MethemoglobinemiaFerMetNCT06958822
Ferric Carboxymaltose Methemoglobinemia Study
An observational study of Methemoglobinemia and Anemia, Iron-Deficiency, run by Ordu University at 23 sites in Turkey (Türkiye).
Trial summary
Anemia that develops due to iron deficiency is called iron deficiency anemia. This common condition is treated with iron supplements taken either orally or given through an intravenous (IV) infusion. Ferric carboxymaltose (FCM) is one of the widely used, comparably newer IV iron preparations. Read more about this study
- Who is it for?
- Ages 18 years and olderHealthy volunteers can take part
- Conditions the study is for
- Methemoglobinemia, Anemia, Iron-Deficiency, Parenteral Iron Therapy
- What is being tested?
- Ferric Carboxymaltose (FCM)
- How many people
- 977 participants
- Where
- 23 sitesTurkey (Türkiye)
- Study dates
- 14 Apr 2025to 30 Sep 2025
- How long will I take part?
- 1 Day
- Phase
- Observational
- Are there results?
- None posted in the registry
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
- Healthy volunteers accepted
- Adult, Older adult
Study population: Study participants will consist of persons admitted to a total of 21 different secondary or tertiary care hospitals in 16 different provinces across Turkey.
Who may be able to join
- FCM Group:
- Adults (≥18 years)
- Presence of anemia (Hb <12 g/dl in women, <13 g/dl in men)
- Low ferritin (<30 mcg/l)
- Patients for whom FCM administration has been decided in routine medical care practice
- Control Group:
- Healthy adult (≥18 years) individuals who applied to the internal medicine outpatient clinic, who had no current or pre-existing chronic disease, who did not have anemia and iron deficiency (ferritin ≥30 mcg/L).
Who cannot join
- Known methemoglobinemia-related diseases (Hb M disease, cytochrome b5 reductase deficiency, etc.)
- Use of drugs associated with methemoglobinemia (acetylsalicylic acid, dapsone, chloroquine, metoclopramide, benzocaine, lidocaine, prilocaine, rasburicase, primaquine, sulfonamide, nitric oxide)
- Those with B12 and/or folate deficiency
- Those with Charlson Comorbidity Index ≥3
- Presence of advanced organ failure (Stage 4 and 5 chronic kidney disease, Child C cirrhosis, NYHA class 3 and 4 chronic heart failure, respiratory failure requiring oxygen supplementation and similar processes)
- Presence of malignancy (with or without cure)
- Presence of active infection (CRP > 5 mg/dL) and/or other acute disorder/disease
- Pregnancy status
Trial locations and contacts
23 sites in 1 country.
23 sites in 1 country
Turkey (Türkiye)23 sites
University of Health Sciences Adana City Health Application and Research Center
Adana, Adana, 01100
Sakarya University Training and Research Hospital
Adapazarı, Sakarya, 54100
Ordu University Training and Research Hospital
Altinordu, Ordu, 52200
Antalya City Hospital
Antalya, Kepez, 07080
Mehmet Yılmaz Aydınlar Acıbadem University
Ataşehir, Istanbul, 34758
Bursa Kestel State Hospital
Bursa, Kestel, 16450
Bursa Yuksek Ihtisas Training and Research
Bursa, Yıldırım, 16310
Çankırı State Hospital
Çankırı, Çankırı, 18100
Izmir Bakircay University Cigli Training and Research Hospital
Çiğli, İzmir, 35610
Karabuk University Training and Research Hospital
Karabük, Karabük Province, 78100
University of Health Sciences Diyarbakır Gazi Yaşargil Training and Research Hospital
Kayapınar, Diyarbakır, 21070
Kayseri City Hospital
Kocasinan, Kayseri, 38080
Akdeniz University Hospital
Konyaalti, Antalya, 07070
Mardin Kızıltepe State Hospital
Mardin, Kızıltepe, 47400
Balıkesir University Health Practice and Research Hospital
Merkez, Balıkesir, 10145
Mardin Artuklu University Training and Research Hospital
Merkez, Mardin, 47100
Van Yüzüncü Yıl University Training and Research Hospital
Merkez, Van, 65000
Bursa City Hospital
Nilufer, Bursa, 16110
Marmara University Training and Research Hospital
Pendik, Istanbul, 34890
Recep Tayyip Erdoğan University Faculty of Medicine Training and Research Hospital
Rize, Rize Province, 53100
Siirt University Faculty of Medicine Training and Research Hospital
Siirt, Siirt, 56100
Çorlu Vatan Hospital
Tekirdağ, Çorlu, 59850
Umraniye Training and Research Hospital
Ümraniye, Istanbul, 34764
About this study
Official title: Estimation of the Incidence of Methemoglobinemia Associated With Ferric Carboxymaltose Administration
Anemia that develops due to iron deficiency is called iron deficiency anemia. This common condition is treated with iron supplements taken either orally or given through an intravenous (IV) infusion. Ferric carboxymaltose (FCM) is one of the widely used, comparably newer IV iron preparations. Recently, several publications have raised the possibility that FCM may be associated with mild elevations in methemoglobin (metHb), a form of hemoglobin that cannot effectively deliver oxygen to tissues.
