Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12617000458336
Ethics application status
Approved
Date submitted
27/03/2017
Date registered
30/03/2017
Date last updated
3/12/2020
Date data sharing statement initially provided
3/12/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
An interventional study to evaluate the effects of dosages on the Pharmacokinetics (PK, the measure of how the human body processes a substance), Pharmacodynamics (PD, the measure of what a substance does to the human body), Tolerability (how well a substance is tolerated by participants), and Safety of different dosages of IONIS-TMPRSS6-Lrx when given to healthy participants as either a single subcutaneous (SC, an injection just under the skin) dose, or as multiple SC doses.
Scientific title
A Double-Blind, Placebo-Controlled, Dose-Escalation, Phase 1 Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single and Multiple Doses of IONIS-TMPRSS6-Lrx Administered Subcutaneously to Healthy Volunteers
Secondary ID [1] 291540 0
Nil known
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Thalassaemia 302631 0
Condition category
Condition code
Blood 302151 302151 0 0
Haematological diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Cohort A: 20mg IONIS-TMPRSS6-Lrx/ placebo as 0.2mL SC injection on Days 1, 22, 25, 29, 36, 43, 50, and 57, for a total dosage of 160mg IONIS-TMPRSS6-Lrx or placebo.
Cohort B: 40mg IONIS-TMPRSS6-Lrx/ placebo as 0.4mL SC injection on Days 1, 22, 25, 29, 36, 43, 50, and 57, for a total dosage of 320mg IONIS-TMPRSS6-Lrx or placebo.
Cohort C: 60mg IONIS-TMPRSS6-Lrx/ placebo as 0.6mL SC injection on Days 1, 22, 25, 29, 36, 43, 50, and 57, for a total dosage of 480mg IONIS-TMPRSS6-Lrx or placebo.
Cohort D: 120mg IONIS-TMPRSS6-Lrx/ placebo as 1.2mL SC injection on Day 1.
Intervention code [1] 297610 0
Treatment: Drugs
Comparator / control treatment
0.9% sterile saline
Control group
Placebo

Outcomes
Primary outcome [1] 301576 0
To evaluate the safety and tolerability of IONIS-TMPRSS6-Lrx when administered as a single ascending dose and as a multiple ascending dose to healthy participants. This will be assessed by looking at the incidence, causality, severity, and seriousness of adverse events; changes in clinical laboratory evaluations; changes in vital signs parameters, physical examinations, ECGs
Timepoint [1] 301576 0
Adverse event information will be recorded from the time of admission to the study unit until 13 weeks after the last dose of study drug.
Clinical laboratory evaluations will be conducted at screening and pre-dose on Day 1 for all cohorts.
They will also be conducted at the following time points:
Cohorts A, B, and C: Day 2/ 24hr post dose (complement and coagulation only); Day 8 (chemistry, haematology, and urinalysis only); Day 22; Days 29, 36, 43, and 50 (chemistry, haematology, and urinalysis only); Day 57; Days 64, 71, 85, 99, and 120 (chemistry, haematology, and urinalysis only); and Day 148.
Cohort D: Day 2/ 24hr post dose (complement and coagulation only); Days 8, 29, 43, 64, and 92 (chemistry, haematology, and urinalysis only).
Chemistry, haematology, and urinalysis will also be collected at the Early Termination visit for all cohorts (if it occurs).
Vital signs will be measured at Screening and Day -1 for all cohorts.
They will also occur at the following time points:
Cohorts A, B, and C: Day 1 (pre-dose, and 2 and 4 hours post-dose); Days 2 and 8; pre-dose on Days 22, 29, 36, 43, 50, and 57; Days 58, 64, 71, 85, 99, 120, and 148.
Cohort D: Day 1 (pre-dose, and 2 and 4 hours post-dose); Days 2, 8, 15, 29, 43, 64, and 92.
They will also be measured at the Early Termination visit for all cohorts (if it occurs).
A full physical examination will be performed at Screening for all cohorts, with abbreviated examinations to be performed at the following time points:
Cohorts A, B, and C: Days -1, 22, 43, 64, and 148.
Cohort D: Days -1, 8, 29, and 92.
Abbreviated physical exams will also be conducted at the Early Termination visit for all cohorts (if it occurs).
ECGs will be collected in triplicate at Screening for all cohorts.
They will also be collected in triplicate at the following time points:
Cohorts A, B, and C: Day 1 (45, 30, and 15 minutes prior to scheduled dose; 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 12 hours post-dose); Day 2/ 24 hr post-dose; pre-dose at Day 57; Days 24 and 148.
Cohort D: Day 1 (45, 30, and 15 minutes prior to scheduled dose; 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 12 hours post-dose); Day 2/ 24 hr post-dose; Day 8.
Triplicate ECGs will also be performed at Early Termination visit for all cohorts (if it occurs).
ECGs may be collected by continuous Holter monitoring.
Secondary outcome [1] 333148 0
To determine the PK profile of single and multiple doses of IONIS-TMPRSS6-Lrx in healthy participants. Blood (plasma) and urine will be collected and the following PK parameters will be assessed: Peak plasma concentration (Cmax) Time to peak plasma concentration (Tmax) Area under the concentration-time curve from time 0 to selected time point (AUC0-t) Terminal elimination half-life (t1/2 delta z)
Timepoint [1] 333148 0
Blood samples for IONIS-TMPRSS6-Lrx PK will be collected at the following time points: Cohorts A, B, and C: Day 1 (Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours post-dose); Day 2/ 24 hours post-dose); Day 8; pre-dose on Days 29, 36, 43, and 50; Day 57 (Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours post-dose); Day 58/ 24 hours post last dose; Days 64, 71, 85, 99, 120, and 148. Cohort D: Day 1 (Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours post-dose); Day 2/ 24 hours post-dose); Days 8, 15, 29, 43, 64, and 92. Blood samples for IONIS-TMPRSS6-Lrx PK will also be collected at the Early Termination visit for all cohorts (if it occurs). Urine for IONIS-TMPRSS6-Lrx PK will be collected at the following intervals: Cohorts A, B, and C: time of dosing on Day 1 to 24 hours post-dose on Day 2; time of dosing on Day 57 to 24 hours post-dose on Day 58. Cohort D: time of dosing on Day 1 to 24 hours post-dose on Day 2.
Secondary outcome [2] 333185 0
To determine the PD profile of single and multiple SC doses of IONIS-TMPRSS6-Lrx in healthy participants. Blood samples will be collected and the following parameters assessed: Hepcidin, Iron, Transferrin Saturation.
Timepoint [2] 333185 0
Blood samples for PD analysis will be collected at the following time points:
Cohorts A, B, and C: Screening (with only transferrin saturation considered for eligibility); pre-dose on Day 1; Day 8; pre-dose on Days 22, 29, 36, 43, 50, and 57; Days 64, 71, 85, 99, 120, and 148.
Cohort D: Screening (with only transferrin saturation considered for eligibility); pre-dose on Day 1; Days 8, 15, 29, 43, 64, and 92.
A PD sample will also be collected at the Early Termination visit for all cohorts (if it occurs).

