Clinical Trials Register

Summary
EudraCT Number:	2014-004972-49
Sponsor's Protocol Code Number:	CLFG316X2202
National Competent Authority:	Germany - PEI
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2015-10-13
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

2014-004972-49

A.3

Full title of the trial

A randomized, open label, controlled, multiple dose study
to evaluate the clinical efficacy, safety, tolerability,
pharmacokinetics and pharmacodynamics of LFG316 in
patients with transplant associated microangiopathy after
hematopoietic precursor cell transplantation

A.3.1

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

The study is to gather evidence of LFG316 efficacy in
treatment of transplant associated microangiopathy (TAM) after hematopoetic precursor cell transplantation.

A.3.2

Name or abbreviated title of the trial where available

CLFG316X2202

A.4.1

Sponsor's protocol code number

CLFG316X2202

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	Novartis Pharma Services AG
B.1.3.4	Country	Switzerland
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	Novartis Pharma Services AG
B.4.2	Country	Switzerland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Novartis Pharma AG
B.5.2	Functional name of contact point	Clinical Trial Information Desk
B.5.3	Address:
B.5.3.1	Street Address	Forum 1, Novartis Campus
B.5.3.2	Town/ city	Basel
B.5.3.3	Post code	4056
B.5.3.4	Country	Switzerland
B.5.4	Telephone number	+4161324 1111
B.5.5	Fax number	+4161324 8001
B.5.6	E-mail	clinicaltrial.enquiries@novartis.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.3.2	Product code	LFG316
D.3.4	Pharmaceutical form	Powder 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	NA
D.3.9.2	Current sponsor code	LFG316
D.3.9.4	EV Substance Code	SUB32390
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	100
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.3.2	Product code	LFG316
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	NA
D.3.9.2	Current sponsor code	LFG316
D.3.9.4	EV Substance Code	SUB32390
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.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

Transplant associated microangiopathy (TAM)

E.1.1.1

Medical condition in easily understood language

Transplant associated microangiopathy

E.1.1.2

Therapeutic area

Diseases [C] - Immune System Diseases [C20]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	19.0
E.1.2	Level	LLT
E.1.2	Classification code	10050444
E.1.2	Term	Microangiopathy NOS
E.1.2	System Organ Class	100000004866

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 assess the hematological response rate in
patients with TAM receiving LFG316
compared to standard of care (SoC)

E.2.2

Secondary objectives of the trial

To assess the safety and tolerability of
LFG316 in patients with TAM
To describe the pharmacokinetics of total
LFG316
To evaluate non-relapse mortality in TAM
patients treated with LFG316 as compared to
patients on SoC
To assess complete response rate at 17 weeks
in TAM patients treated with LFG316
compared to patients receiving standard of
care

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1.Written informed consent/assent before any study-specific screening procedures.
For pediatric patients, consent will be obtained from parent(s) or legal guardian(s) and the
signature of at least 1 parent or guardian will be required. Investigators will also obtain
assent of patients according to local, regional or national guidelines.
2. Patients after allogeneic stem cell transplantation from a related or unrelated, HLAmatched
or mismatched donor with the diagnosis of transplant related microangiopathy.
Patients having received any of the following stem cell sources are eligible: G-CSF Mobilized
peripheral blood stem cells, G-CSF bone marrow, umbilical cord blood.
3. Male and female TAM patients ≥ 2 years old at the time of first dose administration.
Patients < 12 years old can only be included in the study after first IA has shown that it is
safe and well tolerated in patients ≥ 12 years old (Section 3.5).
4. The presence of TAM as per below diagnostic criteria at baseline (or screening if baseline visit is skipped). All the criteria have to be met for the patients included in the study:  Elevated lactate dehydrogenase (any elevation above normal range)
 Thrombocytopenia with platelet count < 50x10e9/L or more than 50% decrease in
platelet count from the highest value achieved after transplant
 Anemia below lower limit of normal or anemia requiring transfusion support as per
center standard
 Schistocytes on peripheral blood smear (>2 per HPF) OR histologic evidence of
microangiopathy
 Absence of coagulopathy (no uncompensated disseminated intravascular coagulation, DIC) at screening
5. The presence of TAM high risk features at baseline (or screening if baseline visit is
skipped): Patients ≤ 16 years must have a Lansky score of ≤ 70 and patients > 16 must
have Karnofsky score ≤ 70% and/or proteinuria (> 30 mg/dL) measured in two urine spot analyses.
6. Hypertension, defined for adults by SBP ≥ 160 mmHg and/or DBP ≥ 100 mmHg at baseline
(or screening if baseline visit is skipped), and for pediatric patients by blood pressure
greater than the 95th percentile for age, sex, and height (see Table 16-1). Additionally,
patients who were started on antihypertensive medication after HSCT or who have received additional antihypertensive medication after HSCT will be eligible, even if they don’t have elevated blood pressure
7. Able to receive antibiotic prophylaxis against N. meningitides for the
duration of the study.
8. Meningococcal vaccine(s) prior to LFG316 treatment if prior
vaccination cannot be confirmed. The choice of vaccine(s) should take
into account the serotypes prevalent in the geographic areas in which
study patients will be enrolled. In case vaccination is not possible or will
result in an unfavorable risk benefit ratio as judged by the investigator,
vaccination can
be postponed until deemed likely to be effective.
9. Patients <18 years old should receive vaccination for the prevention
of S. pneumoniae and H. influenzae type b prior to LFG316
administration. In case vaccination is not possible or will result in an
unfavorable risk benefit ratio as judged by the investigator, vaccination
can be postponed until deemed likely to be effective.
10. Weight of at least 10kg.

