Study to Evaluate the Efficacy and Safety of Deferasirox Film-coated Tablet Versus Phlebotomy in Patients With Hereditary Hemochromatosis (HH)

A Phase II, Multicenter, Open-label, Randomized Two-year Study to Evaluate the Efficacy and Safety of Deferasirox Film-coated Tablet Versus Phlebotomy in Patients With Hereditary Hemochromatosis.

The purpose of this study was to evaluate the efficacy and safety of deferasirox film coated tablet (FCT) versus phlebotomy for the management of iron overload in adults with Hereditary Hemochromatosis (HH) at risk of iron-related morbidity. This evaluation provided information on the two treatment options in terms of the rate of response of proportion of patients reaching the study target SF ≤ 100 μg/L and their associated safety profiles.

In addition to exploring the safety and efficacy of deferasirox FCT in hereditary hemochromatosis (HH), this study is being conducted to fulfill an FDA post-marketing requirement [PMC 750-10 (Exjade) /PMR 2888-8 (Jadenu)] to provide additional randomized data to confirm the ocular safety profile of deferasirox through detailed ocular assessments in patients treated with deferasirox FCT for 2 years.

Study Overview

• Status: Terminated
• Conditions: Hereditary Hemochromatosis
• Intervention / Treatment: Procedure: Phlebotomy; Drug: Deferasirox FCT

Detailed Description

This was a Phase II, multicenter, open-label, randomized two-year study in adults with Hereditary Hemochromatosis (HH) confirmed by HH genotype with iron overload. Eligible subjects were identified during a 4-week screening period, then randomized in a 2:1 ratio to be treated with deferasirox FCT or phlebotomy for up to 24 months (104 weeks).

• Study Type: Interventional
• Enrollment (Actual): 45
• Phase: Phase 2

Contacts and Locations

Study Locations

• Belgium
  • Leuven, Belgium, 3000
    • Novartis Investigative Site
• France
  • Limoges cedex, France, 87042
    • Novartis Investigative Site
  • Rennes, France, 35043
    • Novartis Investigative Site
• Romania
  • Sibiu, Romania, 550245
    • Novartis Investigative Site
• Russian Federation
  • Moscow, Russian Federation, 125167
    • Novartis Investigative Site
• Slovakia
  • Bratislava, Slovakia, 85107
    • Novartis Investigative Site
  • Bratislava, Slovakia, 831 01
    • Novartis Investigative Site
• Spain
  • Las Palmas de Gran Canaria, Spain, 35010
    • Novartis Investigative Site
  • Espana
    • Manresa, Espana, Spain, 08241
      • Novartis Investigative Site
  • Vizcaya
    • Baracaldo, Vizcaya, Spain, 48903
      • Novartis Investigative Site
• Switzerland
  • Lugano, Switzerland, 6900
    • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

Written informed consent must be obtained prior to any screening procedures.

Patients eligible for inclusion must meet all following criteria prior to receiving study treatment:

1. Male or female ≥ 18-years-old 2. Documented genotype testing confirming homozygous for the C282Y mutation (C282Y/C282Y) 3. Transferrin saturation ≥ 45% (at either screening visit) 4. Serum ferritin (SF) ≥ 500 μg/L (at either screening visit)

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Exclusion Criteria:

