Pyruvate Kinase DeficiencyPhase 3NCT03548220
A Study to Evaluate Efficacy and Safety of AG-348 in Not Regularly Transfused Adult Participants With Pyruvate Kinase Deficiency (PKD)
A Phase 3 study testing AG-348 in people with Pyruvate Kinase Deficiency and Anemia, Hemolytic, run by Agios Pharmaceuticals, Inc. at 46 sites in 16 countries.
Trial summary
Study AG348-C-006 evaluated the efficacy and safety of orally administered AG-348 as compared with placebo in participants with pyruvate kinase (PK) deficiency, who were not regularly receiving blood transfusions. Participants were randomized 1:1 to receive either AG-348 or a matching placebo. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Pyruvate Kinase Deficiency, Anemia, Hemolytic
- What is being tested?
- AG-348
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 80 participants
- Where
- 46 sitesin 16 countries
- Study dates
- 9 Aug 2018to 9 Oct 2020
- Phase
- Phase 3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Informed consent;
- Male or female, aged 18 years or older;
- Documented clinical laboratory confirmation of pyruvate kinase (PK) deficiency, defined as documented presence of at least 2 mutant alleles in the PKLR gene, of which at least 1 is a missense mutation;
- Hemoglobin (Hb) concentration less than or equal to 10.0 grams per deciliter (g/dL) regardless of gender (average of at least 2 Hb measurements [separated by a minimum of 7 days] during the Screening Period)
- Considered not regularly transfused, defined as having had no more than 4 transfusion episodes in the 12-month period up to the first day of study treatment and no transfusions in the 3 months prior to the first day of study treatment;
- Received at least 0.8 mg oral folic acid daily for at least 21 days prior to the first dose of study treatment, to be continued daily during study participation.
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- 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 following the last dose of study treatment for women and 90 days for men following the last dose of study treatment;
- Willing to comply with all study procedures for the duration of the study;
Who cannot join
- 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. Prior and subsequent participation in the PK Deficiency Natural History Study (NHS) (NCT02053480) or PK Deficiency Registry is permitted however, concurrent participation is not; participants enrolling in this current study will be expected to temporarily suspend participation in the NHS or Registry;
- Exposure to any investigational drug, device, or procedure within 3 months prior to the first dose of study treatment;
- Prior treatment with a pyruvate kinase activator;
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- Prior bone marrow or stem cell transplant;
- Currently pregnant or breastfeeding;
- History of major surgery within 6 months of signing informed consent;
- Currently receiving medications that are strong inhibitors of cytochrome P450 (CYP)3A4, strong inducers of CYP3A4, strong inhibitors of P-glycoprotein (P-gp), or digoxin (a P-gp sensitive substrate medication) that have not been stopped for a duration of at least 5 days or a timeframe equivalent to 5 half-lives (whichever is longer) prior to the first dose of study treatment;
- Currently receiving hematopoietic stimulating agents that have not been stopped for a duration of at least 28 days prior to the first dose of study treatment;
- History of allergy to sulfonamides if characterized by acute hemolytic anemia, drug induced liver injury, anaphylaxis, rash of erythema multiforme type or Stevens-Johnson syndrome, cholestatic hepatitis, or other serious clinical manifestations;
- History of allergy to AG-348 or its excipients;
- Currently receiving anabolic steroids, including testosterone preparations, within 28 days prior to treatment.
Trial locations and contacts
46 sites in 16 countries.
