Efficacy and Safety of Dalbavancin for the Treatment of Acute Bacterial Skin and Skin Structure Infections

• Sponsor: Durata Therapeutics Inc., an affiliate of Allergan plc (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01339091
• Collaborator: (none)
• Enrollment: 573
• Locations: 92
• Arms: 2
• Duration (Months): 20.1
• Patients Per Site: 6.2
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

The primary object is to compare the early clinical efficacy (after 48-72 hours of therapy) of dalbavancin to the comparator regimen (vancomycin with the option to switch to oral linezolid) for the treatment of patients with a suspected or proven gram-positive bacterial skin or skin structure infection.

Condition or Disease	Intervention/Treatment	Phase
Abscess; Wound Infection; Surgical Site Infection; Cellulitis	Drug: Dalbavancin; Drug: Vancomycin / Linezolid	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 573 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 3, Randomized, Double-Blind, Double-Dummy Study to Compare the Efficacy and Safety of Dalbavancin to a Comparator Regiment (Vancomycin and Linezolid) for the Treatment of Acute Bacterial Skin and Skin Structure Infections
• Study Start Date: Mar 1, 2011
• Actual Primary Completion Date: Sep 1, 2012
• Actual Study Completion Date: Nov 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Dalbavancin	Drug: Dalbavancin; IV Dalbavancin 1000 mg on Day 1 and 500 mg on Day 8
Active Comparator: Vancomycin with possible switch to oral linezolid	Drug: Vancomycin / Linezolid; IV Vancomycin (1 gram Q 12 hours or 15mg/Kg Q 12 hours) with optional switch to oral linezolid (600 mg Q12 hours). Total duration of therapy is 10-14 days.

Outcome Measures

Primary Outcome Measures

1. Early Clinical Efficacy [48-72 hours after the initiation of study therapy]

   Clinical response at 48-72 hours post study drug initiation, based on measurements of acute bacterial skin and skin structure infections (ABSSSI) lesion size and temperature

Secondary Outcome Measures

1. >= 20% Reduction in Lesion Area [48-72 hours after the initiation of study therapy]

   Clinical response at 48-72 hours post study drug initiation, based on measurements of acute bacterial skin and skin structure infections (ABSSSI) lesion size

2. Clinical Status [End of Treatment Visit (Day 14-15)]

   Compare the clinical efficacy at end of treatment visit of dalbavancin to the comparator regimen based on lesion size, local signs, temperature and receipt of non-study antibiotics

3. Clinical Status [Follow-Up Visit (day 28)]

   Compare the clinical efficacy at the day 28 follow-up visit of dalbavancin to the comparator regimen based on lesion size, local signs, temperature and receipt of non-study antibiotics

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 85 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Male or female patients 18 - 85 years of age.

2. Signed and dated informed consent document.

3. Major abscess, surgical site infection, traumatic wound infection or cellulitis suspected or confirmed to be caused by Gram-positive bacteria.

4. At least two (2) local signs and symptoms of ABSSSI and at least one (1) systemic sign of infection.

5. Requires a minimum of 3 days of IV therapy.

6. Patient willing and able to comply with study procedures.

Exclusion Criteria:

Patients presenting with any of the following:

1. A contra-indication to any required study drug.

2. Pregnant or nursing females.

3. Sustained shock.

4. Participation in another study of an investigational drug or device within 30 days.

5. Receipt of a systemically or topically administered antibiotic within 14 days prior to randomization, except receipt of a single dose of a short-acting antibacterial drug 3 or more days prior to randomization.

6. Infection due to a dalbavancin or vancomycin-resistant organism.

7. Evidence of meningitis, necrotizing fasciitis, gas gangrene, gangrene, septic arthritis, osteomyelitis, and/or endovascular infection.

8. Exclusively gram-negative bacterial or a fungal ABSSSI.

9. Venous catheter infection.

10. Infection of a diabetic foot ulcer or a decubitus ulcer.

11. Device-related infections.

12. Gram-negative bacteremia.

13. Infected burns.

14. Infected limb with critical ischemia.

15. Superficial/simple skin and skin structure infections.

16. Concomitant condition requiring non-study antibacterial therapy.

17. ABSSSI requiring therapy for longer than 14 days.

18. Adjunctive therapy with hyperbaric oxygen.

19. More than 2 surgical interventions for ABSSSI anticipated.

20. Chronic inflammatory condition precluding assessment of clinical response.

21. Absolute neutrophil count < 500 cells/mm3.

22. Human immunodeficiency virus (HIV) infection with a CD4 cell count < 200 cells/mm3.

23. Recent bone marrow transplant, > 20 mg prednisolone per day (or equivalent) or receiving immunosuppressant drugs after organ transplantation.

