Anemia, Iron-deficiency
Conditions
Keywords
Anemia, Iron-Deficiency
Brief summary
The objective of the study is to compare the safety and gastrointestinal tolerability of ferric maltol oral suspension and ferrous sulfate oral liquid in children and adolescents aged 2 years to 17 years, and assess the safety and tolerability of ferric maltol oral suspension in children 1 month to less than 2 years, in the treatment of iron deficiency anaemia during the 12 weeks treatment period.
Detailed description
The study is a randomised, Open-label, Active-controlled, Multicentre, Comparative Study to Evaluate the Safety and Efficacy of Ferric Maltol (Iron (III)-Maltol Complex) (ST10) Oral Suspension Compared to Ferrous Sulfate Oral Liquid in Children and Adolescents Aged 2 to 17 Years With Iron-deficiency Anaemia, Incorporating a Single Arm Study in Infants Aged 1 Month to Less Than 2 Years. Approximately 110 male and female children from 1 month to 17 years of age, with iron deficiency anaemia. If less than 91 subjects in total have been randomized when 32 ferric maltol subjects have completed, then an interim analysis will be conducted. Subjects aged 2 to 17 years will be 1:1 randomised to ferric maltol and ferrous sulfate, with 49 subjects in each arm. Subjects then will be further divided into 2 age groups: 2 yrs - 9 yrs and 10 yrs -17 yrs. A minimum of 18 subjects must be recruited into the 2 yrs - 9 yrs and 10 yrs - 17 yrs age groups and a minimum of 25% of either sex must be recruited. A maximum of 12 subjects will be recruited in the 1 month to less than 2 years age group. They will only be assigned to the ferric maltol group, once there is evidence of absorption, of serum iron and elimination of maltol from the Pre-assignment PK samples by showing urine maltol return to baseline, or to a low level, confirming no accumulation of maltol or maltol glucuronide, they will continue on to the 12 weeks treatment phase. Design: The study will comprise of the following stages: * Screening: within 14 days prior to randomisation for each subject * Pre-assignment PK phase: only applicable for subjects aged 1 month to less than 2 years. Up to 21 days from Screening. * Randomised treatment: 12 weeks open label treatment * Assigned treatment phase 12 weeks open label treatment for ferric maltol children aged 1 month to less than 2 years * End of study: Week 12 visit * Post-treatment safety follow-up: 10-14 days following study completion of the treatment period or premature discontinuation Investigational Product Product: Ferric maltol oral suspension: oral suspension containing 30 mg elemental iron, in the form of 231.5 mg ferric maltol, in 5 ml suspension. Ferric maltol oral suspension will be taken every morning and evening at least 30 minutes after a meal. Dosing will be supervised by the parent/legal guardian for children/adolescents throughout the treatment period and recorded on a dosing diary. Ferric maltol bottles will be labelled for clinical trials use and each bottle will have a unique bottle number which will be utilised in the randomisation procedure. A final eligibility evaluation must be conducted immediately prior to randomisation. Reference safety information will be the Investigator Brochure. Comparator therapy: Ferrous sulfate 125 mg/ml (25 mg/ml elemental iron) oral liquid or equivalent dose will be administered under this protocol. Dosing will be supervised by the parent/legal guardian for children/adolescents throughout the treatment period and recorded on a dosing diary. Reference safety information will be the currently approved summary of product characteristics. Statistical methods: Safety and gastrointestinal tolerability will be compared between ferric maltol oral suspension and ferrous sulfate oral liquid via summaries of treatment emergent adverse events (TEAEs), treatment emergent serious AEs (TESAEs) and treatment-emergent AEs (TEAEs) leading to premature discontinuation of study drug. Efficacy of ferric maltol will be assessed via the change in Hb concentration from baseline to week 12. If no interim analysis is conducted it will be based on a 95% two-sided confidence interval; If an interim analysis is conducted, a Pocock spending function will be used; the interim analysis will be based on a (100 - 3.45)% two sided confidence interval; if the study does not stop after the interim analysis, the final analysis will be based on a (100 - 2.57)% two sided confidence interval. For the PK analysis, all analytes in serum will be summarised per PK day, for children and adolescents aged 1 month to 17 years receiving ferric maltol. In addition, all analytes in urine will be summarised per PK day, for children aged 1 month to less than 2 years. Full details of the statistical analysis, including the analysis of PK endpoints, will be specified in the statistical analysis plan (SAP).
