Efficacy and Safety of Roxadustat for Treatment of Anemia in Participants With Lower Risk Myelodysplastic Syndrome With Low Red Blood Cell Transfusion Burden

Phase 3

Terminated

• Conditions: Primary MDS (Very Low, Low or Intermediate IPSS-R With <5% Blasts); Anemia
• Interventions: Drug: Placebo; Drug: Roxadustat

• Registration Number: NCT03263091
• Lead Sponsor: FibroGen

Brief Summary

The purpose of this study is to determine whether FG-4592 is safe and effective in the treatment of anemia in participants with lower risk MDS and low red blood cell transfusion burden.

Detailed Description

This study includes an Open-Label Lead in, a Double-Blind component, and an Open-Label High Erythropoietin component. There is a screening period of up to 42 days followed by a treatment period of 52 weeks and a 4-week end of treatment assessment.

Study Timeline

• Study First Submitted: 2017-08-22
• Study First Submitted QC: 2017-08-23
• Study First Posted: 2017-08-28
• Study Start: 2018-01-29
• Primary Completion: 2023-03-09
• Study Completion: 2023-06-20
• Disposition First Submitted: 2024-02-28
• Results First Submitted: 2024-06-14
• Status Verified: 2024-07
• Results First Submitted QC: 2024-07-30
• Last Update Submitted: 2024-07-30
• Results First Posted: 2024-08-01
• Disposition First Posted: 2024-08-01
• Last Update Posted: 2024-08-01

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 184

Inclusion Criteria

• Diagnosis of primary MDS classified by the International Prognostic Scoring System - Revised (IPSS-R) as very low, low or intermediate risk with <5% bone marrow blasts. There is no minimum time from diagnosis to registration/randomization except to allow for proper IPSS-R classification to be made (within 16 weeks prior to randomization), and to show transfusion dependence for participants in both portions of the study.
• RBC transfusion of either 2-4 pRBC units during the 8 weeks prior to registration/randomization or 1 pRBC in two consecutive periods of 8 weeks within the 16 weeks prior to registration/randomization. Open-Label Lead-in participants only, the requirement to demonstrate transfusion dependence can also be met by a Principal Investigator starting this particular participant on pRBC transfusion during the screening period.
• No restriction on prior use of recombinant erythropoietins or analogues (erythropoiesis-stimulating agents [ESAs]), except no ESA use within 8 weeks prior to Day 1 registration/randomization.
• Hemoglobin (Hb) ≤10.0 grams/deciliter (g/dL) during screening
• Eastern Cooperative Oncology Group (ECOG) of 0-2 at screening

Key

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Exclusion Criteria

• Diagnosis of secondary MDS associated with prior chemotherapy, extensive radiation therapy (>25% of bone marrow reserve), and or/other significant chemical or radiation exposure
• Significant myelofibrosis (>2+ fibrosis)
• MDS associated with 5q(del) cytogenetic abnormality
• Screen serum erythropoietin level > 400 milli-international units (mIU)/milliliter (mL) • Clinically significant anemia, as determined by the investigator, due to non-MDS etiologies such as iron deficiency, vitamin B12 or folate deficiency, autoimmune or hereditary hemolysis or anemia or hemorrhage or hereditary anemia such as sickle cell anemia or thalassemia.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	Double-blind: Participants will receive placebo matching to roxadustat for a duration of 52 weeks.
Roxadustat	Roxadustat	Open-label, lead-in: Participants will receive sequential escalating roxadustat doses (1.5 milligrams/kilograms \[mg/kg\], 2.0 mg/kg and 2.5 mg/kg), three times a week (TIW) based upon their actual weight at the randomization visit to identify the starting dose for double-blind period. Double-blind: Participants will receive roxadustat 2.5 mg/kg TIW based upon their body weight for a duration of 52 weeks. Open-label: Participants with high serum erythropoietin levels (\>400 milli-international units \[mIU\]/milliliter \[mL\] mIU/mL) will receive roxadustat 2.5 mg/kg TIW based upon their body weight for a duration of 52 weeks.

Primary Outcome Measures

Name	Time	Method
OL and OL High-EPO Components: Number of Participants Who Achieved Red Blood Cell (RBC) Transfusion Independence (TI) ≥8 Weeks (≥56 Consecutive Days) Since First Dose in the First 28 Weeks of Treatment	28 weeks	The RBC TI was defined as the absence of any intravenous (IV) RBC transfusion (packed cell or whole blood) during any consecutive 56 days during the treatment period. Data presented is for number of participants with RBC TI ≥8 weeks (≥56 consecutive days) since first dose in the first 28 weeks of treatment.
DB Component: Number of Participants Who Achieved RBC TI ≥56 Consecutive Days Since First Dose in the First 28 Weeks of Treatment	28 weeks	RBC TI was defined as the absence of any IV RBC transfusion (packed cell or whole blood) during any consecutive 56 days during the treatment period. Data presented is for number of participants with RBC TI ≥56 consecutive days since first dose in the first 28 weeks of treatment.

