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Report for Clinical Trial NCT01120964

Developed by Shray Alag, 2020.
SNP Clinical Trial Gene

Phase IB Double Blind, Randomized, Placebo Controlled Clinical Trial to Determine the Pharmacokinetics and Safety of a Revised Protocol of Intravenous L-Citrulline (Citrupress®) Versus Placebo in Children Undergoing Cardiopulmonary Bypass

This clinical trial will determine the safety and effectiveness of intravenous L-citrulline in children undergoing cardiopulmonary bypass during heart surgery. Participants will be randomly assigned to either L-citrulline or a placebo (a substance that has no medicine in it). Citrulline is a protein building block in the body that can convert into another substance, nitric oxide (NO), which controls blood pressure in the lungs. Increased blood pressure in the lungs can be an important surgical problem; it may also lead to problems following surgery, such as severe high blood pressure in the lungs (pulmonary hypertension), increased time spent on a breathing machine, and a longer stay in the intensive care unit (ICU). The hypothesis of this study is that perioperative supplementation with intravenous citrulline will increase plasma citrulline, arginine and NO metabolites and prevent elevations in the postoperative PVT leading to a decrease in the duration of postoperative invasive mechanical ventilation. The objective of this study is to determine in a randomized placebo controlled phase IB multicenter clinical trial if a revised protocol of intravenous L-citrulline delivery given perioperatively achieves a plasma citrulline level of > 100 umol/L in children undergoing surgical repair of an atrial septal defect,ventricular septal defect or an atrioventricular septal defect.

NCT01120964 Atrial Septal Defect Ventricular Septal Defect Atrioventricular Se Atrioventricular Septal Defect
MeSH:Heart Septal Defects Heart Septal Defects, Ventricular Heart Septal Defects, Atrial Endocardial Cushion Defects
HPO:Abnormal cardiac septum morphology Atrial septal defect Atrioventricular canal defect Secundum atrial septal defect Ventricular septal defect

2 Interventions

Name: Intravenous L-Citrulline

Description: 150mg bolus X 1 after initiation of cardiopulmonary bypass, the addition of L-citrulline at a concentration of 200 umol/L or placebo to the filtration and hemoconcentration fluid utilized during cardiopulmonary bypass in addition to a 20mg/kg bolus 30 minutes after separation from cardiopulmonary bypass immediately followed by a continuous infusion of 9mg/kg/hr IV, and ending at 48 hours continuous infusion or discharge from the PCCU.
Type: Drug
Group Labels: 1

Intravenous L-Citrulline

Name: Placebo of Intravenous L-Citrulline

Description: Placebo of Intravenous L-Citrulline given at the same prescribed times as L-Citrullne Drug
Type: Drug
Group Labels: 1

Placebo of Intravenous L-Citrulline


Primary Outcomes

Description: Citrulline Blood Levels : 1. Baseline sample in OR prior to Cardiopulmonary Bypass prior to admistration of first bolus of Citrulline or Placebo 2. Immediately after Bolus 1 administered in Operating Room. 3. 30 minutes after separation from Cardiopulmonary Bypass; immediately prior to administration of Bolus 2 and start of continuous infusion of Citrulline or Placebo. 4. Six hours after after start of infusion. 5. 12 hours after start of infusion. 6. 24 hours after start of infusion. 7. 48 hours after start of infusion; or whenever infususion is discontinued if prior to 48 hours.

Measure: To determine if L-citrulline given perioperatively achieves a plasma citrulline level of > 100 umol/L in children undergoing surgical repair of an atrial septal defect, a ventricular septal defect or an atrioventricular septal defect.

Time: Measured in seven blood sample time points from the beginning of surgery until end of IV Citrulline Infusion; at either 48 hours postoperatively or at extubation, whichever comes first.

