BH4 DeficiencyPhase 1/2NCT03519711
A Study of PTC923 (CNSA-001) in Primary Tetrahydrobiopterin (BH4) Deficient Participants With Hyperphenylalaninemia
A Phase 1/2 study testing PTC923 in people with BH4 Deficiency and Hyperphenylalaninemia, run by PTC Therapeutics at 4 sites in United States.
Trial summary
This study has been designed to demonstrate the safety, pharmacokinetics (PK) and preliminary efficacy of PTC923 (CNSA-001) in reducing blood phenylalanine concentrations in participants with hyperphenylalaninemia due to primary BH4 deficiency (PBD). Read more about this study
- Who is it for?
- Ages 12 months and older
- Conditions the study is for
- BH4 Deficiency, Hyperphenylalaninemia
- What is being tested?
- PTC923
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 8 participants
- Where
- 4 sitesUnited States
- Study dates
- 3 Jan 2019to 2 Oct 2020
- Phase
- Phase 1/2
- 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 12 months and older
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- Male or female participants 18 years old and above and 12 months old and above for the remaining participants (age reduction pending analysis of safety, PK, and response, in the adult participant(s) by the Data Safety Monitoring Board (DSMB) and Food and Drug Administration [FDA])
- Confirmed diagnosis of PBD as evidenced by medical history of biallelic pathogenic mutations in PTPS or recessive GTP-CH genes, abnormal enzymatic activity of the PTPS or GTP-CH enzymes, or a cerebrospinal fluid (CSF) biochemical profile indicative of PTPS or GTP-CH deficiencies
- Informed consent and assent (if necessary) with parental consent
- Females must be either postmenopausal for ≥1 year, or surgically sterile (tubal ligation, hysterectomy, or bilateral oophorectomy) for at least 6 months or, if of childbearing potential and not abstinent, willing to use at least 2 of the following highly effective methods of contraception (including adolescents 12 to 18 years old) from screening through 30 days after the last dose of study drug:
- Hormonal contraception (stable dose for 3 months)
- Intrauterine device/intrauterine hormone-releasing system
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- Barrier contraceptive method (diaphragm, cervical cap, contraceptive sponge, condom) with spermicidal foam/gel/cream/suppository Males and females who are abstinent will not be required to use a second contraceptive method unless they become sexually active.
- Males with female partners of childbearing potential must agree to use barrier contraceptive (that is, condom) with spermicidal foam from screening through 90 days after the last dose of study drug. Males must also refrain from sperm donations during this time period.
- Females with a negative pregnancy test at screening and on Day 1 prior to dosing
- Creatinine clearance (CrCl) >90 milliliters (mL)/minute (min) as estimated using the Cockcroft-Gault equation (≥18 years) or Schwartz-Lyon equation (≥12 months <18 years)
- The participant is clinically stable on therapy for management of their signs and symptoms of PBD as determined by the investigator.
- The participant is willing and able to comply with the protocol.
