NCT03263091

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

Terminated Phase 3 Results posted Last updated 1 August 2024

What this trial tests

Phase 3 trial testing Roxadustat in Primary MDS (Very Low, Low or Intermediate IPSS-R With <5% Blasts) in 184 participants. Terminated before completion.

Timeline

29 January 2018

Primary endpoint
9 March 2023

20 June 2023

Quick facts

Lead sponsor	Kyntra Bio
Phase	Phase 3
Status	Terminated
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	quadruple
Primary purpose	treatment
Enrollment	184
Start date	29 January 2018
Primary completion	9 March 2023
Estimated completion	20 June 2023
Sites	124 locations across Denmark, France, Italy, Russia, Belgium, United Kingdom, Germany, Israel

Drugs / interventions tested

• Roxadustat (ROXADUSTAT) — full drug profile →
• Placebo

Conditions studied

• Primary MDS (Very Low, Low or Intermediate IPSS-R With <5% Blasts) — all drugs for Primary MDS (Very Low, Low or Intermediate IPSS-R With <5% Blasts) →
• Anemia — all drugs for Anemia →

Sponsor

Kyntra Bio — full company profile →

Who can join

18 and older, any sex, with Primary MDS (Very Low, Low or Intermediate IPSS-R With <5% Blasts) or Anemia. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

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 Primary · 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.

Group	Value	95% CI
OL Component (Cohort 1): Roxadustat 1.5 mg/kg	3
OL Component (Cohort 2): Roxadustat 2.0 mg/kg	1
OL Component (Cohort 3): Roxadustat 2.5 mg/kg	5
OL High-EPO Component: Roxadustat 2.5 mg/kg	3

DB Component: Number of Participants Who Achieved RBC TI ≥56 Consecutive Days Since First Dose in the First 28 Weeks of Treatment Primary · 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.

Group	Value	95% CI
DB Component: Roxadustat	38
DB Component: Placebo	19

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 Secondary · 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.

Group	Value	95% CI
OL Component (Cohort 1): Roxadustat 1.5 mg/kg	5
OL Component (Cohort 2): Roxadustat 2.0 mg/kg	3
OL Component (Cohort 3): Roxadustat 2.5 mg/kg	7
OL High-EPO Component: Roxadustat 2.5 mg/kg	8

DB Component: Number of Participants Who Achieved TI ≥56 Consecutive Days Since First Dose in 52 Weeks of Treatment Secondary · 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.

Group	Value	95% CI
DB Component: Roxadustat	44
DB Component: Placebo	23

DB Component: Number of Participants Who Achieved TI ≥56 Consecutive Days Anytime During the Study Secondary · 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).

Group	Value	95% CI
DB Component: Roxadustat	52
DB Component: Placebo	29

DB Component: Number of Participants Who Achieved ≥50% Reduction From Baseline in Number of pRBC Transfusions Over 8 Weeks Secondary · 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.

Group	Value	95% CI
DB Component: Roxadustat	59
DB Component: Placebo	37

DB Component: Cumulative Number of Participant Exposure Weeks (PEW) of TI Over the First 28 Weeks of Treatment Secondary · 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.

Group	Value	95% CI
DB Component: Roxadustat	9.60	± 11.537
DB Component: Placebo	7.60	± 11.557

DB Component: Change From Baseline in Number of pRBC Packs Transfused Over the First 28 Weeks of Treatment Secondary · 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.

Group	Value	95% CI
DB Component: Roxadustat	-0.13	± 2.314
DB Component: Placebo	0.44	± 1.833

DB Component: Number of Participants Who Achieved TI ≥20 Consecutive Weeks During the Study Secondary · 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.

Group	Value	95% CI
DB Component: Roxadustat	23
DB Component: Placebo	15

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 Secondary · 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

Group	Value	95% CI
DB Component: Roxadustat	-1.9	± 7.29
DB Component: Placebo	-0.4	± 6.77

DB Component: Mean Change From Baseline in the PROMIS-SF v1.0 Fatigue 13a Score at Week 9 Secondary · 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 fo

Group	Value	95% CI
DB Component: Roxadustat	1.9	± 7.61
DB Component: Placebo	-0.6	± 7.36

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 Secondary · 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.

