Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12617001426370
Ethics application status
Approved
Date submitted
21/09/2017
Date registered
9/10/2017
Date last updated
30/11/2018
Date data sharing statement initially provided
30/11/2018
Date results information initially provided
30/11/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
A study to primarily determine how safe and tolerable the study treatment, PTG-200 is in comparison to a matching placebo, when taken by healthy participants as a single dose or multiple dose treatment.
Scientific title
A Phase 1 Randomized, Double-Blind, Placebo-Controlled Single and Multiple Ascending Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of PTG-200 in Normal Healthy Male Volunteers
Secondary ID [1] 292934 0
Nil
Universal Trial Number (UTN)
Trial acronym
PTG-200-01
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Crohn's Disease 304825 0
Condition category
Condition code
Oral and Gastrointestinal 304127 304127 0 0
Crohn's disease

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Part 1: Single Ascending Dose
Participants will be randomised to receive a single dose of PTG-200 or placebo capsule. Three cohorts of eligible participants are planned:
Cohort 1: 150 mg PTG-200 or placebo
Cohort 2: 300 mg PTG-200 or placebo
Cohort 3: 900 mg PTG-200 or placebo. Participants, in Cohort 3 only, will return to the clinic after at least 7 days and will be administered a second single dose of 900 mg PTG-200 immediately following the consumption of a standard high fat meal.
Part 2: Multiple Ascending Dose
Participants will be randomised to receive oral administration of PTG-200 or placebo capsule daily for 14 days. Participants are not required to fast for dosing purposes. Four cohorts of eligible participants are planned:
Cohort 4: 150 mg PTG-200 or placebo once daily
Cohort 5a: 300 mg PTG-200 or placebo once daily
Cohort 5b: 150 mg PTG-200 or placebo twice daily
Cohort 6: 900 mg PTG-200 or placebo once daily; or 450 mg PTG-200 or placebo twice daily. Cohorts 5a and 5b will be conducted in parallel and the dose of Cohort 6 will be based on their results.

Part 3: Formulation Cross-Over
Part 3 will be a cross over of 2 formulations (tablet and capsule) consisting of the same active pharmaceutical ingredients (API). Part 3 will evaluate the bioavailability of the capsule formulation compared to the tablet formulation. Approximately 10 participants will be enrolled into a single dose cross-over cohort. Participants will be randomized to receive either PTG-200 300 mg capsule formulation or PTG-200 300 mg tablet formulation (5 participants to receive each). Participants will remain in the clinic until Day 3. A minimum of 7 days after the first dose, they will return for the second dosing period and receive a single dose of the alternate formulation of PTG-200, i.e., participants who received the capsule formulation for the first dose will then receive the tablet formulation, and vice versa.
The duration of Part 3 is approximately 14 days. Part 3 is not double-blind and does not include placebo.
Intervention code [1] 299171 0
Treatment: Drugs
Comparator / control treatment
Placebo capsule - Hydroxylproply Cellulose, Mannitol, Colloidal Silicone Dioxide, Magnesium Stearate

In Part 1: Up to 30 participants will be enrolled in 3 Cohorts. In each Cohort, 8 participants will receive PTG-200 and 2 participants will receive Placebo.
In Part 2: Up to 40 participants will be enrolled into 4 Cohorts. In each Cohort, 8 participants will receive PTG-200 and 2 participants will receive placebo.
In Part 3 (Cross-over): Approximately 10 participants will be enrolled into a single dose cross-over cohort to evaluate the bioavailability of the capsule formulation compare to the tablet formulation. This is not a double-blind cohort and does not include placebo.
Control group
Placebo

Outcomes
Primary outcome [1] 303447 0
To assess the safety and tolerability of PTG 200 after single and multiple ascending oral dose administration in normal healthy participants.

The Safety and Tolerability of single dose and multi-dose of PTG-200 will be assessed through AEs and laboratory parameters along with routine medical monitoring and physical examinations.

Safety Laboratory parameters assessed:: Hematology, coagulation, serum chemistry, and urinalysis.
Timepoint [1] 303447 0
The primary timepoints based on the primary outcome are as follows:

Part 1: Single Ascending Dose:

AE/SAEs – Day -1, Pre-Dose (Baseline), and Days: 0, .25, .5, 1, 2, 4, 8, 12, 24, 36, 48, and End of Study 7 +/- 2 days post dose.

Lab Parameters – Screening, Day -1, Pre-Dose (Baseline), Days 8, 24, 48, and End of Study 7 +/- 2 days post dose.