Secondary Outcomes

Measure: Duration of postoperative mechanical ventilation in hours compared between treatment groups

Time: Measured in hours from the end of surgery until extubation

Measure: Incidence of increased PVT (defined as a sustained mean pulmonary artery pressure greater than 20 mm Hg for at least 2 hours, measured during the first 48 hours

Time: Measured in hours from the end of surgery until extubation

Measure: Postoperative intravenous inotrope score

Time: Measured at 48 hours

Measure: Length and volume of chest tube drainage

Time: Measured in hours from the end of surgery until removal of chest tubes

Measure: Length of ICU stay

Time: Measured in hours from the end of surgery to discharge from ICU

Measure: Length of hospitalization

Time: Measured from the day of surgery until discharge from hospital

Measure: Survival

Time: Measured at 28 days post surgical repair

Description: Age specific mean aterial blood pressrue limits compared between the citrulline and placebo groups will be used to determine significant hypotension.

Measure: The incidence of clinically significant hypotension.

Time: Mean Arterial Blood pressure as continuously monitored postoperatively in the PCCU during Citrulline or Placebo infusion.

Purpose: Prevention

Allocation: Randomized

Parallel Assignment


There is one SNP

SNPs


1 T1405N

Finally, a genetic single nucleotide polymorphism (SNP) in the rate limiting urea cycle enzyme (carbamyl phosphate synthetase I [CPSl T1405N]) appeared to affect postoperative plasma arginine levels and PVT. --- T1405N ---