46 sites in 16 countries
United States12 sites
Emory University
Atlanta, Georgia, 30322
Massachusetts General Hospital
Boston, Massachusetts, 02114
The Children's Hospital Corporation d/b/a Boston's Children Hospital
Boston, Massachusetts, 02115
Cincinnati Children's Hospital Medical Center
Cincinnati, Ohio, 45229
Wayne State University School of Medicine, Children's Hospital of Michigan
Detroit, Michigan, 48304
Duke University
Durham, North Carolina, 27705
East Carolina University
Greenville, North Carolina, 27858
Houston Methodist Research Institute
Houston, Texas, 77030
Indiana Hemophilia and Thrombosis Center
Indianapolis, Indiana, 46260
University of Arkansas for Medical Sciences
Little Rock, Arkansas, 72205
Primary Children's Hospital Univ. of Utah
Salt Lake City, Utah, 84112
Seattle Cancer Care Alliance
Seattle, Washington, 98109
Japan6 sites
Kyoto Katsura Hospital
Kyoto
Agios Investigative Site
Mie
Osaka City General Hospital
Osaka, 534-0021
Kansai Medical University, Department of Pediatrics, Hirakata Hospital
Osaka
Tohoku University Hospital
Sendai, Miyagi
Toho University Omori Medical Center
Tokyo
France5 sites
CHU Amiens Picardie
Amiens, 80054
Hopital Saint-Andre
Bordeaux
Hôpital Henri-Mondor
Créteil, 94010
Hôpital de la Timone
Marseille, 13385
Institut Claudius Regaud
Toulouse
United Kingdom5 sites
Addenbrooke's Hospital
Cambridge, 94609
The Royal Liverpool and Broadgreen University
Liverpool, L7 8XP
Imperial College Healthcare NHS Trust, Hammersmith Hospital
London, W12 0NN
University College London
London, W12 0NN
Manchester Royal Infirmary
Manchester, M13 9WL
Italy3 sites
Ospedale Galliera
Genova, 16128
Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico
Milan, 20122
AOU Policlinico, Università della Campania "Luigi Vanvitelli"
Naples, 80138
Spain3 sites
Hospital U. Vall d'Hebron Servicio de Hematología Clínica
Barcelona, 08035
Hospital Clinico Universitario Virgen de la Arricaxa
El Palmar, 30120
Hospital Universitario La Paz
Madrid, 28046
Canada2 sites
McMaster University - Health Sciences Centre
Hamilton, L8S 4LB
Toronto General Hospital, University Health Network
Toronto, M5G 2C4
Germany2 sites
Charite University Medicine
Berlin
Universitätsklinikum Würzburg
Würzburg, 97080
Brazil1 site
Hospital Central da Faculdade de Medicina USP Cidade Universitaria
São Paulo
Switzerland1 site
Centre Hospitalier Universitaire Vaudois (CHUV)
Lausanne, 1011
Thailand1 site
Department of Paediatrics and Thalassaemia Center, Faculty of Medicine Siriraj
Bangkok, 10700
About this study
Official title: A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of AG-348 in Not Regularly Transfused Adult Subjects With Pyruvate Kinase Deficiency
Study AG348-C-006 evaluated the efficacy and safety of orally administered AG-348 as compared with placebo in participants with pyruvate kinase (PK) deficiency, who were not regularly receiving blood transfusions. Participants were randomized 1:1 to receive either AG-348 or a matching placebo.
- Conditions
- Pyruvate Kinase Deficiency, Anemia, Hemolytic
- Being tested
- Placebo, AG-348
- Medical subject headings
- Pyruvate Kinase Deficiency of Red Cells, Anemia, Hemolytic
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
PlaceboDrug
Placebo matching AG-348 tablets, administered to maintain the blind.
AG-348Drug
AG-348 tablets.
