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

Iron Overload Clinical Trial

— MIMAS  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03372083
• Other study ID #: CICL670F2429
• Secondary ID: 2016-003482-25
• Status: Completed
• Phase: Phase 4
• Start date: January 16, 2018
• Est. completion date: December 5, 2019

Study information

• Verified date: August 2020
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study employed a prospective, single-arm, global multi-center interventional open-label, non-randomized design to identify and assess safety profile of the crushed deferasirox FCT when administered up to 24 weeks in pediatric patients aged ≥2 to <6 years with transfusional hemosiderosis. The study was designed to enroll a minimum of 40 patients. Forty-four patients were treated and analyzed.

Description:

The study included a screening period (from Day 0-14) with two visits at least 7 days apart to assess eligibility of patients that were 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) were to occur to determine eligibility. Any current chelation therapy except deferasirox were to be discontinued to undergo a 5-day washout period prior to commencing a 24 week treatment period with crushed deferasirox FCT.

All patients were to have weekly visits for the first month to monitor renal function. Hepatic function were to be assessed biweekly during the first month. Thereafter, monthly safety assessments were to 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.

The planned duration of treatment was 24 weeks followed by a 30-day safety follow up.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 44
• Est. completion date: December 5, 2019
• Est. primary completion date: December 5, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 2 Years to 6 Years

Eligibility

Key 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.

Key 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.

Related Conditions & MeSH terms

• Hemosiderosis
• Iron Overload

Intervention

Drug:
• Deferasirox
Deferosirox was provided in tablet forms of 90, 180 and 360mg. Tablets were crushed in the home environment and administered by sprinkling the full dose on to soft food to be consumed immediately.

Locations

Country	Name	City	State
Egypt	Novartis Investigative Site	Zagazig
Italy	Novartis Investigative Site	Cagliari	ITA
Italy	Novartis Investigative Site	Cona	FE
Italy	Novartis Investigative Site	Napoli
Lebanon	Novartis Investigative Site	Hazmiyeh	Beirut
Oman	Novartis Investigative Site	Muscat
Thailand	Novartis Investigative Site	Bangkok noi	Bangkok
Thailand	Novartis Investigative Site	Muang	Chiangmai
United Arab Emirates	Novartis Investigative Site	Dubai
United Kingdom	Novartis Investigative Site	London

