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 is to evaluate the efficacy and safety of deferasirox film coated tablet (FCT) versus phlebotomy for the management of iron overload in adults with HH at risk of iron-related morbidity. This evaluation will provide 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: Completed
• Conditions: Hereditary Hemochromatosis
• Intervention / Treatment: Drug: Deferasirox FCT; Procedure: Phlebotomy

• 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.

Other protocol-defined inclusion/exclusion may apply. -

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; randomized in a 2:1 ratio: Deferasirox or phebotomy	Drug: Deferasirox FCT; Taken orally once per day (QD); Other Names: ICL670
Experimental: phlebotomy; randomized in a 2:1 ratio: Deferasirox or phebotomy	Procedure: Phlebotomy; according to investigator's decision

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Response rate by month 24	Percentage of participants achieving target serum ferritin (SF) ≤ 100 μg/L on or before 24 months.	Up to 24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of participants with ocular adverse events (AEs)	Percentage of participants with at least one ocular AE (new or worsening from baseline) occurring during on-treatment period. On-treatment period: from the day of the first dose of study medication or the first phlebotomy to 30 days after the last dose of study medication or last phlebotomy.	24 months
Change from baseline at months 6, 12, 18 and 24 in visual acuity	Visual acuity will be measured using a Early Treatment Diabetic Retinopathy Study (ETDRS) chart. The ETDRS letter score is based on the number of letters correctly identified from specified distances. Higher scores correspond to better visual acuity.	At Months 6, 12, 18 and 24
Change from baseline at months 6, 12, 18 and 24 in intra-ocular pressure	Intraocular pressure will be measured by tonometry for each eye side.	At Months 6, 12, 18 and 24
Number of participants with and without opacity	A slit lamp examination with Lens Opacities Classification System III (LOCS III) will be used to assess lens opacities. The number of patients with and without opacity will be provided	At Months 6, 12, 18 and 24
Number of participants with and without abnormality in the fundus occuli	The number of patients with and without abnormalities in the fundus oculi will be provided	At Months 6, 12, 18 and 24
Percentage of participants who interrupt due to reaching target SF ≤ 100 μg/L and re-initiate therapy when ≥ 300 μg/L	Percentage of participants who interrupt deferasirox FCT at least once due to SF level ≤ 100 μg/L and the re-initiate therapy at SF level ≥ 300 μg/L	Up to 24 months
Time to response (TTR)	TTR defined as the time from the date of randomization to the date of the first time the SF is achieving a value ≤ 100 μg/L during the treatment phase	Up to 24 months

Collaborators and Investigators

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

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): December 26, 2023
• Last Update Submitted That Met QC Criteria: December 22, 2023
• Last Verified: December 1, 2023

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