| Study group | Role | What they receive |
|---|---|---|
| Placebo | Placebo comparator | Participants received a matching placebo to AG-348 tablets, for a period of 12 weeks as an optimized dose. This was followed by matching placebo further, for a period of 12 weeks as a fixed-dose. Receives: Drug: Placebo |
| AG-348, 5 mg | Experimental | Participants received AG-348 tablets, 5 milligrams (mg) twice daily (BID), administered orally, for 4 weeks as a starting dose, followed by two potential sequential dose level increases to 20 mg and 50 mg BID at Weeks 4 and 8 respectively as determined by the investigator based on safety and efficacy. The optimized dose for each participant was determined as 5 mg BID at Week 12, and participants then received that optimized dose for a period of 12 weeks as a fixed dose. Receives: Drug: AG-348 |
| AG-348, 20 mg | Experimental | Participants received AG-348 tablets, 5 mg BID, administered orally, for 4 weeks as a starting dose, followed by two potential sequential dose level increases to 20 mg and 50 mg BID at Weeks 4 and 8 respectively as determined by the investigator based on safety and efficacy. The optimized dose for each participant was determined as 20 mg BID at Week 12, and participants then received that optimized dose for a period of 12 weeks as a fixed dose. Receives: Drug: AG-348 |
| AG-348, 50 mg | Experimental | Participants received AG-348 tablets, 5 mg BID, administered orally, for 4 weeks as a starting dose, followed by two potential sequential dose level increases to 20 mg and 50 mg BID at Weeks 4 and 8 respectively as determined by the investigator based on safety and efficacy. The optimized dose for each participant was determined as 50 mg BID at Week 12, and participants then received that optimized dose for a period of 12 weeks as a fixed dose. Receives: Drug: AG-348 |
What is being measured
The primary outcome is the main question the study is designed to answer.
Percentage of Participants Achieving a Hemoglobin (Hb) Response (HR)
Hemoglobin response (HR) is defined as a ≥1.5 g/dL (0.93 mmol/L) increase in Hb concentration from baseline that is sustained at 2 or more scheduled assessments at Weeks 16, 20, and 24. The baseline Hb concentration is the average of all available Hb concentrations for a participant during the Screening Period up to the first dose of study treatment. As pre-specified in the protocol, the data for this outcome measure is summarized between the active arm vs the placebo arm (AG-348 5 mg, 20 mg and 50 mg arms are analyzed and reported together in comparison to Placebo).
Measured: Baseline, Weeks 16, 20, 24
Secondary outcomes (16)
Average Change From Baseline in Hb Concentration at Weeks 16, 20 and 24
This is the change in Hb concentration at Weeks 16, 20 and 24 compared to baseline. Data presented represents the value of the change from baseline averaged over Weeks 16, 20 and 24. Baseline was defined as the average of all screening assessments within 45 (42+3) days before randomization for participants randomized and not dosed or before start of study treatment for participants randomized and dosed. As pre-specified in the protocol, the data for this outcome measure is summarized between the active arm vs the placebo arm (AG-348 5 mg, 20 mg and 50 mg arms are analyzed and reported together in comparison to Placebo).
Measured: Baseline, Weeks 16, 20, 24
Maximum Change From Baseline in Hb Concentration
This is the maximum change from baseline in Hb concentration up to Week 24. As pre-specified in the protocol, the data for this outcome measure is summarized between the active arm vs the placebo arm (AG-348 5 mg, 20 mg and 50 mg arms are analyzed and reported together in comparison to Placebo).
Measured: Baseline, up to Week 24
Time to Achieve an Increase in Hb Concentration of 1.5 g/dL or More
This is the time taken to first achieve an increase of hemoglobin concentration of 1.5 g/dL or more from baseline. As pre-specified in the protocol, the data for this outcome measure is summarized between the active arm vs the placebo arm (AG-348 5 mg, 20 mg and 50 mg arms are analyzed and reported together in comparison to Placebo).
Measured: Baseline, up to Week 24
Average Change From Baseline in Indirect Bilirubin at Weeks 16, 20 and 24
The change from baseline in indirect bilirubin levels was summarized. Indirect bilirubin is a marker for hemolysis. Data presented represents the value of the change from baseline averaged over Weeks 16, 20 and 24. Baseline was defined as the average of all screening assessments within 45 (42+3) days before randomization for participants randomized and not dosed or before the start of study treatment for participants randomized and dosed. As pre-specified in the protocol, the data for this outcome measure is summarized between the active arm vs the placebo arm (AG-348 5 mg, 20 mg and 50 mg arms are analyzed and reported together in comparison to Placebo).
