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Trial registered on ANZCTR


Registration number
ACTRN12618001031257
Ethics application status
Approved
Date submitted
4/06/2018
Date registered
19/06/2018
Date last updated
22/08/2019
Date data sharing statement initially provided
23/04/2019
Date results information initially provided
22/08/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
A Phase 2, Randomized, Double Crossover, Open-Label, Active-Controlled Proof-of-Concept Study of CNSA-001 in Phenylketonuria Patients
Scientific title
A Phase 2, Randomized, Double Crossover, Open-Label, Active-Controlled Proof-of-Concept Study of CNSA-001 in Phenylketonuria Patients
Secondary ID [1] 294875 0
PKU-002
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Phenylketonuria 307826 0
Condition category
Condition code
Metabolic and Endocrine 306874 306874 0 0
Metabolic disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Study PKU-002 is a Phase 2, randomized, double crossover, open-label, active-controlled Proof of Concept study of CNSA-001 (sepiapterin) powder for suspension in patients with PKU. This is an outpatient study in which approximately 30 patients will be enrolled at approximately 5 centers.

All eligible patients will be randomized to 1 of 6 sequence groups consisting of up to 5 patients each (4 minimum, 5 maximum). Each sequence group will include 3 treatment periods in which patients will receive each of the following open-label treatments for 7 days in random order: CNSA-001 20 mg/kg/day, CNSA-001 60 mg/kg/day, and Kuvan 20 mg/kg/day.

The following are the six assigned Sequence Groups, where Treatment A receives CNSA-001 20mg/kg/day, Treatment B receives CNSA-001 60mg/kg/day and Treatment C recieves Kuvan 20mg/kg/day. All treatments will be administered daily for 7 days.

Sequence Group 1 will receive Treatment C in Week 1, Washout in Week 2, Treatment A in Week 3, Washout in Week 4 and Treatment B in Week 5.
Sequence Group 2 will receive Treatment A in Week 1, Washout in Week 2, Treatment B in Week 3, Washout in Week 4 and Treatment C in Week 5.
Sequence Group 3 will receive Treatment B in Week 1, Washout in Week 2, Treatment C in Week 3, Washout in Week 4 and Treatment A in Week 5.
Sequence Group 4 will receive Treatment C in Week 1, Washout in Week 2, Treatment B in Week 3, Washout in Week 4 and Treatment A in Week 5.
Sequence Group 5 will received Treatment A in Week 1, Washout in Week 2, Treatment C in Week 3, Washout in Week 4 and Treatment B in Week 5.
Sequence Group 6 will received Treatment B in Week 1, Washout in Week 2, Treatment A in Week 3, Washout in Week 4 and Treatment C in Week 5.

Dosing will take place daily on Days 1-7 of the treatment periods. Study compliance will be documented in the eCRF and in the participant dosing diary. The dosage, date and time of each oral administration and if the entire dose was taken will be recorded.

Kuvan 20mg/kg/day will be provided in tablet form, which the patients will take orally with water.

CNSA-001 will be prepared by a pharmacist and provided to the patient as a powder reconstituted in Medisca® Oral Mix (which is commercially available, with microcrystalline cellulose, colloidal silicon dioxide, croscarmellose, ascorbic acid and colorant.)
Intervention code [1] 301190 0
Treatment: Drugs
Comparator / control treatment
The active control will be Kuvan (sapropterin dihydrochloride). Kuvan tablets will be used for this study and provided free of charge by the Sponsor.
Control group
Active

Outcomes
Primary outcome [1] 305865 0
The primary objective of the study is to evaluate the Phenylalanine level as assessed by plasma and dried blood spot assay in adult PKU patients.
Timepoint [1] 305865 0
The primary efficacy measures will be reduction in plasma and dried blood spot Phe levels (Day 1, pre-dose) to each post-Day 1 assessment.

Samples will be taken during the screening period to confirm eligibility. Baseline will occur at Day -7, Day -5, Day-3 and Day-1. Samples for comparison to baseline will be taken Day 1, Day 3, Day 5 and Day 7 of all treatment and washout periods.

Secondary outcome [1] 346833 0
The secondary objective of this study is to assess the safety and tolerability of 2 dose levels of CNSA-001 in PKU patients.

Safety and tolerability of CNSA-001 as measured by the severity and number of treatment-emergent adverse events (TEAEs), including assessment of severity of TEAEs, clinical lab tests, vital signs, physical examinations, and ECGs will be compared to Kuvan.
Timepoint [1] 346833 0
Safety and tolerability assessments will be completed in clinic during Day 1 and Day 7 of all treatment and washout periods. This will include review of treatment-emergent adverse events (TEAEs), including assessment of severity of TEAEs, clinical lab tests, vital signs, physical examinations, and ECGs.

Review of safety and tolerability, including the review treatment-emergent adverse events (TEAEs), including assessment of severity of TEAEs will be assessed and at home Phe dried blood spot testing testing via phone or clinic visits on Day 3 and 5 of treatment and washout periods.

