Ignite Creation Date:
2024-05-05 @ 12:04 PM
Last Modification Date:
2024-10-26 @ 9:20 AM
Study NCT ID:
NCT00234143
Status:
UNKNOWN
Last Update Posted:
2009-03-12
First Post:
2005-10-05
Brief Title:
Erythropoietin EPO and Granulocyte-Colony Stimulating Factor G-CSF for Low-Risk Myelodysplastic Syndromes MDS
Sponsor:
St Bartholomews Hospital
Organization:
St Bartholomews Hospital
Study Overview
Official Title:
A Randomised Controlled Trial of Prolonged Treatment With Darbepoetin Alpha With or Without Recombinant Human Granulocyte Colony Stimulating Factor G-CSF Versus Best Supportive Care in Patients With Low-Risk Myelodysplastic Syndromes
Status:
UNKNOWN
Status Verified Date:
2009-03
Last Known Status:
ACTIVE_NOT_RECRUITING
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Myelodysplastic syndromes MDS are acquired clonal disorders of the bone marrow The clinical consequences of MDS are bone marrow failure and a predisposition to develop acute myeloid leukaemia AML Patients with low risk MDS have less than 10 myeloblasts in the marrow and include the World Health Organization WHO subtypes refractory anaemia RA refractory anaemia with ring sideroblasts RARS and refractory anaemia with excess blasts-I RAEB-I This group of patients has a relatively low risk of leukaemic transformation and the major clinical problem is the manifestation of bone marrow failure Up to 80 of these patients become red cell transfusion dependent To date the only curative therapy is allogeneic stem cell transplantation Unfortunately a median age at diagnosis of 65 years excludes this type of therapy for most patients with MDS The aim of treatment is therefore supportive therapy Long term red cell transfusion therapy carries the problems of acute transfusion reactions iron overload alloantibody formation poor venous access and the risk of transfusion transmitted infection With time such patients require increasing frequency of transfusion and obtain decreased length of benefit from transfusion The quality of life of such patients is significantly reduced Alternative therapies therefore aimed at promoting more effective haemopoiesis and reducing the need for red cell transfusion may improve quality of life reduce the use of expensive resources such as red cells and iron chelation and perhaps enhance survival
Combined darbepoetin alfa Aranesp plus G-CSF Neupogen filgrastim in low risk MDS is better than best supportive care with respect to haemoglobin and quality of life The study will assess
the costs of this approach
long-term outcomes
clinicallaboratory parameters allowing early cessation of therapy in patients destined not to respond
Combined darbepoetin alfa Aranesp plus G-CSF Neupogen filgrastim in low risk MDS is better than best supportive care with respect to haemoglobin and quality of life The study will assess
the costs of this approach
long-term outcomes
clinicallaboratory parameters allowing early cessation of therapy in patients destined not to respond
Detailed Description:
STUDY OBJECTIVES
Primary objectives
To compare the Quality of Life of Low-risk MDS patients randomised to receive prolonged treatment with EPO alone EPO with G-CSF or best supportive care alone
Secondary objectives
To compare the haemoglobin response and transfusion requirements of patients in each of these arms
To compare the economics costs of treating patients in each arm in order to derive a costbenefit analysis
To assess the utility of prognostic factor and predictive factor assessment in particular against the predictive model proposed by Hellstrom-Lindberg
STUDY DESIGN
This trial is a multi-centre randomised triple arm open-label trial of EPO alone with best supportive care EPO plus G-CSF with best supportive care and best supportive care only in patients with low-risk myelodysplastic syndrome with symptomatic anaemia andor red cell transfusion dependence Screening procedures will take place within 42 days of randomisation
Patients will be randomised in a 111 ratio to EPO and best supportive care EPO with G-CSF and best supportive care or best supportive care only Patients randomised to drug therapy arms will receive EPO subcutaneously every fortnight G-CSF at least weekly together with red cell transfusions and other supportive care if required Patients randomised to best supportive care only will receive red cell transfusions and supportive care as required Study visits and selected study investigations will occur every 4 weeks for the first 24 weeks then at 36 and 52 weeks
Quality of life FACT-An and EQ-5D measures will be used for all arms of the study
Analysis Reporting
Data will be analysed and reported for all endpoints after the final patient has completed the 52 week follow-up
Data Monitoring Committee
An independent Data Monitoring Committee DMC will ensure the safety of patients enrolled in the trial This group will be the MRC Leukaemia LDMEC Chair Prof Gordon Murray The DMC will meet at the commencement of recruitment and will formulate its guidelines for safety and efficacy monitoring The DMC will provide a report of their meetings to the TSC The DMC will meet at least annually and more frequently if needed
