CTRI/2011/10/002076 [Registered on: 19/10/2011] Trial Registered Prospectively
Last Modified On:
25/04/2012
Post Graduate Thesis
No
Type of Trial
Interventional
Type of Study
Drug
Study Design
Randomized, Parallel Group, Active Controlled Trial
Public Title of Study
A clinical study to estimate the safety, tolerability and efficacy of two medications for treatment of complicated intra abdominal infections in adults.
Scientific Title of Study
A Phase 2, Randomized, Double-Blind, Double-Dummy, Multicenter,
Prospective Study to Assess the Efficacy, Safety and Pharmacokinetics of 2
Dose Regimens of TP-434 Compared with Ertapenem in Adult Community-
Acquired Complicated Intra-abdominal Infections
Trial Acronym
Secondary IDs if Any
Secondary ID
Identifier
NCT01265784
ClinicalTrials.gov
2010-022548-19
EudraCT
TP-434-P2-cIAI-1
Protocol Number
Details of Principal Investigator or overall Trial Coordinator (multi-center study)
Name
Sunil Garg
Designation
Senior Manager
Affiliation
Address
INC GVK Bio Pvt Ltd.
14th Floor, Tower B, Building No 14
DLF Cyber City, Phase III, Gurgaon 122002, Haryana (INDIA)
Gurgaon HARYANA 122002 India
Phone
0124-4642469
Fax
0124-4642401
Email
sgarg@incresearch.com
Details of Contact Person Scientific Query
Name
Dr Mamta Singh
Designation
Senior Manager
Affiliation
Address
INC GVK Bio Pvt Ltd.
14th Floor, Tower B, Building No 14
DLF Cyber City, Phase III, Gurgaon 122002, Haryana (INDIA)
Gurgaon HARYANA 122002 India
Phone
0124-4642449
Fax
0124-4642401
Email
masingh@incresearch.com
Details of Contact Person Public Query
Name
Dr Mamta Singh
Designation
Senior Manager
Affiliation
Address
INC GVK Bio Pvt Ltd.
14th Floor, Tower B, Building No 14
DLF Cyber City, Phase III, Gurgaon 122002, Haryana (INDIA)
Gurgaon HARYANA 122002 India
Phone
0124-4642449
Fax
0124-4642401
Email
masingh@incresearch.com
Source of Monetary or Material Support
Tetraphase Pharmaceuticals Inc,
480 Arsenal Street, Suite 110
Watertown, MA 02472, USA
Primary Sponsor
Name
Tetraphase Pharmaceuticals Inc
Address
480 Arsenal Street, Suite 110
Watertown, MA 02472, USA
Type of Sponsor
Pharmaceutical industry-Global
Details of Secondary Sponsor
Name
Address
NIL
NIL
Countries of Recruitment
India Latvia Lithuania Romania United States of America
Sites of Study
No of Sites = 11
Name of Principal
Investigator
Name of Site
Site Address
Phone/Fax/Email
Dr Surendran
Amrita Institute of Medical Science
Dept of Gastrointestinal surgery and Vascular surgery,
AIMS Post, Ponekkara, Kochi-682041 Kozhikode KERALA
0484-2802134 0484-2802134 sudhi@aims.amrita.edu
Dr Swastik Nandi
BP Poddar Hospital & Medical Research Ltd.
