A Study to Evaluate Efficacy and Safety of AG-348 in Not Regularly Transfused Adult Participants With Pyruvate Kinase Deficiency (PKD)

Pyruvate Kinase Deficiency Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03548220
• Other study ID #: AG348-C-006
• Status: Completed
• Phase: Phase 3
• Start date: August 9, 2018
• Est. completion date: October 9, 2020

Study information

• Verified date: May 2022
• Source: Agios Pharmaceuticals, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 80
• Est. completion date: October 9, 2020
• Est. primary completion date: October 9, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• 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.
• 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;

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. 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;
• 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.

Related Conditions & MeSH terms

• Anemia, Hemolytic
• Pyruvate Kinase Deficiency

Intervention

Drug:
• Placebo
Placebo matching AG-348 tablets, administered to maintain the blind.
• AG-348
AG-348 tablets.

Locations

Country	Name	City	State
Brazil	Hospital Central da Faculdade de Medicina USP Cidade Universitaria	São Paulo
Canada	McMaster University - Health Sciences Centre	Hamilton
Canada	Toronto General Hospital, University Health Network	Toronto
Czechia	Institute of Hematology and Blood Transfusion	Prague
Denmark	University of Copenhagen, Herlev Hospital	Herlev
France	CHU Amiens Picardie	Amiens
France	Hopital Saint-Andre	Bordeaux
France	Hôpital Henri-Mondor	Créteil
France	Hôpital de la Timone	Marseille, Cedex 5
France	Institut Claudius Regaud	Toulouse
Germany	Charite University Medicine	Berlin
Germany	Universitätsklinikum Würzburg	Würzburg
Italy	Ospedale Galliera	Genova
Italy	Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico	Milano
Italy	AOU Policlinico, Università della Campania "Luigi Vanvitelli"	Napoli
Japan	Kyoto Katsura Hospital	Kyoto
Japan	Agios Investigative Site	Mie
Japan	Kansai Medical University, Department of Pediatrics, Hirakata Hospital	Osaka
Japan	Osaka City General Hospital	Osaka
Japan	Tohoku University Hospital	Sendai-City	Miyagi
Japan	Toho University Omori Medical Center	Tokyo
Korea, Republic of	Yeungnam University Hospital	Daegu 705-703
Netherlands	Universitair Medisch Centrum Utrecht	Utrecht
Spain	Hospital U. Vall d'Hebron Servicio de Hematología Clínica	Barcelona
Spain	Hospital Clinico Universitario Virgen de la Arricaxa	El Palmar
Spain	Hospital Universitario La Paz	Madrid
Switzerland	Centre Hospitalier Universitaire Vaudois (CHUV)	Lausanne
Thailand	Department of Paediatrics and Thalassaemia Center, Faculty of Medicine Siriraj	Bangkok
Turkey	Hacettepe University	Ankara
United Kingdom	Addenbrooke's Hospital	Cambridge
United Kingdom	The Royal Liverpool and Broadgreen University	Liverpool
United Kingdom	Imperial College Healthcare NHS Trust, Hammersmith Hospital	London
United Kingdom	University College London	London
United Kingdom	Manchester Royal Infirmary	Manchester
United States	Emory University	Atlanta	Georgia
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	The Children's Hospital Corporation d/b/a Boston's Children Hospital	Boston	Massachusetts
United States	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio
United States	Wayne State University School of Medicine, Children's Hospital of Michigan	Detroit	Michigan
United States	Duke University	Durham	North Carolina
United States	East Carolina University	Greenville	North Carolina
United States	Houston Methodist Research Institute	Houston	Texas
United States	Indiana Hemophilia and Thrombosis Center	Indianapolis	Indiana
United States	University of Arkansas for Medical Sciences	Little Rock	Arkansas
United States	Primary Children's Hospital Univ. of Utah	Salt Lake City	Utah
United States	Seattle Cancer Care Alliance	Seattle	Washington

Sponsors (1)

Lead Sponsor	Collaborator
Agios Pharmaceuticals, Inc.

Countries where clinical trial is conducted

United States,  Brazil,  Canada,  Czechia,  Denmark,  France,  Germany,  Italy,  Japan,  Korea, Republic of,  Netherlands,  Spain,  Switzerland,  Thailand,  Turkey,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Percentage of Participants With Adverse Events of Special Interest (AESI)	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. An AESI can be serious or non-serious.	Through 4 weeks after last dose (approximately Week 31)
Other	Change From Baseline in Bone Mineral Density Z-Score at Week 24		Baseline, Week 24
Other	Change From Baseline in Bone Mineral Density T-Score at Week 24		Baseline, Week 24
Primary	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).	Baseline, Weeks 16, 20, 24
Secondary	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).	Baseline, Weeks 16, 20, 24
Secondary	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).	Baseline, up to Week 24
Secondary	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).	Baseline, up to Week 24
Secondary	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).	Baseline, Weeks 16, 20, 24
Secondary	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).	Baseline, Weeks 16, 20, 24
Secondary	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).	Baseline, Weeks 16, 20, 24
Secondary	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).	Baseline, Weeks 16, 20, 24
Secondary	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).	Baseline, Week 24
Secondary	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).	Baseline, Week 24
Secondary	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.	From signing of informed consent form to the end of study, including follow-up (up to Day 197)
Secondary	Area Under the Curve From Time 0 to the Last Quantifiable Concentration [AUC(0-last)] for AG-348 at Week 12		Pre-dose, 30 minutes and 1, 2, 4 and 8 hours post-dose on Day 85 (Week 12)
Secondary	Maximum Plasma Concentration (Cmax) for AG-348		Pre-dose, 30 minutes and 1, 2, 4 and 8 hours post-dose on Day 85 (Week 12)
Secondary	Time to Cmax (Tmax) for AG-348		Pre-dose, 30 minutes and 1, 2, 4 and 8 hours post-dose on Day 85 (Week 12)
Secondary	Time to Last Measurable Concentration (Tlast) for AG-348		Pre-dose, 30 minutes and 1, 2, 4 and 8 hours post-dose on Day 85 (Week 12)
Secondary	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.	From first dose of mitapivat to the end of study, including follow-up (up to Day 197)
Secondary	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.	Baseline, Week 24