Clinical Trial Results:
CONgenital Cytomegalovirus: Efficacy of antiviral treatment in a non-Randomized Trial with historical control group
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Summary
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EudraCT number |
2013-003068-30 |
Trial protocol |
NL |
Global end of trial date |
17 May 2018
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Results information
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Results version number |
v1(current) |
This version publication date |
22 Oct 2022
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First version publication date |
22 Oct 2022
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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 |
CMV-MM-2
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02005822 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Leiden University Medical Center
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Sponsor organisation address |
Albinusdreef 2, Leiden, Netherlands, 2333 ZA
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Public contact |
Aloysius Cornelis Maria Kroes, MD PhD, Leiden University Medical Center, 0031 71526 3931, A.C.M.Kroes@lumc.nl
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Scientific contact |
Aloysius Cornelis Maria Kroes, MD PhD, Leiden University Medical Center, 0031 71526 3931, A.C.M.Kroes@lumc.nl
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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 |
04 Oct 2022
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
26 Jan 2017
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Global end of trial reached? |
Yes
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Global end of trial date |
17 May 2018
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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 |
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.
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Protection of trial subjects |
- By participating in the study, parents learned their child had cCMV while this might otherwise have been undetected. This knowledge could have posed a possible extra burden. We have tried to diminish stress by providing clear information before consent, providing time to consider and ask questions. The advantages of the awareness of the presence of the congenital CMV infection were explained, for instance additional hearing evaluations. We provided contact information of the lead investigator and an independent pediatrician to answer any questions at any time.
- Potential side effects of the study drug were monitored by regular blood tests
- Regular blood tests were performed at the home of the study subject to minimise burden burden of travel and stress for the child
- Blood tests in control subjects were only performed at baseline and 7 weeks after inclusion
- Urine samples were collected on filter paper by parents at home and sent via postal service to minimise burden of travel
- Parents of historic controles approached for the study might have experienced distress from realising their child could have been treated in the CONCERT 2.0 trial if the trial were started earlier. We stressed the advantages of the possibility of follow-up with the extra physical examination, extra developmental tests and extra hearing evaluation for the children in the historical control group.
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Background therapy |
no medicinal treatment, regular care and follow-up by pediatrician, audiologist and possible other specialists such as ophthalmologists. | ||
Evidence for comparator |
Current views on treatment are based on two seminal randomized controlled trials (Kimberlin 2003, Kimberlin 2015), which show that antiviral treatment has a favorable effect on long-term neurodevelopmental and audiologic outcome, the latter more notably in those with evidence of CNS disease. While there is widespread consensus on the treatment of infants with cCMV and clinically detectable symptoms and CNS involvement (Luck 2017), evidence from prospective controlled trials for antiviral treatment of cCMV infants with isolated hearing loss was long lacking. An observational study reported favorable long term hearing outcome in infants with cCMV and isolated hearing loss, after treatment with (val)ganciclovir (Pasternak 2018) | ||
Actual start date of recruitment |
02 Sep 2013
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Long term follow-up planned |
Yes
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Long term follow-up rationale |
Safety, Efficacy, Scientific research | ||
Long term follow-up duration |
2 Years | ||
Independent data monitoring committee (IDMC) involvement? |
Yes
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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 |
Netherlands: 37
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Worldwide total number of subjects |
37
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EEA total number of subjects |
37
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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) |
37
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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) |
0
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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 |
Between September 1 2013 and 19 December 2016, subjects were recruited through a nationwide targeted screening approach using the national Newborn Hearing Screening (NHS) program. Parents or legal guardians of infants who failed three subsequent rounds of the NHS were informed about the trial and offered CMV testing. | |||||||||
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Pre-assignment
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Screening details |
1381 infants tested for CMV, of which 1374 (99%) were successfully tested; 59 (4.3%) CMV positive, of which 35 were included in the prospective trial; 24 were not: 19 were ineligible due to exclusion criteria and 5 due to procedural(1) or logistical reasons(2) or no interest(2). | |||||||||
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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 |
Non-randomised - controlled
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Blinding used |
Not blinded | |||||||||
Blinding implementation details |
A blinded audiologist reassessed all raw data from baseline and follow-up audiological tests.
Blinded psychologists assessed (performed and interpreted) the developmental tests at follow-up.
