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Trial registered on ANZCTR


Registration number
ACTRN12618001027202
Ethics application status
Approved
Date submitted
7/06/2018
Date registered
19/06/2018
Date last updated
29/09/2020
Date data sharing statement initially provided
6/02/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
A first in Human single-Center Study To Evaluate the effectiveness and Safety Of A Live Attenuated Dengue Vaccine (KD-382) In Healthy Adults
Scientific title
A Phase I, Randomized, Placebo-Controlled, Double-Blind, Ascending-Dose And Single-Center Study To Evaluate Immunogenicity And Safety Of A Live Attenuated Tetravalent Dengue Vaccine (KD-382) In Flavivirus Antibody-Naïve Healthy Adults
Secondary ID [1] 295059 0
None
Universal Trial Number (UTN)
Trial acronym
KD-382-001
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Dengue Fever 308106 0
Condition category
Condition code
Infection 307144 307144 0 0
Other infectious diseases
Inflammatory and Immune System 307303 307303 0 0
Normal development and function of the immune system

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Name of the study vaccine: KD-382 (live attenuated tetravalent dengue
vaccine)
Dose: KD-382 Low (1000 Focus forming units of the virus serotype 1,2,3,4), KD-382 STD[STD refers to standard dose](100000 Focus forming units of the virus serotype 1,2,3,4) or placebo
Route of administration: subcutaneous
Frequency: The study vaccine (KD-382 or placebo) will be administered twice during the study-on Day 1 and Day 29.
The study will be dosed in 2 sequential parts. In Part 1, 30 subjects will be randomized to 1 of 3 treatment sequences in a ratio of 3:2:1 and dosed with low dose of KD-382 or placebo. A safety review will be conducted in a blinded fashion, including safety data from the 3 sequences. After completion of the safety review using the safety data from Day 1 to Day 15 in Part 1, and if safety criteria are satisfied, second dosing on Day 29 for Part 1 and first dosing on Day 1 for Part 2 may commence. Again, 30 subjects in Part 2 will be randomized to 1 of 3 treatment sequences in a ratio of 3:2:1 and receive the standard dose (STD) of KD-382 or placebo. Safety and tolerability will be reviewed after Day 15 using the safety data from Day 1 to Day 15 in Part 2 and the data from Day 29 to Day 43 in Part 1. If all the safety criteria are satisfied, second dosing for Part 2 may commence.
In both Parts, subjects in Sequence 1 and 2 will receive low or standard dose of KD-382 and subjects in Sequence 3 will receive placebo on Day 1. For the second dose, subjects in Sequence 1 and 3 will receive placebo and subjects in Sequence 2 will receive low or standard dose of KD-382 on Day 29.
The study vaccine (KD-382 or placebo) will be administered subcutaneously on Day 1 and Day 29.
To minimize risk to subjects in this first-in-human trial, modified sentinel dosing will be employed for the first inoculation for all dose groups. In Part 1, 6 subjects (Cohort 1) will be randomized in a ratio of 3:2:1 to treatment sequences 1, 2 and 3 and administered with low dose KD-382 or placebo. After completion of the post Day 15 safety review using the safety data from Day 1 to Day 15 for Cohort 1, if the safety criteria are satisfied, 24 subjects (Cohort 2) will be dosed. After completion of post Day 15 safety review using the safety data from Day 1 to Day 15 for both Cohort 1 and Cohort 2 in Part 1, if safety criteria are satisfied, 6 subjects (Cohort 3) will be randomized in a ratio of 3:2:1 to treatment sequences 1, 2 and 3, and dosed with STD of KD-382 or placebo. After completion of the post Day 15 safety review for Cohort 3 using the safety data from Day 1 to Day 15 in Part 2 and the safety data from Day 29 to Day 43 in Part 1, if safety criteria are satisfied in both Parts, 24 subjects (Cohort 4) will be dosed.
Intervention code [1] 301391 0
Prevention
Comparator / control treatment
Commercially available physiological saline (0.9% sodium chloride)
Control group
Placebo

Outcomes
Primary outcome [1] 306102 0
Primary Safety Objective:
• To evaluate the safety and tolerability of KD-382 in flavivirus
antibody-naïve healthy adults
The Primary objective will be assessed using a diary card review and AE review by Investigator at site.
Timepoint [1] 306102 0
Day 57.
Primary outcome [2] 306262 0
• To evaluate the immunogenicity of KD-382 as assessed by seroconversion rates for each serotype wild-type parental virus (i.e., dengue virus [DENV]1/03135, DENV2/99345, DENV3/16562 and DENV4/1036). This objective will be assessed by Serology samples for DENV FRNT .
Timepoint [2] 306262 0
Days 29 and 57.
Secondary outcome [1] 347591 0
•To evaluate the immunogenicity of KD-382 as assessed by geometric mean titer (GMT) of FRNT50, geometric mean ratio (GMR) of FRNT50, number of seroconverted serotypes (i.e., monovalent, bivalent, trivalent, or tetravalent) for each subject and effective boosting* rate.

*Effective boosting is defined as >/= 4-fold increase in FRNT50 from Day 29 to Day 57 for subjects with FRNT50 >/= 1:10 at Day 29. Blood samples for DENV FRNT for each serotype wild-type parental virus (i.e., DENV1/03135, DENV2/99345, DENV3/16562 and DENV4/1036) will be collected at screening, day 29, and day 57.
Timepoint [1] 347591 0
Number of seroconverted serotypes (i.e., monovalent, bivalent, trivalent,
or tetravalent) for each subject at Days 29 and 57.