Measured: Baseline, Weeks 16, 20, 24
Average Change From Baseline in Lactic Acid Dehydrogenase (LDH) at Weeks 16, 20 and 24
The change from baseline in LDH levels was summarized. LDH is a marker for hemolysis. Data presented represents the value of the change from baseline averaged over Weeks 16, 20 and 24. Baseline was defined as the average of all screening assessments within 45 (42+3) days before randomization for participants randomized and not dosed or before the start of study treatment for participants randomized and dosed. As pre-specified in the protocol, the data for this outcome measure is summarized between the active arm vs the placebo arm (AG-348 5 mg, 20 mg and 50 mg arms are analyzed and reported together in comparison to Placebo).
Measured: Baseline, Weeks 16, 20, 24
Average Change From Baseline in Haptoglobin at Weeks 16, 20 and 24
The change from baseline in haptoglobin levels was summarized. Haptoglobin levels are markers for hemolysis. Data presented represents the value of the change from baseline averaged over Weeks 16, 20 and 24. Baseline was defined as the average of all screening assessments within 45 (42+3) days before randomization for participants randomized and not dosed or before the start of study treatment for participants randomized and dosed. As pre-specified in the protocol, the data for this outcome measure is summarized between the active arm vs the placebo arm (AG-348 5 mg, 20 mg and 50 mg arms are analyzed and reported together in comparison to Placebo).
Measured: Baseline, Weeks 16, 20, 24
Average Change From Baseline in Reticulocyte Percentages at Weeks 16, 20 and 24
The change from baseline in reticulocyte percentage was summarized. Reticulocyte levels are markers for hematopoietic activity. Data presented represents the value of the change from baseline averaged over Weeks 16, 20 and 24. Baseline was defined as the average of all screening assessments within 45 (42+3) days before randomization for participants randomized and not dosed or before the start of study treatment for participants randomized and dosed. As pre-specified in the protocol, the data for this outcome measure is summarized between the active arm vs the placebo arm (AG-348 5 mg, 20 mg and 50 mg arms are analyzed and reported together in comparison to Placebo).
Measured: Baseline, Weeks 16, 20, 24
Change From Baseline in Pyruvate Kinase Deficiency Diary (PKDD) Score at Week 24
The PKDD is a 7-item patient reported outcome (PRO) measure of the core signs and symptoms associated with PK deficiency in adults. Participants rate their experience with symptoms of PK deficiency on the present day. The symptoms include those associated with tiredness, jaundice, bone pain, shortness of breath, and energy level. The score ranges from 25 to 76, with higher scores indicating a higher disease burden. The change from baseline in PKDD weekly scores was evaluated. A negative change from baseline indicates a lower disease burden. As pre-specified in the protocol, the data for this outcome measure is summarized between the active arm vs the placebo arm (AG-348 5 mg, 20 mg and 50 mg arms are analyzed and reported together in comparison to Placebo).
Measured: Baseline, Week 24
Change From Baseline in Pyruvate Kinase Deficiency Impact Assessment (PKDIA) Score at Week 24
The PKDIA is a 12-item patient reported outcome (PRO) measure of the common impacts of PK deficiency on activities of daily living. Participants rate how PK deficiency has impacted aspects of daily living in the past 7 days, including impacts on relationships; perceived appearance; work performance; and leisure, social, mental, and physical activities. The score range is 30 to 76, with higher scores indicating a higher disease burden. The change from baseline in PKDIA scores was evaluated. A negative change from baseline indicates a lower disease burden. As pre-specified in the protocol, the data for this outcome measure is summarized between the active arm vs the placebo arm (AG-348 5 mg, 20 mg and 50 mg arms are analyzed and reported together in comparison to Placebo).
Measured: Baseline, Week 24
Percentage of Participants With Adverse Events
An AE is any untoward medical occurrence in a participant or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the study treatment. An AE can, therefore, be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.
