Pyruvate Kinase DeficiencyPhase 3NCT03559699
A Study Evaluating the Efficacy and Safety of AG-348 in 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 19 sites in 9 countries.
Trial summary
Study AG348-C-007 was a multicenter study designed to evaluate the efficacy and safety of treatment with AG-348 in a minimum of 20, with up to 40, participants with pyruvate kinase (PK) deficiency, who were regularly receiving blood transfusions. The study was composed of two parts. 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?
- No, everyone receives an active treatment
- How many people
- 27 participants
- Where
- 19 sitesin 9 countries
- Study dates
- 26 Jun 2018to 12 Nov 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 or older;
- Presence of at least 2 mutant alleles in the Pyruvate Kinase Liver and RBC (PKLR) gene, of which at least 1 is a missense mutation;
- History of a minimum of 6 transfusion episodes in the 52-week period prior to date of informed consent;
- Complete records of transfusion history for the 52 weeks prior to the date of informed consent, including all transfusion dates, number of blood units transfused for all the transfusions, and Hb concentrations within 1 week prior to transfusion for at least 80% of the transfusions;
- Have received at least 0.8 mg of oral folic acid daily for at least 21 days prior to the first dose of study drug, to be continued daily during study participation;
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- Have adequate organ function;
- Negative serum pregnancy test for women of reproductive potential;
- For women of reproductive potential as well as fertile men and their partners who are women of reproductive potential: be abstinent 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 AG-348;
- Willing to comply with all study procedures, in particular the individual transfusion trigger (TT) calculated based on 52 weeks of transfusion history, 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 participate in the study, and/or that could confound the interpretation of the study data;
- History of transfusions occurring on average more frequently than once every 3 weeks during the 52 weeks prior to date of informed consent;
- 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. Prior participation in the PK Deficiency Natural History Study (NHS) (NCT02053480) or PK Deficiency Registry is permitted;
- Exposure to any investigational drug, device, or procedure within 3 months prior to the first dose of study drug;
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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 CYP3A4, 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 5 times their half-lives (whichever is longer) prior to start of study drug;
- Currently receiving hematopoietic stimulating agents (eg, erythropoietins [EPOs], granulocyte colony stimulating factors, thrombopoietins) that have not been stopped for a duration of at least 28 days prior to the first dose of study drug;
- 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;
- Allergy to AG-348 or its excipients;
- Currently receiving anabolic steroids, including testosterone preparations, within 28 days prior to the first dose of study drug.
Trial locations and contacts
19 sites in 9 countries.
19 sites in 9 countries
United States4 sites
Emory University
Atlanta, Georgia, 30322
Massachusetts General Hospital
Boston, Massachusetts, 02115
UCSF Benioff Children's Hospital
Oakland, California, 94609
Seattle Cancer Care Alliance
Seattle, Washington, 98109
Italy4 sites
Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico
Milan, 20122
AORN Cardarelli
Naples, 80131
Ospedale Galliera
Naples, 80131
AOU Policlinico, Università della Campania "Luigi Vanvitelli"
Naples, 80138
United Kingdom4 sites
Addenbrooke's Hospital
Cambridge, CB2 0QQ
Imperial College Healthcare NHS Trust, Hammersmith Hospital
London, W12 0NN
University College London
London, WC1E 6BT
Manchester Royal Infirmary
Manchester, M13 9WL
France2 sites
Hopital Universitaire Henri Mondor
Créteil, 94010
Hôpital de la Timone
Marseille, 13385
Canada1 site
Toronto General Hospital, University Health Network
Toronto, M5G 2C4
Thailand1 site
Department of Paediatrics and Thalassaemia Center, Faculty of Medicine Siriraj Hospital, Mahidol University
Bangkok, 10700
About this study
Official title: An Open-Label Study To Evaluate the Efficacy and Safety of AG-348 in Regularly Transfused Adult Subjects With Pyruvate Kinase (PK) Deficiency
Study AG348-C-007 was a multicenter study designed to evaluate the efficacy and safety of treatment with AG-348 in a minimum of 20, with up to 40, participants with pyruvate kinase (PK) deficiency, who were regularly receiving blood transfusions. The study was composed of two parts. During Part 1, Dose Optimization Period, participants started on a dose of 5 mg AG-348 administered twice daily. Over the course of Part 1 each participant's dose of AG-348 was sequentially increased to 20 mg twice a day, followed by 50 mg twice a day depending on their tolerance. During Part 2, Fixed-Dose Period, participants received AG-348 at their optimized dose from Part 1.
