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A Dose-Finding Study of AG-348 in Sickle Cell Disease

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04000165
Recruitment Status : Completed
First Posted : June 27, 2019
Results First Posted : July 12, 2022
Last Update Posted : July 12, 2022
Sponsor:
Collaborators:
National Heart, Lung, and Blood Institute (NHLBI)
Agios Pharmaceuticals, Inc.
Information provided by (Responsible Party):
Swee Lay Thein, M.D., National Institutes of Health Clinical Center (CC)

Study Type Interventional
Study Design Allocation: N/A;   Intervention Model: Sequential Assignment;   Masking: None (Open Label);   Primary Purpose: Basic Science
Condition Sickle Cell Disease
Intervention Drug: AG-348
Enrollment 17
Recruitment Details Participants were enrolled at the National Institutes of Health in Bethesda, Maryland from July 2019 to June 2021.
Pre-assignment Details  
Arm/Group Title AG-348 in Participants With Sickle Cell Disease
Hide Arm/Group Description Intra-patient dose escalating study, starting with 5 mg twice a day, increasing to 20 mg twice a day, to maximum 50 mg or 100 mg twice a day. Dosing period is every 2 weeks at each dose level. Dose taper will start on Day 42 (50 mg) or Day 56 (100 mg) with dose reduced over 12 to 15 days.
Period Title: Overall Study
Started 17
Completed Study at 50 mg Dose 7
Escalated to 100 mg 10
Completed 15
Not Completed 2
Reason Not Completed
Physician Decision             1
Withdrawal by Subject             1
Arm/Group Title AG-348 in Participants With Sickle Cell Disease
Hide Arm/Group Description Intra-patient dose escalating study, starting with 5 mg twice a day, increasing to 20 mg twice a day, to maximum 50 mg or 100 mg twice a day. Dosing period is every 2 weeks at each dose level. Dose taper will start on Day 42 (50 mg) or Day 56 (100 mg) with dose reduced over 12 to 15 days.
Overall Number of Baseline Participants 17
Hide Baseline Analysis Population Description
[Not Specified]
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 17 participants
<=18 years
0
   0.0%
Between 18 and 65 years
17
 100.0%
>=65 years
0
   0.0%
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 17 participants
Female
6
  35.3%
Male
11
  64.7%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 17 participants
Hispanic or Latino
0
   0.0%
Not Hispanic or Latino
17
 100.0%
Unknown or Not Reported
0
   0.0%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 17 participants
American Indian or Alaska Native
0
   0.0%
Asian
0
   0.0%
Native Hawaiian or Other Pacific Islander
0
   0.0%
Black or African American
17
 100.0%
White
0
   0.0%
More than one race
0
   0.0%
Unknown or Not Reported
0
   0.0%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 17 participants
17
1.Primary Outcome
Title Number Participants With Most Common Reported Drug Related Adverse Events
Hide Description To assess the clinical safety and tolerability of multiple escalating doses of AG-348, an allosteric activator of the enzyme pyruvate kinase, in subjects with stable sickle cell disease (SCD). Safety and tolerability were assessed by frequency and severity of adverse events (AEs) using Common Terminology Criteria for Adverse Events (CTCAE) 5.0.
Time Frame 14 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title AG-348 in Participants With Sickle Cell Disease
Hide Arm/Group Description:
Intra-patient dose escalating study, starting with 5 mg twice a day, increasing to 20 mg twice a day, to maximum 50 mg or 100 mg twice a day. Dosing period is every 2 weeks at each dose level. Dose taper will start on Day 42 (50 mg) or Day 56 (100 mg) with dose reduced over 12 to 15 days.
Overall Number of Participants Analyzed 17
Measure Type: Count of Participants
Unit of Measure: Participants
Insomnia
6
  35.3%
Arthralgia
3
  17.6%
Hypertension
3
  17.6%
2.Primary Outcome
Title Number Participants With Serious Adverse Events That Were Possibly Drug-related Serious Adverse Events
Hide Description To assess the clinical safety and tolerability of multiple escalating doses of AG-348, an allosteric activator of the enzyme pyruvate kinase, in subjects with stable sickle cell disease (SCD). Safety and tolerability were assessed by frequency and severity of adverse events (AEs) using Common Terminology Criteria for Adverse Events (CTCAE) 5.0.
