Study Comparing the Safety and Efficacy of Intravenous CXA-201 and Intravenous Levofloxacin in Complicated Urinary Tract Infection, Including Pyelonephritis

• Sponsor: Cubist Pharmaceuticals LLC (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01345929
• Collaborator: (none)
• Enrollment: 558
• Locations: 76
• Arms: 2
• Actual Duration (Months): 26.5
• Patients Per Site: 7.3
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

This is a Phase 3, multicenter, prospective, randomized, double-blind, double dummy study of CXA 201 IV infusions (1500 mg q8h) versus levofloxacin IV infusions (750 mg qd) for the treatment of adults with a cUTI (including pyelonephritis).

Condition or Disease	Intervention/Treatment	Phase
Complicated Urinary Tract Infection; Pyelonephritis	Drug: CXA-201; Drug: Levofloxacin	Phase 3

Detailed Description

Approximately 500 subjects will be enrolled into this study and randomized 1:1 to receive CXA-201 or comparator (levofloxacin) resulting in 250 subjects per treatment arm. Subject participation will require a minimum commitment of 35 days and a maximum of 42 days. Subjects will be hospitalized for the administration of all doses of IV study therapy. A test of cure visit will occur at 7 days after the last dose of study drug and a late follow-up evaluation or contact will occur a minimum of 28 days and a maximum of 35 days after the last dose of study drug.

Study Design

• Study Type: Interventional
• Actual Enrollment: 558 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Multicenter, Double-Blind, Randomized, Phase 3 Study to Compare the Safety and Efficacy of Intravenous CXA-201 and Intravenous Levofloxacin in Complicated Urinary Tract Infection, Including Pyelonephritis
• Actual Study Start Date: Jun 20, 2011
• Actual Primary Completion Date: Aug 11, 2013
• Actual Study Completion Date: Sep 4, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: CXA-201 as treatment for cUTI CXA-201 IV infusion (1500mg q8) for 7 days	Drug: CXA-201; CXA-201 IV infusion (1500mg q8) for 7 days
Active Comparator: Levofloxacin as treatment for cUTI Levofloxacin IV infusion (750mg qd) for 7 days	Drug: Levofloxacin; Levofloxacin IV infusion (750mg qd) for 7 days

Outcome Measures

Primary Outcome Measures

1. The Percentage of Subjects Who Have Both a Per-subject Microbiological Outcome of Eradication and a Clinical Outcome of Cure at the Test of Cure (TOC) Visit in the Microbiological Modified ITT (mMITT) Population [Test of Cure Visit (7 Days [± 2 days] after completion of study drug administration)]

Secondary Outcome Measures

1. The Percentage of Subjects Who Have Both a Per-subject Microbiological Outcome of Eradication and a Clinical Outcome of Cure at the TOC Visit in the Microbiologically Evaluable (ME) Population. [Test of Cure Visit (7 Days [± 2 days] after completion of study drug administration)]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Provide written informed consent prior to any study-related procedure not part of normal medical care (a legally acceptable representative may provide consent if the subject is unable to do so, provided this is approved by local country and institution specific guidelines).

2. Be males or females ≥ 18 years of age

3. If female, subject is non-lactating, and is either:

4. Not of childbearing potential, defined as postmenopausal for at least 1 year or surgically sterile due to bilateral tubal ligation, bilateral oophorectomy, or hysterectomy; or

5. Of childbearing potential and is practicing a barrier method of birth control (e.g., a diaphragm or contraceptive sponge) along with 1 of the following methods: oral or parenteral contraceptives (for 3 months prior to study drug administration), or a vasectomized partner. Or, subject is practicing abstinence from sexual intercourse. Subjects must be willing to practice these methods for the duration of the trial and for at least 35 days after last dose of study medication.

6. Males are required to practice reliable birth control methods (condom or other barrier device) during the conduct of the study and for at least 35 days after last dose of study medication.

