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Trial registered on ANZCTR


Registration number
ACTRN12617001192370
Ethics application status
Approved
Date submitted
21/07/2017
Date registered
15/08/2017
Date last updated
21/02/2019
Date data sharing statement initially provided
20/02/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
A phase I/IIa study to assess safety, tolerability, pharmacokinetic, pharmacodynamic effects and exploratory efficacy of two doses of AGMG0201 in patients with essential hypertension.
Scientific title
A phase I/IIa study to assess safety, tolerability, pharmacokinetic, pharmacodynamic effects and exploratory efficacy of two doses of AGMG0201 in patients with essential hypertension.
Secondary ID [1] 292339 0
AGMG0201-AU-01
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Essential Hypertension 303888 0
Condition category
Condition code
Cardiovascular 303251 303251 0 0
Hypertension

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This will be a dose escalation study of AGMG0201 delivered at two doses (high and low) in up to 24 volunteers.

Each participant will be randomised to receive either low dose AGMG0201 (0.2 mg plasmid DNA and 0.25 mg Angiotensin II-KLH conjugate), high dose AGMG0201 (0.2 mg plasmid DNA and 0.5 mg Angiotensin II-KLH conjugate), or placebo (saline) according to the study randomisation schedule. Each dose will be administered as a single intramuscular injection to the deltoid muscle.

A booster vaccination will be administered 30 days after the first vaccination, providing there are no contraindications to a booster dose at Visit B0 in accordance with the pre-defined eligibility criteria (defined below), as determined by the PI or delegate:
- Mean systolic blood pressure (SBP) < 180 mmHg and/or mean diastolic blood pressure (DBP) <110 mmHg.
- No orthostatic hypotension
- No use of antihypertensive medications since Visit V0.
- No new clinically significant changes to participant’s health that would contraindicate administration of the booster dose.

Participants receiving the booster dose will receive the same treatment (i.e. AGMG0201 or placebo) administered at their first vaccination.

All participants enrolled in the study will receive a single dose of AGMG0201 (high or low dose) or placebo at Visit V0 and will be required to remain in the clinical unit until 24 hours post vaccination. Participants will attend outpatient visits for study procedures at 7, 14 and 30 days post-vaccine. At Visit B0, 30 days after receiving the first vaccine, participants will be re-assessed according to pre-defined eligibility criteria, and those who remain eligible will be administered a booster vaccine of the same treatment administered at Visit V0, then monitored for adverse events during a second 24 hour post-vaccination confinement period. Participants will return for additional outpatient visits at 7, 14, 30, 60, 90, 180 and 360 days after the booster vaccination. Participants who receive the first vaccine but are not eligible for the booster dose will receive no further IP but will be followed intention-to-treat (ITT), i.e. will undergo all scheduled assessments as per the protocol, unless consent is withdrawn.

Up to 24 participants will be enrolled in two groups of 12 participants: Group 1 (low dose or placebo) and Group 2 (high dose or placebo). In both groups, two sentinel participants will initially receive study drug (randomly assigned 1 active: 1 placebo). After a minimum of 7 days and following review of safety data by the Safety Review Committee, an additional 2 sentinel participants will receive study drug (randomly assigned 1 active: 1 placebo). A review of all available sentinel safety data, including a minimum of 30 days post-booster vaccination of data from sentinel subjects 3 and 4, will be reviewed prior to administration of study drug in the remaining 8 participants in both groups (randomly assigned 7 active: 1 placebo).

Dose administration for the first Group 2 sentinel participants will not commence until all Group 1 participants have completed study procedures up to 30 days post-booster vaccination (Visit B30), and their safety data reviewed.

An interim analysis will be performed for each participant group at 90 days following the last study vaccination (Group 1 and Group 2, respectively). The study will then be unblinded, and any placebo participants still active in the study will no longer be required for follow up. Participants randomised to AGMG0201 will continue in the study as per the schedule of assessments.
Intervention code [1] 298519 0
Treatment: Drugs
Comparator / control treatment
Placebo controlled treatment: 0.9% saline injection
Control group
Placebo

Outcomes
Primary outcome [1] 302636 0
To evaluate the safety and tolerability of AGMG0201 vaccine administered as an intramuscular injection in adult participants with essential hypertension at two dose levels (low dose; high dose) compared with placebo.