Time Frame 14 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title AG-348 in Participants With Sickle Cell Disease
Hide Arm/Group Description:
Intra-patient dose escalating study, starting with 5 mg twice a day, increasing to 20 mg twice a day, to maximum 50 mg or 100 mg twice a day. Dosing period is every 2 weeks at each dose level. Dose taper will start on Day 42 (50 mg) or Day 56 (100 mg) with dose reduced over 12 to 15 days.
Overall Number of Participants Analyzed 17
Measure Type: Count of Participants
Unit of Measure: Participants
2
  11.8%
3.Primary Outcome
Title Number Participants With Increase of ≥ 1 g/dL in Hemoglobin
Hide Description To assess the clinical safety and tolerability of multiple escalating doses of AG-348, an allosteric activator of the enzyme pyruvate kinase, in subjects with stable sickle cell disease (SCD). Safety and tolerability were assessed by defined as a ≥ 1 g/dL increase in hemoglobin at any dose level compared to baseline.
Time Frame 14 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
One participant, withdrawn 3 days after starting the study for a pre-existing pulmonary embolus, was not evaluable for response. Intention to treat analysis.
Arm/Group Title AG-348 in Participants With Sickle Cell Disease
Hide Arm/Group Description:
Intra-patient dose escalating study, starting with 5 mg twice a day, increasing to 20 mg twice a day, to maximum 50 mg or 100 mg twice a day. Dosing period is every 2 weeks at each dose level. Dose taper will start on Day 42 (50 mg) or Day 56 (100 mg) with dose reduced over 12 to 15 days.
Overall Number of Participants Analyzed 16
Measure Type: Count of Participants
Unit of Measure: Participants
9
  56.3%
4.Secondary Outcome
Title Change in Hemoglobin at Each Dose Level of AG-348
Hide Description To assess change in hemoglobin in stable sickle cell disease participants at each dose level of AG-348
Time Frame 14 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
One participant, withdrawn 3 days after starting the study for a pre-existing pulmonary embolus, was not evaluable for response. 10 participants escalated to 100 mg dose with 1 participant self-discontinued 3 days after escalating to 100 mg dose. Intention to treat analysis.
Arm/Group Title AG-348 in Participants With Sickle Cell Disease
Hide Arm/Group Description:
Intra-patient dose escalating study, starting with 5 mg twice a day, increasing to 20 mg twice a day, to maximum 50 mg or 100 mg twice a day. Dosing period is every 2 weeks at each dose level. Dose taper will start on Day 42 (50 mg) or Day 56 (100 mg) with dose reduced over 12 to 15 days.
Overall Number of Participants Analyzed 16
Mean (Standard Error)
Unit of Measure: g/dL
Baseline Number Analyzed 16 participants
8.73  (0.51)
5 mg dose of AG-348 Number Analyzed 16 participants
0.34  (0.22)
20 mg dose AG-348 Number Analyzed 16 participants
0.76  (0.22)
50 mg dose AG-348 Number Analyzed 16 participants
1.19  (0.22)
100 mg dose AG-348 Number Analyzed 9 participants
0.92  (0.26)
End of Taper Dose AG-348 Number Analyzed 15 participants
0.34  (0.22)
End of Study AG-348 Number Analyzed 16 participants
0.37  (0.22)
5.Secondary Outcome
Title Change in Lactic Acid Dehydrogenase (LDH) at Each Dose Level of AG-348
Hide Description To assess change in lactic acid dehydrogenase (LDH) in stable sickle cell disease participants at each dose level of AG-348
Time Frame 14 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
One participant, withdrawn 3 days after starting the study for a pre-existing pulmonary embolus, was not evaluable for response. 10 participants escalated to 100 mg dose with 1 participant self-discontinued 3 days after escalating to 100 mg dose. Intention to treat analysis.