24. Regular, chronic antipyretic use in patients unable to modify during the first three days of study drug therapy.

25. Life expectancy less than 3 months.

26. Conditions that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results.

27. Prior participation in the study.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Durata Study Site	Anaheim	California	United States	92804
2	Durata Study Site	Azusa	California	United States	91702
3	Durata Study Site	Bellflower	California	United States	90706
4	Durata Study Site	Buena Park	California	United States	90620
5	Durata Study Site	Carmel	California	United States	46032
6	Durata Study Site	Chula Vista	California	United States	92911
7	Durata Study Site	Covina	California	United States	91723
8	Durata Study Site	Fountain Valley	California	United States	92708
9	Durata Study Site	La Mesa	California	United States	91942
10	Durata Study Site	Long Beach	California	United States	90813
11	Durata Study Site	Los Alamitos	California	United States	90720
12	Durata Study Site	Los Angeles	California	United States	90015
13	Durata Study Site	Oceanside	California	United States	92056
14	Durata Study Site	Palm Desert	California	United States	92211
15	Durata Study Site	Pasadena	California	United States	91105
16	Durata Study Site	Sacramento	California	United States	95817
17	Durata Study Site	San Diego	California	United States	92120
18	Durata Study Site	Santa Ana	California	United States	92701
19	Durata Study Site	Sylmar	California	United States	91342
20	Durata Study Site	Torrance	California	United States	90509
21	Durata Study Site	Upland	California	United States	91786
22	Durata Study Site	Whittier	California	United States	90602
23	Durata Study Site	Miami	Florida	United States	33144
24	Durata Study Site	Miami	Florida	United States	33155
25	Durata Study Site	Orlando	Florida	United States	32837
26	Durata Study Site	St. Cloud	Florida	United States	34769
27	Durata Study Site	Tampa	Florida	United States	33613
28	Durata Study Site	Columbus	Georgia	United States	31904
29	Durata Study Site	Savannah	Georgia	United States	31406
30	Durata Study Site	Idaho Falls	Idaho	United States	83404
31	Durata Study Site	Pocatello	Idaho	United States	83202
32	Durata Study Site	Moline	Illinois	United States	61265
33	Durata Study Site	Rock Island	Illinois	United States	31201
34	Durata Study Site	Baton Rouge	Louisiana	United States	70808
35	Durata Study Site	Lafayette	Louisiana	United States	70503
36	Durata Clinical Site	New Orleans	Louisiana	United States	70112
37	Durata Study Site	Opelousas	Louisiana	United States	70570
38	Durata Study Site	Detroit	Michigan	United States	48202
39	Durata Study Site	Minneapolis	Minnesota	United States	55422
40	Durata Study Site	Las Vegas	Nevada	United States	89109
41	Durata Study Site	Somers Point	New Jersey	United States	08244
42	Durata Study Site	Bronx	New York	United States	10467
43	Durata Study Site	Buffalo	New York	United States	14215
44	Durata Study Site	Lake Success	New York	United States	11042
45	Durata Study Site	New Hyde Park	New York	United States	11040
46	Durata Study Site	Staten Island	New York	United States	10305
47	Durata Study Site	Winston Salem	North Carolina	United States	27103
48	Durata Study Site	Winston-Salem	North Carolina	United States	27103
49	Durata Study Site	Columbus	Ohio	United States	43215
50	Durata Study Site	Lima	Ohio	United States	45801
51	Durata Study Site	Toledo	Ohio	United States	43608
52	Durata Study Site	Pittsburgh	Pennsylvania	United States	15213
53	Durata Study Site	Houston	Texas	United States	77030
54	Durata Study Site	Houston	Texas	United States	77036
55	Durata Study Site	Madison	Wisconsin	United States	53717
56	Durata Study Site	Middleton	Wisconsin	United States	53562
57	Durata Study Site	Winnipeg	Manitoba	Canada	R3E 0J9
58	Durata Study Site	Trois-Rivieres	Quebec	Canada	G9A 1Y1
59	Durata Study Site	Dubrovnik		Croatia	2000
60	Durata Clinical Site	Slavonski Brod		Croatia	35000
61	Durata Study Site	Zagreb		Croatia	10000
62	Durata Study Site	Zagreb		Croatia	1000
63	Durata Clinical Site	Tbilisi		Georgia
64	Durata Study Site	Bochum		Germany	44791
65	Durata Study Site	Munster		Germany	48149
66	Durata Study Site	Krakow		Poland	31-501
67	Durata Study Site	Legionowo		Poland	05-120
68	Durata Study Site	Warszawa		Poland	03-401
69	Durata Study Site	Wroclaw		Poland	51-124
70	Durata Study Site	Kharkiv	Ukraine	Russian Federation	61037
71	Durata Study Site	Kyiv city	Ukraine	Russian Federation	02125
72	Durata Study Site	Ekaterinburg		Russian Federation	620095
73	Durata Study Site	Moscow		Russian Federation	111020
74	Durata Clinical Site	Moscow		Russian Federation	111539
75	Durata Study Site	Moscow		Russian Federation	129327
76	Durata Study Site	Perm		Russian Federation	614036
77	Durata Study Site	Saratov		Russian Federation	410053
78	Durata Study Site	Smolensk		Russian Federation	214018
79	Durata Study Site	St. Petersburg		Russian Federation	191104
80	Durata Study Site	St. Petersburg		Russian Federation	192242
81	Durata Study Site	St. Petersburg		Russian Federation	194354
82	Durata Study Site	St. Petersburg		Russian Federation	198099
83	Durata Clinical Site	St. Petersburg		Russian Federation	94354
84	Durata Study Site	Tomsk		Russian Federation	634064
85	Durata Study Site	Cherkasy		Ukraine	18009
86	Durata Study Site	Ivano-Frankivsk		Ukraine	76018
87	Durata Study Site	Kharkiv		Ukraine	61037
88	Durata Study Site	Kyiv		Ukraine	02125
89	Durata Study Site	Kyiv		Ukraine	03110
90	Durata Study Site	Uzhgorod		Ukraine	88018
91	Durata Study Site	Zaporizhzhya		Ukraine	69032
92	Durata Study Site	Zhytomyr		Ukraine	10002