- No tobacco use (for example; cigarettes, e-cigarettes, cigars, smokeless tobacco) for 2 weeks prior to the screening visit and willingness to abstain from these products through the last dose of study drug
Who cannot join
- PBD caused by biallelic pathogenic mutations in PCD, SR, DHPR, or single dominant mutations in GTP-CH
- Significant chronic medical illness other than PBD, as determined by the investigator
- Gastrointestinal disease (such as irritable bowel syndrome, inflammatory bowel disease, chronic gastritis, 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
- Inability to tolerate oral medication
- History of allergies or adverse reactions to BH4 or related compounds, or any excipients in the study drug formulation
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- Any clinically significant medical or psychiatric condition or medical history, that in the opinion of the investigator, would interfere with the participant's ability to participate in the study or increase the risk of participation for that participant
- Known infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV)
- Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) laboratory values >2 * the upper limit of normal (ULN)
- Any other clinically significant laboratory abnormality unrelated to PBD at the screening visit or prior to the administration of the first dose of study drug, as determined by the investigator
- Clinically significant cardiac arrhythmia at screening or prior to the first dose of study drug
- QTcF (QT with Fridericia's correction) ≥460 milliseconds (msec) in males and ≥480 msec in females (based on the mean of triplicate measurements taken at screening)
- Resting heart rate ≤40 or ≥110 beats/minute (bpm) for ages 12 and older, ≥130 bpm for ages 3 to 12, ≥150 bpm for ages 1 to 2 years, or resting blood pressure <85/40 millimeters of mercury (mmHg) or >150/90 mmHg at screening or prior to the first administration of study drug
- Current participation in any other investigational drug study or participation within 30 days prior to screening
- History of alcohol or drug abuse within last 6 months prior to screening or current evidence of substance dependence as determined by the investigator
- Currently taking an antifolate including, but not limited to, methotrexate, pemetrexed, or trimetrexate
- A female who is nursing or who is pregnant or planning to become pregnant.
- The participant, in the opinion of the investigator, is unwilling or unable to adhere to the requirements of the study.
Trial locations and contacts
4 sites in 1 country.
United States4 sites
UT Southwestern
Dallas, Texas, 75390
Marshfield Clinic
Marshfield, Wisconsin, 54449
University of Minnesota
Minneapolis, Minnesota, 55454
University of Utah Hospital
Salt Lake City, Utah, 84132
About this study
Official title: A Phase 1/2, Open-Label, Randomized Parallel Arm, Intra-patient Dose Escalation Study to Evaluate the Safety, Pharmacokinetics and Preliminary Efficacy of CNSA-001(Sepiapterin) in Primary Tetrahydrobiopterin Deficient Patients With Hyperphenylalaninemia
This study has been designed to demonstrate the safety, pharmacokinetics (PK) and preliminary efficacy of PTC923 (CNSA-001) in reducing blood phenylalanine concentrations in participants with hyperphenylalaninemia due to primary BH4 deficiency (PBD).
Read the detailed description
BH4 is an essential cofactor for phenylalanine hydroxylase, tyrosine hydroxylase, tryptophan hydroxylase, fatty acid glycerylether oxygenase, and nitric oxide (NO) synthase. The PBD is caused by deficiency of GTP cyclohydrolase I (GTP-CH), 6-pyruvoyl-tetrahydropterin synthase (PTPS), or sepiapterin reductase (SR) that impairs the biosynthesis of BH4 or by defects in BH4 recycling (pterin-4a-carbinolamine dehydratase [PCD] or dihydropteridine reductase [DHPR] deficiency).
Participants will be randomized into one of 2 cohorts, with each cohort assessing 2 dose levels of PTC923 via intra-participant escalation.
- Conditions
- BH4 Deficiency, Hyperphenylalaninemia
- Being tested
- PTC923
- Medical subject headings
- Phenylketonurias
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
PTC923Drug
Also called CNSA-001, Sepiapterin
PTC923 will be administered per dose and schedule specified in arm description.
| Study group | Role | What they receive |
|---|---|---|
| Cohort 1: PTC923 2.5 and 10 mg/kg/day | Experimental | Participants will receive PTC923 suspension 2.5 milligrams (mg)/kilogram (kg)/day (dose divided in 2 for twice daily administration) orally for 7 days in Period 1, undergo a 3 (±1) day washout period, then escalate to a dose of 10 mg/kg/day (dose divided in 2 for twice daily administration) administered orally for 7 days in Period 2 (14 days total treatment). Receives: Drug: PTC923 |
| Cohort 2: PTC923 5 and 20 mg/kg/day | Experimental | Participants will receive PTC923 suspension 5 mg/kg/day (dose divided in 2 for twice daily administration) orally for 7 days in Period 1, undergo a 3 (±1) day washout period, then escalate to a dose of 20 mg/kg/day (dose divided in 2 for twice daily administration) administered orally for 7 days in Period 2 (14 days total treatment). Receives: Drug: PTC923 |
What is being measured
The primary outcome is the main question the study is designed to answer.
Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
An adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. AEs included both SAEs and non-serious AEs. TEAEs were defined as AEs that commenced or worsened after the first dose of study drug. A summary of other non-serious AEs and all SAEs, regardless of causality is located in the 'Reported AE section'.
Measured: From first dose of study drug (Day 1) up to 30 (±3) days after last dose of study drug (up to 50 days)
Secondary outcomes (9)
Maximum Observed Plasma Concentration (Cmax) of PTC923 and Tetrahydrobiopterin (BH4)
Measured: Day 1 (pre-dose, within 30 minutes of dosing), 0.5, 1, 2, 4, 6, 8 hours postdose (prior to Day 1 evening dose), and 24 hours postdose (prior to Day 2 morning dose)
Cmax of Phenylalanine (Phe) and Tyrosine (Tyr)
Measured: Day 1 (pre-dose, within 30 minutes of dosing), 0.5, 1, 2, 4, 6, 8 hours postdose (prior to Day 1 evening dose), 24 hours postdose (prior to Day 2 morning dose), 72 hours postdose (Day 4), on Day 7, and at the end of study (48 hours after last dose)
Area Under the Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUC0-last) of PTC923 and BH4
Measured: Day 1 (pre-dose, within 30 minutes of dosing), 0.5, 1, 2, 4, 6, 8 hours postdose (prior to Day 1 evening dose), and 24 hours postdose (prior to Day 2 morning dose)
AUC0-last of Phe and Tyr
Measured: Day 1 (pre-dose, within 30 minutes of dosing), 0.5, 1, 2, 4, 6, 8 hours postdose (prior to Day 1 evening dose), 24 hours postdose (prior to Day 2 morning dose), 72 hours postdose (Day 4), on Day 7, and at the end of study (48 hours after last dose)
Time to Reach Cmax (Tmax) of PTC923 and BH4
Measured: Day 1 (pre-dose, within 30 minutes of dosing), 0.5, 1, 2, 4, 6, 8 hours postdose (prior to Day 1 evening dose), and 24 hours postdose (prior to Day 2 morning dose)
Tmax of Phe and Tyr
Measured: Day 1 (pre-dose, within 30 minutes of dosing), 0.5, 1, 2, 4, 6, 8 hours postdose (prior to Day 1 evening dose), 24 hours postdose (prior to Day 2 morning dose), 72 hours postdose (Day 4), on Day 7, and at the end of study (48 hours after last dose)
Change From Baseline (Day 1) in Plasma Phe Concentration at Day 7
Measured: Baseline (Day 1, pre-dose); Day 7
Number of Participants With Phe Concentrations in Acceptable Treatment Range of 130 to 360 μmol/L at Day 7
Measured: Day 7
Number of Participants With Normal Blood Phe Concentrations <130 μmol/L at Day 7
Measured: Day 7
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted9 May 2018
- Study start3 Jan 2019
- Primary completion2 Oct 2020
- Study completion2 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.
- Other trials for BH4 DeficiencyStudies of the same condition, open and under way.
