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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 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

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

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:
Abnormal cardiac septum morphology
Genes 657
PEX1 MRAS LETM1 ARID1B GTF2H5 UBR1 NONO STXBP1 EPHB4 RPL35A ALKBH8 UPF3B BCOR COX15 NIPBL PORCN STRA6 CRELD1 PIGL MMP2 MTFMT PHGDH WDPCP SALL1 RMRP HYMAI GLI1 TAB2 NSDHL SURF1 DHCR7 TBX5 FBN1 TBX1 MYH6 SLC19A3 C2CD3 ZMPSTE24 WNT4 KCNA1 PEX19 ADK ECE1 IFT172 ERCC4 TXNL4A CTU2 FLNA SMC3 VIPAS39 COL11A1 PAH NKX2-6 OTUD6B GNAO1 RAB23 DYNC2LI1 GLI3 PLAGL1 CDKL5 FANCF FTO LARS2 TBX1 FOXF1 NKX2-1 HOXD13 DGCR2 FBN2 RPS17 KIAA0586 ALG8 HIRA SLC19A2 PKD1L1 ALG9 CEP57 MLXIPL BRAF PUF60 MCTP2 CLIP2 NRXN1 MYPN KAT6B PUF60 CTBP1 EP300 BUB1B EXT2 ESS2 GPX4 SHANK3 BRAF GATA6 KAT6B NDUFS1 STRADA TLL1 KIF11 PEX5 SF3B4 MMP21 TRAIP COL5A1 EOGT YY1AP1 TBL2 SNRPB NPHP3 FANCI NKX2-5 ARVCF ACTC1 B3GLCT DGCR6 SEC24C FANCG NDUFAF2 ADAMTS10 MEOX1 ARID2 TBX5 TSFM CITED2 SH2B1 FLI1 MGP MED12 NKX2-5 CHST14 JMJD1C ASCC1 FBN1 FGFR1 ECHS1 COMT NONO ATIC ZIC3 CACNA1D GPC6 CWC27 SKI GPC3 TTC37 RNU4ATAC SRCAP LONP1 GTF2I CDC45 TBX22 BMP2 MGAT2 SLC25A22 MEIS2 PEX14 FLNB SPECC1L TBX2 LRP5 PEX2 DNMT3A FOXC2 PEX10 PIEZO2 MPL RPS26 VPS33B MPLKIP PRDM16 NUP107 LARP7 RECQL4 PACS1 CCDC174 PIK3R2 RNU4ATAC GATA4 GATA4 SOX4 SDHA NAA10 ARCN1 FANCB TBX3 KMT2A RAD51 SHOC2 DPF2 GABRD GP1BB DTNA FANCD2 COG1 SKIV2L ZDHHC9 BCOR TACO1 GATA6 CCNQ FGFR3 NOTCH2 CHD7 SEMA3E IGBP1 TTC7A CHD4 CRB2 RPL5 LZTR1 BRCA1 MAP2K1 ZIC3 AMMECR1 PACS2 ACVR2B POLR1A LETM1 NEK1 NDUFAF5 MAP2K2 WHCR PEX11B KRAS BRAF ASXL1 TP63 XRCC2 FIG4 SYNE1 MEIS2 NIPBL GPC4 COL1A1 FGFR2 ARX HAAO STK4 ZEB2 FOXC1 RERE HNRNPU TMEM94 PCGF2 PEX16 NDUFA12 DGCR8 NDUFA13 GATA6 EVC2 SPECC1L FANCL