FORTIS: Evaluate the Safety and Efficacy of Ferric Maltol Oral Suspension vs. Ferrous Sulfate Oral Liquid in Children and Adolescents Aged 2 to 17 Years With Iron-deficiency Anaemia, With a Single Arm Study in Infants Aged 1 Month to Less Than 2 Years
Study Details
Study Description
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 3 |
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.
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, metabolism of serum iron and elimination of maltol from the Pre-assignment PK samples by showing plasma maltol return to baseline, 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:
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Screening: within 14 days prior to randomisation for each subject
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Pre-assignment PK phase: only applicable for subjects aged 1 month to less than 2 years. Up to 21 days from Screening.
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Randomised treatment: 12 weeks open label treatment
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Assigned treatment phase 12 weeks open label treatment for ferric maltol children aged 1 month to less than 2 years
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End of study: Week 12 visit
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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: 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.
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, summarised as the mean across all subjects, with 95% 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.
Population PK analysis will be conducted for maltol and maltol glucuronide in plasma and for serum iron and TSAT in children and adolescents aged 1 month - 17 years.
Full details of the statistical analysis, including the analysis of PK endpoints, will be specified in the statistical analysis plan (SAP).
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: 1 month to 2 year old subjects (infants) Subjects aged 1 month to less than 2 years will enter a Pre-assignment phase: baseline pre-dose blood and urine sample are collected and subjects will take a single dose of 0.1 ml/kg ferric maltol suspension under supervision. Further 3 PK blood samples up to 6 h and urine samples from 2 timepoints will be taken. Subjects showing evidence of absorption, metabolism of serum iron and elimination of maltol will enter the treatment phase and be assigned to the ferric maltol arm. Subjects will be assigned to receive ferric maltol oral suspension and start the 0.1 ml/kg BID dose on V2 and continue for 7-10 days. On V3 they will perform the same PK assessments as on Pre-assignment PK visit. |
Drug: Ferric 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.
Other Names:
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| Experimental: 2 to 17 year old subjects - Ferric Maltol Subjects aged 2-17 will be randomised 1:1 to receive ferric maltol oral suspension or ferrous sulfate oral liquid. The first 18 subjects randomised to ferric maltol in each age sub-group (2 - 9 yrs, 10 - 17 yrs) 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 will be used for all children/adolescents. To maximise the iron replenishment for subjects within this group as well; aged 2 - 17 yrs will be dosed 6 mg/kg to the maximum of 4 ml BID. Subjects randomised to ferrous sulfate oral liquid will not need to complete the PK period. |
Drug: Ferric 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.
Other Names:
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| Active Comparator: 2 to 17 year old subjects - Ferrous Sulfate Subjects aged 2-17 will be randomised 1:1 to receive ferric maltol oral suspension or ferrous sulfate oral liquid. The first 18 subjects randomised to ferric maltol in each age sub-group (2 - 9 yrs, 10 - 17 yrs) 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 will be used for all children/adolescents. To maximise the iron replenishment for subjects within this group as well; aged 2 - 17 yrs will be dosed 6 mg/kg to the maximum of 4 ml BID. Subjects randomised to ferrous sulfate oral liquid will not need to complete the PK period. |
Drug: Ferrous 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.
|
Outcome Measures
Primary Outcome Measures
- 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 [12 weeks]
Safety and gastrointestinal tolerability will be compared between ferric maltol oral suspension and ferrous sulfate oral liquid via the incidence of treatment emergent adverse events (TEAEs), treatment emergent serious AEs (TESAEs) and treatment-emergent AEs (TEAEs) leading to premature discontinuation of study drug, estimated as the number of subjects with at least one event divided by the number of subjects in the safety population. AEs will be categorised by primary system organ class and MedDRA preferred term as coded using the MedDRA dictionary. The number, intensity, relation to study medication and action taken will be described by incidence tables. SAEs will be discussed separately.
Secondary Outcome Measures
- Assess the PK in children and adolescents aged 2 to 17 years [12 weeks]
To assess the pharmacokinetics (PK) in children and adolescents aged 2 to 17 years after a single dose of ferric maltol oral suspension Visit 2 (PK Day 1), and after twice daily administration for at least 6 days, on Visit 3 (PK Day 2) after a single morning dose, through measurement of serum iron, transferrin saturation (TSAT) and plasma maltol and maltol glucuronide
- Assess the effect on haemoglobin and iron markers in children and adolescents aged 1 month to 17 years after twice daily ferric maltol oral suspension administration for 12 weeks [12 weeks]
- Assess the PK, in children aged 1 month to less than 2 years of age [12 weeks]
To assess the PK, in children aged 1 month to less than 2 years of age after a single dose of ferric maltol oral suspension (Pre-assignment PK visit) and after twice daily administration for at least 6 days, on Visit 3 (PK Day 2) after a single morning dose, through measurement of serum iron, transferrin saturation (TSAT), plasma and urine concentration of maltol and maltol glucuronide
- Assess the effect, in children aged 1 month to less than 2 years of age [12 weeks]
To assess the effect, in children aged 1 month to less than 2 years of age after a single dose of ferric maltol suspension (Pre-assignment PK visit), and after twice daily administration for at least 6 days, on Visit 3 (PK Day 2) after a single morning dose, on serum transferrin, total and unsaturated iron binding capacity (TIBC, UIBC), ferritin
- Assess the effect, in children aged 2 to 17 [12 weeks]
To assess the effect, in children aged 2 to 17 after a single dose of ferric maltol suspension Visit 2 (PK Day 1), and after twice daily administration for at least 6 days, on Visit 3 (PK Day 2) after a single morning dose, on serum transferrin, total and unsaturated iron binding capacity (TIBC, UIBC), ferritin.
- To compare the palatability from age-appropriate scoring system of ferric maltol oral suspension and ferrous sulfate oral liquid [12 weeks]
Eligibility Criteria
Criteria
Inclusion Criteria:
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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.
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Age ≥1 month and ≤17 years at the time of informed consent
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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:
- Subject with anaemia due to any cause other than iron deficiency, including, but not limited to,
- Untreated or untreatable severe malabsorption syndrome
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Subjects who have received prior to Screening:
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Within 28 days intramuscular or intravenous (IV) injection or administration of depot iron preparation.
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Within 7 days single agent iron preparations and during the study.
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Within 12 weeks of blood transfusion or is scheduled to have blood transfusion or donation during the study period
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Within 28 days erythropoiesis stimulating agents and during the study period
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Within 7 days multivitamins that includes iron and during the study period
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Within 14 days COVID-19 vaccination
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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.
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Has concomitant disease that would significantly compromise iron absorption or absorbed iron utilization such as swallowing disorders and/or extensive small bowel resection.
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History of active peptic ulcer
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Has chronic renal disease (eGFR <60 mL/min/m2), as assessed at Screening based on serum creatinine.
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Known hypersensitivity or allergy to either the active substance or excipients of ferric maltol or ferrous sulfate.
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Has a known contraindication for treatment with iron preparations, e.g. haemochromatosis, chronic haemolytic disease, sideroblastic anaemia, thalassemia, or lead intoxication induced anaemia.
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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.
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Active acute inflammatory disease, including IBD flare or disease exacerbation, which in the opinion of the Investigator, is clinically significant.
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Active chronic or acute infectious diseases requiring antibiotic treatment.
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Pregnant or breast feeding.
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Concomitant medical conditions with extensive active bleeding, other than menstrual cycles; subjects who suffer from menorrhagia may be included at the Investigator's discretion.
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Scheduled or expected hospitalisation and/or surgery during the course of the study
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Participation in any other interventional clinical study within 28 days prior to Screening.
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Diagnosed to be COVID-19 positive by (SARS-CoV-2-RT-PCR positive) within 28 days prior to screening.
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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.
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Any other unspecified reason that, in the opinion of the Investigator or the Sponsor make the subject unsuitable for enrolment.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | The Center for Clinical Trials | Saraland | Alabama | United States | 36571 |
| 2 | Homestead Research Institute | Homestead | Florida | United States | 33030 |
| 3 | Kissimmee Clinical Research Corp | Kissimmee | Florida | United States | 34743 |
| 4 | Miami Clinical Research | Miami | Florida | United States | 33155 |
| 5 | Eminent Clinical Research and Associates | N. Lauderdale | Florida | United States | 33068 |
| 6 | Sierra Clinical Research | Las Vegas | Nevada | United States | 89106 |
| 7 | Levine Cancer Institute | Charlotte | North Carolina | United States | 28204 |
| 8 | Penn State Hershey Children's Hospital | Hershey | Pennsylvania | United States | 17033 |
| 9 | Hasbro Children's Hospital | Providence | Rhode Island | United States | 02903 |
| 10 | Sun Research Institute | San Antonio | Texas | United States | 78215 |
| 11 | BRCR Global Puerto | San Juan | Puerto Rico | 00907 | |
| 12 | Noah's Ark Children's Hospital for Wales | Cardiff | United Kingdom | CF14 4XW | |
| 13 | Royal Hospital for Sick Children - Edinburgh | Edinburgh | United Kingdom | EH16 4TJ | |
| 14 | Leicester Royal Infirmary | Leicester | United Kingdom | LE1 5WW | |
| 15 | King's College Hospital | London | United Kingdom | SE5 9RS | |
| 16 | Royal Manchester Children's Hospital | Manchester | United Kingdom | M13 9WL | |
| 17 | Nottingham University Hospitals | Nottingham | United Kingdom | NG7 2UH | |
| 18 | Sheffield Children's NHS Foundation Trust | Sheffield | United Kingdom | S10 2TH |
Sponsors and Collaborators
- Shield Therapeutics
Investigators
None specified.Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- ST10-01-305