Clinical trial NCT03181451: Evaluate the PK, Safety, Tolerability of Ferric Maltol at 3 Dosage Levels in Paediatric Subjects With Iron Deficiency
Official title: A Phase 1, Open-Label, Randomised, Repeat Dose, Parallel Group Study to Evaluate the PK, Safety, Tolerability of Ferric Maltol at 3 Dosage Levels in Paediatric Subjects Aged 10-17 Years of Age With Iron Deficiency
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Iron Deficiency, Anaemia in Children
Iron-Deficiency
Lead sponsor: Shield Therapeutics
Sponsor class: INDUSTRY
Collaborators: name: Medpace, Inc.
First posted: 2017-06-08
Enrollment: 37
Sex: ALL
Minimum age (years): 10
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Subjects will be randomized in a 1:1:1 ratio and stratified by co-variates for age and sex. This will ensure that a minimum of 25% of each gender and at least 3 children per age group are enrolled in each Ferric Maltol dose group.
Primary purpose: OTHER

Brief summary: The study has been designed to establish the pharmacokinetics (PK) and iron uptake of Ferric Maltol in children and adolescents aged 10-17 years using two (2) lower dose strengths in comparison to the EU-approved 30mg BID dose in adults with IDA in IBD.

Detailed description: Phase I, open label, randomized, repeat dose, multicentre, pharmacokinetic study to assess the Safety and Tolerability of Ferric Maltol in 3 different dosages.

36 eligible patients will be randomized in a 1:1:1 ratio to one of the following 3 dosages for 9 days BID and a single dose on Day 10:

* 30mg ferric maltol capsules
* 16.6 mg ferric maltol capsules
* 7.8 mg ferric maltol capsules

Subject participation in the study will consist of 3 stages:

Screening: up to 14 days Treatment period: 10 days treatment period with 2 visits on Day 1 and Day 10 for PK blood sampling. Patients will be randomly allocated to one of the three Ferric Maltol dose groups according to centralized treatment allocation scheme.

Post-treatment Safety Follow-up:3-10 days following completion of the treatment period or premature discontinuation of study medication

Eligibility criteria: Inclusion Criteria:

1. Ability to understand the information given in the Independent Ethics Committee (IEC) approved Information Sheet and Consent form. The parent or guardian of the study subject must sign and date the informed consent and authorisation to use protected health information (PHI) in accordance with national and local subject privacy regulations prior to any study mandated procedure. The study participant will be asked to provide their assent to participate in the study using the IEC approved Assent form.
2. Willing and able to comply with study requirements.
3. Age ≥10 to ≤17 years at the time of informed consent and throughout duration of the study.
4. A current diagnosis of iron deficiency (with or without anaemia); iron deficiency defined by ferritin \<30 µg/L, or ferritin \<50 µg/L with transferrin saturation (TSAT) \<20%, as measured by the central laboratory at the Screening visit (subjects with or without anaemia may be enrolled providing Hb is ≥8.5 g/dL as measured at the Screening visit).
5. Where appropriate, female subjects of childbearing potential must agree to use a reliable method of contraception until study completion and for at least 4 weeks following their final study visit. Reliable 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), complete sexual abstinence, a vasectomized partner and oral contraceptive medications.

Exclusion Criteria:

1. Has untreated or untreatable severe malabsorption syndrome e.g., untreated coeliac disease
2. Has received within 28 days prior to Screening intramuscular or intravenous (IV) injection or administration of depot iron preparation.
3. Has received oral iron supplementation within 7 days prior to Screening
4. Has received blood transfusion within 12 weeks prior to Screening or is scheduled to have blood transfusion or donations during the study period.
5. Has concomitant disease that would significantly compromise iron absorption or absorbed iron utilisation such as swallowing disorders and/or extensive small bowel resection.
6. Has chronic renal disease (eGFR \<30mL/min), as assessed at Screening based on serum creatinine.
7. Known hypersensitivity or allergy to either the active substance or excipients of Ferric Maltol capsules.
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. 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.
17. Any other unspecified reason that, in the opinion of the Investigator or the Sponsor make the subject unsuitable for enrolment.

