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Trial registered on ANZCTR


Registration number
ACTRN12618000459224p
Ethics application status
Submitted, not yet approved
Date submitted
9/03/2018
Date registered
29/03/2018
Date last updated
29/03/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Evaluation of the Safety, Tolerability and Pharmacokinetics of Intravenous TIMP-GLIA in Healthy Volunteers.
Scientific title
A Phase 1 Subject-Blinded, Placebo-Controlled Dose Escalation and Repeat Dose Study of the Safety, Tolerability and Pharmacokinetics of TIMP-GLIA in Healthy Subjects
Secondary ID [1] 294248 0
TGLIA-5.003 Cour Pharmaceutical Development Company Inc.
Universal Trial Number (UTN)
U1111-1210-1868
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Coeliac Disease 306931 0
Condition category
Condition code
Inflammatory and Immune System 306030 306030 0 0
Autoimmune diseases
Diet and Nutrition 306322 306322 0 0
Other diet and nutrition disorders
Metabolic and Endocrine 306323 306323 0 0
Other metabolic disorders
Oral and Gastrointestinal 306324 306324 0 0
Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The study is a two-part design, the first part consisting of single ascending doses (SAD) of TIMP-GLIA (Gliadin, a glutenoid protein encapsulated in poly lactic-co-glycolic acid nanoparticles) or saline placebo delivered over a 30-minute controlled infusion under the supervision of study nurses, to 6 cohorts of 6 subjects. All subjects will be resident in the clinic for 48 hours after each dose for medical observation.
In each cohort one drug-treated (sentinel subject) and one placebo subject will be dosed first with the the remainder of the cohort (3 drug-treated and 1 placebo) to be dosed after 48 hours has elapsed. A Safety Management Committee (SMC) meeting will be held after completion of each cohort to review safety observations against predefined stopping rules before continuation to the next dose level. Cohort dosing is shown below:
SAD
Cohort 1 TIMP-GLIA 8 mg or saline placebo
Cohort 2 TIMP-GLIA 40 mg or saline placebo
Cohort 3 TIMP-GLIA 120 mg or saline placebo
Cohort 4 TIMP-GLIA 300 mg or saline placebo
Cohort 5 TIMP-GLIA 600 mg or saline placebo
Cohort 6 TIMP-GLIA 800 mg or saline placebo
In the second part of the study two further cohorts (n=6) will be given two doses of TIMP-GLIA, 7 days apart as follows:
Level 4 dosing TIMP-GLIA 300 mg or saline placebo
Level 6 dosing TIMP-GLIA 800 mg or saline placebo
SMC review will occur between cohorts.

Intervention code [1] 300547 0
Treatment: Drugs
Comparator / control treatment
Placebo (0.9% sodium chloride solution)
Control group
Placebo

Outcomes
Primary outcome [1] 305331 0
Safety and tolerability of single ascending doses of TIMP-GLIA and repeat dose (two doses only) including adverse events as measured by laboratory tests, vital signs, physical examination, ECG pulse oximetry and clinical observation
Timepoint [1] 305331 0
Baseline to day 42 in SAD subjects and baseline to day 49 in repeat dose subjects.
AEs - Screening Day -1, Day 0, Day 1, Day 2, Day 3, days 4-7, Day 14, Day 21, Day 28 and Days 42 (and for repeat dose subjects) Day 49.
Urinalysis - Screen, Day -1, Day 2, Day 4, Day 7 sand day 42 (and 49) -repeat dose subjects
Haematology - Screen, Day -1, Day 2, Day 3, Day 7, and Day 42 (and 49) - repeat dose subjects
Coagulation - Screen, Day -1, Day 2, Day 3, Day 7, and Day 42 (and 49) - repeat dose subjects
Pregnancy testing - Screen, Day -1, Day 7 and Day 42
Biochemistry - Screen, Day -1, Day 2, Day 3, Day 7, and Day 42 (and 49) - repeat dose subjects
Anti-Drug Assay - Screen, Predose, Day 2, Day 3, Day 7 and Day 42 (and Day 49) - repeat dose subjects
Immunology - Predose, Day 2, Day 3, Day 7 and day 42 (and day 49) - repeat dose subjects
Secondary outcome [1] 344130 0
Assessment of the Pharmacokinetics (PK) of TIMP-GLIA (measured as gliadin antigen by serum assay) after single, ascending doses in healthy volunteers.
PK parameters for measurement include, Cmax, Clast, Tmax, Tlast. AUCinfinity, AUClast, T1/2, CL, Vd, accumulation index and terminal half-life.

