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Safety Evaluation of Tadalafil Treatment for Fetuses with Early-Onset Growth Restriction (TADAFER): Results from the Phase II Trial.

ABSTRACT: Tadalafil is a phosphodiesterase 5 (PDE5) inhibitor with a long half-life, high selectivity, and rapid onset of action. Because the safety of using PDE5 inhibitors as therapeutic agents for fetal growth restriction (FGR) has been a problem worldwide, this paper primarily focuses on the safety assessments performed in the Tadalafil Treatment for Fetuses with Early-Onset Growth Restriction (TADAFER) II population. Neonatal and maternal adverse events were analyzed, in addition to fetal, neonatal, and infant death cases, six months after stopping the trial. Eighty-nine pregnant women with FGR were studied between September 2016 and March 2018 (45 and 44 in the tadalafil and conventional treatment groups, respectively). Seven (16%) deaths (four fetal, one neonatal, and two infant) in the control group, whereas only one neonatal death occurred in the tadalafil group. Although headache, facial flushing, and nasal hemorrhage occurred more frequently in the tadalafil group, these symptoms were Grade 1 and transient. In conclusion, this trial showed that tadalafil decreased the fetal and infant deaths associated with FGR. This is thought to be primarily due to pregnancy prolongation. Further studies are warranted to evaluate the efficacy of tadalafil in treating early-onset FGR.

SUBMITTER: Maki S

PROVIDER: S-EPMC6617029 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Safety Evaluation of Tadalafil Treatment for Fetuses with Early-Onset Growth Restriction (TADAFER): Results from the Phase II Trial.

Maki Shintaro S Tanaka Hiroaki H Tsuji Makoto M Furuhashi Fumi F Magawa Shoichi S Kaneda Michiko K MK Nii Masafumi M Tanaka Kayo K Kondo Eiji E Tamaru Satoshi S Ogura Toru T Nishimura Yuki Y Endoh Masayuki M Kimura Tadashi T Kotani Tomomi T Sekizawa Akihiko A Ikeda Tomoaki T

Journal of clinical medicine 20190615 6

Tadalafil is a phosphodiesterase 5 (PDE5) inhibitor with a long half-life, high selectivity, and rapid onset of action. Because the safety of using PDE5 inhibitors as therapeutic agents for fetal growth restriction (FGR) has been a problem worldwide, this paper primarily focuses on the safety assessments performed in the Tadalafil Treatment for Fetuses with Early-Onset Growth Restriction (TADAFER) II population. Neonatal and maternal adverse events were analyzed, in addition to fetal, neonatal, ...[more]

PMID: 31208060

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Project description:ObjectiveTo describe the incidence, clinical features and perinatal outcome of late-onset fetal growth restriction (FGR) associated with genetic syndrome or aneuploidy, structural malformation or congenital infection.MethodsThis was a retrospective multicenter cohort study of patients who attended one of four tertiary maternity hospitals in Italy. We included consecutive singleton pregnancies between 32 + 0 and 36 + 6 weeks' gestation with either fetal abdominal circumference (AC) or estimated fetal weight < 10th percentile for gestational age or a reduction in AC of > 50 percentiles from the measurement at an ultrasound scan performed between 18 and 32 weeks. The study group consisted of pregnancies with late-onset FGR and a genetic syndrome or aneuploidy, structural malformation or congenital infection (anomalous late-onset FGR). The presence of congenital anomalies was ascertained postnatally in neonates with abnormal findings on antenatal investigation or detected after birth. The control group consisted of pregnancies with structurally and genetically normal fetuses with late-onset FGR. Composite adverse perinatal outcome was defined as the presence of at least one of stillbirth, 5-min Apgar score < 7, admission to the neonatal intensive care unit (NICU), need for respiratory support at birth, neonatal jaundice and neonatal hypoglycemia. The primary aims of the study were to assess the incidence and clinical features of anomalous late-onset FGR, and to compare the perinatal outcome of such cases with that of fetuses with non-anomalous late-onset FGR.ResultsOverall, 1246 pregnancies complicated by late-onset FGR were included in the study, of which 120 (9.6%) were allocated to the anomalous late-onset FGR group. Of these, 11 (9.2%) had a genetic syndrome or aneuploidy, 105 (87.5%) had an isolated structural malformation, and four (3.3%) had a congenital infection. The most frequent structural defects associated with late-onset anomalous FGR were genitourinary malformations (28/105 (26.7%)) and limb malformation (21/105 (20.0%)). Compared with the non-anomalous late-onset FGR group, fetuses with anomalous late-onset FGR had an increased incidence of composite adverse perinatal outcome (35.9% vs 58.3%; P < 0.01). Newborns with anomalous, compared to those with non-anomalous, late-onset FGR showed a higher frequency of need for respiratory support at birth (25.8% vs 9.0%; P < 0.01), intubation (10.0% vs 1.1%; P < 0.01), NICU admission (43.3% vs 22.6%; P < 0.01) and longer hospital stay (median, 24 days (range, 4-250 days) vs 11 days (range, 2-59 days); P < 0.01).ConclusionsMost pregnancies complicated by anomalous late-onset FGR have structural malformations rather than genetic abnormality or infection. Fetuses with anomalous late-onset FGR have an increased incidence of complications at birth and NICU admission and a longer hospital stay compared with fetuses with isolated late-onset FGR. © 2022 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Project description:IntroductionAntiprogestins have demonstrated promising activity against breast and gynecological cancers, but liver-related safety concerns limited the advancement of this therapeutic class. Onapristone is a full progesterone receptor antagonist originally developed as an oral contraceptive and later evaluated in phase II studies for metastatic breast cancer. Because of liver enzyme elevations identified during clinical studies, further development was halted. Evaluation of antiprogestin pharmacology and pharmacokinetic data suggested that liver enzyme elevations might be related to off-target or metabolic effects associated with clinical drug exposure.ObjectiveWe explored whether the use of a pharmaceutic strategy targeting efficacious systemic dose concentrations, but with diminished peak serum concentrations and/or total drug exposure would mitigate hepatotoxicity. Twice-daily dosing of an extended-release formulation of onapristone was developed and clinically evaluated in light of renewed interest in antiprogestin therapy for treating progesterone receptor-positive breast and gynecologic cancers. The hepatotoxic potential of extended-release onapristone was assessed from two phase I-II studies involving patients with breast, ovarian, endometrial, and prostate cancer.ResultsAmong the 88 patients in two phase I-II studies in progesterone receptor-positive malignancies treated with extended-release onapristone, elevated alanine aminotransferase/aspartate aminotransferase levels were found in 20% of patients with liver metastases compared with 6.3% without metastases. Of five patients with grade 3 or higher alanine aminotransferase elevations with or without bilirubin elevations (four with breast cancer and one with endometrial cancer), four were assessed as unrelated to extended-release onapristone by the safety data review committee. Furthermore, while the fifth patient's liver enzyme elevations were considered possibly drug related by the study investigator, they were adjudicated as unlikely to be related (< 25% likelihood) by a subsequent independent hepatologist.ConclusionsThese results suggest that the extended-release formulation by reducing drug exposure may be associated with a reduced risk of hepatotoxicity, and supports the continued clinical evaluation of extended-release onapristone for treating progesterone receptor-positive cancers.

Dataset Information

Safety Evaluation of Tadalafil Treatment for Fetuses with Early-Onset Growth Restriction (TADAFER): Results from the Phase II Trial.

Publications

Safety Evaluation of Tadalafil Treatment for Fetuses with Early-Onset Growth Restriction (TADAFER): Results from the Phase II Trial.

Similar Datasets

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