Measured: From signing of informed consent form to the end of study, including follow-up (up to Day 197)
Area Under the Curve From Time 0 to the Last Quantifiable Concentration [AUC(0-last)] for AG-348 at Week 12
Measured: Pre-dose, 30 minutes and 1, 2, 4 and 8 hours post-dose on Day 85 (Week 12)
Maximum Plasma Concentration (Cmax) for AG-348
Measured: Pre-dose, 30 minutes and 1, 2, 4 and 8 hours post-dose on Day 85 (Week 12)
Time to Cmax (Tmax) for AG-348
Measured: Pre-dose, 30 minutes and 1, 2, 4 and 8 hours post-dose on Day 85 (Week 12)
Time to Last Measurable Concentration (Tlast) for AG-348
Measured: Pre-dose, 30 minutes and 1, 2, 4 and 8 hours post-dose on Day 85 (Week 12)
Exposure-Response Relationship of Adverse Event (Hot Flush) and AG-348 Concentration and Relevant AG-348 Pharmacokinetic Parameters
Predicted probability of experiencing all grade hot flush at the doses of 5, 20, and 50 mg mitapivat BID based on exposure-response model.
Measured: From first dose of mitapivat to the end of study, including follow-up (up to Day 197)
Exposure-Response Relationship Between Safety Parameters (Sex Hormone in Male Subjects) and AG-348 Concentration and Relevant AG-348 Pharmacokinetic Parameters
Predicted percent change from baseline at Week 24 in the sex hormone measures (total testosterone, free testosterone, and estrone) at the doses of 5, 20, and 50 mg mitapivat BID in male participants.
Measured: Baseline, Week 24
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted7 Jun 2018
- Study start9 Aug 2018
- Primary completion9 Oct 2020
- Study completion9 Oct 2020
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (5)Papers the sponsor has linked to this study.
- Other trials for Pyruvate Kinase DeficiencyStudies of the same condition, open and under way.
- More trials run by Agios Pharmaceuticals, Inc.The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind
- Who is masked
- Participant, Care provider, Investigator
- Enrolment
- 80 participants (actual)
Sponsor and investigators
- Lead sponsor
- Agios Pharmaceuticals, Inc.
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Medical Affairs, Study chair, Agios Pharmaceuticals, Inc.
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03548220
- Sponsor's protocol ID
- AG348-C-006
- Status last verified
- May 2022
- First submitted
- 24 May 2018
- Last updated
- 24 May 2022
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
van Beers EJ, Al-Samkari H, Grace RF, Barcellini W, Glenthoj A, DiBacco M, Wind-Rotolo M, Xu R, Beynon V, Patel P, Porter JB, Kuo KHM. Mitapivat improves ineffective erythropoiesis and iron overload in adult patients with pyruvate kinase deficiency. Blood Adv. 2024 May 28;8(10):2433-2441. doi: 10.1182/bloodadvances.2023011743.
PubMed 38330179Andrae DA, Grace RF, Jewett A, Foster B, Klaassen RJ, Salek S, Li J, Tai F, Boscoe AN, Zagadailov E. Psychometric validation of the Pyruvate Kinase Deficiency Diary and Pyruvate Kinase Deficiency Impact Assessment in adults in the phase 3 ACTIVATE trial. J Patient Rep Outcomes. 2023 Nov 9;7(1):112. doi: 10.1186/s41687-023-00650-3.
PubMed 37943362Al-Samkari H, Grace RF, Glenthoj A, Andres O, Barcellini W, Galacteros F, Kuo KHM, Layton DM, Morado Arias M, Viprakasit V, Dong Y, Tai F, Hawkins P, Gheuens S, Morales-Arias J, Gilroy KS, Porter JB, van Beers EJ. Early-onset reduced bone mineral density in patients with pyruvate kinase deficiency. Am J Hematol. 2023 Mar;98(3):E57-E60. doi: 10.1002/ajh.26830. Epub 2023 Jan 9. No abstract available.