Interventions
DRUGFerric Maltol
Ferric maltol oral suspension: 150 ml amber glass bottle with graduated syringe and adaptor. Oral suspension containing 30 mg elemental iron, in the form of 231.5 mg ferric maltol, in 5 ml suspension Study dosage: The dose of ferric maltol oral suspension that will be administered for children aged 1 month to \< 2 yrs: 0.1 ml/kg BID, 2 to - 11 yrs: 2.5 ml BID, 12-17 yrs: 5 ml BID.
DRUGFerrous sulfate
Ferrous sulfate 125 mg/ml (25 mg/ml elemental iron) oral liquid : 15 ml glass bottle. Study dosage: For ferrous sulfate oral liquid, the dose administered will be for children and adolescents aged 2 years to 17 yrs: 6 mg/kg to the maximum of 4 ml BID.
Sponsors
Shield Therapeutics
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Masking description
12 weeks open label treatment
Intervention model description
The study will include 98 subjects in the 2 - 17 years age group, randomised 1:1 between ferric maltol and ferrous sulfate: 49 in each treatment group. The study will also include up to 12 subjects in the 1 month to less than 2 years age group. If less than 91 subjects in total have been randomized when 32 ferric maltol subjects have completed, then an interim analysis will be conducted. If significant, the study will stop recruitment. If not significant, the study will continue until 54 subjects have been recruited in the ferric maltol arm.
Eligibility
Sex/Gender
ALL
Age
1 Months to 17 Years
Healthy volunteers
No
Inclusion criteria
1. Patient is willing and able to comply with the study requirements and to provide written informed consent. In the case of patients under the age of legal consent, the legal guardian(s) must provide informed consent and the patient should provide assent per local and national requirements. 2. Age ≥1 month and ≤17 years at the time of informed consent 3. Subjects must have iron deficiency anaemia defined by the following criteria, as measured by the central laboratory at the screening visit Haemoglobin thresholds define anaemia by age and gender: Children (1 m - \< 5 yrs) \<11.0 g/dl Children (5 yrs - \< 12 yrs) \<11.5 g/dl Children (12 yrs) \<12.0 g/dl Female child (≥13 yrs) \<12.0 g/dl Male child (≥13 yrs) \<13.0 g/dl and Ferritin thresholds define anaemia by: ferritin \<30 µg/L, or ferritin \<50 µg/L with transferrin saturation (TSAT) \<20%, 4. Female subjects of childbearing potential must agree to use a highly effective method of contraception (which includes complete abstinence) until study completion and for at least 4 weeks following their final study visit. Highly effective contraception is defined as a method which results in a low failure rate, i.e., less than 1% per year when used consistently and correctly, such as implants, injectables, some intrauterine contraceptive devices (IUDs), a vasectomised partner and oral contraceptive medications. The need for contraception and compliance with contraception requirements will be assessed at every visit for adolescent patients, and urine pregnancy testing will be performed at each visit for female subjects of childbearing potential.
Exclusion criteria
1. Subject with anaemia due to any cause other than iron deficiency, including, but not limited to, a. Untreated or untreatable severe malabsorption syndrome 2. Subjects who have received prior to Screening: 1. Within 28 days intramuscular or intravenous (IV) injection or administration of depot iron preparation. 2. Within 7 days single agent iron preparations and during the study. 3. Within 12 weeks of blood transfusion or is scheduled to have blood transfusion or donation during the study period 4. Within 28 days erythropoiesis stimulating agents and during the study period 5. Within 14 days COVID-19 vaccination 3. Subjects with vitamin B12 or folic acid deficiency as determined by the central laboratory screening results. Subjects may start vitamin B12 or folate replacement and rescreen after at least 2 weeks. 4. Has concomitant disease that would significantly compromise iron absorption or absorbed iron utilization such as swallowing disorders and/or extensive small bowel resection. 5. History of active peptic ulcer 6. Has chronic renal disease (eGFR \<60 mL/min/m2), as assessed at Screening based on serum creatinine. 7. Known hypersensitivity or allergy to either the active substance or excipients of ferric maltol or ferrous sulfate. 8. Has a known contraindication for treatment with iron preparations, e.g. haemochromatosis, chronic haemolytic disease, sideroblastic anaemia, thalassemia, or lead intoxication induced anaemia. 9. Impaired liver function as indicated by alanine aminotransferase (ALT) or aspartate transaminase (AST)\>2.0 times upper normal limit as measured at the Screening visit. 10. Active acute inflammatory disease, including IBD flare or disease exacerbation, which in the opinion of the Investigator, is clinically significant. 11. Active chronic or acute infectious diseases requiring antibiotic treatment. 