E.4

Principal exclusion criteria

1.Use of other investigational drugs at the time of enrollment, or within 5 half-lives of enrollment, or until the expected PD effect has returned to baseline, whichever is longer; or even longer if required by local regulations.
Concomitant investigational treatment, including treatment in the context of a clinical trial with marketed drugs (off-label) may be acceptable but requires approval by the sponsor on the case by case basis.

2. Known hypersensitivity to any constituent of the study medication.
3. Patients with steroid refractory graft versus host disease (SRGvHD). SRGvHD is defined as progression (=increase in overall grade) after 5 days on ≥2mg/kg methylprednisolone or equivalent OR no improvement
(no decrease in overall grade) after 10 days on ≥ 2mg/kg methylprednisolone or equivalent. If patients are receiving steroids forGvHD prophylaxis as per center standard, progression after 5 days and no response after 10 days after doubling the steroid dose will be regarded as steroid refractory.

4. Patients with ALT > 10x ULN at screening.
5. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of
gestation, confirmed by a positive hCG laboratory test (at screening or baseline).
6. Women of child-bearing potential, defined as all women
physiologically capable of becoming pregnant, unless they are using
highly effective methods of contraception during dosing and for 45 days
after stopping study medication. Highly effective contraception methods
include:
 Total abstinence (when this is in line with the preferred and usual
lifestyle of the subject. Periodic abstinence (i.e., calendar, ovulation,
symptothermal, postovulation methods) and withdrawal are not
acceptable methods of contraception.
 Female sterilization (have had surgical bilateral oophorectomy (with
or without hysterectomy), total hysterectomy or tubal ligation at least
six weeks before taking study treatment. In case of oophorectomy alone,
only when the reproductive status of the woman has been confirmed by
follow up hormone level assessment.
 Male sterilization (at least 6 m prior to screening). The vasectomized
male partner should be the sole partner for that subject.
 Use of oral, injected or implanted hormonal methods of contraception
or placement of an intrauterine device (IUD) or intrauterine system
(IUS) or other forms of hormonal contraception that have comparable
efficacy (failure rate <1%), for example hormone vaginal ring or
transdermal hormone contraception.
 In case of use of oral contraception women should have been stabile
on the same pill for a minimum of 3 months before taking study
treatment.
7. Sexually active males unwilling to use a condom during intercourse
while taking drug and for 45 days after stopping investigational
medication. A condom is required to be used also by vasectomized men
in order to prevent delivery of the drug via seminal fluid. Male patients
should not father a child in this period.
8. Positive HIV (ELISA and Western blot) test result (checked at
screening). Historical local data will be acceptable if it the test was done
within one month before start of HSCT conditioning and not more than 3
months before study visit 3.
9. A positive Hepatitis B surface antigen or Hepatitis C test result at
screening. Historical local data will be acceptable if it the test was done
within one month before start of HSCT conditioning and not more than 3
months before study visit 3.
10. Patients with any severe, progressive or uncontrolled acute or
chronic medical condition (such as uncontrolled infectious disease or
sepsis) or clinical laboratory abnormalities that in the investigator's
opinion would make the patient inappropriate for entry into this study
(at screening or baseline).
11. Patients with proven TTP as per historical data (as defined by
ADAMST13 activity test) and if already available results of ADAMST13
test done at screening.
12. Patients previously treated with eculizumab for TAM.
13. Patients with known or suspected hereditary complement pathway deficiency. This exclusion criterion is not applicable to patients with complement pathway abnormalities/upregulation known to be associated with increased risk of transplant associated microangiopathy.

E.5 End points

E.5.1

Primary end point(s)

Hematological response at 17 weeks where a
patient is considered to be a responder if both
of the following criteria are met:
1. Schistocytes <2/microscopic high power field
(HPF).
2.Transfusion independent (no need for
TAM-related transfusions (platelets and
erythrocytes))

E.5.1.1

Timepoint(s) of evaluation of this end point

17 weeks

E.5.2

Secondary end point(s)

All safety parameters including: blood
chemistry, hematology, proteinuria, body
height/weight, urinalysis, ECG evaluation,
Adverse events, body temperature, blood
pressure, physical examination, pulse rate,
Lansky/Karnofsky score
Serum total LFG316 concentrations
Non-relapse mortality is any death not
considered to be related to a relapse of
underlying disease
Complete response is defined
as hematological response and no proteinuria
as determined by
 proteinuria <30mg/dL and
 eGFR doubled or not less than 0.85 x
lower limit of normal

E.5.2.1

Timepoint(s) of evaluation of this end point

45weeks

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

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

Yes

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Tolerability

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

Yes

E.8.1.1

Randomised

Yes

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

Yes

E.8.2.3.1

Comparator description

Standard of care

E.8.2.4

Number of treatment arms in the trial

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

Yes

E.8.5.1

Number of sites anticipated in the EEA

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

France

Germany

United States

E.8.7

Trial has a data monitoring committee

Yes

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

LVLS

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

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

For pediatric patients, consent will be obtained from parent(s) or legal guardian(s) and the
signature of at least 1 parent or guardian will be required.

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)

At a minimum, subjects will be contacted for safety evaluations during the 30 days following the Study Completion visit, including a final post-study safety contact at the 30-day point.

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

2016-03-07

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-12-10

P. End of Trial
P.	End of Trial Status	Prematurely Ended

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