Iron Deficiency Anaemia, Iron Deficiency Anemia
Conditions
Keywords
Iron Deficiency Anemia, Iron Deficiency Anaemia, IDA, Intravenous iron replacement therapy, Chronic Kidney Disease, CKD, Iron isomaltoside, Ferric derisomaltose, Monofer, Monoferric, Monover, Monofar, Monoferro
Brief summary
Evaluate safety and efficacy of intravenous (IV) iron isomaltoside/ferric derisomaltose re-dosing, in subjects who were previously treated with iron isomaltoside/ferric derisomaltose.
Detailed description
Among the various formulations of parenteral iron that are currently available, iron isomaltoside/ferric derisomaltose may allow flexibility in terms of high and rapid dosing. Up to now, most clinical trials with intravenous (IV) iron treatment were of 4-12 weeks in duration; longer trials are warranted to follow-up on long-term safety. The aim of the trial was to evaluate the safety and efficacy of IV iron isomaltoside/ferric derisomaltose re-dosing in subjects who were previously treated with iron isomaltoside/ferric derisomaltose in lead-in trials. This was a 6-months extension trial lasting 26 weeks. Eligible subjects attended 5 visits: screening, baseline (subjects treated with a single IV dose of 1000 mg iron isomaltoside/ferric derisomaltose), and follow-up visits at week 2, 13, and 26 weeks after the IV dose, for safety and efficacy assessments.
Interventions
Iron isomaltoside/ferric derisomaltose (Monofer®/Monoferric®; 100 mg/mL) was the test product in this trial. The dose of iron isomaltoside/ferric derisomaltose for the individual subject was set to 1000 mg. The dose was diluted in 100 mL 0.9 % sodium chloride from the site's supply and administered over approximately 20 minutes using IV infusion.
Sponsors
Pharmacosmos A/S
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Completed one of the lead-in trials 2. Randomised and dosed with iron isomaltoside/ferric derisomaltose in one of the lead-in trials. 3. Haemoglobin (Hb) of ≤ 11 g/dL 4. Screening serum ferritin (s-ferritin) ≤ 100 ng/mL, or ≤ 300 ng/mL if transferrin saturation (TSAT) ≤ 30 % 5. Willingness to participate and signing the informed consent form (ICF)
Exclusion criteria
1. Intravenous (IV) iron treatment between the lead-in trial and screening 2. During 30-day period prior to screening or during the trial period; has or will be treated with a red blood cell transfusion, radiotherapy, and/or chemotherapy 3. Received an investigational drug within 30 days of screening 4. Decompensated liver cirrhosis or active hepatitis 5. Pregnant or nursing women. 6. Any other laboratory abnormality, medical condition, or psychiatric disorders which, in the opinion of the Investigator, will put the subject's disease management at risk or may result in the subject being unable to comply with the trial requirements
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects With Adverse Drug Reactions (ADR) | Baseline to week 26 | Safety Evaluate the number of subjects with adverse drug reactions (ADRs), defined as AEs that were assessed by the investigator as related or possible related to the investigational product. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Composite Cardiovascular Adverse Events (AEs) | Baseline to week 26 | Safety Results show the composite cardiovascular AEs, that started on or after the first dose of treatment (i.e. treatment emergent) up to month 6. The reported potential cardiovascular AEs were adjudicated in a blinded fashion by an independent Clinical Endpoint Adjudication Committee (CEAC). The potential cardiovascular AEs included the following: * Death due to any cause * Non-fatal myocardial infarction * Non-fatal stroke * Unstable angina requiring hospitalisation * Congestive heart failure requiring hospitalisation or medical intervention * Arrhythmias * Hypertension * Hypotension Results show only those participants that had adjudicated and confirmed treatment-emergent composite cardiovascular AEs. |