Arm/Group Title AG-348 in Participants With Sickle Cell Disease
Hide Arm/Group Description:
Intra-patient dose escalating study, starting with 5 mg twice a day, increasing to 20 mg twice a day, to maximum 50 mg or 100 mg twice a day. Dosing period is every 2 weeks at each dose level. Dose taper will start on Day 42 (50 mg) or Day 56 (100 mg) with dose reduced over 12 to 15 days.
Overall Number of Participants Analyzed 16
Mean (Standard Error)
Unit of Measure: U/L
Baseline Number Analyzed 16 participants
348.4  (51.21)
5 mg dose of AG-348 Number Analyzed 16 participants
-7.81  (27.81)
20 mg dose AG-348 Number Analyzed 16 participants
-39.94  (27.81)
50 mg dose AG-348 Number Analyzed 16 participants
-25.31  (27.81)
100 mg dose AG-348 Number Analyzed 9 participants
-37.89  (34.95)
End of Taper Dose AG-348 Number Analyzed 15 participants
20.63  (28.35)
End of Study AG-348 Number Analyzed 16 participants
30.72  (28.34)
6.Secondary Outcome
Title Change in Total Bilirubin at Each Dose Level of AG-348
Hide Description To assess change in total bilirubin in stable sickle cell disease participants at each dose level of AG-348
Time Frame 14 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
One participant, withdrawn 3 days after starting the study for a pre-existing pulmonary embolus, was not evaluable for response. 10 participants escalated to 100 mg dose with 1 participant self-discontinued 3 days after escalating to 100 mg dose. Intention to treat analysis.
Arm/Group Title AG-348 in Participants With Sickle Cell Disease
Hide Arm/Group Description:
Intra-patient dose escalating study, starting with 5 mg twice a day, increasing to 20 mg twice a day, to maximum 50 mg or 100 mg twice a day. Dosing period is every 2 weeks at each dose level. Dose taper will start on Day 42 (50 mg) or Day 56 (100 mg) with dose reduced over 12 to 15 days.
Overall Number of Participants Analyzed 16
Mean (Standard Error)
Unit of Measure: mg/dL
Baseline Number Analyzed 16 participants
1.82  (0.28)
5 mg dose of AG-348 Number Analyzed 16 participants
-0.19  (0.17)
20 mg dose AG-348 Number Analyzed 16 participants
-0.56  (0.17)
50 mg dose AG-348 Number Analyzed 16 participants
-0.77  (0.17)
100 mg dose AG-348 Number Analyzed 9 participants
-0.87  (0.2)
End Of Taper Dose AG-348 Number Analyzed 15 participants
-0.19  (0.17)
End of Study AG-348 Number Analyzed 16 participants
0.1  (0.17)
7.Secondary Outcome
Title Change in Absolute Reticulocyte Count at Each Dose Level of AG-348
Hide Description To assess change in absolute reticulocyte count in stable sickle cell disease participants at each dose level of AG-348
Time Frame 14 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
One participant, withdrawn 3 days after starting the study for a pre-existing pulmonary embolus, was not evaluable for response. 10 participants escalated to 100 mg dose with 1 participant self-discontinued 3 days after escalating to 100 mg dose. Intention to treat analysis.
Arm/Group Title AG-348 in Participants With Sickle Cell Disease
Hide Arm/Group Description:
Intra-patient dose escalating study, starting with 5 mg twice a day, increasing to 20 mg twice a day, to maximum 50 mg or 100 mg twice a day. Dosing period is every 2 weeks at each dose level. Dose taper will start on Day 42 (50 mg) or Day 56 (100 mg) with dose reduced over 12 to 15 days.