- Conditions
- Pyruvate Kinase Deficiency, Anemia, Hemolytic
- Being tested
- 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.
AG-348Drug
Part 1 (Dose Optimization Period): Participants began by receiving 5 mg orally, BID. Each participant's dose of AG-348 was sequentially increased to 20 mg BID followed by 50 mg BID depending on their response to AG-348 and their tolerance.
Part 2 (Fixed Dose Period): Optimized dose determined in Part 1.
| Study group | Role | What they receive |
|---|---|---|
| AG-348 | Experimental | Participants received AG-348 tablets, administered orally, at a starting dose of 5 milligrams (mg), twice daily (BID), followed by two sequential dose level increases to 20 mg and 50 mg BID, for a period of 16 weeks in Part 1. This was followed by optimized dose BID, as determined by the investigator in Part 1, for a period of 24 weeks in Part 2. 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 Reduction in Transfusion Burden in Part 2
Reduction in transfusion burden is defined as a ≥33% reduction in the number of RBC units transfused during the Fixed Dose Period standardized to 24 weeks compared with the historical transfusion burden standardized to 24 weeks (Standardized Control Period). The on-study (Fixed Dose Period) transfusion burden was calculated as the total number of transfused RBC units received in the Fixed Dose Period standardized to 24 weeks.
Measured: From Part 2, Day 1 to Part 2 Week 24
Secondary outcomes (5)
Annualized Number of RBC Units Transfused During the Study
The annualized total number of RBC units transfused during the entire study (both Part 1 and Part 2) is reported. It was calculated as the total number of RBC units transfused up to the end of Fixed Dose Period divided by the total number of days from the first dose date until the end date of Fixed Dose Period × 52.
Measured: Part 1 Day 1 to Part 2 Week 24
Number of Transfusion Episodes in Part 2
This is the number of transfusion episodes in Part 2. The number of transfusion episodes were standardized to 24 weeks. Transfusions received over up to 3 consecutive days were counted as 1 episode.
Measured: From Part 2 Day 1 to Part 2 Week 24
Percentage of Transfusion-Free Participants in Part 2
Transfusion-free responders were the participants who were transfusion-free in Part 2.
Measured: From Part 2 Day 1 to Part 2 Week 24
Percentage of Participants Achieving Normal Hemoglobin (Hb) Concentrations in Part 2
This is the percentage of participants who achieved hemoglobin (Hb) concentrations in the normal range at least once, 8 weeks or more after a transfusion in Part 2.
Measured: From Part 2 Day 1 to Part 2 Week 24
Percentage of Participants With Adverse Events
An AE is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the study drug. 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: Through 4 weeks after last dose (approximately Part 2, Week 31)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted18 Jun 2018
- Study start26 Jun 2018
- Primary completion12 Nov 2020
- Study completion12 Nov 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 (3)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
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 27 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
- NCT03559699
- Sponsor's protocol ID
- AG348-C-007
- Other IDs
- 2017-003803-22, 2017
- Status last verified
- Dec 2021
- First submitted
- 26 Mar 2018
- Last updated
- 4 Jan 2022
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Al-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 36594181Glenthoj A, van Beers EJ, Al-Samkari H, Viprakasit V, Kuo KHM, Galacteros F, Chonat S, Porter J, Zagadailov E, Xu R, Oluyadi A, Hawkins P, Gheuens S, Beynon V, Barcellini W; ACTIVATE-T investigators. Mitapivat in adult patients with pyruvate kinase deficiency receiving regular transfusions (ACTIVATE-T): a multicentre, open-label, single-arm, phase 3 trial. Lancet Haematol. 2022 Oct;9(10):e724-e732. doi: 10.1016/S2352-3026(22)00214-9. Epub 2022 Aug 18.