Methemoglobinemia is a known, though uncommon, side effect of some drugs. While usually mild and self-limiting, in certain cases it can become clinically significant or even life-threatening. This observational study is being conducted across multiple centers to better understand how often methemoglobinemia occurs after administration of FCM. As part of routine care, venous blood samples will be used to measure metHb levels in patients receiving FCM, and these results will be compared with those from individuals not exposed to the drug.
Read the detailed description
Methemoglobinemia, which results from the conversion of ferrous iron (Fe2+) to ferric iron (Fe3+) in hemoglobin (Hb), is a potentially life-threatening disorder resulting in functional anemia due to reduced oxygen-carrying capacity. Methemoglobin (metHb) levels above one percent (>1%) are considered abnormal, and ≥3% metHb is considered clinically significant methemoglobinemia. Severe elevation of this level (>20%) leads to more dangerous clinical manifestations such as shortness of breath, confusion, arrhythmias, and seizures. Cases are usually asymptomatic until metHb levels reach 20%, and only discoloration of the blood and/or skin can be detected. Levels exceeding 70 percent are fatal.
The more common acquired form of methemoglobinemia, which can be congenital or acquired, is often caused by the use of drugs or toxic substances. Exposure to certain compounds that exceed the enzymatic reduction capacity of erythrocytes causes signs/symptoms. Benzocaine, phenazopyridine, dapsone, and nitrates/nitrites are the substances most commonly associated with methemoglobinemia.
Ferric carboxymaltose (FCM) is a third-generation intravenous iron drug with a ferric iron (Fe³⁺) compound that is widely used in the intravenous treatment of iron deficiency anemia. There are only three studies on the relationship between FCM and metHb reflected in the literature, one as a case report and two as congress proceedings. Given the expanding clinical use of FCM and the potential implications of undetected methemoglobinemia, there is a need to evaluate this association in a structured and systematic manner under routine care conditions. This study is designed to contribute to pharmacovigilance efforts by generating incidence data and exploring potential patient-related or treatment-related risk factors. Therefore, the investigators plan to determine the incidence of this comparably rare adverse effect with a prospective multicenter observational study.
The primary objective is to estimate the incidence of methemoglobinemia - defined as venous blood methemoglobin (metHb) levels ≥3%-within 30 min. following intravenous administration of ferric carboxymaltose in adult patients receiving routine care.
Secondary objectives include (i) description of the full distribution of metHb values post-infusion (ii) determination of whether metHb levels remain elevated beyond 30 min. in affected individuals, (iii) estimation of the background distribution of metHb levels in an unexposed, healthy outpatient population (iv) comparison of the metHb levels between FCM-exposed patients and unexposed controls (v) identification of potential associations between methemoglobinemia and relevant covariates, including patient demographics, total iron dose administered, baseline hemoglobin and venous oxygen saturation, or other potential oxidant exposures.
This study is a multicenter, prospective observational study. Ferric carboxymaltose recipients are determined based on routine medical care practices; the researchers do not define which participants will receive ferric carboxymaltose. Patient recruitment will take place between April 14, 2025, and September 15, 2025, per protocol, in 21 different health institutions.
Statistical analysis:
Methemoglobinemia rates (≥3% metHb) between the exposed (FCM) and unexposed groups will be compared using Fisher's exact test. Subgroup differences in continuous metHb levels will be analyzed using analysis of variance (ANOVA) with appropriate post hoc comparisons. Correlations between metHb levels and continuous clinical variables will be evaluated using correlation tests. Independent predictors of methemoglobinemia will be assessed through multivariable regression modeling. A two-sided significance threshold of α = 0.05 will be used for all tests.
- Conditions
- Methemoglobinemia, Anemia, Iron-Deficiency, Parenteral Iron Therapy, Ferric Carboxymaltose
- Being tested
- Ferric Carboxymaltose (FCM)
- Keywords
- iron deficiency anemia, ferric carboxymaltose, intravenous iron, methemoglobinemia
- Medical subject headings
- Methemoglobinemia, Anemia, Iron-Deficiency
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Ferric Carboxymaltose (FCM)Drug
As this is an observational study, ferric carboxymaltose recipients are determined based on routine medical care practices. The researchers do not define which participants will receive ferric carboxymaltose.
| Study group | Role | What they receive |
|---|---|---|
| FCM Group | It will represent the group of patients who will be administered ferric carboxymaltose (FCM), i.e., the exposed group. Receives: Drug: Ferric Carboxymaltose (FCM) | |
| Control Group | It will represent the control group of patients who do not receive FCM or any form of iron therapy, i.e., the unexposed group. |
What is being measured
The primary outcome is the main question the study is designed to answer.
Number of Participants with Treatment-Related Clinically Significant Methemoglobinemia
Methemoglobin levels will be measured just before the infusion and at the 15th and 30th minutes post-infusion through venous sampling. The levels equal to or above 3% will be regarded as clinically significant methemoglobinemia.
Measured: From the time of enrollment through 30 minutes following completion of the infusion. If methemoglobin level is ≥3% after infusion, blood sampling will continue every half hour after the last blood gas for 24 hours until methemoglobinemia is <3%.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted6 May 2025
- Study start14 Apr 2025
- Primary completion30 Sep 2025
- Study completion30 Sep 2025
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for MethemoglobinemiaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Cohort
- Time perspective
- Prospective
- Enrolment
- 977 participants (actual)
- Target duration
- 1 Day
Sponsor and investigators
- Lead sponsor
- Ordu University
- Sponsor type
- University, hospital or other
- Collaborators
- Marmara University Pendik Training and Research Hospital
- Responsible party
- Principal investigator, Muhammet Özbilen, MD, Ordu University
- Investigators
- Muhammet Özbilen, MD, Study director, Ordu University Faculty of MedicineGökhan Tazegül, MD, Study director, Marmara UniversityVolkan Aydın, MD PhD, Study director, Marmara University School of DentistryMurat Bahadır, MD, Principal investigator, Ordu University Faculty of Medicine, Department of Internal MedicineBilge Ada Özcan, MD, Principal investigator, Marmara University Training and Research HospitalMehmet Bankir, MD, Principal investigator, University of Health Sciences Adana City Health Application and Research CenterMehmet Can Erişen, MD, Principal investigator, University of Health Sciences Adana City Health Application and Research CenterNurhayat Özkan Sevencan, MD, Principal investigator, Karabuk University Training and Research Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06958822
- Sponsor's protocol ID
- 2024-KAEK-30 / 2025-43
- Acronym
- FerMet
- Status last verified
- Aug 2025
- First submitted
- 13 Apr 2025
- Last updated
- 19 Nov 2025
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: Age, gender, hemoglobin, MCV, MCHC, ferritin, CRP, transferrin saturation, ferric carboxymaltose (FCM) drug dose, FCM infusion concentration, infusion duration, methemoglobin levels
Publications
Tazegul Gokhan, Kimyon Yusuf, Odabasi Zekaver. Ferric carboxymaltose induced methaemoglobinemia: Preliminary data of a novel side effect. 22nd European Congress of Internal Medicine , İstanbul, Turkey, 2024.
Özbilen M, Savrun ŞT, Aygün A, Kaya Y. P1492: A New Potential And Prevalent Side Effect of Ferric Carboxymaltose: Methemoglobinemia. A Case-Control Study. Hemasphere. 2023 Aug 8;7(Suppl 3):e825173f.
Ozbilen M, Savrun ST, Aygun A, Kaya Y. Ferric Carboxymaltose-mediated Methemoglobinemia. Curr Drug Saf. 2024;19(1):134-137. doi: 10.2174/1574886318666230213111038.
