Safety Study of Crushed Deferasirox Film Coated Tablets in Pediatric Patients With Transfusional Hemosiderosis (MIMAS)

• ClinicalTrials.gov Identifier: NCT03372083
• Recruitment Status: Active, not recruiting
• First Posted: December 13, 2017
• Last Update Posted: July 15, 2019
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Study Description

Brief Summary:

The study employs an interventional, prospective, single arm, open label, global, multicenter,non-randomized trial design to monitor and assess the safety profile of the crushed deferasirox FCT in pediatric patients between age ≥2 to <6 with transfusional hemosiderosis over 24 weeks. This study will aim to enroll at least 40 patients.

Condition or disease	Intervention/treatment	Phase
Iron Over Load	Drug: Deferasirox	Phase 4

Detailed Description:

• The study will include a screening period (from Day 0-14) with two visits at least 7 days apart to assess eligibility of patients that are chelation naïve or on a prior iron chelator treatment other than DFX. For Patients on DFX treatment prior to study entry only one screening visit (screening visit 1) will occur to determine eligibility. Any current chelation therapy except deferasirox will be discontinued to undergo a 5-day washout period prior to commencing a 24 week treatment period with crushed deferasirox FCT.
• All patients will have weekly visits for the first month to monitor renal function. Hepaticfunction will be assessed biweekly during the first month. Thereafter, monthly safety assessments will be performed, including the monitoring of serum ferritin values and trends in order to adapt patient treatment.

Eligibility, application of dosing standards and adjustments, as well as safety and serum ferritin assessments as specified in the protocol, will occur in accordance with the EU label throughout the study.

- Patients will continue therapy up to 24 weeks.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 44 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Single-arm Interventional Phase IV, Post-authorisation Study Evaluating the Safety of Pediatric Patients With Transfusional Hemosiderosis Treated With Deferasirox Crushed Film Coated Tablets
• Actual Study Start Date: January 16, 2018
• Estimated Primary Completion Date: November 14, 2019
• Estimated Study Completion Date: December 30, 2019

Arms and Interventions

Arm	Intervention/treatment
Experimental: Deferasirox; Crushed deferasirox (ICL670) FCT for oral use daily. Deferasirox FCT dosing is based on subject's weight	Drug: Deferasirox; Deferosirox is provided in tablet forms of 90, 180 and 360mg. Tablets must be crushed.; Other Name: ICL670

Outcome Measures

Primary Outcome Measures :

1. Percentage of patients with selected gastrointestinal disorders up to 24 weeks [ Time Frame: Baseline up to approximately 24 weeks ]
   To assess the safety of crushed deferasirox FCT with respect to selected gastrointestinal (GI) disorders (esophagitis, stomatitis, mouth ulceration, gastric ulcers, haemorrhage, abdominal pain, diarrhea, nausea, and vomiting)

Secondary Outcome Measures :

1. Percentage of patients who experienced AEs suspected to be related to study drug up to 24 weeks [ Time Frame: Baseline up to approximately 24 weeks ]
   Evaluate AEs suspected to be related to the crushed deferasirox FCT
2. Change from baseline ECGs up to 24 weeks [ Time Frame: Baseline up to approximately 24 weeks ]
   12-lead ECGs will be obtained for each subject during the study. ECG data will be read and interpreted centrally. Any clinically significant (notable) changes will be reported (which may include PR, QRS, QT, QTcF and HR intervals, if appropriate). Clinically significant abnormalities will be reported as adverse events.
3. Change from baseline serum ferritin (SF) up to 24 weeks [ Time Frame: Baseline up to approximately 24 weeks ]
   To assess the efficacy of deferasirox FCT treatment.Absolute change from baseline over time in SF values up to 24 weeks of treatment will be provided
4. Absolute change for serum creatinine up to 24 weeks [ Time Frame: Baseline up to approximately 24 weeks ]
   To assess the overall safety of crushed FCT of deferasirox for predetermined acceptable lab values
5. Absolute change for creatinine clearance UPCR up to 24 weeks [ Time Frame: Baseline up to approximately 24 weeks ]
   To assess the overall safety of crushed FCT of deferasirox for predetermined acceptable lab values. UPCR=urine protein to creatinine ratio
6. Absolute change for total bilirubin up to 24 weeks [ Time Frame: Baseline up to approximately 24 weeks ]
   To assess the overall safety of crushed FCT of deferasirox for predetermined acceptable lab values
7. Absolute change for alkaline phosphatase (ALP) up to 24 weeks [ Time Frame: Baseline up to approximately 24 weeks ]
   To assess the overall safety of crushed FCT of deferasirox for predetermined acceptable lab values of ALP(alkaline phosphatase).
8. Change in Mean Domain Scores of the Modified Satisfaction With Iron Chelation Therapy (Modified SICT) up to 24 weeks [ Time Frame: Baseline up to approximately 24 weeks ]
   The mSICT questionnaire will be completed at screening visit 1, week 4, week 12 and EOT. The responses from screening visit 1 for mSICT questionnaire will be considered as baseline. The modified SICT consists of 20 items that represent 3 domains: Adherence, Preference and Concerns
9. Palatability Questionnaire Score up to 24 weeks [ Time Frame: Baseline (screening Visit 1) up to approximately 24 weeks ]