7. Pyuria (white blood cell [WBC] count > 10/μL in unspun urine or ≥ 10 per high power field in spun urine).

8. Clinical signs and/or symptoms of cUTI, either of:

9. Pyelonephritis, as indicated by at least 2 of the following:

• Documented fever (oral temperature > 38°C) accompanied by patient symptoms of rigors, chills, or "warmth";

• Flank pain;

• Costovertebral angle tenderness or suprapubic tenderness on physical exam; or

• nausea or vomiting; OR

1. Complicated lower UTI, as indicated by at least 2 of the following:

• At least 2 of the following new or worsening symptoms of cUTI:

• Dysuria; urinary frequency or urinary urgency;

• Documented fever (oral temperature > 38°C) accompanied by patient symptoms of rigors, chills, or "warmth";

• Suprapubic pain or flank pain;

• Costovertebral angle tenderness or suprapubic tenderness on physical exam; or

• Nausea or vomiting; plus,

• At least 1 of the following complicating factors:

• Males with documented history of urinary retention;

• Indwelling urinary catheter that is scheduled to be removed during IV study therapy and before the EOT;

• Current obstructive uropathy that is scheduled to be medically or surgically relieved during IV study therapy and before the EOT; or

• Any functional or anatomical abnormality of the urogenital tract (including anatomic malformations or neurogenic bladder) with voiding disturbance resulting in at least 100 mL residual urine.

1. Have a pretreatment baseline urine culture specimen obtained within 24 hours before the start of administration of the first dose of study drug.

NOTE: Subjects may be enrolled in this study and start IV study drug therapy before the Investigator knows the results of the baseline urine culture.

1. Require IV antibacterial therapy for the treatment of the presumed cUTI.

Exclusion Criteria:

1. Have a documented history of any moderate or severe hypersensitivity or allergic reaction to any β-lactam or quinilone antibacterial (Note: for β-lactams, a history of a mild rash followed by uneventful re-exposure is not a contraindication to enrollment)

2. Have a concomitant infection at the time of randomization, which requires non-study systemic antibacterial therapy in addition to IV study drug therapy. (Drugs with only gram-positive activity [e.g., vancomycin, linezolid] are allowed.)

3. Receipt of any amount of potentially therapeutic antibacterial therapy after collection of the pretreatment baseline urine culture and before administration of the first dose of study drug.

4. Receipt of any dose of a potentially therapeutic antibacterial agent for the treatment of the current UTI within 48 hours before the study-qualifying pretreatment baseline urine is obtained (exceptions: subjects with an active cUTI who have received prior antibiotics may be enrolled provided a minimum of 48 hours have elapsed between the last dose of the prior antibiotic and the time of obtaining the baseline urine specimen. Subjects receiving current antibiotic prophylaxis for cUTI who present with signs and symptoms consistent with an active new cUTI may be enrolled provided all other eligibility criteria are met including obtaining a pre-treatment qualifying baseline urine culture).

5. Intractable urinary infection at baseline that the Investigator anticipates would require more than 7 days of study drug therapy.

6. Complete, permanent obstruction of the urinary tract.

7. Confirmed fungal urinary tract infection at time of randomization (with ≥ 103 fungal CFU/mL).

8. Permanent indwelling bladder catheter or urinary stent including nephrostomy.

9. Suspected or confirmed perinephric or intrarenal abscess.

10. Suspected or confirmed prostatitis.

11. Ileal loop or known vesico-ureteral reflux.

12. Severe impairment of renal function including an estimated CrCl < 30 mL/min, requirement for peritoneal dialysis, hemodialysis or hemofiltration, or oliguria (< 20 mL/h urine output over 24 hours).

13. Current urinary catheter that is not scheduled to be removed before the EOT (intermittent straight catheterization during the IV study drug administration period is acceptable).

14. Any condition or circumstance that, in the opinion of the Investigator, would compromise the safety of the subject or the quality of study data.

15. Any rapidly progressing disease or immediately life-threatening illness including acute hepatic failure, respiratory failure, and septic shock.

16. Immunocompromising condition, including established AIDS, hematological malignancy, or bone marrow transplantation, or immunosuppressive therapy including cancer chemotherapy, medications for prevention of organ transplantation rejection, or the administration of corticosteroids equivalent to or greater than 40 mg of prednisone per day administered continuously for more than 14 days preceding randomization.

17. One or more of the following laboratory abnormalities in baseline specimens: aspartate aminotransferase (AST [SGOT]), alanine aminotransferase (ALT [SGPT]), alkaline phosphatase, or total bilirubin level greater than 3 times the upper limit of normal (ULN), absolute neutrophil count less than 500/μL, platelet count less than 40,000/μL, or hematocrit less than 20%.

18. Participation in any clinical study of an investigational product within 30 days prior to the proposed first day of study drug.