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

Egypt,  Italy,  Lebanon,  Oman,  Thailand,  United Arab Emirates,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants With Selected Gastrointestinal Disorders up to 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). Only descriptive analysis performed.	Baseline (Week 1 Day 1) up to Week 24, plus 30 day safety follow-up.
Secondary	Adverse Events Profile	Analysis of frequencies for treatment emergent Adverse Event (TEAEs), Serious Adverse Event TEAEs and Deaths due to AEs, through the monitoring of relevant clinical and laboratory safety parameters. Only descriptive analysis performed.	Baseline (Week 1 Day 1) up to Week 24, plus 30 day safety follow-up.
Secondary	Number of Participants With Notable Changes in ECG Values From Baseline	Safety measured by the notable post-baseline changes in ECG values (PR, QRS, QT, QTcF and HR intervals) compared to baseline. Baseline was defined as the last non-missing value on or prior to the first dose. Only descriptive analysis performed.	Baseline (Week 1 Day 1) up to Week 24, plus 30 day safety follow-up.
Secondary	Absolute Change From Baseline in Serum Ferritin (SF)	Absolute change from baseline over time in SF values up to 24 weeks of treatment were to be provided. Only descriptive analysis performed.	Baseline (BL), Week 4, Week 8, Week 12, Week 16, EOT (Week 24)
Secondary	Number of Participants With Worst Post-baseline Values in Selected Chemistry Parameters	Safety measured by the worst post-baseline severity grade observed in a patient calculated using the normal/low/high classifications based on local laboratory normal ranges, regardless of the baseline status. Baseline was defined as the last non-missing value on or prior to the first dose. The selected chemistry parameters were: Alanine aminotransferase (ALT), Alkaline phosphatase (ALP), Aspartate aminotransferase (AST), total bilirubin, direct bilirubin, serum creatinine and Urine protein creatinine ratio (UPCR) (Protein/Creatinine represented UPCR). Only descriptive analysis performed.	Baseline (Week 1 Day 1) up to Week 24, plus 30 day safety follow-up.
Secondary	Number of Participants With Clinically Significant Auditory Assessments Changes From Baseline	Safety measured by notable post-baseline changes in Auditory assessments (comprehensive audiometry threshold examination and speech recognition). Baseline was defined as the last non-missing value on or prior to the first dose. Only descriptive analysis performed.	Baseline (Week 1 Day 1) up to Week 24, plus 30 day safety follow-up.
Secondary	Number of Participants With Clinically Significant Ocular Assessments Changes From Baseline	Safety measured by notable post-baseline changes in Ocular assessments (Distance visual acuity test, Applanation tonometry, lens photography, wide angle fundus photography of the retina and optic nerve). Ocular assessment were required at screening and end of Treatment; during treatment, they were to be performed at the discretion of the investigator based on patient reporting symptoms. Baseline was defined as the last non-missing value on or prior to the first dose. Only descriptive analysis performed.	Baseline (Week 1 Day 1) up to Week 24, plus 30 day safety follow-up.
Secondary	Absolute Change From Baseline in Systolic and Diastolic Blood Pressures (mmHg)	Absolute change from baseline over time in systolic and diastolic blood pressures measurements were to be provided. Only descriptive analysis performed.	Baseline (BL), Week 2, Week 3, Week 4, Week 8, Week 12, Week 16, Week 20, EOT (Week 24)
Secondary	Absolute Change From Baseline in Pulse Rate (Bpm)	Absolute change from baseline over time in supine pulse rate was to be provided. Only descriptive analysis performed.	Baseline (BL), Week 2, Week 3, Week 4, Week 8, Week 12, Week 16, Week 20, EOT (Week 24)
Secondary	Absolute Change From Baseline in Body Temperature (°C)	Absolute change from baseline over time in body temperature measurements was to be provided. Only descriptive analysis performed.	Baseline (BL), Week 2, Week 3, Week 4, Week 8, Week 12, Week 16, Week 20, EOT (Week 24)
Secondary	Absolute Change From Baseline in Body Weight (kg)	Absolute change from baseline over time in body weight measurements was to be provided. Only descriptive analysis performed.	Baseline (BL), Week 4, Week 8, Week 12, Week 16, Week 20, EOT (Week 24)
Secondary	Modified Satisfaction With Iron Chelation Therapy (Modified SICT) in Participants Pre-treated With Deferasirox: Mean Change From Baseline in Adherence	The mSICT questionnaire was to be completed at screening visit 1, week 4, week 12 and EOT. The responses from screening visit 1 for mSICT questionnaire were to be considered as baseline. The modified SICT consisted of 20 items that represented 3 domains: Adherence, Preference and Concerns. The mSICT adherence domain consisted of 6 items from the child's perspective and 6 items from the caregiver's perspective, each with a possible score of 1 to 5, for an overall possible score range of 6 to 30. A higher score indicates poorer adherence. Only descriptive analysis performed.	Week 4, Week 12, EOT (Week 24)
Secondary	Modified SICT in Participants Pre-treated With Deferasirox: Number of Participants With Type of Medicine Child Like Scoring	The mSICT questionnaire was to be completed at screening visit 1, week 4, week 12 and EOT. The responses from screening visit 1 for mSICT questionnaire were to be considered as baseline. The modified SICT consisted of 20 items that represented 3 domains: Adherence, Preference and Concerns. The mSICT preference domain consisted of 3 items including the type of medicine the child said he/she liked best (tablet to dissolve in liquid, tablet (taken once a day), tablet (taken 3 times a day), tablet crushed, sprinkle powder on food, injection and I don't know). These items were presented descriptively using frequency counts.	Baseline (BL), Week 4, Week 12, EOT (Week 24)
