Clinical Trials Register

Summary
EudraCT Number:	2012-002523-14
Sponsor's Protocol Code Number:	A536-03
National Competent Authority:	Germany - PEI
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2012-08-22
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Germany - PEI

A.2

EudraCT number

2012-002523-14

A.3

Full title of the trial

A Phase 2, Open-Label, Ascending Dose Study of ACE-536 for the
Treatment of Anemia in Patients with Low or Intermediate-1 Risk
Myelodysplastic Syndromes (MDS)

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

A Phase 2 study for the treatment of anemia in patients with myelodysplastic syndrome of low and intermediate risk groups with increasing doses of ACE-536

A.4.1

Sponsor's protocol code number

A536-03

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Acceleron Pharma Inc.
B.1.3.4	Country	United States
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Acceleron Pharma Inc.
B.4.2	Country	United Kingdom
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Acceleron Pharma Inc.
B.5.2	Functional name of contact point	Peter G. Linde
B.5.3	Address:
B.5.3.1	Street Address	128 Sidney Street
B.5.3.2	Town/ city	Cambridge, MA
B.5.3.3	Post code	02139
B.5.3.4	Country	United States
B.5.4	Telephone number	+16176499202
B.5.5	Fax number	+16176499988
B.5.6	E-mail	plinde@acceleronpharma.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	ACE-536
D.3.2	Product code	ACE-536
D.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Luspatercept
D.3.9.1	CAS number	1373715-00-4
D.3.9.2	Current sponsor code	ACE-536
D.3.9.3	Other descriptive name	ACE-536
D.3.9.4	EV Substance Code	not assigned
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	50
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Yes
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	ACE-536
D.3.2	Product code	ACE-536
D.3.4	Pharmaceutical form	Lyophilisate for solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Luspatercept
D.3.9.1	CAS number	1373715-00-4
D.3.9.2	Current sponsor code	ACE-536
D.3.9.3	Other descriptive name	ACE-536
D.3.9.4	EV Substance Code	not assigned
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	50
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Yes
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Myelodysplastic Syndromes (MDS)

E.1.1.1

Medical condition in easily understood language

Group of disorders of the bone marrow, in which the formation of blood cells from their precursors is disturbed. MDS patients are no longer capable to form fully mature and functional blood cells.

E.1.1.2

Therapeutic area

Diseases [C] - Blood and lymphatic diseases [C15]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	SOC
E.1.2	Classification code	10029104
E.1.2	Term	Neoplasms benign, malignant and unspecified (incl cysts and polyps)
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	HLT
E.1.2	Classification code	10028536
E.1.2	Term	Myelodysplastic syndromes
E.1.2	System Organ Class	100000004851

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

To evaluate the proportion of patients who have a modified erythroid response (mHI-E), defined as a hemoglobin increase of ≥ 1.5 g/dL from baseline for ≥ 14 days (in the absence of red blood cell [RBC] transfusions) in non-transfusion dependent patients, or a reduction of either ≥ 4 units or ≥ 50% of units of RBCs transfused compared to pretreatment in transfusion-dependent patients

E.2.2

Secondary objectives of the trial

Secondary:
-To evaluate safety and tolerability of ACE-536
-To examine rates of erythroid, neutrophil and platelet (HI-E, HI-N and HI-P) responses (International Working Group [IWG] 2006 criteria)
-To evaluate time to mHI-E and HI-E response and duration of mHI-E and HI-E response
-To evaluate frequency of RBC transfusions in transfusion dependent patients
-To examine the pharmacokinetic (PK) profile of ACE-536
-To examine other pharmacodynamic (PD) effects (e.g., iron metabolism, erythropoietin, reticulocytes, and bone biomarkers)

Exploratory:
-To evaluate biomarkers related to the TGFb superfamily
-Evaluation of self-reported quality of life in the expansion cohort using tools including but not limited to the FACT-An questionnaire

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1.Men or women ≥ 18 years of age.
2.Documented diagnosis of idiopathic/de novo MDS or non-proliferative chronic myelomonocytic leukemia (CMML) according to WHO criteria16 (white blood count [WBC] < 13,000/μL) that meets IPSS classification (Appendix 2) of low or intermediate-1 risk disease as determined by the microscopic and standard cytogenetic analyses of the bone marrow and peripheral complete blood count (CBC) obtained during screening.
3.Anemia defined as:
•Mean hemoglobin concentration < 10.0 g/dL of 2 measurements (one performed within one day prior to Cycle 1 Day 1 and the other performed 7-28 days prior to Cycle 1 Day 1, not influenced by RBC transfusion within 7 days of measurement) for non-transfusion dependent patients (defined as having received < 4 units of RBCs within 8 weeks prior to Cycle 1 Day 1) (Participation in all cohorts), OR,
•Transfusion-dependent, defined as having received ≥ 4 units of RBCs within 8 weeks prior to Cycle 1 Day 1. (transfusion dependent patients are allowed in dose escalation cohorts and expansion cohort 1 only; patients with ≤ 6 units of RBCs within 8 weeks prior to Cycle 1 Day 1 may be allowed in cohort 2B and expansion cohort 3)
4.Serum erythropoietin levels, prior erythropoiesis-stimulating agent (ESA) treatment, and RS status:
-Dose escalation cohorts and expansion cohort 1 patients: Serum erythropoietin level > 500 U/L, OR, if ≤ 500 U/L, patient is non-responsive, refractory, or intolerant to erythropoiesis-stimulating agents (ESAs), or ESAs are contraindicated or unavailable.
-Expansion cohort 2 patients: If patient is RS+ (defined as having ≥ 15% ring sideroblasts in the bone marrow), has less than 4 weeks' exposure to ESAs and serum erythropoietin level ≤ 200 U/L. If a patient is RS- (defined as having < 15% ring sideroblasts in the bone marrow), prior ESA treatment and any serum erythropoietin level is allowed.
- Expansion cohort 3 patients: baseline EPO levels ≤ 500 U/L, no prior ESA, and RS- (defined as having < 15% ring sideroblasts in the bone marrow).
5.No alternative treatment options, per national MDS guidelines, are available and/or appropriate for the patient, at the discretion of the investigator.
6.ECOG performance status of 0, 1, or 2 (if related to anemia).
7.Adequate renal (creatinine ≤ 2.0 x upper limit of normal [ULN]) and hepatic (total bilirubin < 2 x ULN and AST and ALT < 3 x ULN) function.
8.Adequate transferrin saturation (≥ 15%), ferritin (≥ 50 µg/L), folate (≥ 4.5 nmol/L [≥ 2.0 µg/L]) and vitamin B12 (≥ 148 pmol/L [≥ 200 pg/mL]) during screening (supplementation and retest during screening is acceptable).
9.Females of child bearing potential (defined as sexually mature women who have not undergone hysterectomy or bilateral oophorectomy, or are not naturally postmenopausal ≥ 24 consecutive months) must have negative urine or blood pregnancy test prior to enrollment and use adequate birth control methods (abstinence, oral contraceptives, barrier method with spermicide, or surgical sterilization) during study participation and for 12 weeks following the last dose of ACE-536. Males must agree to use a latex condom during any sexual contact with females of child-bearing potential while participating in the study and for 12 weeks following the last dose of ACE 536, even if he has undergone a successful vasectomy. Patients must be counseled concerning measures to be used to prevent pregnancy and potential toxicities prior to the first dose of ACE 536.
10.Patients are able to adhere to the study visit schedule, understand and comply with all protocol requirements.
11.Patient understands and is able to provide written informed consent.

E.4

Principal exclusion criteria

1.Prior treatment with azacitidine or decitabine.
2.Treatment within 28 days prior to Cycle 1 Day 1 with:
a.Erythropoiesis stimulating agent (ESA),
b.Granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony stimulating factor (GM-CSF),
c.Lenalidomide.
3.Iron chelation therapy if initiated within 56 days prior to Cycle 1 Day 1.
4.Treatment with another investigational drug or device, or approved therapy for investigational use ≤ 28 days prior to Cycle 1 Day 1, or if the half-life of the previous product is known, within 5 times the half-life prior to Cycle 1 Day 1, whichever may be longer.
5.Major surgery within 28 days prior to Cycle 1 Day 1. Patients must have completely recovered from any previous surgery prior to Cycle 1 Day 1.
6.Platelet count < 30 x 10^9/L.
7.Any active infection requiring parenteral antibiotic therapy within 28 days prior to Cycle 1 Day 1 or oral antibiotics within 14 days of Cycle 1 Day 1.
8.History of stroke, deep venous thrombosis (DVT) or arterial embolism within 6 months prior to Cycle 1 Day 1.
9.Known positive for human immunodeficiency virus (HIV), active infectious hepatitis B (HBV) or active infectious hepatitis C (HCV).
10.Any malignancy other than MDS which has not been in remission and/or has required systemic therapy including radiation, chemotherapy, hormonal therapy or surgery, within the last year prior to Cycle 1 Day 1.
11.Uncontrolled hypertension defined as systolic blood pressure (BP) ≥ 150 mm Hg or diastolic BP ≥ 100 mm Hg.
12.Pregnant or lactating females.
13.History of severe allergic or anaphylactic reactions or hypersensitivity to recombinant proteins or excipients in the investigational drug.
14.Any other condition not specifically noted above which, in the judgment of the investigator, would preclude the patient from participating in the study.
15. Transfusion event within 7 days prior to Cycle 1 Day 1.
16. Prior treatment with sotatercept (ACE-011) or ACE-536.
17. Secondary MDS

E.5 End points

E.5.1

Primary end point(s)

The primary efficacy endpoint is modified erythroid response (mHI-E), defined as the proportion of patients who have a hemoglobin increase of ≥ 1.5 g/dL from baseline for ≥ 14 days (in the absence of RBC transfusions) in non-transfusion dependent patients, or, a reduction of either ≥ 4 units or ≥ 50% of units of RBCs transfused over a period of 8 consecutive weeks, compared to the number of units of RBCs transfused in the 8 weeks immediately prior to Cycle 1 Day 1 in transfusion dependent patients (defined as having received ≥ 4 units of RBCs within 8 weeks prior to Cycle 1 Day 1).

E.5.1.1

Timepoint(s) of evaluation of this end point

End of Treatment (day 113)

E.5.2

Secondary end point(s)

The secondary efficacy/pharmacodynamic analysis will be performed using the ITT and EE populations and include:
- Modified erythroid response (mHI-E), as described above for primary endpoint, performed using the ITT population.
- HI-E response rate as defined by IWG 2006 criteria (Appendix 5). Improvements must last ≥ 8 weeks. For non-transfusion dependent patients, an increase of ≥ 1.5 g/dL from pretreatment hemoglobin. For transfused patients, a reduction by ≥ 4 units of RBCs transfused (for a hemoglobin ≤ 9.0 g/dL) during any 8-week period on study, compared with the 8-week period prior to Cycle 1 Day 1.
- Time to mHI-E and HI-E response and duration of mHI-E and HI-E response as per the IWG 2006 criteria.
- Frequency of RBC transfusion, and rate of RBC transfusion independence in transfusion-dependent patients.
- Other pharmacodynamic (PD) endpoints including:
o Biomarkers for iron metabolism
o Biomarkers for bone metabolism
o Relationship of biomarkers to response
o Rates of HI-N and HI-P
The exploratory endpoints will include:
- Evaluation of biomarkers related to the TGFb superfamily
- Evaluation of self-reported quality of life in the expansion cohort using tools including but not limited to the FACT-An questionnaire

E.5.2.1

Timepoint(s) of evaluation of this end point

End of Treatment (day 113)

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

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

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

E.8.3

The trial involves single site in the Member State concerned

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

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

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 the last subject undergoing the trial

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

153

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

Patients who have completed the trial have the option to roll over to the follow up study A536-05 with the same IP. Patients who will not participate in A536-05 will return to standard-of care after study completion.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2012-11-26

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-12-20

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2018-10-22

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