Secondary Outcome Measures

Name	Time	Method
DB Component: Number of Participants Who Achieved TI ≥56 Consecutive Days Since First Dose in 52 Weeks of Treatment	52 weeks	RBC TI was defined as the absence of any IV RBC transfusion (packed cell or whole blood) during any consecutive 56 days during the treatment period. Data presented is for number of participants with RBC TI ≥56 consecutive days since first dose in the 52 weeks of treatment.
DB Component: Number of Participants Who Achieved ≥50% Reduction From Baseline in Number of pRBC Transfusions Over 8 Weeks	Baseline up to Week 8	Baseline number of transfusions (pRBC/8-weeks) = total number of packs of rRBCs within 16 weeks prior to first dose/2. A pRBC transfusion reduction responder was defined as a participant who achieved ≥50% reduction in number of pRBC transfusions over 8 weeks compared to their baseline for any 8 week period in the duration begining with the first dose date (Day 1) and ending with the end of study or treatment discontinuation due to adverse event (AE)/serious adverse event (SAE) or death, whichever came earlier.
DB Component: Mean Change From Baseline in the Patient-Reported Outcomes Measurement Information System-Short Form (PROMIS-SF) v2.0 Physical Function (PF) 10b Score at Week 9	Baseline, Week 9	The PROMIS physical function item measures self-reported, current capability to carry out activities that require physical actions, ranging from self-care (activities of daily living) to more complex activities that require a combination of skills, often within a social context. The PF 10-item short form which contains 10 questions was used in this study, and each item was scored on a 5-point rating scale (1 \[unable to do\] to 5 \[without any difficulty\]), with higher scores indicating better functioning. Total raw score was the sum of the response to each question, with the lowest possible raw score 10 (poor physical function) and the highest possible raw score 50 (better physical function). Raw scores converted to T-scores (as detailed in the T-score conversion table for PROMIS-SF v2.0 Physical Function 10b) with a mean of 50 and a standard deviation (SD) of 10. T-scores ranged from minimum 13.8 to maximum 61.3 possible scores with higher scores indicating better physical functioning.
DB Component: Mean Change From Baseline in the PROMIS-SF v1.0 Fatigue 13a Score at Week 9	Baseline, Week 9	Fatigue was measured using the 13-item fatigue scale of the Functional Assessment of Chronic Illness Therapy (FACIT) Measurement System, each item was scored on a 5-point rating scale ranging from 1 "not at all" to 5 "very much", with lower scores indicating better functioning. Total raw score was the sum of the response to each question, with the lowest possible raw score 13 (lowest level of fatigue) and the highest possible raw score 65 (highest level of fatigue), with lower scores indicating better functioning. Raw scores converted to T-scores (as detailed in the T-score conversion table for PROMIS-SF v1.0 Fatigue 13a) with a mean of 50 and a SD of 10. T-scores ranged from minimum 30.3 to maximum 83.5 possible scores with lower scores indicating better functioning.
OL and OL High-EPO Components: Number of Participants Who Achieved TI ≥50% Reduction From Baseline in Number of Packs of Red Blood Cells (pRBC) Transfusions Over 8 Weeks	Baseline up to Week 8	Number of pRBC transfusions at baseline was defined as pRBC transfusions requirement during 8-week period prior to the start of first study medication. Responders were defined as participants with at least a 50% reduction in the number of pRBC transfusions over any 8-week (56 consecutive days) period during the study as compared with the baseline.
DB Component: Number of Participants Who Achieved TI ≥56 Consecutive Days Anytime During the Study	Baseline up to Week 56	RBC TI was defined as the absence of any IV RBC transfusion (packed cell or whole blood) during any consecutive 56 days anytime during the study (up to Week 56).
DB Component: Cumulative Number of Participant Exposure Weeks (PEW) of TI Over the First 28 Weeks of Treatment	28 weeks	The PEW of TI periods over the first 28 weeks was added up to a cumulative number of weeks. For a participant with at least 1 TI response period over the first 28 weeks, the last TI response period was ended with the date of a subsequent RBC transfusion, visit date at Week 28, date of the end of study or treatment discontinuation due to AE/SAE or death, whichever came earlier. For a participant with no TI response period over the first 28 weeks, the cumulative number of PEW was set to zero.
DB Component: Change From Baseline in Number of pRBC Packs Transfused Over the First 28 Weeks of Treatment	Baseline, Week 28	Number of pRBC transfusions at baseline was defined as pRBC transfusions requirement during 8-week period prior to the start of first study medication.
DB Component: Number of Participants Who Achieved TI ≥20 Consecutive Weeks During the Study	Baseline up to Week 56	≥20 consecutive weeks TI was defined as the absence of any IV RBC transfusion (packed cell or whole blood) during any consecutive 140 days anytime during the study (up to 56 weeks). TI was estimated between the first dose date (Day 1) and the end of study (Week 56) or treatment discontinuation due to AE/SAE or death, whichever came earlier.
DB Component: Mean Change From Baseline in the European Quality of Life Five Dimensional Five Level Health Questionnaire (EQ-5D-5L) Visual Analogue Scale Score at Week 9	Baseline, Week 9	The EQ-5D questionnaire is designed for self-completion by participants. The EQ-5D-5L descriptive system comprises the following 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: no problems, slight problem, moderate problems, severe problems, and unable to/extreme problems. The questionnaire also included a visual analogue scale, where the participant was asked to rate current health status on a scale of 0-100, with 0 being the worst imaginable health state and 100 being the best imaginable health.

Trial Locations

Locations (4)

Investgational site; 🇺🇸 Atlanta, Georgia, United States

Investiational Site; 🇺🇸 Weston, Florida, United States

Investigational site; 🇮🇱 Tel HaShomer, Israel

Investigational Site; 🇬🇧 Manchester, United Kingdom