PubMed 36594181Al-Samkari H, Galacteros F, Glenthoj A, Rothman JA, Andres O, Grace RF, Morado-Arias M, Layton DM, Onodera K, Verhovsek M, Barcellini W, Chonat S, Judge MP, Zagadailov E, Xu R, Hawkins P, Beynon V, Gheuens S, van Beers EJ; ACTIVATE Investigators. Mitapivat versus Placebo for Pyruvate Kinase Deficiency. N Engl J Med. 2022 Apr 14;386(15):1432-1442. doi: 10.1056/NEJMoa2116634.
PubMed 35417638Rab MAE, Van Oirschot BA, Kosinski PA, Hixon J, Johnson K, Chubukov V, Dang L, Pasterkamp G, Van Straaten S, Van Solinge WW, Van Beers EJ, Kung C, Van Wijk R. AG-348 (Mitapivat), an allosteric activator of red blood cell pyruvate kinase, increases enzymatic activity, protein stability, and ATP levels over a broad range of PKLR genotypes. Haematologica. 2021 Jan 1;106(1):238-249. doi: 10.3324/haematol.2019.238865.
PubMed 31974203
Study at a glance
From the registry record, last updated by the sponsor on 24 May 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of AG-348 in Not Regularly Transfused Adult Subjects With Pyruvate Kinase Deficiency
- ClinicalTrials.gov ID
- NCT03548220
- Acronym / sponsor ID
- AG348-C-006
- Conditions
- Pyruvate Kinase Deficiency, Anemia, Hemolytic
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 80 participants (actual)
- Lead sponsor
- Agios Pharmaceuticals, Inc.Industry (pharma, biotech, devices)
- Study start
- 9 Aug 2018 (actual)
- Primary completion
- 9 Oct 2020 (actual)
- Study completion
- 9 Oct 2020 (actual)
- First posted
- 7 Jun 2018 (actual)
- Results
- Posted 24 May 2022
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Study AG348-C-006 evaluated the efficacy and safety of orally administered AG-348 as compared with placebo in participants with pyruvate kinase (PK) deficiency, who were not regularly receiving blood transfusions. Participants were randomized 1:1 to receive either AG-348 or a matching placebo.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (participant, care provider, investigator)
- Number of arms
- 4
| Arm | Type | Receives |
|---|---|---|
| Placebo | Placebo comparator | Drug: PlaceboParticipants received a matching placebo to AG-348 tablets, for a period of 12 weeks as an optimized dose. This was followed by matching placebo further, for a period of 12 weeks as a fixed-dose. |
| AG-348, 5 mg | Experimental | Drug: AG-348Participants received AG-348 tablets, 5 milligrams (mg) twice daily (BID), administered orally, for 4 weeks as a starting dose, followed by two potential sequential dose level increases to 20 mg and 50 mg BID at Weeks 4 and 8 respectively as determined by the investigator based on safety and efficacy. The optimized dose for each participant was determined as 5 mg BID at Week 12, and participants then received that optimized dose for a period of 12 weeks as a fixed dose. |
| AG-348, 20 mg | Experimental | Drug: AG-348Participants received AG-348 tablets, 5 mg BID, administered orally, for 4 weeks as a starting dose, followed by two potential sequential dose level increases to 20 mg and 50 mg BID at Weeks 4 and 8 respectively as determined by the investigator based on safety and efficacy. The optimized dose for each participant was determined as 20 mg BID at Week 12, and participants then received that optimized dose for a period of 12 weeks as a fixed dose. |
| AG-348, 50 mg | Experimental | Drug: AG-348Participants received AG-348 tablets, 5 mg BID, administered orally, for 4 weeks as a starting dose, followed by two potential sequential dose level increases to 20 mg and 50 mg BID at Weeks 4 and 8 respectively as determined by the investigator based on safety and efficacy. The optimized dose for each participant was determined as 50 mg BID at Week 12, and participants then received that optimized dose for a period of 12 weeks as a fixed dose. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (10 listed)
- Informed consent;
- Male or female, aged 18 years or older;
- Documented clinical laboratory confirmation of pyruvate kinase (PK) deficiency, defined as documented presence of at least 2 mutant alleles in the PKLR gene, of which at least 1 is a missense mutation;
- Hemoglobin (Hb) concentration less than or equal to 10.0 grams per deciliter (g/dL) regardless of gender (average of at least 2 Hb measurements [separated by a minimum of 7 days] during the Screening Period)