Dept of Surgery,
71/1, Humayun Kabir Sarani, Block-G, New Alipore, Kolkata, 700053 Kolkata WEST BENGAL
033-23997009 033-23997009 swastiknandi@yahoo.com
Hosmath Vijayakumar
Gokula Metropolis Clinical Research Centre
Department of Surgery, MSR Nagar, MSRIT Post, New BEL Road, Bangalore-560054 Bangalore KARNATAKA
080-40528402 080-40528402 drvkhosmath@gmail.com
Dr Hariprasad Taluru
K.R. Hospital
Dept of General Surgery,
No. 979, 25th Main Road, BSK, 1st Stage, 50 Feet Road,
Bangalore 560050 Bangalore KARNATAKA
080-26743596 080-26743596 harishermi@hotmail.com
Dr Nitin Pai
KEM Hospital
Dept of Gastroenterology, Sardar Moodliar Road, Rasta Peth, Pune-411011 Pune MAHARASHTRA
020-26125603 020-26125603 drnitinpai@gmail.com
Dr Manish Bhatnagar
Medisurge Hospital
Room No. 101, Research and Development Department, Mithakhali Six Roads,
Ellisbridge, Ahmedabad-380006 Ahmadabad GUJARAT
079-26441401
man_bhatnagar@yahoo.com
Dr Mukesh Kalla
S.R.Kalla Memorial Gastro. & Gen. Hospital
Dept of gastroenterology,78, Dhuleshwar Garden,
Behind HSBC Bank,
Sardar Patel Marg, C-Scheme, Jaipur-302001 Jaipur RAJASTHAN
0141-4020622 0141-4020622 drmkalla@rediffmail.com
Dr Suresh Jain
Sahyadri Munot Hospital
Dept of Gastroenterology,
387/5 Bhavani Peth, New Timbermarket Road,
Near Seven Loves Chowk, Pune-411042 Pune MAHARASHTRA
020-67213800 020-67213800 scjdr@yahoo.com
Dr P P Sethu Babu
Sai Vani Hospitals Ltd
Department of Gastroenterology,
1-2-365/36/6 & 7, Ramakrishna Math Road, Opp. Indira Park, Domalguda, Hyderabad-500029 Hyderabad ANDHRA PRADESH
040-27634462 040-27636882 sethu9@rediffmail.com
Dr Yogishwara Chowdipallaya Nagappa
Santosh Hospital,
Department of Surgery,
No.6/1, Promenade Road, Near Good Will School, Behind Coles Park, Bangalore-560005 Bangalore KARNATAKA
B.P Poddar Hospital & Medical Research Ltd Ethical Committee
Submittted/Under Review
Bangalore Central Ethics Committee
Approved
Bangalore Medical College and Research Institute
Submittted/Under Review
Bangalore, central ethics committee
Approved
Ethics Committee KEM Hospital Research
Submittted/Under Review
Ethics Committee, KEM Hospital Research
Submittted/Under Review
HCG Medi-Surge Ethics Committee
Approved
M.S. Ramaiah Medical College and Technical Hospital
Approved
S.R. Kalla Memorial Ethical Committee for Human research
Approved
Sahyadri Hospital Ltd. Ethics Committee
Submittted/Under Review
Virtuous Independent Ethics Committee
Approved
Regulatory Clearance Status from DCGI
Status
Approved/Obtained
Health Condition / Problems Studied
Health Type
Condition
Patients
Acutely hospitalized subjects with a clinical diagnosis of CA-cIAI requiring
surgery will be recruited into this study.,
Intervention / Comparator Agent
Type
Name
Details
Comparator Agent
Ertapenam 1g
Ertapenem 1g administered by IV q24h. Ertapenem infusion solutions will be prepared according to the full prescribing
information of Invanz® (comparator)
Duration of Therapy: No longer than 7 days
Intervention
TP 434 for Intravenous administration
TP-434-046 was synthesized under current good manufacturing practices and the drug product contains 52.5 mg
(TP-434 free base equivalents) of lyophilized powder in a 30 mL vial. TP-434 will be reconstituted with 10 mL of
sterile water and further diluted with sterile 0.5x normal saline, to generate 0.3 mg/mL TP 434 solution for 1.5mg / Kg q 24h IV infusion. Duration of Therapy: no longer than 7 days
Intervention
TP-434 for intravenous administration
TP-434-046 was synthesized under current good manufacturing practices and the drug product contains 52.5 mg
(TP-434 free base equivalents) of lyophilized powder in a 30 mL vial. TP-434 will be reconstituted with 10 mL of
sterile water and further diluted with sterile 0.5x normal saline, to generate 0.2 mg/mL TP-434 solution
for 1.0 mg/kg q12 h IV infusion.
Duration of Therapy: no longer than 7 days
Inclusion Criteria
Age From
18.00 Year(s)
Age To
75.00 Year(s)
Gender
Both
Details
1. Abdominal pain or discomfort with onset prior to hospitalization
2. Evidence of a systemic inflammatory response with at least one of the following
a. Fever (oral temperature greater than 100.4 degree Fahrenheit or 38 degree Celsius) or hypothermia (oral temperature less than 35 degree Celsius/95 degree Fahrenheit).