Central Morphology Review
Bone marrow biopsiesaspirates for all patients will be sent for central morphology review to determine eligibility for the study All screening aspirates and biopsies will be reviewed centrally to confirm the diagnosis of MDS and the categorisation of the WHOFAB subtype On-study and end of study bone marrows will also be reviewed In addition centralised testing of specialist investigations will be performed
STUDY ENDPOINTS
Primary end point
Quality of life at 24 weeks FACT-An EQ-5D - the latter for use in health economic analyses
Secondary end points
Quality of life at 12 36 and 52 weeks FACT-An EQ-5D
Overall erythroid response major and minor at 24 weeks main analysis point and also at 12 and 52 weeks as defined by the International Working Group IWG criteria
Incidence of disease progression ie to RAEB or AML
Overall survival
Economic costs of managing anaemia in each arm of the study
STUDY DURATION
Patients will be monitored for all study endpoints up to 52 weeks Patients responding to EPO G-CSF will remain on therapy for 52 weeks Beyond 52 weeks patients will be followed up indefinitely in order to assess duration of response incidence of disease progression and overall survival through the Office of National Statistics
TOTAL SAMPLE SIZE
Three hundred sixty360 patients one hundred twenty 120 in each arm
DOSING REGIMEN
The treatment schedule uses the concept of frontloading to give patients the highest doses of EPO at the start of therapy in order to induce a response as quickly as possible The long-acting nature of darbepoetin alpha avoids excessive frequency of injections but allows delivery of high doses of EPO At week 24 if no response is achieved the study treatment is deemed to have failed and is stopped and patients will receive best supportive care only
Darbepoetin 120 patients
EPO Aranesp 500 mcg sc once every 2 weeks
1 If a rapid response is obtained Hb increase or 2 gdl in any 4 week period titrate down the dose frequency of EPO
2 If major response titrate EPO to lowest dose frequency that maintains the response
At 24 weeks
1 If no response stop EPO and give supportive therapy only
2 If minor response continue EPO 500 mcg once every 2 weeks sc
3 If major response titrate EPO to lowest dose frequency that maintains the response
Darbepoetine with Filgrastim 120 patients
G-CSF Neupogen 300 mcg sc twice a week 3-4 days apart
EPO Aranesp 500 mcg sc once every 2 weeks
1 If a rapid response is obtained Hb increase or 2 gdl in any 4 week period titrate down the dose frequency of EPO
2 If major response titrate EPO and G-CSF to lowest dose frequency that maintains the response
At 24 weeks
1 If no response stop EPO and G-CSF and give supportive therapy only
2 If minor response continue EPO 500 mcg every 2 weeks sc and G-CSF 300 mcg sc twice a week 3-4 days apart
3 If major response titrate EPO and G-CSF to lowest dose frequency that maintains the response
Best Supportive Care 120 patients
Patients randomised to no growth factor treatment will receive best supportive care defined as
Red cell transfusion support to achieve a predicted post-transfusion haemoglobin of 110 to 120 gdl at a quantity frequency such that the trough haemoglobin is never 80 gdl OR
such that the patient is never excessively symptomatic according to local transfusion guidelinespolicy
STUDY DRUG SUPPLIES
Darbepoetin Aranesp pre-filled syringes 500 mcg and filgrastim Neupogen pre-filled syringes 300 mcg will be supplied by Amgen UKand provided free of charge
SAFETY ASSESSMENTS
Vital signs
Physical examination
Clinical laboratory assessments
Concomitant medications
Adverse events
EFFICACY ASSESSMENTS
Quality of life assessments
Number and frequency of red cell transfusions
Clinical laboratory assessments
Bone marrow aspirate assessments
Primary objectives
To compare the Quality of Life of Low-risk MDS patients randomised to receive prolonged treatment with EPO alone EPO with G-CSF or best supportive care alone
Secondary objectives
To compare the haemoglobin response and transfusion requirements of patients in each of these arms
To compare the economics costs of treating patients in each arm in order to derive a costbenefit analysis
To assess the utility of prognostic factor and predictive factor assessment in particular against the predictive model proposed by Hellstrom-Lindberg
STUDY DESIGN
This trial is a multi-centre randomised triple arm open-label trial of EPO alone with best supportive care EPO plus G-CSF with best supportive care and best supportive care only in patients with low-risk myelodysplastic syndrome with symptomatic anaemia andor red cell transfusion dependence Screening procedures will take place within 42 days of randomisation
Patients will be randomised in a 111 ratio to EPO and best supportive care EPO with G-CSF and best supportive care or best supportive care only Patients randomised to drug therapy arms will receive EPO subcutaneously every fortnight G-CSF at least weekly together with red cell transfusions and other supportive care if required Patients randomised to best supportive care only will receive red cell transfusions and supportive care as required Study visits and selected study investigations will occur every 4 weeks for the first 24 weeks then at 36 and 52 weeks
Quality of life FACT-An and EQ-5D measures will be used for all arms of the study
Analysis Reporting
Data will be analysed and reported for all endpoints after the final patient has completed the 52 week follow-up
Data Monitoring Committee
An independent Data Monitoring Committee DMC will ensure the safety of patients enrolled in the trial This group will be the MRC Leukaemia LDMEC Chair Prof Gordon Murray The DMC will meet at the commencement of recruitment and will formulate its guidelines for safety and efficacy monitoring The DMC will provide a report of their meetings to the TSC The DMC will meet at least annually and more frequently if needed
Central Morphology Review
Bone marrow biopsiesaspirates for all patients will be sent for central morphology review to determine eligibility for the study All screening aspirates and biopsies will be reviewed centrally to confirm the diagnosis of MDS and the categorisation of the WHOFAB subtype On-study and end of study bone marrows will also be reviewed In addition centralised testing of specialist investigations will be performed
STUDY ENDPOINTS
Primary end point
Quality of life at 24 weeks FACT-An EQ-5D - the latter for use in health economic analyses
Secondary end points
Quality of life at 12 36 and 52 weeks FACT-An EQ-5D
Overall erythroid response major and minor at 24 weeks main analysis point and also at 12 and 52 weeks as defined by the International Working Group IWG criteria
Incidence of disease progression ie to RAEB or AML
Overall survival
Economic costs of managing anaemia in each arm of the study
STUDY DURATION
Patients will be monitored for all study endpoints up to 52 weeks Patients responding to EPO G-CSF will remain on therapy for 52 weeks Beyond 52 weeks patients will be followed up indefinitely in order to assess duration of response incidence of disease progression and overall survival through the Office of National Statistics
TOTAL SAMPLE SIZE
Three hundred sixty360 patients one hundred twenty 120 in each arm
DOSING REGIMEN
The treatment schedule uses the concept of frontloading to give patients the highest doses of EPO at the start of therapy in order to induce a response as quickly as possible The long-acting nature of darbepoetin alpha avoids excessive frequency of injections but allows delivery of high doses of EPO At week 24 if no response is achieved the study treatment is deemed to have failed and is stopped and patients will receive best supportive care only
Darbepoetin 120 patients
EPO Aranesp 500 mcg sc once every 2 weeks
1 If a rapid response is obtained Hb increase or 2 gdl in any 4 week period titrate down the dose frequency of EPO
2 If major response titrate EPO to lowest dose frequency that maintains the response
At 24 weeks
1 If no response stop EPO and give supportive therapy only
2 If minor response continue EPO 500 mcg once every 2 weeks sc
3 If major response titrate EPO to lowest dose frequency that maintains the response
Darbepoetine with Filgrastim 120 patients
G-CSF Neupogen 300 mcg sc twice a week 3-4 days apart
EPO Aranesp 500 mcg sc once every 2 weeks
1 If a rapid response is obtained Hb increase or 2 gdl in any 4 week period titrate down the dose frequency of EPO
2 If major response titrate EPO and G-CSF to lowest dose frequency that maintains the response
At 24 weeks
1 If no response stop EPO and G-CSF and give supportive therapy only
2 If minor response continue EPO 500 mcg every 2 weeks sc and G-CSF 300 mcg sc twice a week 3-4 days apart
3 If major response titrate EPO and G-CSF to lowest dose frequency that maintains the response
Best Supportive Care 120 patients
Patients randomised to no growth factor treatment will receive best supportive care defined as
Red cell transfusion support to achieve a predicted post-transfusion haemoglobin of 110 to 120 gdl at a quantity frequency such that the trough haemoglobin is never 80 gdl OR
such that the patient is never excessively symptomatic according to local transfusion guidelinespolicy
STUDY DRUG SUPPLIES
Darbepoetin Aranesp pre-filled syringes 500 mcg and filgrastim Neupogen pre-filled syringes 300 mcg will be supplied by Amgen UKand provided free of charge
SAFETY ASSESSMENTS
Vital signs
Physical examination
Clinical laboratory assessments
Concomitant medications
Adverse events
EFFICACY ASSESSMENTS
Quality of life assessments
Number and frequency of red cell transfusions
Clinical laboratory assessments
Bone marrow aspirate assessments
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None