Secondary	Modified SICT in Participants Pre-treated With Deferasirox: Number of Participants With Reasons Child Preferred Crushed Medicine Scoring	The mSICT questionnaire was to be completed at screening visit 1, week 4, week 12 and EOT. The responses from screening visit 1 for mSICT questionnaire were to be considered as baseline. The modified SICT consisted of 20 items that represented 3 domains: Adherence, Preference and Concerns. The mSICT preference domain consisted of 3 items including the reason child preferred crushed medicine (taste, aftertaste, convenience, number of pills, no/less side effects, can correctly prepare the medicine, easier to remember to take the medicine, number of times he/she has to take the medicine, no/less pain on the injection site, gain personal time with their family and friends, and other). These items were presented descriptively using frequency counts.	Baseline (BL), Week 4, Week 12, EOT (Week 24)
Secondary	Modified SICT in Participants Pre-treated With Deferasirox: Number of Participants With Rank Based on Child's Preference Scoring	The mSICT questionnaire was to be completed at screening visit 1, week 4, week 12 and EOT. The responses from screening visit 1 for mSICT questionnaire were to be considered as baseline. The modified SICT consisted of 20 items that represented 3 domains: Adherence, Preference and Concerns. The mSICT preference domain consisted of 3 items including the rank of the medicine (tablet to dissolve in liquid, tablet taken once a day, tablet taken 3 times a day, tablet crushed, sprinkle powder on food and injection), with a range of 1 to 6 (1 being most preferred and 6 being least preferred), based on what the child prefers. These items were presented descriptively using frequency count.	Baseline (BL), Week 4, Week 12, EOT (Week 24)
Secondary	Modified Satisfaction With Iron Chelation Therapy (Modified SICT) in Participants Pre-treated With Deferasirox: Mean Change From Baseline in Concerns	The mSICT questionnaire was to be completed at screening visit 1, week 4, week 12 and EOT. The responses from screening visit 1 for mSICT questionnaire were to be considered as baseline. The modified SICT consisted of 20 items that represented 3 domains: Adherence, Preference and Concerns. The mSICT concerns domain scale for child's response had a possible range from 2 to 10, based on two questions and the mSICT concerns domain scale for caregiver's responses had the possible range of 1 to 5 based on one question. A higher score indicated fewer concerns. Only descriptive analysis performed.	Week 4, Week 12, EOT (Week 24)
Secondary	Modified Satisfaction With Iron Chelation Therapy (Modified SICT) in Chelation Naive Participants: Mean Change From Baseline in Adherence	The mSICT questionnaire was to be completed at screening visit 1, week 4, week 12 and EOT. The responses from screening visit 1 for mSICT questionnaire were to be considered as baseline. The modified SICT consisted of 20 items that represented 3 domains: Adherence, Preference and Concerns. The mSICT adherence domain consisted of 6 items from the child's perspective and 6 items from the caregiver's perspective, each with a possible score of 1 to 5, for an overall possible score range of 6 to 30. A higher score indicates poorer adherence. Only descriptive analysis performed.	Week 4, Week 12, EOT (Week 24)
Secondary	Modified Satisfaction With Iron Chelation Therapy (Modified SICT) in Chelation Naive Participants: Number of Participants With Type of Medicine Child Like Scoring	The mSICT questionnaire was to be completed at screening visit 1, week 4, week 12 and EOT. The responses from screening visit 1 for mSICT questionnaire were to be considered as baseline. The modified SICT consisted of 20 items that represented 3 domains: Adherence, Preference and Concerns. The mSICT preference domain consisted of 3 items including the type of medicine the child said he/she liked best (tablet to dissolve in liquid, tablet (taken once a day), tablet (taken 3 times a day), tablet crushed, sprinkle powder on food, injection and I don't know). These items were presented descriptively using frequency counts.	Week 4, Week 12, EOT (Week 24)
Secondary	Modified Satisfaction With Iron Chelation Therapy (Modified SICT) in Chelation Naive Participants: Number of Participants With Reasons Child Preferred Crushed Medicine Scoring	The mSICT questionnaire was to be completed at screening visit 1, week 4, week 12 and EOT. The responses from screening visit 1 for mSICT questionnaire were to be considered as baseline. The modified SICT consisted of 20 items that represented 3 domains: Adherence, Preference and Concerns. The mSICT preference domain consisted of 3 items including the reason child preferred crushed medicine (taste, aftertaste, convenience, number of pills, no/less side effects, can correctly prepare the medicine, easier to remember to take the medicine, number of times he/she has to take the medicine, no/less pain on the injection site, gain personal time with their family and friends, and other). These items were presented descriptively using frequency counts.	Week 4, Week 12, EOT (Week 24)
Secondary	Modified Satisfaction With Iron Chelation Therapy (Modified SICT) in Chelation Naive Participants: Number of Participants With Rank Based on Child's Preference Scoring	The mSICT questionnaire was to be completed at screening visit 1, week 4, week 12 and EOT. The responses from screening visit 1 for mSICT questionnaire were to be considered as baseline. The modified SICT consisted of 20 items that represented 3 domains: Adherence, Preference and Concerns. The mSICT preference domain consisted of 3 items including the rank of the medicine (tablet to dissolve in liquid, tablet taken once a day, tablet taken 3 times a day, tablet crushed, sprinkle powder on food and injection), with a range of 1 to 6 (1 being most preferred and 6 being least preferred), based on what the child prefers. These items were presented descriptively using frequency counts.	Week 4, Week 12, EOT (Week 24)
Secondary	Modified Satisfaction With Iron Chelation Therapy (Modified SICT) in Chelation Naive Participants: Mean Change From Baseline in Concerns	The mSICT questionnaire was to be completed at screening visit 1, week 4, week 12 and EOT. The responses from screening visit 1 for mSICT questionnaire were to be considered as baseline. The modified SICT consisted of 20 items that represented 3 domains: Adherence, Preference and Concerns. The mSICT concerns domain scale for child's response had a possible range from 2 to 10, based on two questions and the mSICT concerns domain scale for caregiver's responses had the possible range of 1 to 5 based on one question. A higher score indicated fewer concerns. Only descriptive analysis performed.	Week 4, Week 12, EOT (Week 24)
Secondary	Palatability Score in Chelation Naive Participants	The palatability (taste and ability to consume medicine) questionnaire consisted of 4 items, three items measuring taste or ability to consume medicine and one item measuring aftertaste. The aftertaste item was treated separately. Among the taste items, first one measured taste on a five point response scale. The last two items measured what happened after taking the medicine, i.e., swallowed or vomited etc. and how the perceived amount of liquid taken with the medicine was, enough, not enough or too much. The palatability summary score was calculated from these three items using a scoring matrix and the score ranges from 0 to 11. A higher score indicates better palatability. Only descriptive analysis was performed.	Week 4, Week 12, EOT (Week 24)
Secondary	Number of Chelation Naive Participants With Palatability After Taste Item Scoring	The palatability (taste and ability to consume medicine) questionnaire consisted of 4 items, three items measuring taste or ability to consume medicine and one item measuring aftertaste. The aftertaste item was treated as a separate item and scored on a 5-point response scale with the response format Very good = 1 (best), Good = 2, Neither good nor bad = 3, Bad = 4, Very bad = 5 (worst). Only descriptive analysis performed using frequency counts.	Week 4, Week 12, EOT (Week 24)
Secondary	Palatability Score in Participants Pre-treated With Deferasirox	The palatability (taste and ability to consume medicine) questionnaire consisted of 4 items, three items measuring taste or ability to consume medicine and one item measuring aftertaste. The aftertaste item was treated separately. Among the taste items, first one measured taste on a five point response scale. The last two items measured what happened after taking the medicine, i.e., swallowed or vomited etc. and how the perceived amount of liquid taken with the medicine was, enough, not enough or too much. The palatability summary score was calculated from these three items using a scoring matrix and the score ranges from 0 to 11. A higher score indicates better palatability. Only descriptive analysis was performed.	Week 4, Week 12, EOT (Week 24)
Secondary	Number of Participants Pre-treated With Deferasirox With Palatability After Taste Item Scoring	The palatability (taste and ability to consume medicine) questionnaire consisted of 4 items, three items measuring taste or ability to consume medicine and one item measuring aftertaste. The aftertaste item was treated as a separate item and scored on a 5-point response scale with the response format Very good = 1 (best), Good = 2, Neither good nor bad = 3, Bad = 4, Very bad = 5 (worst). Only descriptive analysis performed using frequency counts.	Baseline, Week 4, Week 12, EOT (Week 24)
Secondary	GI Symptom Score in Chelation Naive Participants	The GI symptom score was calculated from responses to 5 questions, each with a possible score of 1 to 5, for an overall possible score range of 5 to 25, where a lower score represents a less severe GI symptom and a higher score represents a more severe GI symptom. GI symptom scores were summarized using descriptive statistics at week 2, week 3, week 4, week 8, week 12, week 16, week 20 and EOT.	Week 2, Week 3, Week 4, Week 8, Week 12, Week 16, Week 20, EOT (Week 24)
Secondary	Number of Participants With GI Bowel Movements Item Scoring in Chelation Naive Participants	The GI symptom questionnaire consisted of 6 items, 5 of which were scored using a 1-5 rating scale. The sixth item assessed bowel movement frequency during the past week, using 7 response options 0 = 0 ("None"), 1 = 1, 2 = 2, 3 = 3, 4 = 4, 5 = "5 - 10" and 6 = "11 or more". The GI bowel movements item score was presented descriptively using frequency counts.	Week 2, Week 3, Week 4, Week 8, Week 12, Week 16, Week 20, EOT (Week 24)
Secondary	GI Symptom Score in Participants Pre-treated With Deferasirox	The GI symptom score was calculated from responses to 5 questions, each with a possible score of 1 to 5, for an overall possible score range of 5 to 25, where a lower score represents a less severe GI symptom and a higher score represents a more severe GI symptom. GI symptom scores were summarized using descriptive statistics at week 2, week 3, week 4, week 8, week 12, week 16, week 20 and EOT.	Week 2, Week 3, Week 4, Week 8, Week 12, Week 16, Week 20, EOT (Week 24)
Secondary	Number of Participants With GI Bowel Movements Item Scoring in Participants Pre-treated With Deferasirox	The GI symptom questionnaire consisted of 6 items, 5 of which were scored using a 1-5 rating scale. The sixth item assessed bowel movement frequency during the past week, using 7 response options 0 = 0 ("None"), 1 = 1, 2 = 2, 3 = 3, 4 = 4, 5 = "5 - 10" and 6 = "11 or more". The GI bowel movements item score was presented descriptively using frequency counts.	Baseline, Week 2, Week 3, Week 4, Week 8, Week 12, Week 16, Week 20, EOT (Week 24)