b. Elevated white blood cell (WBC) count (greater than 10,500 per cubic mm)
c. Tachycardia (Heart rate greater 90 beats per min)
d. Tachypnea (greater than 20 breaths per min)
3. Physical findings consistent with intra-abdominal infection (IAI, defined as localized or diffuse abdominal tenderness (Other supportive findings include presence of a mass, ileus, or rebound tenderness)
4. Clinical diagnosis of community-acquired intra-abdominal infection requiring urgent surgical or percutaneous intervention and not expected to require antibacterial therapy for longer than 14 days
5. At least 18 years and no older than 75 years of age
6. Body mass index (BMI) of less than or equal to 30 kg per meter square
7. Able to provide informed consent. If the patient is unable to provide informed consent, the patient’s legally acceptable representative may provide written consent in accordance with institutional guidelines
If female:
a. Not pregnant or nursing
b. If of child-bearing potential will commit to either:
i. use at least two medically accepted, effective methods of birth control (e.g., condom, oral contraceptive, indwelling intrauterine device, hormonal implant/patch, injections, approved cervical ring) during study drug dosing and for 90 days following last study drug dose
ii. Sexual abstinence
And either
9A. Meets Inclusion Criteria for Pre-operative Enrollment
a) Has a sonogram or radiographic imaging result congruent with the diagnosis of cIAI
b) Acute surgical or percutaneous intervention (open laparotomy, laparoscopic surgery, or percutaneous drainage of an abscess) is foreseen
c) Specimens from the surgical intervention representative of the material associated with infection will be collected by aspiration or tissue sample and sent for culture and susceptibility testing
d) Clinical diagnoses consistent with one or more of the following
1. Appendiceal perforation and periappendiceal abscess
2. Diverticular abscess
3. Acute gastric or duodenal perforation (only if operated on greater than 24 hrs after perforation occurs)
4. Traumatic perforation of the intestines (only if operated on greater than 12 hrs after perforation occurs)
5. Abscess or peritonitis due to other perforated viscus, or other gastrointestinal source
or
9B. Meets Inclusion Criteria for Intra-operative or Post-operative Enrollment
a) Visual confirmation (presence of pus within the abdominal cavity)
b) Samples taken for aerobic and anaerobic cultures should be taken by aspiration or tissue sample and immediately inoculated to appropriate media
c) Surgical intervention includes open laparotomy, laparoscopic surgery, or percutaneous draining of an abscess
d) Initial intervention is adequate, that is a procedure in which all communications between the GI tract and the peritoneal cavity are closed, no necrotic intestine is left, and all infected collections are drained at the initial procedure
e) Intra-operative diagnoses include one or more of the following
1. Appendiceal perforation and periappendiceal abscess
2. Diverticular abscess
3. Acute gastric and duodenal perforations (only if operated on greater than 24 hrs after perforation occurs)
4. Traumatic perforation of the intestines (only if operated on greater than 12 hrs after perforation occurs)
5. Abscess or peritonitis due to perforated viscus, or other focus of infection (but not spontaneous bacterial peritonitis associated with cirrhosis and chronic ascites)
6. Other intra-abdominal abscess (excluding liver and spleen) from a gastrointestinal source
ExclusionCriteria
Details
Subjects must NOT meet any of the following exclusion criteria
1 Symptoms related to diagnosis of complicated appendicitis (if current diagnosis) for less than 24 hrs prior to current hospitalization
2 Previously hospitalized or admitted to a healthcare facility (including nursing or convalescent home) within the last 6 months
3 Managed by Staged Abdominal Repair or other open abdomen technique
4 Known at study entry to have an IAI caused by a pathogen(s) resistant to one of the study drug antibiotics
5 Acute Physiology and Chronic Health Evaluation (APACHE) II score grater than25
6 Considered unlikely to survive the 6-8 week study period
7 Any rapidly-progressing disease or immediately life-threatening illness, including acute hepatic failure, respiratory failure and septic shock
8 Requirement for vasopressors at therapeutic dosages (ie dopamine greater than 5 μgperkgpermin, any dose of norepinephrine, epinephrine or phenylephrine) to maintain a systolic blood pressure greater than or equal to90 mm Hg or a mean arterial pressure greater than or equal to 70 mm Hg
9 Renal failure as defined as
a Threefold increase of serum creatinine to a known previous value or
b Decrease in estimated glomerular filtration rate greater than 75 percent to a known previous value or
c Urine output of less than 0.3 mL per kg per h for greater than 24 h or
d Anuria for greater than 12 h or
e Serum creatinine of greater than 4 mg per dL (353.6 μmol per L) with an acute rise of 0.5 mg per dL (42.2 μ mol per L) compared with a previous value