Eligibility
Key inclusion criteria
1. Male or female volunteers aged between 18 and 65 years (both inclusive) at the time
of screening.
2. Individuals in good health as determined by the outcome of medical history, physical
examination, and clinical judgement by the Investigator.
3. Be willing and able to give written informed consent to participate in this study.
4. Be willing and able to communicate with the Investigator and understand the
requirements of the study.
5. Provision of signed, written and dated informed consent for optional genetic research.
If a subject declines to participate in the genetic component of the study, there will be
no penalty or loss of benefit to the subject. The subject will not be excluded from
other aspects of the study described in this protocol.
Minimum age
18 Years
Maximum age
65 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Subjects will not be entered into this study if they meet any of the following criteria:
1. History of flavivirus (Dengue, Japanese Encephalitis, Zika, Yellow Fever, West Nile, Kunjin) infection or vaccination or prolonged habitation in a Dengue endemic area (continuously for more than 1 year).
2. Seropositivity to any of the 4 Dengue serotypes. Seropositivity is defined as a FRNT titer >/= 1:10.
3. Seropositivity to Japanese Encephalitis, Zika, Yellow Fever, West Nile virus, or Kunjin assessed by commercial Enzyme Linked Immune Sorbent Assay (ELISA).
4. Blood tests positive for human immunodeficiency virus (HIV) antibodies, hepatitis B virus (HBV) surface antigen or Hepatitis C virus (HCV) antibodies.
5. Malignancies (subjects with multiple basal cell cancers but who had their last basal cell cancer removed completely [confirmed pathologically] are allowed to be entered into this study).
6. Hematologic conditions that may lead to bleeding tendencies or abnormality in platelets, white blood cell count, and neutrophil count.
7. Body mass index > 40, regardless of comorbidities.
8. Autoimmune conditions (e.g., rheumatoid arthritis).
9. Taking more than 4 regular medications.
10. Participation in another clinical study of any investigational product (vaccine, drug, medical device) or medical procedure within 4 weeks from last study visit before screening.
11. Plan to participate in another clinical study from 4 weeks before screening until the end of the treatment period.
12. Plan to receive any vaccine from 4 weeks before screening until the end of the treatment period.
13. Have received blood or blood-derived products in the last 3 months before screening, which might interfere with assessment of the immune response.
14. Known or suspected congenital or acquired immunodeficiency; or receipt of immunosuppressive therapy such as anti-cancer chemotherapy or radiation therapy within the last 6 months before screening; or long-term systemic corticosteroid therapy (prednisone or equivalent for more than 2 consecutive weeks within the last 3 months before screening).
15. Known systemic hypersensitivity to any of the vaccine components, or history of a life-threatening reaction to a vaccine containing any of the same substances.
16. Current alcohol abuse or drug addiction that might interfere with the ability to comply with study procedures.
17. Chronic illness that, in the opinion of the Investigator, is at a stage where it might interfere with study conduct or completion.
Subjects with any of the following conditions are allowed to be entered into this study:
• History of mild to moderate allergic reaction to food or medication and does not meet the exclusion criteria 15.
• Well-controlled hypertension, defined as < 140 mmHg systolic and < 90 mmHg diastolic blood pressure, using no more than 2 antihypertensive drugs, and have been on the same dose of antihypertensive for at least 3 months.
• Well-controlled diabetes, defined as the most recent HbA1c (performed within the last 3 months) < 6.5%, controlled with diet or on metformin alone.
• History of intermittent or mild persistent asthma but not requiring systemic corticosteroid therapy that falls under the exclusion criteria 14.
18. Identified as a site employee of the Investigator or study center, with direct involvement in the proposed study or other studies under the direction of that Investigator or study center, as well as family members (i.e., immediate, husband, wife and their children, adopted or natural) of the site employees or the Investigator.
19. Plan to travel to Dengue endemic areas* during study period.
* See Appendix 11.2 for countries and areas considered as endemic for Dengue.
20. Pregnant or breastfeeding women, or women planning to become pregnant or breastfeed during the subject’s participation in this study.
21. Women of child-bearing potential (WOCBP)** and sexually active who are unwilling to use adequate birth control. Adequate birth control is defined as agreement to consistently practice an effective and accepted method of contraception during the treatment period and until 120 days after last dose of study vaccine. These include hormonal contraceptives, intrauterine device or double barrier contraception (i.e., condom + diaphragm) or a male partner with documented vasectomy.
**Considered WOCBP, i.e., fertile and following menarche until becoming post menopausal, unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A post menopausal state is defined as no menses for 12 months without an alternative medical cause.
22. Male volunteers must agree to abstain, between dosing and 120 days post dosing, from sexual intercourse with pregnant or lactating women and, if sexually active with a female partner (of child bearing potential), to use a condom in addition to his female partner’s use of another form of contraception (e.g., intrauterine device, diaphragm, oral contraceptive, injectable progesterone contraceptive, subdermal implant contraceptive, or tubal ligation). A male volunteer practicing abstinence is also acceptable (if this is in line with their normal lifestyle).
23. Any condition which would limit the subject’s ability to complete the study in the opinion of the Investigator.
*Appendix 11.2: Countries and Areas Considered as Endemic for Dengue
Countries and areas considered as endemic for dengue (classified as frequent or
continuous dengue risk areas ):
Americas and the Caribbean:
• American Samoa
• Argentina
• Aruba
• Barbados
• Belize
• Bolivia
• Brazil
• British Virgin Islands
• Colombia
• Costa Rica
• Cuba
• Curacao
• Dominica
• Dominican Republic
• Ecuador
• El Salvador
• Fiji
• French Guiana
• French Polynesia
• Grenada
• Guadeloupe
• Guatemala
• Guyana
• Haiti
• Honduras
• Jamaica
• Martinique
• Mexico
• Nicaragua
• Panama
• Paraguay
• Peru
. Puerto Rico
• Saint Kitts and Nevis
• Saint Lucia
• Saint Vincent and the Grenadines
• Suriname
• Tonga
• Trinidad and Tobago
• US Virgin Islands
• Venezuela
Africa and the Middle East:
• Kenya
• Tanzania
• Yemen
Asia and Oceania:
• Bangladesh
• Bhutan
• Brunei
• Burma
• Cambodia
• Federated States of Micronesia
• India
• Indonesia
• Laos
• Malaysia
• Maldives
• Nepal
• New Caledonia
• Pakistan
• Palau
• Papua New Guinea
• Philippines
• Sri Lanka
• Taiwan
• Thailand
• Timor-Leste
• Vietnam