   The palatable questionnaire will be completed at screening visit 1, week 4, week 12, and EOT. The responses at screening visit 1 for palatable questionnaire will be considered as baseline. The palatability questionnaire consists of 4 items. Two items measure the taste Item 1 and aftertaste (Item 2) of the medication and are scored on a 5-point response scale with the response format Very good =1 (best), Good=2,Neither good nor bad =3, Bad=4, and Very bad=5 (worst).

   The aftertaste item will be treated as an independent item (and will not be part of the scoring) and will be presented descriptively.

10. Change in GI Symptoms to 24 weeks [ Time Frame: Baseline (screening Visit 1) up to approximately 24 weeks ]
    The GI symptom questionnaire consists of 6 items, 5 of which are scored using a 1-5 rating scale with appropriate end anchors to rate the symptom. The items are Pains in the belly, Nausea (feeling like throwing up), Vomiting, Constipation and Diarrhea. All are scored as Always=5 (worst), Most of the time=4, Sometimes=3, Rarely=2, Never=1 (best). The sixth item assesses number of bowel movements during the past week with 7 possible responses: 0 to 4, 5=5 to 10 and 6 = greater than 11
11. Change from baseline in systolic and diastolic blood pressures(mmHg) up to 24 weeks [ Time Frame: Baseline up to approximately 24 weeks ]
    The change from baseline in systolic and diastolic blood pressures(mmHg) will be summarized using descriptive statistics.
12. Change from baseline Ocular assessments up to 24 weeks [ Time Frame: Baseline up to approximately 24 weeks ]
    Ocular assessments will be performed at screening, EOT and as needed basis and will include: Distance visual acuity test, Applanation tonometry, lens photography, wide angle fundus photography of the retina and optic nerve. Clinically significant abnormalities will be reported as adverse events.
13. Change from baseline auditory assessments up to 24 weeks [ Time Frame: Baseline up to approximately 24 weeks ]
    Auditory assessments will be performed at screening, EOT and as needed basis: comprehensive audiometry threshold examination, speech recognition. The data will be summarized using the Safety set. Clinically significant abnormalities will be reported as adverse events.
14. Absolute change for ALT(alanine aminotransferase) up to 24 weeks [ Time Frame: Baseline up to approximately 24 weeks ]
    To assess the overall safety of crushed FCT of deferasirox for predetermined acceptable lab values for ALT(alanine aminotransferase)
15. Absolute change for AST( Aspartate aminotransferase) up to 24 weeks [ Time Frame: Baseline up to approximately 24 weeks ]
    To assess the overall safety of crushed FCT of deferasirox for predetermined acceptable lab values for AST ( Aspartate aminotransferase)
16. Change from baseline height(cm) up to 24 weeks [ Time Frame: Baseline up to approximately 24 weeks ]
    The change from baseline in height(cm) will be summarized using descriptive statistics.
17. Change from baseline in weight(kg) up to 24 weeks [ Time Frame: Baseline up to approximately 24 weeks ]
    The change from baseline in weight(kg) will be summarized using descriptive statistics.
18. Change from baseline in temperature(°C), up to 24 weeks [ Time Frame: Baseline up to approximately 24 weeks ]
    The change from baseline in temperature(°C) will be summarized using descriptive statistics.
19. Change from baseline in supine bolld pressure (mmHg) up to 24 weeks [ Time Frame: Baseline up to approximately 24 weeks ]
    The change from baseline in supine blood pressure (mmHg) will be summarized using descriptive statistics.
20. Change from baseline in supine pulse rate(bpm) up to 24 weeks [ Time Frame: Baseline up to approximately 24 weeks ]
    The change from baseline in supine pulse rate(bpm) will be summarized using descriptive statistics.