- Considered not regularly transfused, defined as having had no more than 4 transfusion episodes in the 12-month period up to the first day of study treatment and no transfusions in the 3 months prior to the first day of study treatment;
Key exclusion criteria (14 listed)
- 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. Prior and subsequent participation in the PK Deficiency Natural History Study (NHS) (NCT02053480) or PK Deficiency Registry is permitted however, concurrent participation is not; participants enrolling in this current study will be expected to temporarily suspend participation in the NHS or Registry;
- Exposure to any investigational drug, device, or procedure within 3 months prior to the first dose of study treatment;
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| PlaceboPlacebo matching AG-348 tablets, administered to maintain the blind. | Drug | Placebo |
| AG-348AG-348 tablets. | Drug | AG-348, 20 mg, AG-348, 5 mg, AG-348, 50 mg |
Primary outcome
Percentage of Participants Achieving a Hemoglobin (Hb) Response (HR)
Time frame: Baseline, Weeks 16, 20, 24
Hemoglobin response (HR) is defined as a ≥1.5 g/dL (0.93 mmol/L) increase in Hb concentration from baseline that is sustained at 2 or more scheduled assessments at Weeks 16, 20, and 24. The baseline Hb concentration is the average of all available Hb concentrations for a participant during the Screening Period up to the first dose of study treatment. As pre-specified in the protocol, the data for this outcome measure is summarized between the active arm vs the placebo arm (AG-348 5 mg, 20 mg and 50 mg arms are analyzed and reported together in comparison to Placebo).
16 secondary outcomes
Average Change From Baseline in Hb Concentration at Weeks 16, 20 and 24
Time frame: Baseline, Weeks 16, 20, 24
Maximum Change From Baseline in Hb Concentration
Time frame: Baseline, up to Week 24
Time to Achieve an Increase in Hb Concentration of 1.5 g/dL or More
Time frame: Baseline, up to Week 24
Average Change From Baseline in Indirect Bilirubin at Weeks 16, 20 and 24
Time frame: Baseline, Weeks 16, 20, 24
Average Change From Baseline in Lactic Acid Dehydrogenase (LDH) at Weeks 16, 20 and 24
Time frame: Baseline, Weeks 16, 20, 24
Average Change From Baseline in Haptoglobin at Weeks 16, 20 and 24
Time frame: Baseline, Weeks 16, 20, 24
Average Change From Baseline in Reticulocyte Percentages at Weeks 16, 20 and 24
Time frame: Baseline, Weeks 16, 20, 24
Change From Baseline in Pyruvate Kinase Deficiency Diary (PKDD) Score at Week 24
Time frame: Baseline, Week 24
Change From Baseline in Pyruvate Kinase Deficiency Impact Assessment (PKDIA) Score at Week 24
Time frame: Baseline, Week 24
Percentage of Participants With Adverse Events
Time frame: From signing of informed consent form to the end of study, including follow-up (up to Day 197)
Area Under the Curve From Time 0 to the Last Quantifiable Concentration [AUC(0-last)] for AG-348 at Week 12
Time frame: Pre-dose, 30 minutes and 1, 2, 4 and 8 hours post-dose on Day 85 (Week 12)
Maximum Plasma Concentration (Cmax) for AG-348
Time frame: Pre-dose, 30 minutes and 1, 2, 4 and 8 hours post-dose on Day 85 (Week 12)
Time to Cmax (Tmax) for AG-348
Time frame: Pre-dose, 30 minutes and 1, 2, 4 and 8 hours post-dose on Day 85 (Week 12)
Time to Last Measurable Concentration (Tlast) for AG-348
Time frame: Pre-dose, 30 minutes and 1, 2, 4 and 8 hours post-dose on Day 85 (Week 12)
Exposure-Response Relationship of Adverse Event (Hot Flush) and AG-348 Concentration and Relevant AG-348 Pharmacokinetic Parameters
Time frame: From first dose of mitapivat to the end of study, including follow-up (up to Day 197)
Exposure-Response Relationship Between Safety Parameters (Sex Hormone in Male Subjects) and AG-348 Concentration and Relevant AG-348 Pharmacokinetic Parameters
Time frame: Baseline, Week 24
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 24 May 2022.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 38330179van Beers EJ, Al-Samkari H, Grace RF, Barcellini W, Glenthoj A, DiBacco M, Wind-Rotolo M, Xu R, Beynon V, Patel P, Porter JB, Kuo KHM. Mitapivat improves ineffective erythropoiesis and iron overload in adult patients with pyruvate kinase deficiency. Blood Adv. 2024 May 28;8(10):2433-2441. doi: 10.1182/bloodadvances.2023011743.
