Clinical Trial Results:
An Open-Label Extension Study to Evaluate the Long-Term Effects of ACE-536 in Patients with β-Thalassemia Previously Enrolled in Study A536-04
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Summary
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EudraCT number |
2014-001281-94 |
Trial protocol |
IT GR |
Global end of trial date |
28 Apr 2020
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Results information
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Results version number |
v1(current) |
This version publication date |
14 May 2021
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First version publication date |
14 May 2021
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
A536-06
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02268409 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Acceleron Pharma, Inc.
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Sponsor organisation address |
128 Sidney Street , Cambridge , United States, 01239
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Public contact |
Mark Turnak, Sr. Director Medical Affairs, Acceleron Pharma, Inc., +1 6173019516, mturnak@acceleronpharma.com
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Scientific contact |
Mark Turnak, Sr. Director Medical Affairs, Acceleron Pharma, Inc., +1 6173019516, mturnak@acceleronpharma.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
18 Jun 2020
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
28 Apr 2020
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Global end of trial reached? |
Yes
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Global end of trial date |
28 Apr 2020
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
To evaluate the long-term safety and tolerability of ACE-536 in patients with β-thalassemia who were previously enrolled in study A536-04.
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Protection of trial subjects |
N/A
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
20 Oct 2014
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Greece: 7
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Country: Number of subjects enrolled |
Italy: 44
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Worldwide total number of subjects |
51
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EEA total number of subjects |
51
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
51
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
Consenting participants who met the Study A536-06 eligibility criteria immediately rolled over from Study A536-04 following the last luspatercept dose. These participants did not undero end of study visit in study A536-04 but instead were initiated immediately into the extension study. | ||||||||||||||||||||||
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Pre-assignment
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Screening details |
Other than informed consent, procedures listed as part of the 28-day screening period were only applicable to participants with treatment interruption. | ||||||||||||||||||||||
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Period 1
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Period 1 title |
Overall trial (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||||||||||
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Arms
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Arm title
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Overall trial | ||||||||||||||||||||||
Arm description |
- | ||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||
Investigational medicinal product name |
Luspatercept
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Investigational medicinal product code |
ACE-536
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Other name |
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Pharmaceutical forms |
Injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Luspatercept was administered by subcutaneous injection at 0.2, 0.4, 0.6, 0.6, 1.0 or 1.25 mg/kg. No more than 4 injections were administered per dose. Participants received the dose level of luspatercept that they were assigned at study enter unless a dose modification was required.
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Baseline characteristics reporting groups
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Reporting group title |
Overall trial
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Overall trial
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Reporting group description |
- | ||
Subject analysis set title |
Non-Transfusion Dependent Population
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
All treated patients who are Non-Transfusion Dependent at baseline. Non-Transfusion Dependence is defined as having received < 4 units of RBCs within 8 weeks prior to Cycle 1 Day 1. In this study, Efficacy Evaluable population is the same as Intention-to-treat population.
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Subject analysis set title |
Transfusion-Dependent Population
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
All treated patients who are Non-Transfusion Dependent at baseline. Transfusion Dependence is defined as having received >= 4 units of RBCs within 8 weeks prior to Cycle 1 Day 1.
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End point title |
Hemoglobin Response [1] | ||||||||
End point description |
Mean Hgb increase > 1.0g/dL during rolling 12 weeks
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End point type |
Primary
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End point timeframe |
Any rolling 12 week interval
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: The response rate for each dose group is reported in earlier section of EudraCT result posting, however, per protocol, no statistical testing is performed to compare the dose groups. Consequently, no p-value is reported in this section. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Transfusion Reduction Response | ||||||||
End point description |
>= 33% reduction in RBC transfusion burden over 12 weeks, compared to pre-treatment, in transfusion dependent subjects
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End point type |
Secondary
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End point timeframe |
First dose to last dose + 56 days
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| No statistical analyses for this end point | |||||||||
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End point title |
BSAP - End of Treatment - Percent Change from Baseline | ||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
First dose to End of Treatment visit
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| No statistical analyses for this end point | |||||||||
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End point title |
CTX - End of Treatment - Percent Change from Baseline | ||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
First dose to End of treatment visit
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| No statistical analyses for this end point | |||||||||
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End point title |
Erythropoeitin - End of Treatment- Change from Baseline | ||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
First dose to End of treatment visit
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| No statistical analyses for this end point | |||||||||
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End point title |
Reticulocytes - End of Treatment - Change from Baseline | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
First dose to End of treatment visit
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Transferrin - End of Treatment - Percent Change from Baseline | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
First dose to End of treatment visit
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Soluble Transferrin Receptor - End of Treatment - Percent Change from Baseline | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
First dose to End of treatment visit
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Ferritin - End of Treatment - Percent Change from Baseline | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
First dose to End of treatment visit
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| No statistical analyses for this end point | |||||||||||||
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End point title |
nRBC Smear- End of Treatment - Change from Baseline | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
First dose to End of treatment visit
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| No statistical analyses for this end point | |||||||||||||
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End point title |
LDH- End of Treatment - Percent Change from Baseline | ||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
First dose to End of treatment visit.
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| No statistical analyses for this end point | |||||||||
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End point title |
Bilirubin - End of Treatment - Percent Change from Baseline | ||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
First dose to End of treatment visit.
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| No statistical analyses for this end point | |||||||||
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End point title |
Indirect Bilirubin - End of Treatment - Percent Change from Baseline | ||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
First dose to End of treatment visit.
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| Notes [2] - -2.4 |
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| No statistical analyses for this end point | |||||||||
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Adverse events information
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Timeframe for reporting adverse events |
Treatment emergent adverse events
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Adverse event reporting additional description |
Treatment emergent adverse events related to study drug ( reported >=5%)
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
20.0
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Reporting groups
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Reporting group title |
Non-Serious Adverse Events
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Reporting group description |
Treatment emergent adverse events | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 2% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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08 Dec 2014 |
• The approved International Nonproprietary Name for the investigational product was added.
• Chiltern Pharmacovigilance’s fax number was updated.
• Exploratory objectives added were as follows:
− To evaluate change in BMD by DXA
− To evaluate change in the 6MWT distance in NTD participants
• Clarification was added on how the pretransfusion Hgb threshold is to be used during study.
• Dose titration rules were revised to allow for the dose level to be assessed on Day 1 of each cycle, clarification was provided that dose titration requires evaluation of 2 previous cycles at the same dose level, and clarification was provided on how Hgb measurements following transfusions should be used.
• Study drug information was updated to add that a lyophilized powder formulation may be used in the study.
• Clarification was provided that for EMH masses, MRI of the chest and abdomen should be performed.
• Repeat assessment of blood pressure was added to confirm abnormal blood pressure measurements.
• Clarification was provided for gonadal assessment as an optional procedure.
• Serum iron studies were added to central laboratory testing |
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03 Jun 2015 |
The study was extended by an additional year in order to obtain longer-term safety and efficacy data.
• Clarification around transfusion status was added. For participants with low transfusion burden, the goal of therapy is sustained increase in Hgb level. Over time, these participants may become TD due to underlying disease. If this occurred prior to entering this extension study, the participant was classified as TD and assessed for reduction in transfusion burden. For TD participants, the goal of therapy is reduced
transfusion burden. Participants with reduced transfusions following treatment in the base study (Study A536-04) and prior to entry into the extension study were continued to be assessed for persistence of reduced transfusion burden.
• The starting dose for participants with treatment interruption was changed to 0.8 mg/kg
• The maximum dose titration tested on Study A536-04 was changed to 1.25 mg/kg.
• For participants continuing treatment without interruption, ongoing treatment with ICT was allowed to continue without affecting eligibility.
• Analysis of Hgb increase ≥ 1.0 g/dL was included to further explore the magnitude and duration of the effect.
• MRI or DXA scans did not need to be repeated within a period of 3 months, unless clinically indicated. MRI for EMH masses were repeated to measure change in volume, and MRI of the spleen was repeated if there was an enlarged spleen or if clinically indicated.
• ICT was allowed during the study as long as it was initiated at least 56 days prior to C1D1 (for interruption participants) or if required during the study. |
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23 May 2016 |
• The study was extended to up to 5 years of treatment in order to obtain longer-term safety and efficacy data.
• The number of participants who enrolled in Study A536-04 was updated to reflect the actual number of participants enrolled.
• LMW heparin for the treatment of SVT was allowed due to short-term treatment for SVT being common in this patient population.
• A testing window was added to better accommodate participant scheduling.
• Section 10.2.1, Prohibited Concomitant Medications and Procedures, was added for further clarification regarding prohibited medications and procedures.
• Language was added to clarify timing of transfusions in relation to study drug administration.
• The option to delay a participant’s dose was added.
• Cycle language regarding participant treatment interruption for site administrative reasons was updated to reflect study extension and allow time for the approval of amendments by sites.
• A formal interim analysis of the safety and efficacy data was added to support registration filings |
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16 Aug 2016 |
• Language was added to better define reporting of AEs of special interest based on the Investigator’s Brochure. |
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12 Sep 2017 |
• Follow-up was extended to 3 years after the last dose of luspatercept to increase the chance of detecting new malignancies.
The schedule for post-treatment follow-up and long-term follow-up visits was defined.
• Treatment discontinuation in response to Grade 3 leukocytosis was added to the dose modification rules in order to ensure treatment discontinuation for participants with WBC elevations highly suspicious for development of a new hematologic malignancy or other significant myeloproliferative disorder. |
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29 Mar 2019 |
• Language was updated to allow for the use of vials containing either 25 mg, 50 mg, or 75 mg of lyophilized ACE-536. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| N/A | |||