PubMed 35988546Rab 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 4 Jan 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- An Open-Label Study To Evaluate the Efficacy and Safety of AG-348 in Regularly Transfused Adult Subjects With Pyruvate Kinase (PK) Deficiency
- ClinicalTrials.gov ID
- NCT03559699
- Acronym / sponsor ID
- AG348-C-007
- Conditions
- Pyruvate Kinase Deficiency, Anemia, Hemolytic
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 27 participants (actual)
- Lead sponsor
- Agios Pharmaceuticals, Inc.Industry (pharma, biotech, devices)
- Study start
- 26 Jun 2018 (actual)
- Primary completion
- 12 Nov 2020 (actual)
- Study completion
- 12 Nov 2020 (actual)
- First posted
- 18 Jun 2018 (actual)
- Results
- Posted 10 Dec 2021
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-007 was a multicenter study designed to evaluate the efficacy and safety of treatment with AG-348 in a minimum of 20, with up to 40, participants with pyruvate kinase (PK) deficiency, who were regularly receiving blood transfusions. The study was composed of two parts. During Part 1, Dose Optimization Period, participants started on a dose of 5 mg AG-348 administered twice daily. Over the course of Part 1 each participant's dose of AG-348 was sequentially increased to 20 mg twice a day, followed by 50 mg twice a day depending on their tolerance. During Part 2, Fixed-Dose Period, participants received AG-348 at their optimized dose from Part 1.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| AG-348 | Experimental | Drug: AG-348Participants received AG-348 tablets, administered orally, at a starting dose of 5 milligrams (mg), twice daily (BID), followed by two sequential dose level increases to 20 mg and 50 mg BID, for a period of 16 weeks in Part 1. This was followed by optimized dose BID, as determined by the investigator in Part 1, for a period of 24 weeks in Part 2. |
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 or older;
- Presence of at least 2 mutant alleles in the Pyruvate Kinase Liver and RBC (PKLR) gene, of which at least 1 is a missense mutation;
- History of a minimum of 6 transfusion episodes in the 52-week period prior to date of informed consent;
- Complete records of transfusion history for the 52 weeks prior to the date of informed consent, including all transfusion dates, number of blood units transfused for all the transfusions, and Hb concentrations within 1 week prior to transfusion for at least 80% of the transfusions;
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 participate in the study, and/or that could confound the interpretation of the study data;
- History of transfusions occurring on average more frequently than once every 3 weeks during the 52 weeks prior to date of informed consent;
- 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. Prior participation in the PK Deficiency Natural History Study (NHS) (NCT02053480) or PK Deficiency Registry is permitted;
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 |
|---|---|---|
| AG-348Part 1 (Dose Optimization Period): Participants began by receiving 5 mg orally, BID. Each participant's dose of AG-348 was sequentially increased to 20 mg BID followed by 50 mg BID depending on their response to AG-348 and their tolerance. Part 2 (Fixed Dose Period): Optimized dose determined in Part 1. | Drug | AG-348 |
Primary outcome
Percentage of Participants Achieving a Reduction in Transfusion Burden in Part 2
Time frame: From Part 2, Day 1 to Part 2 Week 24
Reduction in transfusion burden is defined as a ≥33% reduction in the number of RBC units transfused during the Fixed Dose Period standardized to 24 weeks compared with the historical transfusion burden standardized to 24 weeks (Standardized Control Period). The on-study (Fixed Dose Period) transfusion burden was calculated as the total number of transfused RBC units received in the Fixed Dose Period standardized to 24 weeks.
5 secondary outcomes
Annualized Number of RBC Units Transfused During the Study
Time frame: Part 1 Day 1 to Part 2 Week 24
Number of Transfusion Episodes in Part 2
Time frame: From Part 2 Day 1 to Part 2 Week 24
Percentage of Transfusion-Free Participants in Part 2
Time frame: From Part 2 Day 1 to Part 2 Week 24
Percentage of Participants Achieving Normal Hemoglobin (Hb) Concentrations in Part 2
Time frame: From Part 2 Day 1 to Part 2 Week 24
Percentage of Participants With Adverse Events
Time frame: Through 4 weeks after last dose (approximately Part 2, Week 31)
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 4 Jan 2022.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- 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 35988546Glenthoj A, van Beers EJ, Al-Samkari H, Viprakasit V, Kuo KHM, Galacteros F, Chonat S, Porter J, Zagadailov E, Xu R, Oluyadi A, Hawkins P, Gheuens S, Beynon V, Barcellini W; ACTIVATE-T investigators. Mitapivat in adult patients with pyruvate kinase deficiency receiving regular transfusions (ACTIVATE-T): a multicentre, open-label, single-arm, phase 3 trial. Lancet Haematol. 2022 Oct;9(10):e724-e732. doi: 10.1016/S2352-3026(22)00214-9. Epub 2022 Aug 18.
- 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.
19 sites in 9 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 19 sites in 9 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 4 Jan 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 19 sites in United States, Italy, United Kingdom, France, Canada and 4 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. 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 10 Dec 2021). 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 Reduction in Transfusion Burden in Part 2 (time frame: From Part 2, Day 1 to Part 2 Week 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 NCT03559699, which also lists 3 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 4 Jan 2022.