PubMed 36779493
Study at a glance
From the registry record, last updated by the sponsor on 19 Nov 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Estimation of the Incidence of Methemoglobinemia Associated With Ferric Carboxymaltose Administration
- ClinicalTrials.gov ID
- NCT06958822
- Acronym / sponsor ID
- FerMet / 2024-KAEK-30 / 2025-43
- Conditions
- Methemoglobinemia, Anemia, Iron-Deficiency, Parenteral Iron Therapy, Ferric Carboxymaltose
- Keywords
- iron deficiency anemia, ferric carboxymaltose, intravenous iron, methemoglobinemia
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 977 participants (actual)
- Lead sponsor
- Ordu UniversityUniversity, hospital or other
- Collaborators
- Marmara University Pendik Training and Research Hospital
- Study start
- 14 Apr 2025 (actual)
- Primary completion
- 30 Sep 2025 (actual)
- Study completion
- 30 Sep 2025 (actual)
- First posted
- 6 May 2025 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Anemia that develops due to iron deficiency is called iron deficiency anemia. This common condition is treated with iron supplements taken either orally or given through an intravenous (IV) infusion. Ferric carboxymaltose (FCM) is one of the widely used, comparably newer IV iron preparations. Recently, several publications have raised the possibility that FCM may be associated with mild elevations in methemoglobin (metHb), a form of hemoglobin that cannot effectively deliver oxygen to tissues.
Methemoglobinemia is a known, though uncommon, side effect of some drugs. While usually mild and self-limiting, in certain cases it can become clinically significant or even life-threatening. This observational study is being conducted across multiple centers to better understand how often methemoglobinemia occurs after administration of FCM. As part of routine care, venous blood samples will be used to measure metHb levels in patients receiving FCM, and these results will be compared with those from individuals not exposed to the drug.
Detailed description
Methemoglobinemia, which results from the conversion of ferrous iron (Fe2+) to ferric iron (Fe3+) in hemoglobin (Hb), is a potentially life-threatening disorder resulting in functional anemia due to reduced oxygen-carrying capacity. Methemoglobin (metHb) levels above one percent (>1%) are considered abnormal, and ≥3% metHb is considered clinically significant methemoglobinemia. Severe elevation of this level (>20%) leads to more dangerous clinical manifestations such as shortness of breath, confusion, arrhythmias, and seizures. Cases are usually asymptomatic until metHb levels reach 20%, and only discoloration of the blood and/or skin can be detected. Levels exceeding 70 percent are fatal.
The more common acquired form of methemoglobinemia, which can be congenital or acquired, is often caused by the use of drugs or toxic substances. Exposure to certain compounds that exceed the enzymatic reduction capacity of erythrocytes causes signs/symptoms. Benzocaine, phenazopyridine, dapsone, and nitrates/nitrites are the substances most commonly associated with methemoglobinemia.
Ferric carboxymaltose (FCM) is a third-generation intravenous iron drug with a ferric iron (Fe³⁺) compound that is widely used in the intravenous treatment of iron deficiency anemia. There are only three studies on the relationship between FCM and metHb reflected in the literature, one as a case report and two as congress proceedings. Given the expanding clinical use of FCM and the potential implications of undetected methemoglobinemia, there is a need to evaluate this association in a structured and systematic manner under routine care conditions. This study is designed to contribute to pharmacovigilance efforts by generating incidence data and exploring potential patient-related or treatment-related risk factors. Therefore, the investigators plan to determine the incidence of this comparably rare adverse effect with a prospective multicenter observational study.
The primary objective is to estimate the incidence of methemoglobinemia - defined as venous blood methemoglobin (metHb) levels ≥3%-within 30 min. following intravenous administration of ferric carboxymaltose in adult patients receiving routine care.
Secondary objectives include (i) description of the full distribution of metHb values post-infusion (ii) determination of whether metHb levels remain elevated beyond 30 min. in affected individuals, (iii) estimation of the background distribution of metHb levels in an unexposed, healthy outpatient population (iv) comparison of the metHb levels between FCM-exposed patients and unexposed controls (v) identification of potential associations between methemoglobinemia and relevant covariates, including patient demographics, total iron dose administered, baseline hemoglobin and venous oxygen saturation, or other potential oxidant exposures.
This study is a multicenter, prospective observational study. Ferric carboxymaltose recipients are determined based on routine medical care practices; the researchers do not define which participants will receive ferric carboxymaltose. Patient recruitment will take place between April 14, 2025, and September 15, 2025, per protocol, in 21 different health institutions.
Statistical analysis:
Methemoglobinemia rates (≥3% metHb) between the exposed (FCM) and unexposed groups will be compared using Fisher's exact test. Subgroup differences in continuous metHb levels will be analyzed using analysis of variance (ANOVA) with appropriate post hoc comparisons. Correlations between metHb levels and continuous clinical variables will be evaluated using correlation tests. Independent predictors of methemoglobinemia will be assessed through multivariable regression modeling. A two-sided significance threshold of α = 0.05 will be used for all tests.