12. Pregnant or breast feeding. 13. Concomitant medical conditions with extensive active bleeding, other than menstrual cycles; subjects who suffer from menorrhagia may be included at the Investigator's discretion. 14. Scheduled or expected hospitalisation and/or surgery during the course of the study 15. Participation in any other interventional clinical study within 28 days prior to Screening. 16. Diagnosed to be COVID-19 positive by (SARS-CoV-2-RT-PCR positive) within 28 days prior to screening. 17. Cardiovascular, liver, renal, hematologic, psychiatric, neurologic, gastrointestinal, immunologic, endocrine, metabolic, respiratory or central nervous system disease that, in the opinion of the Investigator, may adversely affect the safety of the subject and/or objectives of the study drug or severely limit the lifespan of the subject. 18. Any other unspecified reason that, in the opinion of the Investigator or the Sponsor make the subject unsuitable for enrolment.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Hemoglobin Concentration | From baseline to week 12. | The change in Hb concentration from baseline to Week 12 is summarized based on the mITT Population for each treatment group using descriptive statistics summarized by mean, standard deviation, median, and range (minimum and maximum). The Randomized/ITT Population is defined as all patients who were randomized/assigned to treatment arms. The mITT Population is defined as all patients in the ITT Population who received at least 1 treatment dose. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Iron Concentration | From baseline to week 12. | Change in iron concentration from baseline to week 12 summarized based on the mITT Population for each treatment group. The Randomized/ITT Population is defined as all patients who were randomized/assigned to treatment arms. The mITT Population is defined as all patients in the ITT Population who received at least 1 treatment dose. |
| Change in the Percentage of Transferrin Saturation | From baseline to week 12. | Change from baseline to Day 84 summarized based on the mITT Population for each treatment group. The Randomized/ITT Population is defined as all patients who were randomized/assigned to treatment arms. The mITT Population is defined as all patients in the ITT Population who received at least 1 treatment dose. |
| Cmax for Plasma Maltol Glucuronide | PK parameters assessed at Day 1 (Visit 2) and Day 7-10 (Visit 3). | Measured maximum plasma concentration (Cmax) (ng/mL) for plasma maltol glucuronide after a single dose of ferric maltol oral suspension on Visit 2 (PK Day 1) and after twice daily administrations for at least 6 days, on Visit 3 (PK Day 2) after a single morning dose. Because of the limitations of PK sampling in the pediatric patient population, data from multiple patients in the same treatment and age group had to be combined, using the naïve pooled approach, to achieve a complete set of observations over time for PK analysis. The data did not support PK parameters generation using noncompartmental analysis (NCA) without combining patients. Using validated PK software WinNonlin, the 'sparse sampling' option was utilized to treat the data as one virtual subject and thus the resulting data did not support reliable error estimates of the PK parameters. |
| Tmax for Plasma Maltol Glucuronide | PK parameters assessed at Day 1 (Visit 2) and Day 7-10 (Visit 3). | Time to maximum plasma concentration (Tmax) (h) for plasma maltol glucuronide after a single dose of ferric maltol oral suspension on Visit 2 (PK Day 1) and after twice daily administrations for at least 6 days, on Visit 3 (PK Day 2) after a single morning dose. Because of the limitations of PK sampling in the pediatric patient population, data from multiple patients in the same treatment and age group had to be combined, using the naïve pooled approach, to achieve a complete set of observations over time for PK analysis. The data did not support PK parameters generation using noncompartmental analysis (NCA) without combining patients. Using validated PK software WinNonlin, the 'sparse sampling' option was utilized to treat the data as one virtual subject and thus the resulting data did not support reliable error estimates of the PK parameters. |
| Changes in Ferritin Concentration | From baseline to week 12. | Changes in ferritin concentration from baseline to week 12 summarised based on the mITT Population for each treatment group. The Randomized/ITT Population is defined as all patients who were randomized/assigned to treatment arms. The mITT Population is defined as all patients in the ITT Population who received at least 1 treatment dose. |
