Primary Objective:To evaluate RBC transfusion independence in the 2 treatment arms (oral azacitidine plus best supportive care versus placebo plus best supportive care) in subjects with RBC transfusion-dependent anemia and thrombocytopenia (platelet…
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Source
Brief title
Condition
- Haematopoietic neoplasms (excl leukaemias and lymphomas)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Proportion of subjects in the overall population achieving RBC transfusion
independence with duration >= 84 days (12 weeks)
Secondary outcome
• OS;
• HI-P (IWG 2006 criteria; Cheson et al., Blood, 2006);
• Duration of RBC transfusion independence;
• Time to RBC transfusion independence;
• Proportion of subjects progressing to AML and time to AML progression;
• HI-E (IWG 2006 criteria; Cheson et al., Blood, 2006);
• Proportion of platelet transfusion-dependent subjects at baseline achieving
platelet transfusion independence with duration >= 56 days (8 weeks);
• Duration of platelet transfusion-independence;
• Time to platelet transfusion independence;
• Hematologic response (IWG 2006 criteria; Cheson et al., Blood, 2006);
• Proportion of subjects experiencing clinically significant bleeding events;
• Safety (type, frequency, severity of AEs and relationship of AEs to oral
azacitidine/placebo; monitoring for progression to AML and second primary
malignancy);
• HRQoL utilizing the Functional Assessment of Cancer Therapy-Anemia (FACT An)
and EuroQoL Group EQ-5D-3L (EQ-5D) instruments;
• Measures of healthcare resource utilization.
Background summary
While, amongst others, subcutaneous azacatidine is approved for the treatment
of low-risk MDS in some countries, this treatment is not used often. The
primary treatment still remains treatment with ESAs and erythrocytes and/or
platelets transfusions. Bone marrow transplantation is only possible for a
small group of patients. An oral formulation of azacitidine provides an
opportunity to deliver the drug at lower doses over a more prolonged schedule
than can be practically achieved with parenteral therapy. In addition, an oral
formulation can be taken at home. At least, oral administration may offer
better quality of life and possibly a survival advantage. Please refer to
protocol dated 01May2012, page 7 (Study Rationale).
Study objective
Primary Objective:
To evaluate RBC transfusion independence in the 2 treatment arms (oral
azacitidine plus best supportive care versus placebo plus best supportive care)
in subjects with RBC transfusion-dependent anemia and thrombocytopenia
(platelet count <= 75 x 109/L) due to IPSS lower-risk MDS.
Secondary Objectives:
To evaluate in both treatment arms overall survival (OS); hematologic
improvement-platelet response (HI-P); duration of RBC transfusion independence
and time to RBC transfusion independence; progression to acute myeloid leukemia
(AML), and time to AML progression;
hematologic improvement-erythroid response (HI-E); platelet-transfusion
independence, duration of platelet transfusion independence,
and time to platelet transfusion independence; hematologic response* clinically
significant bleeding events; safety; health-related quality-of-life (HRQoL);
and healthcare resource utilization.
Study design
This is a phase 3, multicenter, randomized, double-blind, placebo-controlled,
parallel-group study in subjects with RBC transfusion-dependent anemia and
thrombocytopenia (ie, platelet count <= 50 x 109/L) due to IPSS lower-risk
myeloplastic syndromes. The study consists of 3 phases: screening, double-blind
treatment, and follow-up.
Because a hematologic response to treatment with azacitidine may frequently be
delayed, it is recommended that subjects receive at least 6 cycles of treatment
with IP; however, subjects may be discontinued from treatment at the
investigator*s discretion prior to reaching the
recommended minimum number of cycles. Reasons for treatment discontinuation may
include disease progression (Appendix A), AE, withdrawal of consent, death,
lost to follow-up, or protocol violation. Subjects will be assessed for disease
status at the end of Cycle 6, prior to starting Cycle 7. If subjects have met
the following criteria, subjects can continue on to Cycle 7 and beyond. If
subjects have failed to meet the criteria at the end of Cycle 6, subjects will
be discontinued from protocol-prescribed therapy.
Intervention
Patients will receive 300 mg oral azacitidine or placebo after screening during
21 days of each 28 days cycle. Dosage can be amended if needed.
Study burden and risks
Oral azacitidine can have the following side-effects:
Very common (a 10% or more chance that this will happen): anemia (low number of
red blood cells which may make you feel weak or tired); low number of white
blood cells with or without fever; a decrease in the number platelets (the
cells that help your blood to clot); infections (including pneumonia or of the
lung, mouth, skin, or urinary tract which may be bacterial, fungal or viral);
nausea; vomiting; diarrhea; stomach pain; constipation; feeling tired, unwell,
or weak; fever; sore throat with swelling or pain of the nasal membranes or
nose; decreased appetite; weight loss; low levels of blood potassium (which may
cause fatigue, muscle weakness or cramps, or an irregular heart beat); pain
(including muscle, joints, back and chest pain); dizziness; headache;
difficulty sleeping; shortness of breath with or without exercise; rash;
itchiness; bruising (including tiny red or purple spots under the skin or other
tissue); nosebleeds.