| Time to First Composite Cardiovascular Safety AE | Baseline, week 2, 13, and 26 | Safety Time to first composite cardiovascular AE was defined as the actual time in days from first dose of treatment until the date of the composite cardiovascular AE. For subjects not reporting a composite cardiovascular AE, the time was censored at the date of the last attended visit. Only the adjudicated and confirmed composite cardiovascular safety AEs, as judged by the Clinical Endpoint Adjudication Committee (CEAC), were considered for this endpoint. Time to first composite cardiovascular AE was defined as the actual time in days from first dose of treatment until the date of the composite cardiovascular AE. For subjects not reporting a composite cardiovascular AE, the time was censored at the date of the last attended visit. |
| S-phosphate <2 mg/dL at Any Time From Baseline to Week 26 | Baseline to week 26 | Safety Results show the number of trial participants and their status of s-phosphate \<2 mg/dL, at any time from baseline to week 26. |
| Incidence of Protocol-defined Serious or Severe Hypersensitivity Reactions | Baseline to week 26 | Safety. For this endpoint, the number of participants with serious or severe hypersensitivity reactions were evaluated. The hypersensitivity terms that were included in the analysis were those that started or after the first dose of treatment (i.e. treatment emergent). The terms used to define hypersensitivity were those specified by the Standardised MedDRA Queries (SMQ) for hypersensitivity, plus four additional terms: Loss of consciousness; Seizure; Syncope; Unresponsiveness. The potential hypersensitivity AEs were adjudicated in a blinded fashion by an independent Clinical Endpoint Adjudication Committee (CEAC). Results show only those participants that had adjudicated and confirmed serious or severe hypersensitivity reactions. |
| Change in S-ferritin From Baseline to Week 2, 13, and 26 | Baseline, week 2, 13, and 26 | Efficacy. Change in s-ferritin from baseline to week 2, 13, and 26. |
| Change in Transferrin Saturation (TSAT) From Baseline to Week 2, 13, and 26 | Baseline, week 2, 13, and 26 | Efficacy Change in transferrin saturation (TSAT) from baseline to week 2, 13, and 26. TSAT is the value of serum iron divided by the total iron-binding capacity and the unit is %, which referrers to % of iron-binding sites of transferrin being occupied by iron. |
| Change in S-iron From Baseline to Week 2, 13, and 26 | Baseline, week 2, 13, and 26 | Efficacy. Change in s-iron from baseline to week 2, 13, and 26. |
| Change in Hb From Baseline to Week 2, 13, and 26 | Baseline, week 2, 13, and 26 | Efficacy. Change in Hb from baseline to week 2, 13, and 26. |
Countries
United States
Participant flow
Recruitment details
A total of 193 subjects were screened and 103 subjects were enrolled into the trial.
Pre-assignment details
Subjects enrolled in this extension trial had previously participated in the lead-in trials IDA-03 (52%, NCT02940886), CKD-04 (32%, NCT02940860), and IDA-01 (16%, NCT02130063).
Participants by arm
| Arm | Count |
|---|---|
| Iron Isomaltoside/Ferric Derisomaltose Iron isomaltoside/ferric derisomaltose, administered IV | 103 |
| Total | 103 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Lost to Follow-up | 3 |
| Overall Study | Physician Decision | 1 |
| Overall Study | Subject had problems with transportation | 2 |
| Overall Study | Withdrawal by Subject | 3 |
Baseline characteristics
| Characteristic | Iron Isomaltoside/Ferric Derisomaltose |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 21 Participants |
| Age, Categorical Between 18 and 65 years | 82 Participants |
| Age, Continuous | 49.9 years STANDARD_DEVIATION 15.7 |
| Age, Customized 18-64 years | 82 Participants |
| Age, Customized 65-84 years | 18 Participants |
| Age, Customized >84 years | 3 Participants |
| Current smoker No | 95 Participants |
| Current smoker Yes | 8 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 46 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 57 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 41 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 60 Participants |
| Region of Enrollment United States | 103 participants |
| Sex: Female, Male Female | 87 Participants |
| Sex: Female, Male Male | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 193 |
| other Total, other adverse events | 17 / 102 |
| serious Total, serious adverse events | 13 / 102 |
Outcome results
Primary
Number of Subjects With Adverse Drug Reactions (ADR)
Safety Evaluate the number of subjects with adverse drug reactions (ADRs), defined as AEs that were assessed by the investigator as related or possible related to the investigational product.