- Derived from this study: PubMed 37943362Andrae DA, Grace RF, Jewett A, Foster B, Klaassen RJ, Salek S, Li J, Tai F, Boscoe AN, Zagadailov E. Psychometric validation of the Pyruvate Kinase Deficiency Diary and Pyruvate Kinase Deficiency Impact Assessment in adults in the phase 3 ACTIVATE trial. J Patient Rep Outcomes. 2023 Nov 9;7(1):112. doi: 10.1186/s41687-023-00650-3.
- Derived from this study: PubMed 36594181Al-Samkari H, Grace RF, Glenthoj A, Andres O, Barcellini W, Galacteros F, Kuo KHM, Layton DM, Morado Arias M, Viprakasit V, Dong Y, Tai F, Hawkins P, Gheuens S, Morales-Arias J, Gilroy KS, Porter JB, van Beers EJ. Early-onset reduced bone mineral density in patients with pyruvate kinase deficiency. Am J Hematol. 2023 Mar;98(3):E57-E60. doi: 10.1002/ajh.26830. Epub 2023 Jan 9. No abstract available.
- Derived from this study: PubMed 35417638Al-Samkari H, Galacteros F, Glenthoj A, Rothman JA, Andres O, Grace RF, Morado-Arias M, Layton DM, Onodera K, Verhovsek M, Barcellini W, Chonat S, Judge MP, Zagadailov E, Xu R, Hawkins P, Beynon V, Gheuens S, van Beers EJ; ACTIVATE Investigators. Mitapivat versus Placebo for Pyruvate Kinase Deficiency. N Engl J Med. 2022 Apr 14;386(15):1432-1442. doi: 10.1056/NEJMoa2116634.
- Derived from this study: PubMed 31974203Rab MAE, Van Oirschot BA, Kosinski PA, Hixon J, Johnson K, Chubukov V, Dang L, Pasterkamp G, Van Straaten S, Van Solinge WW, Van Beers EJ, Kung C, Van Wijk R. AG-348 (Mitapivat), an allosteric activator of red blood cell pyruvate kinase, increases enzymatic activity, protein stability, and ATP levels over a broad range of PKLR genotypes. Haematologica. 2021 Jan 1;106(1):238-249. doi: 10.3324/haematol.2019.238865.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Medical Affairs study chair
Agios Pharmaceuticals, Inc.
46 sites in 16 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing AG-348 in people with Pyruvate Kinase Deficiency and Anemia, Hemolytic, run by Agios Pharmaceuticals, Inc. at 46 sites in 16 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 10 inclusion and 14 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 24 May 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 46 sites in United States, Japan, France, United Kingdom, Italy and 11 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 24 May 2022). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Percentage of Participants Achieving a Hemoglobin (Hb) Response (HR) (time frame: Baseline, Weeks 16, 20, 24). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03548220, which also lists 5 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 24 May 2022.