Physical Exam – Screening, Day -1, Pre-Dose (Baseline) Days 8, 24, 48, and End of Study 7 +/- 2 days post dose
Routine Medical Monitoring – Screening, Day -1, Days 1 through End of Study


Part 2: Multiple Ascending Dose:

AE/SAEs:
- Screening, Day -1, Days 1 – 21.

Lab Parameters:
- Screening
- Day -1
- Day1: Pre-Dose (Baseline) and at 4 hours
- Day 2: at 24 hours
- Days 3, 8 and 11
- Day 14: Pre-Dose
- Day 15: @ 24 hrs
- Day 21

Physical Exam:
Screening
Day -1
Day 1: Pre-Dose (Baseline) and 8 hours
Days: 3 – 13
Days: 14 (pr-dose), 15, 16, and 21.
Routine Medical Monitoring – Screening, Day -1, Days 1 through End of Study
Secondary outcome [1] 338946 0
To evaluate the plasma pharmacokinetics (PK) of PTG-200 after single and multiple ascending oral dose administration in normal healthy participants.

Plasma PTG-200 non-compartmental analysis (NCA) PK parameters time of the maximum plasma drug concentration (Tmax), maximum observed drug plasma concentration (Cmax), area under the curve (AUC) from time zero to the time of the last measurable concentration (AUC0-t) apparent terminal elimination (disposition) rate constant (Kel), AUC from time zero to infinity (AUC0 inf), apparent elimination (disposition) half-life (t1/2), apparent clearance (CL/F) and apparent volume of distribution at the terminal phase (Vz/F) will be estimated (where data are sufficient for parameter determination). In addition, minimum concentration (Cmin), AUC over the dosing interval (AUCtau), apparent clearance at steady-state (CL/Fss), average steady-state concentration (Cssave) and accumulation index (AI) will be calculated for Part 2 (MAD).

Faecal PTG-200 NCA PK parameters amount recovered and %Dose recovered will be estimated.

Individual PTG-200 concentration data will be listed and summarised by treatment group with descriptive statistics (sample size [N], arithmetic mean, standard deviation [SD], median, minimum, maximum and geometric mean). Individual and mean PTG-200 concentration-time profiles for each treatment group will also be presented graphically.
Timepoint [1] 338946 0
The PK samples will be analysed approximately within two to four weeks of collection.

Part 1:
Pre-dose, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, and 8 hours.

Part 2:
Dose 1: Pre-dose, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, and 32 hours post dose.
Dose 2: Pre-dose, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, and 32 hours post dose.

Part 3:
Pre-dose, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 32 hours, and 48 hours post dose.
Secondary outcome [2] 338952 0
To evaluate the PK of PTG-200 in stool and urine samples of participants after multiple ascending oral dose administration.

PK of PTG-200 is measured in plasma, stool, and urine by using LC Mass Spectrometry method.

PK parameters will be summarized by cohort using descriptive statistics (arithmetic means, SD, coefficients of variation [CV], sample size [N] minimum, maximum, median and geometric mean).
No value for kel, t1/2, AUC0-inf, CL/F, Vz/F, as appropriate, will be reported for cases that do not exhibit a terminal log-linear phase in the concentration versus time profile or do not contain sufficient data during this phase for parameter estimation.
Additional analyses will be performed as deemed necessary upon review of the data.

These are not composite endpoints.
Timepoint [2] 338952 0
PK in stool and urine will be assessed at the end of the study. Approximately within two to four weeks after the end of the study.

Part 2: Urine PK Day 10 to Day 11 post dose, pooled at 6 hour intervals for 24 hours.
Faeces PK Day 11 to Day 12, pooled over 24 hours.
Secondary outcome [3] 338953 0
To assess the effect of a high fat meal on the plasma PK of a single oral dose administration of PTG-200 in normal healthy participants.

Relative Bioavailability of Capsule and Tablet Formulations
Analysis of variance (ANOVA) will be performed on the ln-transformed AUC0-t, AUC0-inf, and Cmax (tablet vs capsule). The 90% confidence intervals (CIs) for the ratio of the geometric means of the tablet formulation data compared to the capsule formulation data will be obtained, based on the least-squares means (LSM) from the ANOVA of the ln-transformed parameters. The ratios and confidence intervals will be expressed as a percentage relative to the capsule formulation.
Timepoint [3] 338953 0
The PK on patients who received high fat meal will be assessed approximately within two to four weeks post sample collection.

Part 1, Cohort 3:
Pre-dose, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, and 8 hours
Secondary outcome [4] 338954 0
To evaluate the PK of PTG-200 tablets compared to capsules.

Relative Bioavailability of Capsule and Tablet will be assessed with Pharmacokinetic information from the Plasma samples.