Overall Number of Participants Analyzed 16
Mean (Standard Error)
Unit of Measure: K/mcL
Baseline Number Analyzed 16 participants
196.44  (39.88)
5 mg dose of AG-348 Number Analyzed 16 participants
-20.97  (13.95)
20 mg dose AG-348 Number Analyzed 16 participants
-20.72  (13.95)
50 mg dose AG-348 Number Analyzed 16 participants
-44.99  (13.95)
100 mg dose AG-348 Number Analyzed 9 participants
-34.1  (16.82)
End of Taper Dose AG-348 Number Analyzed 15 participants
-13.77  (14.22)
End of Study AG-348 Number Analyzed 16 participants
8.1  (14.22)
8.Secondary Outcome
Title Change in Aspartate Aminotransferase (AST) at Each Dose Level of AG-348
Hide Description To assess change in aspartate aminotransferase (AST) in stable sickle cell disease participants at each dose level of AG-348
Time Frame 14 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
One participant, withdrawn 3 days after starting the study for a pre-existing pulmonary embolus, was not evaluable for response. 10 participants escalated to 100 mg dose with 1 participant self-discontinued 3 days after escalating to 100 mg dose. Intention to treat analysis.
Arm/Group Title AG-348 in Participants With Sickle Cell Disease
Hide Arm/Group Description:
Intra-patient dose escalating study, starting with 5 mg twice a day, increasing to 20 mg twice a day, to maximum 50 mg or 100 mg twice a day. Dosing period is every 2 weeks at each dose level. Dose taper will start on Day 42 (50 mg) or Day 56 (100 mg) with dose reduced over 12 to 15 days.
Overall Number of Participants Analyzed 16
Mean (Standard Error)
Unit of Measure: U/L
Baseline Number Analyzed 16 participants
33.88  (5.94)
5 mg dose of AG-348 Number Analyzed 16 participants
-3.31  (3.43)
20 mg dose AG-348 Number Analyzed 16 participants
-3.37  (3.43)
50 mg dose AG-348 Number Analyzed 16 participants
-2  (3.43)
100 mg dose AG-348 Number Analyzed 9 participants
-3.54  (4.13)
End of Taper Dose AG-348 Number Analyzed 15 participants
-2.49  (3.49)
End of Study AG-348 Number Analyzed 16 participants
3.02  (3.49)
9.Secondary Outcome
Title Change in Mean Corpuscular Volume (MCV) at Each Dose Level of AG-348
Hide Description To assess change in mean corpuscular volume (MCV) in stable sickle cell disease participants at each dose level of AG-348
Time Frame 14 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
One participant, withdrawn 3 days after starting the study for a pre-existing pulmonary embolus, was not evaluable for response. 10 participants escalated to 100 mg dose with 1 participant self-discontinued 3 days after escalating to 100 mg dose. Intention to treat analysis.
Arm/Group Title AG-348 in Participants With Sickle Cell Disease
Hide Arm/Group Description:
Intra-patient dose escalating study, starting with 5 mg twice a day, increasing to 20 mg twice a day, to maximum 50 mg or 100 mg twice a day. Dosing period is every 2 weeks at each dose level. Dose taper will start on Day 42 (50 mg) or Day 56 (100 mg) with dose reduced over 12 to 15 days.
Overall Number of Participants Analyzed 16
Mean (Standard Error)
Unit of Measure: fL
Baseline Number Analyzed 16 participants
103.32  (7.42)
5 mg dose of AG-348 Number Analyzed 16 participants
-0.5  (0.8)
20 mg dose AG-348 Number Analyzed 16 participants
0.52  (0.8)
50 mg dose AG-348 Number Analyzed 16 participants
0.42  (0.8)
100 mg dose AG-348 Number Analyzed 9 participants
1.98  (1.01)
End of Taper Dose AG-348 Number Analyzed 15 participants
-0.25  (0.84)
End of Study AG-348 Number Analyzed 16 participants
-0.64  (0.82)
10.Secondary Outcome
Title Change in Fetal Hemoglobin at Each Dose Level of AG-348
Hide Description To assess the change in fetal hemoglobin (HbF) in stable sickle cell disease participants at each dose level of AG-348
Time Frame 14 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
One participant, withdrawn 3 days after starting the study for a pre-existing pulmonary embolus, was not evaluable for response. 10 participants escalated to 100 mg dose with 1 participant self-discontinued 3 days after escalating to 100 mg dose. Intention to treat analysis.