Eligibility Criteria

• Ages Eligible for Study: 2 Years to 6 Years (Child)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Patients ≥2 to <6 years old diagnosed with transfusional hemosiderosis
2. Documented history of red blood cell transfusions
3. Written informed consent/assent before any study-specific procedures. The consent will be obtained from caregiver(s) or patient's legal representative. Investigators will also obtain assent of patients according to local, regional, or national regulations.
4. For patients on prior DFX: Serum ferritin (SF) >500 ng/mL, measured at screening visit 1 and requiring a DFX daily dose equivalent to FCT ≥ 7mg/kg/day.
5. For patients on a prior chelator other than DFX (e.g. deferiprone or deferoxamine) or chelation naive: Serum ferritin (SF) >1000 ng/mL measured at screening visits 1 and 2.

Exclusion Criteria:

1. Patients that receive more than one iron chelator at the same time as current iron chelation treatment. (Patients who have received combination therapy in their medical history but are currently being treated with a single ICT agent are eligible.)

2. Patients continuing on deferoxamine or deferiprone in addition to study treatment.

   (Patients switching to or continuing on deferasirox are eligible).

3. Unresolved adverse events if the patient was previously treated with deferiprone or deferoxamine or deferasirox.
4. Significant proteinuria as indicated by a urinary protein/creatinine ratio > 0.5 mg/mg in a non-first void sample urine measured at screening visit 1.
5. Serum creatinine > age adjusted ULN measured at any screening visit
6. Creatinine clearance below 90 mL/minute measured at any screening visit. Creatinine clearance using the Schwartz formula will be estimated from serum creatinine measured at each respective visit.
7. ALT and/or AST > 2.5 x ULN measured at screening visit 1.
8. Total bilirubin (TBIL) >1.5 x ULN measured at screening visit 1.
9. Patients with significant impaired GI function or GI disease that may significantly alter the absorption of oral deferasirox FCT (e.g. ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection).
10. History of and/or laboratory evidence of active Hepatitis B or Hepatitis C (HBsAg in the absence of HBsAb OR HCV Ab positive with HCV RNA positive.
11. Liver disease with severity of Child-Pugh Class B or C.
12. History of hypersensitivity to any of the study drug or excipients.
13. Patients participating in another clinical trial or receiving an investigational drug.
14. Patients with a known history of HIV seropositivity.
15. Patients unwilling or unable to comply with the protocol.
16. History of malignancy of any organ system, treated or untreated, within the past 5 years whether or not there is evidence of local recurrence or metastases, with the exception of localized basal cell carcinoma of the skin.

17. Significant medical condition interfering with the ability to partake in this study (e.g.

    uncontrolled hypertension, unstable cardiac disease not controlled by standard medical therapy, systemic disease: cardiovascular, renal, hepatic, etc.).

18. Female patients who reach menarche and they or their caregivers refuse pregnancy testing and/or if there is a positive pregnancy test result.

Contacts and Locations

Locations

Egypt

Novartis Investigative Site

Zagazig, Egypt, 44519

Italy

Novartis Investigative Site

Cona, FE, Italy, 44100

Novartis Investigative Site

Cagliari, ITA, Italy, 09121

Novartis Investigative Site

Napoli, Italy, 80138

Lebanon

Novartis Investigative Site

Hazmiyeh, Beirut, Lebanon, PO BOX 213

Oman

Novartis Investigative Site

Muscat, Oman, 123

Russian Federation

Novartis Investigative Site

Moscow, Russian Federation, 117198

Thailand

Novartis Investigative Site

Bangkok noi, Bangkok, Thailand, 10700

Novartis Investigative Site

Muang, Chiangmai, Thailand, 50200

United Arab Emirates

Novartis Investigative Site

Dubai, United Arab Emirates, 9115

United Kingdom

Novartis Investigative Site

London, United Kingdom, NW1 2BU

Sponsors and Collaborators

Novartis Pharmaceuticals

More Information

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT03372083 History of Changes
• Other Study ID Numbers: CICL670F2429
• First Posted: December 13, 2017
• Last Update Posted: July 15, 2019
• Last Verified: July 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Novartis ( Novartis Pharmaceuticals ):

Iron Chelation Therapy; Deferasirox; Asunra; Jadenu; Exjade; ICL 670; Pediatric

Additional relevant MeSH terms:

Hemosiderosis; Iron Overload; Iron Metabolism Disorders; Metabolic Diseases; Deferasirox; Iron Chelating Agents; Chelating Agents; Sequestering Agents; Molecular Mechanisms of Pharmacological Action