Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12622000523707
Ethics application status
Approved
Date submitted
19/03/2021
Date registered
1/04/2022
Date last updated
14/10/2022
Date data sharing statement initially provided
1/04/2022
Type of registration
Retrospectively registered

Titles & IDs
Public title
A Phase 1, Randomized, Open-Label, Crossover Study to Evaluate the Relative Oral Bioavailability of 2 Formulations of PTC923 and the Food Effect on the Phase 3 Formulation When Administered as a Single Dose to Healthy Subjects
Scientific title
A Phase 1, Randomized, Open-Label, Crossover Study to Evaluate the Relative Oral Bioavailability of 2 Formulations of PTC923 and the Food Effect on the Phase 3 Formulation When Administered as a Single Dose to Healthy Subjects
Secondary ID [1] 303493 0
PTC923-MD-005-HV
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Phenylketonuria (PKU) 320827 0
Condition category
Condition code
Metabolic and Endocrine 318651 318651 0 0
Metabolic disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is a Phase 1, open-label, randomized, single dose, crossover study consisting of 2 independent parts: a relative bioavailability study of 2 formulations (Formulation A and Formulation B) and 2 doses of PTC923 (Part A); and a food effect study of Formulation B (Part B) in in healthy adult subjects. Subjects are permitted to participate in one study part (Part A or Part B) only.

Part A is a cross over study between Formulation A and Formulation B. Part A and Part B are independent of each other. Part B is a cross over study between fasted and fed of Formulation B.

Mode of administration: Oral suspension. Formulation B is a powder mixed with water and Formulation A is a powder mixed with ‘Medisca Oral Mix’ oral suspension.

Ingestion will be under clinical monitoring. Subjects are inpatients at CMAX. Laboratory tests for PK will also confirm ingestion.

Part A
Subjects will be randomized into the 2 treatment sequences of PTC923 in a 1:1 ratio. Each treatment is a single dose, and each treatment will be separated from the next by a minimum of 3-day washout period.
Sequence 1: 20 mg/kg Formulation A PTC923, 20 mg/kg Formulation B PTC923, 60 mg/kg Formulation A PTC923, and 60 mg/kg Formulation B PTC923 -all administered concurrent with a low-fat meal.
Sequence 2: 20 mg/kg Formulation B PTC923, 20 mg/kg Formulation A PTC923, 60 mg/kg Formulation B PTC923, and 60 mg/kg Formulation A PTC923 -all administered concurrent with a low-fat meal.
Part B

Subjects will be randomized into the 2 treatment sequences of PTC923 in a 1:1 ratio. Each treatment is a single dose, and each treatment will be separated from the next by a minimum of 3-day washout period. Subjects will only receive Formulation B PTC923 in this study part.
Sequence 3: 20 mg/kg Formulation B PTC923 fasted, 20 mg/kg Formulation B PTC923 high-fat fed, 60 mg/kg
Formulation B PTC923 fasted, and 60 mg/kg Formulation B PTC923 high-fat fed
Sequence 4: 20 mg/kg Formulation B PTC923 high-fat fed, 20 mg/kg Formulation B PTC923 fasted, 60 mg/kg Formulation B PTC923 high-fat fed, and 60 mg/kg Formulation B PTC923 fasted.

Formulation B is a powder mixed with water and Formulation A is a powder mixed with ‘Medisca Oral Mix’ oral suspension.

Low fat is a 400-500 calorie meal with 25% of the calories from fat. An example of a low fat meal is one boiled egg, one packet of instant oatmeal made with water and one cup of low fat milk – with the whole meal containing approximately 25% fat.

High fat is a 800-1000 calorie meal with 60% of the calories from fat. An example of a high fat meal is two eggs fried in butter, two strips of bacon, two slices of toast with butter, four ounces of hash brown potatoes and eight ounces of whole milk – with the whole meal containing approximately 60% fat.

Fasting is for 10 hours overnight fast.

Formulation B is provided 30 minutes after the high fat meal is consumed.

The fasting is an overnight fast of 10 hours with up to 240 mL of water allowed during the fast. Water (except water provided with each dosing) will be restricted 1 hour prior to and 1 hour after each study drug administration. After the dose subjects may consume water ad libitum from 1 hour a snack from 4 hours post dose, if desired.

Intervention code [1] 319790 0
Treatment: Drugs
Comparator / control treatment
For Part A, Formulation A is the reference comparator. For Part B, the fasted state is the reference comparator.
Control group
Active

Outcomes
Primary outcome [1] 326598 0
Part A, Primary Outcome - This is a composite outcome.

