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Trial registered on ANZCTR


Registration number
ACTRN12622000799752
Ethics application status
Approved
Date submitted
24/05/2022
Date registered
7/06/2022
Date last updated
18/11/2022
Date data sharing statement initially provided
7/06/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
A Phase 2, Randomized, Open Label Study of Bitopertin administered orally to Evaluate the Safety, Tolerability, Efficacy, and Protoporphyrin IX (PPIX) Concentrations in Participants with Erythropoietic Protoporphyria (EPP)
Scientific title
A Phase 2, Randomized, Open Label Study of Bitopertin to Evaluate the Safety, Tolerability, Efficacy, and Protoporphyrin IX (PPIX) Concentrations in Participants with Erythropoietic Protoporphyria (EPP)
Secondary ID [1] 307034 0
DISC-1459-202
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Erythropoietic Protoporphyria (EPP) 326179 0
Condition category
Condition code
Metabolic and Endocrine 323483 323483 0 0
Metabolic disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This study is an open label study of bitopertin to evaluate the safety, tolerability, efficacy, and Protoporphyrin IX (PPIX) concentration change in participants with Erythropoietic Protoporphyria (EPP).

Participants will be screened for study eligibility within 28 days before Baseline (Day 1). All participants will undergo light tolerance assessment during Screening that includes a diary assessment.

Up to 22 participants aged 18 and older are planned to be enrolled and completing 24 weeks of treatment in each group as follows:

• Bitopertin 20 mg administered as 2 x 10 mg tablets
• Bitopertin 60 mg administered as 2 x 30 mg tablets

Study drug dosing will begin on Day 1 and continue over a 24-week treatment period. Tablets will be taken orally, once daily, in the morning on an empty stomach after at least a 2 hour fast. Participants will remain fasted for at least 30 minutes following study drug administration. Water intake is not restricted during the fasting period. Participants will be required to maintain a daily sun exposure diary throughout the study.

After completion of the 24-week (168 days) treatment period, including assessment of light tolerance and End-of-Study (EOS) visit (Day 169), participants may continue on bitopertin (60 mg every day) for an additional 24 weeks or up to 1-year total treatment period from Day 1.

During the extension period, study visits will be scheduled every 8 weeks, the last of which is to be conducted at the end of study after 1-year total treatment period. At each extension treatment period visit the following assessments will be conducted: vital signs, urine or serum pregnancy test for female participants of childbearing potential, blood chemistry and hematology, porphyrins and iron study biomarkers, diary collection, concomitant medications, adverse events and dispensation/collection of study drug. Each visit during this period will last for approximately 1 hour.

Adherence to the intervention will be done via completion of a study drug diary daily for 24 weeks.
Intervention code [1] 323484 0
Treatment: Drugs
Comparator / control treatment
This is an open-label study and will assess the safety and tolerability of bitopertin at two dose levels. The dose comparator will be bitopertin 20mg.
Control group
Dose comparison

Outcomes
Primary outcome [1] 331248 0
To assess changes in Protoporphyrin IX (PPIX) concentrations in response to bitopertin treatment.

Measured by Percent change from baseline in erythrocyte metal-free PPIX levels. Blood samples will be collected to analyse markers relevant to the mechanism of action to bitopertin.
Timepoint [1] 331248 0
Day 15 (after starting treatment) to Day 169 (End of Study) at all visits during treatment and Extension (every 8 weeks up to 1 year from Day 1)
Secondary outcome [1] 409296 0
To characterize the effect of bitopertin on daily daylight tolerance.

Measured as a composite outcome by:
1. a two-week average daily sunlight exposure time (minutes) to first prodromal symptom (burning, tingling, itching, or stinging) associated with sunlight exposure between 1 hour post-sunrise and 1 hour pre-sunset.
2. Pain intensity of phototoxic reactions according to a Likert scale (0-10)
Timepoint [1] 409296 0
Total hours of direct sunlight exposure to skin on days with no pain from 1000 to 1800 hours (10:00 AM to 6:00 PM)

Diaries are to be completed daily for 2 weeks during Screening and daily during the bitopertin dosing period (Day 1 and Day 15 to Day 169 (End of Study). Once a week participants will measure and record in the diary the time (minutes) it takes to experience first prodromal symptom (burning, tingling, itching, or stinging) associated with sunlight exposure.
Secondary outcome [2] 409297 0
To assess the safety and tolerability of bitopertin at two dose levels.

Measured by the incidence of treatment-emergent adverse events (TEAEs), vital signs, physical examinations, and clinical laboratory parameters.
Timepoint [2] 409297 0
• Incidence, severity, and relationship of AEs/TEAEs graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) (Version 5). AEs that begin after the first administration of study drug, or existing AEs that worsen after the first dose of study drug will be considered TEAEs. Timepoint: Daily from Screening to Day 169 (End of Study) and Extension (every 8 weeks). After Day 1, AEs may be assessed by phone.

• Clinical laboratory parameters: Blood sample for safety haematology and blood chemistry, Screening, Baseline (Day 1), pre-dose from Day 15 to Day 169 (End of Study) and Extension (every 8 weeks). Urine sample for Urinalysis.: Baseline (Day 1), Day 29, Day 71, Day 169 (End of Study)

• Vital signs: Blood pressure and heart rate is assessed using a sphygmomanometer and temperature by thermometer. Timepoint: Daily from Screening to Day 169 (End of Study) and Extension (every 8 weeks).

• Physical Examination: Screening only
Secondary outcome [3] 409298 0
To characterize the relationship between bitopertin dose level and key biological indicators of mechanism engagement

Measured by assessment of Erythrocyte total PPIX concentrations, Plasma and blood total PPIX concentrations and Plasma bitopertin concentrations
Timepoint [3] 409298 0
Screening, Day 15 (after starting treatment) to Day 169 (End of Study) and Extension (every 8 weeks up to 1 year from Day 1)
Secondary outcome [4] 409299 0
To evaluate bitopertin pharmacokinetics (PK):

Measured by blood/plasma (if data permits) as follows:
• Cmax
• Observed time of the maximum drug concentration (Tmax)
• AUC from time 0 to 24 hours post-dose on Day 1 (AUC0-24)
Timepoint [4] 409299 0
Assess PK parameters Day 1 (first treatment day): pre-dose, 2, 4 and 6 hours post-dose, Day 2: 24 hours post-dose and Day 29: pre-dose and 4 hours post-dose

Eligibility
Key inclusion criteria
1. Aged 18 years or older
2. Diagnosis of EPP or XLP, based on medical history of FECH or ALAS2 genotyping or by biochemical porphyrin analysis.
3. Body weight greater than or equal to 50 kg.
4. Washout of at least 2 months prior to Screening of afamelanotide or dersimelagon, if applicable.
5. Aspartate aminotransferase (AST) and alanine transaminase (ALT) less than 2×upper limit of normal (ULN) and total bilirubin less than ULN (unless documented Gilbert syndrome) at Screening. Albumin greater than lower limit of normal (LLN).
6. If male with female sexual partner(s) of childbearing potential, agrees he and partner will use one of the following acceptable methods of birth control during the study and for 30 days after the last study drug dose:
a. abstinence
b. stable hormonal contraceptive or a barrier method (e.g., condom [male or female] or diaphragm)
c. intrauterine device, in place for at least 3 months
d. surgically sterile by hysterectomy, bilateral oophorectomy, or bilateral tubal ligation
7. If female of childbearing potential, defined as prior menarche, no hysterectomy, no bilateral oophorectomy, not postmenopausal (at least 12 months natural, spontaneous amenorrhea), must commit to one of the following methods of acceptable birth control during the study and for 30 days after the last study drug dose:
a. abstinence
b. stable hormonal contraceptive in conjunction with a barrier method (e.g., condom [male or female] or diaphragm)
c. intrauterine device, in place for at least 3 months
8. Negative urine or serum pregnancy test (females of childbearing potential) at Screening (Days -28 to -1) AND Baseline (Day 1), prior to dosing.
9. Able to understand the study aims, procedures, and requirements, and provide written informed consent.
10. Able to comply with all study procedures.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Major surgery within 8 weeks before Screening or incomplete recovery from any previous surgery.
2. Other than EPP, an inherited or acquired red cell disease associated with anemia.
3. A history or known allergic reaction to any investigational product excipients or history of anaphylaxis to any food or drug.
4. History of liver transplantation.
5. History of alcohol dependence or excessive alcohol consumption, as assessed by the Investigator.
6. Human immunodeficiency virus (HIV), active Hepatitis B, or C. A positive Hepatitis B result, indicating active disease status, should be discussed between the Investigator and Sponsor prior to enrollment.
7. Other medical or psychiatric condition or laboratory finding not specifically noted above that, in the judgment of the Investigator or Sponsor, would put the participant at unacceptable risk or otherwise preclude the participant from participating in the study
8. Condition or concomitant medication that would confound the ability to interpret clinical, clinical laboratory, or participant diary data, including a major psychiatric condition that has had an exacerbation or required hospitalization in the last 6 months.
9. Concurrent or planned treatment with afamelanotide or dersimelagon.
10. Treatment with opioids for any period greater than 7 days in the 2 months prior to screening or anticipated to require opioid use for greater than 7 days at any point during the study.
11. Treatment for anemia, including iron supplementation, in the 2 months prior to Screening.
12. Current or planned use of any drugs or herbal remedies known to be strong inhibitors or inducers of CYP3A4 enzymes for 28 days prior to the first dose and throughout the study
13. Hemoglobin less than 10 g/dL at Screening.
14. If female, pregnant or breastfeeding.
15. Participation in any other clinical protocol or investigational trial that involves administration of experimental therapy and/or therapeutic devices within 30 days of Screening.
16. Grapefruit/Seville orange and food products containing these, for 14 days prior to first dose and throughout the study

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)
Adult participants will be randomized on Day 1 in a 1:1 allocation ratio to one of the following two treatment dose groups:

• Bitopertin 20 mg once daily (n=11)
• Bitopertin 60 mg once daily (n=11)

On Day 1, participants will begin study drug according to their random assignment.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomisation will be stratified by average sunlight exposure time to prodromal symptom (less than 30 minutes or greater than or equal to 30 minutes), as assessed during a 2-week run-in period. Randomization will also be stratified by site.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
A formal sample size calculation was not performed. Rather, as the first study of bitopertin in people with EPP/XLP, a sample of n=10 participants per group completing 24 weeks of
treatment (enrolment is planned at n=11, with 1 drop out assumed) was considered appropriate to assess the preliminary safety and tolerability in this population.

Up to an additional 3 cohorts of n=11 may be added to the study to evaluate safety,
tolerability, or biomarker changes at different dose levels, in clinical subgroups, or an
expanded clinical group to further evaluate safety and tolerability.

Full Analysis Set: To be included in the Full Analysis Set (FAS), participants must be
randomized and take at least one dose of study drug, and have a baseline measurement
and at least one post baseline measurement of the primary efficacy variable. All
analyses of the FAS will be based on each participant’s randomized treatment. If a
participant is randomized according to the incorrect stratification, the participant will
be analyzed under the randomized treatment for the stratum recorded in the
randomization system. All efficacy analyses will be performed on the FAS.

Intent-to-Treat Analysis Set: To be included in the Intent-to-Treat (ITT) analysis set,
participants must be randomized to study drug.