Relative Bioavailability of Capsule and Tablet Formulations
Analysis of variance (ANOVA) will be performed on the ln-transformed AUC0-t, AUC0-inf, and Cmax (tablet vs capsule). The 90% confidence intervals (CIs) for the ratio of the geometric means of the tablet formulation data compared to the capsule formulation data will be obtained, based on the least-squares means (LSM) from the ANOVA of the ln-transformed parameters. The ratios and confidence intervals will be expressed as a percentage relative to the capsule formulation.
Timepoint [4] 338954 0
The PTG-200 tablet compared to capsule PK will be assessed within two to four weeks post sample collection.

Part 3:
Pre-dose, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 32 hours, and 48 hours post dose.

Eligibility
Key inclusion criteria
1. Male normal healthy volunteers (NHV), age 18 to 55 years, inclusive.
2. Participants must be in good general health, with no significant medical history, have no clinically significant abnormalities on physical examination at screening, and/or before administration of the initial dose of study drug.
3. Participants must have a Body Mass Index (BMI) between 18 and 30 kg/m2 inclusive.
4. Participants must have clinical laboratory values within normal range as specified by the testing laboratory, unless deemed not clinically significant by the Investigator.
5. Male participants with female partners should use a condom during sexual intercourse for 3 months after the last dose of study drug. In addition, male participants with female partners must agree to use a second highly-effective method of contraception (e.g. hormonal contraception or an intrauterine device) for 3 months after the last dose of study drug.
6. Participants must be a non-smoker, and must not have regularly used nicotine products within six months prior to screening; those who have had social or accidental exposure to nicotine/nicotine-containing products over the 3 months prior to screening may be enrolled in the study at the discretion of the Investigator.
7. Participants must have no dietary restrictions, and be willing to consume the standard meals provided.
8. Participants must have the ability and willingness to attend the necessary visits to the study centre.
9. Written informed consent signed prior to entry into the study.
Minimum age
18 Years
Maximum age
55 Years
Sex
Males
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. History of clinically significant endocrine, neurological, gastrointestinal, cardiovascular, haematological, hepatic, immunological, renal, respiratory, or genitourinary abnormalities or diseases. Participants with a history of gastrointestinal disease including inflammatory bowel disease (IBD), toxic megacolon, dysplasia, gastroesophageal reflux disease (GERD), colon cancer, intestinal stenosis, or fistula will be excluded. History of surgical resection of the stomach, small or large intestine (excluding appendectomy, cholecystectomy, or resection of benign polyps) will be excluded. Note: NHVs with histories of uncomplicated kidney stones or childhood asthma may be enrolled in the study at the discretion of the Investigator.
2. History of neoplastic disease, with the exception of adequately treated non melanomatous skin carcinoma.
3. Mentally or legally incapacitated, has significant emotional problems at the time of Screening Visit or expected during the conduct of the study, or has a history of a clinically significant psychiatric disorder within the last 5 years. Note: NHVs who have had situational depression may be enrolled in the study at the discretion of the Investigator.
4. Fever (body temperature >38°C) or symptomatic viral or bacterial infection within 2 weeks prior to Screening; evidence of intestinal infection within 30 days prior to screening.
5. History of severe allergic or anaphylactic reactions
6. Blood pressure (BP) >140/90 mm Hg or heart rate (HR) >100 beats per minute at Screening and at Day -1
7. Clinically significant laboratory abnormalities including:
a) Impaired renal function (serum creatinine levels >106 µmol/L) at Screening; estimated creatinine clearance (CrCl) of <80 mL/minute based on the Cockcroft-Gault equation below:
Males: CrCl = (140 - age [years]) (body weight [kg])/(72)(serum creatinine [mg/dL])
b) Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) laboratory values >1.2 × upper normal limits
8. Clinically significant abnormality on ECG performed at the Screening Visit or prior to administration of the initial dose of study drug. (Screening and predose ECG conduction intervals must be within gender specific normal ranges [QT interval corrected for heart rate (QTc) in males less than or equal to 450 msec], however participants with out of normal range PR which is deemed not clinically significant by the PI may be enrolled).
9. Positive test for hepatitis B surface antigen or human immunodeficiency virus (HIV) antibody at Screening. Patients positive for hepatitis C antibody are excluded unless they have had a history of sustained virologic response 12 weeks (SVR12) after the end of treatment for a prior infection.
10. Participants with a positive toxicology screening panel (urine test including qualitative identification of barbiturates, tetrahydrocannabinol (THC), amphetamines, benzodiazepines, opiates and cocaine).
11. Participants with a history of substance abuse or dependency or history of recreational intravenous drug use (by self-declaration).
12. Regular alcohol consumption by males defined as >21 alcohol units per week (where 1 unit = 284 mL of beer, 25 ml of 40% spirit or a 125 ml glass of wine).
13. Unable to refrain from or anticipates the use of any medications, including prescription and non-prescription drugs and herbal remedies (such as St. John’s Wort [Hypericum perforatum]), beginning 14 days (or 5 half-lives, whichever is longer) before administration of the initial dose of study drug and continuing throughout the study until the final study visit. There may be certain medications that are permitted at the discretion of the Investigator and Sponsor (including paracetamol/acetaminophen, medications for the treatment of AEs following administration of study drug, and multivitamins).
14. Participants who are unlikely to comply with the study protocol or, in the opinion of the Investigator, would not be a suitable candidate for participation in 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)
Sealed opaque envelopes will be used to conceal treatment allocation.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software; via SAS programming
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s

Intervention assignment
Parallel
Other design features
Part 3 has a formulation crossover (not parallel) design.
Phase
Phase 1
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
A detailed Statistical Analysis Plan will be prepared.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
8/11/2017
Actual
8/11/2017
Date of last participant enrolment
Anticipated
31/10/2018
Actual
28/08/2018
Date of last data collection
Anticipated
Actual
22/09/2018
Sample size
Target
80
Accrual to date
Final
82
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 9080 0
Nucleus Network - Melbourne
Recruitment postcode(s) [1] 17573 0
3004 - Melbourne

Funding & Sponsors
Funding source category [1] 297562 0
Commercial sector/Industry
Name [1] 297562 0
Protagonist Therapeutics
Country [1] 297562 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Protagonist Therapeutics
Address
7707 Gateway Boulevard, Suite 140
Newark, CA 94560-1160
USA
Country
United States of America
Secondary sponsor category [1] 296573 0
Commercial sector/Industry
Name [1] 296573 0
Clinical Network Services
Address [1] 296573 0
Level 4,
88 Jephson St
Toowong, 4066
QLD
Country [1] 296573 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 298657 0
The Alfred Hospital Ethics Committee
Ethics committee address [1] 298657 0
Ethics committee country [1] 298657 0
Australia
Date submitted for ethics approval [1] 298657 0
23/08/2017
Approval date [1] 298657 0
12/10/2017
Ethics approval number [1] 298657 0

Summary
Brief summary
PTG-200 is an experimental drug being developed by Protagonist Therapeutics as a treatment for moderate to severely active Crohn’s Disease (CD) which is an inflammatory bowel disease (IBD). CD causes gastrointestinal signs and symptoms such as diarrhoea, abdominal pain, weight loss and passing blood or mucous. Current treatments for this highly complex disease have unacceptable side effects or cannot be used long term as they suppress the immune system and may increase the risk of serious infection or cancer.

PTG-200 is believed to reduce the swelling that contributes to CD by blocking a specific part of your immune response pathway. There are a number of new treatments for CD which have been approved for use in other countries . PTG-200 is thought to be a better treatment for CD compared to these other medications as PTG-200 is restricted to the gut and very unlikely to spread to other parts of the body, meaning it would have fewer side effects and remain in the gut.

The primary purpose of the study is to evaluate the safety and tolerability of the study drug referred to as PTG-200 in healthy individuals using single or multiple dose over number of days. The study will also evaluate how the PTG-200 is absorbed, spread in the body, and the body’s response to the drug.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 77790 0
Dr Jason Lickliter
Address 77790 0
Centre for Clinical Studies
Level 5 Burnet Building
AMREP Precinct
89 Commercial Road
Prahran, VIC 3181
Country 77790 0
Australia
Phone 77790 0
+61 3 9076 8960
Fax 77790 0
Email 77790 0
j.licklicter@nucleusnetwork.com.au
Contact person for public queries
Name 77791 0
Chrishni Williams
Address 77791 0
Nucleus Network Limited
Level 5 Burnet Building
AMREP Precinct
89 Commercial Road
Prahran, VIC 3181
Country 77791 0
Australia
Phone 77791 0
+61 438 622 992
Fax 77791 0
Email 77791 0
C.Williams@nucleusnetwork.com.au
Contact person for scientific queries
Name 77792 0
Bittoo Kanwar
Address 77792 0
Protagonist Therapeutics Inc.,
7707 Gateway Blvd., Suite 140,
Newark CA 94560
Country 77792 0
United States of America
Phone 77792 0
+1 (510) 474-0170
Fax 77792 0
Email 77792 0
b.kanwar@ptgx-inc.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 data sharing statement was marked NO’ due to the reason that it’s a healthy volunteer study and the individual participant results are not useful to the participants or to others outside of the sponsor.


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

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No documents have been uploaded by study researchers.

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