| Cmax for Baseline Corrected Serum Iron | PK parameters assessed at Day 1 (Visit 2) and Day 7-10 (Visit 3). | Measured maximum plasma concentration (Cmax) (μg/dL) for baseline corrected serum iron after a single dose of ferric maltol oral suspension on Visit 2 (PK Day 1) and after twice daily administrations for at least 6 days, on Visit 3 (PK Day 2) after a single morning dose. Because of the limitations of PK sampling in the pediatric patient population, data from multiple patients in the same treatment and age group had to be combined, using the naïve pooled approach, to achieve a complete set of observations over time for PK analysis. The data did not support PK parameters generation using noncompartmental analysis (NCA) without combining patients. Using validated PK software WinNonlin, the 'sparse sampling' option was utilized to treat the data as one virtual subject and thus the resulting data did not support reliable error estimates of the PK parameters. |
| Tmax for Baseline Corrected Serum Iron | PK parameters assessed at Day 1 (Visit 2) and Day 7-10 (Visit 3). | Time to maximum plasma concentration (Tmax) (h) for baseline corrected serum iron after a single dose of ferric maltol oral suspension on Visit 2 (PK Day 1) and after twice daily administrations for at least 6 days, on Visit 3 (PK Day 2) after a single morning dose. Because of the limitations of PK sampling in the pediatric patient population, data from multiple patients in the same treatment and age group had to be combined, using the naïve pooled approach, to achieve a complete set of observations over time for PK analysis. The data did not support PK parameters generation using noncompartmental analysis (NCA) without combining patients. Using validated PK software WinNonlin, the 'sparse sampling' option was utilized to treat the data as one virtual subject and thus the resulting data did not support reliable error estimates of the PK parameters. |
| AUC0-t for Baseline Corrected Serum Iron | PK parameters assessed at Day 1 (Visit 2) and Day 7-10 (Visit 3). | Area under the plasma concentration-time curve from pre-dose (time 0) to the time of last quantifiable plasma concentration for baseline corrected serum iron (AUC0-t) (hxng/mL) after a single dose of ferric maltol oral suspension on Visit 2 (PK Day 1) and after twice daily administrations for at least 6 days, on Visit 3 (PK Day 2) after a single morning dose. Because of the limitations of PK sampling in the pediatric patient population, data from multiple patients in the same treatment and age group had to be combined, using the naïve pooled approach, to achieve a complete set of observations over time for PK analysis. The data did not support PK parameters generation using noncompartmental analysis (NCA) without combining patients. Using validated PK software WinNonlin, the 'sparse sampling' option was utilized to treat the data as one virtual subject and thus the resulting data did not support reliable error estimates of the PK parameters. |
| AUC0-t for Plasma Maltol Glucuronide | PK parameters assessed at Day 1 (Visit 2) and Day 7-10 (Visit 3). | Area under the plasma concentration-time curve from pre-dose (time 0) to the time of last quantifiable plasma concentration for plasma maltol glucuronide (AUC0-t) (hxng/mL) after a single dose of ferric maltol oral suspension on Visit 2 (PK Day 1) and after twice daily administrations for at least 6 days, on Visit 3 (PK Day 2) after a single morning dose. Because of the limitations of PK sampling in the pediatric patient population, data from multiple patients in the same treatment and age group had to be combined, using the naïve pooled approach, to achieve a complete set of observations over time for PK analysis. The data did not support PK parameters generation using noncompartmental analysis (NCA) without combining patients. Using validated PK software WinNonlin, the 'sparse sampling' option was utilized to treat the data as one virtual subject and thus the resulting data did not support reliable error estimates of the PK parameters. |
Countries
Puerto Rico, United Kingdom, United States
Participant flow
Recruitment details
This was a multicenter study with a total of 23 clinical sites located in the United States(including Puerto Rico) and United Kingdom. A total of 65 patients were enrolled in the study.
Pre-assignment details
All eligible subjects aged 1 month to less than 2 years entered a Pre-assignment phase, 1-day Pharmacokinetic assessment day following a single dose of ferric maltol oral suspension.
Participants by arm
| Arm | Count |
|---|---|
| Ferric Maltol Assigned 12 weeks open-label Treatment Period for ferric maltol children aged 1 month to \<2 years | 4 |
| Ferric Maltol Randomized Subjects aged 2-17 will be randomised 1:1 to receive ferric maltol oral suspension or ferrous sulfate oral liquid.
The first 12 subjects randomised to ferric maltol in each age sub-group (2 - 9 yrs, 10 - 17 yrs respectively) will enter a PK phase with 2 PK days.
Following PK Day 2 subjects will continue until Week 12. Once the 18 subjects in each age subgroup have finished their PK visits, they will continue until week 12.
