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Trial registered on ANZCTR


Registration number
ACTRN12608000607370
Ethics application status
Approved
Date submitted
19/08/2008
Date registered
4/12/2008
Date last updated
10/08/2010
Type of registration
Retrospectively registered

Titles & IDs
Public title
A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Study to Assess The Effects of Intravenous BG9928 on Body Weight in Subjects with Acute Decompensated Heart Failure and Renal Insufficiency
Scientific title
A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Study to Assess The Effects of Intravenous BG9928 on Body Weight in Subjects with Acute Decompensated Heart Failure and Renal Insufficiency
Secondary ID [1] 617 0
The ClinicalTrials.gov Identifier is NCT00709865
Universal Trial Number (UTN)
Trial acronym
TRIDENT-1 , 160HF301
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Acute Decompensated Heart Failure 3382 0
Condition category
Condition code
Cardiovascular 3530 3530 0 0
Other cardiovascular diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Chemical Name (CAS): 3-[4-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yl]propionic acid
Laboratory Codes: BIO-9002
CAS number: 340021-17-2
Other names: BG9928, Adentri
The BG9928 drug product for intravenous (IV) use is supplied as a sterile, lyophilized powder in vials containing 20 mg of BG9928. The active drug product contains the following inactive ingredients: mannitol, histidine, sodium chloride, and sodium hydroxide. BG9928 is reconstituted with sterile water for injection and will be administered intravenously, in an appropriate volume as defined in the Directions for Handling and Administration (DHA), via syringe or infusion pump over 30 minutes, to subjects randomized to receive active treatment.
Study treatment should be initiated within 24 hours of the first dose of IV diuretic for the treatment of the current episode of Acute Decompensated Heart Failure (ADHF), and will be administered daily every 12 hours (q12h) for up to 5 days. Each subject will receive placebo or BG9928 at 0.03 mg/kg, 0.15 mg/kg, or 0.3 mg/kg every 12 hours (q12h) at randomization evenly (1:1:1:1) resulting in 225 patients per treatment group.
Intervention code [1] 3109 0
Treatment: Drugs
Comparator / control treatment
Placebo. The placebo drug product contains the following inactive ingredients: mannitol, histidine, sodium chloride, and sodium hydroxide. Placebo is reconstituted with sterile water for injection and will be administered intravenously, in an appropriate volume as defined in the directions for handling and administration (DHA), via syringe or infusion pump over 30 minutes to subjects randomized to receive placebo treatment. Study treatment should be initiated within 24 hours of the first dose of intravenous (IV) diuretic for the treatment of the current episode of Acute Decompensated Heart Failure (ADHF), and will be administered daily every 12 hours (q12h) for up to 5 days. Each subject will receive placebo or BG9928 at 0.03 mg/kg, 0.15 mg/kg, or 0.3 mg/kg every 12 hours (q12h).
Control group
Active

Outcomes
Primary outcome [1] 4436 0
Change in body weight at 24 hours following the first dose in subjects hospitalized with ADHF and renal insufficiency.
Timepoint [1] 4436 0
24 hours
Secondary outcome [1] 7482 0
Effect of BG9928 when added to standard therapy in subjects with ADHF and renal insufficiency on:

Worsening renal function during the double-blind treatment period up to Day 5 (or discharge if prior to Day 5). Incidence of worsening renal function defined as an increase in serum creatinine (based on data from the central laboratory) at any time by at least 0.3 mg/dL from baseline up to Day 5 or discharge if prior to Day 5. Measured at Baseline and daily from day 2 to day 5.
Timepoint [1] 7482 0
We will have different frequency for different outcomes. Worsening renal function during the double-blind treatment period up to Day 5 (or discharge if prior to Day 5). Daily till day 5; Days of hospital-free survival (DHFS) over 30 days after the first dose of study treatment. On day 30; Improvement in Dyspnea Symptom Score at 6 hours following the first dose. On day 1; Improvement in Subject Global Clinical Assessments at 24 hours following the first dose. On day 2.
Secondary outcome [2] 7483 0
Effect of BG9928 when added to standard therapy in subjects with ADHF and renal insufficiency on:

Days of hospital-free survival (DHFS) over 30 days after the first dose of study treatment.
Timepoint [2] 7483 0
over 30 days
Secondary outcome [3] 7484 0
Effect of BG9928 when added to standard therapy in subjects with ADHF and renal insufficiency on: Improvement in Dyspnea Symptom Score at 6 hours following the first dose.
Timepoint [3] 7484 0
6 hours following the first dose
Secondary outcome [4] 7485 0
Effect of BG9928 when added to standard therapy in subjects with ADHF and renal insufficiency on: Improvement in Subject Global Clinical Assessments at 24 hours following the first dose. In order to understand the degree to which BG9928 can contribute to improvements in
overall clinical status, a baseline assessment of each subject's overall clinical status will be obtained at different time points and compared with the baseline status. Factors to be
considered by the subject when assessing global status include the following: fatigue, overall discomfort, breathing status, edema, ability to ambulate, etc. Measurements will be made via questionnaire.
Timepoint [4] 7485 0
24 hours following the first dose

Eligibility
Key inclusion criteria
1. Must have previous diagnosis of heart failure.
2. Renal insufficiency at the time of screening as defined by eGFR greater than or equal to 20 and less than or equal to 70 mL/min/1.73 m2
3. Subject requires hospitalization for treatment with IV diuretics for the current episode of ADHF meets both of the following:
3.1 Has received at least 40 mg of furosemide (or equivalent) the treatment of the current episode of ADHF within 24 hrs prior to randomization unless a rationale for a lower dose is provided by the enrolling Investigator and
3.2 is randomized within 24 hours of first dose of IV diuretic administered for this episode of ADHF.
4. Must have ADHF with clinical evidence for volume overload requiring hospitalization as demonstrated by at least 2 of the following features:
4.1 Dyspnea or orthopnea
4.2 Rales
4.3 Peripheral edema
4.4 Increased jugular venous pressure
4.5 Chest X-ray consistent with congestive heart failure (CHF)
4.6 Plasma B-type natriuretic peptide (BNP) greater than or equal to 150 pg/ml or N-terminal (NT) pro-BNP greater than or equal to 450 pg/ml
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. Anticipated hospitalization <48 hours at Screening (as judged by the enrolling Investigator).
2. Current hospitalization initiated by transfer from another acute care inpatient setting.
3. Acute coronary syndrome (ACS) within 48 hours of Screening evidenced by significant changes in cardiac biomarkers and electrocardiogram (ECG) changes consistent with Ischemia.
4. Anticipated need for cardiac catheterization during the current hospitalization (as judged at screening by the enrolling Investigator).
5. Myocardial infarction (MI) within 30 days of Screening.
6. Screening laboratory findings as follows:
6.1 Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) greater than or equal to 3 times the upper limit of normal
6.2 Total bilirubin >2.0 mg/dL
6.3 Hematocrit <28% or an anticipated need for a blood transfusion

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)
Randomization will take place across all study sites using a centralized Interactive Voice/Web Response System (IVRS/IWRS).
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The protocol operates a telephone and Web based system for IVRS.The randomization will be stratified by region. Subjects will be randomized to dose groups in a 1:1:1:1 ratio. Subjects withdrawn from the study will not be replaced. At randomization, the IVRS/IWRS will assign a unique 6-digit subject identification number to each subject (the first segment of the number represents the study site and the second segment of the number represents the subject at that study site). The subject’s identification number will be used on all of that subject’s Case Report Forms (CRFs). More details will be provided in the Study Reference Manual. The random sequence is computer generated. Randomization was stratified by geographic region and within each region permuted block randomisation is used to assign treatment groups.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
N/A
Phase
Phase 3
Type of endpoint/s
Efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Stopped early
Data analysis
Reason for early stopping/withdrawal
Date of first participant enrolment
Anticipated
1/09/2008
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
65
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
Recruitment postcode(s) [1] 979 0
2601
Recruitment postcode(s) [2] 980 0
2010
Recruitment postcode(s) [3] 981 0
3004
Recruitment postcode(s) [4] 982 0
6847
Recruitment postcode(s) [5] 983 0
5035
Recruitment postcode(s) [6] 984 0
7001
Recruitment postcode(s) [7] 985 0
1871
Recruitment postcode(s) [8] 986 0
3168
Recruitment postcode(s) [9] 987 0
3050
Recruitment outside Australia
Country [1] 1017 0
United States of America
State/province [1] 1017 0
Country [2] 1018 0
India
State/province [2] 1018 0
Country [3] 1019 0
Argentina
State/province [3] 1019 0
Country [4] 1020 0
Brazil
State/province [4] 1020 0
Country [5] 1021 0
Bulgaria
State/province [5] 1021 0
Country [6] 1022 0
Czech Republic
State/province [6] 1022 0
Country [7] 1023 0
Hungary
State/province [7] 1023 0
Country [8] 1024 0
Poland
State/province [8] 1024 0
Country [9] 1025 0
Romania
State/province [9] 1025 0
Country [10] 1026 0
Russian Federation
State/province [10] 1026 0
Country [11] 1027 0
Finland
State/province [11] 1027 0
Country [12] 1028 0
France
State/province [12] 1028 0
Country [13] 1029 0
Germany
State/province [13] 1029 0
Country [14] 1030 0
Israel
State/province [14] 1030 0
Country [15] 1031 0
Italy
State/province [15] 1031 0
Country [16] 1032 0
Netherlands
State/province [16] 1032 0
Country [17] 1033 0
Sweden
State/province [17] 1033 0
Country [18] 1034 0
United Kingdom
State/province [18] 1034 0
Country [19] 1035 0
Canada
State/province [19] 1035 0

