Clinical trial NCT05099640: A Study of PTC923 in Participants With Phenylketonuria
Official title: A Phase 3 Study of PTC923 in Subjects With Phenylketonuria
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Phenylketonuria
Lead sponsor: PTC Therapeutics
Sponsor class: INDUSTRY
First posted: 2021-10-29
Enrollment: 157
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The main purpose of this trial is to evaluate the efficacy of PTC923 in reducing blood phenylalanine (Phe) levels in participants with phenylketonuria as measured by mean change in blood Phe levels from baseline to Weeks 5 and 6 (that is, the average of each respective treatment dose 2-week period of double-blind treatment).

Detailed description: The study includes 2 parts: Part 1 and 2. Part 1 of the study tests for responsiveness to PTC923, with 14 days of open-label treatment with PTC923. At the end of treatment in Part 1, the mean change in blood Phe levels over the 14-day treatment period for all participants will be assessed against their pretreatment (baseline) blood Phe level. Participants ≥2 years of age who experience a \<15% reduction in blood Phe levels will be classified as non-responsive and participation in the study will be terminated. Participants (≥2 years of age) who experience a ≥15% reduction in blood Phe levels will continue into Part 2. Participants \<2 years of age who experience ≥15% reduction in blood Phe levels will be offered the option to enroll directly into an open-label extension Study PTC923-MD-004-PKU. Participants \<2 years of age who experience a \<15% reduction in blood Phe levels will be classified as nonresponsive, and participation in the study will be terminated. Following the minimum 14-day PTC923 washout period, all eligible participants will be randomized in Part 2 to receive either PTC923 or placebo. After 6 weeks of treatment with either PTC923 or placebo, participants will be offered the option to enter an open-label extension Study PTC923-MD-004-PKU (NCT05166161).

Eligibility criteria: Inclusion Criteria:

* Uncontrolled blood Phe level ≥360 μmol/L on current therapy anytime during screening and uncontrolled blood Phe level ≥360 μmol/L on current therapy when taking the average of the 3 most recent Phe levels from the participant's medical history (inclusive of the screening value).
* Clinical diagnosis of phenylketonuria with hyperphenylalaninemia (HPA) documented by past medical history of at least 2 blood Phe measurements ≥600 μmol/L.
* Women of childbearing potential must have a negative pregnancy test at screening and agree to abstinence or the use of at least one highly effective form of contraception for the duration of the study, and for up to 90 days after the last dose of study drug.
* Males who are sexually active with women of childbearing potential who have not had a vasectomy must agree to use a barrier method of birth control during the study and for up to 90 days after the last dose of study drug. Males must also refrain from sperm donations during this time period.
* Willing to continue current diet unchanged while participating in the study.

Exclusion Criteria:

* Gastrointestinal disease (such as irritable bowel syndrome, inflammatory bowel disease, chronic gastritis, and peptic ulcer disease, etc.) that could affect the absorption of study drug.
* History of gastric surgery, including Roux-en-Y gastric bypass surgery or an antrectomy with vagotomy, or gastrectomy.
* History of allergies or adverse reactions to synthetic tetrahydrobiopterin (BH4) or sepiapterin.
* Current participation in any other investigational drug study or use of any investigational agent within 30 days prior to screening.
* Any clinically significant laboratory abnormality as determined by the investigator.
* A female who is pregnant or breastfeeding, or considering pregnancy.
* Serious neuropsychiatric illness (for example, major depression) not currently under medical control, that in the opinion of the investigator or sponsor, would interfere with the participant's ability to participate in the study or increase the risk of participation for that participant.
* Past medical history and/or evidence of renal impairment and/or condition including moderate/severe renal insufficiency (glomerular filtration rate \[GFR\] \<60 milliliters \[mL\]/minute \[min\]) and/or under care of a nephrologist.
* Any abnormal physical examination and/or laboratory findings indicative of signs or symptoms of renal disease, including calculated GFR \<60 mL/min/1.73 square meter (m\^2).
* Requirement for concomitant treatment with any drug known to inhibit folate synthesis (for example, methotrexate).
* Confirmed diagnosis of a primary BH4 deficiency as evidenced by biallelic pathogenic mutations in 6-pyruvoyltetrahydropterin synthase, recessive guanosine-5'-triphosphate (GTP) cyclohydrolase I, sepiapterin reductase, quinoid dihydropteridine reductase, or pterin-4-alpha-carbinolamine dehydratase genes.
* Major surgery within the prior 90 days of screening.
* Concomitant treatment with BH4 supplementation (for example, sapropterin dihydrochloride, KUVAN) or pegvaliase-pqpz (PALYNZIQ).
* Unwillingness to washout from BH4 supplementation (for example, sapropterin dihydrochloride, KUVAN) or pegvaliase-pqpz (PALYNZIQ)