1. Medical conditions that preclude inclusion:

   • Iron overload not due to HH
   • Condition which might significantly alter the absorption, distribution, metabolism or excretion of oral deferasirox
   • Systemic disease which prevents taking study treatment or any contraindication to phlebotomy
   • Inflammatory condition or immunological disease which may interfere with the SF interpretation, such as an active infection, collagen vascular disorders, irritable bowel syndrome, lupus, or immune thrombocytopenia
   • Significantly impaired gastrointestinal function or disease that may significantly alter the absorption of oral deferasirox, e.g. ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection.
   • Psychiatric or addictive disorder which prevent giving informed consent or undergoing any of the treatment options or unwilling or unable to comply with the protocol
   • Uncontrolled or significant cardiac disease or symptomatic cardiac arrhythmias, e.g., sustained ventricular tachycardia and clinically significant second or third degree AV block without a pacemaker.
   • Illicit drug use and/or alcohol use, defined as an average alcohol consumption greater than one standard drink a day for women or two standard drinks a day for men within the 12 months prior to enrolment. A standard drink is generally considered to be 12 ounces of beer, 5 ounces of wine, or 1.5 ounces of 80-proof distilled spirits
   • Cirrhosis, including Child-Pugh class A, B, and C, diagnosed by liver biopsy, elastography, radiologic exams, or clinical criteria
   • Active hepatitis B or C (hepatitis B carrier will be allowed)
   • History of HIV seropositivity (ELISA or Western blot)
   • Organ transplant recipient
   • Malignancy of any organ system, treated or untreated, within the past 5 years whether or not there is evidence of local recurrence or metastases, except localized basal cell carcinoma of the skin, or any history of hepatocellular carcinoma

2. Concomitant therapy that precludes enrollment:

   • Prior iron chelation therapy
   • Prohibited concomitant medications with deferasirox

3. Abnormal Laboratory Values:

   • Significant anemia that contraindicates phlebotomy (males with hemoglobin < 130g/L, females with hemoglobin < 120g/L) in both screening visit samples
   • Platelets ≤ 50 x 109/L in both screening visit samples
   • Urine protein/urine creatinine ratio > 1.0 mg/mg in both non-first void urine screening visit samples
   • Creatinine clearance ≤ 40 ml/min, or use the locally approved contraindication limit in prescribing information if it is stricter, in both screening visit samples
   • Serum creatinine > 1.5 x ULN in both screening visit samples
   • ALT ≥ 5 x ULN in both screening visit samples
   • Total bilirubin > 1.5 x ULN in both screening visit samples

4. Participation in an investigational study:

   • Observational registry study is allowable
   • Within 30 days prior to enrollment or within 5-half-lives of an investigational product, whichever is longer
   • Treatment with a systemic investigational drug within 4 weeks or topical investigational drug within 7 days of starting the study

5. Pregnancy and contraception:

   • Pregnant or nursing (lactating) women
   • Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless using basic methods of contraception, such as:
   • Total abstinence Periodic abstinence (calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are unacceptable methods.
   • Female sterilization (bilateral oophorectomy with or without hysterectomy), total hysterectomy, or tubal ligation at least six weeks before taking study treatment. If oophorectomy alone, hormone levels must confirm menopause.
   • Male sterilization (at least 6 months prior to screening). The vasectomized male must be the sole partner.
   • Barrier methods of contraception: condom or occlusive cap For UK: spermicidal foam/gel/film/cream/vaginal suppository
   • Placement of an intrauterine device or intrauterine system
   • Women considered as post-menopausal and not of childbearing potential are allowed to be enrolled in the trial if they have had 12 months of natural (spontaneous) amenorrhea with an expected clinical profile, e.g., age appropriate and history of vasomotor symptoms.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Deferasirox FCT Arm; An initial dose of deferasirox FCT 7 mg/kg/day was used for 3 months (12 weeks), then was adjusted according to the serum ferritin (SF) level. Deferasirox was interrupted when the study-defined target SF ≤ 100 μg/L was achieved. Deferasirox was to be reinitiated when SF ≥ 300 μg/L, according to deferasirox label.	Drug: Deferasirox FCT; Taken orally once per day (QD) as a film coated tablet (FCT); Other Names: ICL670
Active Comparator: phlebotomy; Phlebotomy was conducted at a frequency determined by the physician. Phlebotomy was interrupted when the study-defined target SF ≤ 100 μg/L was achieved. Phlebotomy was to be reinitiated when SF > 100 μg/L, based on standard of care practice.	Procedure: Phlebotomy; according to investigator's decision

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of Patients Achieving Target SF ≤ 100 μg/L for the First Time	Proportion of participants achieving target serum ferritin (SF) ≤ 100 μg/L on or before Month 24. Participants were considered responders if they met response criteria (target SF ≤100 µg/L) on or before Month 24 (Week 104) during the treatment phase. Any participant who discontinued treatment prematurely before meeting such criterion and participants with unknown or missing SF by Month 24 were counted as non-responder.	Up to Month 24

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Ocular Treatment Emergent Adverse Events (AEs)	Number of participants with at least one ocular treatment emergent adverse event (new or worsening from baseline).	Adverse events were reported from first dose of study treatment until end of study treatment plus 30 days post treatment, up to a maximum duration of approximately 108 weeks.
Number of Participants With Ocular Treatment Emergent Adverse Events (AEs) by Preferred Term	Number of participants with at least one ocular treatment emergent adverse event (new or worsening from baseline). Preferred terms are based on Medical Dictionary of Regulatory Activities (MedDRA) version 26.0.	Adverse events were reported from first dose of study treatment until end of study treatment plus 30 days post treatment, up to a maximum duration of approximately 108 weeks.
Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)	Number of participants with treatment emergent AEs (any AE regardless of seriousness), AEs leading to study treatment discontinuation, and SAEs.	Adverse events were reported from first dose of study treatment until end of study treatment plus 30 days post treatment, up to a maximum duration of approximately 108 weeks.
Number of Adverse Events in Participants Who Had Study Treatment Interrupted Due to SF ≤ 100 μg/L and Re-initiated Study Treatment When ≥ 300 μg/L	Number of participants with Adverse Events who interrupt deferasirox FCT at least once due to SF level ≤ 100 μg/L and re-initiate therapy at SF level ≥ 300 μg/L. There were no participants that re-initiated therapy when reached 300 ug/L.	Up to 24 months
Categorical Analysis of logMAR Score Changes From Baseline to Best Post-baseline Changes in One Eye With More Extreme Change	Visual acuity was measured using an Early Treatment Diabetic Retinopathy Study (ETDRS) chart. A letter score was calculated based on the number of letters that could correctly be identified from specified distances. For low luminance and standard acuity measures, visual acuity was described on a logMAR scale for all measures. For including acuity obtained with the ETDRS letter score, the values were converted to a logMAR scale, using the following formula: logMAR = 1.7-0.02*ETDRS score. With this conversion, a difference from baseline of 0.1 logMAR = 5-letter difference in visual acuity, 0.2 logMAR = 10-letter difference, 0.3 logMAR = 15-letter difference, 0.4 logMAR = 20-letter difference, 0.5 logMAR = 25-letter difference and 0.6 logMAR = 30-letter difference. Decrease in logMAR score category from baseline indicates improvement in visual acuity. The best change from baseline amongst all post baseline visit is presented.	Baseline, Weeks 24, 52, 76 and 104.
Categorical Analysis of logMAR Score Changes From Baseline to Worst Post-baseline Changes in One Eye With More Extreme Change	Visual acuity was measured using an Early Treatment Diabetic Retinopathy Study (ETDRS) chart. A letter score was calculated based on the number of letters that could correctly be identified from specified distances. For low luminance and standard acuity measures, visual acuity was described on a logMAR scale for all measures. For including acuity obtained with the ETDRS letter score, the values were converted to a logMAR scale, using the following formula: logMAR = 1.7-0.02*ETDRS score. With this conversion, a difference from baseline of 0.1 logMAR = 5-letter difference in visual acuity, 0.2 logMAR = 10-letter difference, 0.3 logMAR = 15-letter difference, 0.4 logMAR = 20-letter difference, 0.5 logMAR = 25-letter difference and 0.6 logMAR = 30-letter difference. Increase in logMAR score from baseline indicates worsening in visual acuity. The worst change from baseline amongst all post baseline visit is presented.	Baseline, Weeks 24, 52, 76 and 104.
Categorical Analysis of Worst Post-baseline Values of Intraocular Pressure in One Eye With More Extreme Change	Intraocular pressure was measured by tonometry. Intraocular pressure values >5 to ≤21 mmHg were considered normal. The worst post-baseline value corresponds to the worst outcome amongst all post baseline visit	Weeks 24, 52, 76 and 104
Categorical Analysis of Changes in Intraocular Pressure From Baseline to Best/Worst Post-baseline Changes in One Eye With More Extreme Change	Intraocular pressure was measured by tonometry. A decrease in intraocular pressure from baseline indicated improvement.	Baseline, up to Week 104
Number of Participants With Slit Lamp Results for Any Evaluation and Worst Eye	Slit lamp examination was used to evaluate lids, cornea, conjunctiva, iris, anterior chamber, aqueous flare, aqueous inflammatory cells and lens. Any post-baseline abnormalities (not present at baseline) in slit lamp examination were assesses by the investigator and classified as insignificant or clinically significant. Number of participants with slit lamp results (normal, insignificant, significant, missing) for any evaluation and worst eye are reported.	Baseline, up to Week 104
Number of Participants With an Increase From Baseline of ≥1 and ≥2 in LOCS III Grades	Lens Opacities Classification System III (LOCS III) grading scales include lens opacities defined as nuclear opalescence (NO), nuclear color (NC), cortical (C) cataract and posterior subcapsular (P) cataract with several degrees of extend, i.e. severity. The LOCS III scale for nuclear opalescence and for nuclear color ranges from 0 to 6. The LOCS III scale for cortical cataract and posterior subcapsular cataract opacity ranges from 0 to 5. For all scales, higher values indicate higher opacity, opalescence, or color (range: NO0/NC0/C0/P0 to NO6/NC6/C5/P5). Number of participants with an increase from baseline of ≥1 and increase of ≥2 in LOCS III grades is reported.	Baseline, up to Week 104
Number of Participants With Fundus Oculi Results for Any Evaluation and Worst Eye	Fundus oculi examination was used to evaluate peripheral retina, macula, optic nerve, and vitreous hemorrhage. Any post-baseline abnormalities (not present at baseline) in fundus oculi examination were assessed by the investigator and classified as insignificant or clinically significant. Number of participants with fundus oculi results (normal, insignificant, significant, missing) for any evaluation and worst eye are reported.	Baseline, up to Week 104
Time to Response (TTR)	Time to response (TTR) is defined as the time from the date of randomization to the date of the first time the SF achieved a value ≤ 100 μg/L during the treatment phase. Participants who did not achieve SF ≤ 100 μg/L were censored as follows: at the last serum ferritin assessment date on or before month 24 (week 104), at the day of randomization if a subject does not have any post-baseline serum ferritin value or at the death date. TTR was analyzed using the Kaplan-Meier method.	Up to Month 24

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals
• Investigators: Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Publications and helpful links

Helpful Links

• A Plain Language Trial Summary is available on novctrd.com

Study record dates

Study Major Dates

• Study Start (Actual): January 11, 2018
• Primary Completion (Actual): April 17, 2023
• Study Completion (Actual): April 17, 2023

Study Registration Dates

• First Submitted: June 22, 2017
• First Submitted That Met QC Criteria: June 28, 2017
• First Posted (Actual): June 29, 2017

Study Record Updates

• Last Update Posted (Actual): October 9, 2024
• Last Update Submitted That Met QC Criteria: October 7, 2024
• Last Verified: May 1, 2024

More Information

Terms related to this study

• Keywords: iron overload; ICL670; hereditary hemochromatosis; deferasirox FCT
• Additional Relevant MeSH Terms: Metabolic Diseases; Genetic Diseases, Inborn; Iron Metabolism Disorders; Metabolism, Inborn Errors; Metal Metabolism, Inborn Errors; Iron Overload; Hemochromatosis; Hemosiderosis; Molecular Mechanisms of Pharmacological Action; Chelating Agents; Sequestering Agents; Iron Chelating Agents; Deferasirox
• Other Study ID Numbers: CICL670F2203; 2016-002529-12 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No