The TAPS Trial - Fetoscopic Laser Surgery for Twin Anemia Polycythemia Sequence

The TAPS Trial - Fetoscopic Laser Surgery for Twin Anemia-Polycythemia Sequence - a Multicenter Open-Label Randomized Controlled Trial

This multicenter open-label randomized controlled trial is set up to evaluate the effect of fetoscopic laser surgery on the gestational age at birth for monochorionic twin pregnancies diagnosed with twin anemia-polycythemia sequence. Half op the patients will be treated with fetoscopic laser surgery, while the other half will be managed with standard treatment. The hypothesis is that fetoscopic laser therapy will improve neonatal outcome by prolonging pregnancy.

Study Overview

• Status: Recruiting
• Conditions: Twin Anemia Polycythemia Sequence
• Intervention / Treatment: Procedure: Fetoscopic Laser Surgery; Other: Standard Treatment

Detailed Description

Rationale: Monochorionic twins share one placenta and are connected to each other via vascular anastomoses at the placental surface, allowing the blood to transfer bi-directionally between the two fetuses. Unbalanced inter-twin blood transfusion can result in twin anemia-polycythemia sequence (TAPS). Management options include: fetoscopic laser surgery, intrauterine blood transfusion (IUT) with or without partial exchange transfusion (PET), preterm delivery, selective feticide and expectant management. The optimal treatment for TAPS is not clear. Fetoscopic laser surgery is the only causative treatment option, but data on the feasibility of this procedure are mainly based on case reports and small cohort studies. A large randomized controlled trial is needed to evaluate the possible beneficial effect of fetoscopic laser surgery and to determine the optimal treatment option for TAPS.

Objective: The aim of this trial is to investigate whether fetoscopic laser surgery improves the outcome for TAPS twins as compared to the control group (standard care consisting of expectant management, IUT, preterm delivery). The hypothesis is that fetoscopic laser therapy will improve neonatal outcome by prolonging pregnancy.

Study design: International multi-centered open-label randomized controlled trial to assess whether fetoscopic laser surgery (experimental group) improves the outcome of TAPS twins compared to standard care (control group).

Study population: Monochorionic twin pregnancies with TAPS stage ≥ 2 (spontaneous or post-laser) diagnosed between 20 and 28 weeks of gestation.

Intervention: In the experimental group fetoscopic laser surgery is performed, whereas the control group is treated with standard care (expectant management, IUT (with PET), selective feticide and/or preterm delivery, depending on the opinion of the fetal surgeon).

Main study endpoints: The primary outcome is gestational age at birth. Secondary outcomes include: perinatal mortality or severe neonatal morbidity, hematological complication, procedure related complications and long-term neurodevelopmental outcome at 2 years.

• Study Type: Interventional
• Enrollment (Anticipated): 44
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Femke Slaghekke, MD PhD; Phone Number: +31 71 52 97211; Email: f.slaghekke@lumc.nl
• Study Contact Backup: Name: Lisanne Tollenaar, BSc; Phone Number: +31653413875; Email: l.s.a.tollenaar@lumc.nl

Study Locations

• Italy
  • Lombardy
    • Milan, Lombardy, Italy, 20154
      • Recruiting
      • Vittore Buzzi Children's Hospital
      • Contact: Mariano Lanna, MD PhD; Email: info@terapiafetale.it
      • Principal Investigator: Mariano Lanna, MD PhD
• Netherlands
  • South-Holland
    • Leiden, South-Holland, Netherlands, 2333ZA
      • Recruiting
      • Leiden University Medical Center
      • Contact: Dick Oepkes, MD PhD; Phone Number: +31715261688; Email: d.oepkes@lumc.nl
      • Contact: Femke Slaghekke, MD PhD; Phone Number: +31715297211; Email: f.slaghekke@lumc.nl
      • Principal Investigator: Dick Oepkes, MD PhD
      • Sub-Investigator: Enrico Lopriore, MD PhD
      • Sub-Investigator: Femke Slaghekke, MD PhD
      • Sub-Investigator: Lisanne Tollenaar, BSc
• Spain
  • Barcelona, Spain, 08035
    • Recruiting
    • Vall D'Hebron University Hospital
    • Contact: Carlota Rodo, MD PhD; Email: crodo@vhebron.net
    • Contact: Silivia Arevalo, MD PhD; Email: siareval@vhebron.net
    • Principal Investigator: Carlota Rodo, MD PhD
    • Sub-Investigator: Silivia Arevalo, MD PhD
    • Sub-Investigator: Pablo Garcia-Manau, MD PhD
• Sweden
  • Södermanland
    • Stockholm, Södermanland, Sweden, 141 86
      • Not yet recruiting
      • Karolinska University Hospital
      • Contact: Lotta Herling, MD PhD; Email: lotta.herling@sll.se
      • Principal Investigator: Lotta Herling, MD PhD
• United States
  • Connecticut
    • New Haven, Connecticut, United States, 208327
      • Not yet recruiting
      • Yale University
      • Contact: Ozan Bahtiyar, MD PhD
      • Principal Investigator: Ozan Bahtiyar, MD PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 50 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• Monochorionic twin pregnancy complicated by either spontaneous or post-laser twin anemia polycythemia sequence (TAPS), stage ≥ 2, diagnosed between 20+0 and till 28+0 weeks of gestation
• Women aged 18 years or more, who are able to consent.
• Written informed consent to participate in this randomized controlled trial, forms being approved by the Ethical Committees.

Exclusion Criteria:

• TAPS stage 1
• TAPS stage≥ 2, diagnosed within 1 week after laser surgery for twin-twin transfusion syndrome (TTTS) (a large inter-twin middle cerebral artery peak systolic velocity difference within a week after laser for TTTS is likely to related to hemodynamic reequilibration, and is usually not based on TAPS)
• Triplet pregnancies, or higher order multiple pregnancies
• TAPS cases that already underwent an intrauterine treatment (with the exception of laser surgery for TTTS in post-laser TAPS cases)
• Congenital abnormalities (including severe cerebral injury) in one or both twins

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Fetoscopic Laser Surgery; fetoscopic laser coagulation of the vascular anastomoses at the placental surface	Procedure: Fetoscopic Laser Surgery; Fetoscopic Photocoagulation of the connecting vascular anastomoses on the surface of the placenta.; Other Names: Fetoscopic Laser Coagulation; Laser therapy; Fetoscopic Laser Ablation
Other: Standard Treatment; Expectant management, IUT (with or without PET), preterm delivery	Other: Standard Treatment; In the control group, the choices of treatment include expectant management, intrauterine transfusion (IUT) (with or without partial exchange transfusion (PET)) or preterm delivery, depending on the judgment of the fetal surgeon with regard to the gestational age and state of the disease.; Expectant management will consist of close monitoring with ultrasound including Doppler measurements of the middle cerebral artery peak systolic velocity (MCA-PSV), at least every week.; IUT: the intrauterine infusion of red blood cells into the circulation of the donor twin treat anemia.; PET: the intrauterine infusion of saline into the circulation of the recipient twin to treat polycythemia.; Preterm delivery: Induction of labor or cesarean section before 36 weeks of gestation.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Gestational Age at Birth	Gestational age: completed weeks + additional days since the first day of the last menstruational period of the mother.	2 weeks after expected date of birth