Primary outcomes:
measure: Maximum Plasma Concentration [Cmax] of Maltol Glucuronide on Day 1
timeFrame: Day 1 pre-first dose of Ferric Maltol and up to 6 hours post-dose (0h, 0.5-1h, 1-2h, 2-3h, 3-4h, 4-6h)
measure: Maximum Plasma Concentration [Cmax] of Maltol Glucuronide on Day 10
timeFrame: Day 10 pre-final dose of Ferric Maltol and up to 6 hours post-dose (0h, 0.5-1h, 1-2h, 2-3h, 3-4h, 4-6h)
measure: Area Under The Curve [AUC] of Maltol Glucuronide on Day 1
timeFrame: Day 1 pre-first dose of Ferric Maltol and up to 6 hours post-dose (0h, 0.5-1h, 1-2h, 2-3h, 3-4h, 4-6h)
measure: Area Under The Curve [AUC] of Maltol Glucuronide on Day 10
timeFrame: Day 10 pre-final dose of Ferric Maltol and up to 6 hours post-dose (0h, 0.5-1h, 1-2h, 2-3h, 3-4h, 4-6h)
measure: Average Plasma Concentration [Cave(0-6h)] of Maltol Glucuronide on Day 10
timeFrame: Day 10 pre-final dose of Ferric Maltol and up to 6 hours post-dose (0h, 0.5-1h, 1-2h, 2-3h, 3-4h, 4-6h)
measure: Time of Maximum Plasma Concentration [Tmax] of Maltol Glucuronide on Day 1
timeFrame: Day 1 pre-first dose of Ferric Maltol and up to 6 hours post-dose (0h, 0.5-1h, 1-2h, 2-3h, 3-4h, 4-6h)
measure: Time of Maximum Plasma Concentration [Tmax] of Maltol Glucuronide on Day 10
timeFrame: Day 10 pre-final dose of Ferric Maltol and up to 6 hours post-dose (0h, 0.5-1h, 1-2h, 2-3h, 3-4h, 4-6h)
measure: Half Life [t1/2] of Maltol Glucuronide on Day 1
timeFrame: Day 1 pre-first dose of Ferric Maltol and up to 6 hours post-dose (0h, 0.5-1h, 1-2h, 2-3h, 3-4h, 4-6h)
measure: Ratio of Maximum Plasma Concentration [Cmax] of Maltol Glucuronide on Day 10/Day 1
timeFrame: Day 1 and Day 10, pre-dose and up to 6 hours post-dose (0h, 0.5-1h, 1-2h, 2-3h, 3-4h, 4-6h)
measure: Ratio of Area Under The Curve [AUC] of Maltol Glucuronide on Day 10/Day 1
timeFrame: Day 1 and Day 10, pre-dose and up to 6 hours post-dose (0h, 0.5-1h, 1-2h, 2-3h, 3-4h, 4-6h)
measure: Average Serum Concentration [Cave(0-6h)] of Iron on Day 10
timeFrame: Day 10 pre-final dose of Ferric Maltol and up to 6 hours post-dose (0h, 0.5-1h, 1-2h, 2-3h, 3-4h, 4-6h)
measure: Change From Pre-Dose (Ctrough) to Maximum Post-Dose (Cmax) in Serum Iron on Day 1
timeFrame: Day 1 pre-first dose of Ferric Maltol and up to 6 hours post-dose (0h, 0.5-1h, 1-2h, 2-3h, 3-4h, 4-6h)
measure: Change From Pre-Dose (Ctrough) to Maximum Post-Dose (Cmax) in Serum Iron on Day 10
timeFrame: Day 10 pre-final dose of Ferric Maltol and up to 6 hours post-dose (0h, 0.5-1h, 1-2h, 2-3h, 3-4h, 4-6h)
measure: Pre-dose Adjusted Incremental Area Under the Curve [AUC(0-6h)] of Serum Iron on Day 1
timeFrame: Day 1 pre-first dose of Ferric Maltol and up to 6 hours post-dose (0h, 0.5-1h, 1-2h, 2-3h, 3-4h, 4-6h)
measure: Pre-dose Adjusted Incremental Area Under the Curve [AUC(0-6h)] of Serum Iron on Day 10
timeFrame: Day 10 pre-final dose of Ferric Maltol and up to 6 hours post-dose (0h, 0.5-1h, 1-2h, 2-3h, 3-4h, 4-6h)
measure: Pre-dose Adjusted Incremental Area Under the Curve [AUC(0-6h)] of Transferrin Saturation (TSAT) on Day 1
