Clinical Trials Register

Summary
EudraCT Number:	2013-003068-30
Sponsor's Protocol Code Number:	CMV-MM-2
National Competent Authority:	Netherlands - Competent Authority
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2013-09-05
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

Netherlands - Competent Authority

A.2

EudraCT number

2013-003068-30

A.3

Full title of the trial

CONgenital Cytomegalovirus: Efficacy of antiviral treatment in a non-Randomized Trial with historical control group

CONgenitaal Cytomegalovirus: Effectiviteit van antivirale behandeling in een niet-geRandomiseerde studie met historische controle groep

A.3.1

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

Efficacy of antiviral treatment of congenital cytomegalovirus in a non-randomized trial with historical control group

Effectiviteit van antivirale behandeling van congenitale cytomegalovirus in een niet-gerandomiseerde studie met historische controle groep

A.3.2

Name or abbreviated title of the trial where available

CONCERT study 2.0

CONCERT studie 2.0

A.4.1

Sponsor's protocol code number

CMV-MM-2

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	LUMC
B.1.3.4	Country	Netherlands
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	Fonds NutsOhra
B.4.2	Country	Netherlands
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	LUMC
B.5.2	Functional name of contact point	Fleurtje Schornagel
B.5.3	Address:
B.5.3.1	Street Address	Albinusdreef 2
B.5.3.2	Town/ city	Leiden
B.5.3.3	Post code	2333 ZA
B.5.3.4	Country	Netherlands
B.5.4	Telephone number	00310715265383
B.5.5	Fax number	00310715266761
B.5.6	E-mail	f.a.j.schornagel@lumc.nl

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	Valcyte
D.2.1.1.2	Name of the Marketing Authorisation holder	Roche
D.2.1.2	Country which granted the Marketing Authorisation	Netherlands
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	Valganciclovir
D.3.2	Product code	34730
D.3.4	Pharmaceutical form	Powder for oral solution
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	VALGANCICLOVIR HYDROCHLORIDE
D.3.9.1	CAS number	175865-59-5
D.3.9.4	EV Substance Code	SUB16471MIG
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	32
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

Congenital cytomegalovirus infection.
Sensorineural Hearingloss.

Congenitale cytomegalovirus infectie.
Sensorineurale Gehoorverlies.

E.1.1.1

Medical condition in easily understood language

Congenital cytomegalovirus infection.
Hearingloss.

Aangeboren (via de baarmoeder) cytomegalovirus infectie.
Gehoorverlies.

E.1.1.2

Therapeutic area

Diseases [C] - Virus Diseases [C02]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	18.0
E.1.2	Level	LLT
E.1.2	Classification code	10010420
E.1.2	Term	Congenital CMV infection
E.1.2	System Organ Class	100000004850

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Investigate whether early valganciclovir treatment of children with SNHL of ≥ 20 dB, unilateral or bilateral, and a confirmed congenital CMV infection can prevent deterioration of the hearing loss at 18-22 months follow-up.

Onderzoeken of vroege behandeling met valganciclovir bij kinderen met gehoorverlies van ≥ 20 dB, unilateraal of bilateraal, en een congenitale CMV infectie de verergering van het gehoorverlies bij 18-22 maanden follow-up kan tegegaan.

E.2.2

Secondary objectives of the trial

1) Investigate whether early valganciclovir treatment of children with
SNHL of ≥ 20 dB, unilateral or bilateral, and a confirmed congenital CMV infection can prevent cognitive and motor retardation. Communicative and speech development will be extensively assessed.
2) Investigate whether early valganciclovir treatment of children with
SNHL of ≥ 20 dB, unilateral or bilateral, and a confirmed congenital CMV infection reduces the CMV viral load in urine and blood samples during 6 weeks treatment and one week after completion of treatment. At age 18-22 months (follow-up) solely the urine sample will be investigated for the viral load.
3) Investigate whether drug resistance has evolved.