Sponsors and Collaborators

• Durata Therapeutics Inc., an affiliate of Allergan plc

Investigators

• Study Director: Michael Dunne, MD, Durata Therapeutics Inc., an affiliate of Allergan plc

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Durata Therapeutics Inc., an affiliate of Allergan plc
• ClinicalTrials.gov Identifier: NCT01339091
• Other Study ID Numbers: DUR001-301
• First Posted: Apr 20, 2011
• Last Update Posted: Jan 31, 2014
• Last Verified: Dec 1, 2013

• Additional relevant MeSH terms: Infections; Communicable Diseases; Surgical Wound Infection; Wound Infection; Cellulitis; Vancomycin; Linezolid; Dalbavancin

Study Results

Participant Flow

Arm/Group Title	Dalbavancin	Vancomycin +/- Oral Linezolid
Arm/Group Description	Dalbavancin : IV Dalbavancin 1000 mg on Day 1 and 500 mg on Day 8	Vancomycin : IV Vancomycin (dosed per standard of care) with optional switch to oral linezolid (600 mg Q12 hours). Total duration of therapy is 10-14 days.
Period Title: Overall Study
STARTED	288	285
Safety Population	284	284
COMPLETED	261	257
NOT COMPLETED	27	28

Baseline Characteristics

Arm/Group Title	Dalbavancin	Vancomycin +/- Oral Linezolid	Total
Arm/Group Description	Dalbavancin : IV Dalbavancin 1000 mg on Day 1 and 500 mg on Day 8	Vancomycin : IV Vancomycin (dosed per standard of care) with optional switch to oral linezolid (600 mg Q12 hours). Total duration of therapy is 10-14 days.	Total of all reporting groups
Overall Participants	288	285	573
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	48.8 (15.3)	48.9 (15.08)	48.9 (15.18)
Sex: Female, Male (Count of Participants)
Female	118 41%	112 39.3%	230 40.1%
Male	170 59%	173 60.7%	343 59.9%

Outcome Measures

1. Primary Outcome

Title	Early Clinical Efficacy
Description	Clinical response at 48-72 hours post study drug initiation, based on measurements of acute bacterial skin and skin structure infections (ABSSSI) lesion size and temperature
Time Frame	48-72 hours after the initiation of study therapy

Outcome Measure Data

Analysis Population Description

The ITT population consisted of all randomly assigned patients regardless of whether or not they received study drug.

Arm/Group Title	Dalbavancin	Vancomycin +/- Oral Linezolid
Arm/Group Description	Dalbavancin : IV Dalbavancin 1000 mg on Day 1 and 500 mg on Day 8	Vancomycin : IV Vancomycin (dosed per standard of care) with optional switch to oral linezolid (600 mg Q12 hours). Total duration of therapy is 10-14 days.
Measure Participants	288	285
Clinical Responder	240 83.3%	233 81.8%
Clinical Non-Responder	48 16.7%	52 18.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Dalbavancin, Vancomycin +/- Oral Linezolid
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	The non-inferiority hypothesis test is a one-sided hypothesis test performed at the 2.5% level of significance. If the lower limit of the 95% CI for the difference in response rates in the ITT population is greater than -10% the NI of dalbavancin to vancomycin/linezolid will be concluded.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in Proportions
	Estimated Value	1.5
	Confidence Interval	(2-Sided) 95%; -4.6 to 7.9
	Parameter Dispersion	Type: Value:
	Estimation Comments	Confidence intervals were adjusted for fever at baseline

2. Secondary Outcome

Title	>= 20% Reduction in Lesion Area
Description	Clinical response at 48-72 hours post study drug initiation, based on measurements of acute bacterial skin and skin structure infections (ABSSSI) lesion size
Time Frame	48-72 hours after the initiation of study therapy

Outcome Measure Data

Analysis Population Description

The ITT population consisted of all randomly assigned patients regardless of whether or not they received study drug.

Arm/Group Title	Dalbavancin	Vancomycin +/- Oral Linezolid
Arm/Group Description	Dalbavancin : IV Dalbavancin 1000 mg on Day 1 and 500 mg on Day 8	Vancomycin : IV Vancomycin (dosed per standard of care) with optional switch to oral linezolid (600 mg Q12 hours). Total duration of therapy is 10-14 days.
Measure Participants	288	285
Clinical Responder	259 89.9%	259 90.9%
Clinical Non-Responder	29 10.1%	26 9.1%

3. Secondary Outcome

Title	Clinical Status
Description	Compare the clinical efficacy at end of treatment visit of dalbavancin to the comparator regimen based on lesion size, local signs, temperature and receipt of non-study antibiotics
Time Frame	End of Treatment Visit (Day 14-15)

Outcome Measure Data

Analysis Population Description

Clinical Evaluable Population based on certain inclusion/exclusion criteria, length of study therapy, concomitant antibacterials, concomitant surgical procedure and non-missing data.

Arm/Group Title	Dalbavancin	Vancomycin +/- Oral Linezolid
Arm/Group Description	Dalbavancin : IV Dalbavancin 1000 mg on Day 1 and 500 mg on Day 8	Vancomycin : IV Vancomycin (dosed per standard of care) with optional switch to oral linezolid (600 mg Q12 hours). Total duration of therapy is 10-14 days.
Measure Participants	246	243
Clinical Success	214 74.3%	222 77.9%
Clinical Failure	32 11.1%	21 7.4%

4. Secondary Outcome

Title	Clinical Status
Description	Compare the clinical efficacy at the day 28 follow-up visit of dalbavancin to the comparator regimen based on lesion size, local signs, temperature and receipt of non-study antibiotics
Time Frame	Follow-Up Visit (day 28)

Outcome Measure Data

Analysis Population Description

Clinical Evaluable Population based on certain inclusion/exclusion criteria, length of study therapy, concomitant antibacterials, concomitant surgical procedure and non-missing data.

Arm/Group Title	Dalbavancin	Vancomycin +/- Oral Linezolid
Arm/Group Description	Dalbavancin : IV Dalbavancin 1000 mg on Day 1 and 500 mg on Day 8	Vancomycin : IV Vancomycin (dosed per standard of care) with optional switch to oral linezolid (600 mg Q12 hours). Total duration of therapy is 10-14 days.
Measure Participants	226	229
Clinical Success	212 73.6%	220 77.2%
Clinical Failure	14 4.9%	9 3.2%

Adverse Events

Time Frame	Begins from the time that the patient provides informed consent through the last follow up visit, Day 70. Any SAE occurring any time after the reporting period must be promptly reported if a causal relationship to investigational product is suspected.
Adverse Event Reporting Description	Adverse events were analyzed in the safety population which is defined as all patients in the ITT population who received at least 1 dose of dalbavancin or vancomycin (active) study drug.
Arm/Group Title	Dalbavancin		Vancomycin +/- Oral Linezolid
Arm/Group Description	Dalbavancin : IV Dalbavancin 1000 mg on Day 1 and 500 mg on Day 8		Vancomycin : IV Vancomycin (dosed per standard of care) with optional switch to oral linezolid (600 mg Q12 hours). Total duration of therapy is 10-14 days.
All Cause Mortality
	Dalbavancin		Vancomycin +/- Oral Linezolid
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Dalbavancin		Vancomycin +/- Oral Linezolid
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/284 (1.8%)		12/284 (4.2%)
Cardiac disorders
Atrial fibrillation	1/284 (0.4%)		0/284 (0%)
Cardiac failure	0/284 (0%)		1/284 (0.4%)
Cardiac failure acute	0/284 (0%)		1/284 (0.4%)
Cardiac failure congestive	0/284 (0%)		1/284 (0.4%)
Cardiopulmonary failure	0/284 (0%)		1/284 (0.4%)
Gastrointestinal disorders
Gastrointestinal haemorrhage	1/284 (0.4%)		1/284 (0.4%)
Enterocutaneous fistula	0/284 (0%)		1/284 (0.4%)
Small intestinal obstruction	0/284 (0%)		1/284 (0.4%)
Infections and infestations
Arthritis bacterial	1/284 (0.4%)		0/284 (0%)
Bacteraemia	1/284 (0.4%)		0/284 (0%)
Embolic pneumonia	1/284 (0.4%)		0/284 (0%)
Abscess limb	0/284 (0%)		1/284 (0.4%)
Cellulitis	0/284 (0%)		1/284 (0.4%)
Diabetic foot infection	0/284 (0%)		1/284 (0.4%)
Rectal abscess	0/284 (0%)		1/284 (0.4%)
Injury, poisoning and procedural complications
Procedural complication	1/284 (0.4%)		0/284 (0%)
Metabolism and nutrition disorders
Hypovolaemia	0/284 (0%)		1/284 (0.4%)
Musculoskeletal and connective tissue disorders
Systemic lupus erythematosus	0/284 (0%)		1/284 (0.4%)
Renal and urinary disorders
Nephropathy toxic	0/284 (0%)		1/284 (0.4%)
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism	0/284 (0%)		1/284 (0.4%)
Other (Not Including Serious) Adverse Events
	Dalbavancin		Vancomycin +/- Oral Linezolid
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	36/284 (12.7%)		54/284 (19%)
Gastrointestinal disorders
Nausea	12/284 (4.2%)		13/284 (4.6%)
Diarrhoea	4/284 (1.4%)		11/284 (3.9%)
Vomiting	3/284 (1.1%)		6/284 (2.1%)
General disorders
Asthenia	1/284 (0.4%)		6/284 (2.1%)
Nervous system disorders
Headache	14/284 (4.9%)		14/284 (4.9%)
Skin and subcutaneous tissue disorders
Rash	6/284 (2.1%)		6/284 (2.1%)
Dermatitis contact	1/284 (0.4%)		6/284 (2.1%)
Pruritus	1/284 (0.4%)		11/284 (3.9%)
Vascular disorders
Hypertension	7/284 (2.5%)		7/284 (2.5%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The PI will provide Durata an opportunity to review any proposed publication or other type of disclosure at least 30 days before they are submitted. If any patent action is required to protect intellectual property rights, the Investigator agrees to delay the disclosure for a period not to exceed an additional 60 days. If the study is part of a multi-center study, the Investigator agrees that the first publication is to be a joint publication covering all centers.