MEGF8 PACS1 LMNA FOXF1 RBM10 RREB1 MASP1 AGGF1 GYG1 NF1 LONP1 GTF2E2 NOTCH1 MAP2K1 PIGA GDF6 GJA1 GJA1 MYT1 CCDC22 CTCF ARX GDF3 MTFMT TBX1 CANT1 NEK9 WDR60 USP9X EVC2 ARHGAP31 GLI3 CKAP2L LMNA AFF4 TFAP2B CEP290 GPC3 RPL15 ATP6V1E1 FANCB TRIM8 PTPN11 MED13L NDUFB11 SETD5 DYNC2LI1 GATA6 DSG1 HYLS1 KRAS XYLT2 ADAMTS10 FOXRED1 HRAS CREBBP LTBP4 NFE2L2 RAD51C GATA5 FLNA APC2 BMP2 G6PC3 COL5A2 NSD1 SETD2 SON BAZ1B SOS2 NDUFA4 ERCC2 ECHS1 RPL11 BSCL2 CRELD1 TXNL4A NKX2-5 PSMD12 MEOX1 MED12 ATP6V0A2 TARS1 NXN KMT2D KIF15 RFWD3 MYH7 ATRX RFC2 TKT CKAP2L WASHC5 RERE DACT1 DLL4 IFT81 PTEN GATA4 NDUFS3 MMP14 MAP2K2 GDF1 UBE3B RAP1A LBR IRX5 RPL27 FGFR2 SIX6 SLC19A2 PCNT ATN1 BMPR1A NDUFS4 PIGQ SIK1 TBX1 PIGL GTF2IRD1 TGFBR1 ALG12 COL11A2 SALL4 FIBP ANK1 MPLKIP SMC3 FANCI SMARCE1 UMPS NDUFS7 MKKS DVL3 AUTS2 SOS1 NSD2 PTPN11 RARB KIF7 CCBE1 SLC29A3 RNF113A GATA4 EFTUD2 MAD2L2 ATP6V0A2 PEX3 SPECC1L MGP SCN2A ROBO4 SETD5 NAA10 PIGP CFC1 TTC7A PQBP1 MYRF KAT6A GATA6 INTU FANCA STAT1 NR2F2 ABL1 AMER1 TALDO1 FGFRL1 ANKRD11 CDK13 CD96 MAP3K7 SLX4 CACNA1C RPL10 RAD21 TRIP13 GLA STAG2 B3GLCT NOTCH2 JAG1 TAPT1 TBX20 KDM6A NEUROD2 PTF1A RAP1B KRAS GDF1 MKS1 ROR2 HSPG2 TMCO1 MAP3K7 FLNA WNT4 THOC6 NDUFS2 ELN FLCN KMT2D NOTCH1 PALB2 GATA4 SIK3 COX7B PEX26 TGFB3 TALDO1 BUB3 SMG9 PPP1CB FANCE FUT8 WT1 NR2F2 FANCM HCCS B3GALT6 RAF1 DNMT3A KDM6A BRAF SLC29A3 HDAC8 ELN PDHA1 HCCS PIK3CA NOTCH2 B3GALT6 DSE PLD1 PIGN FGFR3 NCAPG2 BBS2 RAC1 PIGN KAT6B VPS13B SMAD4 NODAL UFD1 KANSL1 CCND2 PALB2 TBX4 SMAD4 FIG4 LRP2 ACADVL KAT6A NDUFA2 ABCD4 GJA1 OTUD6B HOXA13 TTC37 IGF1R NSD2 WDR35 MYH7 WASHC5 ERBB3 CHST3 FADD TP63 RBM8A NUP107 EFTUD2 PEX1 CASK BUB1 LRP2 XYLT1 PEX13 ESCO2 PIEZO1 EHMT1 LYST RAF1 PEX12 CRKL NKX2-5 CPLX1 NDUFAF6 TRRAP SETBP1 PIGO SLC25A24 SOX2 BRAF POLA1 GJA1 RSPO2 MED25 TBX3 EXOC6B NELFA NDUFA10 ZMPSTE24 TMEM260 NDUFV2 POR PAX3 