HPO Nodes


HPO:
HP:0001671: Abnormal cardiac septum morphology
Genes 689
NDUFS7 WHCR GATA6 TP63 IGBP1 PEX13 ESCO2 PORCN GPC4 TRAIP AMMECR1 COL1A1 PEX1 GATA1 NAA10 PEX6 XYLT2 MAP2K2 TTC37 OTUD6B BCR CFC1 HYMAI SIX6 EVC2 BRAF MPL MAP3K7 MYH7 NKX2-6 VPS33A GABRD FOXF1 CTBP1 NOTCH1 CEP290 SETD5 PSMD12 BUB1 GYG1 NKX2-1 IGF1R PEX12 ESS2 PACS1 DPF2 HSPA9 RNU4ATAC THOC6 ZMPSTE24 DNMT3A CCND2 PPP2CA LRP5 ASXL1 RAF1 TGFBR2 EXOC6B KIF7 ALKBH8 MAP2K1 TACO1 NELFA RPL35A DPH1 GPC4 BMPR1A GATA6 GATA4 AMER1 HDAC8 PEX2 TGFB3 POLA1 TBX1 ATP6V0A2 PEX11B PIEZO1 BRAF NKX2-5 NFIX MED13L SETBP1 KMT2A NEUROD2 SETD2 COL1A2 EVC KRAS CRELD1 ALG9 DNMT3A RAP1B G6PC3 FGFR3 DVL3 EVC2 FKTN COL11A1 GNAO1 UFD1 BSCL2 KIAA0586 NDUFS3 B3GLCT FGFRL1 SNRPB SMN1 FGFR1 KDM1A SMG9 LTBP2 GDF1 TGDS FLNA XRCC2 LARP7 VPS33B SH2B1 SLC29A3 CACNA1D DSG1 GDF1 NKX2-1 STAMBP CKAP2L LONP1 TBX20 FGFR3 NDUFB11 HRAS JMJD1C MEIS2 RSPRY1 TRIM8 PALB2 UBE2A HSPG2 COX7B NSD1 KDM5B C2CD3 CTCF PQBP1 RPL10 NODAL PTF1A STAG2 KDM6A TGFBR1 FANCE FUT8 NCAPG2 ZDHHC9 PIGN RAD21 DGCR2 NSD1 CCBE1 MKS1 PTPN11 CITED2 RAD51 PIK3R2 RAB23 SMC3 KANSL1 NEK1 NDUFS2 MAP3K7 PIGL PEX19 SEC24C SEMA3E PIGQ FLNA ZIC3 CRB2 SMC1A B3GLCT NPHP3 ASXL2 COX7B PIGN FANCD2 EVC SOX2 TRRAP NEK1 RPL5 ANKRD11 MMP2 PLD1 MMP21 BMP2 MRAS USP9X SPECC1L SDHA ABL1 GATA6 FLNA GLA C2CD3 NEK9 SHOC2 COL5A2 SPATA5 NDUFA12 COG1 TBCK ECHS1 PHGDH MKKS MED25 CHST3 RPL27 ASCC1 NDUFV2 MYH7 LTBP4 FIBP EXT2 SOX4 RAC1 STRA6 GJA1 COMT NAA10 GJA1 ERCC4 CWC27 B3GALT6 STRADA LRP2 ARX WASHC5 FOXF1 PEX16 MTFMT GATA6 MGP GJA1 CCDC22 RNF113A UMPS CDC42 TSFM PPP1CB PEX5 MAP2K1 SOX2 CDK10 BRCA1 RERE FADD SMARCE1 GATA4 STXBP1 FIG4 RFWD3 KIF15 GLI1 DTNA BRAF ELN TP63 RPS17 CKAP2L TBX1 AGGF1 NDUFAF6 PEX3 ACADVL ZMPSTE24 GPC3 PIGP PEX10 RPL15 CANT1 NUP107 MEGF8 ADAT3 CDK13 MGP ELN CEP57 GPX4 NONO PEX19 CASK EXT2 DGCR6 RREB1 BUB3 GPC6 SLC19A3 DYNC2LI1 SPECC1L DYNC2LI1 COX7B FANCC RAI1 PET100 MASP1 MAD2L2 BCOR PAX3 CACNA1D ERCC2 KAT6B NOTCH1 EPHB4 XYLT1 NSDHL MMP14 PIK3R2 VIPAS39 WASHC5 TAPT1 PIGA GP1BB GLI3 TKT NKX2-5 CEP57 KRAS ARHGAP31 TLL1 RFC2 PIEZO2 ERBB3 MAPK1 ERCC3 SLC19A2 WNT4 SNRPB STRADA PUF60 ZIC3 NDUFV1 STK4 PTPN11 CCNQ PALB2 UBR1 PEX1 FIBP RECQL4 SYT1 RARB PIGL THOC6 EP300 ADAMTS10 NEK9 SLC25A22 HOXD13 SF3B4 COX15 LONP1 NDUFA10 DGCR8 PKD1L1 CRELD1 