Primary outcomes:
measure: Part 2 Double-blind Phase: Mean Change From Baseline in Blood Phenylketonuria (Phe) Level to Weeks 5 and 6 (Averaged Over a 2-week Period) in Participants With Phe Reduction From Baseline ≥30% During Part 1
timeFrame: Baseline, Weeks 5 and 6 (average of the 2-week period)
measure: Part 2 Double-blind Phase: Percent Change From Baseline in Blood Phe Level to Weeks 5 and 6 (Averaged Over a 2-week Period) in Participants With Phe Reduction From Baseline ≥30% During Part 1
timeFrame: Baseline, Weeks 5 and 6 (average of the 2-week period)
Secondary outcomes:
measure: Part 2 Double-blind Phase: Percentage of Participants With Baseline Phe Levels ≥600 μmol/L Who Achieved Phe Levels <600 μmol/L in Participants With Phe Reduction From Baseline ≥30% During Part 1
timeFrame: Weeks 5 and 6 (average of the 2-week period)
measure: Part 2 Double-blind Phase: Percentage of Participants With Baseline Phe Levels ≥360 μmol/L Who Achieved Phe Levels <360 μmol/L in Participants With Phe Reduction From Baseline ≥30% During Part 1
timeFrame: Weeks 5 and 6 (average of the 2-week period)
measure: Part 2 Double-blind Phase: Mean Change From Baseline in Blood Phe Level at Each 2-Week Period (Averaged Over Each 2-Week Period) in Participants With Phe Reduction From Baseline ≥30% During Part 1
timeFrame: Baseline, Weeks 1 and 2, Weeks 3 and 4, and Weeks 5 and 6 (average of each 2-week period)
measure: Part 2 Double-blind Phase: Percent Change From Baseline in Blood Phe Level at Each 2-Week Period (Averaged Over Each 2-Week Period) in Participants With Phe Reduction From Baseline ≥30% During Part 1
timeFrame: Baseline, Weeks 1 and 2, Weeks 3 and 4, and Weeks 5 and 6 (average of each 2-week period)
measure: Part 1 Open-label Run-in Phase: Plasma Concentration of Tetrahydrobiopterin (BH4) and Sepiapterin
timeFrame: Predose, 0.5, 1, 2, 4, 6, 8, and 24 hours postdose at Day 1; 2 and 6 hours postdose at Day 14
measure: Part 2 Double-blind Phase: Plasma Concentration of BH4 and Sepiapterin
timeFrame: Predose and 4 hours postdose at Days 1, 14, 28, and 42
measure: Part 1 Open-label Run-in Phase: Area Under the Concentration-time Curve From Time 0 to 24 Hours Postdose (AUC0-24h) of Sepiapterin and BH4 Following the First Dose of Sepiapterin at 60 mg/kg
timeFrame: 0 to 24 hours postdose at Day 1
measure: Number of Participants With Treatment-emergent Adverse Events (TEAEs)
timeFrame: Baseline up to Day 42
Other outcomes:
measure: Part 2 Double-blind Phase: Mean Change From Baseline in Blood Phe Level to Weeks 5 and 6 (Averaged Over a 2-week Period) in Classical PKU Participants With Phe Reduction From Baseline ≥30% During Part 1
timeFrame: Baseline, Weeks 5 and 6 (average of the 2-week period)
measure: Part 2 Double-blind Phase: Percent Change From Baseline in Blood Phe Level to Weeks 5 and 6 (Averaged Over a 2-week Period) in Classical PKU Participants With Phe Reduction From Baseline ≥30% During Part 1
timeFrame: Baseline, Weeks 5 and 6 (average of the 2-week period)
measure: Part 1 Open-label Run-in Phase: Mean Change From Baseline (Part 1) in Blood Phe Level to Weeks 1 and 2 (Averaged Over a 2-week Period) in Participants With Phe Reduction From Baseline ≥30% During Part 1
timeFrame: Baseline (Part 1), Weeks 1 and 2 (average of the 2-week period)
measure: Part 1 Open-label Run-in Phase: Percent Change From Baseline (Part 1) in Blood Phe Level to Weeks 1 and 2 (Averaged Over a 2-week Period) in Participants With Phe Reduction From Baseline ≥30% During Part 1
timeFrame: Baseline (Part 1), Weeks 1 and 2 (average of the 2-week period)
Locations:
city: Stanford
country: United States
facility: Stanford University Center for Academic Medicine
state: California
city: Aurora
country: United States
facility: University of Colorado and the Children's Hospital CO
state: Colorado
city: Gainesville
country: United States
facility: UF College of Medicine, Department of Pediatrics Division of Genetics and Metabolism
state: Florida
city: Indianapolis
country: United States
facility: Indiana University School of Medicine
state: Indiana
city: Boston