19. Previous participation in any study of CXA-101 or CXA-201.

20. Women who are pregnant or nursing.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		San Diego	California	United States
2		Wheat Ridge	Colorado	United States
3		Hialeah	Florida	United States
4		Teaneck	New Jersey	United States
5		Charleston	South Carolina	United States
6		Belo Horizonte	Minas Gerais	Brazil
7		Porto Alegre	Rio Grande De Sul	Brazil
8		Joinville	Santa Catarina	Brazil
9		Campinas	Sao Paulo	Brazil
10		Sao Jose De Rio Preto	Sao Paulo	Brazil
11		Rio de Janeiro		Brazil
12		Sao Paulo		Brazil
13		Cali	Valle Del Cauca	Colombia
14		Armenia		Colombia
15		Barranquilla		Colombia
16		Bogota		Colombia
17		Kohtla-Jarve		Estonia
18		Tallinn		Estonia
19		Tartu		Estonia
20		Tbilsi		Georgia
21		Giessen	Hessen	Germany
22		Lubeck	Schleswig-Holstein	Germany
23		Miskolc	Borsod-Abauj-Zemplen	Hungary
24		Gyor	Budapest	Hungary
25		Szentes	Csongrad	Hungary
26		Sopron	Gyor-moson-sopron	Hungary
27		Salgotarjan	Nograd	Hungary
28		Nyiregyhaza	Szabolcs-Szatmar-Bereg	Hungary
29		Zalaegerszeg	Zala	Hungary
30		Budapest		Hungary
31		Tatabánya		Hungary
32		Kfar Saba	Sharon	Israel
33		Petach Tikva	Teah Tiqwa	Israel
34		Tel Hashomer	Tel Aviv	Israel
35		Haifa		Israel
36		Jerusalem		Israel
37		Safed		Israel
38		Daugavpils		Latvia
39		Liepaja		Latvia
40		Riga		Latvia
41		Valmiera		Latvia
42		Ventspills		Latvia
43		Guadalajara	Jalisco	Mexico
44		Chihuahua		Mexico
45		San Luis Potosi		Mexico
46		Veracruz		Mexico
47		Chisinau		Moldova, Republic of
48		Oradea	Bihor	Romania
49		Bucharest	Bucuresti	Romania
50		Timisoara	Timis	Romania
51		Brasov		Romania
52		Bucuresti		Romania
53		Iasi		Romania
54		Sibiu		Romania
55		Kemerovo		Russian Federation
56		Moscow		Russian Federation
57		Nizhniy Novgorod		Russian Federation
58		Novosibirsk		Russian Federation
59		Penza		Russian Federation
60		Saratov		Russian Federation
61		St. Petersburg		Russian Federation
62		Belgrade		Serbia
63		Banska Bystrica		Slovakia
64		Levice		Slovakia
65		Martin		Slovakia
66		Presov		Slovakia
67		Skalica		Slovakia
68		Bloemfontein	Free State	South Africa
69		Pretoria	Gauteng	South Africa
70		Soweto	Gauteng	South Africa
71		Middleburg	Mpumalanga	South Africa
72		Bellville	Western Cape	South Africa
73		Nakorn Ratchasima	Nakhon Ratchasima	Thailand
74		Chiang Mai		Thailand
75		Lop Buri		Thailand
76		Prachuap Khiri Khan		Thailand

Sponsors and Collaborators

• Cubist Pharmaceuticals LLC

Investigators

• Study Director: Obiamiwe Umeh, M.D., MSc., Cubist Pharmaceuticals LLC

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Cubist Pharmaceuticals LLC
• ClinicalTrials.gov Identifier: NCT01345929
• Other Study ID Numbers: 7625A-005; CXA-cUTI-10-04; CXA-cUTI-10-05; NCT01345955
• First Posted: May 2, 2011
• Last Update Posted: Oct 25, 2018
• Last Verified: Sep 1, 2018

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by Cubist Pharmaceuticals LLC: cUTI
• Additional relevant MeSH terms: Infections; Communicable Diseases; Urinary Tract Infections; Pyelonephritis; Levofloxacin; Ofloxacin

Study Results

Participant Flow

Pre-assignment Detail	Two P3 protocols were initiated (NCT01345929 and NCT01345955) subsequently, Cubist and FDA agreed that integrated data from the 2 protocols could be analyzed and reported in a single Clinical Study Report. A total of 1083 subjects were randomized to both arms, 558 to NCT01345929 and 525 to NCT01345955. Of these, 552 and 516 received treatment.

