SNPMiner Trials: Clinical Trial Report
Report for Clinical Trial NCT03548220
Developed by Shray Alag, 2019.
SNP Clinical Trial Gene
Study AG348-C-006 will evaluate the efficacy and safety of orally administered AG-348 as
compared with placebo in participants with pyruvate kinase deficiency (PKD), who are not
regularly receiving blood transfusions. Participants will be randomized 1:1 to receive either
AG-348 or matching placebo. The study is comprised of two parts. During the Part 1 Dose
Optimization Period of the study, participants will start on a dose of 5 mg AG-348
administered twice daily. Over the course of Part 1 each participant's dose will be optimized
individually, up to a maximum dose of 50 milligrams (mg), twice daily. During the Part 2
Fixed-Dose Period, participants will receive AG-348 at their optimized dose from Part 1.
Name: AG-348
Description: Part 1 (Dose Optimization Period): Participants will begin by receiving 5 milligrams (mg) orally, twice a day. Each participant's dose of AG-348 may be increased to 20 mg twice a day or 50 mg twice a day depending on their response to AG-348 and their tolerance.
Part 2 (Fixed Dose Period): Last dose received in Part 1, twice daily.Type: Drug
AG-348
Name: Placebo
Description: Part 1 (Dose Optimization Period): Participants will begin by receiving placebo matching AG-348 orally, twice a day. Each participant's dose of placebo matching AG-348 may be increased to 20 mg twice a day or 50 mg twice a day depending on their response to the placebo matching AG-348 and their tolerance.
Part 2 (Fixed Dose Period): Last dose received in Part 1, twice daily.Type: Drug
Placebo
Primary Outcomes
Measure: Percentage of Participants Achieving a Hemoglobin Response (HR) in Part 2
Time: Baseline, Part 2: Weeks 16, 20, 24
Secondary Outcomes
Measure: Change from Baseline in Hb Concentration at Weeks 16, 20 and 24 in Part 2
Time: Baseline, Part 2: Weeks 16, 20, 24
Measure: Maximum Change from Baseline in Hb Concentration
Time: Baseline, Part 2, up to Week 24
Measure: Time to Achieve an Increase in Hb Concentration of 1.5 g/dL or More
Time: Baseline, Part 2, up to Week 24
Measure: Change from Baseline in Bilirubin at Weeks 16, 20 and 24 in Part 2
Time: Baseline, Part 2: Weeks 16, 20, 24
Measure: Change from Baseline in Lactic Acid Dehydrogenase (LDH) at Weeks 16, 20 and 24 in Part 2
Time: Baseline, Part 2: Weeks 16, 20, 24
Measure: Change from Baseline in Haptoglobin at Weeks 16, 20 and 24 in Part 2
Time: Baseline, Part 2: Weeks 16, 20, 24
Measure: Change from Baseline in Reticulocyte Percentages at Weeks 16, 20 and 24 in Part 2
Time: Baseline, Part 2: Weeks 16, 20, 24
Measure: Change from Baseline in Pyruvate Kinase Deficiency Diary (PKDD) Score
Time: Baseline, up to Week 24
Measure: Change from Baseline in Pyruvate Kinase Deficiency Impact Assessment (PKDIA) Score
Time: Baseline, up to Week 24
Measure: Percentage of Participants Experiencing an Adverse Event
Time: Through 4 weeks after last dose (approximately Part 2, Week 31)
Measure: Percentage of Participants Experiencing an Adverse Event of Special Interest (AESI)
Time: Through 4 weeks after last dose (approximately Part 2, Week 31)
Measure: Change from Baseline in Bone Mineral Density Z-Score at Week 24 in Part 2
Time: Baseline, Part 2: Week 24
Measure: Change from Baseline in Bone Mineral Density T-Score at Week 24 in Part 2
Time: Baseline, Part 2: Week 24
Measure: Area Under the Curve From Time 0 to the Last Quantifiable Concentration [AUC(0-last)] for AG-348 at Week 12
Time: Week 12, pre-dose, 30 minutes and 1, 2, 4 and 8 hours post-dose
Measure: Maximum Plasma Concentration (Cmax) for AG-348
Time: Week 12, pre-dose, 30 minutes and 1, 2, 4 and 8 hours post-dose
Measure: Time to Cmax (Tmax) for AG-348
Time: Week 12, pre-dose, 30 minutes and 1, 2, 4 and 8 hours post-dose
Measure: Time to Last Measurable Concentration (Tlast) for AG-348
Time: Week 12, pre-dose, 30 minutes and 1, 2, 4 and 8 hours post-dose
Purpose: Treatment
Allocation: Randomized
Parallel Assignment
There is one SNP
SNPs
1 R479H
- Adequate organ function;
- Women of reproductive potential, have a negative serum pregnancy test;
- For women of reproductive potential as well as men with partners who are women of
reproductive potential, be abstinent as part of their usual lifestyle, or agree to use
2 forms of contraception, 1 of which must be considered highly effective, from the
time of giving informed consent, during the study, and for 28 days (both men and
women) following the last dose of study treatment;
- Willing to comply with all study procedures for the duration of the study;
Exclusion Criteria:
- Homozygous for the R479H mutation or have 2 non-missense mutations, without the
presence of another missense mutation, in the PKLR gene;
- Significant medical condition that confers an unacceptable risk to participating in
the study, and/or that could confound the interpretation of the study data;
- Splenectomy scheduled during the study treatment period or have undergone splenectomy
within 12 months prior to signing informed consent;
- Currently enrolled in another therapeutic clinical trial involving ongoing therapy
with any investigational or marketed product or placebo. --- R479H ---
HPO Nodes
HPO:Hemolytic anemia
Genes 104
COL4A1 CFH GPI KRAS TPP2 RAG1 HK1 ATP7B NRAS ANK1 WAS GALT WIPF1 TNFSF12 NT5C3A HLA-DRB1 PIEZO1 SPTA1 SPTB GPX1 GATA1 ABCB6 CASP10 NBN NLRP1 DGKE CD46 ADAMTS13 NHLRC2 HMOX1 CPOX LCAT PFKM CFI FAS ADA FASLG CR2 ADAR RFX5 RFXAP PGK1 ZAP70 SLC2A1 STAT1 RHAG PGM3 STAT3 GSS SLC4A1 HELLPAR CASK TNFRSF4 TTC7A STIM1 RASGRP1 PIGT CD3G KMT2D ICOS BPGM PIGA LAT CD19 MS4A1 CIITA GCLC RFXANK GYPC BTNL2 NFKB1 NFKB2 FECH CD40LG PKLR TNFRSF13C CD59 KCNN4 TNFRSF13B AK1 PRKCD ATP11C CD81 ALAD CTLA4 TNFAIP3 LRBA UROD UROS HBA1 HBA2 ALDOA HBB IL2RA G6PD KDM6A ABCG5 ABCG8 EPB41 EPB42 GP1BA PNP FOXP3 TPI1 hr>Microangiopathic hemolytic anemia
Genes 5
CFI CFH CD46 ADAMTS13 HELLPAR hr>