Safety and Efficacy Study of Oral Ferric Maltol Compared to Intravenous Iron To Treat Iron Deficiency Anaemia in IBD

A phase 3b, randomized, controlled, multicentre study with oral ferric maltol or intravenous iron (FCM), for the treatment of iron deficiency anaemia in subjects with inflammatory bowel disease.

Approximately 242 eligible subjects will be randomised (1:1) to receive one of the following treatments for the duration of the study treatment period (52 weeks):

* Oral ferric maltol, 30 mg capsule bid.
* Intravenous iron (ferric carboxy maltose) as per SPC

In the FCM arm IV iron treatment will be repeated if the subject is iron deficient at any of the study visits.

Subject participation in the study will consist of 3 periods:

* Screening: Up to 14 days
* Randomised Treatment: 52 weeks
* Post-treatment safety follow-up: 14 days after study medication discontinuation

Primary efficacy and safety of ferric maltol and Intravenous iron (ferric carboxy maltose) will be evaluated after the first 12 weeks.

End of study evaluations will occur at Week 52 or premature discontinuation.

• Ferric Maltol (Drug), also known as Feraccru, Ferric Trimaltol, ST10, ST10-01
• Ferric Carboxy Maltose (Drug)

Primary outcomes

• Number of Subjects Achieving Either a 2g/dL Increase in Hb OR Normalization of Hb at Week 12 [Baseline to Week 12]: Number of subjects achieving either a 2g/dL increase in Hb OR normalization of Hb (>=12g/dL women,>=13g/dL men) at Week 12
• Number of Subjects Achieving Either a 2g/dL Increase in Hb OR Normalization of Hb at Week 12 [Baseline to Week 12]: Number of subjects achieving either a 2g/dL increase in Hb OR normalization of Hb (>=12g/dL women, >=13g/dL men) at Week 12

Secondary outcomes

• Change in Hb Concentration From Baseline to Week 12 [Baseline to Week 12]: Change in hemoglobin concentration from baseline to Week 12.
• Change in Hb Concentration From Baseline to Week 12 in Subjects With a Baseline Hb <9.5 g/dL [Baseline to Week 12]: Change in hemoglobin concentration from baseline to Week 12 in subjects with a baseline hemoglobin <9.5 g/dL.
• Number of Subjects Who Experience a Change From Baseline in Hb Concentration ≥1.0 g/dL at Week 12 [Baseline to Week 12]: Number of subjects who experience a change from baseline in hemoglobin concentration ≥1.0 g/dL at Week 12.
• Number of Subjects With Baseline Hb <9.5g/dL That Achieve an Increase in Hb Concentration of ≥1 g/dL at Week 12 [Baseline to Week 12]: Number of subjects with baseline hemoglobin <9.5g/dL that achieve an increase in hemoglobin concentration of ≥1 g/dL at Week 12.
• Number of Subjects With Hb Concentration Within Normal Limits at Week 12 [Baseline to Week 12]: Number of subjects with Hb concentration within normal limits at Week 12 (normal limit definition: >=12g/dL women, >=13g/dL men)
• Number of Subjects With Baseline Hb Concentration <9.5 g/dL That is Within Normal Limits at Week 12 [Baseline to Week 12]: Number of subjects with baseline Hb concentration <9.5 g/dL that is within normal limits at Week 12 (normal limit definition: >=12g/dL women, >=13g/dL men)
• Proportion of Subjects Who Are Non-anaemic at 6 Months and 12 Months [Baseline to Month 6]: Long term efficacy endpoints i.e. proportion of subjects who are non-anaemic at 6 months and 12 months (normal limit definition: >=12g/dL women, >=13g/dL men)
• Change in Hb Concentration From Baseline to Week 4 [Baseline to Week 4]: Change in hemoglobin concentration from baseline to Week 4.
• Change in Hb Concentration From Baseline to Week 4 in Subjects With a Baseline Hb <9.5 g/dL [Baseline to Week 4]: Change in hemoglobin concentration from baseline to Week 4 in subjects with a baseline hemoglobin <9.5 g/dL.
• Number of Subjects Who Experience a Change From Baseline in Hb Concentration ≥2.0 g/dL at Week 12 [Baseline to Week 12]: Number of subjects who experience a change from baseline in hemoglobin concentration ≥2.0 g/dL at Week 12.
• Number of Subjects With Baseline Hb <9.5g/dL That Achieve an Increase in Hb Concentration of ≥2 g/dL at Week 12 [Baseline to Week 12]: Number of subjects with baseline hemoglobin <9.5g/dL that achieve an increase in hemoglobin concentration of ≥2 g/dL at Week 12.
• Number of Subjects Who Experience a Change From Baseline in Hb Concentration ≥1.0 g/dL at Week 4 [Baseline to Week 4]: Number of subjects who experience a change from baseline in hemoglobin concentration ≥1.0 g/dL at Week 4.
• Number of Subjects With Baseline Hb <9.5g/dL That Achieve an Increase in Hb Concentration of ≥1 g/dL at Week 4 [Baseline to Week 4]: Number of subjects with baseline hemoglobin <9.5g/dL that achieve an increase in hemoglobin concentration of ≥1 g/dL at Week 4.
• Number of Subjects With Hb Concentration Within Normal Limits at Week 4 [Baseline to Week 4]: Number of subjects with Hb concentration within normal limits at Week 4 (normal limit definition: >=12g/dL women, >=13g/dL men)
• Number of Subjects With Baseline Hb Concentration <9.5 g/dL That is Within Normal Limits at Week 4 [Baseline to Week 4]: Number of subjects with baseline Hb concentration <9.5 g/dL that is within normal limits at Week 4 (normal limit definition: >=12g/dL women, >=13g/dL men)
• Number of Subjects Who Experience a Change From Baseline in Hb Concentration ≥2.0 g/dL at Week 4 [Baseline to Week 4]: Number of subjects who experience a change from baseline in hemoglobin concentration ≥2.0 g/dL at Week 4.
• Number of Subjects With Baseline Hb <9.5g/dL That Achieve an Increase in Hb Concentration of ≥2 g/dL at Week 4 [Baseline to Week 4]: Number of subjects with baseline hemoglobin <9.5g/dL that achieve an increase in hemoglobin concentration of ≥2 g/dL at Week 4

Other outcomes

• Change From Baseline Physical Component and Mental Component Score [Baseline to Week 52 (LOCF)]: A multipurpose, proprietary health survey with 36 questions. It was constructed to survey health status in the Medical Outcomes Study and designed for use in clinical practice and research \& general population surveys. The SF-36 includes one multi-item scale that assesses 8 health components: Physical Functioning Component; Social Functioning Component; Role-Physical Component; Bodily Pain Component; Mental Health Component; Role-Emotional Component; Vitality Component; \& General Health Component. These 8 health component scales can be further summarised into 2 summary scores, the Mental Component Score \& the Physical Component Score where higher values mean a better outcome. Both scales range from 0 to 100, where higher scores indicate better health status. The survey will be administered at study visits as indicated in the schedule of assessments, commencing pre-randomization at Visit 2. The survey will be completed by the subjects in their native language.
• Number of Patients With Treatment-emergent Adverse Events (AEs) [Baseline to Week 52]: Number of Patients with Treatment-emergent Adverse Events (AEs).
• Number of Patients With Treatment-emergent Serious Adverse Events (SAEs) [Baseline to Week 52]: Number of Patients with Treatment-emergent Serious Adverse Events (SAEs).

Sex: All, ages: 18 Years to any

All of the following criteria must be met to randomize a subject in the study:

1. Subjects must be competent to understand the information given in the Independent Ethics Committee (IEC) or Institutional Review Board (IRB) approved informed consent form and must sign and date the informed consent prior to any study mandated procedure
2. Subjects must be willing and able to comply with study requirements
3. Age ≥ 18 years
4. Subjects must have a confirmed diagnosis of IBD (endoscopic and/or biopsy)
5. Subjects must be considered suitable for intravenous iron treatment by the Investigator
6. Subjects must have iron deficiency anaemia defined by the following criteria:

   1. Hb 8.0 g/dL and ≤11.0 g/dL for women OR a Hb 8.0 g/dL and ≤12.0 g/dL for men
   2. AND Ferritin <30ng/ml OR Ferritin <100 ng/ml WITH Transferrin saturation (TSAT) <20%
7. Female subjects of childbearing potential (including perimenopausal females who have had a menstrual period within 1 year prior to screening) must agree to use a reliable method of contraception until they have completed the study 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, or a vasectomized partner. Oral contraceptive medications are allowed in this study. Female subjects who are surgically sterile (bilateral tubal ligation, bilateral oophorectomy or hysterectomy) or postmenopausal (defined as no menstrual period within 1 year of screening) are also allowed to participate.