KCNA1 DLL4 TBX22 PQBP1 SPECC1L NDUFS1 B3GAT3 DNAJC19 FBN2 PTEN KDM6A PRDM16 ABCD4 FLI1 PAH LETM1 NFE2L2 SMC3 PIGT IFT172 TBX1 CNTNAP2 MYBPC3 CITED2 SKI NR2F2 PEX26 ATIC KCNAB2 PIK3R2 INSR CHD7 BRAF CTCF RBM10 GLI3 SRCAP CD96 KDM6A FGFR2 FBN1 LIMK1 CHRM3 TBX4 TBL2 RIT1 UBE2T SHANK3 COL11A2 NDUFA9 NKX2-5 MPLKIP CDC45 PIGO SCN2A ROBO4 WNT4 LMNA MEIS2 NF1 YY1 RERE AFF4 RPS26 GATA5 GATA6 NDUFAF2 FANCL KIF11 TKT PEX14 ATRX CHD7 TMCO1 SOS1 HIRA FOXRED1 MAP2K2 AFF4 NSD2 SNX14 TRIP4 GDF3 ARCN1 RAD21 KMT2D EFTUD2 RAP1A GATA4 WT1 CLIP2 MED12 BRIP1 SLC19A2 AKT3 KRAS CHD4 SETD5 NIPBL FANCF SIK1 WDR60 ALG8 PCGF2 NRXN1 MEOX1 TALDO1 XYLT2 ADAMTS10 DHCR7 ACVR2B FANCI BUB1B NOTCH2 DACT1 ACTC1 AUTS2 NDUFB11 ARID2 TGDS BRAF EHMT1 GTF2E2 STAT1 TTC37 HOXA13 TXNL4A RSPO2 TMEM260 SLC25A24 DHCR7 POR FBN1 GATA4 MED13L SIK3 NFIX NOTCH2 UBE3B MTFMT FOXC2 WDR35 RMRP TAB2 HNRNPU CCDC22 FANCA NDUFA13 FLNA BCOR TBX2 ROR2 SYNE1 NDUFS4 NSD2 INTU GTF2H5 SON MGAT2 SKIV2L FANCM TARS1 CCDC174 MED25 ATN1 CHST14 BRF1 SCN1B RBM8A NOTCH2 ECE1 TBX1 CYTB MYL2 RAF1 RBM8A FANCB NDUFAF5 SMAD4 LBR MCTP2 TRIP13 ANK1 UBR1 TBX5 MPLKIP USP9X IRX5 PIGN HAAO MEOX1 LZTR1 NXN BBS2 TBX5 TCTN3 NKX2-5 SALL4 PDHA1 NKX2-5 CHST3 LETM1 BRCA2 PUF60 ATP6V1E1 LRP2 RAD51C PCNT OTUD6B GJA1 ARVCF GTF2I MYMK LARS2 NOTCH3 ATP6V0A2 TFAP2B RPL11 EFTUD2 RNU4ATAC UPF3B CDKL5 FTO SOS2 ARID1B APC2 TBX1 COL5A1 JAG1 PACS2 NDUFA4 SLX4 IFT81 ATP6V1A KMT2D KAT6A GATA6 NUP107 PPP2R5D ALG12 DDX11 RPS19 NDUFA2 TBX1 EOGT PUF60 GDF6 HCCS ZEB2 FLNB B3GALT6 MLXIPL HRAS TBX3 FANCG WDR26 FANCI LYST NKX2-5 TRIO WDPCP ADK TBX3 NR2F2 KAT6A PACS1 FLCN TXNL4A FIG4 BAZ1B NPHP3 DSE PIK3CA RPL10 SLC29A3 FANCB DPH1 NDUFS8 CPLX1 GPC3 YY1AP1 MYPN PEX16 VPS13B KAT6B CACNA1C MYRF ECHS1 GATA4 ROR2 TTC7A FADD TTC7A PQBP1 CTU2 HCCS HYLS1 LIPT1 MED12 VAC14 FGFR2 MYH6 NONO SALL1 KAT6B MED12 POLR1A ARX PNKP SALL1 CRKL TMEM94 SURF1 BMP2 TALDO1 NIPBL PLAGL1 SEMA3E SMAD4 RERE FOXC1 GTF2IRD1 CREBBP LMNA
Protein Mutations 1
T1405N
SNP 0
HP:0001631: Atrial septal defect
Genes 378