Arm/Group Title	CXA-201 as Treatment for cUTI	Levofloxacin as Treatment for cUTI
Arm/Group Description	CXA-201 IV infusion (1500mg q8) for 7 days CXA-201: CXA-201 IV infusion (1500mg q8) for 7 days Of the 1083 subjects in the integrated analysis set, 533 received CXA.	Levofloxacin IV infusion (750mg qd) for 7 days Levofloxacin: Levofloxacin IV infusion (750mg qd) for 7 days Of the 1083 subjects in the integrated analysis set, 535 received levofloxacin.
Period Title: Overall Study
STARTED	533	535
COMPLETED	512	516
NOT COMPLETED	21	19

Baseline Characteristics

Arm/Group Title	CXA-201 as Treatment for cUTI	Levofloxacin as Treatment for cUTI	Total
Arm/Group Description	CXA-201 IV infusion (1500mg q8) for 7 days CXA-201: CXA-201 IV infusion (1500mg q8) for 7 days	Levofloxacin IV infusion (750mg qd) for 7 days Levofloxacin: Levofloxacin IV infusion (750mg qd) for 7 days	Total of all reporting groups
Overall Participants	533	535	1068
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	49.7 (19.52)	48.6 (20.05)	49.1 (19.79)
Sex: Female, Male (Count of Participants)
Female	374 70.2%	380 71%	754 70.6%
Male	159 29.8%	155 29%	314 29.4%

Outcome Measures

1. Primary Outcome

Title	The Percentage of Subjects Who Have Both a Per-subject Microbiological Outcome of Eradication and a Clinical Outcome of Cure at the Test of Cure (TOC) Visit in the Microbiological Modified ITT (mMITT) Population
Time Frame	Test of Cure Visit (7 Days [± 2 days] after completion of study drug administration)

Outcome Measure Data

Analysis Population Description

mMITT: Treated subjects, with baseline pathogen.

Arm/Group Title	CXA-201 as Treatment for cUTI	Levofloxacin as Treatment for cUTI
Arm/Group Description	CXA-201 IV infusion (1500mg q8) for 7 days CXA-201: CXA-201 IV infusion (1500mg q8) for 7 days	Levofloxacin IV infusion (750mg qd) for 7 days Levofloxacin: Levofloxacin IV infusion (750mg qd) for 7 days
Measure Participants	398	402
Number [percentage of subjects]	76.9	68.4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	CXA-201 as Treatment for cUTI, Levofloxacin as Treatment for cUTI
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Noninferiority was concluded if the lower bound of the 2-sided 95% CI was greater than -10%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	8.5
	Confidence Interval	(2-Sided) 95%; 2.31 to 14.57
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	The Percentage of Subjects Who Have Both a Per-subject Microbiological Outcome of Eradication and a Clinical Outcome of Cure at the TOC Visit in the Microbiologically Evaluable (ME) Population.
Time Frame	Test of Cure Visit (7 Days [± 2 days] after completion of study drug administration)

Outcome Measure Data

Analysis Population Description

ME: Treated patients, with baseline pathogen, complied with protocol.