Time frame: Baseline to week 26
Population: Safety analysis set: included all subjects who received at least one dose of the investigational product.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Iron Isomaltoside/Ferric Derisomaltose | Number of Subjects With Adverse Drug Reactions (ADR) | 5 Participants |
Secondary
Change in Hb From Baseline to Week 2, 13, and 26
Efficacy. Change in Hb from baseline to week 2, 13, and 26.
Time frame: Baseline, week 2, 13, and 26
Population: Intention-to-treat (ITT) analysis set: included all subjects, except for screening failures and subjects withdrawn before visit 2 (baseline).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Iron Isomaltoside/Ferric Derisomaltose | Change in Hb From Baseline to Week 2, 13, and 26 | Week 2 | 1.23 g/dL | Standard Deviation 1.4 |
| Iron Isomaltoside/Ferric Derisomaltose | Change in Hb From Baseline to Week 2, 13, and 26 | Week 13 | 1.73 g/dL | Standard Deviation 1.83 |
| Iron Isomaltoside/Ferric Derisomaltose | Change in Hb From Baseline to Week 2, 13, and 26 | Week 26 | 1.34 g/dL | Standard Deviation 1.93 |
Secondary
Change in S-ferritin From Baseline to Week 2, 13, and 26
Efficacy. Change in s-ferritin from baseline to week 2, 13, and 26.
Time frame: Baseline, week 2, 13, and 26
Population: Intention-to-treat (ITT) analysis set: included all subjects, except for screening failures and subjects withdrawn before visit 2 (baseline).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Iron Isomaltoside/Ferric Derisomaltose | Change in S-ferritin From Baseline to Week 2, 13, and 26 | Week 2 | 255.6 ng/mL | Standard Deviation 177.9 |
| Iron Isomaltoside/Ferric Derisomaltose | Change in S-ferritin From Baseline to Week 2, 13, and 26 | Week 13 | 87.9 ng/mL | Standard Deviation 123.6 |
| Iron Isomaltoside/Ferric Derisomaltose | Change in S-ferritin From Baseline to Week 2, 13, and 26 | Week 26 | 93.9 ng/mL | Standard Deviation 180.4 |
Secondary
Change in S-iron From Baseline to Week 2, 13, and 26
Efficacy. Change in s-iron from baseline to week 2, 13, and 26.
Time frame: Baseline, week 2, 13, and 26
Population: Intention-to-treat (ITT) analysis set: included all subjects, except for screening failures and subjects withdrawn before visit 2 (baseline).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Iron Isomaltoside/Ferric Derisomaltose | Change in S-iron From Baseline to Week 2, 13, and 26 | Week 2 | 21.1 μg/dL | Standard Deviation 50.5 |
| Iron Isomaltoside/Ferric Derisomaltose | Change in S-iron From Baseline to Week 2, 13, and 26 | Week 13 | 10.7 μg/dL | Standard Deviation 45.4 |
| Iron Isomaltoside/Ferric Derisomaltose | Change in S-iron From Baseline to Week 2, 13, and 26 | Week 26 | 4.0 μg/dL | Standard Deviation 44.1 |
Secondary
Change in Transferrin Saturation (TSAT) From Baseline to Week 2, 13, and 26
Efficacy Change in transferrin saturation (TSAT) from baseline to week 2, 13, and 26. TSAT is the value of serum iron divided by the total iron-binding capacity and the unit is %, which referrers to % of iron-binding sites of transferrin being occupied by iron.