WHCR TBX22 PQBP1 SPECC1L ESCO2 GPC4 B3GAT3 TRAIP AMMECR1 FBN2 COL1A1 PTEN KDM6A ABCD4 LETM1 NFE2L2 XYLT2 MAP2K2 SMC3 TTC37 OTUD6B PIGT BCR EVC2 MAP3K7 MYH7 ATIC VPS33A INSR BRAF FOXF1 CTBP1 NOTCH1 CEP290 SETD5 CTCF RBM10 SRCAP BUB1 LIMK1 NKX2-1 IGF1R CHRM3 TBX4 TBL2 RIT1 PACS1 UBE2T HSPA9 THOC6 ZMPSTE24 DNMT3A ASXL1 TGFBR2 MAP2K1 CDC45 NELFA DPH1 PIGO ROBO4 LMNA MEIS2 BMPR1A NF1 YY1 GATA4 AMER1 HDAC8 TGFB3 GATA5 POLA1 TBX1 GATA6 PIEZO1 BRAF FANCL KIF11 NKX2-5 TKT MED13L SETBP1 KMT2A CHD7 TMCO1 COL1A2 EVC KRAS HIRA DNMT3A G6PC3 AFF4 NSD2 FGFR3 DVL3 EVC2 SNX14 FKTN COL11A1 TRIP4 RAD21 UFD1 KIAA0586 KMT2D EFTUD2 GATA4 WT1 CLIP2 MED12 BRIP1 SLC19A2 FGFRL1 SNRPB SMN1 KRAS CHD4 FGFR1 KDM1A NIPBL FANCF GDF1 TGDS XRCC2 PCGF2 LARP7 VPS33B SH2B1 SLC29A3 TALDO1 CACNA1D GDF1 NKX2-1 STAMBP DHCR7 LONP1 TBX20 FANCI BUB1B FGFR3 DACT1 JMJD1C ACTC1 MEIS2 RSPRY1 AUTS2 NDUFB11 ARID2 PALB2 UBE2A HSPG2 BRAF NSD1 KDM5B C2CD3 STAT1 CTCF PQBP1 RPL10 NODAL PTF1A TXNL4A TMEM260 KDM6A TGFBR1 FANCE SLC25A24 NCAPG2 ZDHHC9 DHCR7 POR CCBE1 MED13L SIK3 NFIX CITED2 RAD51 RAB23 SMC3 KANSL1 UBE3B WDR35 SEC24C SEMA3E ZIC3 CCDC22 SMC1A FANCA B3GLCT NPHP3 TBX2 ASXL2 ROR2 COX7B PIGN FANCD2 EVC TRRAP NSD2 SON NEK1 SKIV2L RPL5 FANCM MMP2 CHST14 PLD1 MMP21 MRAS RBM8A USP9X NOTCH2 ECE1 SPECC1L ABL1 RAF1 SMAD4 GATA6 TRIP13 ANK1 NEK9 UBR1 TBX5 SHOC2 COL5A2 SPATA5 USP9X IRX5 PIGN HAAO PHGDH MKKS MED25 CHST3 RPL27 NXN BBS2 ASCC1 TBX5 LTBP4 RAC1 STRA6 GJA1 NKX2-5 SALL4 COMT NAA10 LETM1 BRCA2 ERCC4 B3GALT6 STRADA ATP6V1E1 WASHC5 FOXF1 RAD51C PCNT OTUD6B GJA1 ARVCF GTF2I GATA6 GJA1 RPL11 CCDC22 EFTUD2 RNU4ATAC UMPS UPF3B TSFM PPP1CB MAP2K1 CDK10 BRCA1 ARID1B SMARCE1 COL5A1 JAG1 RFWD3 KIF15 SLX4 GLI1 ATP6V1A KAT6A BRAF ELN RPS17 PPP2R5D ALG12 RPS19 TBX1 EOGT AGGF1 ACADVL ZMPSTE24 ZEB2 FLNB MLXIPL HRAS MEGF8 FANCG ADAT3 CDK13 ELN FANCI CEP57 LYST GPX4 NONO PEX19 NKX2-5 EXT2 ADK RREB1 BUB3 GPC6 KAT6A PACS1 FLCN DYNC2LI1 FIG4 SPECC1L BAZ1B COX7B FANCC NPHP3 RAI1 DSE MASP1 MAD2L2 BCOR PAX3 FANCB KAT6B CPLX1 GPC3 EPHB4 KAT6B CACNA1C MYRF MMP14 PIK3R2 WASHC5 PIGA GATA4 GP1BB GLI3 PQBP1 CTU2 TKT CEP57 KRAS HCCS ARHGAP31 TLL1 RFC2 MAPK1 MED12 VAC14 SLC19A2 FGFR2 MYH6 STRADA NONO KAT6B MED12 STK4 PTPN11 SALL1 CRKL SYT1 TMEM94 BMP2 TALDO1 EP300 RERE FOXC1 GTF2IRD1 CREBBP LMNA
Protein Mutations 0
SNP 0
HP:0001629: Ventricular septal defect
Genes 408
NDUFS7 WHCR TP63 IGBP1 PEX13 ESCO2 PORCN GPC4 TRAIP PEX1 NAA10 PEX6 TTC37 OTUD6B BCR HYMAI SIX6 EVC2 FOXF1 CTBP1 CEP290 SETD5 PSMD12 NKX2-1 IGF1R PEX12 ESS2 RNU4ATAC THOC6 CCND2 LRP5 ASXL1 ALKBH8 TACO1 RPL35A GPC4 AMER1 HDAC8 PEX2 TGFB3 POLA1 TBX1 PEX11B NKX2-5 NFIX KMT2A NEUROD2 DVL3 GNAO1 UFD1 NDUFS3 FGFRL1 SNRPB SMN1 FGFR1 SMG9 LTBP2 GDF1 TGDS VPS33B SLC29A3 CACNA1D DSG1 GDF1 NKX2-1 STAMBP CKAP2L LONP1 HRAS JMJD1C MEIS2 TRIM8 UBE2A NSD1 C2CD3 PQBP1 RPL10 NODAL KDM6A RAD21 DGCR2 CCBE1 PIK3R2 RAB23 SMC3 KANSL1 NDUFS2 PIGL PEX19 SEC24C SEMA3E PIGQ ZIC3 CRB2 SMC1A B3GLCT COX7B EVC SOX2 NEK1 RPL5 ANKRD11 MMP2 BMP2 SPECC1L SDHA ABL1 GATA6 C2CD3 NEK9 SHOC2 NDUFA12 TBCK ECHS1 PHGDH MKKS MED25 NDUFV2 FIBP EXT2 SOX4 RAC1 STRA6 COMT NAA10 GJA1 CWC27 B3GALT6 LRP2 ARX WASHC5 PEX16 MTFMT MGP GJA1 CCDC22 RNF113A UMPS PPP1CB PEX5 MAP2K1 SOX2 RERE FADD STXBP1 FIG4 GLI1 DTNA BRAF ELN TP63 CKAP2L TBX1 NDUFAF6 PEX3 ACADVL GPC3 PIGP PEX10 RPL15 CANT1 NUP107 CDK13 MGP ELN CEP57 NONO CASK DGCR6 RREB1 GPC6 SLC19A3 DYNC2LI1 SPECC1L RAI1 PET100 MASP1 BCOR CACNA1D ERCC2 KAT6B NOTCH1 XYLT1 MMP14 PIK3R2 VIPAS39 WASHC5 TAPT1 GP1BB GLI3 TKT KRAS ARHGAP31 RFC2 PIEZO2 ERBB3 MAPK1 ERCC3 SLC19A2 WNT4 SNRPB PUF60 NDUFV1 PTPN11 PALB2 PEX1 FIBP RARB PIGL THOC6 EP300 ADAMTS10 NEK9 SLC25A22 SF3B4 COX15 LONP1 NDUFA10 DGCR8 PKD1L1 KCNA1 DLL4 SPECC1L NDUFS1 DNAJC19 FBN2 FLI1 PAH SMC3 IFT172 TBX1 CNTNAP2 CITED2 PEX26 PIK3R2 INSR GLI3 CD96 FGFR2 FBN1 LIMK1 CHRM3 TBL2 RIT1 SHANK3 COL11A2 NDUFA9 MPLKIP CDC45 SCN2A WNT4 MEIS2 RPS26 GATA5 GATA6 NDUFAF2 TKT PEX14 ATRX CHD7 SOS1 HIRA FOXRED1 AFF4 NSD2 GDF3 ARCN1 RAD21 KMT2D EFTUD2 GATA4 WT1 CLIP2 MED12 SLC19A2 AKT3 CHD4 SETD5 NIPBL SIK1 WDR60 NRXN1 MEOX1 XYLT2 ADAMTS10 DHCR7 ACVR2B FANCI NOTCH2 NDUFB11 TGDS GTF2E2 TTC37 HOXA13 TXNL4A RSPO2 TMEM260 DHCR7 FBN1 MED13L UBE3B MTFMT FOXC2 TAB2 CCDC22 NDUFA13 ROR2 NDUFS4 GTF2H5 MGAT2 SKIV2L TARS1 CCDC174 BRF1 SCN1B RBM8A ECE1 TBX1 CYTB NDUFAF5 SMAD4 LBR UBR1 TBX5 MPLKIP MEOX1 NXN TBX5 TCTN3 NKX2-5 SALL4 PDHA1 NKX2-5 CHST3 LETM1 LRP2 OTUD6B ARVCF GTF2I LARS2 NOTCH3 TFAP2B RPL11 CDKL5 FTO ARID1B JAG1 NDUFA4 IFT81 KAT6A GATA6 NUP107 PPP2R5D DDX11 RPS19 NDUFA2 TBX1 EOGT PUF60 GDF6 ZEB2 FLNB MLXIPL HRAS TBX3 WDR26 TBX3 NR2F2 KAT6A PACS1 FIG4 BAZ1B PIK3CA SLC29A3 DPH1 NDUFS8 CPLX1 GPC3 YY1AP1 PEX16 VPS13B KAT6B CACNA1C MYRF ECHS1 GATA4 ROR2 TTC7A FADD TTC7A CTU2 HCCS HYLS1 LIPT1 VAC14 NONO SALL1 ARX PNKP CRKL TMEM94 SURF1 TALDO1 NIPBL PLAGL1 RERE GTF2IRD1 CREBBP
Protein Mutations 1
T1405N
SNP 0