Ferrous sulfate 125 mg/ml (25 mg elemental iron) or equivalent dose was used for all children/adolescents. To maximise the iron replenishment for subjects within this group as well; aged 2
\- 17 yrs were dosed 6 mg/kg to the maximum of 4 ml BID. | 31 |
| Ferrous Sulfate Randomized Patients aged 2 to 17 years were randomized 1:1 to receive ferric maltol oral suspension or ferrous sulfate oral liquid. | 30 |
| Total | 65 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 1 |
| Overall Study | Lost to Follow-up | 0 | 2 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 1 | 4 |
Baseline characteristics
| Characteristic | Ferric Maltol Assigned | Total | Ferrous Sulfate Randomized | Ferric Maltol Randomized |
|---|---|---|---|---|
| Age, Customized 85 years and over | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized Adolescents (12-17 years) | 0 Participants | 40 Participants | 19 Participants | 21 Participants |
| Age, Customized Adults (18-64 years) | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized Children (2-11 years) | 0 Participants | 21 Participants | 11 Participants | 10 Participants |
| Age, Customized From 65-84 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized Infants and toddlers (28 days-23 months) | 4 Participants | 4 Participants | 0 Participants | 0 Participants |
| Age, Customized Newborns (0-27 days) | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized Preterm newborn infants (gestational age < 37 wks) | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 27 Participants | 12 Participants | 13 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 1 Participants | 37 Participants | 18 Participants | 18 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 7 Participants | 3 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 20 Participants | 11 Participants | 9 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 3 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 1 Participants | 35 Participants | 16 Participants | 18 Participants |
| Sex: Female, Male Female | 3 Participants | 48 Participants | 22 Participants | 23 Participants |
| Sex: Female, Male Male | 1 Participants | 17 Participants | 8 Participants | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 0 / 31 | 0 / 30 |
| other Total, other adverse events | 2 / 3 | 4 / 31 | 3 / 30 |
| serious Total, serious adverse events | 1 / 3 | 0 / 31 | 0 / 30 |
Outcome results
Primary
Change in Hemoglobin Concentration
The change in Hb concentration from baseline to Week 12 is summarized based on the mITT Population for each treatment group using descriptive statistics summarized by mean, standard deviation, median, and range (minimum and maximum). The Randomized/ITT Population is defined as all patients who were randomized/assigned to treatment arms. The mITT Population is defined as all patients in the ITT Population who received at least 1 treatment dose.
Time frame: From baseline to week 12.
Population: All patients that finalized Day 84 measurement were reported and analyzed. All patients with a missing Day 84 measurement were imputed using a last observation carried forward approach in which the last available post-baseline measurement was used. Post-baseline measurement was missing in 5 patients in the 2. group (mITT Ferric Maltol) , and 6 patients in the 3. group (mITT Ferrous Sulfate).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| mITT Ferric Maltol Assigned | Change in Hemoglobin Concentration | 17.7 g/L | Standard Deviation 13.61 |
| mITT Ferric Maltol | Change in Hemoglobin Concentration | 12.5 g/L | Standard Deviation 13.89 |
| mITT Ferrous Sulfate | Change in Hemoglobin Concentration | 11.5 g/L | Standard Deviation 13.97 |
Secondary
AUC0-t for Baseline Corrected Serum Iron
Area under the plasma concentration-time curve from pre-dose (time 0) to the time of last quantifiable plasma concentration for baseline corrected serum iron (AUC0-t) (hxng/mL) after a single dose of ferric maltol oral suspension on Visit 2 (PK Day 1) and after twice daily administrations for at least 6 days, on Visit 3 (PK Day 2) after a single morning dose. Because of the limitations of PK sampling in the pediatric patient population, data from multiple patients in the same treatment and age group had to be combined, using the naïve pooled approach, to achieve a complete set of observations over time for PK analysis. The data did not support PK parameters generation using noncompartmental analysis (NCA) without combining patients. Using validated PK software WinNonlin, the 'sparse sampling' option was utilized to treat the data as one virtual subject and thus the resulting data did not support reliable error estimates of the PK parameters.
Time frame: PK parameters assessed at Day 1 (Visit 2) and Day 7-10 (Visit 3).
Population: A total of 20 patients in the ferric maltol group were included in the PK Population. Of these patients, there were 7 patients (3 female patients and 4 male patients) who were 2 to 9 years of age, 3 patients (all female patients) who were 10 to 17 years of age and who received 15 mg BID of ferric maltol, and 10 patients (9 female patients and 1 male patient) who were 10 to 17 years of age and who received 30 mg BID of ferric maltol.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| mITT Ferric Maltol Assigned | AUC0-t for Baseline Corrected Serum Iron | 64.4 hxμg/dL |
| mITT Ferric Maltol | AUC0-t for Baseline Corrected Serum Iron | 60.1 hxμg/dL |
| mITT Ferrous Sulfate | AUC0-t for Baseline Corrected Serum Iron | 374 hxμg/dL |
| PK Population Ferric Maltol 15mg (2-9 y) Day 7-10 | AUC0-t for Baseline Corrected Serum Iron | 100 hxμg/dL |
| PK Population Ferric Maltol 15mg (10-17 y) Day 7-10 | AUC0-t for Baseline Corrected Serum Iron | 1.93 hxμg/dL |
| PK Population Ferric Maltol 30mg (10-17 y) Day 7-10 | AUC0-t for Baseline Corrected Serum Iron | 1180 hxμg/dL |
Secondary
AUC0-t for Plasma Maltol Glucuronide
Area under the plasma concentration-time curve from pre-dose (time 0) to the time of last quantifiable plasma concentration for plasma maltol glucuronide (AUC0-t) (hxng/mL) after a single dose of ferric maltol oral suspension on Visit 2 (PK Day 1) and after twice daily administrations for at least 6 days, on Visit 3 (PK Day 2) after a single morning dose. Because of the limitations of PK sampling in the pediatric patient population, data from multiple patients in the same treatment and age group had to be combined, using the naïve pooled approach, to achieve a complete set of observations over time for PK analysis. The data did not support PK parameters generation using noncompartmental analysis (NCA) without combining patients. Using validated PK software WinNonlin, the 'sparse sampling' option was utilized to treat the data as one virtual subject and thus the resulting data did not support reliable error estimates of the PK parameters.