timeFrame: Day 1 pre-first dose of Ferric Maltol and up to 6 hours post-dose (0h, 0.5-1h, 1-2h, 2-3h, 3-4h, 4-6h)
measure: Pre-dose Adjusted Incremental Area Under the Curve [AUC(0-6h)] of Transferrin Saturation (TSAT) on Day 10
timeFrame: Day 10 pre-final dose of Ferric Maltol and up to 6 hours post-dose (between (0h, 0.5-1h, 1-2h, 2-3h, 3-4h, 4-6h)
measure: Apparent Systemic Clearance (CL/F) of Iron on Day 1
timeFrame: Day 1 pre-first dose of Ferric Maltol and up to 6 hours post-dose (0h, 0.5-1h, 1-2h, 2-3h, 3-4h, 4-6h)
measure: Apparent Systemic Clearance (CL/F) of Iron on Day 10
timeFrame: Day 10 pre-final dose of Ferric Maltol and up to 6 hours post-dose (0h, 0.5-1h, 1-2h, 2-3h, 3-4h, 4-6h)
measure: Apparent Volume of Distribution (V/F) of Iron on Day 1
timeFrame: Day 1 pre-first dose of Ferric Maltol and up to 6 hours post-dose (0h, 0.5-1h, 1-2h, 2-3h, 3-4h, 4-6h)
measure: Apparent Volume of Distribution (V/F) of Transferrin Saturation (TSAT) on Day 1
timeFrame: Day 1 pre-first dose of Ferric Maltol and up to 6 hours post-dose (0h, 0.5-1h, 1-2h, 2-3h, 3-4h, 4-6h)
measure: Apparent Volume of Distribution (V/F) of Transferrin Saturation (TSAT) on Day 10
timeFrame: Day 10 pre-final dose of Ferric Maltol and up to 6 hours post-dose (0h, 0.5-1h, 1-2h, 2-3h, 3-4h, 4-6h)
measure: Ratio Auc(0-6) Maltol Glucuronide Day 10/Day 1
timeFrame: Day 1 to Day 10 (0h, 0.5-1h, 1-2h, 2-3h, 3-4h, 4-6h)
measure: Serum Iron - RAUC(0-6h) D10/D1
timeFrame: Measured after first and last dose of Ferric Maltol on Day 1 & Day 10 (0h, 0.5-1h, 1-2h, 2-3h, 3-4h, 4-6h)
measure: Transferrin Saturation (%) Day 1, Baseline
timeFrame: Measured after first dose of Ferric Maltol on Day 1 (0h)
measure: Transferrin Saturation (%) Day 1, Maximum Response (%)
timeFrame: Measured after first dose of Ferric Maltol on Day 1 (0h, 0.5-1h, 1-2h, 2-3h, 3-4h, 4-6h)
measure: Transferrin Saturation Day 1, Time to Maximum Response Tmax
timeFrame: Measured after first dose of Ferric Maltol on Day 1. (0h, 0.5-1h, 1-2h, 2-3h, 3-4h, 4-6h)
measure: Transferrin Saturation (%) Day 10, Maximum Response (%)
timeFrame: Measured after last dose of Ferric Maltol on Day 10. (0.5-1h, 1-2h, 2-3h, 3-4h, 4-6h)
measure: Transferrin Saturation Day 10, Time to Maximum Response Tmax
timeFrame: Measured after first dose of Ferric Maltol on Day 10. (0h, 0.5-1h, 1-2h, 2-3h, 3-4h, 4-6h).
measure: AUC0-inf Day 1 for Maltol Glucuronide
timeFrame: Measured after first dose of Ferric Maltol on Day 1 (0.5-1h, 1-2h, 2-3h, 3-4h, 4-6h)
measure: AUC0-tau Day 10 for Maltol Glucuronide
timeFrame: Measured after last dose of Ferric Maltol on Day 10. (0.5-1h, 1-2h, 2-3h, 3-4h, 4-6h)
measure: Cthrough for Maltol Glucuronide Day 10
timeFrame: Day 10 pre-dose to last (0h, 0.5-1h, 1-2h, 2-3h, 3-4h, 4-6h)
measure: Serum Iron Cmax Day 1
timeFrame: Day 1 (0h, 0.5-1h, 1-2h, 2-3h, 3-4h, 4-6h)
measure: Serum Iron Cmax on Day 10
timeFrame: Day 10 (0h, 0.5-1h, 1-2h, 2-3h, 3-4h, 4-6h)
measure: Plasma Maltol Glucuronide Cthrough D10/Day1