Primary endpoints:
- Solicited AEs (local and systemic reactogenicity events) collected for 90 days following vaccination. - Unsolicited events collected for 90 days following vaccination.
- Safety and clinical laboratory parameters (biochemistry, haematology, coagulation, and urinalysis).
- Vital signs, ECG measurements and physical examination findings.
Timepoint [1] 302636 0
Recorded at baseline (screening), and measured at 7, 14 and 30 days after the first vaccination of AGMG0201, and at 7, 14, 30, 60, 90, 180 and 360 days after a booster vaccination of AGMG0201.
Secondary outcome [1] 336603 0
To evaluate the Immunological response to AGMG0201 vaccine administered as an intramuscular injection in adult participants with essential hypertension at two dose levels (low dose; high dose) compared with placebo, as determined by changes to Angiotensin II titer from baseline (pre-dose). Serum samples will be collected for pharmacodynamic analysis
Timepoint [1] 336603 0
Measured at baseline (pre-dose) and 7, 14 and 30 days after the first vaccination of AGMG0201, and at 7, 14, 30, 60, 90, 180 and 360 days after a booster vaccination of AGMG0201.
Secondary outcome [2] 336604 0
Whole blood samples will be collected to analyse pharmacokinetic changes to AGMG0201 vaccine administered as an intramuscular injection in adult participants with essential hypertension at two dose levels (low dose; high dose) compared with placebo, as measured by changes to plasmid DNA concentration from baseline (pre-dose).
Timepoint [2] 336604 0
Recorded at baseline (pre-dose), and at 1, 7 and 14 days after each vaccination of AGMG0201.
Secondary outcome [3] 337345 0
Plasma samples will be collected to analyse pharmacodynamic changes to hormone levels of renin, aldosterone, angiotensin I, and angiotensin II measured from baseline (screening). The hormone levels mentioned above are composite secondary outcomes.
Timepoint [3] 337345 0
Recorded at baseline (screening), and measured at 7, 14 and 30 days after the first vaccination of AGMG0201, and at 7, 14, 30, 60, 90, 180 and 360 days after a booster vaccination of AGMG0201.
Secondary outcome [4] 337346 0
Plasma samples will be collected to analyse pharmacodynamic changes to metanephrine hormone levels measured from baseline (screening).
Timepoint [4] 337346 0
Recorded at baseline (screening), and measured at 30, 60 and 90 days after the booster vaccination of AGMG0201
Secondary outcome [5] 337347 0
To evaluate the efficacy of AGMG0201 vaccine administered as an intramuscular injection in adult participants with essential hypertension at two dose levels (low dose; high dose) compared with placebo, by assessing changes to 24 hour blood pressure measurements as measured by Ambulatory Blood Pressure Monitoring (ABPM)
Timepoint [5] 337347 0
Recorded at baseline (pre-dose), and at 30, 60, 90 and 180 days after booster vaccination of AGMG0201.
Secondary outcome [6] 337348 0
To evaluate the efficacy of AGMG0201 vaccine administered as an intramuscular injection in adult participants with essential hypertension at two dose levels (low dose; high dose) compared with placebo, by assessing changes to ‘clinic’ BP measurements
Timepoint [6] 337348 0
Recorded at baseline (pre-dose), and at 1, 7, 14, 30 days after vaccination of AGMG0201, and at 1, 7, 14, 30, 60, 90, 180 and 360 days after the booster vaccination of AGMG0201.
Secondary outcome [7] 337349 0
To evaluate the efficacy of AGMG0201 vaccine administered as an intramuscular injection in adult participants with essential hypertension at two dose levels (low dose; high dose) compared with placebo, by assessing time to commencement of rescue medication for treatment of hypertension or hypotension assessed by participant self reporting which is confirmed by the PI or delegate.
Timepoint [7] 337349 0
Measured by time to return to conventional antihypertensive therapy.

Eligibility
Key inclusion criteria
1. Provided voluntarily written informed consent. Willing and able to comply with protocol, and attend all study visits
2. Males or females of non-childbearing potential, aged more than or equal to 18 years and less than 80 years.
3. Body Mass Index (BMI) less than or equal to 35 kg/m2
4. Adequate venous access
5. Mild to moderate hypertension, defined as mean systolic blood pressure (SBP) 140-179 mmHg AND/OR mean diastolic blood pressure (DBP) of 90-109 mmHg (inclusive), who are either not currently using antihypertensive medications or on a single or on a regimen of a combination of ACEi + CCB, ACEi + diuretic, ARB + CCB or ARB + diuretic, and are willing to discontinue current antihypertensive medications for at least 14 days prior to first vaccination and 90 days after the booster vaccination. No clinically significant abnormalities that would contraindicate participation
6. Willing and able to comply with requirements of study protocol, and attend all study visits.
Minimum age
18 Years
Maximum age
79 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Participants with any of the following criteria will not be eligible for participation in this study:
1. Participants who have been using two or more antihypertensive medications, excluding the combination of ACEi plus CCB, ACEi plus diuretic, ARB plus CCB or ARB plus diuretic, prior to the first screening visit (Screen1)
2. Participants unable to safely discontinue antihypertensive medications for a minimum of 4.5 months, as required by protocol
3. Severe hypertension at screening, defined as mean SBP greater than or equal to 180 mmHg OR mean DBP greater than or equal to 110 mmHg
4. Orthostatic hypotension, defined as a decrease in mean SBP of greater than or equal to 15 mmHg within three minutes of standing when compared with blood pressure from the semi-supine position at screening (assessed at the second screening visit (Screen2) if volunteer on antihypertensive medication at the first screening visit (Screen1))
5. Any history of intolerance to dihydropyridine CCBs
6. Any history of intolerance to ACE inhibitors or Angiotensin II antagonists
7. Participants of African descent, defined as having both parents identifying themselves as being of African origin
8. Renal insufficiency, defined as Creatinine Clearance less than or equal to 40 ml per min, as determined by the Cockcroft Gault equation at screening (assessed at the second screening visit (Screen2) if volunteer on antihypertensive medication at the first screening visit (Screen1))
9. Serum potassium greater than upper limit of normal (ULN) at Screening (assessed at the Screen2 visit if volunteer on antihypertensive medication at Screen1; if the volunteer was taking ARBs at the Screen1 and potassium level is still elevated at Screen2, the participant may be re-screened 2 weeks later)
10. Proteinuria or hematuria with urine dipstick greater than or equal to 2+ protein or greater than or equal to 1+ blood at screening or at any time within the 6 months prior to screening (assessed at the second screening visit (Screen2) if volunteer on antihypertensive medication at the first screening visit (Screen1))
11. Participants with secondary hypertension
12. Participants with mental health conditions requiring current pharmacological treatment
13. History of macrovascular complications resulting from type II diabetes mellitus or poorly controlled diabetes as evidenced by a haemoglobin A1c (HbA1c) greater than or equal to 8.5 % at screening.
14. AST greater than 3 times ULN and/or ALT greater than 3 times ULN at screening
15. History or presence of allergic symptoms such as bronchial asthma (within past three months), or drug-induced immediate hypersensitivity
16. History or presence of malignancy, HIV, hepatitis (B or C), syphilis, immunosuppressive disease or clinically significant autoimmune disease which may affect the participant’s normal immune response. Treated basal cell or squamous cell carcinoma of the skin, or low grade cancers that are stable and not interfering with exercise may be allowed with permission from the Medical Monitor
17. Presence of any clinically significant central nervous system disease associated with persistent neurological abnormalities.
18. Presence or history of any ischaemic heart disease, arrhythmias, or cerebrovascular disease
19. Family history (1st degree family member) of sudden death of collapse indicative of long QT syndrome
20. QTcF greater than or equal to 450 milliseconds at screening
21. Participants on medications that could affect blood pressure, e.g. continued use of COX-2 inhibitors and NSAIDS for pain management, that are unable to safely discontinue these medications for the study period
22. Presence of any chronic condition which has been unstable or associated with medication changes for these conditions within the 4 weeks prior to screening
23. Systemic (oral or injected) steroid use in the last 3 months, or the presence of a condition which may result in systemic steroid use (e.g. asthma, gout, chronic obstructive airways disease) for the month after initial and booster vaccination
24. Any history of hypersensitivity after administration of any vaccines, and allergic, including anaphylactic, reactions to any vaccines
25. Participation in another clinical study involving the administration of an investigational drug within 12 weeks or 5 half-lives of the planned date of first vaccination, whichever is the longest
26. Donation or collection of greater than or equal to 400 mL of blood for any purpose within 12 weeks prior to the first planned vaccination, greater than or equal to 200 mL within 4 weeks prior to the first planned vaccination, or donation of any amount of blood by apheresis within 2 weeks prior to the planned first vaccination, or planned blood donation or collection of any amount for 90 days after the booster vaccination
27. Planned administration of a non-study vaccine anytime between Screening (Visit Screen1) and 30 days following the booster vaccination (Visit B30)
28. Current consumption of more than 21 units of alcohol per week for male participants, or 14 units per week for female participants (1 alcohol unit equal to 270 mL full strength beer, 470 mL light beer, 1 glass [100 mL] wine, or 1 measure [30 mL] spirits)
29. Unwilling to use appropriate contraception from the first screening visit (Screen1) until 30 days after the final administration of the study drug (excluding females confirmed non-childbearing potential, except via tubal ligation). Adequate contraception is defined as a contraceptive method with failure rate of less than 1% per year when used consistently and correctly and when applicable, in accordance with the product label. Male participants must practice true abstinence* from heterosexual contact or, during sexual contact with a female of childbearing potential, agree to use a condom, in addition to having the female partner use another form of contraception such as an IUD, oral contraceptives, hormonal implants, injectable contraceptive medications, or a tubal ligation. Males with any sexual partners: Males must also agree to use a condom during sexual contact with pregnant women, women of non-childbearing potential or male partners. This criterion must also be followed from the time of first study drug administration until 30 days after the final administration of study drug. Females having undergone tubal ligation as method of sterilisation: must agree to use barrier method of contraception from Screen1 to B360 (or at point of termination).
*True abstinence is acceptable when this is in line with the preferred and usual lifestyle of the participant. [Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception]. For this study, a female is considered to be of non-childbearing potential if they are post-menopausal (defined as greater than 12 months since last menstrual period) or surgically sterilized (i.e., tubal ligation or hysterectomy at least 6 months prior to enrolment).
30. Participants who, in the opinion of the Principal Investigator or delegate, should not participate in the study or are not capable of following the study schedule for any reason
31. Current smokers who have smoked in the last 3 months and who are unwilling to refrain from smoking for the duration of the study
32. Participants who return a positive alcohol or drug screen at Screen1