- 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 1/2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 8 participants (actual)
Sponsor and investigators
- Lead sponsor
- PTC Therapeutics
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Neil Smith, PharmD, Study director, Censa Pharmaceuticals
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03519711
- Sponsor's protocol ID
- PBD-001
- Status last verified
- May 2022
- First submitted
- 11 Apr 2018
- Last updated
- 14 Nov 2023
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 14 Nov 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase 1/2, Open-Label, Randomized Parallel Arm, Intra-patient Dose Escalation Study to Evaluate the Safety, Pharmacokinetics and Preliminary Efficacy of CNSA-001(Sepiapterin) in Primary Tetrahydrobiopterin Deficient Patients With Hyperphenylalaninemia
- ClinicalTrials.gov ID
- NCT03519711
- Acronym / sponsor ID
- PBD-001
- Conditions
- BH4 Deficiency, Hyperphenylalaninemia
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 8 participants (actual)
- Lead sponsor
- PTC TherapeuticsIndustry (pharma, biotech, devices)
- Study start
- 3 Jan 2019 (actual)
- Primary completion
- 2 Oct 2020 (actual)
- Study completion
- 2 Oct 2020 (actual)
- First posted
- 9 May 2018 (actual)
- Results
- Posted 14 Nov 2023
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This study has been designed to demonstrate the safety, pharmacokinetics (PK) and preliminary efficacy of PTC923 (CNSA-001) in reducing blood phenylalanine concentrations in participants with hyperphenylalaninemia due to primary BH4 deficiency (PBD).
Detailed description
BH4 is an essential cofactor for phenylalanine hydroxylase, tyrosine hydroxylase, tryptophan hydroxylase, fatty acid glycerylether oxygenase, and nitric oxide (NO) synthase. The PBD is caused by deficiency of GTP cyclohydrolase I (GTP-CH), 6-pyruvoyl-tetrahydropterin synthase (PTPS), or sepiapterin reductase (SR) that impairs the biosynthesis of BH4 or by defects in BH4 recycling (pterin-4a-carbinolamine dehydratase [PCD] or dihydropteridine reductase [DHPR] deficiency).
Participants will be randomized into one of 2 cohorts, with each cohort assessing 2 dose levels of PTC923 via intra-participant escalation.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Cohort 1: PTC923 2.5 and 10 mg/kg/day | Experimental | Drug: PTC923Participants will receive PTC923 suspension 2.5 milligrams (mg)/kilogram (kg)/day (dose divided in 2 for twice daily administration) orally for 7 days in Period 1, undergo a 3 (±1) day washout period, then escalate to a dose of 10 mg/kg/day (dose divided in 2 for twice daily administration) administered orally for 7 days in Period 2 (14 days total treatment). |
| Cohort 2: PTC923 5 and 20 mg/kg/day | Experimental | Drug: PTC923Participants will receive PTC923 suspension 5 mg/kg/day (dose divided in 2 for twice daily administration) orally for 7 days in Period 1, undergo a 3 (±1) day washout period, then escalate to a dose of 20 mg/kg/day (dose divided in 2 for twice daily administration) administered orally for 7 days in Period 2 (14 days total treatment). |
Who may qualify
- Ages
- 12 months and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (13 listed)
- Male or female participants 18 years old and above and 12 months old and above for the remaining participants (age reduction pending analysis of safety, PK, and response, in the adult participant(s) by the Data Safety Monitoring Board (DSMB) and Food and Drug Administration [FDA])
- Confirmed diagnosis of PBD as evidenced by medical history of biallelic pathogenic mutations in PTPS or recessive GTP-CH genes, abnormal enzymatic activity of the PTPS or GTP-CH enzymes, or a cerebrospinal fluid (CSF) biochemical profile indicative of PTPS or GTP-CH deficiencies
- Informed consent and assent (if necessary) with parental consent
- Females must be either postmenopausal for ≥1 year, or surgically sterile (tubal ligation, hysterectomy, or bilateral oophorectomy) for at least 6 months or, if of childbearing potential and not abstinent, willing to use at least 2 of the following highly effective methods of contraception (including adolescents 12 to 18 years old) from screening through 30 days after the last dose of study drug:
- Males with female partners of childbearing potential must agree to use barrier contraceptive (that is, condom) with spermicidal foam from screening through 90 days after the last dose of study drug. Males must also refrain from sperm donations during this time period.