Ongoing review of concomitant medications will be conducted throughout the study period from informed consent at the screening visit and throughout the 5-week study period, until the End of Study Visit. .
Secondary outcome [2] 348068 0
The secondary efficacy measure will be the percent of patients with a reduction in plasma Phe by 10%, 20% and 30% overall, and by disease severity on Day 3, Day 5, and Day 7.
Timepoint [2] 348068 0
The percent of patients with Phe concentrations in acceptable treatment range of 120 to 360 µmol/L on Day 3, Day 5 and Day 7. Percent of patients with normalized Phe concentrations less than 120 µmol/L on Day 3, Day 5 and Day 7.

Eligibility
Key inclusion criteria
1. Informed consent
2. Male or female patients greater than or equal 18 and less than or equal to 60 years of age
3. Blood Phe level greater than or equal to 450 µmol/L anytime during Screening, or blood Phe level great than or equal to 450 µmol/L when taking the average of the 3 most recent Phe levels from the patient’s medical history (inclusive of the Screening value)
4. Clinical diagnosis of PKU with hyperphenylalaninemia documented by past medical history of at least 1 blood Phe measurement greater than or equal to 360 µmol/L
5. Females must be either postmenopausal for great than or equal to 1 year or surgically sterile (having undergone tubal ligation, hysterectomy, or bilateral oophorectomy) for at least 6 months or, if of childbearing potential and not abstinent, willing to use a highly effective method of contraception throughout the study such as 1 of the following:
- Hormonal contraception (stable dose for 3 months)
- Intrauterine device/Intrauterine Hormone-releasing System
- Barrier contraceptive method (diaphragm, cervical cap, contraceptive sponge, condom)
Females who are abstinent will not be required to use a contraceptive method unless they become sexually active.
6. Males (if sexually active and nonsterile) with female partners of childbearing potential must be using highly effective birth control measures when sexually active (e.g., less than 1% failure rate/year barrier protection method such as condom), and willing to continue to use such highly effective birth control measures while participating in the study (and for 90 days following participation in study). Males must also refrain from sperm donations during this time period.
7. Willing and able to comply with the protocol and study procedures
8. Willing to continue current diet unchanged while participating in the study
9. Have not used tobacco (e.g., cigarettes, e-cigarettes, cigars, smokeless tobacco, nicotine replacement) for 2 weeks prior to Day -8 and willingness to abstain from these products through EOS.
Minimum age
18 Years
Maximum age
60 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. The individual, in the opinion of the Investigator, is unwilling or unable to adhere to the requirements of the study
2. Gastrointestinal disease (such as irritable bowel syndrome, inflammatory bowel disease, chronic gastritis, peptic ulcer disease, etc.) that could affect the absorption of study drug
3. History of gastric surgery, including Roux-en-Y gastric bypass surgery or an antrectomy with vagotomy, or gastrectomy
4. Inability to tolerate oral medication
5. History of allergies or adverse reactions to tetrahydrobiopterin (BH4) or related compounds, or to any excipients in the study drug formulation
6. Current participation in any other investigational drug study or use of any investigational agent within 30 days prior to Screening
7. Any clinically significant laboratory abnormality. 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
8. A female who is pregnant or breastfeeding, or considering pregnancy
9. Serious neuropsychiatric illness (e.g., major depression) not currently under medical control, that in the opinion of the Investigator or Sponsor, would interfere with the patient’s ability to participate in the study or increase the risk of participation for that patient
10. Requirement for concomitant treatment with any drug known to inhibit folate synthesis (e.g., methotrexate)
11. Clinical diagnosis of primary BH4 deficiency
12. Major surgery within the prior 90 days
13. History of alcohol or drug abuse within 6 months prior to Screening or current evidence of substance dependence as determined by the Investigator

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)
Patients who fulfill the eligibility criteria and provide informed consent will be enrolled into the study and randomized to 1 of 6 sequence groups via the assigned electronic data capture system. It will be a central randomisation via web-based system.. Within each sequence group, patients will receive each of the 3 study treatments in random order.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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
Crossover
Other design features
Phase
Phase 2
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
Phe concentrations at each visit and changes from baseline will be summarized using summary statistics (number of patients, mean, standard deviation, median, range) by treatment group. In addition, the absolute mean and percent mean change from baseline of plasma Phe concentrations will be summarized by treatment group using summary statistics. Changes from baseline will also be summarized by treatment group and disease severity at baseline (i.e., Phe concentrations less than 600 µmol/L, 600 to 900 µmol/L, 900 to 1200 µmol/L, greater than 1200 µmol/L). The change from baseline in Phe levels will be modeled using a linear mixed model for repeated measures (MMRM). The model will include fixed effects for baseline Phe, treatment group, sequence, period, and a random subject effect within each sequence. Changes from baseline in Phe will be estimated in each treatment group and will be compared between each CNSA-001 treatment group and the Kuvan treatment group.

