Fetal medicine

 FLAMINGO
 PLUTO
 Solomon
 > TTTS1
 
 


TTTS-1 trial

A cluster randomized controlled trial comparing a conservative management and primary laser surgery in stage 1 Twin to Twin Transfusion Syndrome.


Objective
This study aims to compare two management strategies of stage 1 TTTS by an international randomized controlled trial: the first relies on the overall conclusion from the Eurofoetus trial and advocates immediate percutaneous fetoscopic surgery for all stages of TTTS including stage 1 disease; the second is a conservative strategy, in which patients are monitored weekly until delivery or until progression warranting laser surgery. The primary end-point for this comparison encompasses both survival and neurological morbidity in a composite outcome, using a cluster-designed trial allowing the use of a per-fetus outcome rather than a per-pregnancy outcome.

Study design

International multicenter randomized controlled trial

Study population
Eligible participants are women with monochorionic, diamniotic twin pregnancies presenting with stage 1 TTTS defined according to the Eurofoetus criteria between 16+0 and 26+6 weeks of gestation. Patients with a cervix less than 15 mm on transvaginal scan (5th percentile) [9] or severe maternal discomfort are excluded as these may require immediate treatment. Similarly, patients presenting with PPROM or with fetal malformations will be excluded. Patients referred after any therapeutic amniocenteses are also excluded since they represent an at-risk subgroup of patients for whom a selective laser procedure is generally anticipated to be difficult.

Eurofetus criteria:

  • Deepest vertical pocket in the Recipient > 8 cm before 20 weeks and > 10 cm thereafter
  • Deepest vertical pocket in the Donor < 2 cm
  • Bladder visible in the Donor
  • Positive end-diastolic flow in umbilical artery and positive a-wave in the ductus venosus in both twins
  • Neither twin is Hydropic

Intervention
The purpose of this study is to compare immediate percutaneous laser surgery to conservative management in stage 1 TTTS.

Primary percutaneous laser surgery:
Surgery will be planned within 72 hours following randomization. The procedure will be performed under local, IV conscious sedation or regional anaesthesia, with a percutaneous approach using a 2-4 mm fetoscope and a Diode or Nd:YAG laser beam. Coagulations will be delivered as selectively as possible [11, 12]. The procedure will end by an amniodrainage aiming to leave a deepest vertical pool of 4-6 cm. 

Conservative management:
Patients will be monitored with weekly ultrasounds to ensure the absence of progression in disease or obstetrical worsening. The follow-up will be planned on randomization to ensure that patients allocated to conservative management will be monitored no more frequently than every 5-7 days. Parameters collected at follow-up includes amniotic fluid levels, Doppler flow studies of umbilical artery (UA) and vein, ductus venosus (DV) and middle cerebral arteries (MCA), and cervical length.  Progression to stage 2 and higher or the occurrence of severe maternal discomfort as well as a cervical shortening < 15 mm during follow-up will warrant laser surgery between 16+0 and 26+6 weeks. In case of disease progression or maternal discomfort occurring after 26+6 weeks, treatment will comprise of amnioreduction and steroids or delivery.  Other indications for steroids will be based upon local protocols. Otherwise, in non-progressive syndromes, follow-up will be sustained weekly up until 27+0   and every other week thereafter. A progression rate between 30 - 45% is expected from small retrospective studies of stage 1 TTTS managed expectantly.  Follow-up can be performed at the participating trial center or at the referring center depending on the confidence of the trial center on those referring centers.  If the trial center has low confidence in the referring center to fulfil the requirements of follow-up, this must be done at the trial center.

Outcome measures
All babies born alive will be followed until the age of 6 months corrected from estimated date of delivery.

Primary end-point: Overall intact survival at 6 months
This composite outcome characterizes the babies alive at 6 months without neurological sequelae. Neurological sequelae are defined as cystic periventricular leukomalacia, severe intraventricular hemorrhage (stage 3 or 4), blindness or deafness. Neonatal imaging within the first month of life will be collected.  Ultrasound or MRI can be used. Pragmatically, using this outcome in a trial consists of counting the number of babies alive and well at 6 months in each arm taking into account the correlation between the twins of each pregnancy for a statistical comparison. This outcome is used for the calibration of the trial.

Secondary end-points
  • 6 months and 2 year intact survival of both twins
  • Perinatal, 6 months and 2 year survival of at least one twin
  • Perinatal, 6 months and 2 year survival of both twins
  • Complications of prematurity at 6 months and 2 years (necrotizing enterocolitis ≥ stage 2, bronchopulmonary dysplasia, renal failure, retinopathy of prematurity, time spent in NICU)
  • Neurological morbidity at 2 years as defined by any of: cerebral palsy according to the European CP network, blindness, severe deafness requiring amplification, or abnormal scores on the Bayley's test. A Bayley's test will be considered abnormal if the mental developmental indexes (MDI) or psychomotor development indexes (PDI) are under 70.
  • Maternal and obstetrical morbidity


Power/data analysis
The trial has been powered according to a single bilateral test of two proportions. An estimation of the required intra-cluster correlation coefficient ρ in a cluster design was computed using the data from the laser group in the Eurofoetus trial. As expected in such a disease, these data yielded a high estimation of the correlation coefficient with a value of ρ = 0.26 meaning that the outcomes of the siblings are tightly correlated. The following power calculations were precociously based on a ρ = 0.30, using the formula of the Variance Inflation Factor VIF=1+ρ*(k-1) and N=VIF*n, where n is the number of fetuses per arm in a classical test, k the cluster size (k=2), and ρ the intra-cluster correlation coefficient. Combining stages 1 and 2, the Eurofoetus trial data also yielded a 64% rate of overall intact survival as estimation for a reference rate.
The null hypothesis for the test: there is no difference in the rates of intact survival at 6 months between the two allocation groups.
With α=0.05, 1-β=0.8, P1=60%, P2=75% meaning a clinically relevant difference of 15% between the groups, 200 fetuses or equivalently 100 pregnancies would be needed in each arm.

Time schedule
TTTS1 is a 2,5 -year study with a cluster randomization of willing participants

Projectleaders
Professor Yves Ville, Principal investigator
Maternité Necker - Brune
Hôpital Necker - Enfants Malades
Tél: 01 71 19 64 82
Email : ville.yves@gmail.com

More centers are going to be added here

Methodology
Unité de Recherche Clinique
Paris Ouest-Ambroise Paré 
9 avenue Charles de Gaulle 92104 Boulogne Cedex

Méthodologie, Coordination, Monitoring :

Dr Laurence Bussières,
Tel : 01 49 09 46 36
laurence.bussieres@apr.aphp.fr
Dr Philippe Aegerter
Tel : 01 49 09 56 68
philippe.aegerter@apr.aphp.fr

Sylvain Goupil, Attache de Recherche Clinique
Tel : 01 49 09 46 22
Fax :01 49 09 44 71
sylvain.goupil@apr.aphp.fr

Pr Jean Christophe Thalabard
jean-christophe.thalabard@math-info.univ-paris5.fr

Contact
Professor Yves Ville, Principal investigator
Maternité Necker - Brune
Hôpital Necker - Enfants Malades
Tél: 01 71 19 64 82
Email : ville.yves@gmail.com