Timepoint [1] 344130 0
Blood samples for analysis of PK (as serum) will be taken according to the schedule below:
Day 1 – Predose, 30 minutes, 35 minutes, 1 hour, 4 hours, 12 hours
Day 2 – 24 hours
Day 3 - 48 hours
Day 7 – 144 hours

Repeat dose subjects (level 4 and level 6) will have samples taken at these same timepoints after each of the two doses.


Eligibility
Key inclusion criteria
1. In the opinion of the investigator, the healthy subject is capable of understanding and complying with protocol requirements and agrees to comply with protocol requirements.
2. The healthy subject provides written informed consent to participate.
3. The healthy subject is an adult man or woman, 18 to 65 years of age, inclusive, at Screening Visit.
4. Has a minimum body weight greater than 45 kg up to a maximum body weight of 121 kg, inclusive, and if BMI is less than18 (classified as “underweight”) or greater than 25 (classified as “overweight”) is otherwise healthy in the opinion of the investigator.
5. If male, agrees to practice medically approved contraception that may include, but is not limited to, abstinence, monogamous relationship with a female who is not of child-bearing potential, surgical sterilization procedure (vasectomy), and or condoms throughout the study.
6. If female, is not of child bearing potential (postmenopausal or premenopausal with surgical sterilization) or agrees to practice medically approved contraception that may include, but is not limited to, abstinence, monogamous relationship with a male who is post-surgical sterilization procedure (vasectomy), or agrees to use medically acceptable and highly effective birth control methods (e.g., an intrauterine device, a double-barrier method such as condom and diaphragm, a contraceptive implant, injectable contraceptive, or oral contraceptive) throughout the study.
7. Agrees not to participate in another interventional study while participating in the present study.
Minimum age
18 Years
Maximum age
65 Years
Gender
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. Has a history of clinically confirmed immunoglobulin E (IgE)-mediated reaction and/or anaphylaxis to wheat, barley or rye.
2. Has a known history of hypersensitivity or allergies to TIMP-GLIA components or any other known severe hypersensitivity or allergic reaction (any reaction that resulted in hospitalization [initial or prolonged], congenital anomaly, or disability, or that required medical intervention to prevent permanent impairment or damage) to any other allergens (medications, food or environmental).
3. Has any history or evidence of splenectomy (removal of the spleen) or any clinically significant cardiovascular, gastrointestinal endocrinologic, haematologic, hepatic, immunologic, metabolic, urologic, pulmonary, neurologic, dermatologic, psychiatric, renal, and/or other major disease, in the opinion of the investigator.
4. Uses any prescribed or non-prescribed drugs (including vitamins, natural and herbal remedies, in the 2 weeks prior to study drug administration, except for occasional use of acetaminophen (up to 2 g/day) or PI-approved contraceptives or hormone replacement therapy.
5. Received immunosuppressive doses of corticosteroids (more than 20 mg of prednisone given daily for 2 weeks or more) within 2 months prior to Day 1, any dose of corticosteroids within 30 days of Day 1, or high dose inhaled corticosteroids greater than or equal to 960 µg/day of beclomethasone dipropionate or equivalent]) within 30 days of Day 1.
6. Has known human immunodeficiency virus (HIV) infection or positive for HIV antibodies at Screening.
7. Has a history of any acute illness including, fever greater than or equal to 38 degrees C) within 14 days of check-in Day -1.
8. Has an active malignancy, or history of malignancy or chemotherapy, within the past 5 years other than history of localized or surgical removal of focal basal cell skin cancer, cervical cancer in situ treated successfully in the past by local treatment or by hysterectomy.
9. Has known liver disease or serology positive for hepatitis C infection; positive hepatitis B surface antigen (HBsAg) at Screening Visit.
10. Has a positive test result for drugs of abuse in urine or alcohol in urine or breath at Screening Visit or at Check-in.
11. Has a history of any drug or alcohol abuse in the past 5 years, or alcohol consumption greater than 21 units per week that, in the opinion of the investigator, would interfere with the subject’s ability to comply with the study requirements.. Alcohol consumption will be prohibited 24 hours prior to entry into the clinical research unit until discharge.
12. Has the inability to undergo venepuncture or tolerate venous access as determined by the investigator or designee.
13. If female, is pregnant or lactating or intending to become pregnant before or during the study.
14. Has clinically significant laboratory results at Screening, as determined by the investigator, which are indicative of hepatic, renal or haematological disorders or other condition that would indicate the subject should not participate in the trial.
15. Has clinically significant, abnormal electrocardiogram (EGC) at Screening, as determined by the investigator.
16. Has received any investigational drug within 30 days or 5 half-lives prior to first dosing/Day 1.
17. Received a live or inactive vaccine within 28 days prior or a subunit vaccine within 14 days prior to first dosing/Day 1 or the subject has a planned vaccination during the study.
18. Has donated blood or plasma within 56 days prior to Screening and plans to donate blood or plasma within 5 weeks of completing the study.
19. Has received blood products, monoclonal antibody, or other systemic protein therapy within 6 months prior to first dosing/Day 1.
20. Is an immediate family member, study site employee, or is in a dependent relationship with a study site employee who is involved in conduct of this study or may consent under duress.
21. Is unsuitable for enrolment in the opinion of the investigator for any other reason not specified above.