Time frame: PK parameters assessed at Day 1 (Visit 2) and Day 7-10 (Visit 3).
Population: A total of 20 patients in the ferric maltol group were included in the PK Population. Of these patients, there were 7 patients (3 female patients and 4 male patients) who were 2 to 9 years of age, 3 patients (all female patients) who were 10 to 17 years of age and who received 15 mg BID of ferric maltol, and 10 patients (9 female patients and 1 male patient) who were 10 to 17 years of age and who received 30 mg BID of ferric maltol.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| mITT Ferric Maltol Assigned | AUC0-t for Plasma Maltol Glucuronide | 7670 hxng/mL |
| mITT Ferric Maltol | AUC0-t for Plasma Maltol Glucuronide | 12000 hxng/mL |
| mITT Ferrous Sulfate | AUC0-t for Plasma Maltol Glucuronide | 14600 hxng/mL |
| PK Population Ferric Maltol 15mg (2-9 y) Day 7-10 | AUC0-t for Plasma Maltol Glucuronide | 5900 hxng/mL |
| PK Population Ferric Maltol 15mg (10-17 y) Day 7-10 | AUC0-t for Plasma Maltol Glucuronide | 8070 hxng/mL |
| PK Population Ferric Maltol 30mg (10-17 y) Day 7-10 | AUC0-t for Plasma Maltol Glucuronide | 16700 hxng/mL |
Secondary
Change in Iron Concentration
Change in iron concentration from baseline to week 12 summarized based on the mITT Population for each treatment group. The Randomized/ITT Population is defined as all patients who were randomized/assigned to treatment arms. The mITT Population is defined as all patients in the ITT Population who received at least 1 treatment dose.
Time frame: From baseline to week 12.
Population: All patients that finalized Day 84 measurement were reported and analyzed. All patients with a missing Day 84 measurement were imputed using a last observation carried forward approach in which the last available post-baseline measurement was used. Post-baseline measurement was missing in 2 patients in the 3. group (mITT Ferrous Sulfate).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| mITT Ferric Maltol Assigned | Change in Iron Concentration | 1.07 μmol/L | Standard Deviation 0.577 |
| mITT Ferric Maltol | Change in Iron Concentration | 5.77 μmol/L | Standard Deviation 8.518 |
| mITT Ferrous Sulfate | Change in Iron Concentration | 3.64 μmol/L | Standard Deviation 8.911 |
Secondary
Change in the Percentage of Transferrin Saturation
Change from baseline to Day 84 summarized based on the mITT Population for each treatment group. The Randomized/ITT Population is defined as all patients who were randomized/assigned to treatment arms. The mITT Population is defined as all patients in the ITT Population who received at least 1 treatment dose.
Time frame: From baseline to week 12.
Population: All patients that finalized Day 84 measurement were reported and analyzed. All patients with a missing Day 84 measurement were imputed using a last observation carried forward approach in which the last available post-baseline measurement was used. Post-baseline measurement was missing in 1 patient in the 1. group (mITT Ferric Maltol Assigned) and 2 patients in the 3. group (mITT Ferrous Sulfate).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| mITT Ferric Maltol Assigned | Change in the Percentage of Transferrin Saturation | 2.0 Percentage of Transferrin Saturation | Standard Deviation 0 |
| mITT Ferric Maltol | Change in the Percentage of Transferrin Saturation | 7.7 Percentage of Transferrin Saturation | Standard Deviation 10.14 |
| mITT Ferrous Sulfate | Change in the Percentage of Transferrin Saturation | 6.5 Percentage of Transferrin Saturation | Standard Deviation 12.39 |
Secondary
Changes in Ferritin Concentration
Changes in ferritin concentration from baseline to week 12 summarised based on the mITT Population for each treatment group. The Randomized/ITT Population is defined as all patients who were randomized/assigned to treatment arms. The mITT Population is defined as all patients in the ITT Population who received at least 1 treatment dose.