Eligibility
Key inclusion criteria
1. Must have given written informed consent (signed and dated) and any authorizations
required by local law and be able to comply with all study requirements
2. Healthy males or females of non-childbearing potential, aged 18 to 65 inclusive at the time of informed consent
3. Females must be non-pregnant, non-lactating, non-menstruating (including withdrawal bleeds from hormone replacement therapy in postmenopausal women), and either surgically sterile (by hysterectomy or bilateral oophorectomy) or postmenopausal (defined as 12 months of spontaneous amenorrhea without an alternative medical cause and follicle-stimulating hormone (FSH) levels in the postmenopausal range for the laboratory involved).
Males must be either abstinent* or, if engaged in sexual relations with a female of childbearing potential, using double methods of contraception that are acceptable from the time of signing the informed consent form until at least 13 weeks after the last dose of Study Drug.
Males must refrain from sperm donation from the time of signing the informed consent form until at least 13 weeks after the last dose of Study Drug
*Abstinence is only acceptable as true abstinence, i.e., when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods), declaration of abstinence for the duration of a trial, and withdrawal are not acceptable methods of contraception
4. Willing to refrain from strenuous exercise/activity (e.g., heavy lifting, weight training,
intense aerobics classes) for at least 72 hours prior to study visits
5. Body mass index (BMI) < 32 kg
Minimum age
18 Years
Maximum age
65 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. Clinically significant abnormalities in medical history (e.g., previous acute coronary
syndrome within 6 months of Screening, major surgery within 3 months of Screening) or
physical examination
2. Screening laboratory results as follows, or any other clinically significant abnormalities in screening laboratory values that would render a subject unsuitable for inclusion
- Urine protein/creatinine (P/C) ratio greater than or equal to 200 mg/mg. In the event of P/C ratio above this threshold, eligibility may be confirmed by a quantitative total urine protein measurement of < 150 mg/24 hours
- Positive test (including trace) for blood on urinalysis. In the event of a positive test,
eligibility may be confirmed with urine microscopy showing < 5 RBC per microliter
- Alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, alkaline
phosphatase, serum creatinine, blood urea nitrogen (BUN) > the upper limit of the normal range (ULN)
- Fasting blood glucose > ULN
- Platelet count < LLN
- Thyroid-stimulating hormone (TSH) value outside normal range unless approved by the Sponsor Medical Monitor
- Hgb < 15.0 g/dL (male) or < 13.0 g/dL (female)
- Any of the following hematologic parameters outside normal range: MCH, MCV, RBC, and RDW
- Ferritin outside normal range
- Transferrin saturation < 20% or > 50%