Each secondary efficacy measure will be summarized by treatment group.
Safety will be assessed by the number and percentage of patients with TEAEs (events that begin after first dose of study drug) will be tabulated by treatment group, system organ class, and MedDRA preferred term. The treatment group for each AE is based on the last study drug taken before the start of the AE. Severity of AEs and SAEs will be summarized similarly. AEs leading to premature discontinuation from the study drug and serious TEAEs will be presented in a table or a listing. Clinical laboratory test results, vital signs, and ECGs, will be summarized by treatment group at each visit as well as corresponding changes from baseline. A frequency distribution of abnormal physical examination results will be provided.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA
Recruitment hospital [1] 10885 0
Westmead Hospital - Westmead
Recruitment hospital [2] 10886 0
Mater Private Hospital - South Brisbane
Recruitment hospital [3] 10887 0
The Royal Adelaide Hospital - Adelaide
Recruitment postcode(s) [1] 22646 0
2145 - Westmead
Recruitment postcode(s) [2] 22647 0
4101 - South Brisbane
Recruitment postcode(s) [3] 22648 0
5000 - Adelaide
Recruitment outside Australia
Country [1] 10397 0
Georgia
State/province [1] 10397 0

Funding & Sponsors
Funding source category [1] 299461 0
Commercial sector/Industry
Name [1] 299461 0
Censa Pharmaceuticals Australia Pty Ltd
Address [1] 299461 0
C/-PRIME FG Level 9 HWT Tower Building 40 City Road Southbank, VIC 3006
Country [1] 299461 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Censa Pharmaceuticals Australia Pty Ltd
Address
C/-PRIME FG
Level 9 HWT Tower Building
40 City Road
Southbank, VIC 3006
Country
Australia
Secondary sponsor category [1] 298759 0
None
Name [1] 298759 0
Address [1] 298759 0
Country [1] 298759 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 300369 0
Central Adelaide Local Health Network (CALHN) Human Research Ethics Committee
Ethics committee address [1] 300369 0
Level 3, Roma Mitchell House
136 North Terrace, ADELAIDE SA 5000
Ethics committee country [1] 300369 0
Australia
Date submitted for ethics approval [1] 300369 0
11/05/2018
Approval date [1] 300369 0
23/07/2018
Ethics approval number [1] 300369 0
Ethics committee name [2] 304157 0
Bellberry Limited
Ethics committee address [2] 304157 0
123 Glen Osmond Road, Eastwood, SA 5063
Ethics committee country [2] 304157 0
Australia
Date submitted for ethics approval [2] 304157 0
26/07/2018
Approval date [2] 304157 0
25/09/2019
Ethics approval number [2] 304157 0
2018-07-502
Ethics committee name [3] 304158 0
LTD Unimedi Kakheti - Local Ethics Committee
Ethics committee address [3] 304158 0
LTD Unimedi Kakheti
21 Ljubljana Street
Tbilisi 0159, Georgia
Ethics committee country [3] 304158 0
Georgia
Date submitted for ethics approval [3] 304158 0
05/10/2018
Approval date [3] 304158 0
12/10/2018
Ethics approval number [3] 304158 0
NA

Summary
Brief summary
CNSA-001 represents the first viable formulation of sepiapterin intended for the treatment of hyperphenylalaninemia (HPA) in PKU patients.

This Phase 2 study will assess 2 doses of CNSA-001 in comparison to the maximum recommended dose of Kuvan. This is a proof-of-concept (PoC) study that will help to establish dose selection and support the design of future Phase 2/3 studies in PKU patients.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 83426 0
Dr Drago Bratkovic
Address 83426 0
PARC Clinical Research, wayfinding number 4G116.01. Royal Adelaide Hospital, Port Rd Adelaide. 5000
Country 83426 0
Australia
Phone 83426 0
+61 8 7074 1544
Fax 83426 0
Email 83426 0
drago.bratkovic@sa.gov.au
Contact person for public queries
Name 83427 0
Mr Taylor Kilfoil
Address 83427 0
Censa Pharmaceuticals Australia Pty Ltd Floor 19, HWT Tower 40 City Road Southbank, VIC, 3006
Country 83427 0
Australia
Phone 83427 0
+61 408880403
Fax 83427 0
Email 83427 0
taylorkilfoil@censapharma.com
Contact person for scientific queries
Name 83428 0
Dr Neil Smith
Address 83428 0
Censa Pharmaceuticals Inc. 222 Third Street, Suite #2240 Cambridge, Massachusetts, 02142 USA
Country 83428 0
United States of America
Phone 83428 0
+1 317-443-2706
Fax 83428 0
Email 83428 0
nsmith@censapharma.com

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
To maintain data confidentiality
What supporting documents are/will be available?
No other documents available
Summary results
Have study results been published in a peer-reviewed journal?
No
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary