A Study of PTC923 in Participants With Phenylketonuria

Phenylketonuria Clinical Trial

Official title:

A Phase 3 Study of PTC923 in Subjects With Phenylketonuria

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT05099640
• Other study ID #: PTC923-MD-003-PKU
• Secondary ID: 2021-000474-29
• Status: Completed
• Phase: Phase 3
• Start date: September 30, 2021
• Est. completion date: May 3, 2023

Study information

• Verified date: December 2023
• Source: PTC Therapeutics
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 157
• Est. completion date: May 3, 2023
• Est. primary completion date: April 3, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A and older

Eligibility

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)

Related Conditions & MeSH terms

• Phenylketonuria
• Phenylketonurias

Intervention

Drug:
• PTC923
PTC923 powder for oral use will be suspended in water or apple juice prior to administration.
• Placebo
Placebo matching to PTC923

Locations

Country	Name	City	State
Australia	PARC Clinical Research	Adelaide	South Australia
Australia	Royal Melbourne Hospital	Melbourne	Victoria
Australia	Westmead Hospital	Westmead	New South Wales
Brazil	Hospital de clinicas de Porto Alegre	Porto Alegre	Rio Grande Do Sul
Brazil	Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo	Ribeirão Preto	São Paulo
Canada	Metabolics and Genetics in Calgary (MAGIC) Clinic, Ltd.	Calgary	Alberta
Canada	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	Toronto	Ontario
Denmark	Copenhagen University Hospital, Rigshospitalet	Copenhagen
France	Bretonneau Hospital - CHRU de Tours	Tours	Centre-Val De Loire
France	CHRU de Tours- Hôpital Pédiatrique de Clocheville	Tours	Centre-Val De Loire
Georgia	Pediatric Surgery Center	Tbilisi
Germany	University Children's Hospital Hamburg Eppendorf (Kinder-UKE) Klinik für Kinder- und Jugendmedizin (Kinder-UKE)	Hamburg
Germany	Universitätsklinikum Heidelberg / Zentrum für Kinder- und Jugendmedizin / Sektion für Neuropädiatrie & Stoffwechselmedizin	Heidelberg
Germany	Universitätsklinikum Münster	Münster
Italy	Division of Inherited Metabolic Diseases, Azienda Ospedaliera-Università Padova	Padua	Veneto
Italy	Policlinico Umberto I	Rome	Lazio
Mexico	Grupo Médico Camino SC	Benito Juarez	Mexico City
Mexico	PanAmerican Clinical Research	Guadalajara	Jalisco
Netherlands	UMCG Beatrix Children's Hospital	Groningen
Portugal	CENTRO HOSPITALAR UNIVERSITÁRIO LISBOA NORTE Hospital de Santa Maria	Lisboa	Estremadura
Portugal	CENTRO HOSPITALAR UNIVERSITÁRIO LISBOA NORTE Hospital de Santa Maria,	Lisboa	Estremadura
Portugal	Centro Hospitalar Universitário Do Porto, Epe	Porto	Douro Litoral
Spain	Hospital Sant Joan de Déu	Barcelona	Esplugues De Llobregat
Spain	Hospital Universitario Ramón y Cajal	Madrid
Turkey	Cukurova Üniversity Balcali Hospital Health Application and Research Center	Adana
Turkey	Hacettepe University Medical Faculty	Altindag	Ankara
Turkey	Ege University Faculty of Medicine Children Hospital	Bornova	Izmir
Turkey	Istanbul Üniversitesi Cerrahpasa Tip Fakültesi	Fatih	Istanbul
Turkey	Gazi Üniversitesi Tip Fakültesi	Yenimahalle	Ankara
United Kingdom	Birmingham Children's Hospital NHS Foundation Trust	Birmingham
United Kingdom	Great Ormond Street Hospital	London
United States	University of Colorado and the Children's Hospital CO	Aurora	Colorado
United States	Boston Children's Hospital	Boston	Massachusetts
United States	Children's Medical Center Dallas	Dallas	Texas
United States	UF College of Medicine, Department of Pediatrics Division of Genetics and Metabolism	Gainesville	Florida
United States	University of Texas Health Science Center of Texas	Houston	Texas
United States	Indiana University School of Medicine	Indianapolis	Indiana
United States	Medical College of Wisconsin	Milwaukee	Wisconsin
United States	Icahn School of Medicine at Mount Sinai (ISMMS)	New York	New York
United States	The Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	UPMC Children's Hospital of Pittsburgh	Pittsburgh	Pennsylvania
United States	University of Utah, Division of Medical Genetics (pediatric and adult clinic)	Salt Lake City	Utah
United States	Stanford University Center for Academic Medicine	Stanford	California

Sponsors (1)

Lead Sponsor	Collaborator
PTC Therapeutics

Countries where clinical trial is conducted

United States,  Australia,  Brazil,  Canada,  Denmark,  France,  Georgia,  Germany,  Italy,  Mexico,  Netherlands,  Portugal,  Spain,  Turkey,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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	Classical PKU participants: Participants with severe forms of PKU, typically very high blood Phe levels (>1200 µmol/L). Baseline was defined as the average of Day -1 and Day 1 predose blood Phe levels in Part 2, and mean level at Weeks 5 and 6 was calculated as the average of blood Phe levels collected during the Week 5-6 analysis visit window. LS mean and SE were calculated using MMRM method.	Baseline, Weeks 5 and 6 (average of the 2-week period)
Other	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	Classical PKU participants: Participants with severe forms of PKU, typically very high blood Phe levels (>1200 µmol/L). Baseline was defined as the average of Day -1 and Day 1 predose blood Phe levels in Part 2, and mean level at Weeks 5 and 6 was calculated as the average of blood Phe levels collected during the Week 5-6 analysis visit window. LS mean and SE were calculated using MMRM method.	Baseline, Weeks 5 and 6 (average of the 2-week period)
Other	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	Baseline was defined as the average of Day -1 and Day 1 predose blood Phe levels in Part 1 Open-label Run-in Phase, and mean level at Weeks 1 and 2 was calculated as the average of blood Phe levels collected during the Week 1-2 analysis visit window. LS mean and SE were calculated using MMRM method.	Baseline (Part 1), Weeks 1 and 2 (average of the 2-week period)
Other	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	Baseline was defined as the average of Day -1 and Day 1 predose blood Phe levels in Part 1 Open-label Run-in Phase, and mean level at Weeks 1 and 2 was calculated as the average of blood Phe levels collected during the Week 1-2 analysis visit window. LS mean and SE were calculated using MMRM method.	Baseline (Part 1), Weeks 1 and 2 (average of the 2-week period)
Primary	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	Baseline was defined as the average of Day -1 and Day 1 predose blood Phe levels in Part 2, and mean level at Weeks 5 and 6 was calculated as the average of blood Phe levels collected during the Week 5-6 analysis visit window. Least square (LS) mean and standard error (SE) were calculated using mixed model repeated measures (MMRM) method.	Baseline, Weeks 5 and 6 (average of the 2-week period)
Primary	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	Baseline was defined as the average of Day -1 and Day 1 predose blood Phe levels in Part 2, and mean level at Weeks 5 and 6 was calculated as the average of blood Phe levels collected during the Week 5-6 analysis visit window. LS mean and SE were calculated using MMRM method.	Baseline, Weeks 5 and 6 (average of the 2-week period)
Secondary	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	Baseline was defined as the average of Day -1 and Day 1 predose blood Phe levels in Part 2, and mean level at Weeks 5 and 6 was calculated as the average of blood Phe levels collected during the Week 5-6 analysis visit window.	Weeks 5 and 6 (average of the 2-week period)
Secondary	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	Baseline was defined as the average of Day -1 and Day 1 predose blood Phe levels in Part 2, and mean level at Weeks 5 and 6 was calculated as the average of blood Phe levels collected during the Week 5-6 analysis visit window.	Weeks 5 and 6 (average of the 2-week period)
Secondary	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	Baseline was defined as the average of Day -1 and Day 1 predose blood Phe levels in Part 2, and mean levels at Weeks 1 and 2, Weeks 3 and 4, and Weeks 5 and 6 were calculated as the average of blood Phe levels collected during the Week 1-2, Week 3-4, and Week 5-6 analysis visit windows, respectively.	Baseline, Weeks 1 and 2, Weeks 3 and 4, and Weeks 5 and 6 (average of each 2-week period)
Secondary	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	Baseline was defined as the average of Day -1 and Day 1 predose blood Phe levels in Part 2, and mean levels at Weeks 1 and 2, Weeks 3 and 4, and Weeks 5 and 6 were calculated as the average of blood Phe levels collected during the Week 1-2, Week 3-4, and Week 5-6 analysis visit windows, respectively.	Baseline, Weeks 1 and 2, Weeks 3 and 4, and Weeks 5 and 6 (average of each 2-week period)
Secondary	Part 1 Open-label Run-in Phase: Plasma Concentration of Tetrahydrobiopterin (BH4) and Sepiapterin		Predose, 0.5, 1, 2, 4, 6, 8, and 24 hours postdose at Day 1; 2 and 6 hours postdose at Day 14
Secondary	Part 2 Double-blind Phase: Plasma Concentration of BH4 and Sepiapterin		Predose and 4 hours postdose at Days 1, 14, 28, and 42
Secondary	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		0 to 24 hours postdose at Day 1
Secondary	Number of Participants With Treatment-emergent Adverse Events (TEAEs)	An adverse event (AE) was as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. TEAEs were considered: Part 1 TEAEs, which included all AEs occurring after first dose in Part 1 but before first dose in Part 2; Part 2 TEAEs, which included all AEs after first randomized dose in Part 2. A summary of all Serious Adverse Events and Other Adverse Events (nonserious) regardless of causality is located in the 'Reported Adverse Events' Section.	Baseline up to Day 42