3. Eligibility of subjects with a known history of anemia must be approved by the Sponsor
Medical Monitor
4. Active infection requiring systemic antiviral or antimicrobial therapy that will not be
completed prior to Study Day 1
5. Unwillingness to comply with study procedures, including follow-up, as specified by this protocol, or unwillingness to cooperate fully with the Investigator
6. Known history of or positive test for human immunodeficiency virus (HIV), hepatitis C, or chronic hepatitis B
7. Uncontrolled hypertension (BP > 160/100 mm Hg) at Screening
8. Malignancy within 5 years, except for basal or squamous cell carcinoma of the skin or
carcinoma in situ of the cervix that has been successfully treated
9. Treatment with another investigational drug, biological agent, or device within 1 month of Screening or 5 half-lives of investigational agent, whichever is longer
10. Any history of previous treatment with an oligonucleotide (including siRNA). Subjects who have previously received only a single dose of an Ionis oligonucleotide as part of a clinical study may be included as long as a duration greater than or equal to 4 months has elapsed since dosing
11. History of bleeding, diathesis, or coagulopathy
12. Regular excessive use of alcohol within 6 months prior to Screening (> 7 drinks/week for females, > 14 drinks/week for males; 1 drink equals 5 ounces [150 mL] of wine or 12 ounces [360 mL] of beer or 1.5 ounces [45 mL] of hard liquor), or use of soft drugs (such as marijuana) within 3 months prior to Screening, or hard drugs (such as cocaine and phencyclidine) within 1 year prior to Screening, or positive urine drug screen at Screening
13. Current use of concomitant medications other than occasional acetaminophen (paracetamol) or ibuprofen unless approved by Sponsor Medical Monitor
14. Use of oral anticoagulants
15. Smoking > 10 cigarettes per day
16. Blood donation of 50 to 499 mL within 30 days of Screening or of > 499 mL within 90 days of Screening
17. Have any other conditions that, in the opinion of the Investigator or Sponsor, would make the subject unsuitable for inclusion, or could interfere with the subject participating in or completing 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)
Allocation involves contacting the holder of the allocation schedule who is the off-site pharmacist with no contact with participants.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software (i.e. computerised sequence generation).
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Other
Other design features
Participants will be assigned to different dosages depending on which cohort they are enrolled into.
Phase
Phase 1
Type of endpoint/s
Safety
Statistical methods / analysis
There is no statistical rationale for the selected sample size of the single-dose and multiple-dose treatment cohorts. The sample size was based on prior experience to ensure that the safety and tolerability of IONIS-TMPRSS6-Lrx will be adequately assessed while minimizing unnecessary subject exposure.
All eCRF data, lab data transfers, and any outcomes derived from the data will be provided in the subject data listings. Subject data listings will be presented for all subjects enrolled into the study. Descriptive summary statistics including n (number of subjects), mean, median, standard deviation, standard error, interquartile range (25th percentile, 75th percentile), and range (minimum, maximum) for continuous variables, and counts and percentages for categorical variables will be used to summarize most data. Where appropriate, p-values will be reported.
All statistical tests will be conducted using 2-sided tests with 5% Type I error rate unless
otherwise stated.
For analysis of Cohorts A-C, the placebo subjects in these cohorts will be pooled into a placebo group.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
1/05/2017
Actual
8/06/2017
Date of last participant enrolment
Anticipated
Actual
26/06/2018
Date of last data collection
Anticipated
Actual
25/09/2018
Sample size
Target
44
Accrual to date
Final
36
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 7732 0
Nucleus Network - Melbourne
Recruitment postcode(s) [1] 15657 0
3004 - Melbourne

Funding & Sponsors
Funding source category [1] 296031 0
Commercial sector/Industry
Name [1] 296031 0
Ionis Pharmaceuticals, Inc.
Country [1] 296031 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
INCResearch Australia Pty Ltd
Address
159 Port Road
Hindmarsh SA 5007
Country
Australia
Secondary sponsor category [1] 294919 0
None
Name [1] 294919 0
Address [1] 294919 0
Country [1] 294919 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 297290 0
Alfred Hospital Ethics Committee
Ethics committee address [1] 297290 0
Ethics committee country [1] 297290 0
Australia
Date submitted for ethics approval [1] 297290 0
29/03/2017
Approval date [1] 297290 0
15/05/2017
Ethics approval number [1] 297290 0
130/17

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

Contacts
Principal investigator
Name 73598 0
Dr Jason Lickliter
Address 73598 0
Nucleus Network
Level 5, Burnet Tower, AMREP Precinct Commercial Road
Melbourne VIC 3004
Country 73598 0
Australia
Phone 73598 0
+61 390768609
Fax 73598 0
Email 73598 0
[email protected]
Contact person for public queries
Name 73599 0
Pavina Pavina
Address 73599 0
INCResearch Australia Pty Ltd
159 Port Road
Hindmarsh SA 5007 (Head Office)
Suite 1, Level 2, 924 Pacific Highway
Gordon NSW 2072
Country 73599 0
Australia
Phone 73599 0
+61 284379249
Fax 73599 0
Email 73599 0
[email protected]
Contact person for scientific queries
Name 73600 0
David Fuller
Address 73600 0
INCResearch Australia Pty Ltd 159 Port Road Hindmarsh SA 5007 (Head Office) Suite 1, Level 2, 924 Pacific Highway Gordon NSW 2072
Country 73600 0
Australia
Phone 73600 0
+61450965709
Fax 73600 0
Email 73600 0
[email protected]

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


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.