A subject who meets any of the following criteria is not eligible for participation in the study.

1. Subject with anaemia due to any cause other than iron deficiency, including, but not limited to:

   1. Untreated or untreatable severe malabsorption syndrome
   2. Immunosuppressant use. Immunosuppressants are permitted so long as there is no clinical evidence or suspicion of the immunosuppressant contributing to the subject's anaemia or affecting erythropoiesis.

   Variations to dosing are permitted at the discretion of the investigator so long as there is no clinical evidence or suspicion of the immunosuppressant contributing to the subject's anaemia or affecting erythropoiesis
2. Subject who has received prior to screening:

   1. Within 8 weeks intramuscular or intravenous (IV) iron or administration of depot iron preparation
   2. Within 2 weeks a blood transfusion
   3. Oral iron supplementation, taken specifically to treat anaemia, within the previous 4 weeks (Over the Counter (OTC) multivitamins containing iron are permitted)
3. Subjects with active inflammatory bowel disease as defined by a SCCAI score greater than 5 at Screening or a CDAI score greater than 300 in the Screening period (as assessed using the Screening haematocrit (HCT) and CDAI diary card completed by the subject for 7 days prior to planned randomization).
4. Subjects with known hypersensitivity or allergy to either the active substance or excipients of ferric maltol capsules or ferric carboxymaltose solution for IV administration
5. Subjects who have had serious adverse reactions to previous doses of ferric carboxymaltose or any other intravenous iron.
6. Subjects with contraindication for treatment with iron preparations, e.g. hemochromatosis, chronic hemolytic disease, sideroblastic anaemia, thalassemia, or lead intoxication induced anaemia.
7. 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.
8. Subjects who are pregnant or breast feeding.
9. Concomitant medical conditions with significant active bleeding likely to initiate or prolong anaemia.
10. Participation in any other interventional clinical study within 30 days prior to screening.
11. Subject with cardiovascular, liver, renal, haematologic, gastrointestinal, immunologic, endocrine, metabolic, or central nervous system disease that, in the opinion of the Investigator, may adversely affect the safety of the subject or severely limit the lifespan of the subject (i.e. unlikely to complete the full duration of the study).
12. Subject with significant neurologic or psychiatric symptoms resulting in disorientation, memory impairment, or inability to report accurately that might interfere with treatment compliance, study conduct or interpretation of the results (e.g., Alzheimer's disease, schizophrenia or other psychosis, active or current alcohol or drug abuse)
13. Subject who is an inmate of a psychiatric ward, prison, or other state institution.
14. Subject who is an Investigator or any other team member involved directly or indirectly in the conduct of the clinical study.
15. Subjects with severe renal impairment: creatinine clearance <30 mL/min. (Applicable to US sites Only)