Funding & Sponsors
Funding source category [1] 3568 0
Commercial sector/Industry
Name [1] 3568 0
Biogen Idec Pty Ltd
Country [1] 3568 0
United States of America
Funding source category [2] 3569 0
Commercial sector/Industry
Name [2] 3569 0
Biogen Idec Limited
Country [2] 3569 0
United Kingdom
Primary sponsor type
Commercial sector/Industry
Name
Biogen Idec Pty Ltd
Address
14 Cambridge Center
Cambridge, MA 02142, USA
Country
United States of America
Secondary sponsor category [1] 3209 0
Commercial sector/Industry
Name [1] 3209 0
Biogen Idec Limited
Address [1] 3209 0
5 Roxborough Way
Foundation Park
Maidenhead SL6 3UD, UK
Country [1] 3209 0
United Kingdom
Secondary sponsor category [2] 3210 0
Commercial sector/Industry
Name [2] 3210 0
Quintiles, Inc
Address [2] 3210 0
Quintiles, Inc
1007 Slater Road
Durham
NC27703
USA
Country [2] 3210 0
United States of America
Other collaborator category [1] 329 0
Commercial sector/Industry
Name [1] 329 0
Almac Clinical Technologies
Address [1] 329 0
Seagoe Industrial Estate
Building 14
Craigavon
BT63 5UA
Northern Ireland
United Kingdom
Country [1] 329 0
United Kingdom
Other collaborator category [2] 374 0
Commercial sector/Industry
Name [2] 374 0
PPD (Pharmaceutical Product Development)
Address [2] 374 0
Fleming House
Phoenix Cresent
Strathclyde Business Park
Bellshill, ML4 3NJ
Scotland
Country [2] 374 0
United Kingdom
Other collaborator category [3] 375 0
Commercial sector/Industry
Name [3] 375 0
Convance Central Laboratory Services
Address [3] 375 0
1 International Business Park
#05-12A/B
The Synergy, Singapore 609917
Country [3] 375 0
Singapore

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 5810 0
West Fort Hi-Tech Hospital Ltd.
Ethics committee address [1] 5810 0
West Fort Hi-Tech Hospital Ltd.
P.B. No-930
Punkunnam Thrissur
Kerela- 680 002
INDIA
Ethics committee country [1] 5810 0
India
Date submitted for ethics approval [1] 5810 0
Approval date [1] 5810 0
01/07/2008
Ethics approval number [1] 5810 0
N/A (This is not applicable in India)

Summary
Brief summary
The Trident-1 study is an International multi-center, randomized, double-blind, placebo controlled phase 3 clinical trial with plans to randomise a total of 900 patients. The purpose of the study is to determine the effects and safety on the body weight of 3 different doses of BG9928 (0.03 mg/kg, 0.15 mg/kg, or 0.3 mg/kg) and placebo given up to a maximum 5 days to subjects hospitalized due to Acute Decompensated Heart Failure (ADHF) and Renal Insufficiency. BG9928 is a A1 receptor antagonist, which from previous studies have demonstrated ability to preserve renal function and promote urine production. The effect of BG9928 on body weight is thus related to the urine output. The study drug will be given in addition to the medication that would normally be given to ADHF patients. This means that patients on placebo still receive normal standard care.
The primary objective of the study is to determine the effect of BG9928, when added to standard therapy, on the change in body weight at 24 hours following the first dose in these subjects. The secondary efficacy objectives of this study are to determine the effect of BG9928, when added to standard therapy, on worsening renal function during the treatment period, the number of days of hospital-free survival (DHFS), the improvement in Dyspnea Symptom and Edema Score, Subject Global Clinical Assessments and Physician Global Clinical Assessment. Additionally the secondary efficacy objectives are measuring the use of concomitant medications to treat heart failure, length of hospital stay, cardiovascular and all-cause mortality and re-hospitalization up to 180 days after the initial dose. The safety objective of the study is to assess the safety and tolerability of BG9928.
Upon screening patients will be randomized evenly into either of the 4 treatment arms and will receive IV study drug infusions twice daily for a maximum treatment period of 5 days 910 doses). Prior to and during hospitalisation period, for a maximum of 7 days, the patients will be monitored via physical exam, vital signs, body weight, ECG diagram, questionnaires, blood samples (including pregnancy test for women of childbearing potential, haematology, chemistry, special kidney tests (BNP, Cystatin C), bone markers ,genetic and PK testing. Safety monitoring and concomitant medication monitoring will be conducted from screening and up to day 30 . Telephone follow-up done at 2, 3 and 6 months after the first study dose.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 28733 0
Address 28733 0
Country 28733 0
Phone 28733 0
Fax 28733 0
Email 28733 0
Contact person for public queries
Name 11890 0
Dr Atsumi Fukui
Address 11890 0
Biogen Idec Australia Pty Ltd
Suite 2, Level 4, 123 Epping Road
North Ryde NSW 2113
Country 11890 0
Australia
Phone 11890 0
+61 2 8875 3900
Fax 11890 0
+61 2 9889 1162
Email 11890 0
[email protected]
Contact person for scientific queries
Name 2818 0
Dr Atsumi Fukui
Address 2818 0
Biogen Idec Australia Pty Ltd
Suite 2, Level 4, 123 Epping Road
North Ryde NSW 2113
Country 2818 0
Australia
Phone 2818 0
+61 2 8875 3900
Fax 2818 0
+61 2 9889 1162
Email 2818 0
[email protected]

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