To assess the relative bioavailability of the analytes BH4 and sepiapterin following administration of 2 dose levels (20 and 60 mg/kg/day) and 2 formulations (Formulation B: the Phase 3 formulation powder in water, and Formulation A: the Phase 1/2 formulation powder in Medisca Oral Mix) of PTC923 under fed conditions (low-fat diet) in healthy adult subjects
Timepoint [1] 326598 0
For each dose, blood samples will be collected for PK analysis of sepiapterin and BH4 from subjects at:
Day 1, Predose, 0.25, 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16, and 24 hours postdose.
Day 4, Predose, 0.25, 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16, and 24 hours postdose.
Day 7 Predose, 0.25, 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16, and 24 hours postdose.
Day 10 Predose, 0.25, 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16, and 24 hours postdose.
Primary outcome [2] 330653 0
Part B, Primary Outcome

To assess the effect of food on 2 dose levels of PTC923 Formulation B in healthy adult subjects.
Timepoint [2] 330653 0
For each dose, blood samples will be collected for PK analysis of sepiapterin and BH4 from subjects at:
Day 1, Predose, 0.25, 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16, and 24 hours postdose.
Day 4, Predose, 0.25, 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16, and 24 hours postdose.
Day 7 Predose, 0.25, 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16, and 24 hours postdose.
Day 10 Predose, 0.25, 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16, and 24 hours postdose.
Secondary outcome [1] 392048 0
To assess the safety and tolerability of a single oral administration of PTC923 under fed conditions in healthy adult subjects.
This is assessed by the following:
12-Lead ECG , Physician exam, Vital Signs, Height, PK blood sample, Adverse events monitoring, Safety follow up, and Clinical laboratory tests including clinical chemistry panel, hematology panel, and urinalysis.
Timepoint [1] 392048 0
Day 7 (24-48 hours after Day 5). The timepoint noted as Day 7 is really Day 6 or 7, as this timepoint is between 24-48 hours after Day 5 timepoint.
See timepoints for assessment here:
12-Lead ECG at Screening, Day-1, D1, D3, D4, D6, D7, D9, D10. ECGs performed in triplicate at Screening, D1, D4, D7, D10
Physician exam at Screening, Day-1, D1, D2, D3, D4, D5, D6, D7, D8, D9, D10, D11.
Vital Signs at Screening, Day-1, D1, D2, D3, D4, D5, D6, D7, D8, D9, D10, D11. Height assessed with vital signs only at the Screening visit.
PK blood sample at Day 1, D2, D4, D5, D7, D8, D10, D11
Adverse events monitoring at Screening, Day-1, D1, D2, D3, D4, D5, D6, D7, D8, D9, D10, D11, EOS 48 hours after discharge, Safety follow up 30 days after last dose
Clinical laboratory tests include clinical chemistry panel, hematology panel, and urinalysis. Clinical labs will be taken at Screening, Day-1, D1, D2, D3, D4, D5, D6, D7, D8, D9, D10, D11
Secondary outcome [2] 392049 0
To assess the palatability of Formulation B using a visual analogue scale to rate formulation parameters of odor, taste, and aftertaste. This is a composite potability scale.
Timepoint [2] 392049 0
Day 7 (24-48 hours after Day 5). The timepoint noted as Day 7 is really Day 6 or 7, as this timepoint is between 24-48 hours after Day 5 timepoint.