Key exclusion criteria (18 listed)
- PBD caused by biallelic pathogenic mutations in PCD, SR, DHPR, or single dominant mutations in GTP-CH
- Significant chronic medical illness other than PBD, as determined by the investigator
- Gastrointestinal disease (such as irritable bowel syndrome, inflammatory bowel disease, chronic gastritis, 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
- Inability to tolerate oral medication
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 |
|---|---|---|
| PTC923Also: CNSA-001, SepiapterinPTC923 will be administered per dose and schedule specified in arm description. | Drug | Cohort 1: PTC923 2.5 and 10 mg/kg/day, Cohort 2: PTC923 5 and 20 mg/kg/day |
Primary outcome
Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
Time frame: From first dose of study drug (Day 1) up to 30 (±3) days after last dose of study drug (up to 50 days)
An adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. AEs included both SAEs and non-serious AEs. TEAEs were defined as AEs that commenced or worsened after the first dose of study drug. A summary of other non-serious AEs and all SAEs, regardless of causality is located in the 'Reported AE section'.
9 secondary outcomes
Maximum Observed Plasma Concentration (Cmax) of PTC923 and Tetrahydrobiopterin (BH4)
Time frame: Day 1 (pre-dose, within 30 minutes of dosing), 0.5, 1, 2, 4, 6, 8 hours postdose (prior to Day 1 evening dose), and 24 hours postdose (prior to Day 2 morning dose)
Cmax of Phenylalanine (Phe) and Tyrosine (Tyr)
Time frame: Day 1 (pre-dose, within 30 minutes of dosing), 0.5, 1, 2, 4, 6, 8 hours postdose (prior to Day 1 evening dose), 24 hours postdose (prior to Day 2 morning dose), 72 hours postdose (Day 4), on Day 7, and at the end of study (48 hours after last dose)
Area Under the Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUC0-last) of PTC923 and BH4
Time frame: Day 1 (pre-dose, within 30 minutes of dosing), 0.5, 1, 2, 4, 6, 8 hours postdose (prior to Day 1 evening dose), and 24 hours postdose (prior to Day 2 morning dose)
AUC0-last of Phe and Tyr
Time frame: Day 1 (pre-dose, within 30 minutes of dosing), 0.5, 1, 2, 4, 6, 8 hours postdose (prior to Day 1 evening dose), 24 hours postdose (prior to Day 2 morning dose), 72 hours postdose (Day 4), on Day 7, and at the end of study (48 hours after last dose)
Time to Reach Cmax (Tmax) of PTC923 and BH4
Time frame: Day 1 (pre-dose, within 30 minutes of dosing), 0.5, 1, 2, 4, 6, 8 hours postdose (prior to Day 1 evening dose), and 24 hours postdose (prior to Day 2 morning dose)
Tmax of Phe and Tyr
Time frame: Day 1 (pre-dose, within 30 minutes of dosing), 0.5, 1, 2, 4, 6, 8 hours postdose (prior to Day 1 evening dose), 24 hours postdose (prior to Day 2 morning dose), 72 hours postdose (Day 4), on Day 7, and at the end of study (48 hours after last dose)
Change From Baseline (Day 1) in Plasma Phe Concentration at Day 7
Time frame: Baseline (Day 1, pre-dose); Day 7
Number of Participants With Phe Concentrations in Acceptable Treatment Range of 130 to 360 μmol/L at Day 7
Time frame: Day 7
Number of Participants With Normal Blood Phe Concentrations <130 μmol/L at Day 7
Time frame: Day 7
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 14 Nov 2023.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Individual participant dataSharing planned: No
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Recruiting
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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.
Neil Smith, PharmD study director
Censa Pharmaceuticals
4 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing PTC923 in people with BH4 Deficiency and Hyperphenylalaninemia, run by PTC Therapeutics at 4 sites in United States.
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 13 inclusion and 18 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 14 Nov 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 4 sites in United States. 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 combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
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 14 Nov 2023). 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?
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) (time frame: From first dose of study drug (Day 1) up to 30 (±3) days after last dose of study drug (up to 50 days)). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
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 14 Nov 2023.