Safety and Efficacy Study of Oral Ferric Iron To Treat Iron Deficiency Anaemia in Quiescent Crohn's Disease (AEGIS-2) (AEGIS-2)

• ClinicalTrials.gov Identifier: NCT01352221
• Recruitment Status: Completed
• First Posted: May 11, 2011
• Results First Posted: October 27, 2017
• Last Update Posted: October 30, 2020
• Sponsor: Shield Therapeutics
• Information provided by (Responsible Party): Shield Therapeutics

Study Description

Brief Summary:

The purpose of this study is to determine whether ST10-021, an oral ferric iron preparation, is safe and effective in the treatment of iron deficiency anaemia (IDA) in subjects with non-active Crohn's Disease (CD).

Condition or disease	Intervention/treatment	Phase
Iron Deficiency Anaemia; Inflammatory Bowel Disease; Crohn's Disease	Drug: ST10; Drug: Placebo oral capsule	Phase 3

Detailed Description:

As no curative treatment is currently available for Crohn's Disease (CD), treatment options are restricted to controlling symptoms, maintaining remission and preventing relapse. As such, treatment of iron deficiency anaemia (IDA), a key symptom of the disease, is integral to the medical management of CD. Iron deficiency anaemia in CD is a chronically debilitating disorder which has a significant impact on the quality of life of affected subjects. Characteristic symptoms of IDA include chronic fatigue, headache, and subtle impairment of cognitive function. Up to one third of subjects with CD suffer from recurrent anaemia, with hospitalization required in severe cases. First line standard therapy for mild to moderate IDA in CD is typically oral ferrous products (OFP), however this is often not successful. Many subjects are intolerant and suffer from continuously occurring side effects, occasional exacerbation of inflammatory lesions and failure to correct iron deficiency. Common adverse effects of OFP include nausea, epigastric discomfort and constipation, all of which are dose-related and appear especially evident in subjects with CD.

As compared to oral ferrous iron, oral ferric iron can be administered with improved tolerability and the total dose exposure of unabsorbed iron within the gastrointestinal tract is significantly reduced. In addition, the iron is retained in its chelated form if not absorbed and this may reduce the risk of irritation within the gastrointestinal tract. Clinical studies conducted to date provide preliminary evidence for the therapeutic potential of ST10-021 in patients with IDA in Inflammatory Bowel Disease, including CD.

The purpose of this study is to determine whether ST10-021 is safe and effective in the treatment of IDA in subjects with non-active CD. In an effort to target an underserved population, the study will include only those subjects who have failed OFP in the past, or where OFP cannot be used.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 128 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Prospective, Multicentre, Randomised, Double-blind, Placebo Controlled Study With Oral ST10-021 for the Treatment of Iron Deficiency Anaemia in Subjects With Quiescent Crohn's Disease Where Oral Ferrous Preparations Have Failed or Cannot be Used (AEGIS 2)
• Study Start Date: August 2011
• Actual Primary Completion Date: October 2013
• Actual Study Completion Date: October 2014

Arms and Interventions

Arm	Intervention/treatment
Experimental: ST10; ST10 (Ferric Maltol) 30mg capsules, taken orally twice a day	Drug: ST10; 30 mg capsules to be taken orally twice a day for 12 weeks in double-blind phase; Other Names: Ferric Trimaltol; Ferric Maltol
Placebo Comparator: Placebo; Matching placebo capsules for ST10 (Ferric Maltol), taken orally twice a day	Drug: Placebo oral capsule; Matching placebo capsules for ST10 to be taken orally twice a day for 12 weeks in double-blind phase

Outcome Measures

Primary Outcome Measures :

1. Change in Haemoglobin (Hb) Concentration From Baseline to Week 12 (Full Analysis Set, FAS) [ Time Frame: Baseline to Week 12 - double-blind phase ]
   Primary efficacy endpoint, defined as the change in Hb concentration from Baseline to Week 12. Baseline was defined as the pre-dose Hb concentration measured at the Randomisation Visit (Week 0). Missing Randomisation Hb values were replaced by Screening Hb values, if the randomisation was within the protocol-specified window. Hb concentration (g/dL) was analysed by a central laboratory from blood samples collected at every clinic visit: Screening, Randomisation (Week 0), Weeks 4, 8, 12, 14, 16, 20, 24, 36, 48, 64, Weeks 14 to 64 were open-label. The baseline, absolute concentration and change from baseline in Hb at all post-randomisation visits were listed and summarised by week using descriptive statistics. An analysis of covariance (ANCOVA) was used to analyse the primary endpoint; this included treatment, gender and disease as factors and baseline Hb as a covariate.

Secondary Outcome Measures :

1. Proportion of Subjects That Achieved ≥1 g/dL Change From Baseline in Hb Concentration at Week 12 (Full Analysis Set, FAS) [ Time Frame: Subjects that achieved ≥1 g/dL change from baseline in Hb concentration at Week 12 - double-blind phase ]
   Logistic regression analysis of proportion of subjects that achieved ≥1 g/dL change from baseline in Hb concentration at Week 12 in the double-blind phase
2. Proportion of Subjects That Achieved ≥2 g/dL Change From Baseline in Hb Concentration at Week 12 (Full Analysis Set, FAS) [ Time Frame: Baseline to Week 12 - double-blind phase ]
   Logistic regression analysis of proportion of subjects that achieved ≥2 g/dL change from baseline in Hb concentration at Week 12 in the double-blind phase
3. Proportion of Subjects That Achieved Hb Concentration Within Normal Range at Week 12 (Full Analysis Set, FAS) [ Time Frame: Baseline to Week 12 - double-blind phase ]
   Logistic regression analysis of proportion of subjects that achieved Hb concentration within normal range at Week 12 end of double-blind phase
4. Change in Hb Concentration From Baseline to Week 4 (Full Analysis Set, FAS) [ Time Frame: Baseline to Week 4 - double-blind phase ]
   ANCOVA analysis of the change in Hb concentration from Baseline to Week 4 of the double-blind phase - Full Analysis Set, multiple imputation
5. Change in Hb Concentration From Baseline to Week 8 (Full Analysis Set, FAS) [ Time Frame: Baseline to Week 8 - double-blind phase ]
   ANCOVA analysis of Change in Hb concentration from Baseline to Week 8 of double-blind phase - FAS, multiple imputation
6. Change in Haemoglobin Concentration From Baseline to Week 16 (Full Analysis Set, FAS) [ Time Frame: Baseline to Week 16 - open-label phase ]
   Change in Haemoglobin Concentration from Baseline to Week 16 (FAS), after 12-week double-blind phase and first 4 weeks of open-label ST10 treatment.
7. Change in Haemoglobin Concentration From Baseline to Week 20 (Full Analysis Set, FAS) [ Time Frame: Baseline to Week 20 - open-label phase ]
   Change in Haemoglobin Concentration from Baseline to Week 20 (FAS), after 12-week double-blind phase and then 8 weeks of open-label ST10 treatment
8. Change in Haemoglobin Concentration From Baseline to Week 24 (Full Analysis Set, FAS) [ Time Frame: Baseline to Week 24 - open-label phase ]
   Change in Haemoglobin Concentration from Baseline to Week 24 (FAS), after 12-week double-blind phase and then 12 weeks of open-label ST10 treatment
9. Change in Haemoglobin Concentration From Baseline to Week 36 (Full Analysis Set, FAS) [ Time Frame: Baseline to Week 36 - open-label phase ]
   Change in Haemoglobin Concentration from Baseline to Week 36 (FAS), after 12-week double-blind phase and then 24 weeks of open-label ST10 treatment
10. Change in Haemoglobin Concentration From Baseline to Week 48 (Full Analysis Set, FAS) [ Time Frame: Baseline to Week 48 - open-label phase ]
    Change in Haemoglobin Concentration from Baseline to Week 48 (FAS), after 12-week double-blind phase and then 36 weeks of open-label ST10 treatment
11. Change in Haemoglobin Concentration From Baseline to Week 64 (Full Analysis Set, FAS) [ Time Frame: Baseline to Week 64 - open-label phase ]
    Change in Haemoglobin Concentration from Baseline to Week 64 (FAS), after 12-week double-blind phase and then 52 weeks of open-label ST10 treatment
12. Change in Haemoglobin Concentration From Baseline to Week 64 EOS (Full Analysis Set, FAS) [ Time Frame: Baseline to Week 64 EOS - open-label phase ]
    Change in Haemoglobin Concentration from Baseline to Week 64 EOS (FAS) - Week 64 was re-categorised as Week 64 EOS for those subjects who withdrew from the study early and the 'Week 64' visit was outside the visit window of 64 weeks ± 2 days
13. Proportion of Subjects That Achieved Haemoglobin Concentration Within Normal Range at Week 16 (Full Analysis Set, FAS) [ Time Frame: Baseline to Week 16 - open-label phase ]
    Proportion of subjects that achieved Haemoglobin Concentration within normal range at Week 16 (Full Analysis Set), after 12-week double-blind phase and first 4 weeks of open-label ST10 treatment
14. Proportion of Subjects That Achieved Haemoglobin Concentration Within Normal Range at Week 36 (Full Analysis Set, FAS) [ Time Frame: Baseline to Week 36 - open-label phase ]
    Proportion of subjects that achieved Haemoglobin Concentration within normal range at Week 36 (Full Analysis Set), after 12-week double-blind phase and 24 weeks of open-label ST10 treatment
15. Proportion of Subjects That Achieved Haemoglobin Concentration Within Normal Range at Week 64 (Full Analysis Set, FAS) [ Time Frame: Baseline to Week 64 - open-label phase ]
    Proportion of subjects that achieved Haemoglobin Concentration within normal range at Week 64 (Full Analysis Set), after 12-week double-blind phase and 52 weeks of open-label ST10 treatment
16. Change in Haemoglobin Concentration From Baseline to Week 12 (Per Protocol Analysis Set, PPAS) [ Time Frame: Baseline to Week 12 - double-blind phase ]
    ANCOVA sensitivity analysis of the Primary efficacy endpoint analysis on the PPAS - Change in Haemoglobin Concentration from Baseline to Week 12
17. Change in Haemoglobin Concentration From Baseline to Week 12 (Full Analysis Set [FAS] LOCF) [ Time Frame: Baseline to Week 12 - double-blind phase ]
    ANCOVA sensitivity analysis of the Primary efficacy endpoint analysis on the FAS LOCF - Change in Haemoglobin Concentration from Baseline to Week 12

