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

Phase 2

Terminated

• Conditions: Hereditary Hemochromatosis
• Interventions: Drug: Deferasirox FCT; Procedure: Phlebotomy

• Registration Number: NCT03203850
• Lead Sponsor: Novartis Pharmaceuticals

Brief Summary

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.

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 Timeline

• Study First Submitted: 2017-06-22
• Study First Submitted QC: 2017-06-28
• Study First Posted: 2017-06-29
• Study Start: 2018-01-11
• Primary Completion: 2023-04-17
• Study Completion: 2023-04-17
• Results First Submitted: 2024-04-10
• Status Verified: 2024-05
• Results First Submitted QC: 2024-06-06
• Results First Posted: 2024-06-07
• Last Update Submitted: 2024-10-07
• Last Update Posted: 2024-10-09

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 45

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.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Deferasirox FCT Arm	Deferasirox FCT	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.
phlebotomy	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.

Primary Outcome Measures

Name	Time	Method
Proportion of Patients Achieving Target SF ≤ 100 μg/L for the First Time	Up to Month 24	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.

Secondary Outcome Measures

Name	Time	Method
Number of Participants With Ocular Treatment Emergent Adverse Events (AEs) by Preferred Term	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 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.
Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (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 participants with treatment emergent AEs (any AE regardless of seriousness), AEs leading to study treatment discontinuation, and SAEs.
Categorical Analysis of logMAR Score Changes From Baseline to Best Post-baseline Changes in One Eye With More Extreme Change	Baseline, Weeks 24, 52, 76 and 104.	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.
Categorical Analysis of logMAR Score Changes From Baseline to Worst Post-baseline Changes in One Eye With More Extreme Change	Baseline, Weeks 24, 52, 76 and 104.	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.
Number of Participants With Ocular Treatment Emergent Adverse Events (AEs)	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 at least one ocular treatment emergent adverse event (new or worsening from baseline).
Number of Participants With Slit Lamp Results for Any Evaluation and Worst Eye	Baseline, up to Week 104	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.
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	Up to 24 months	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.
Categorical Analysis of Worst Post-baseline Values of Intraocular Pressure in One Eye With More Extreme Change	Weeks 24, 52, 76 and 104	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
Categorical Analysis of Changes in Intraocular Pressure From Baseline to Best/Worst Post-baseline Changes in One Eye With More Extreme Change	Baseline, up to Week 104	Intraocular pressure was measured by tonometry. A decrease in intraocular pressure from baseline indicated improvement.
Number of Participants With an Increase From Baseline of ≥1 and ≥2 in LOCS III Grades	Baseline, up to Week 104	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.
Number of Participants With Fundus Oculi Results for Any Evaluation and Worst Eye	Baseline, up to Week 104	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.
Time to Response (TTR)	Up to Month 24	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.

Trial Locations

Locations (1)

Novartis Investigative Site; 🇨🇭 Lugano, Switzerland