Time frame: Baseline, week 2, 13, and 26
Population: Intention-to-treat (ITT) analysis set: included all subjects, except for screening failures and subjects withdrawn before visit 2 (baseline).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Iron Isomaltoside/Ferric Derisomaltose | Change in Transferrin Saturation (TSAT) From Baseline to Week 2, 13, and 26 | Week 2 | 8.16 percentage of saturation | Standard Deviation 11.87 |
| Iron Isomaltoside/Ferric Derisomaltose | Change in Transferrin Saturation (TSAT) From Baseline to Week 2, 13, and 26 | Week 13 | 4.42 percentage of saturation | Standard Deviation 10.81 |
| Iron Isomaltoside/Ferric Derisomaltose | Change in Transferrin Saturation (TSAT) From Baseline to Week 2, 13, and 26 | Week 26 | 1.78 percentage of saturation | Standard Deviation 10.63 |
Secondary
Composite Cardiovascular Adverse Events (AEs)
Safety Results show the composite cardiovascular AEs, that started on or after the first dose of treatment (i.e. treatment emergent) up to month 6. The reported potential cardiovascular AEs were adjudicated in a blinded fashion by an independent Clinical Endpoint Adjudication Committee (CEAC). The potential cardiovascular AEs included the following: * Death due to any cause * Non-fatal myocardial infarction * Non-fatal stroke * Unstable angina requiring hospitalisation * Congestive heart failure requiring hospitalisation or medical intervention * Arrhythmias * Hypertension * Hypotension Results show only those participants that had adjudicated and confirmed treatment-emergent composite cardiovascular AEs.
Time frame: Baseline to week 26
Population: Safety analysis set: included all subjects who received at least one dose of the investigational product.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Iron Isomaltoside/Ferric Derisomaltose | Composite Cardiovascular Adverse Events (AEs) | 6 Participants |
Secondary
Incidence of Protocol-defined Serious or Severe Hypersensitivity Reactions
Safety. For this endpoint, the number of participants with serious or severe hypersensitivity reactions were evaluated. The hypersensitivity terms that were included in the analysis were those that started or after the first dose of treatment (i.e. treatment emergent). The terms used to define hypersensitivity were those specified by the Standardised MedDRA Queries (SMQ) for hypersensitivity, plus four additional terms: Loss of consciousness; Seizure; Syncope; Unresponsiveness. The potential hypersensitivity AEs were adjudicated in a blinded fashion by an independent Clinical Endpoint Adjudication Committee (CEAC). Results show only those participants that had adjudicated and confirmed serious or severe hypersensitivity reactions.
Time frame: Baseline to week 26
Population: Safety analysis set: included all subjects who received at least one dose of the investigational product.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Iron Isomaltoside/Ferric Derisomaltose | Incidence of Protocol-defined Serious or Severe Hypersensitivity Reactions | 0 Participants |
Secondary
S-phosphate <2 mg/dL at Any Time From Baseline to Week 26
Safety Results show the number of trial participants and their status of s-phosphate \<2 mg/dL, at any time from baseline to week 26.
Time frame: Baseline to week 26
Population: Safety analysis set: included all subjects who received at least one dose of the investigational product.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Iron Isomaltoside/Ferric Derisomaltose | S-phosphate <2 mg/dL at Any Time From Baseline to Week 26 | Yes | 8 Participants |
| Iron Isomaltoside/Ferric Derisomaltose | S-phosphate <2 mg/dL at Any Time From Baseline to Week 26 | No | 94 Participants |
Secondary
Time to First Composite Cardiovascular Safety AE
Safety Time to first composite cardiovascular AE was defined as the actual time in days from first dose of treatment until the date of the composite cardiovascular AE. For subjects not reporting a composite cardiovascular AE, the time was censored at the date of the last attended visit. Only the adjudicated and confirmed composite cardiovascular safety AEs, as judged by the Clinical Endpoint Adjudication Committee (CEAC), were considered for this endpoint. Time to first composite cardiovascular AE was defined as the actual time in days from first dose of treatment until the date of the composite cardiovascular AE. For subjects not reporting a composite cardiovascular AE, the time was censored at the date of the last attended visit.
Time frame: Baseline, week 2, 13, and 26
Population: Safety analysis set: included all subjects who received at least one dose of the investigational product.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Iron Isomaltoside/Ferric Derisomaltose | Time to First Composite Cardiovascular Safety AE | NA week |