Other Outcome Measures:

1. Change in Serum Ferritin Concentration From Baseline to Week 12 (Full Analysis Set, FAS) [ Time Frame: Baseline to Week 12 - double-blind phase ]
   Change in serum Ferritin concentration from Baseline to Week 12 (Full Analysis Set), after 12-week double-blind phase
2. Change in Serum TSAT% From Baseline to Week 12 (Full Analysis Set, FAS) [ Time Frame: Baseline to Week 12 - double-blind phase ]
   Change in serum TSAT% from Baseline to Week 12 (FAS), after 12-week double-blind phase
3. Change in Serum Ferritin Concentration From Baseline to Week 64 (Full Analysis Set, FAS) [ Time Frame: Baseline to Week 64 - open-label phase ]
   Change in serum Ferritin concentration from Baseline to Week 64 (FAS), after 12-week double-blind phase and 52 weeks open-label ST10 treatment
4. Change in Serum TSAT% From Baseline to Week 64 (Full Analysis Set, FAS) [ Time Frame: Baseline to Week 64 - open-label phase ]
   Change in serum TSAT% from Baseline to Week 64 (Full Analysis Set), after 12-week double-blind phase and 52 weeks open-label ST10 treatment
5. Irritable Bowel Disease Questionnaire (IBDQ) Score at Week 12 (Full Analysis Set, FAS) [ Time Frame: Week 12 - double-blind phase ]

   Irritable Bowel Disease Questionnaire (IBDQ) score at Week 12 (FAS), end of double-blind phase.

   The IBDQ was developed as an activity index for determining the effect of Crohn's disease symptoms on perceived quality of life. It is a 32-item questionnaire with four dimensions: bowel function, emotional status, systemic symptoms and social function. Total IBDQ score ranges from 32 to 224, with higher scores indicating better quality of life. The score of patients in remission usually is between 170 and 190.

6. Irritable Bowel Disease Questionnaire (IBDQ) Score at Week 64 (Full Analysis Set, FAS) [ Time Frame: Week 64 - open-label phase ]

   Irritable Bowel Disease Questionnaire (IBDQ) score at Week 64 (FAS), after 12-week double-blind phase and 52 weeks of open-label ST10 treatment.

   The IBDQ was developed as an activity index for determining the effect of Crohn's disease symptoms on perceived quality of life. It is a 32-item questionnaire with four dimensions: bowel function, emotional status, systemic symptoms and social function. Total IBDQ score ranges from 32 to 224, with higher scores indicating better quality of life. The score of patients in remission usually is between 170 and 190.

7. Change From Baseline in Crohn's Disease Activity Index (CDAI) Score at Week 12 (Full Analysis Set, FAS) [ Time Frame: Baseline to Week 12 - double-blind phase ]

   Change from baseline (randomisation) in Crohn's Disease Activity Index (CDAI) score at Week 12 (FAS), end of double-blind phase (in subjects with CD).

   The CDAI is a research tool used to quantify the symptoms of patients with Crohn's disease. CDAI score can range from 0 to approximately 600. Traditionally, for clinical trials, clinical remission is defined as a CDAI score <150, clinical response is a decrease in CDAI score of 70-100. Mildly active Crohn's disease is defined as a CDAI score 150-220, moderate-severe Crohn's is typically a CDAI 220-450, and severe disease is defined as a CDAI >450.

8. Change From Baseline in Crohn's Disease Activity Index (CDAI) Score at Week 64 (Full Analysis Set, FAS) [ Time Frame: Baseline to Week 64 - open-label phase ]

   Change from baseline in Crohn's Disease Activity Index (CDAI) score at Week 64 (FAS), after 12-week double blind phase and 52 weeks open-label ST10 treatment (in participants with CD only).

   The CDAI is a research tool used to quantify the symptoms of patients with Crohn's disease. CDAI score can range from 0 to approximately 600. Traditionally, for clinical trials, clinical remission is defined as a CDAI score <150, clinical response is a decrease in CDAI score of 70-100. Mildly active Crohn's disease is defined as a CDAI score 150-220, moderate-severe Crohn's is typically a CDAI 220-450, and severe disease is defined as a CDAI >450.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Competency to understand and sign the IEC/IRB approved informed consent form prior to any study mandated procedure, and willing/able to comply with study requirements
• Age ≥ 18 years
• Current diagnosis of quiescent CD as defined by CDAI score of < 220
• Current diagnosis of IDA as defined by Hb ≥ 9.5 g/dl and <12.0 g/dl for women and ≥ 9.5 g/dl and <13.0 g/dl for men; ferritin < 30 µg/l
• Prior OFP failure as defined per protocol
• If receiving protocol-allowed immunosuppressant must be on stable dose
• Females of childbearing potential must agree to use a reliable method of contraception

Exclusion Criteria:

• Anaemia due to any cause other than iron deficiency
• Intramuscular or intravenous injection or administration of depot iron preparation, blood infusions, or erythropoietin within 3 months
• Oral iron supplementation use within 1 month
• Use of immunosuppressant with known effect of anaemia induction within 1 month
• Vitamin B12 or Folic Acid injection/infusion within 4 weeks
• Untreated Vitamin B-12 or Folic Acid deficiency
• Known hypersensitivity or allergy to ST10-021 or components of the study medication, or contraindication for treatment with iron preparations
• Other chronic or acute inflammatory or infectious diseases
• Creatinine > 2.0 mg/dl
• AST or ALT levels ≥ 5 times the upper limit of normal
• Cardiovascular, liver, renal, hematologic, gastrointestinal, immunologic, endocrine, metabolic, or central nervous system disease that may adversely affect the safety of the subject and/or efficacy of the study drug or severely limit the lifespan of the subject
• History of malignancy within the past 5 years (except in situ removal of basal cell carcinoma)
• 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
• Participation in another interventional clinical study within 30 days or during the study
• Inmates of a psychiatric ward, prison, or other state institution
• Investigator or any other team member involved directly or indirectly in the conduct of the clinical study
• Scheduled or expected hospitalization and/or surgery during the course of the study
• Females who are pregnant or lactating

Contacts and Locations

Sponsors and Collaborators

Shield Therapeutics

Investigators

• Study Director: Nicholas Mallard, PhD; Shield Therapeutics

More Information

Publications of Results:

Gasche C, Ahmad T, Tulassay Z, Baumgart DC, Bokemeyer B, Buning C, Howaldt S, Stallmach A; AEGIS Study Group. Ferric maltol is effective in correcting iron deficiency anemia in patients with inflammatory bowel disease: results from a phase-3 clinical trial program. Inflamm Bowel Dis. 2015 Mar;21(3):579-88. doi: 10.1097/MIB.0000000000000314.

Schmidt C, Ahmad T, Tulassay Z, Baumgart DC, Bokemeyer B, Howaldt S, Stallmach A, Buning C; AEGIS Study Group. Ferric maltol therapy for iron deficiency anaemia in patients with inflammatory bowel disease: long-term extension data from a Phase 3 study. Aliment Pharmacol Ther. 2016 Aug;44(3):259-70. doi: 10.1111/apt.13665. Epub 2016 May 29.

• Responsible Party: Shield Therapeutics
• ClinicalTrials.gov Identifier: NCT01352221
• Other Study ID Numbers: ST10-01-302; 2010-023589-39 ( EudraCT Number )
• First Posted: May 11, 2011
• Results First Posted: October 27, 2017
• Last Update Posted: October 30, 2020
• Last Verified: October 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

Keywords provided by Shield Therapeutics:

iron deficiency; anaemia; inflammatory bowel disease; Crohn's Disease

Additional relevant MeSH terms:

Crohn Disease; Intestinal Diseases; Inflammatory Bowel Diseases; Anemia; Anemia, Iron-Deficiency; Iron Deficiencies; Deficiency Diseases; Hematologic Diseases; Gastroenteritis; Gastrointestinal Diseases; Digestive System Diseases; Iron Metabolism Disorders; Metabolic Diseases; Anemia, Hypochromic; Malnutrition; Nutrition Disorders; Ferric maltol; Hematinics