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of patients with perinatal mortality	Perinatal mortality is defined as fetal death or neonatal death (demise of a liveborn child within 28 days after birth)	42 days (28 days neonatal period+2 weeks postdates) after expected date of birth
Number of patients with severe neonatal morbidity	Severe neonatal morbidity is defined as the presence of at least one of the following: Respiratory distress syndrome requiring surfactant or mechanical ventilation; Proven early onset neonatal sepsis with positive blood cultures within 72 hours postpartum; Retinopathy of prematurity stage 3 or higher; Necrotizing enterocolitis stage 2 or higher; Patent ductus arteriosus requiring medical therapy or surgical closure; Severe cerebral injury (defined as intraventricular hemorrhage grade 3 or higher, cystic periventricular leukomalacia grade 2 or higher, ventricular dilatation greater than the 97th centile, porencephalic or parenchymal cysts or other severe cerebral lesions)	42 days (28 days neonatal period+2 weeks postdates) after expected date of birth
Number of patients with hematological complications	Hematological complications are defined as the presence of at least one of the following: Anemia in donor requiring a blood transfusion within 24 hours after birth; Polycythemia in recipient requiring a partial exchange transfusion within 24 hours after birth; necrotic skin injury; limb ischemia; platelet count < 150,000/microL; albumin levels < 20 g/L; protein levels < 40 g/L	2 weeks after expected date of birth
Number of patients with procedure-related complications	Procedure-related complications are defined as at least one of the following: amniotic band syndrome; iatrogenic monoamnionicity; Preterm premature rupture of the membranes; Placental abruption; clinical chorioamnionitis; histological chorioamnionitis and/or funisitis	2 weeks after expected date of birth
Number of patient with mild neurodevelopmental impairment	Mild neurodevelopmental impairment is defined as at least one of the following: cerebral palsy (spastic bilateral, spastic unilateral, or mixed); Impaired cognitive or motor development defined as Score < 85 (1 standard deviation (SD) below the mean) as assessed by Bayley Scales of Infant and Toddler Development version 3 (BSID-III); Impaired functioning in communication, fine and gross motor, problem solving, personal and social functioning defined as Score > 1 SD below the mean as assessed by Ages and Stages Questionnaire version 3 (ASQ-III); severe visual loss (blind or partially sighted); severe hearing loss (needing hearing aids)	2 years after expected date of birth
Number of patients with severe neurodevelopmental impairment	Severe neurodevelopmental impairment is defined as at least one of the following: cerebral palsy defined as a gross motor function classification system (CMFCS) grade > 1; Impaired cognitive or motor development defined as a score < 70 (2 SD below the mean) as assessed by the Bayley Scales of Infant and Toddler Development version 3 (BSID-III); Impaired functioning in communication, fine and gross motor, problem solving, personal and social functioning defined as a score > 2 SD below the mean as assessed by Ages and Stages Questionnaire version 3 (ASQ-III); Bilateral blindness defined as visual acuity of less than 3/60 in the better eye; Bilateral deafness defined as severe or profound hearing loss in both ears (severe hearing loss: a person can only hear sounds > 70-89 decibel , profound hearing loss: a person can only hear sounds > 90 decibel	2 years after expected date of birth
Number of patients with behavioral problems	Behavioral problems are defined as a T-score ≥ 64 for one of the following broad band scales: total problem score, Internalizing problems (anxious/depressed, withdrawn, somatic complaints), Externalizing problems (rule-breaking, aggressive behavior) as measured with the Child Behaviour Checklist 1.5-5 years	2 years after expected date of birth

Collaborators and Investigators

• Sponsor: Leiden University Medical Center
• Investigators: Principal Investigator: Dick Oepkes, MD PhD, Leiden University Medical Center

Publications and helpful links

General Publications

• Lopriore E, Middeldorp JM, Oepkes D, Kanhai HH, Walther FJ, Vandenbussche FP. Twin anemia-polycythemia sequence in two monochorionic twin pairs without oligo-polyhydramnios sequence. Placenta. 2007 Jan;28(1):47-51. doi: 10.1016/j.placenta.2006.01.010. Epub 2006 Mar 3.
• Robyr R, Lewi L, Salomon LJ, Yamamoto M, Bernard JP, Deprest J, Ville Y. Prevalence and management of late fetal complications following successful selective laser coagulation of chorionic plate anastomoses in twin-to-twin transfusion syndrome. Am J Obstet Gynecol. 2006 Mar;194(3):796-803. doi: 10.1016/j.ajog.2005.08.069.
• Sananes N, Veujoz M, Severac F, Barthoulot M, Meyer N, Weingertner AS, Kohler M, Guerra F, Gaudineau A, Nisand I, Favre R. Evaluation of the Utility of in utero Treatment of Twin Anemia-Polycythemia Sequence. Fetal Diagn Ther. 2015;38(3):170-8. doi: 10.1159/000380822. Epub 2015 Mar 17.
• Slaghekke F, Favre R, Peeters SH, Middeldorp JM, Weingertner AS, van Zwet EW, Klumper FJ, Oepkes D, Lopriore E. Laser surgery as a management option for twin anemia-polycythemia sequence. Ultrasound Obstet Gynecol. 2014 Sep;44(3):304-10. doi: 10.1002/uog.13382. Epub 2014 Aug 4.

Study record dates

Study Major Dates

• Study Start (Actual): April 30, 2019
• Primary Completion (Anticipated): April 30, 2022
• Study Completion (Anticipated): April 30, 2024

Study Registration Dates

• First Submitted: May 11, 2020
• First Submitted That Met QC Criteria: June 11, 2020
• First Posted (Actual): June 16, 2020

Study Record Updates

• Last Update Posted (Actual): June 16, 2020
• Last Update Submitted That Met QC Criteria: June 11, 2020
• Last Verified: June 1, 2020

More Information

Terms related to this study

• Keywords: Monochorionic Twins; Twin-Twin Transfusion Syndrome; Fetoscopic Laser Surgery; Intrauterine Transfusion; Partial Exchange Transfusion
• Additional Relevant MeSH Terms: Hematologic Diseases; Anemia; Polycythemia
• Other Study ID Numbers: NL6442700018

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No