10 Creatinine clearance less than 30 mLpermin as estimated by the Cockcroft-Gault equation (140-age[years]) (Body Weight in kg) (0.85 if female) per (72 Serum Creatinine [mg per dL]); or requires peritoneal dialysis, hemodialysis, or hemofiltration
11 Presence or possible signs of hepatic disease:
a Alanine aminotransferase or aspartate aminotransferase greater than 3 x upper limit of normal (ULN) or
b Total bilirubin greater than 3 x ULN unless isolated hyperbilirubinemia is directly related to the acute process
or
c Alkaline phosphatase greater than 3 x ULN or
d Subjects with diagnosis of hepatic failure
12 Hematocrit less than 25 percent or hemoglobin less than 8 g per dL
13 Neutropenia with absolute neutrophil count less than 1000 per cubic mm
14 Platelet count less than 50000 per cubic mm
15 Coagulation tests greater than 1.5 x ULN (that is prothrombin time partial thromboplastin time, or international normalized ratio)
16 Patient on anticoagulants prior to hospitalization (excluding low dose aspirin therapy)
17 Immunocompromised condition, including known HIV positivity or AIDS organ (bone marrow) transplant recipients, and hematological malignancy. Immunosuppressive therapy, including use of high-dose corticosteroids
(eg greater than 40 mg prednisone or equivalent per day for greater than 2 weeks)
18 History of moderate or severe hypersensitivity reactions to tetracyclines carbapenems or β-lactam antibiotics
19 Participation in any investigational drug or device study within 30 days prior to study entry
20 Known or suspected current central nervous system (CNS) disorder that may predispose to seizures or lower seizure threshold (eg severe cerebral arteriosclerosis epilepsy)
21 Previously received TP-434 in a clinical trial
22 Antibiotic-related exclusions
aMore than 24 hours duration of systemic antibiotic coverage for current condition (24 hrs duration as defined by recommended dosing interval in the respective prescribing information)
b Received ertapenem or any other carbapenem or tigecycline for the current infection
c Need for concomitant systemic antimicrobial agents other than study drug (including female subjects with clinical diagnosis of pelvic inflammatory disease)
d Known to have received systemic antibiotics (oral or IV) in the last 3 months (except for current acute condition or single dose such as for dental prophylaxis)
23 Refusal of mechanical ventilation, dialysis or hemofiltration, cardioversion or any other resuscitative measures and drugperfluid therapy at time of consent
24 Known or suspected inflammatory bowel disease or associated visceral abscess
Method of Generating Random Sequence
Computer generated randomization
Method of Concealment
Centralized
Blinding/Masking
Double Blind Double Dummy
Primary Outcome
Outcome
TimePoints
Compare clinical response at the test-of-cure (TOC) visit in the microbiologically evaluable (ME) population for
subjects in the 3 treatment arms
primary endpoint of this study will be clinical response at the TOC visit that is 10-14 days after last dose of study drug
Secondary Outcome
Outcome
TimePoints
1) Compare clinical response for subjects in the 3 treatment arms in the following populations
a) Modified intent-to-treat (MITT)
b) Clinically modified intent-to-treat(c-MITT)
c) Microbiologically modified intent-to-treat(m-MITT)
d)Clinically evaluable (CE) e)Microbiologically evaluable (ME) (EOT and FU)
2)Compare microbiologic response at EOT and TOC in
a) m-MITT,CE,ME population
b) To assess safety & tolerability of TP-434 administration
c) (PK) parameters after TP-434 infusion
Clinical response at end-of-treatment (EOT that is Day 4-7) , TOC( Day 10-14 after last dose of study drug), and follow-up (FU that is 28-42 days after last dose of study drug) visits
1. Microbiologic response for subjects in the 3 treatment arms at EOT and TOC visits
2. Safety endpoints:
a) Physical exam including vital signs
b) Adverse events
c) ECGs at specified time points
d) Safety Labs at specified time points
Target Sample Size
Total Sample Size="150" Sample Size from India="45" Final Enrollment numbers achieved (Total)= "Applicable only for Completed/Terminated trials" Final Enrollment numbers achieved (India)="Applicable only for Completed/Terminated trials"
Individual Participant Data (IPD) Sharing Statement
Will individual participant data (IPD) be shared publicly (including data dictionaries)?
Brief Summary
The proposed clinical trial is a Phase 2, randomized, double-blind, double-dummy, multicenter, prospective study to assess the efficacy, safety, and pharmacokinetics of 2 dose regiments of TP‑434 (1.5 mg/kg every 24 hours [q24h], or 1.0 mg/kg every 12 hours [q12h]) compared with Ertapenem (1g q24h) in adult community-acquired complicated intra-abdominal infections.Randomization to the TP-434 (1.5 mg/kg q24h), TP-434 (1.0 mg/kg q12h), or ertapenem (1g q24h) treatment arms will occur in a 2:2:1 ratio.TP-434 is a novel antibiotic of the tetracycline class. The in vitro and in vivo potency and spectrum of TP-434 makes it an excellent candidate as a new single therapy treatment option for serious nosocomial infections, including skin, respiratory, urinary tract, and intra-abdominal infections.Bulgaria, India, Lithuania, Romania, and USA are the participating countries.