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)
Participant allocation will be made by the holder of the randomisation schedule (unblinded pharmacist) at the investigational site. Blinding of the treatment infusion will be made at the time of reconstitution of TIMP-GLIA/Placebo which will be placed into infusion bags labelled only with the subject number and initials.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Computerised sequence generation.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s


Intervention assignment
Parallel
Other design features
Phase
Phase 1
Type of endpoint(s)
Safety
Statistical methods / analysis
Sfety data will be analysed by descriptive statistical methods. Pharmacokinetic parameters will be analysed by custom PK software by cohort and treatment allocation.

Recruitment
Recruitment status
Not yet recruiting
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)
QLD
Recruitment hospital [1] 10360 0
Q-Pharm Pty - Clive Berghofer Research Centre (CBCRC) - Herston
Recruitment postcode(s) [1] 21995 0
4006 - Herston

Funding & Sponsors
Funding source category [1] 298888 0
Commercial sector/Industry
Name [1] 298888 0
Cour Pharmaceutical Development Company Inc.
Address [1] 298888 0
2215 Sanders Road, Northbrook IL 60062 USA
Country [1] 298888 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
Delpharm Consultants Pty Ltd
Address
89, Roland Avenue, Wahroonga NSW 2076
Country
Australia
Secondary sponsor category [1] 298102 0
None
Name [1] 298102 0
Address [1] 298102 0
Country [1] 298102 0

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 299832 0
Bellberry Ltd
Ethics committee address [1] 299832 0
129, Glen Osmond Road, Eastwood SA 5063
Ethics committee country [1] 299832 0
Australia
Date submitted for ethics approval [1] 299832 0
28/02/2018
Approval date [1] 299832 0
Ethics approval number [1] 299832 0

Summary
Brief summary
The phase 1 trial will be conducted in two parts, initially, it will comprise of a single-centre, subject blinded randomised single ascending dose study of TIMP-GLIA to 6 cohorts. Each cohort will contain six participants two will be randomised to placebo and four to TIMP-GLIA. At the beginning of each dose level, one sentinel (TIMP-GLIA) participant and one placebo participant will be dosed. The remaining four participants will be dosed 48 hours after the sentinel participants. A Safety Committee will meet after the completion of each cohort dosing to ascertain safety prior to the next dose level is given. In the second part of the trial, a repeat dosing strategy will be employed (maximum, two doses seven days apart) at the Level 4 and Level 6 dose.
Following a screening period (up to 28 days), eligible participants will be randomised to TIMP-GLIA or placebo using a computer generated randomisation schedule which will be held by an unblinded pharmacist.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 81698 0
Dr Paul Griffin
Address 81698 0
QPharm Pty Ltd, Level 5, 300C Herston Road, Herston QLD 4006
Country 81698 0
Australia
Phone 81698 0
+61 (07) 3845 3630
Fax 81698 0
Email 81698 0
p.griffin@qpharm.com.au
Contact person for public queries
Name 81699 0
Ms Mary Beth Holum
Address 81699 0
Cour Pharmaceutical Development Company Inc.
2215, Sanders Road, Northbrook IL 60062
Country 81699 0
United States of America
Phone 81699 0
+1 224 306 1910
Fax 81699 0
Email 81699 0
mbholum@courpharma.com
Contact person for scientific queries
Name 81700 0
Dr Roy First
Address 81700 0
Cour Pharmaceutical Development Company Inc.
2215, Sanders Road, Northbrook IL 60062
Country 81700 0
United States of America
Phone 81700 0
+1 773 677 8682
Fax 81700 0
Email 81700 0
roy@transplantgenomics.com

No data has been provided for results reporting
Summary results
Not applicable