Data was subsequently analysed by non-blinded investigator.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Treatment group | |||||||||
Arm description |
Infants in the treatment group received valgancivlovir 16mg/kg bid during six weeks. Per protocol, dosages were fixed for the entire treatment period. Initial home visit at inclusion: medical history taking, physical examination, child development test (van Wiechen), blood sampling (complete blood count with differential, liver function tests and viral load). Hereafter, weekly visits until one week after treatment for blood and urine filter paper sampling. Parents were asked keep diaries with abnormalities or signs during treatment and instructed to contact investigators in case of possible adverse events. Follow-up visit ate age 18-22 months: physical examination, developmental examination (BSID-III) and BERA. | |||||||||
Arm type |
Experimental | |||||||||
Investigational medicinal product name |
Valcyte
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Investigational medicinal product code |
SUB16471MIG
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Other name |
Valganciclovir
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Pharmaceutical forms |
Powder for oral solution
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Routes of administration |
Oral use
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Dosage and administration details |
16mg/kg twice daily (32 mg/kg daily) during six weeks. The specific dosage was determined at inclusion according to the weight of the infant, registered at inclusion. The dosage remained unchanged during the 6 weeks treatment. Suspension was prepared by pharmacy and supplied to parents, along with (needleless) syringes for administration, which were marked to ensure that the correct dosage is administered by the parents.
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Arm title
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Combined control group | |||||||||
Arm description |
2 groups: Refusal control group: Subjects of which parents/guardians refused medicinal treatment. Subjects received regular care after cCMV diagnosis. Referral to pediatrician was advised. Initial home visit at inclusion: medical history taking, physical examination, child development test, blood sampling (complete blood count with differential, liver function tests and viral load). Urine filter papers were collected by parents and mailed, at baseline and during 7 weeks hereafter. Parents were asked to keep diaries. Follow-up visit at age 18-22 months: physical examination, developmental examination (BSID-III) and BERA. Historical control group: Children with hearing loss born between November 2011 and July 2012 were informed by audiologists about CONCERT trial and retrospective dried blood spot (DBS) testing was offered. After retrospective diagnosis, children were included for follow-up visit at age 18-22 months. | |||||||||
Arm type |
No intervention | |||||||||
Investigational medicinal product name |
No investigational medicinal product assigned in this arm
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Baseline characteristics reporting groups
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Reporting group title |
Treatment group
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Reporting group description |
Infants in the treatment group received valgancivlovir 16mg/kg bid during six weeks. Per protocol, dosages were fixed for the entire treatment period. Initial home visit at inclusion: medical history taking, physical examination, child development test (van Wiechen), blood sampling (complete blood count with differential, liver function tests and viral load). Hereafter, weekly visits until one week after treatment for blood and urine filter paper sampling. Parents were asked keep diaries with abnormalities or signs during treatment and instructed to contact investigators in case of possible adverse events. Follow-up visit ate age 18-22 months: physical examination, developmental examination (BSID-III) and BERA. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Combined control group
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Reporting group description |
2 groups: Refusal control group: Subjects of which parents/guardians refused medicinal treatment. Subjects received regular care after cCMV diagnosis. Referral to pediatrician was advised. Initial home visit at inclusion: medical history taking, physical examination, child development test, blood sampling (complete blood count with differential, liver function tests and viral load). Urine filter papers were collected by parents and mailed, at baseline and during 7 weeks hereafter. Parents were asked to keep diaries. Follow-up visit at age 18-22 months: physical examination, developmental examination (BSID-III) and BERA. Historical control group: Children with hearing loss born between November 2011 and July 2012 were informed by audiologists about CONCERT trial and retrospective dried blood spot (DBS) testing was offered. After retrospective diagnosis, children were included for follow-up visit at age 18-22 months. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Treatment group
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Reporting group description |
Infants in the treatment group received valgancivlovir 16mg/kg bid during six weeks. Per protocol, dosages were fixed for the entire treatment period. Initial home visit at inclusion: medical history taking, physical examination, child development test (van Wiechen), blood sampling (complete blood count with differential, liver function tests and viral load). Hereafter, weekly visits until one week after treatment for blood and urine filter paper sampling. Parents were asked keep diaries with abnormalities or signs during treatment and instructed to contact investigators in case of possible adverse events. Follow-up visit ate age 18-22 months: physical examination, developmental examination (BSID-III) and BERA. | ||
Reporting group title |
Combined control group
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Reporting group description |
2 groups: Refusal control group: Subjects of which parents/guardians refused medicinal treatment. Subjects received regular care after cCMV diagnosis. Referral to pediatrician was advised. Initial home visit at inclusion: medical history taking, physical examination, child development test, blood sampling (complete blood count with differential, liver function tests and viral load). Urine filter papers were collected by parents and mailed, at baseline and during 7 weeks hereafter. Parents were asked to keep diaries. Follow-up visit at age 18-22 months: physical examination, developmental examination (BSID-III) and BERA. Historical control group: Children with hearing loss born between November 2011 and July 2012 were informed by audiologists about CONCERT trial and retrospective dried blood spot (DBS) testing was offered. After retrospective diagnosis, children were included for follow-up visit at age 18-22 months. | ||