All analyses of the ITT analysis set will be based on each participant’s randomized
treatment. If a participant is randomized according to the incorrect stratification, the
participant will be analyzed under the randomized treatment for the stratum recorded in
the randomization system. The ITT analysis set will be used be used for a sensitivity
analysis of the primary and key secondary efficacy endpoints.

Per Protocol Analysis Set: The Per Protocol (PP) Analysis Set will include all
participants in the FAS who meet the study eligibility requirements and have no major
protocol deviations that affect the validity of the efficacy measurements. The PP
Analysis Set will be used for a sensitivity analysis of the primary efficacy endpoint.
The criteria for inclusion in the PP Analysis Set will be finalized prior to database lock
and detailed in the Statistical Analysis Plan (SAP).

Safety Analysis Set: All participants who are randomized and take at least one dose of
study drug will be included in the Safety Analysis Set. Safety analyses will be based on
the study drug that was dispensed to each participant.

Pharmacokinetic Population Analysis Set: All participants who received at least one
dose of study drug and have sufficiently evaluable concentration-time profile to allow
determination of at least one PK parameter will be included in the PK population. An
evaluable PK profile will be determined at the discretion of the pharmacokineticist
following examination of participants with dosing or protocol deviations that could potentially affect the PK profile. The PK population will be used for the summaries of all PK data

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
1/07/2022
Actual
29/09/2022
Date of last participant enrolment
Anticipated
28/02/2023
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
22
Accrual to date
1
Final
Recruitment in Australia
Recruitment state(s)
NSW,VIC
Recruitment hospital [1] 22319 0
Royal Melbourne Hospital - City campus - Parkville
Recruitment hospital [2] 22320 0
Royal Prince Alfred Hospital - Camperdown
Recruitment postcode(s) [1] 37480 0
3050 - Parkville
Recruitment postcode(s) [2] 37481 0
2050 - Camperdown

Funding & Sponsors
Funding source category [1] 311346 0
Commercial sector/Industry
Name [1] 311346 0
Disc Medicine, Inc.
Country [1] 311346 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
Disc Medicine, Inc.
Address
321 Arsenal Street, Suite 101
Watertown, MA 02472
Country
United States of America
Secondary sponsor category [1] 312733 0
Commercial sector/Industry
Name [1] 312733 0
Avance Clinical Pty Ltd
Address [1] 312733 0
Level 1, 2 Ann Nelson Drive
Thebarton, SA 5031, Australia
Country [1] 312733 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 310841 0
Royal Melbourne Hospital HREC
Ethics committee address [1] 310841 0
Ethics committee country [1] 310841 0
Australia
Date submitted for ethics approval [1] 310841 0
27/04/2022
Approval date [1] 310841 0
16/05/2022
Ethics approval number [1] 310841 0
HREC/86095/MH-2022

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

Contacts
Principal investigator
Name 119058 0
Dr Gayle Ross
Address 119058 0
The Royal Melbourne Hospital
Dermatology Research, City Campus, Level 8 CMR Building, Grattan Street, Parkville, Victoria 3050
Country 119058 0
Australia
Phone 119058 0
+61 3 93424542
Fax 119058 0
Email 119058 0
gayle.ross@mh.org.au
Contact person for public queries
Name 119059 0
Gayle Ross
Address 119059 0
The Royal Melbourne Hospital
Dermatology Research, City Campus, Level 8 CMR Building, Grattan Street, Parkville, Victoria 3050
Country 119059 0
Australia
Phone 119059 0
+61 3 93424542
Fax 119059 0
Email 119059 0
gayle.ross@mh.org.au
Contact person for scientific queries
Name 119060 0
Gayle Ross
Address 119060 0
The Royal Melbourne Hospital
Dermatology Research, City Campus, Level 8 CMR Building, Grattan Street, Parkville, Victoria 3050
Country 119060 0
Australia
Phone 119060 0
+61 3 93424542
Fax 119060 0
Email 119060 0
gayle.ross@mh.org.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Privacy and intellectual property considerations


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.