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Myelodysplastic SyndromesPhase 2EVI-3NCT03999723

Combining Active and Passive DNA Hypomethylation

A Phase 2 study testing Vitamin C in people with Myelodysplastic Syndromes and Acute Myeloid Leukemia, run by Kirsten Grønbæk at 10 sites in 2 countries.

Recruiting

Looking for participants now. Contact the study team or a site below to ask about taking part.

Sites and contacts
Official record
Search all trials

Trial 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 or low-blast count AML. Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Vitamin C
Type of treatment
Pill or oral medicine
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
196 participants
Where
10 sitesin 2 countries
Study dates
11 Sep 2019to Dec 2027
Phase
Phase 2
Are there results?
Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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.

Who cannot join

  • Patient eligible for allogeneic stem cell transplantation
  • Prior therapy with hypomethylating agents
  • Any matter constituting an exclusion criterion for treatment with azacitidine
  • Patient receiving other active cancer treatment, including investigational agents, with the exception of hydroxyurea for white blood cell (WBC) control, G-CSF, and low permanent doses of steroid (≤ 25 mg oral prednisolone per day) for inflammatory disorders
  • Therapeutic radiation or chemotherapy within the past 6 months
  • History of allergic reactions to ascorbic acid
Show all 13Show fewer
  • 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
  • Eastern Cooperative Oncology Group (ECOG) performance status ≥3
  • Uncontrolled comorbidity including impaired hepatic function (total serum bilirubin >1.5 × upper limit of the normal range (ULN), serum alanine transaminase >3 × ULN, chronic hepatitis with decompensated cirrhosis), disabling psychiatric disease, severe neurologic disease, severe metabolic disease, or severe cardiac disease (NYHA class 3-4)

Trial locations and contacts

10 sites in 2 countries. Contact the study team or a site near you to ask about taking part.

Kirsten Grønbæk, Prof., MD contact

+45 35 45 60 86

kirsten.groenbaek@regionh.dk

Krista Smidt Bech, BSc, Nurse contact

+45 35 45 60 80

krista.smidt.bech.01@regionh.dk

10 sites in 2 countries

Denmark6 sites, 4 recruiting

  • Aalborg University Hospital

    Aalborg, 9100

    Marianne Tang Severinsen, MD, PhD, +45 97666745, m.severinsen@rn.dk

    Recruiting

  • Aarhus University Hospital

    Aarhus

    Anne S Roug, MD, annrou@rm.dk

    Recruiting

  • Rigshospitalet

    Copenhagen, 2100

    Kirsten Grønbæk, Prof., MD, +45 35 45 60 86, kirsten.groenbaek@regionh.dk

    Krista Smidt Bech, BSc, Nurse, +45 35 45 60 80, krista.smidt.bech.01@regionh.dk

    Recruiting

  • Herlev University Hospital

    Copenhagen, 2730

    Bo Kok Mortensen, MD, PhD, +45 38686483, bo.kok.mortensen@regionh.dk

    Recruiting

  • Odense University Hospital

    Odense, 5000

    Active, not recruiting

  • Zealand University Hospital

    Roskilde

    Terminated

Other trials in Denmark

Sweden4 sites, 4 recruiting

  • Sahlgrenska University Hospital

    Gothenburg

    Hege Gravdahl Garelius, MD, hege.garelius@vgregion.se

    Recruiting

  • Skåne University Hospital

    Lund

    Lars Nilsson, MD, PhD, lars.nilsson@skane.se

    Recruiting

  • Karolinska University Hospital

    Stockholm

    Eva Hellström-Lindberg, Prof., MD, eva.hellstrom-lindberg@ki.se

    Recruiting

  • Uppsala University Hospital

    Uppsala

    Elisabeth Ejerblad, MD, elisabeth.ejerblad@akademiska.se

    Recruiting

Other trials in Sweden

About this study

Official title: Combining Active and Passive DNA Hypomethylation: A Randomized, Placebo-Controlled Phase II Study of the Efficacy and Safety of Oral Vitamin C in Combination With Azacitidine in Patients With Higher-Risk MDS, CMML-2 or Low-Blast Count AML

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 or 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.

Read the 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 (vitamin C vs. placebo) 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 48 months and 6 months follow-up, thus, maximum treatment duration will be approximately 54 months. A total of 196 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, adverse events and compliance. 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 duration of AZA therapy, 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.

Being tested
Vitamin C, Placebo
Keywords
Vitamin C, Ascorbic acid, Azacitidine, Hypomethylating agents, Randomized, Placebo-Controlled Trial
Medical subject headings
Myelodysplastic Syndromes, Leukemia, Myeloid, Acute, Leukemia, Myelomonocytic, Chronic

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Vitamin CDietary supplement

    Also called Ascorbic acid

    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.

  • PlaceboDietary supplement

    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.

Study groups in NCT03999723
Study groupRoleWhat they receive
Vitamin CExperimentalOral 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.
Receives: Dietary Supplement: Vitamin C
PlaceboPlacebo comparatorPlacebo 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.
Receives: Dietary Supplement: Placebo

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Event-free survival

    Event-free survival in months in the group of patients receiving oral vitamin C + AZA (arm A) vs. the group of patients receiving placebo + AZA (arm B) calculated from the time of randomization to EOS. Event is defined as death, relapse, progression or lack of a response at 6 AZA cycles as defined by IWG 2006 (MDS and CMML) and ELN 2017 (AML) response criteria

    Measured: 0-54 months

Secondary outcomes (10)

  1. Adverse events and serious adverse events

    Number and ratio of patients with adverse events 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

    Measured: 0-54 months

  2. Overall survival

    Overall survival in months in arm A vs. arm B calculated from the time of randomization to EOS

    Measured: 0-54 months

  3. Overall response rate

    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

    Measured: 0-54 months

  4. Patient-reported outcome (PRO) measures

    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

    Measured: 0-54 months

  5. Variant allele frequency (VAF) of mutated clones

    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)

    Measured: 0-54 months

  6. Global 5-hydroxymethylcytosine (5-hmC)/5-methylcytosine (5-mC)

    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

    Measured: 0-54 months

  7. Site specific 5-hmC/5-mC

    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

    Measured: 0-54 months

  8. Gene expression

    Change in expression of genes involved in viral defense pathways, cell differentiation and tumor suppression and oncogenes 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

    Measured: 0-54 months

  9. mRNA expression of HERV and HERV specific T-cell responses

    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.

    Measured: 0-54 months

  10. Duration of azacitidine (AZA) therapy

    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)

    Measured: 0-54 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted27 Jun 2019
  2. Study start11 Sep 2019
  3. Primary completionDec 2025 (estimated)
  4. Study completionDec 2027 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Model description
A multicentre, randomized, parallel-group, placebo-controlled, double-blind phase 2 study
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
196 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03999723
Sponsor's protocol ID
H-18040929
Acronym
EVI-3
Status last verified
Apr 2024
First submitted
25 Jun 2019
Last updated
17 Apr 2024
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Publications

  • Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, Filiberti A, Flechtner H, Fleishman SB, de Haes JC, et al. The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst. 1993 Mar 3;85(5):365-76. doi: 10.1093/jnci/85.5.365.

    PubMed 8433390

  • Goswami P, Oliva EN, Ionova T, Else R, Kell J, Fielding AK, Jennings DM, Karakantza M, Al-Ismail S, Lyness J, Collins GP, McConnell S, Langton C, Al-Obaidi MJ, Oblak M, Salek S. Paper and electronic versions of HM-PRO, a novel patient-reported outcome measure for hematology: an equivalence study. J Comp Eff Res. 2019 May;8(7):523-533. doi: 10.2217/cer-2018-0108. Epub 2019 Apr 30.

    PubMed 31037971

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Vitamin C in people with Myelodysplastic Syndromes and Acute Myeloid Leukemia, run by Kirsten Grønbæk at 10 sites in 2 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 5 inclusion and 13 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: looking for participants now, as of the sponsor's last update on 17 Apr 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 10 sites in Denmark, Sweden. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

Contact Kirsten Grønbæk, Prof., MD (+45 35 45 60 86, kirsten.groenbaek@regionh.dk), or a site near the patient. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Event-free survival (time frame: 0-54 months). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03999723, which also lists 2 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 17 Apr 2024.

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