Common (between a 1%-10% chance that this will happen): Bone marrow failure
which is a severe reduction of red and white blood cells and platelets (at
nearly the same time) which can cause weakness, bruising, or make infections
more likely; a very severe infection of the blood which may include a decrease
in blood pressure; shivering (chills); indigestion or upset stomach; a disease
affecting the gut which can result in fever, vomiting and stomach pain
(diverticulitis); pain, swelling, or sores on the inside of the mouth; runny
nose or sinus infection; bleeding including from the gums, eye, brain, stomach
or rectum (hemorrhoids) or due to a catheter line; muscle spasms; anxiety;
sleepiness; blood in the urine; hair loss; redness of the skin; hives; high
blood pressure; low blood pressure or dizziness upon standing; fainting;
dehydration; fluid around the lungs (pleural effusion).
Uncommon (between a 0.1%-1% chance that this will happen): Allergic reaction
(may include difficulty breathing, swelling of the lips, itching, rash or
dizziness ).
Rare (less than 0.1% that this will happen):
Abnormal kidney function test; kidneys not functioning properly that has rarely
led to too much acid in the blood or kidney failure (sometimes fatal); in
patient with certain types of cancer, abnormal liver function may occur that
has rarely led to decreased level of consciousness related to liver toxicity
(sometimes fatal).
For a complete overview please refer to the schedule of events in the protocol.
Patients must take two tablets of study medication one time a day with the
prescribed amount water during 21 of the 28 days + anti-nausea medication.
Patients are asked to complete a diary, herein they note the time of intake of
the tablets, amount of tablets taken, if anti-nausea medication is used and the
prescribed amount of water has been taken during the intake of the tablets.
There is an extended and partly mandatory genetic research together with this
research (cytogenetics, pharmacokinetics, biomarkers). Two questionnaires will
be taken during the research.
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Age
Inclusion criteria
1. Age >= 18 years at the time of signing the informed consent document
2. Have a documented diagnosis of MDS according to WHO 2008
classification
3. Be RBC transfusion-dependent as defined by:
• Average transfusion requirement of >= 2 units** per 28 days of RBCsconfirmed for a minimum of 56 days immediately preceding
randomization (please note that the period covering the transfusion
history overlaps with the screening phase)
• Hemoglobin levels at the time of or within 7 days prior to
administration of an RBC transfusion must have been <= 10.0 g/dL in
order for the transfusion to be counted towards RBC transfusiondependent
status. Red blood cell transfusions administered when Hgb
levels were > 10.0 g/dL and/or RBC transfusions administered for
elective surgery will not qualify as a required transfusion for the purpose
of providing evidence of RBC transfusion-dependent status
- No consecutive 28 days that are RBC-transfusion-free during the 56
days immediately preceding randomization
4. Have thrombocytopenia as defined by two platelet counts that are <=
75 x 109/L and >= 21 days apart. The second confirmatory platelet count
must be obtained <= 14 days prior to randomization
• At least one platelet count must be centrally analyzed within the 56
day screening period with results of <= 75 x 109/L; the second platelet
count may be centrally or locally analyzed, with results that are also <=
75 x 109/L.
• Prior documented medical history of thrombocytopenia may be used
to demonstrate
eligibility for the study if at least one historical platelet count of <= 75 x
109/L was obtained within 56 days of randomization and >= 21 days
apart from the centrally
analyzed platelet count.
• If additional platelet counts were obtained during the interim period,
these must also have been <= 75 x 109/L. If platelet counts within the
interim period are >75 x 109/L, this would be acceptable only if directly
associated with a platelet transfusion administered within 7 days prior
to the date of the platelet count.
5. Have an ECOG performance status of 0, 1, or 2
6. Females of childbearing potential (FCBP)** may participate, providing
they meet the following conditions:
• Agree to use at least two effective contraceptive methods (oral,
injectable, or implantable hormonal contraceptive; tubal ligation; intrauterine
device; barrier contraceptive with spermicide; or vasectomized
partner) throughout the study, and for 3 months following the last dose
of IP; and
• Have a negative serum pregnancy test at screening ; and
• Have a negative serum or urine pregnancy test (investigator's
discretion; sensitivity of at least 25 mIU/mL) within 72 hours prior to
starting IP in the treatment phase (note that the screening serum
pregnancy test can be used as the test prior to starting study therapy in
the treatment phase if it is performed within the 72-hour timeframe)
7. Male subjects with a female partner of childbearing potential must
agree to the use of at least two physician-approved contraceptive
methods throughout the course of the study and should avoid fathering a
child during the course of the study and for 3 months following the last
dose of IP
Exclusion criteria
1. IPSS higher-risk (INT-2 or High risk) MDS
2. Secondary MDS
3. Hypoplastic MDS or other subtype with eligibility for treatment with
immunotherapy based on investigator's judgment, unless subject
received last dose from prior Chemo~ or Immunotherapy >= 24 weeks
prior to randomization
4. CMML, atypical chronic myeloid leukemia (CML) and unclassifiable
myeloproliferative disease (MPD)
5. Prior treatment with any of the following:
• Azacitidine (any formulation), decitabine or other hypomethylating
agent
• Lenalidomide, unless the subject received the last dose >= 8 weeks
prior to randomization
6. Prior allogeneic or autologous stem cell transplant
7. History of inflammatory bowel disease (eg, Crohn's disease, ulcerative
colitis), celiac disease (ie, sprue), prior gastrectomy or upper bowel
removal, or any other gastrointestinal disorder or defect that would
interfere with the absorption, distribution, metabolism or excretion of
the IP and/or predispose the subject to an increased risk of
gastrointestinal toxicity
8. Thrombocytopenia secondary to other possible causes, including
medication(s), congenital disorder(s), immune disorder(s) (eg,
idiopathic thrombocytopenic purpura [ITP]), or microvascular
disorder(s) (eg, disseminated intravascular coagulation, hemolytic
uremic syndrome, thrombotic thrombocytopenic purpura)
9. Use of any of the following within 28 days prior to randomization:
• cytotoxic, chemotherapeutic, targeted or investigational
agents/therapies
• thrombopoiesis-stimulating agents (TSAs; eg, Romiplostim,
Eltrombopag, Interleukin-11)
• ESAs and other RBC hematopoietic growth factors (eg, Interleukin-3)
• hydroxyurea
10. Ongoing medically significant adverse events from previous
treatment, regardless of the
time period
11. Concurrent use of any of the following:
• iron-chelating agents, except for subjects on a stable or decreasing
dose for at least 8 weeks (56 days) prior to randomization
• corticosteroid, except for subjects on a stable or decreasing dose for >=
1 week prior to randomization for medical conditions other than MDS
12. Prior history of malignancies, other than MDS, unless the subject has
been free of the disease for >= 3 years. However, subjects with the
following history/concurrent conditions are allowed:
• Basal or squamous cell carcinoma of the skin
• Carcinoma in situ of the cervix
• Carcinoma in situ of the breast
• Incidental histologic finding of prostate cancer (T1a or T1b using the
tumor, nodes, metastasis [TNM] clinical staging system)
13. Significant active cardiac disease within the previous 6 months,
including:
• New York Heart Association (NYHA) class IV congestive heart failure;
• Unstable angina or angina requiring surgical or medical intervention;
and/or
• Myocardial infarction
14. Uncontrolled systemic fungal, bacterial, or viral infection (defined as
ongoing signs/symptoms related to the infection without improvement
despite appropriate antibiotics, antiviral therapy, and/or other
treatment)
15. Known Human Immunodeficiency Virus (HIV) or Hepatitis C (HCV)
infection, or evidence of active Hepatitis B Virus (HBV) infection
16. Abnormal coagulation parameters (PT > 15 seconds, PTT > 40
seconds, and/or INR > 1.5). After consultation with the medical monitor,
higher than normal range levels may be acceptable if the subject is being
treated with a stable dose of anticoagulants for thrombotic prophylaxis
(ie with atrial fibrillation, previous thromboembolic event, mechanical
cardiac valve replacement or presence of lupus or
antiphospholipid antibodies). The decision to include such patients
would be the responsibility of the investigator.
17. Any of the following laboratory abnormalities:
• Serum AST/SGOT or ALT/SGPT > 2.5 x upper limit of normal (ULN)
unless these abnormal liver function test(s) can be attributed to iron
overload as demonstrated by a serum transferrin saturation of > 65%
and a serum ferritin of > 1000 µg/L
• Serum bilirubin > 1.5 x ULN. Higher levels are acceptable if these can
be attributed to active red blood cell precursor destruction within the
bone marrow (ie, ineffective erythropoiesis) or in the presence of known
history of Gilbert Syndrome. Subjects are excluded if there is evidence of
autoimmune hemolytic anemia manifested as a corrected reticulocyte
count of > 2% with either a positive Coombs' test or over 50% of
indirect bilirubin
• Serum creatinine > 2.5 x ULN
18. Known clinically significant anemia due to iron, vitamin B12, or folate
deficiencies, or autoimmune or hereditary hemolytic anemia, or
gastrointestinal bleeding. Iron deficiency would be determined by a bone
marrow aspirate stain for iron, the transferrin saturation (iron/total iron
binding capacity [Fe/TIBC] <= 20%), or serum ferritin <= 15 ng/mL
19. Known or suspected hypersensitivity to azacitidine or mannitol
20. Pregnant or lactating females
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2012-002471-34-NL |
| ClinicalTrials.gov | NCT01566695 |
| CCMO | NL42297.042.13 |