Time frame: From baseline to week 12.
Population: All patients that finalized Day 84 measurement were reported and analyzed. All patients with a missing Day 84 measurement were imputed using a last observation carried forward approach in which the last available post-baseline measurement was used. Post-baseline measurement was missing in 2 patients in the 3. group (mITT Ferrous Sulfate).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| mITT Ferric Maltol Assigned | Changes in Ferritin Concentration | 6.3 μg/L | Standard Deviation 8.74 |
| mITT Ferric Maltol | Changes in Ferritin Concentration | 8.1 μg/L | Standard Deviation 11.06 |
| mITT Ferrous Sulfate | Changes in Ferritin Concentration | 20.6 μg/L | Standard Deviation 30.97 |
Secondary
Cmax for Baseline Corrected Serum Iron
Measured maximum plasma concentration (Cmax) (μg/dL) for baseline corrected serum iron after a single dose of ferric maltol oral suspension on Visit 2 (PK Day 1) and after twice daily administrations for at least 6 days, on Visit 3 (PK Day 2) after a single morning dose. Because of the limitations of PK sampling in the pediatric patient population, data from multiple patients in the same treatment and age group had to be combined, using the naïve pooled approach, to achieve a complete set of observations over time for PK analysis. The data did not support PK parameters generation using noncompartmental analysis (NCA) without combining patients. Using validated PK software WinNonlin, the 'sparse sampling' option was utilized to treat the data as one virtual subject and thus the resulting data did not support reliable error estimates of the PK parameters.
Time frame: PK parameters assessed at Day 1 (Visit 2) and Day 7-10 (Visit 3).
Population: A total of 20 patients in the ferric maltol group were included in the PK Population. Of these patients, there were 7 patients (3 female patients and 4 male patients) who were 2 to 9 years of age, 3 patients (all female patients) who were 10 to 17 years of age and who received 15 mg BID of ferric maltol, and 10 patients (9 female patients and 1 male patient) who were 10 to 17 years of age and who received 30 mg BID of ferric maltol.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| mITT Ferric Maltol Assigned | Cmax for Baseline Corrected Serum Iron | 87.0 μg/dL |
| mITT Ferric Maltol | Cmax for Baseline Corrected Serum Iron | 40.0 μg/dL |
| mITT Ferrous Sulfate | Cmax for Baseline Corrected Serum Iron | 119 μg/dL |
| PK Population Ferric Maltol 15mg (2-9 y) Day 7-10 | Cmax for Baseline Corrected Serum Iron | 96.5 μg/dL |
| PK Population Ferric Maltol 15mg (10-17 y) Day 7-10 | Cmax for Baseline Corrected Serum Iron | 21.0 μg/dL |
| PK Population Ferric Maltol 30mg (10-17 y) Day 7-10 | Cmax for Baseline Corrected Serum Iron | 364 μg/dL |
Secondary
Cmax for Plasma Maltol Glucuronide
Measured maximum plasma concentration (Cmax) (ng/mL) for plasma maltol glucuronide after a single dose of ferric maltol oral suspension on Visit 2 (PK Day 1) and after twice daily administrations for at least 6 days, on Visit 3 (PK Day 2) after a single morning dose. Because of the limitations of PK sampling in the pediatric patient population, data from multiple patients in the same treatment and age group had to be combined, using the naïve pooled approach, to achieve a complete set of observations over time for PK analysis. The data did not support PK parameters generation using noncompartmental analysis (NCA) without combining patients. Using validated PK software WinNonlin, the 'sparse sampling' option was utilized to treat the data as one virtual subject and thus the resulting data did not support reliable error estimates of the PK parameters.
Time frame: PK parameters assessed at Day 1 (Visit 2) and Day 7-10 (Visit 3).
Population: A total of 20 patients in the ferric maltol group were included in the PK Population. Of these patients, there were 7 patients (3 female patients and 4 male patients) who were 2 to 9 years of age, 3 patients (all female patients) who were 10 to 17 years of age and who received 15 mg BID of ferric maltol, and 10 patients (9 female patients and 1 male patient) who were 10 to 17 years of age and who received 30 mg BID of ferric maltol.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| mITT Ferric Maltol Assigned | Cmax for Plasma Maltol Glucuronide | 4350 ng/mL |
| mITT Ferric Maltol | Cmax for Plasma Maltol Glucuronide | 6810 ng/mL |
| mITT Ferrous Sulfate | Cmax for Plasma Maltol Glucuronide | 6420 ng/mL |
| PK Population Ferric Maltol 15mg (2-9 y) Day 7-10 | Cmax for Plasma Maltol Glucuronide | 4250 ng/mL |
| PK Population Ferric Maltol 15mg (10-17 y) Day 7-10 | Cmax for Plasma Maltol Glucuronide | 5940 ng/mL |
| PK Population Ferric Maltol 30mg (10-17 y) Day 7-10 | Cmax for Plasma Maltol Glucuronide | 8160 ng/mL |
Secondary
Tmax for Baseline Corrected Serum Iron
Time to maximum plasma concentration (Tmax) (h) for baseline corrected serum iron after a single dose of ferric maltol oral suspension on Visit 2 (PK Day 1) and after twice daily administrations for at least 6 days, on Visit 3 (PK Day 2) after a single morning dose. Because of the limitations of PK sampling in the pediatric patient population, data from multiple patients in the same treatment and age group had to be combined, using the naïve pooled approach, to achieve a complete set of observations over time for PK analysis. The data did not support PK parameters generation using noncompartmental analysis (NCA) without combining patients. Using validated PK software WinNonlin, the 'sparse sampling' option was utilized to treat the data as one virtual subject and thus the resulting data did not support reliable error estimates of the PK parameters.
Time frame: PK parameters assessed at Day 1 (Visit 2) and Day 7-10 (Visit 3).
Population: A total of 20 patients in the ferric maltol group were included in the PK Population. Of these patients, there were 7 patients (3 female patients and 4 male patients) who were 2 to 9 years of age, 3 patients (all female patients) who were 10 to 17 years of age and who received 15 mg BID of ferric maltol, and 10 patients (9 female patients and 1 male patient) who were 10 to 17 years of age and who received 30 mg BID of ferric maltol.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| mITT Ferric Maltol Assigned | Tmax for Baseline Corrected Serum Iron | 2.37 h |
| mITT Ferric Maltol | Tmax for Baseline Corrected Serum Iron | 2.13 h |
| mITT Ferrous Sulfate | Tmax for Baseline Corrected Serum Iron | 2.00 h |
| PK Population Ferric Maltol 15mg (2-9 y) Day 7-10 | Tmax for Baseline Corrected Serum Iron | 2.10 h |
| PK Population Ferric Maltol 15mg (10-17 y) Day 7-10 | Tmax for Baseline Corrected Serum Iron | 2.78 h |
| PK Population Ferric Maltol 30mg (10-17 y) Day 7-10 | Tmax for Baseline Corrected Serum Iron | 6.63 h |
Secondary
Tmax for Plasma Maltol Glucuronide
Time to maximum plasma concentration (Tmax) (h) for plasma maltol glucuronide after a single dose of ferric maltol oral suspension on Visit 2 (PK Day 1) and after twice daily administrations for at least 6 days, on Visit 3 (PK Day 2) after a single morning dose. Because of the limitations of PK sampling in the pediatric patient population, data from multiple patients in the same treatment and age group had to be combined, using the naïve pooled approach, to achieve a complete set of observations over time for PK analysis. The data did not support PK parameters generation using noncompartmental analysis (NCA) without combining patients. Using validated PK software WinNonlin, the 'sparse sampling' option was utilized to treat the data as one virtual subject and thus the resulting data did not support reliable error estimates of the PK parameters.
Time frame: PK parameters assessed at Day 1 (Visit 2) and Day 7-10 (Visit 3).
Population: A total of 20 patients in the ferric maltol group were included in the PK Population. Of these patients, there were 7 patients (3 female patients and 4 male patients) who were 2 to 9 years of age, 3 patients (all female patients) who were 10 to 17 years of age and who received 15 mg BID of ferric maltol, and 10 patients (9 female patients and 1 male patient) who were 10 to 17 years of age and who received 30 mg BID of ferric maltol.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| mITT Ferric Maltol Assigned | Tmax for Plasma Maltol Glucuronide | 1.00 h |
| mITT Ferric Maltol | Tmax for Plasma Maltol Glucuronide | 2.13 h |
| mITT Ferrous Sulfate | Tmax for Plasma Maltol Glucuronide | 0.52 h |
| PK Population Ferric Maltol 15mg (2-9 y) Day 7-10 | Tmax for Plasma Maltol Glucuronide | 0.98 h |
| PK Population Ferric Maltol 15mg (10-17 y) Day 7-10 | Tmax for Plasma Maltol Glucuronide | 2.78 h |
| PK Population Ferric Maltol 30mg (10-17 y) Day 7-10 | Tmax for Plasma Maltol Glucuronide | 3.63 h |