Study design
Purpose of the study
Prevention
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Central randomization by Phone / web
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Allocation of randomization numbers will be performed centrally using an
interactive voice/web response allocation system (IV/WRS).
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
Intervention assignment
Parallel
Other design features
Phase
Phase 1
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
All statistical analysis will be performed using the latest available version
of SAS®(SAS Institute Inc., Cary, North Carolina, United States of America [USA]),
version 9.2 or higher.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
20/08/2018
Actual
20/08/2018
Date of last participant enrolment
Anticipated
30/03/2019
Actual
6/06/2019
Date of last data collection
Anticipated
30/09/2020
Actual
10/06/2020
Sample size
Target
60
Accrual to date
Final
60
Recruitment in Australia
Recruitment state(s)
SA
Recruitment hospital [1] 11052 0
CMAX Clinical Research Pty Ltd - Adelaide
Recruitment postcode(s) [1] 22848 0
5000 - Adelaide

Funding & Sponsors
Funding source category [1] 299640 0
Commercial sector/Industry
Name [1] 299640 0
KM Biologics Co., Ltd.
Country [1] 299640 0
Japan
Primary sponsor type
Commercial sector/Industry
Name
KM Biologics Co., Ltd.
Address
KM Biologics Co., Ltd.
1-6-1 Okubo, Kita-ku, Kumamoto-shi, Kumamoto 860-8568, Japan
Country
Japan
Secondary sponsor category [1] 298967 0
None
Name [1] 298967 0
Address [1] 298967 0
Country [1] 298967 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 300538 0
Bellberry Human Research Ethics Committee A [EC00372]]
Ethics committee address [1] 300538 0
129 Glen Osmond Road Eastwood South Australia 5063
Ethics committee country [1] 300538 0
Australia
Date submitted for ethics approval [1] 300538 0
28/03/2018
Approval date [1] 300538 0
06/06/2018
Ethics approval number [1] 300538 0
2018-03-196

Summary
Brief summary
This is a first in human single-center vaccine study on Dengue Vaccine.The research vaccine is being developed to help protect against a type of virus called dengue virus. Infection with dengue virus can cause a flu-like illness (dengue fever) that sometimes develops into a severe complication (dengue haemorrhagic fever) The study will consist of 3 periods including the Screening Period,Treatment Period and Follow-up Period. After providing the written consent, subject will be screened for eligibility between Day -45 and Day -1. . Approximately 60 participants will participate in this study at one study centre in Australia. All participants will receive two vaccinations, with either the research vaccine or placebo given each time. A placebo is a sterile fluid that has no active vaccine in it. The study consists of 2 parts-Part 1 or Part 2.Participants in Part 1 will receive either low dose research vaccine or placebo. Participants in Part 2 will receive either standard dose research vaccine or placebo.The purpose of this research study is to check whether the research vaccine is safe and how well the subject can tolerate vaccination with the research vaccine (tolerability). The study will also test whether the research vaccine activates an immune response against dengue virus by measuring levels of antibodies (a type of protein involved in the immune response that may protect from future dengue infection) and immune response cells in the blood.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 83990 0
Dr Nicholas Farinola
Address 83990 0
CMAX Clinical Research Pty Ltd
Level 5, 18a
North Terrace
Adelaide SA 5000 Australia
Country 83990 0
Australia
Phone 83990 0
+610870887900
Fax 83990 0
Email 83990 0
[email protected]
Contact person for public queries
Name 83991 0
Samantha Smith
Address 83991 0
CMAX Clinical Research Pty Ltd
Level 5, 18a
North Terrace
Adelaide SA 5000 Australia
Country 83991 0
Australia
Phone 83991 0
+610870887900
Fax 83991 0
Email 83991 0
[email protected]
Contact person for scientific queries
Name 83992 0
Nicholas Farinola
Address 83992 0
CMAX Clinical Research Pty Ltd
Level 5, 18a
North Terrace
Adelaide SA 5000 Australia
Country 83992 0
Australia
Phone 83992 0
+610870887900
Fax 83992 0
Email 83992 0
[email protected]

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


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
973Ethical approval    375233-(Uploaded-08-01-2019-16-53-50)-Study-related document.pdf



Results publications and other study-related documents

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