Arm/Group Title AG-348 in Participants With Sickle Cell Disease
Hide Arm/Group Description:
Intra-patient dose escalating study, starting with 5 mg twice a day, increasing to 20 mg twice a day, to maximum 50 mg or 100 mg twice a day. Dosing period is every 2 weeks at each dose level. Dose taper will start on Day 42 (50 mg) or Day 56 (100 mg) with dose reduced over 12 to 15 days.
Overall Number of Participants Analyzed 16
Mean (Standard Error)
Unit of Measure: Percent HbF
Baseline Number Analyzed 16 participants
20.39  (4.26)
5 mg dose of AG-348 Number Analyzed 16 participants
-0.42  (0.49)
20 mg dose AG-348 Number Analyzed 16 participants
-1.02  (0.49)
50 mg dose AG-348 Number Analyzed 16 participants
-1.31  (0.49)
100 mg dose AG-348 Number Analyzed 9 participants
-0.34  (0.56)
End of Taper Dose AG-348 Number Analyzed 15 participants
0.19  (0.47)
End of Study AG-348 Number Analyzed 16 participants
0.81  (0.47)
11.Secondary Outcome
Title Percent Change From Baseline of 2,3-DPG at Each Dose Level of AG-348
Hide Description To understand the mechanisms of action of AG- 348 on the glycolytic pathway in sickle cell disease through laboratory studies of specific pharmacodynamics of 2,3-DPG at each dose level of AG-348.
Time Frame 14 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
One participant, withdrawn 3 days after starting the study for a pre-existing pulmonary embolus, was not evaluable for response. 10 participants escalated to 100 mg dose with 1 participant self-discontinued 3 days after escalating to 100 mg dose. Intention to treat analysis.
Arm/Group Title AG-348 in Participants With Sickle Cell Disease
Hide Arm/Group Description:
Intra-patient dose escalating study, starting with 5 mg twice a day, increasing to 20 mg twice a day, to maximum 50 mg or 100 mg twice a day. Dosing period is every 2 weeks at each dose level. Dose taper will start on Day 42 (50 mg) or Day 56 (100 mg) with dose reduced over 12 to 15 days.
Overall Number of Participants Analyzed 16
Mean (Standard Error)
Unit of Measure: percent change
5 mg Dose AG-348 Number Analyzed 16 participants
-3.74  (3.65)
20 mg Dose AG-348 Number Analyzed 16 participants
-16.08  (3.65)
50 mg Dose AG-348 Number Analyzed 16 participants
-23.49  (3.65)
100 mg Dose AG-348 Number Analyzed 9 participants
-24.13  (4.12)
End of Taper Dose AG-348 Number Analyzed 15 participants
1.97  (3.68)
End of Study AG-348 Number Analyzed 16 participants
9.11  (3.68)
12.Secondary Outcome
Title Percent Change From Baseline of Adenosine Triphosphate (ATP) at Each Dose Level of AG-348
Hide Description To understand the mechanisms of action of AG- 348 on the glycolytic pathway in sickle cell disease through laboratory studies of specific pharmacodynamics of adenosine triphosphate (ATP) at each dose level of AG-348.
Time Frame 14 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
One participant, withdrawn 3 days after starting the study for a pre-existing pulmonary embolus, was not evaluable for response. 10 participants escalated to 100 mg dose with 1 participant self-discontinued 3 days after escalating to 100 mg dose. Intention to treat analysis.
Arm/Group Title AG-348 in Participants With Sickle Cell Disease
Hide Arm/Group Description:
Intra-patient dose escalating study, starting with 5 mg twice a day, increasing to 20 mg twice a day, to maximum 50 mg or 100 mg twice a day. Dosing period is every 2 weeks at each dose level. Dose taper will start on Day 42 (50 mg) or Day 56 (100 mg) with dose reduced over 12 to 15 days.
Overall Number of Participants Analyzed 16
Mean (Standard Error)
Unit of Measure: percent change
5 mg Dose AG-348 Number Analyzed 16 participants
13.68  (6.29)
20 mg Dose AG-348 Number Analyzed 16 participants
26.95  (6.29)
50 mg Dose AG-348 Number Analyzed 16 participants
33.43  (6.29)
100 mg Dose AG-348 Number Analyzed 9 participants
39.84  (6.74)
End of Taper Dose AG-348 Number Analyzed 15 participants
15.51  (6.31)
End of Study AG-348 Number Analyzed 16 participants
12.03  (6.31)
13.Secondary Outcome
Title Percent Change From Baseline in Oxygen Binding p50 Value at Each Dose Level of AG-348
Hide Description Measure percent change from baseline in oxygen binding p50 value at each dose level of AG-348
Time Frame 14 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
One participant, withdrawn 3 days after starting the study for a pre-existing pulmonary embolus, was not evaluable for response. 10 participants escalated to 100 mg dose with 1 participant self-discontinued 3 days after escalating to 100 mg dose. Intention to treat analysis.
Arm/Group Title AG-348 in Participants With Sickle Cell Disease
Hide Arm/Group Description:
Intra-patient dose escalating study, starting with 5 mg twice a day, increasing to 20 mg twice a day, to maximum 50 mg or 100 mg twice a day. Dosing period is every 2 weeks at each dose level. Dose taper will start on Day 42 (50 mg) or Day 56 (100 mg) with dose reduced over 12 to 15 days.
Overall Number of Participants Analyzed 16
Mean (Standard Error)
Unit of Measure: Percent Change
5 mg Dose AG-348 Number Analyzed 16 participants
0.5  (2.88)
20 mg Dose AG-348 Number Analyzed 16 participants
-2.09  (3.01)
50 mg Dose AG-348 Number Analyzed 16 participants
-3.84  (3.19)
100 mg Dose AG-348 Number Analyzed 9 participants
-4.88  (3.9)
End of Taper Dose AG-348 Number Analyzed 15 participants
7.97  (3.1)
End of Study AG-348 Number Analyzed 16 participants
10.79  (3.39)
14.Secondary Outcome
Title Percent Change in Time (Mins) at Which 50% of Red Blood Cells Are Sickled (t50) Value at Each Dose Level of AG-348
Hide Description Measure percent change in Time (mins) at which 50% of red blood cells are sickled (t50) Value at Each Dose Level of AG-348
Time Frame 14 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
One participant, withdrawn 3 days after starting the study for a pre-existing pulmonary embolus, was not evaluable for response. 10 participants escalated to 100 mg dose with 1 participant self-discontinued 3 days after escalating to 100 mg dose. Intention to treat analysis.
Arm/Group Title AG-348 in Participants With Sickle Cell Disease
Hide Arm/Group Description:
Intra-patient dose escalating study, starting with 5 mg twice a day, increasing to 20 mg twice a day, to maximum 50 mg or 100 mg twice a day. Dosing period is every 2 weeks at each dose level. Dose taper will start on Day 42 (50 mg) or Day 56 (100 mg) with dose reduced over 12 to 15 days.
Overall Number of Participants Analyzed 16
Mean (Standard Error)
Unit of Measure: percent change
5 mg Dose AG-348 Number Analyzed 16 participants
-0.46  (9.68)
20 mg Dose AG-348 Number Analyzed 16 participants
10.19  (9.75)
50 mg Dose AG-348 Number Analyzed 16 participants
7.11  (9.84)
100 mg Dose AG-348 Number Analyzed 9 participants
13.98  (12.44)
End of Taper AG-348 Number Analyzed 15 participants
-11.38  (9.76)
End of Study AG-348 Number Analyzed 16 participants
1.67  (10.13)
15.Secondary Outcome
Title Percent Change of PK-R at Each Dose Level of AG-348
Hide Description To understand the mechanisms of action of AG- 348 on the glycolytic pathway in sickle cell disease through laboratory studies of specific pharmacodynamics of PK-R at each dose level of AG-348.
Time Frame 14 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
One participant, withdrawn 3 days after starting the study for a pre-existing pulmonary embolus, was not evaluable for response. 10 participants escalated to 100 mg dose with 1 participant self-discontinued 3 days after escalating to 100 mg dose. Intention to treat analysis.
Arm/Group Title AG-348 in Participants With Sickle Cell Disease
Hide Arm/Group Description:
Intra-patient dose escalating study, starting with 5 mg twice a day, increasing to 20 mg twice a day, to maximum 50 mg or 100 mg twice a day. Dosing period is every 2 weeks at each dose level. Dose taper will start on Day 42 (50 mg) or Day 56 (100 mg) with dose reduced over 12 to 15 days.
Overall Number of Participants Analyzed 16
Mean (Standard Error)
Unit of Measure: percent change
5 mg Dose AG-348 Number Analyzed 16 participants
-6.89  (6.94)
20 mg Dose AG-348 Number Analyzed 16 participants
-2.82  (6.94)
50 mg Dose AG-348 Number Analyzed 16 participants
-10.66  (6.94)
100 mg Dose AG-348 Number Analyzed 9 participants
-28.99  (7.7)
End of Taper AG-348 Number Analyzed 15 participants
-8.38  (6.98)
End of Study AG-348 Number Analyzed 16 participants
-16.47  (6.98)
Time Frame 1 year
Adverse Event Reporting Description All Adverse Events (serious and non-serious) spontaneously reported by the subject and/or in response to an open question from study personnel or revealed by observation, physical examination, or other diagnostic procedures will be recorded. AE were pre-specified to be collected as a single Arm/Group irrespective of dose level.
 
Arm/Group Title AG-348 in Participants With Sickle Cell Disease
Hide Arm/Group Description Intra-patient dose escalating, starting with 5 mg twice a day, increasing to 20 mg twice a day, to maximum 50 mg or 100 mg twice a day. Dosing period is every 2 weeks at each dose level. Dose taper will start on Day 42 (50 mg) or Day 56 (100 mg) with dose reduced over 12 to 15 days.
All-Cause Mortality
AG-348 in Participants With Sickle Cell Disease
Affected / at Risk (%)
Total   0/17 (0.00%)    
Hide Serious Adverse Events
AG-348 in Participants With Sickle Cell Disease
Affected / at Risk (%) # Events
Total   6/17 (35.29%)    
Congenital, familial and genetic disorders   
Sickle cell anemia with crisis † 1  4/17 (23.53%)  4
General disorders   
Pain † 1  1/17 (5.88%)  1
Vascular disorders   
Thromboembolic event: Pulmonary embolism † 1  1/17 (5.88%)  1
1
Term from vocabulary, CTCAE 5.0
†
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
AG-348 in Participants With Sickle Cell Disease
Affected / at Risk (%) # Events
Total   16/17 (94.12%)    
Blood and lymphatic system disorders   
Anemia † 1  3/17 (17.65%)  3
Elevated C-Reactive Protein (CRP) † 1  1/17 (5.88%)  1
Iron deficiency anemia † 1  1/17 (5.88%)  1
Cardiac disorders   
Palpitations † 1  1/17 (5.88%)  1
Eye disorders   
Corneal scar † 1  1/17 (5.88%)  1
Red eye (bilateral) † 1  1/17 (5.88%)  2
Gastrointestinal disorders   
Diarrhea † 1  2/17 (11.76%)  2
Helicobacter Pylori † 1  2/17 (11.76%)  2
Vomiting and diarrhea † 1  1/17 (5.88%)  1
Gingival pain † 1  1/17 (5.88%)  1
General disorders   
Chills † 1  1/17 (5.88%)  1
Edema limbs † 1  1/17 (5.88%)  1
Fatigue † 1  1/17 (5.88%)  3
Fever † 1  1/17 (5.88%)  1
Non-cardiac chest pain † 1  1/17 (5.88%)  1
Pain † 1  4/17 (23.53%)  4
Infections and infestations   
Upper respiratory infection † 1  2/17 (11.76%)  2
Injury, poisoning and procedural complications   
Fall † 1  1/17 (5.88%)  1
Finger laceration † 1  1/17 (5.88%)  1
Investigations   
Aspartate aminotransferase increased † 1  3/17 (17.65%)  3
Blood bicarbonate decreased † 1  2/17 (11.76%)  2
Blood bilirubin increased † 1  2/17 (11.76%)  3
CPK increased † 1  4/17 (23.53%)  4
Creatinine increased † 1  1/17 (5.88%)  1
Blood urea nitrogen increased † 1  1/17 (5.88%)  1
Chloride increased † 1  1/17 (5.88%)  1
Heart rate increased † 1  3/17 (17.65%)  3
Urine urobilinogen increased † 1  1/17 (5.88%)  1
White blood cell increased † 1  1/17 (5.88%)  1
Lymphocyte count increased † 1  1/17 (5.88%)  1
Neutrophil count decreased † 1  1/17 (5.88%)  1
Metabolism and nutrition disorders   
Hyperglycemia † 1  5/17 (29.41%)  6
Hyperkalemia † 1  1/17 (5.88%)  1
Hyperuricemia † 1  3/17 (17.65%)  3
Hypoglycemia † 1  1/17 (5.88%)  1
Hypokalemia † 1  1/17 (5.88%)  1
Hyponatremia † 1  3/17 (17.65%)  3
Hypophosphatemia † 1  1/17 (5.88%)  1
Musculoskeletal and connective tissue disorders   
Arthralgia † 1  3/17 (17.65%)  3
Back pain † 1  2/17 (11.76%)  2
Chest wall pain † 1  1/17 (5.88%)  3
Myalgia † 1  1/17 (5.88%)  1
Neck pain † 1  1/17 (5.88%)  1
Pain in extremity † 1  1/17 (5.88%)  1
Nervous system disorders   
Dizziness † 1  1/17 (5.88%)  1
Dysesthesia † 1  1/17 (5.88%)  1
Headache † 1  3/17 (17.65%)  3
Psychiatric disorders   
Anxiety † 1  1/17 (5.88%)  1
Insomnia † 1  7/17 (41.18%)  7
Renal and urinary disorders   
Hematuria † 1  1/17 (5.88%)  1
Proteinuria † 1  1/17 (5.88%)  1
Respiratory, thoracic and mediastinal disorders   
Cough † 1  1/17 (5.88%)  1
Dyspnea † 1  2/17 (11.76%)  2
Productive cough † 1  1/17 (5.88%)  1
Lung crackles † 1  1/17 (5.88%)  1
Sneezing † 1  1/17 (5.88%)  1
Sore throat † 1  2/17 (11.76%)  2
Skin and subcutaneous tissue disorders   
Hyperhidrosis † 1  1/17 (5.88%)  1
Pruritus † 1  1/17 (5.88%)  1
Skin ulceration † 1  2/17 (11.76%)  2
Urticaria † 1  1/17 (5.88%)  2
Vascular disorders   
Hypertension † 1  3/17 (17.65%)  4
Thromboembolic event: Pulmonary embolism † 1  1/17 (5.88%)  1
1
Term from vocabulary, CTCAE 5.0
†
Indicates events were collected by systematic assessment
[Not Specified]
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Dr. Swee Lay Thein, Chief of Sickle Cell Branch
Organization: The National Institutes of Health / The National Heart, Lung, and Blood Institute
Phone: 301.402.6699
EMail: sweelay.thein@nih.gov
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Layout table for additonal information
Responsible Party: Swee Lay Thein, M.D., National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov Identifier: NCT04000165    
Other Study ID Numbers: 190097
19-H-0097
First Submitted: June 22, 2019
First Posted: June 27, 2019
Results First Submitted: May 6, 2022
Results First Posted: July 12, 2022
Last Update Posted: July 12, 2022