Clinical Trials Register

Summary
EudraCT Number:	2018-001489-41
Sponsor's Protocol Code Number:	P00003466
National Competent Authority:	Sweden - MPA
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2018-05-08
Trial 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

Sweden - MPA

A.2

EudraCT number

2018-001489-41

A.3

Full title of the trial

Radiation- and alkylator-free hematopoietic cell transplantation for bone marrow failure due to dyskeratosis congenita / telomere disease

A.3.1

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

A clinical trial using cell transplantation as treatment for bone marrow failure due to dyskeratosis congenita / telomere disease, inherited genetic conditions.

A.4.1

Sponsor's protocol code number

P00003466

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	Karolinska Universitetssjukhuset
B.1.3.4	Country	Sweden
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Karolinska Universitetssjukhuset
B.4.2	Country	Sweden
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Karolinska Universitetssjukhuset
B.5.2	Functional name of contact point	Mikael Sundin
B.5.3	Address:
B.5.3.1	Street Address	Barnhematologi, -immunologi och HCT, Astrid Lindgrens Barnsjukhus B76
B.5.3.2	Town/ city	Huddinge
B.5.3.3	Post code	141 86
B.5.3.4	Country	Sweden
B.5.4	Telephone number	00468585 848 43
B.5.6	E-mail	mikael.c.sundin@sll.se

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	Yes
D.2.1.1.1	Trade name	Lemtrada
D.2.1.1.2	Name of the Marketing Authorisation holder	Genzyme Therapeutics Ltd
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
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.3.4	Pharmaceutical form	Concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Alemtuzumab
D.3.9.1	CAS number	216503-57-0
D.3.9.3	Other descriptive name	ALEMTUZUMAB
D.3.9.4	EV Substance Code	SUB12459MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/kg milligram(s)/kilogram
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	0,2
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	No
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	Yes
D.2.1.1.1	Trade name	Fludarabine
D.2.1.1.2	Name of the Marketing Authorisation holder	EBEWE Pharma Ges.m.b.H. Nfg. KG
D.2.1.2	Country which granted the Marketing Authorisation	Austria
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.3.4	Pharmaceutical form	Concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	FLUDARABINE
D.3.9.1	CAS number	21679-14-1
D.3.9.4	EV Substance Code	SUB07678MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/m2 milligram(s)/square meter
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	30
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	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	No
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

Dyskeratosis congenita / telomere disease

E.1.1.1

Medical condition in easily understood language

Dyskeratosis congenita / telomere disease- inherited genetic syndromes

E.1.1.2

Therapeutic area

Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	PT
E.1.2	Classification code	10001756
E.1.2	Term	Allogenic bone marrow transplantation therapy
E.1.2	System Organ Class	10042613 - Surgical and medical procedures

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 ability to achieve an acceptable primary engraftment rate using a reduced intensity conditioning regimen in allogeneic HCT for BMF due to DC.

E.2.2

Secondary objectives of the trial

Secondary objectives are to describe the following after allogeneic HCT for BMF due to DC:
Survival to day+100 post-transplant
- Rate of secondary graft failure
- Regimen-related toxicity (RRT)
- Incidence of acute and chronic graft-versus-host disease (GVHD)
- Rates of viral reactivation and infection
- Peripheral blood and bone marrow engraftment
- Changes in pulmonary function
- Late effects including disease progression, incidence of secondary malignancies, and long-term survival
- Immune reconstitution

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Patients 30 days to 65 years of age at the time of inclusion with a diagnosis of severe aplastic anemia or single lineage cytopenia, defined as follows:
- Bone marrow hypocellular for age on biopsy based on review at the enrolling institution within 90 days of protocol inclusion
AND
- One or more of the following (in peripheral blood):
-neutrophils < 0.5 x 109/L
-platelets < 30 x 109/L, or platelet transfusion dependence*
-reticulocytes < 50 x 109/L in anemic patients, or red cell transfusion dependence*
*transfusion dependence will be defined as greater than ONE transfusion of platelets or red blood cells in the last year prior to protocol inclusion
AND

2. Diagnosis with one of the following DC categories on any prior evaluation:
A. age-adjusted mean telomere length < 1%ile in peripheral blood lymphocytes by flow-FISH on any occasion, as reported by a CLIA-approved laboratory
B. pathogenic mutation(s) in DKC1,TERC, TERT, NOP10, NHP2, TCAB1, TINF2, CTC1, RTEL1, ACD, or PARN as reported by a CLIA-approved laboratory
C. Dyskeratosis congenita diagnosed by:
1. clinical triad: abnormalities of skin pigmentation, nail dystrophy, oral leukoplakia
OR
2. one of clinical triad and presence of two or more associated features:
epiphora, developmental delay, mental retardation, pulmonary disease, short stature, dental caries/loss, esophageal stricture, grey hair, hyperhidrosis, malignancy, intrauterine growth retardation (IUGR), liver disease, enteropathy, ataxia/cerebellar hypoplasia, hypogonadism, microcephaly, urethral stricture, osteoporosis/AVN, scoliosis, deafness
D. Hoyeraal Hreidarsson syndrome: cerebellar hypoplasia, microcephaly, IUGR, “T+B-NK-“ immunodeficiency
E. Revesz syndrome: exudative retinopathy, cerebral calcifications, IUGR, fine sparse hair, ataxia

3. Availability of a HLA-compatible related or unrelated donor, defined as a 7/8 or 8/8 match for HLA-A, B, C, and DRB1. Related donors must be ruled out for telomere disease by appropriate clinical and diagnostic measures (for example, clinical evaluation, flow-FISH telomere length testing, genetic testing, and/or bone marrow examination).