timeFrame: Day 10 (0.5-1h, 1-2h, 2-3h, 3-4h, 4-6h)
measure: Apparent Systemic Clearance (CL/F) of Transferrin Saturation (TSAT) on Day 1
timeFrame: Day 1 pre-first dose of Ferric Maltol and up to 6 hours post-dose (0h, 0.5-1h, 1-2h, 2-3h, 3-4h, 4-6h
measure: Apparent Systemic Clearance (CL/F) of Transferrin Saturation (TSAT) on Day 10
timeFrame: Day 10 pre-final dose of Ferric Maltol and up to 6 hours post-dose (0h, 0.5-1h, 1-2h, 2-3h, 3-4h, 4-6h)
measure: Apparent Systemic Clearance (CL/F) of Maltol Glucuronide on Day 1
timeFrame: Day 1 pre-first dose of Ferric Maltol and up to 6 hours post-dose (0h, 0.5-1h, 1-2h, 2-3h, 3-4h, 4-6h
measure: Apparent Systemic Clearance (CL/F) of Maltol Glucuronide on Day 10
timeFrame: Day 1 pre-first dose of Ferric Maltol and up to 6 hours post-dose (0h, 0.5-1h, 1-2h, 2-3h, 3-4h, 4-6h
Secondary outcomes:
measure: Transferrin - Change From Baseline to Day 10, Predose
timeFrame: Day 1 pre-dose to Day 10 pre-dose (0h on each day)
measure: Ferritin - Change From Baseline to Day 10, Predose
timeFrame: Pre-dose on Day 1 to Day 10 (0h)
measure: Total Iron Binding Capacity - Change From Day 1 to Day 10, Predose
timeFrame: Predose from Day 1 to Day 10 (0h on each day)
measure: UIBC - Change From Day 1 to Day 10, Predose
timeFrame: Pre-dose on Day 1 to Day 10 (0h each day)
measure: Negative and Positive NTBI Tests on Day 1
timeFrame: Day 1 (0h)
measure: Change From Baseline to Day 10 in Haemoglobin Concentration
timeFrame: Screening and Day 10 (1-4 hours post-dose)
measure: Change From Baseline to Day 10 in Absolute Reticulocyte Count
timeFrame: Change calculated as difference in values measured at Screening (Baseline) and on Day 10.
measure: Treatment-emergent Adverse Events (AEs) Leading to Premature Discontinuation of Study Drug/PK Assessments
timeFrame: From first dose of Ferric Maltol on Day 1 through study completion, on average 4 weeks
measure: Changes in 12-lead ECG Parameters From Screening to Day 10
timeFrame: Screening and Day 10 (1-4 hours post-dose)
measure: Concomitant Medications
timeFrame: Screening, Day 1, Day 10 and Post-Study Follow-up visit, on average 4 weeks
measure: Negative and Positive NTBI Tests on Day 10, Predose
timeFrame: Day 10
measure: Treatment-emergent Serious Adverse Event (TESAE)
timeFrame: From first dose of ferric maltol Day 1 through study completions, on average 4 weeks
Other outcomes:
Locations:
city: Leicester
country: United Kingdom
facility: Leicester Royal Infirmary
city: Liverpool
country: United Kingdom
facility: Alder Hey Children's NHS Foundation Trust
city: London
country: United Kingdom
facility: University College London Hospitals NHS Foundation Trust
city: London
country: United Kingdom
facility: King's College Hospital NHS Foundation Trust
city: London
country: United Kingdom
facility: Great Ormond Street Hospital
city: Manchester
country: United Kingdom
facility: Royal Manchester Children's Hospital
city: Nottingham
country: United Kingdom
facility: Nottingham University Hospital
Study officials:
References: