Clinical trial NCT06958822: Ferric Carboxymaltose Methemoglobinemia Study
Official title: Estimation of the Incidence of Methemoglobinemia Associated With Ferric Carboxymaltose Administration
Study type: OBSERVATIONAL
Overall status: ENROLLING_BY_INVITATION
Conditions: Methemoglobinemia
Anemia, Iron-Deficiency
Parenteral Iron Therapy
Ferric Carboxymaltose
Keywords: iron deficiency anemia
ferric carboxymaltose
intravenous iron
methemoglobinemia
Lead sponsor: T.C. ORDU ÜNİVERSİTESİ
Sponsor class: OTHER
Collaborators: name: Marmara University Pendik Training and Research Hospital
First posted: 2025-05-06
Enrollment: 900
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
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.

Brief 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. 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 June 30, 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.

Eligibility criteria: INCLUSION CRITERIA:

FCM Group:

1. Adults (≥18 years)
2. Presence of anemia (Hb \<12 g/dl in women, \<13 g/dl in men)
3. Low ferritin (\<30 mcg/l)
4. 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).

EXCLUSION CRITERIA:

1. Known methemoglobinemia-related diseases (Hb M disease, cytochrome b5 reductase deficiency, etc.)
2. Use of drugs associated with methemoglobinemia (acetylsalicylic acid, dapsone, chloroquine, metoclopramide, benzocaine, lidocaine, prilocaine, rasburicase, primaquine, sulfonamide, nitric oxide)
3. Those with B12 and/or folate deficiency
4. Those with Charlson Comorbidity Index ≥3
5. 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)
6. Presence of malignancy (with or without cure)
7. Presence of active infection (CRP \> 5 mg/dL) and/or other acute disorder/disease
8. Pregnancy status

Primary outcomes:
measure: Number of Participants with Treatment-Related Clinically Significant Methemoglobinemia
timeFrame: 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%.
Secondary outcomes:
Other outcomes:
Locations:
city: Konyaaltı
country: Turkey
facility: Akdeniz University Hospital
state: Antalya
city: Merkez
country: Turkey
facility: Balıkesir University Health Practice and Research Hospital
state: Balıkesir
city: Nilüfer
country: Turkey
facility: Bursa City Hospital
state: Bursa
city: Kayapınar
country: Turkey
facility: University of Health Sciences Diyarbakır Gazi Yaşargil Training and Research Hospital
state: Diyarbakır
city: Merkez
country: Turkey
facility: Erzincan Binali Yıldırım University Training and Research Hospital
state: Erzincan
city: Ataşehir
country: Turkey
facility: Mehmet Yılmaz Aydınlar Acıbadem University
state: İstanbul
city: Pendik
country: Turkey
facility: Marmara University Training and Research Hospital
state: İstanbul
city: Ümraniye
country: Turkey
facility: Umraniye Training and Research Hospital
state: İstanbul
city: Çiğli
country: Turkey
facility: Izmir Bakircay University Cigli Training and Research Hospital
state: İzmir
city: Kocasinan
country: Turkey
facility: Kayseri City Hospital
state: Kayseri
city: İzmit
country: Turkey
facility: Kocaeli City Hospital
state: Kocaeli
city: Merkez
country: Turkey
facility: Mardin Artuklu University Training and Research Hospital
state: Mardin
city: Altınordu
country: Turkey
facility: Ordu University Training and Research Hospital
state: Ordu
city: Adapazarı
country: Turkey
facility: Sakarya University Training and Research Hospital
state: Sakarya
city: Merkez
country: Turkey
facility: Van Yüzüncü Yıl University Training and Research Hospital
state: Van
city: Adana
country: Turkey
facility: University of Health Sciences Adana City Health Application and Research Center
city: Afyon
country: Turkey
facility: Afyonkarahisar University of Health Sciences Health Application and Research Center
city: Karabük
country: Turkey
facility: Karabuk University Training and Research Hospital
city: Rize
country: Turkey
facility: Recep Tayyip Erdoğan University Faculty of Medicine Training and Research Hospital
city: Siirt
country: Turkey
facility: Siirt University Faculty of Medicine Training and Research Hospital
city: Çankırı
country: Turkey
facility: Çankırı State Hospital
Study officials:
affiliation: Ordu University Faculty of Medicine
name: Muhammet Özbilen, MD
role: STUDY_DIRECTOR
affiliation: Marmara University
name: Gökhan Tazegül, MD
role: STUDY_DIRECTOR
affiliation: Marmara University School of Dentistry
name: Volkan Aydın, MD PhD
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: Ozbilen M, Savrun ST, Aygun A, Kaya Y. Ferric Carboxymaltose-mediated Methemoglobinemia. Curr Drug Saf. 2024;19(1):134-137. doi: 10.2174/1574886318666230213111038.