country: United States
facility: Boston Children's Hospital
state: Massachusetts
city: New York
country: United States
facility: Icahn School of Medicine at Mount Sinai (ISMMS)
state: New York
city: Philadelphia
country: United States
facility: The Children's Hospital of Philadelphia
state: Pennsylvania
city: Pittsburgh
country: United States
facility: UPMC Children's Hospital of Pittsburgh
state: Pennsylvania
city: Dallas
country: United States
facility: Children's Medical Center Dallas
state: Texas
city: Houston
country: United States
facility: University of Texas Health Science Center of Texas
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah, Division of Medical Genetics (pediatric and adult clinic)
state: Utah
city: Milwaukee
country: United States
facility: Medical College of Wisconsin
state: Wisconsin
city: Westmead
country: Australia
facility: Westmead Hospital
state: New South Wales
city: Adelaide
country: Australia
facility: PARC Clinical Research
state: South Australia
city: Melbourne
country: Australia
facility: Royal Melbourne Hospital
state: Victoria
city: Porto Alegre
country: Brazil
facility: Hospital de clinicas de Porto Alegre
state: Rio Grande Do Sul
city: Ribeirão Preto
country: Brazil
facility: Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo
state: São Paulo
city: Calgary
country: Canada
facility: Metabolics and Genetics in Calgary (MAGIC) Clinic, Ltd.
state: Alberta
city: Toronto
country: Canada
facility: The Hospital for Sick Children University of Toronto, Adult Clinic: The Fred A Litwin Family Centre in Genetic Medicine University Health Network & Mt. Sinai Hospital
state: Ontario
city: Copenhagen
country: Denmark
facility: Copenhagen University Hospital, Rigshospitalet
city: Tours
country: France
facility: Bretonneau Hospital - CHRU de Tours
state: Centre-Val De Loire
city: Tours
country: France
facility: CHRU de Tours- Hôpital Pédiatrique de Clocheville
state: Centre-Val De Loire
city: Tbilisi
country: Georgia
facility: Pediatric Surgery Center
city: Hamburg
country: Germany
facility: University Children's Hospital Hamburg Eppendorf (Kinder-UKE) Klinik für Kinder- und Jugendmedizin (Kinder-UKE)
city: Heidelberg
country: Germany
facility: Universitätsklinikum Heidelberg / Zentrum für Kinder- und Jugendmedizin / Sektion für Neuropädiatrie & Stoffwechselmedizin
city: Münster
country: Germany
facility: Universitätsklinikum Münster
city: Rome
country: Italy
facility: Policlinico Umberto I
state: Lazio
city: Padua
country: Italy
facility: Division of Inherited Metabolic Diseases, Azienda Ospedaliera-Università Padova
state: Veneto
city: Guadalajara
country: Mexico
facility: PanAmerican Clinical Research
state: Jalisco
city: Benito Juarez
country: Mexico
facility: Grupo Médico Camino SC
state: Mexico City
city: Groningen
country: Netherlands
facility: UMCG Beatrix Children's Hospital
city: Porto
country: Portugal
facility: Centro Hospitalar Universitário Do Porto, Epe
state: Douro Litoral
city: Lisboa
country: Portugal
facility: CENTRO HOSPITALAR UNIVERSITÁRIO LISBOA NORTE Hospital de Santa Maria,
state: Estremadura
city: Lisboa
country: Portugal
facility: CENTRO HOSPITALAR UNIVERSITÁRIO LISBOA NORTE Hospital de Santa Maria
state: Estremadura
city: Barcelona
country: Spain
facility: Hospital Sant Joan de Déu
state: Esplugues De Llobregat
city: Madrid
country: Spain
facility: Hospital Universitario Ramón y Cajal
city: Altındağ
country: Turkey
facility: Hacettepe University Medical Faculty
state: Ankara
city: Yenimahalle
country: Turkey
facility: Gazi Üniversitesi Tıp Fakültesi
state: Ankara
city: Fatih
country: Turkey
facility: İstanbul Üniversitesi Cerrahpaşa Tıp Fakültesi
state: Istanbul
city: Bornova
country: Turkey
facility: Ege University Faculty of Medicine Children Hospital
state: Izmir
city: Adana
country: Turkey
facility: Cukurova Üniversity Balcali Hospital Health Application and Research Center
city: Birmingham
country: United Kingdom
facility: Birmingham Children's Hospital NHS Foundation Trust
city: London
country: United Kingdom
facility: Great Ormond Street Hospital
Study officials:
References: