Dalbavancin For The Treatment of Gram Positive Osteoarticular Infections
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|ClinicalTrials.gov Identifier: NCT03426761|
Recruitment Status : Recruiting
First Posted : February 8, 2018
Last Update Posted : February 4, 2019
|Condition or disease||Intervention/treatment||Phase|
|Bone Infection Osteomyelitis Septic Arthritis Joint Infection Prosthetic Joint Infection||Drug: Dalbavancin Drug: Vancomycin||Phase 4|
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Dalbavancin, currently FDA approved for the treatment of skin and soft tissue infections (SSTI), is a lipoglycopedptide with bactericidal activity in vitro against Staphylococcus aureus, including MRSA and VISA strains, and Streptococcus pyogenes. Its bactericidal action results primarily from inhibition of cell-wall biosynthesis, specifically the prevention of N-acetylmuramic acid (NAM) and N-acetylglucosamine (NAG)-peptide subunits incorporation into the peptidoglycan matrix. Dalbavancin alters bacterial-cell-membrane permeability and RNA synthesis. It is highly protein bound, primarily to albumin, with a half-life of 346 hours. Approximately 33% of unchanged drug is excreted in the urine, 20% via feces and 12% as the minor metabolite, hydroxyl-dalbavancin. There is minimal potential for drug-drug interactions; it is not a substrate, inducer or inhibitor of hepatic CYP450 isoenzymes and the administration of CYP450 substrates, inhibitors or inducers does not affect its clearance rate. In SSTI trials, Dalbavancin was demonstrated to be non-inferior to vancomycin and linezolid.
Prosthetic joint infections (PJI) are an emerging health problem. Although the incidence of these infections is historically low (approximately 0.5%-1.0of implants), because of the rapid increase in the number of hip, knee and other joint implants, the absolute number of cases of infection is increasing. In 2010, 332,000 hip joints and 719,000 knee joints were implanted. This alone conservatively translates to 5,000-10,000 cases, with an economic impact of $1 billion. Management of PJI is particularly challenging because long term antibiotic therapy in most cases is accompanied by removal of the prosthesis and re-implantation.
For long term antimicrobial administration, current standard of care requires a peripherally inserted central catheter (PICC) or other indwelling intravascular catheter, and daily/multiple daily infusions. There is substantial cost of maintaining the intravascular access, drugs, home health care and monitoring, as well as the infection risk of the chronic indwelling line which is being accessed frequently. There is a clear need for alternative care models to the current approach. Dalbavancin, because of its activity profile against Gram-positive organisms and its pharmacokinetics which would allow weekly or every other week dosing, is a favorable option. This option would eliminate the need for long term IV access, because at most, weekly IV infusions would be performed.
In terms of bone infection, dalbavancin has favorable pharmacokinetic properties. A PK study performed in subjects undergoing elective orthopedic surgery found that dalbavancin (dosed at 1000mg IV at enrollment and then 500mg weekly for up to 7 weeks) maintained levels in cortical bone at bactericidal levels , at >50X the MIC of typical staphylococcal organism (including MRSA). Animal studies in a rat osteomyelitis model also found that dalvabancin was comparable to vancomycin. Because of these same PK properties, dalbavancin offers the opportunity to substantially reduce costs and morbidity in native joint and prosthetic joint infections.
This is a two-center, randomized, open label trial of dalbavancin versus standard intravenous therapy control comparator in the treatment of subjects with gram positive native joint or prosthetic joint infections. The primary outcome variable is clinical cure at day 42 after start of treatment in all randomized patients. Safety and tolerability will also be assessed throughout the study period via laboratory measurements and AE monitoring. Additionally, clinical response will be measured by patient reported outcomes with change from baseline symptoms and by Quality of Life questionnaire.
Eligible subjects with confirmed gram positive joint infections, will be randomized in a ratio of 2:1 to receive open label dalbavancin or standard IV therapy. Standard IV therapy will depend on the antibiotic susceptibility of the causative pathogen. Subjects randomized to dalbavancin may have received standard of care therapy for no more than 120 hours prior to first dalbavancin dose. Subjects randomized to standard of care can continue with treatment course if already started, or receive the first dose at the baseline visit.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||50 participants|
|Intervention Model:||Sequential Assignment|
|Intervention Model Description:||
Since it's a pilot study, the sample size is fixed (n = 50). The sample size were not selected based on statistical criteria. However, we would need to know what would be the detectable effect size.
∆^2=((z_(α/2)+z_β )^2 (σ_1^2+σ_2^2 ))/n
|Masking:||None (Open Label)|
|Official Title:||Dalbavancin For The Treatment Of Gram Positive Osteomyelitis Or Joint Infections Including Prosthetic Hip Or Knee Infections|
|Actual Study Start Date :||January 25, 2018|
|Estimated Primary Completion Date :||July 2020|
|Estimated Study Completion Date :||January 2021|
Dalbavancin 1,500mg intravenously every fourteen days for two to four infusions
Dalbavancin 1,500mg intravenously every fourteen days for two to four infusions
Active Comparator: Standard of Care
Standard of care intravenous antibiotic based on microbiology susceptibility testing. Infusions may be one to three times daily for three to eight weeks. Examples of standard of care include vancomycin, daptomycin, nafcillin, cefazolin.
Examples of standard of care arm; infusions one to three times per day depending on the antibiotic for a total of three to eight weeks
- Clinical response (non-failure) to assigned treatment at day #42 [ Time Frame: Evaluated at Day 42 ]This is defined as the absence of wound drainage, sinus tract formation, fever or joint instability at study day 42, without having switched or extended treatment for any reason. This will be reported as the % of participants from each treatment arm, who are determined to be a treatment responder.
- Sustained Clinical Response at day #90 [ Time Frame: Evaluated at Day 90 ]This is defined as the absence of drainage, sinus tract formation, fever, cellulitis, infectious effusion (culture +) or joint instability.
- Sustained Clinical Response at day #180 [ Time Frame: Evaluated at Day 180 ]This is defined as the absence of drainage, cellulitis, infectious effusion (culture +) or joint instability.
- Sustained Clinical Response at day #365 [ Time Frame: Evaluated at Day 365 ]This is defined as the absence of drainage, cellulitis, infectious effusion (culture +) or joint instability.
- CRP Improvement at day #90 [ Time Frame: Evaluated at Day 90 ]Normalized or, at least 75% reduction from baseline
- CRP Improvement at day #180 [ Time Frame: Evaluated at Day 180 ]Normalized or, at least 75% reduction from baseline
- CRP Improvement at day #365 [ Time Frame: Evaluated at Day 365 ]Normalized or, at least 75% reduction from baseline
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03426761
|Contact: Donald Poretz, MDemail@example.com|
|Contact: David Wheeler, MDfirstname.lastname@example.org|
|United States, Virginia|
|Infectious Diseases Physicians, Inc.||Recruiting|
|Annandale, Virginia, United States, 22003|
|Contact: Donald Poretz, MD 703-560-4821 email@example.com|
|Contact: David Wheeler, MD 703-560-4821 firstname.lastname@example.org|
|Principal Investigator: Donald Poretz, MD|
|Sub-Investigator: David Wheeler, MD|
|Principal Investigator:||Donald Poretz, MD||Infectious Diseases Physicians, Inc.|