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)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Phase 1 / Phase 2
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
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)
SA
Recruitment hospital [1] 13216 0
CMAX Clinical Research Pty Ltd - Adelaide
Recruitment postcode(s) [1] 25773 0
5000 - Adelaide

Funding & Sponsors
Funding source category [1] 296887 0
Commercial sector/Industry
Name [1] 296887 0
AnGes, Inc.
Address [1] 296887 0
4-13-3, Shiba, Minato-ku, Tokyo 108-0014
Country [1] 296887 0
Japan
Primary sponsor type
Commercial sector/Industry
Name
Avance Clinical Pty Ltd
Address
Level 1, 2 Ann Nelson Drive, Thebarton SA Australia 5031
Country
Australia
Secondary sponsor category [1] 295894 0
None
Name [1] 295894 0
Address [1] 295894 0
Country [1] 295894 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 298107 0
Bellberry Human Research Ethics Committee
Ethics committee address [1] 298107 0
123 Glen Osmond Road, Eastwood SA 5063
Ethics committee country [1] 298107 0
Australia
Date submitted for ethics approval [1] 298107 0
03/05/2017
Approval date [1] 298107 0
12/07/2017
Ethics approval number [1] 298107 0
2017-04-319

Summary
Brief summary
The purpose of this study is to evaluate the safety, tolerability, pharmacokinetic, pharmacodynamic effects, and exploratory efficacy of AGMG0201 vaccine administered as an intramuscular injection in male and female participants with essential hypertension at two dose levels (low dose; high dose) compared with placebo.

You may be eligible to join this study if you are of non-childbearing potential, between 18 and 79 years of age, and have mild to moderate hypertension

This is a placebo controlled, dose escalation study. Each participant will receive a single injection to the deltoid muscle, followed by a second injection to the deltoid muscle, in the same arm, 30 days later.

A vaccine for hypertension could potentially reduce or halt the use of antihypertensive drugs and reduce long-term medical expenses. Although current antihypertensive drugs appear to fulfill the unmet medical needs of hypertensive patients, there are still serious issues (e.g., daily dosage of the medication, often for life) that may be a significant financial burden, particularly in developing countries.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 76014 0
Prof Sepehr Shakib
Address 76014 0
CMAX Clinical Research Pty Ltd
Level 5, 18a North Terrace
Adelaide
SA, 5000
Country 76014 0
Australia
Phone 76014 0
(+61) 8 7088 7900
Fax 76014 0
(+61) 8 7088 7999
Email 76014 0
sepehr.shakib@health.sa.gov.au
Contact person for public queries
Name 76015 0
Mr Tetsuya Ishihama
Address 76015 0
AnGes, Inc.
4-13-3, Shiba, Minato-ku, Tokyo 108-0014
Country 76015 0
Japan
Phone 76015 0
+81-3-5730-2488
Fax 76015 0
Email 76015 0
tishihama@anges.co.jp
Contact person for scientific queries
Name 76016 0
Prof Sepehr Shakib
Address 76016 0
CMAX Clinical Research Pty Ltd
Level 5, 18a North Terrace
Adelaide
SA, 5000
Country 76016 0
Australia
Phone 76016 0
sepehr.shakib@health.sa.gov.au
Fax 76016 0
Email 76016 0
sepehr.shakib@health.sa.gov.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
What supporting documents are/will be available?
No other documents available
Summary results
No Results