Arm/Group Title	CXA-201 as Treatment for cUTI	Levofloxacin as Treatment for cUTI
Arm/Group Description	CXA-201 IV infusion (1500mg q8) for 7 days CXA-201: CXA-201 IV infusion (1500mg q8) for 7 days	Levofloxacin IV infusion (750mg qd) for 7 days Levofloxacin: Levofloxacin IV infusion (750mg qd) for 7 days
Measure Participants	341	353
Number [percentage of subjects]	83.3	75.4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	CXA-201 as Treatment for cUTI, Levofloxacin as Treatment for cUTI
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Noninferiority was concluded if the lower bound of the 2-sided 95% CI was greater than -10%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	8.0
	Confidence Interval	(2-Sided) 95%; 1.95 to 13.97
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Arm/Group Title	CXA-201 as Treatment for cUTI		Levofloxacin as Treatment for cUTI
Arm/Group Description	CXA-201 IV infusion (1500mg q8) for 7 days CXA-201: CXA-201 IV infusion (1500mg q8) for 7 days		Levofloxacin IV infusion (750mg qd) for 7 days Levofloxacin: Levofloxacin IV infusion (750mg qd) for 7 days
All Cause Mortality
	CXA-201 as Treatment for cUTI		Levofloxacin as Treatment for cUTI
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	CXA-201 as Treatment for cUTI		Levofloxacin as Treatment for cUTI
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	15/533 (2.8%)		18/535 (3.4%)
Cardiac disorders
Angina unstable	0/533 (0%)		1/535 (0.2%)
Cardiac failure congestive	0/533 (0%)		1/535 (0.2%)
Eye disorders
Diabetic retinopaty	1/533 (0.2%)		0/535 (0%)
Gastrointestinal disorders
Gastric ulcer	0/533 (0%)		1/535 (0.2%)
General disorders
Hernia obstructive	0/533 (0%)		1/535 (0.2%)
Immune system disorders
Contrast media allergy	0/533 (0%)		1/535 (0.2%)
Infections and infestations
Urinary tract infection	3/533 (0.6%)		2/535 (0.4%)
Pneumonia	2/533 (0.4%)		0/535 (0%)
Urosepsis	2/533 (0.4%)		0/535 (0%)
Abdominal abscess	1/533 (0.2%)		0/535 (0%)
Clostridium difficile colitis	1/533 (0.2%)		0/535 (0%)
Diverticulitis	1/533 (0.2%)		0/535 (0%)
Liver abscess	1/533 (0.2%)		0/535 (0%)
Pseudomembranous colitis	1/533 (0.2%)		0/535 (0%)
Pyelonephritis	0/533 (0%)		6/535 (1.1%)
Emphysematous pyelonephritis	0/533 (0%)		1/535 (0.2%)
Escherichia sepsis	0/533 (0%)		1/535 (0.2%)
Pyelonephritis acute	0/533 (0%)		1/535 (0.2%)
Sepsis	0/533 (0%)		1/535 (0.2%)
Injury, poisoning and procedural complications
Pneumothorax traumatic	0/533 (0%)		1/535 (0.2%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Bladder cancer	2/533 (0.4%)		0/535 (0%)
Nervous system disorders
Transient ischaemic attack	0/533 (0%)		1/535 (0.2%)
Renal and urinary disorders
Calculus urinary	1/533 (0.2%)		0/535 (0%)
Renal colic	1/533 (0.2%)		0/535 (0%)
Urinary retention	1/533 (0.2%)		0/535 (0%)
Renal tubular acidosis	0/533 (0%)		1/535 (0.2%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	0/533 (0%)		1/535 (0.2%)
Other (Not Including Serious) Adverse Events
	CXA-201 as Treatment for cUTI		Levofloxacin as Treatment for cUTI
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	108/533 (20.3%)		101/535 (18.9%)
Gastrointestinal disorders
Abdominal pain upper	7/533 (1.3%)		6/535 (1.1%)
Constipation	21/533 (3.9%)		17/535 (3.2%)
Diarrhoea	10/533 (1.9%)		23/535 (4.3%)
Nausea	15/533 (2.8%)		9/535 (1.7%)
Vomiting	6/533 (1.1%)		6/535 (1.1%)
General disorders
Pyrexia	8/533 (1.5%)		4/535 (0.7%)
Infections and infestations
Urinary tract infection	6/533 (1.1%)		7/535 (1.3%)
Investigations
Alanine aminotransferase increased	9/533 (1.7%)		5/535 (0.9%)
Aspartate aminotransferase increased	9/533 (1.7%)		5/535 (0.9%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/533 (0.2%)		6/535 (1.1%)
Myalgia	6/533 (1.1%)		4/535 (0.7%)
Nervous system disorders
Dizziness	6/533 (1.1%)		1/535 (0.2%)
Headache	31/533 (5.8%)		26/535 (4.9%)
Psychiatric disorders
Insomnia	7/533 (1.3%)		14/535 (2.6%)
Vascular disorders
Hypertension	16/533 (3%)		7/535 (1.3%)

Limitations/Caveats

Two identical P3 protocols were initiated (NCT01345929 and NCT01345955) subsequently, Cubist and FDA agreed that integrated data from the 2 protocols could be analyzed and reported in a single Clinical Study Report. These analyses are presented here.

More Information

Certain Agreements

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

The investigator(s) must undertake not to submit any part of the data from this protocol for publication without the prior consent of Cubist Pharmaceuticals, Inc.