NKX2-5 XYLT2 CHRM3 KDM6A ERCC3 LIMK1 PQBP1 EVC NDUFV1 FADD CDK10 NSD1 CHST3 MED12 RPS19 TRIP4 BRCA2 ATP6V1A DHCR7 RIT1 SMC1A TCTN3 COX7B TRIO PIK3R2 LIPT1 LTBP2 GPC4 PIGN PQBP1 NEK9 KDM5B CACNA1D RAD21 PEX19 DNAJC19 CDC42 UBR1 PEX16 DPH1 VAC14 TBX1 MAPK1 ASXL2 FLNA SNRPB NDUFA9 NEK1 NKX2-5 NOTCH3 UBE2A NPHP3 NKX2-1 GATA6 HSPA9 TGDS PEX6 FKTN PNKP ROR2 COX7B AKT3 NFIX HRAS SEMA3E MYL2 SOX2 USP9X CCDC22 PET100 FANCC SALL1 BCR CNTNAP2 CHD7 BRIP1 PPP2CA NDUFB11 STAMBP TGFBR2 KCNAB2 MYMK CEP57 MYBPC3 CITED2 EVC TBX1 DDX11 UBE2T B3GAT3 SMN1 GATA1 PIK3R2 TGDS NDUFS8 RBM8A
Atrial septal defect
Genes 355
COL5A2 MRAS LETM1 ARID1B UBR1 NONO EPHB4 SON BAZ1B UPF3B BCOR RPL11 STRA6 MED12 NXN MMP2 KIF15 RFWD3 MYH7 RFC2 TKT WASHC5 PHGDH DACT1 PTEN SALL1 MMP14 GDF1 GLI1 UBE3B IRX5 RPL27 SLC19A2 DHCR7 PCNT BMPR1A TBX5 MYH6 TBX1 C2CD3 ZMPSTE24 GTF2IRD1 TGFBR1 ALG12 SALL4 ADK ECE1 ANK1 ERCC4 SMC3 FANCI SMARCE1 UMPS TXNL4A CTU2 MKKS SMC3 DVL3 AUTS2 COL11A1 NSD2 CCBE1 OTUD6B SLC29A3 GATA4 EFTUD2 MAD2L2 RAB23 DYNC2LI1 SPECC1L GLI3 FANCF ROBO4 SETD5 NAA10 FOXF1 PQBP1 MYRF KAT6A NKX2-1 FANCA STAT1 ABL1 AMER1 FBN2 TALDO1 RPS17 FGFRL1 CDK13 SLX4 KIAA0586 CACNA1C HIRA TRIP13 SLC19A2 NOTCH2 CEP57 JAG1 MLXIPL BRAF TBX20 KDM6A CLIP2 PTF1A KAT6B KRAS GDF1 ROR2 HSPG2 TMCO1 CTBP1 MAP3K7 EP300 ELN BUB1B FLCN GPX4 KMT2D NOTCH1 BRAF PALB2 GATA4 SIK3 COX7B TGFB3 KAT6B TALDO1 BUB3 STRADA TLL1 KIF11 MMP21 TRAIP PPP1CB FANCE WT1 FANCM HCCS COL5A1 EOGT TBL2 SNRPB DNMT3A KDM6A NPHP3 FANCI HDAC8 ELN ARVCF ACTC1 B3GLCT SEC24C FANCG B3GALT6 ARID2 TBX5 DSE TSFM PLD1 FGFR3 NCAPG2 SH2B1 MED12 NKX2-5 CHST14 BBS2 JMJD1C ASCC1 RAC1 FGFR1 PIGN KAT6B SMAD4 COMT NODAL UFD1 KANSL1 NONO ATIC TBX4 GPC6 TTC37 RNU4ATAC SRCAP LONP1 GTF2I ACADVL CDC45 TBX22 BMP2 KAT6A ABCD4 GJA1 OTUD6B MEIS2 FLNB SPECC1L TBX2 IGF1R DNMT3A NSD2 WDR35 WASHC5 RBM8A VPS33B EFTUD2 BUB1 LARP7 PACS1 ESCO2 PIEZO1 PIK3R2 GATA4 LYST RAF1 CRKL FANCB NKX2-5 KMT2A RAD51 SHOC2 CPLX1 TRRAP SETBP1 GP1BB PIGO FANCD2 SLC25A24 SKIV2L ZDHHC9 BRAF POLA1 GJA1 GATA6 FGFR3 CHD7 SEMA3E CHD4 NELFA ZMPSTE24 RPL5 TMEM260 BRCA1 MAP2K1 ZIC3 POR AMMECR1 PAX3 LETM1 NEK1 MAP2K2 WHCR CHRM3 LIMK1 PQBP1 EVC KRAS BRAF ASXL1 CDK10 NSD1 CHST3 XRCC2 MED12 RPS19 TRIP4 FIG4 BRCA2 ATP6V1A MEIS2 DHCR7 NIPBL RIT1 SMC1A COL1A1 FGFR2 GPC4 PIGN PQBP1 HAAO STK4 ZEB2 NEK9 KDM5B FOXC1 RERE TMEM94 PCGF2 CACNA1D RAD21 PEX19 VAC14 MAPK1 EVC2 ASXL2 SPECC1L FANCL MEGF8 PACS1 LMNA FOXF1 RBM10 RREB1 MASP1 AGGF1 NKX2-5 NF1 UBE2A NPHP3 MAP2K1 PIGA NKX2-1 GATA6 HSPA9 GJA1 FKTN CCDC22 CTCF USP9X EVC2 COX7B NFIX ARHGAP31 HRAS LMNA USP9X CCDC22 FANCC CEP290 GPC3 ATP6V1E1 BCR BRIP1 PTPN11 STAMBP MED13L NDUFB11 TGFBR2 GATA6 KRAS CEP57 XYLT2 CREBBP CITED2 EVC LTBP4 NFE2L2 TBX1 RAD51C GATA5 UBE2T B3GAT3 SMN1 TGDS G6PC3
Atrioventricular canal defect
Genes 50
MAP3K7 LONP1 CDC45 PKD1L1 GJA1 PUF60 CRELD1 GDF1 GATA6 CRELD1 EVC2 NEK1 WASHC5 FOXF1 WDPCP GATA4 GATA4 GATA4 GATA6 GDF1 GLI1 MMP21 NR2F2 CCDC22 RAF1 TBX1 KDM6A BRAF FLNA FANCB TBX5 PTPN11 ACVR2B NKX2-6 NKX2-5 GATA4 DYNC2LI1 DYNC2LI1 EVC HYLS1 GLI3 KAT6B CFC1 ZIC3 DHCR7 GATA6 GATA1 INTU NR2F2 TRIO
Secundum atrial septal defect
Genes 9
TBX5 NF1 PTF1A RPL11 TRIP4 MYH6 GATA6 GDF1 NKX2-5
Ventricular septal defect
Genes 390
PEX1 LETM1 ARID1B GTF2H5 UBR1 NONO STXBP1 RPL35A ALKBH8 BCOR COX15 NIPBL PORCN STRA6 PIGL MMP2 MTFMT PHGDH HYMAI GLI1 TAB2 SURF1 DHCR7 TBX5 FBN1 TBX1 SLC19A3 C2CD3 WNT4 KCNA1 PEX19 ECE1 IFT172 TXNL4A CTU2 SMC3 VIPAS39 PAH OTUD6B GNAO1 RAB23 DYNC2LI1 GLI3 PLAGL1 CDKL5 FTO LARS2 TBX1 NKX2-1 DGCR2 FBN2 HIRA SLC19A2 PKD1L1 CEP57 MLXIPL CLIP2 NRXN1 KAT6B PUF60 CTBP1 EP300 EXT2 ESS2 SHANK3 NDUFS1 PEX5 SF3B4 TRAIP EOGT YY1AP1 TBL2 SNRPB FANCI ARVCF B3GLCT DGCR6 SEC24C NDUFAF2 ADAMTS10 MEOX1 TBX5 CITED2 FLI1 MGP JMJD1C FBN1 FGFR1 ECHS1 COMT NONO CACNA1D GPC6 CWC27 GPC3 TTC37 LONP1 GTF2I CDC45 MGAT2 SLC25A22 MEIS2 PEX14 FLNB SPECC1L LRP5 PEX2 FOXC2 PEX10 PIEZO2 RPS26 VPS33B MPLKIP NUP107 CCDC174 PIK3R2 RNU4ATAC GATA4 SOX4 SDHA NAA10 ARCN1 TBX3 KMT2A SHOC2 GP1BB DTNA SKIV2L TACO1 GATA6 NOTCH2 CHD7 SEMA3E IGBP1 TTC7A CHD4 CRB2 RPL5 MAP2K1 ZIC3 ACVR2B NEK1 NDUFAF5 WHCR PEX11B BRAF ASXL1 TP63 FIG4 MEIS2 NIPBL GPC4 ARX ZEB2 RERE TMEM94 PEX16 NDUFA12 DGCR8 NDUFA13 EVC2 SPECC1L PACS1 FOXF1 RREB1 MASP1 LONP1 GTF2E2 NOTCH1 GDF6 GJA1 MYT1 CCDC22 ARX GDF3 MTFMT CANT1 NEK9 WDR60 ARHGAP31 GLI3 CKAP2L TFAP2B CEP290 GPC3 RPL15 TRIM8 PTPN11 NDUFB11 SETD5 GATA6 DSG1 HYLS1 KRAS ADAMTS10 FOXRED1 HRAS CREBBP GATA5 BMP2 BAZ1B NDUFA4 ERCC2 ECHS1 RPL11 NKX2-5 PSMD12 MEOX1 TARS1 NXN ATRX RFC2 TKT CKAP2L WASHC5 DLL4 IFT81 NDUFS3 MMP14 GDF1 UBE3B LBR FGFR2 SIX6 SLC19A2 NDUFS4 PIGQ SIK1 TBX1 PIGL GTF2IRD1 COL11A2 SALL4 FIBP MPLKIP SMC3 UMPS NDUFS7 MKKS DVL3 SOS1 RARB CCBE1 SLC29A3 RNF113A PEX3 SPECC1L MGP SCN2A SETD5 NAA10 PIGP TTC7A MYRF KAT6A GATA6 ABL1 AMER1 FGFRL1 ANKRD11 CDK13 CD96 CACNA1C RAD21 JAG1 TAPT1 KDM6A NEUROD2 GDF1 ROR2 WNT4 THOC6 NDUFS2 ELN KMT2D GATA4 PEX26 TGFB3 TALDO1 SMG9 PPP1CB WT1 NR2F2 HCCS SLC29A3 HDAC8 ELN PDHA1 PIK3CA B3GALT6 RAC1 KAT6B VPS13B SMAD4 NODAL UFD1 KANSL1 CCND2 PALB2 FIG4 LRP2 ACADVL KAT6A NDUFA2 GJA1 OTUD6B HOXA13 TTC37 IGF1R NSD2 WASHC5 ERBB3 CHST3 FADD TP63 RBM8A NUP107 EFTUD2 PEX1 CASK LRP2 XYLT1 PEX13 ESCO2 PEX12 CRKL NKX2-5 CPLX1 NDUFAF6 SOX2 POLA1 RSPO2 TBX3 NDUFA10 TMEM260 NDUFV2 XYLT2 CHRM3 ERCC3 LIMK1 PQBP1 EVC NDUFV1 FADD NSD1 MED12 RPS19 DHCR7 RIT1 SMC1A TCTN3 PIK3R2 LIPT1 LTBP2 GPC4 NEK9 CACNA1D RAD21 DNAJC19 PEX16 DPH1 VAC14 TBX1 MAPK1 SNRPB NDUFA9 NKX2-5 NOTCH3 UBE2A NKX2-1 TGDS PEX6 PNKP ROR2 COX7B AKT3 HRAS SOX2 CCDC22 PET100 SALL1 BCR CNTNAP2 STAMBP TBX1 DDX11 SMN1 PIK3R2 TGDS NDUFS8