Combining Active and Passive DNA Hypomethylation

NCT ID: NCT03999723

Last Updated: 2024-04-17

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

RECRUITING

Clinical Phase

PHASE2

Total Enrollment

196 participants

Study Classification

INTERVENTIONAL

Study Start Date

2019-09-11

Study Completion Date

2027-12-31

Brief Summary

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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.

Detailed Description

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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.

Conditions

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Myelodysplastic Syndromes Acute Myeloid Leukemia Chronic Myelomonocytic Leukemia

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

A multicentre, randomized, parallel-group, placebo-controlled, double-blind phase 2 study
Primary Study Purpose

TREATMENT

Blinding Strategy

QUADRUPLE

Participants Caregivers Investigators Outcome Assessors
Double-blind masking (Participant, Care Provider, Investigator, (some) Outcomes Assessors)

Study Groups

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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.

Group Type EXPERIMENTAL

Vitamin C

Intervention Type DIETARY_SUPPLEMENT

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.

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.

Group Type PLACEBO_COMPARATOR

Placebo

Intervention Type DIETARY_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.

Interventions

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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.

Intervention Type 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.

Intervention Type DIETARY_SUPPLEMENT

Other Intervention Names

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Ascorbic acid

Eligibility Criteria

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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

* 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
* 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)
Minimum Eligible Age

18 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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Van Andel Institute - Stand Up To Cancer Epigenetics Dream Team

UNKNOWN

Sponsor Role collaborator

Karolinska University Hospital

OTHER

Sponsor Role collaborator

Skane University Hospital

OTHER

Sponsor Role collaborator

Sahlgrenska University Hospital

OTHER

Sponsor Role collaborator

University of Southern California

OTHER

Sponsor Role collaborator

Imperial College London

OTHER

Sponsor Role collaborator

University of Copenhagen

OTHER

Sponsor Role collaborator

Zealand University Hospital

OTHER

Sponsor Role collaborator

Aalborg University Hospital

OTHER

Sponsor Role collaborator

Odense University Hospital

OTHER

Sponsor Role collaborator

Technical University of Denmark

OTHER

Sponsor Role collaborator

Aarhus University Hospital

OTHER

Sponsor Role collaborator

Uppsala University Hospital

OTHER

Sponsor Role collaborator

Kirsten Grønbæk

OTHER

Sponsor Role lead

Responsible Party

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Kirsten Grønbæk

Professor, MD, DMSc

Responsibility Role SPONSOR_INVESTIGATOR

Principal Investigators

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Kirsten Grønbæk, Prof., MD

Role: STUDY_DIRECTOR

Rigshospitalet, Denmark

Stine Ulrik Mikkelsen, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Rigshospitalet, Denmark

Ali Al-Mousawi, MD

Role: PRINCIPAL_INVESTIGATOR

Rigshospitalet, Denmark

Locations

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Aalborg University Hospital

Aalborg, , Denmark

Site Status RECRUITING

Aarhus University Hospital

Aarhus, , Denmark

Site Status RECRUITING

Rigshospitalet

Copenhagen, , Denmark

Site Status RECRUITING

Herlev University Hospital

Copenhagen, , Denmark

Site Status RECRUITING

Odense University Hospital

Odense, , Denmark

Site Status ACTIVE_NOT_RECRUITING

Zealand University Hospital

Roskilde, , Denmark

Site Status TERMINATED

Sahlgrenska University Hospital

Gothenburg, , Sweden

Site Status RECRUITING

Skåne University Hospital

Lund, , Sweden

Site Status RECRUITING

Karolinska University Hospital

Stockholm, , Sweden

Site Status RECRUITING

Uppsala University Hospital

Uppsala, , Sweden

Site Status RECRUITING

Countries

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Denmark Sweden

Central Contacts

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Kirsten Grønbæk, Prof., MD

Role: CONTACT

+45 35 45 60 86

Krista Smidt Bech, BSc, Nurse

Role: CONTACT

+45 35 45 60 80

Facility Contacts

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Marianne Tang Severinsen, MD, PhD

Role: primary

+45 97666745

Anne S Roug, MD

Role: primary

Kirsten Grønbæk, Prof., MD

Role: primary

+45 35 45 60 86

Krista Smidt Bech, BSc, Nurse

Role: backup

+45 35 45 60 80

Bo Kok Mortensen, MD, PhD

Role: primary

+45 38686483

Hege Gravdahl Garelius, MD

Role: primary

Lars Nilsson, MD, PhD

Role: primary

Eva Hellström-Lindberg, Prof., MD

Role: primary

Elisabeth Ejerblad, MD

Role: primary

References

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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.

Reference Type BACKGROUND
PMID: 8433390 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 31037971 (View on PubMed)

Other Identifiers

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H-18040929

Identifier Type: -

Identifier Source: org_study_id

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