1) Onderzoeken of vroege behandeling met valganciclovir bij kinderen met gehoorverlies van ≥ 20 dB, unilateraal of bilateraal, en een congenitale CMV infectie cognitieve en bewegings retardatie kan
voorkomen. Communicatieve en spraak ontwikkeling worden getest bij 18-22 maanden leeftijd follow-up.
2) Onderzoeken of vroege behandeling met valganciclovir bij kinderen met gehoorverlies van ≥ 20 dB, unilateraal of bilateraal, en een congenitale CMV infectie de CMV virale load zal verlagen in urine en
bloed dat wekelijks wordt afgenomen gedurende de 7 weken na inclusie, en bij 18-22 maanden. Bij 18-22 maanden zal alleen urine worden afgenomen.
3) Eventuele medicatie resistentie onderzoeken.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Treatment group and refusal control group
- Infants with congenital CMV infection, and hearing loss (≥ 20 dB, in one or both ears).
- Age at time of inclusion is ≤ 12 weeks after birth.
- Born at ≥ 37 weeks gestational age.
- Birth weight ≥ 2500 gram.
- Parental signed informed consent.

Historical control group
- Infants with congenital CMV infection, and hearing loss (≥ 20 dB, in one or both ears).
- Age at time of inclusion is > 13 weeks after birth.
- Born at ≥ 37 weeks gestational age.
- Birth weight ≥ 2500 gram.
- Parental signed informed consent.

Behandel groep en weiger controle groep:
- Kinderen met congenitaal CMV en gehoorverlies (≥ 20 dB unilateraal of bilateraal)
- Leeftijd bij inclusie ≤ 12 weken.
- Geboorte bij ≥ 37 weken na conceptie.
- Geboorte gewicht ≥ 2500 gram.
- Toestemmingsverklaring door ouders ondertekend.

Historische controle groep:
- Kinderen met congenitaal CMV en gehoorverlies (≥ 20 dB, unilateraal of bilateraal).
- Leeftijd bij inclusie > 13 weken na geboorte.
- Geboren bij ≥ 37 na conceptie.
- Geboorte gewicht ≥ 2500 gram.
- Toestemmingsverklaring door ouders ondertekend.

E.4

Principal exclusion criteria

Treatment group and refusal control group
- Previously noted (≤ 12 weeks after birth) symptoms possibly related to congenital CMV, for which medical attention was requested. For example: intra uterine growth retardation, petechiae, hepatosplenomegaly, jaundice, microcephaly, thrombocytopenia, elevated transaminases, elevated bilirubin.
- Treatment with other antiviral agents or immunoglobulins.
- Solely applicable for treatment group: leucopenia < 0,5 x 10*9/L (blood sample tested at t=0).

Historical control group
- Previously encountered (≤ 12 weeks after birth) symptoms possibly related to congenital CMV, for which medical attention was requested For example: intra uterine growth retardation, petechiae, hepatosplenomegaly, jaundice, microcephaly, thrombocytopenia, elevated transaminases, elevated bilirubin.
- Treatment with (val)ganciclovir.
- Treatment with other antiviral agents or immunoglobulins.

Behandel groep en weiger controle groep:
- Eerder gevonden (≤ 12 weken na geboorte) symptomen mogelijk passend bij congenitaal CMV, waarvoor medische zorg werd gezocht. Bijvoorbeeld: intra uteriene groei achterstand, petechieen, hepatosplenomegalie, icterus, microcephalie, thrombocytopenie, verhoogde transaminasen, hyperbilirubine.
- Behandeling met andere antivirale medicatie of immunoglobulines.
- Voor behandel groep: leukopenie < 0,5 x 10*9/L (bloed getest bij t=0).

Historische controle groep:
- Eerder gevonden (≤ 12 weken na geboorte) symptomen mogelijk passend bij congenitaal CMV, waarvoor medische zorg werd gezocht. Bijvoorbeeld: intra uteriene groei achterstand, petechieen, hepatosplenomegalie, icterus, microcephalie, thrombocytopenie, verhoogde transaminasen, hyperbilirubine.
- Behandeling met (val)ganciclovir.
- Behandeling met ander antivirale medicatie of immunoglobulines.

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint is the status of the sensorineural hearing loss expressed in dB, in children with congenital CMV at age 18-22 months follow-up.

Sensorineural gehoorverlies (in dB), bij kinderen met congenitaal CMV bij leeftijd 18-22 maanden.

E.5.1.1

Timepoint(s) of evaluation of this end point

Hearing loss will be evaluated at age 18-22 months.

Gehoorverlies wordt bepaald bij leeftijd 18-22 maanden.

E.5.2

Secondary end point(s)

The secondary endpoint is the development of the infants.

The tertiary endpoint is the viral load (in dried blood spots,blood and urine) during 7 weeks after inclusion and at age 18-22 months follow-up (for infants in the treatment and refusal control group). For infants in the historical control group materials collected previously will be tested when available.

The final endpoint is the possibility of development of drug resistance.

Secundaire eindpunt is de ontwikkeling van de kinderen.

Tertiaire eindpunt is de virale load (in dried blood spot, bloed en urine) gedurende de 7 weken na inclusie en bij 18-22 maanden follow-up (voor kinderen in de behandel en weiger controle groep). Voor kinderen in de historische controle groep zullen deze materialen ook worden getest indien beschikbaar.

Als laatste eindpunt wordt eventuele medicatie resistentie onderzocht.

E.5.2.1

Timepoint(s) of evaluation of this end point

The development of the infants will be tested at age 18-22 months follow-up.
For treated infants and infants in the refusal control group the viral load will be determined at inclusion and weekly in urine during
the first 7 weeks after inclusion (total 8 moments). For treated infants it will be determined at inclusion and weekly in blood samples (total 8 moments). For untreated infants it will be determined twice in blood (at inclusion and in week 6). At age 18-22 months follow-up the viral load will be determined in urine for all infants (also the infants in the historical control group).

De ontwikkeling van de kinderen wordt bij leeftijd 18-22 maanden follow-up onderzocht.

De behandelde kinderen en kinderen in de weiger controle groep wordt de virale load bij inclusie en daarna wekelijks gedurende de 7 weken na inclusie bepaald (totaal 8 momenten). Voor behandelde kinderen wordt bij inclusie en daar wekelijks gedurende de behandeling de virale load in bloed bepaald (totaal 8 momenten). Voor onbehandelde kinderen wordt de virale load in bloed tweemaal bepaald (inclusie en in week 6). Bij leeftijd 18-22 maanden wordt voor alle kinderen de virale load in urine bepaald (ook voor kinderen in de historische controle groep).

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

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)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

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

Yes

E.8.2.3.1

Comparator description

Reguliere behandeling

Regular 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

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

E.8.6.2

Trial being conducted completely outside of the EEA

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

The last visit of the last subject.

Het laatste bezoek van de laatste proefpersoon.

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

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)

Yes

F.1.1.4.1

Number of subjects for this age range:

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

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

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

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

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)

None other than expected normal treatment. All subjects in the treatment group will have been treated at the start of the trial. Treatment of congenital CMV after
1 year of age has not been shown to be effective. Treatment of hearing loss will be continued as standard care in the Netherlands.
It is possible that follow-up after 18-22 months will be provided. However, this is beyond this specific trial.

Niet afwijkend van normale behandeling voor gehoorverlies. Aile proefpersonen in de behandel groep zijn behandeld in het begin van de studie. Er bestaat geen bewijs voor effectiviteit voor de behandeling van congenitaal CMV na de leeftijd van 1 jaar. Behandeling van gehoorverlies zal voortduren zoals in reguliere zorg. Het is mogelijk dat follow-up na 18-22 maanden ook zal worden aangeboden. Dit is echter buiten deze studie om.

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

2013-09-05

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-09-30

P. End of Trial
P.	End of Trial Status	Completed

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