| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Anemia due to Myelodysplastic Syndrome (MDS) in International Prognostic Scoring System – Revised Very Low, Low, or Intermediate Risk with <5% Blasts, and has low red blood cell transfusion burden (requires 1 to 4 packed red blood cell units per 8-week period)
|
|
| E.1.1.1 | Medical condition in easily understood language |
| Anemia in patients with myelodysplastic syndrome (MDS) |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
To evaluate the efficacy of roxadustat in the treatment of anemia in patients with lower risk MDS who have a low burden of RBC transfusion.
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|
| E.2.2 | Secondary objectives of the trial |
- To evaluate the safety of roxadustat
- To evaluate the impact of roxadustat on RBC transfusion requirements
- To evaluate pharmacokinetics (PK) and pharmacodynamics (PD) of roxadustat in MDS patients
- To evaluate effect of roxadustat on quality of life parameters |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Diagnosis of primary MDS (confirmed by bone marrow aspirate and
biopsy prior to treatment Day 1), classified by the 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 patients in both portions of the study.
2. RBC transfusion requirement of either:
a. 2 to 4 pRBC over the 8-weeks prior to registration/randomization,
OR
b. 1 pRBC during the 8-weeks prior to registration/randomization:
Patients with 1 pRBC must have a documented history of requiring 1
pRBC/8-weeks in 2 consecutive periods of 8 weeks in the 16 weeks
preceding registration/randomization
c. The PI and site staff will utilize their own institutional criteria for the
determination of when to transfuse a patient.
d. Open-Label Lead-in patients only, the requirement to demonstrate transfusion
dependence can also be met by a PI starting this particular patient on pRBC transfusion during the screening period.
3. There is no restriction on prior use of recombinant erythropoietins or
analogues (erythropoiesis-stimulating agents (ESAs)), except that the
patient must not have received any ESA within the 8 weeks prior to Day
1 registration/randomization. ESAs include but are not limited to any
recombinant human erythropoietin and other drugs listed in Appendix I
of the Protocol.
4. Hb ≤10.0 g/dL during Screening period. Only 1 central laboratory
value needs to meet the Hb ≤ 10.0 g/dL criteria.
5. Age ≥18 years
6. Body weight ≥45 kg
7. ECOG performance status of 0,1 or 2 during screening
8. Must be capable of giving written informed consent |
|
| E.4 | Principal exclusion criteria |
1. Diagnosis of secondary MDS associated with prior chemotherapy, extensive radiation therapy (>25% of bone marrow reserve), and or/other significant chemical or radiation exposure
2. Previous diagnosis of IPSS-R high risk or very high risk MDS
3. Planned myeloablative or craniospinal radiation during the study
4. Prior bone marrow or stem cell transplantation (SCT)
5. Significant myelofibrosis (>2+ fibrosis)
6. MDS associated with 5q(del) cytogenetic abnormality
7. Screen serum erythropoietin level > 400 mIU/mL
Patients with elevated serum rythropoietin levels (>400 mIU/mL) are allowed to repeat after ≥ 7 days. If the serum erythropoietin remains elevated (>400 mIU/mL) the patient may then qualify for the OL Higherythropoietin cohort.
8. Alanine aminotransferase (ALT) > 3 x ULN, OR aspartate aminotransferase (AST) > 3 × ULN OR TBili > 1.5 × ULN
Patients with TBili up to 2.0 x ULN may be allowed to participate if the AST and ALT are within normal limits
9. Azacitidine, decitabine, thalidomide, lenalidomide, granulocyte colony-stimulating factor (G-CSF), or luspatercept, or any investigational drugs within 8-weeks prior to Day 1 Treatment or plans to use any of these medications during the course of clinical trial participation
10. Anticipated use of dapsone at any dose amount or chronic use of acetaminophen or paracetamol >2.0 g/day during the study for more than 7 days
11. 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
12. Active infection(s) requiring systemic antibiotic therapy (upon treatment with antibiotic, stable asymptomatic patients may qualify to participate.)
13. Cockroft-Gault calculated estimated glomerular filtration rate (eGFR) <30 mL/min
14. Thromboembolic event such as DVT, pulmonary embolism,
myocardial infarction, stroke, or TIA, within previous 6 months of randomization
15. Exclusion criteria 15 has been removed
16. Significant heart disease, including New York Heart Association (NYHA) Class III or IV congestive heart failure, uncontrolled hypertension or hypotension, or significant valvular or endocardial disease that would put the patient at risk for thromboembolism
17. Clinically significant or uncontrolled ongoing inflammatory/autoimmune disease (e.g., rheumatoid arthritis, Crohn’s disease, celiac disease, etc.)
18. History of significant liver disease or active liver disease
19. Major surgery planned during the treatment period
20. Known, active or chronic gastrointestinal bleeding
21. Known human immunodeficiency virus (HIV), hepatitis B or hepatitis C infection
22. Clinically significant or uncontrolled medical condition that would affect the patient's ability to participate in the study or confound the study's efficacy or safety results
23. History of leukemia or other active malignancy except localized and
non-metastatic squamous or basal cell carcinoma of the skin, or cervical
intraepithelial neoplasm; patients with a history of cured malignancy
with no evidence of recurrence for at least 3 years are eligible
24. Previous recipient of roxadustat or another hypoxia-inducible factor
prolyl hydroxylase inhibitor (HIF-PHI)
25. Pregnant or breastfeeding females
-Additional central laboratory samples may be collected via unscheduled
visit to confirm eligibility, as deemed necessary by the investigator.
Medical monitor should be informed.
-A positive Hep-C test will be confirmed via C-RNA testing; C-RNA
negative patient may qualify to participate.
-Patients must meet all eligibility criteria prior to randomization; no
waiver will be granted.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy endpoint is the proportion of patients who achieved transfusion-independence (TI) ≥56 consecutive days in the first 28 weeks of treatment |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The first 28 weeks of treatment |
|
| E.5.2 | Secondary end point(s) |
- Proportion of patients achieved TI ≥56 consecutive days anytime
during the study
- Proportion of patients who achieved ≥50% reduction in number of RBC transfusion over any 8 weeks compared to their baseline
- Cumulative number of patient-exposure-week of TI
- Number of pRBC packs transfused compared to baseline
- Proportion of patients who achieved TI for ≥20 Weeks (140 Days)
- Mean change from baseline in Physical Function as measured by Patient Reported Outcomes Measurement Information System (PROMIS)
- Mean change from baseline in PROMIS Fatigue score.
- Mean change from baseline in Euroqol Quality of Life Five Dimensional Five Level Health Questionnaire (EQ-5D-5L) assessment |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
All secondary and exploratory endpoints will be analyzed at both for the first 28 weeks of treatment and for the end of the 52-week study treatment period, if appropriate.
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|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 46 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Canada |
| Israel |
| United States |
| Belgium |
| France |
| Germany |
| Italy |
| Netherlands |
| Poland |
| Spain |
| Korea, Republic of |
| Taiwan |
| United Kingdom |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| Last visit of last subject |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 11 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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