Study design
- Observational model
- Cohort
- Time perspective
- Prospective
- Target follow-up
- 1 Day
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| FCM Group | – | Drug: Ferric Carboxymaltose (FCM)It will represent the group of patients who will be administered ferric carboxymaltose (FCM), i.e., the exposed group. |
| Control Group | – | –It will represent the control group of patients who do not receive FCM or any form of iron therapy, i.e., the unexposed group. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
- Study population
- Study participants will consist of persons admitted to a total of 21 different secondary or tertiary care hospitals in 16 different provinces across Turkey.
Key inclusion criteria (7 listed)
- Adults (≥18 years)
- Presence of anemia (Hb <12 g/dl in women, <13 g/dl in men)
- Low ferritin (<30 mcg/l)
- Patients for whom FCM administration has been decided in routine medical care practice
- Healthy adult (≥18 years) individuals who applied to the internal medicine outpatient clinic, who had no current or pre-existing chronic disease, who did not have anemia and iron deficiency (ferritin ≥30 mcg/L).
Key exclusion criteria (8 listed)
- Known methemoglobinemia-related diseases (Hb M disease, cytochrome b5 reductase deficiency, etc.)
- Use of drugs associated with methemoglobinemia (acetylsalicylic acid, dapsone, chloroquine, metoclopramide, benzocaine, lidocaine, prilocaine, rasburicase, primaquine, sulfonamide, nitric oxide)
- Those with B12 and/or folate deficiency
- Those with Charlson Comorbidity Index ≥3
- Presence of advanced organ failure (Stage 4 and 5 chronic kidney disease, Child C cirrhosis, NYHA class 3 and 4 chronic heart failure, respiratory failure requiring oxygen supplementation and similar processes)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Ferric Carboxymaltose (FCM)As this is an observational study, ferric carboxymaltose recipients are determined based on routine medical care practices. The researchers do not define which participants will receive ferric carboxymaltose. | Drug | FCM Group |
Primary outcome
Number of Participants with Treatment-Related Clinically Significant Methemoglobinemia
Time frame: From the time of enrollment through 30 minutes following completion of the infusion. If methemoglobin level is ≥3% after infusion, blood sampling will continue every half hour after the last blood gas for 24 hours until methemoglobinemia is <3%.
Methemoglobin levels will be measured just before the infusion and at the 15th and 30th minutes post-infusion through venous sampling. The levels equal to or above 3% will be regarded as clinically significant methemoglobinemia.
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 19 Nov 2025.
- BackgroundTazegul Gokhan, Kimyon Yusuf, Odabasi Zekaver. Ferric carboxymaltose induced methaemoglobinemia: Preliminary data of a novel side effect. 22nd European Congress of Internal Medicine , İstanbul, Turkey, 2024.
- BackgroundÖzbilen M, Savrun ŞT, Aygün A, Kaya Y. P1492: A New Potential And Prevalent Side Effect of Ferric Carboxymaltose: Methemoglobinemia. A Case-Control Study. Hemasphere. 2023 Aug 8;7(Suppl 3):e825173f.
- Background: PubMed 36779493Ozbilen M, Savrun ST, Aygun A, Kaya Y. Ferric Carboxymaltose-mediated Methemoglobinemia. Curr Drug Saf. 2024;19(1):134-137. doi: 10.2174/1574886318666230213111038.
- Individual participant dataSharing planned: Yes. Age, gender, hemoglobin, MCV, MCHC, ferritin, CRP, transferrin saturation, ferric carboxymaltose (FCM) drug dose, FCM infusion concentration, infusion duration, methemoglobin levels
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Muhammet Özbilen, MD study director
Ordu University Faculty of Medicine
Gökhan Tazegül, MD study director
Marmara University
Volkan Aydın, MD PhD study director
Marmara University School of Dentistry
23 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Methemoglobinemia and Anemia, Iron-Deficiency, run by Ordu University at 23 sites in Turkey (Türkiye).
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 7 inclusion and 8 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: finished, as of the sponsor's last update on 19 Nov 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 23 sites in Turkey (Türkiye). 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. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Number of Participants with Treatment-Related Clinically Significant Methemoglobinemia (time frame: From the time of enrollment through 30 minutes following completion of the infusion. If methemoglobin level is ≥3% after infusion, blood sampling will continue every half hour after the last blood gas for 24 hours until methemoglobinemia is <3%.). 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 NCT06958822, which also lists 3 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 19 Nov 2025.