Participant flow

Outcome results

• Number of Subjects Achieving Either a 2g/dL Increase in Hb OR Normalization of Hb at Week 12 (Primary), Count of participants, Participants: Oral Ferric Iron Compound 84; Intravenous Iron 105 (p 0.298)
• Number of Subjects Achieving Either a 2g/dL Increase in Hb OR Normalization of Hb at Week 12 (Primary), Count of participants, Participants: Oral Ferric Iron Compound 53; Intravenous Iron 75 (p 0.341)
• Change in Hb Concentration From Baseline to Week 12 (Secondary), Mean, g/dL: Oral Ferric Iron Compound 2.45 +/- 1.449; Intravenous Iron 3.04 +/- 1.576
• Change in Hb Concentration From Baseline to Week 12 in Subjects With a Baseline Hb <9.5 g/dL (Secondary), Mean, g/dL: Oral Ferric Iron Compound 2.83 +/- 1.493; Intravenous Iron 4.18 +/- 1.686
• Number of Subjects Who Experience a Change From Baseline in Hb Concentration ≥1.0 g/dL at Week 12 (Secondary), Count of participants, Participants: Oral Ferric Iron Compound 107; Intravenous Iron 111
• Number of Subjects With Baseline Hb <9.5g/dL That Achieve an Increase in Hb Concentration of ≥1 g/dL at Week 12 (Secondary), Count of participants, Participants: Oral Ferric Iron Compound 35; Intravenous Iron 32
• Number of Subjects With Hb Concentration Within Normal Limits at Week 12 (Secondary), Count of participants, Participants: Oral Ferric Iron Compound 69; Intravenous Iron 101
• Number of Subjects With Baseline Hb Concentration <9.5 g/dL That is Within Normal Limits at Week 12 (Secondary), Count of participants, Participants: Oral Ferric Iron Compound 12; Intravenous Iron 28
• Proportion of Subjects Who Are Non-anaemic at 6 Months and 12 Months (Secondary), Count of participants, Participants: Oral Ferric Iron Compound 52; Intravenous Iron 58
• Change in Hb Concentration From Baseline to Week 4 (Secondary), Mean, g/dL: Oral Ferric Iron Compound 1.27 +/- 0.974; Intravenous Iron 2.19 +/- 1.133
• Change in Hb Concentration From Baseline to Week 4 in Subjects With a Baseline Hb <9.5 g/dL (Secondary), Mean, g/dl: Oral Ferric Iron Compound 1.35 +/- 0.993; Intravenous Iron 2.99 +/- 1.092
• Number of Subjects Who Experience a Change From Baseline in Hb Concentration ≥2.0 g/dL at Week 12 (Secondary), Count of participants, Participants: Oral Ferric Iron Compound 76; Intravenous Iron 96
• Number of Subjects With Baseline Hb <9.5g/dL That Achieve an Increase in Hb Concentration of ≥2 g/dL at Week 12 (Secondary), Count of participants, Participants: Oral Ferric Iron Compound 26; Intravenous Iron 30
• Number of Subjects Who Experience a Change From Baseline in Hb Concentration ≥1.0 g/dL at Week 4 (Secondary), Count of participants, Participants: Oral Ferric Iron Compound 75; Intravenous Iron 105
• Number of Subjects With Baseline Hb <9.5g/dL That Achieve an Increase in Hb Concentration of ≥1 g/dL at Week 4 (Secondary), Count of participants, Participants: Oral Ferric Iron Compound 22; Intravenous Iron 31
• Number of Subjects With Hb Concentration Within Normal Limits at Week 4 (Secondary), Count of participants, Participants: Oral Ferric Iron Compound 31; Intravenous Iron 60
• Number of Subjects With Baseline Hb Concentration <9.5 g/dL That is Within Normal Limits at Week 4 (Secondary), Count of participants, Participants: Oral Ferric Iron Compound 2; Intravenous Iron 15
• Number of Subjects Who Experience a Change From Baseline in Hb Concentration ≥2.0 g/dL at Week 4 (Secondary), Count of participants, Participants: Oral Ferric Iron Compound 26; Intravenous Iron 75
• Number of Subjects With Baseline Hb <9.5g/dL That Achieve an Increase in Hb Concentration of ≥2 g/dL at Week 4 (Secondary), Count of participants, Participants: Oral Ferric Iron Compound 5; Intravenous Iron 28
• Change From Baseline Physical Component and Mental Component Score (Other pre specified), Mean, score on a scale: Oral Ferric Iron Compound 3.0 +/- 7.62; Intravenous Iron 2.5 +/- 7.52
• 2 more outcome measures not shown.

Adverse events

Time frame: The analysis of AEs focuses on TEAEs, which were defined as any AE that occurred on or worsened after the first dose of IMP and up to 14 days after the last dose of IMP (week 52 if study completed)

Serious adverse events by term

Other adverse events by term

• Study Protocol (PDF, 2018-04-30)
• Statistical Analysis Plan (PDF, 2020-07-23)

• Jackie Mitchell, PhD, Study director, Shield Therapeutics