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End point title |
Best ear hearing analysis | |||||||||||||||||||||
End point description |
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End point type |
Primary
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End point timeframe |
Baseline to Follow-Up (18-22 months)
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Statistical analysis title |
Best ear hearing analysis | |||||||||||||||||||||
Statistical analysis description |
proportional odds model
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Comparison groups |
Treatment group v Combined control group
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Number of subjects included in analysis |
36
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Analysis specification |
Pre-specified
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Analysis type |
equivalence | |||||||||||||||||||||
P-value |
= 0.003 | |||||||||||||||||||||
Method |
Regression, Logistic | |||||||||||||||||||||
Confidence interval |
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End point title |
Best ear hearing analysis, numerical | ||||||||||||
End point description |
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End point type |
Primary
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End point timeframe |
Baseline to Follow-Up (18-22 months)
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Statistical analysis title |
Best ear hearing, numerical | ||||||||||||
Comparison groups |
Treatment group v Combined control group
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Number of subjects included in analysis |
36
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Analysis specification |
Pre-specified
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Analysis type |
equivalence | ||||||||||||
P-value |
= 0.02 | ||||||||||||
Method |
Regression, Linear | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
17
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Confidence interval |
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95% | ||||||||||||
sides |
2-sided
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lower limit |
2.6 | ||||||||||||
upper limit |
31.4 | ||||||||||||
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Adverse events information
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Timeframe for reporting adverse events |
Baseline to Follow-Up (18-22 months)
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
none | ||||||||||||||||||||||||||||||||||
Dictionary version |
1
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Reporting groups
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Reporting group title |
Treatment group
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Reporting group description |
Infants in the treatment group received valgancivlovir 16mg/kg bid during six weeks. Per protocol, dosages were fixed for the entire treatment period. Initial home visit at inclusion: medical history taking, physical examination, child development test (van Wiechen), blood sampling (complete blood count with differential, liver function tests and viral load). Hereafter, weekly visits until one week after treatment for blood and urine filter paper sampling. Parents were asked keep diaries with abnormalities or signs during treatment and instructed to contact investigators in case of possible adverse events. Follow-up visit ate age 18-22 months: physical examination, developmental examination (BSID-III) and BERA. | ||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||
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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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20 Dec 2013 |
Changes in letter for parents to further explain the home visit. The letter to physicians regarding the participation of a child in the follow-up study has been added to further inform practitioners previously informed in CONCERT 1.0 about the follow-up in CONCERT 2.0 |
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24 Feb 2014 |
Adjustment in the inclusion criterion regarding birth weight. The new criterion is: > -2 SD for gestational age and parentage. Previously, the criterion was ≥ 2500 grams. The new criterion is more accurate and more representative as birth weight is related to parentage and gestational age. |
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17 Jul 2014 |
- Recruitment method: Parents of children with hearing loss can also hear about the CONCERT study through another route (internet, friends/family or magazine article). Children who come into contact with the CONCERT study via these routes could also participate in CMV diagnostics. So not just with information from an audiologist.
- Intention to treat for 6 weeks: In case of side effects, the treatment can be temporarily stopped. As soon as the blood values allow, treatment will be resumed with the intention of completing the 6 weeks of treatment.
- Blood collection for neutropenia: after the detection of neutropenia, another blood sample is taken within 5 days.
- The change in the letter concerns a textual change that the CMV diagnosis is offered to children older than 3 months. |
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28 May 2015 |
- Flyer 'Medical Scientific Research': This folder will in future be given by regional coordinators and audiologists who hand over the first information package (CMV diagnostics) to parents in the event of a referral in the hearing screening (region coordinator) or who are diagnosed with hearing loss (audiologist).
- Inclusion of children of minor parents (<18 years): Excluding a child of minor parents is not in the best interests of the child itself. If the guardian(s) have been assigned and known to the researcher, the child can be included.
- Change in letter information CMV diagnostics: In the letter it is added that parents have also received the flyer 'Medical Scientific Research' together with the letter. This is referred to in the consent form.
- Change of consent forms: Two things have been added to the forms. Firstly, having the doctor (researcher) sign it for providing information to parents. Secondly, a textual addition that by signing the form parents / guardians also give permission for access to the research data by persons named in the folder 'Medical Scientific Research'. |
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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. | |||
| Non-randomised trial; this summary is written by another person than the lead researcher who initiated and coordinated the trial. | |||