Eligibility
Key inclusion criteria
Individuals eligible to participate in this study include those who meet all of the following
inclusion criteria:
1. Males or females aged between 18 and 55 years old and have a Body Mass Index between 18.5 and 30.0 kg/m squared
2. Subjects must understand the nature of the study and must provide signed and dated written informed consent before the conduct of any study-related procedures.
3. Women of childbearing potential must have a negative pregnancy testing at Screening and agree to abstinence or the use of effective forms of contraception (with a failure rate of less than 1% per year when used consistently and correctly. Highly effective contraception or abstinence must be continued for the duration of the study and for up to 30 days after the last dose of study drug.
4. Males with female partners of childbearing potential must agree to use barrier contraceptive and their female partners must use a highly effective method of contraception from Screening through 90 days after the last dose of study drug. Males must also refrain from sperm donations during this time period. Males who are abstinent will not be required to use a contraceptive method unless they become sexually active. Males who have undergone a vasectomy are not required to use a contraceptive method if at least 16 weeks after the procedure. Same-sex couples are not required to use contraception.
5. Females with a negative pregnancy test at Screening and on Day -1
6. Willing and able to comply with the protocol
7. Have not used tobacco products of any kind (eg, cigarettes, e-cigarettes, cigars, smokeless tobacco) for at least 2 weeks prior to the Screening Visit and are willing to abstain from these products through end of study.
8. Part A only: Subject must be willing and able to consume the entire low-fat breakfast in the designated timeframe.
9. Part B only: Subject must be willing and able to consume the entire high-fat breakfast in the designated timeframe.
Minimum age
18 Years
Maximum age
55 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Individuals are not eligible to participate in this study if they have met or meet any of the
following exclusion criteria:
1. Gastrointestinal disease (such as irritable bowel syndrome, inflammatory bowel disease, chronic gastritis, peptic ulcer disease, etc.) that could affect the absorption of study drug
2. History of gastric surgery, including Roux-en-Y gastric bypass surgery or an antrectomy with vagotomy, or gastrectomy
3. History of fat malabsorption
4. Dietary restrictions that preclude participation
5. Inability to tolerate oral medication
6. History of allergies or adverse reactions to BH4 or related compounds or to any excipients in the study drug formulation
7. Any clinically significant medical or psychiatric condition or medical history, that in the opinion of the investigator or the medical monitor, would interfere with the subject’s ability to participate in the study or increase the risk of participation for that subject
8. Alanine aminotransferase or aspartate aminotransferase laboratory values greater than 1.5× the
upper limit of normal (ULN)
9. Serum creatinine greater than or equal to 1.5× ULN at Screening
10. Any other clinically significant laboratory abnormality at the Screening Visit or prior to the administration of the first dose of study drug. In general, each laboratory value from screening and baseline chemistry and hematology panels should fall within the limits of the normal laboratory reference range, unless deemed not clinically significant by the investigator. The investigator may repeat laboratory testing one time in the event of an out-of-range laboratory value to confirm eligibility.
11. Current participation in any other investigational drug study or participation within 30 days prior to Screening
12. History of alcohol or drug abuse within last 6 months prior to Screening, current evidence of substance dependence or self-reported alcoholic intake greater than 10 standard drinks/week
13. A female who is nursing or who is planning to become pregnant
14. QTcF (QT with Fredericia’s correction) greater than or equal to 450 msec in males and greater than or equal to 470 msec in females
(based on the mean of triplicate measurements taken at Screening)
15. Resting heart rate less than or equal to 45 or greater than or equal to 100 beats per minute
16. Resting blood pressure less than 90/50 mmHg or greater than 150/95 mmHg at Screening
17. Subject is, in the opinion of the investigator, unwilling or unable to adhere to the requirements of the study
18. Major surgery within the 90 days prior to Screening
19. Use of an antifolate including, but not limited to, methotrexate, within 1 week prior to Screening and through discharge from clinic
20. Use of sapropterin dihydrochloride within 1 week prior to Screening and through discharge from clinic
21. Use of melatonin within 1 week prior to Screening and through discharge from clinic
22. Positive test for human immunodeficiency virus, hepatitis B, or hepatitis C
23. Positive screen for drugs with a high potential for abuse or positive screen for EtOH at
Screening and Check-in
24. Blood donation of greater than or equal to 450 mL of blood within the 90 days prior to Screening

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Randomization allocation is determined in the EDC and the person performing this randomization and the person forming the qualification and recruitment of the participant is not aware at the time of assessment which treatment group the patient will be allocated to first. Eligibility is confirmed in the EDC and then the subject is randomized to a treatment. Allocation of treatment group is not determined by the investigator, or anyone involved in the recruitment process, rather, is determined by the randomization software.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Patients who fulfil the eligibility criteria and provide information consent will be enrolled into the study and randomized to 1 of 2 sequence groups via assigned electronic data capture system. It will be central randomization via a web-based system. Within each sequence group, patients will receive each of the 2 study treatments sequentially.
Study drug assignment will be from a computer-based randomization code list using a validated random generator software.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
Part A will be randomized to 1 of 2 sequence groups as follows:

Sequence 1: Formulation A 20mg PTC923 - wash out - Formulation B 20mg PTC923 wash out Formulation A 60mg PTC923 - wash out - Formulation B 60mg PTC923

Sequence 2: Formulation B 20mg PTC923 - wash out - Formulation A 20mg PTC923 wash out Formulation B 60mg PTC923 - wash out - Formulation A 60mg PTC923

Part B is a food effect study that compares fed vs fasted state. Subjects will only receive Formulation B after fasting, after a low fat meal or after a high fat meal. Sequence for Part B is as follows:

Sequence 3: PTC923 20 mg fasted wash out PTC923 20 mg high-fat fed wash out PTC923 60 mg fasted wash out PTC923 60 mg high-fat fed

Sequence 4: PTC923 20 mg high fat wash out PTC923 20 mg fasted wash out PTC923 60 mg high fat wash out PTC923 60 mg fasted.
Phase
Phase 1
Type of endpoint/s
Bio-availability
Statistical methods / analysis
Criteria for evaluation:

Pharmacokinetics:

The following PK parameters will be calculated for BH4 and sepiapterin in plasma, area under the concentration versus time curve from time zero to last observed concentration AUC0-inf, percent of AUC0-inf extrapolated, Cmax, time to reach Cmax, terminal half-life, elimination rate constant, apparent total plasma clearance, apparent volume of distribution
The PK parameters for BH4 will be derived from both baseline corrected and uncorrected data. A mixed effect analysis of variance model will be performed on the natural log-transformed AUC024h, AUC0-inf, and Cmax of BH4 and sepiapterin with formulation and sequence as fixed effects and subject as a random effect. Tmax will not be log-transformed. The relative bio-availability of Formulation B (Phase 3 powder for suspension) to Formulation A (Phase 1/2 powder for suspension) will be estimated as the ratio of least square means and associated 95% CI of AUC0-t, AUC0-inf, and Cmax for BH4 (primary, baseline corrected) and sepiapterin (secondary).

Safety:

Safety will be monitored through assessment of the incidence and severity of treatment emergent AEs (AEs that begin after start of study drug), oral mucosa assessments, physical
examination findings, results of clinical laboratory tests, and vital sign measurements.

Palatability:

Palatability (ie, odor, taste, and aftertaste) evaluation results will be tabulated and summarized using appropriate descriptive statistics.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
22/11/2021
Date of last participant enrolment
Anticipated
30/04/2022
Actual
13/06/2022
Date of last data collection
Anticipated
11/06/2022
Actual
12/07/2022
Sample size
Target
32
Accrual to date
Final
32
Recruitment in Australia
Recruitment state(s)
SA
Recruitment hospital [1] 18847 0
CMAX Clinical Research Pty Ltd - Adelaide
Recruitment postcode(s) [1] 33346 0
5000 - Adelaide

Funding & Sponsors
Funding source category [1] 307911 0
Commercial sector/Industry
Name [1] 307911 0
PTC Therapeutics Inc.
Country [1] 307911 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
PTC Therapeutics Inc.
Address
PTC Therapeutics Inc.
100 Corporate Court
South Plainfield
NJ 07080
USA
Country
United States of America
Secondary sponsor category [1] 308632 0
Commercial sector/Industry
Name [1] 308632 0
InClin Pty Ltd
Address [1] 308632 0
InClin Pty Ltd
25/29 Berry Street
Suite 210
North Sydney,
NSW 2060
Country [1] 308632 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 307908 0
Bellberry Limited
Ethics committee address [1] 307908 0
Ethics committee country [1] 307908 0
Australia
Date submitted for ethics approval [1] 307908 0
03/02/2021
Approval date [1] 307908 0
12/03/2021
Ethics approval number [1] 307908 0
2021-01-068

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 108894 0
Dr Emir Redzepagic
Address 108894 0
CMAX
Level 5, 18a North Terrace
Adelaide SA
5000
Country 108894 0
Australia
Phone 108894 0
+61870887900
Fax 108894 0
Email 108894 0
Emir.Redzepagic@cmax.com.au
Contact person for public queries
Name 108895 0
Taylor Kilfoil
Address 108895 0
InClin Pty Ltd
25/29 Berry Street
Suite 210
North Sydney,
NSW 2060
Country 108895 0
Australia
Phone 108895 0
+61 408 880 403
Fax 108895 0
Email 108895 0
taylorkilfoil@inclin.com
Contact person for scientific queries
Name 108896 0
Taylor Kilfoil
Address 108896 0
InClin Pty Ltd
25/29 Berry Street
Suite 210
North Sydney,
NSW 2060
Country 108896 0
Australia
Phone 108896 0
+61 408 880 403
Fax 108896 0
Email 108896 0
taylorkilfoil@inclin.com

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
The information developed during the conduct of this clinical study is considered confidential by the sponsor. This information may be disclosed as deemed necessary by the sponsor, except as required by law or regulation. Data from all subjects participating in the study will be pooled and analyzed by the sponsor or their designee. Individual participant data will not be published or made publicly available in a way that is identifiable, except as required by law or regulation.


What supporting documents are/will be available?

No Supporting Document Provided



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