Group	Value	95% CI
DB Component: Roxadustat	-1.7	± 20.31
DB Component: Placebo	1.6	± 16.18

Adverse events — posted to ClinicalTrials.gov

Time frame: Baseline up to Week 56. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

OL Component (Cohort 1): Roxadustat 1.5 mg/kg

Serious: 4/8 (50%)

Deaths: 1/8

OL Component (Cohort 2): Roxadustat 2.0 mg/kg

Serious: 3/8 (38%)

Deaths: 0/8

OL Component (Cohort 3): Roxadustat 2.5 mg/kg

Serious: 1/8 (13%)

Deaths: 0/8

OL High-EPO Component: Roxadustat 2.5 mg/kg

Serious: 6/20 (30%)

Deaths: 3/20

DB Component: Roxadustat

Serious: 22/82 (27%)

Deaths: 7/82

DB Component: Placebo

Serious: 10/58 (17%)

Deaths: 4/58

Serious adverse events (59 terms)

Reaction	System	OL Component (Cohort 1): R…	OL Component (Cohort 2): R…	OL Component (Cohort 3): R…	OL High-EPO Component: Rox…	DB Component: Roxadustat	DB Component: Placebo
Pneumonia	Infections and infestations	—	—	—	—	—	—
Acute kidney injury	Renal and urinary disorders	—	—	—	—	—	—
Febrile neutropenia	Blood and lymphatic system disorders	—	—	—	—	—	—
Acute myocardial infarction	Cardiac disorders	—	—	—	—	—	—
Transient ischaemic attack	Nervous system disorders	—	—	—	—	—	—
Pulmonary embolism	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—	—
Pancytopenia	Blood and lymphatic system disorders	—	—	—	—	—	—
Splenomegaly	Blood and lymphatic system disorders	—	—	—	—	—	—
Anaemia	Blood and lymphatic system disorders	—	—	—	—	—	—
Acute left ventricular failure	Cardiac disorders	—	—	—	—	—	—
Atrial fibrillation	Cardiac disorders	—	—	—	—	—	—
Cardiac failure	Cardiac disorders	—	—	—	—	—	—
Cardiac failure congestive	Cardiac disorders	—	—	—	—	—	—
Supraventricular tachycardia	Cardiac disorders	—	—	—	—	—	—
Abdominal pain upper	Gastrointestinal disorders	—	—	—	—	—	—
Colitis	Gastrointestinal disorders	—	—	—	—	—	—
Diarrhoea	Gastrointestinal disorders	—	—	—	—	—	—
Inguinal hernia	Gastrointestinal disorders	—	—	—	—	—	—
Multiple organ dysfunction syndrome	General disorders	—	—	—	—	—	—
Oedema	General disorders	—	—	—	—	—	—
Pyrexia	General disorders	—	—	—	—	—	—
General physical health deterioration	General disorders	—	—	—	—	—	—
Mucosal inflammation	General disorders	—	—	—	—	—	—
Cholelithiasis	Hepatobiliary disorders	—	—	—	—	—	—
Hepatic function abnormal	Hepatobiliary disorders	—	—	—	—	—	—

Other adverse events (120 terms — click to expand)

Reaction	System	OL Component (Cohort 1): R…	OL Component (Cohort 2): R…	OL Component (Cohort 3): R…	OL High-EPO Component: Rox…	DB Component: Roxadustat	DB Component: Placebo
Nausea	Gastrointestinal disorders	—	—	—	—	—	—
Fatigue	General disorders	—	—	—	—	—	—
Constipation	Gastrointestinal disorders	—	—	—	—	—	—
Asthenia	General disorders	—	—	—	—	—	—
Dizziness	Nervous system disorders	—	—	—	—	—	—
Alanine aminotransferase increased	Investigations	—	—	—	—	—	—
Diarrhoea	Gastrointestinal disorders	—	—	—	—	—	—
Oedema peripheral	General disorders	—	—	—	—	—	—
Insomnia	Psychiatric disorders	—	—	—	—	—	—
Aspartate aminotransferase increased	Investigations	—	—	—	—	—	—
Dyspnoea	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—	—
Pruritus	Skin and subcutaneous tissue disorders	—	—	—	—	—	—
Weight decreased	Investigations	—	—	—	—	—	—
Headache	Nervous system disorders	—	—	—	—	—	—
Vomiting	Gastrointestinal disorders	—	—	—	—	—	—
COVID-19	Infections and infestations	—	—	—	—	—	—
Blood bilirubin increased	Investigations	—	—	—	—	—	—
Decreased appetite	Metabolism and nutrition disorders	—	—	—	—	—	—
Thrombocytopenia	Blood and lymphatic system disorders	—	—	—	—	—	—
Pyrexia	General disorders	—	—	—	—	—	—
Nasopharyngitis	Infections and infestations	—	—	—	—	—	—
Upper respiratory tract infection	Infections and infestations	—	—	—	—	—	—
Arthralgia	Musculoskeletal and connective tissue disorders	—	—	—	—	—	—
Muscle spasms	Musculoskeletal and connective tissue disorders	—	—	—	—	—	—
Neutropenia	Blood and lymphatic system disorders	—	—	—	—	—	—
Abdominal pain	Gastrointestinal disorders	—	—	—	—	—	—
Dyspepsia	Gastrointestinal disorders	—	—	—	—	—	—
Folate deficiency	Metabolism and nutrition disorders	—	—	—	—	—	—
Cough	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—	—
Hypotension	Vascular disorders	—	—	—	—	—	—
Angina pectoris	Cardiac disorders	—	—	—	—	—	—
Non-cardiac chest pain	General disorders	—	—	—	—	—	—
Pneumonia	Infections and infestations	—	—	—	—	—	—
Myalgia	Musculoskeletal and connective tissue disorders	—	—	—	—	—	—
Acute kidney injury	Renal and urinary disorders	—	—	—	—	—	—
Dyspnoea exertional	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—	—
Palpitations	Cardiac disorders	—	—	—	—	—	—
Vertigo	Ear and labyrinth disorders	—	—	—	—	—	—
Hypothyroidism	Endocrine disorders	—	—	—	—	—	—
Abdominal discomfort	Gastrointestinal disorders	—	—	—	—	—	—

Most-reported serious reactions: Pneumonia, Acute kidney injury, Febrile neutropenia, Acute myocardial infarction, Transient ischaemic attack, Pulmonary embolism, Pancytopenia, Splenomegaly.

Data from ClinicalTrials.gov NCT03263091 adverse events section.

Sponsor's own description

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.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. Targeting hypoxia-inducible factors: therapeutic opportunities and challenges.
   Yuan X, Ruan W, Bobrow B, Carmeliet P, et al · · 2024 · cited 144× · PMID 38123660 · DOI 10.1038/s41573-023-00848-6
2. Hypoxia-Inducible Factor Activators in Renal Anemia: Current Clinical Experience.
   Sanghani NS, Haase VH. · · 2019 · cited 139× · PMID 31477256 · DOI 10.1053/j.ackd.2019.04.004
3. Hypoxia-inducible factor-prolyl hydroxylase inhibitors in the treatment of anemia of chronic kidney disease.
   Haase VH. · · 2021 · cited 115× · PMID 33777492 · DOI 10.1016/j.kisu.2020.12.002
4. Current challenges and unmet medical needs in myelodysplastic syndromes.
   Platzbecker U, Kubasch AS, Homer-Bouthiette C, Prebet T. · · 2021 · cited 67× · PMID 34045662 · DOI 10.1038/s41375-021-01265-7
5. Genome-Wide Interrogation of Human Cancers Identifies EGLN1 Dependency in Clear Cell Ovarian Cancers.
   Price C, Gill S, Ho ZV, Davidson SM, et al · · 2019 · cited 44× · PMID 30898838 · DOI 10.1158/0008-5472.can-18-2674
6. Management of patients with lower-risk myelodysplastic syndromes.
   Brunner AM, Leitch HA, van de Loosdrecht AA, Bonadies N. · · 2022 · cited 28× · PMID 36517487 · DOI 10.1038/s41408-022-00765-8
7. Risk-Adapted, Individualized Treatment Strategies of Myelodysplastic Syndromes (MDS) and Chronic Myelomonocytic Leukemia (CMML).
   Bewersdorf JP, Zeidan AM. · · 2021 · cited 21× · PMID 33807279 · DOI 10.3390/cancers13071610
8. Setting Fire to ESA and EMA Resistance: New Targeted Treatment Options in Lower Risk Myelodysplastic Syndromes.
   Kubasch AS, Platzbecker U. · · 2019 · cited 21× · PMID 31394818 · DOI 10.3390/ijms20163853