4. For patients under 18 both parents must give a written informed consent.

5. Matched unrelated donor must consent to provide a bone marrow allograft.

6. The diagnosis of Fanconi anemia must be excluded by mitomycin C or diepoxybutane (DEB) chromosomal breakage testing on peripheral blood at a CLIA-approved laboratory on any prior evaluation. This evaluation is not required for patients with a pathogenic mutation in a known DC-associated gene as defined in 5.1.1.2.B above.

7. Adequate renal function with glomerular filtration rate equal to or greater than 30 ml/min/1.73 m2 measured within 30 days of protocol inclusion.

8.Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, if they are using effective methods of contraception during the study. Acceptable birth control methods are those with a failure rate of less than 1% per year when used consistently and correctly. Such methods include (in “Recommendations related to contraception and pregnancy testing in clinical trials”, supplied from www.hma.eu/):
a. Combined (estrogen and progestogen containing hormonal contraception associated with inhibition of ovulation.
-oral
-intravaginal
-transdermal
b. progestogen-only hormonal contracption associated with inhibition of ovulation
- oral
- injectable
- implantable
c. intrauterine device (IUD)
d. intrauterine hormone-releasing system (IUS)
e. bilateral tubal occlusion
f. total abstinence or vasectomized partner.

E.4

Principal exclusion criteria

1. Clonal cytogenetic abnormalities associated with MDS or AML on bone marrow examination performed within 90 days of protocol inclusion.

2. Karnofsky performance status < 40% for patients 16 years old or older; or Lansky < 40% for patients < 16 years old.

3. Uncontrolled bacterial, viral or fungal infections (currently taking medication and progression of clinical symptoms). Patients with fever despite broad-spectrum antimicrobials but no clinical or hemodynamic evidence of sepsis will be allowed.

4. Positive for the human immunodeficiency virus (HIV) by nucleic acid testing.

5. Pregnancy (positive B-HCG) or breastfeeding.

6. Known severe or life-threatening allergy or intolerance to fludarabine, alemtuzumab, cyclosporine, or mycophenolate mofetil.

7. In HLA mismatched transplants: positive patient anti-donor HLA antibody, defined as clinically significant based on institutional standards.

8. Prior allogeneic marrow or stem cell transplantation.

9. Prior solid organ transplantation.

10. Non-hematological co-morbid condition(s) or other factors (for example, psychological or social factors) that preclude the patient‟s candidacy for performing BMT under the protocol regimen, in the opinion of the treating physician

E.5 End points

E.5.1

Primary end point(s)

- Neutrophil engraftment
- Primary Graft Failure
- Primary engraftment

E.5.1.1

Timepoint(s) of evaluation of this end point

- Neutrophil engraftment: an ANC ≥ 0.5 x 10e9/L for three consecutive measurements on different days. The day of engraftment will be the day of the first of these three measurements.

- Primary graft failure: A) the lack of neutrophil engraftment as of Day +42; i.e., ANC was not ≥ 0.5 x 10e9/L for three consecutive measurements on different days with day +42 post-transplant or earlier as the first day of engraftment. B) Peripheral blood chimerism ≤ 50% donor neutrophil cells on two occasions from Day +30 to Day +100 post-transplant.

For the calculation of the primary engraftment rate, a patient will be considered to have, engrafted‟ if the patient has neutrophil engraftment per section 7.1.1 and if the patient does not have primary graft failure per either 7.1.2.1A or 7.1.2.1B.

E.5.2

Secondary end point(s)

- Day +100 Post-transplant
Survival
- Secondary Graft Failure
- Toxicities
- Acute GVHD of Grades 2-4 and
3-4
- Chronic GVHD
- Viral reactivation/infection and
disease
- Engraftment monitoring
(chimerism)
- Pulmonary function testing
(PFTs)
- Immune function and
reconstitution
- Late effects

E.5.2.1

Timepoint(s) of evaluation of this end point

-Post-transplant survival: 100 days from the time of transplant
-Secondary Graft Failure: Decline in the ANC to < 0.5 x 109/L for 3 consecutive measurements
-The assessment for toxicities will be carried out until day +365 post-transplant.
-Acute GVHD of Grades 2-4 and 3-4 will be monitorered during the course of the study
-Chronic GVHD will be monitorered during the course of the study
-Viral monitoring weekly by quantitative for CMV, EBV, and adenovirus from day 0 to day +100.
- Engraftment monitoring from Days +15 to +365; and when possible yearly thereafter.
-PFTs: within 90 days of treatment start; Day +365; and when possible yearly thereafter
-Immune function and - disease progression within 90 Days of study initiation, at Day +365 and at Day +365 if possible.

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

E.6.7

Pharmacodynamic

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

Yes

E.8.4

The trial involves multiple sites in the 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

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

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

United States

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

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

Yes

F.1.1

Number of subjects for this age range:

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)

Yes

F.1.1.5.1

Number of subjects for this age range:

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.1.6.1

Number of subjects for this age range:

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)

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 For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2018-05-08.

Yes

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

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

Patient and/or legal Guardian/parents must be able to sign informed consent.

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

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)

After the study termination, clinical routine/praxis follow up will be done yearly for 15 years following transplant of the last enrolled patient, and therefore at most 21 years from the date of activation. The following examinations may be performed: Pulmonary function, Immune studies, Late effects studies, Physical examination, CBC/diff, GVHD and morbidity assessments, Peripheral blood chimerism, Bone marrow chimerism, pRBC and Plt transfusions

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

2018-07-02

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-04-18

P. End of Trial
P.	End of Trial Status	Ongoing

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