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 (FORTIS)

Shield Therapeutics

Status and phase: Enrolling; Phase 3

Conditions: Anemia; Iron-deficiency

Treatments: Drug: Ferric Maltol; Drug: Ferrous sulfate

Study type: Interventional

Funder types: Industry

Identifiers

NCT05126901

ST10-01-305

Details and patient eligibility

About

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.

Full 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:

• 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: 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.

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.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).

Enrollment: 98 estimated patients

Sex: All

Ages: 1 month to 17 years old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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98 participants in 3 patient groups

1 month to 2 year old subjects (infants)

Experimental group

Description:

Subjects aged 1 month to less than 2 years will enter a Pre-assignment phase: baseline urine samples are collected and subjects will take a single dose of 0.1 ml/kg ferric maltol suspension. Further 3 samples up to 12h will be taken. Subjects showing evidence of absorption, metabolism and elimination of maltol will enter the treatment phase and be assigned to the ferric maltol arm. The first 6 subjects screened will perform the pre-assignment PK phase. After review by the investigator, and medical monitors , if Maltol Glucuronide is shown to be adequately eliminated, timepoint 20-24 hrs (+ 4hrs) will not be performed on subsequent subjects. 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.

Treatment:

Drug: Ferric Maltol

2 to 17 year old subjects - Ferric Maltol

Experimental group

Description:

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 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.

Treatment:

Drug: Ferric Maltol

2 to 17 year old subjects - Ferrous Sulfate

Active Comparator group

Description:

Subjects aged 2-17 will be randomised 1:1 to receive ferric maltol oral suspension or ferrous sulfate oral liquid. 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.

Treatment:

Drug: Ferrous sulfate