to understand the information given, or lack of willingness to sign a written informed consent document
  • Unwillingness to comply with the protocol
  • Unwillingness to discontinue any and all use of vitamin C medication/supplementation including multivitamin at least 3 days (but preferably longer) prior to inclusion and baseline sampling
  • Planned azacitidine treatment after allogeneic stem cell transplantation

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): NCT03999723


Contacts
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Contact: Kirsten Grønbæk, Prof., MD +45 35 45 60 86 kirsten.groenbaek@regionh.dk
Contact: Astrid Østergaard Mortensen, BSc, Nurse +45 35 45 60 80 astrid.oestergaard.mortensen.01@regionh.dk

Locations
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Denmark
Aalborg University Hospital Not yet recruiting
Aalborg, Denmark, 9100
Contact: Marianne Tang Severinsen, MD, PhD    +45 97666745    m.severinsen@rn.dk   
Rigshospitalet Recruiting
Copenhagen, Denmark, 2100
Contact: Kirsten Grønbæk, Prof., MD    +45 35 45 60 86    kirsten.groenbaek@regionh.dk   
Contact: Astrid Østergaard Mortensen, BSc, Nurse       astrid.oestergaard.mortensen.01@regionh.dk   
Sub-Investigator: Stine Ulrik Mikkelsen, MD         
Sub-Investigator: Amalie Bach Nielsen, MD         
Herlev University Hospital Not yet recruiting
Copenhagen, Denmark, 2730
Contact: Bo Kok Mortensen, MD, PhD    +45 38686483    bo.kok.mortensen@regionh.dk   
Odense University Hospital Not yet recruiting
Odense, Denmark, 5000
Contact: Klas Raaschou-Jensen, MD    +45 23221586    Klas.Raaschou-Jensen@rsyd.dk   
Sponsors and Collaborators
Kirsten Grønbæk
Van Andel Research Institute
Karolinska University Hospital
Skane University Hospital
Sahlgrenska University Hospital, Sweden
Oslo University Hospital
Helsinki University
Royal Sussex County Hospital
University of Southern California
Imperial College London
University of Copenhagen
Zealand University Hospital
Aalborg University Hospital
Odense University Hospital
Technical University of Denmark
The Leeds Teaching Hospitals NHS Trust
Aarhus University Hospital
Investigators
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Study Chair: Kirsten Grønbæk, Prof., MD Rigshospitalet, Denmark
Principal Investigator: Stine Ulrik Mikkelsen, MD Rigshospitalet, Denmark
Principal Investigator: Amalie Bach Nielsen, MD Rigshospitalet, Denmark

Publications:
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Responsible Party: Kirsten Grønbæk, Professor, MD, DMSc, Rigshospitalet, Denmark
ClinicalTrials.gov Identifier: NCT03999723    
Other Study ID Numbers: H-18040929
First Posted: June 27, 2019    Key Record Dates
Last Update Posted: September 17, 2019
Last Verified: September 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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:
Vitamin C
Ascorbic acid
Azacitidine
Hypomethylating agents
Randomized, Placebo-Controlled Trial
Additional relevant MeSH terms:
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Leukemia
Leukemia, Myelomonocytic, Chronic
Leukemia, Myelomonocytic, Juvenile
Myelodysplastic Syndromes
Neoplasms by Histologic Type
Neoplasms
Leukemia, Myeloid
Bone Marrow Diseases
Hematologic Diseases
Myelodysplastic-Myeloproliferative Diseases
Vitamins
Ascorbic Acid
Azacitidine
Micronutrients
Nutrients
Growth Substances
Physiological Effects of Drugs
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Enzyme Inhibitors
Antioxidants
Protective Agents