Ciprofloxacin Extended-release (Page 9 of 12)

Complicated Urinary Tract Infections and Acute Uncomplicated Pyelonephritis

Ciprofloxacin extended-release tablets were evaluated for the treatment of complicated urinary tract infections (cUTI) and acute uncomplicated pyelonephritis (AUP) in a randomized, double-blind, controlled clinical trial conducted in the US and Canada. The study enrolled 1,042 patients (521 patients per treatment arm) and compared ciprofloxacin extended-release tablets (1000 mg once daily for 7 to 14 days) with immediate-release ciprofloxacin (500 mg BID for 7 to 14 days). The primary efficacy endpoint for this trial was bacteriologic eradication of the baseline organism(s) with no new infection or superinfection at 5 to 11 days post-therapy (test-of-cure or TOC) for the Per Protocol and Modified Intent-To-Treat (MITT) populations.

The Per Protocol population was defined as patients with a diagnosis of cUTI or AUP, a causative organism(s) at baseline present at ≥ 105 CFU/mL, no inclusion criteria violation, a valid test-of-cure urine culture within the TOC window, an organism susceptible to study drug, no premature discontinuation or loss to follow-up, and compliance with the dosage regimen (among other criteria). More patients in the ciprofloxacin extended-release tablet arm than in the control arm were excluded from the Per Protocol population and this should be considered in the interpretation of the study results. Reasons for exclusion with the greatest discrepancy between the two arms were no valid test-of-cure urine culture, an organism resistant to the study drug, and premature discontinuation due to adverse events.

An analysis of all patients with a causative organism(s) isolated at baseline and who received study medication, defined as the MITT population, included 342 patients in the ciprofloxacin extended-release tablet arm and 324 patients in the control arm. Patients with missing responses were counted as failures in this analysis. In the MITT analysis of cUTI patients, bacteriologic eradication was 160/271 (59%) versus 156/248 (62.9%) in ciprofloxacin extended-release tablet and control arm, respectively [97.5% CI* (-13.5%, 5.7%)]. Clinical cure was 184/271 (67.9%) for ciprofloxacin extended-release tablet and 182/248 (73.4%) for control arm, respectively [97.5% CI* (-14.4%, 3.5%)]. Bacterial eradication in the MITT analysis of patients with AUP at TOC was 47/71 (66.2%) and 58/76 (76.3%) for ciprofloxacin extended-release tablet and control arm, respectively [97.5% CI* (-26.8%, 6.5%)]. Clinical cure at TOC was 50/71 (70.4%) for ciprofloxacin extended-release tablet and 58/76 (76.3%) for the control arm [97.5% CI* (-22.0%, 10.4%)].

*confidence interval of the difference in rates (ciprofloxacin extended-release tablet minus control).

In the Per Protocol population, the differences between ciprofloxacin extended-release tablet and the control arm in bacteriologic eradication rates at the TOC visit were not consistent between AUP and cUTI patients. The bacteriologic eradication rate for cUTI patients was higher in the ciprofloxacin extended-release tablet arm than in the control arm. For AUP patients, the bacteriologic eradication rate was lower in the ciprofloxacin extended-release tablet arm than in the control arm. This inconsistency was not observed between the two treatment groups for clinical cure rates. Clinical cure rates were 96.1% (198/206) and 92.1% (211/229) for ciprofloxacin extended-release tablet and the control arm, respectively.

The bacterial eradication and clinical cure rates by infection type for ciprofloxacin extended-release tablet and the control arm at the TOC visit and their corresponding 97.5% confidence intervals for the differences between rates (ciprofloxacin extended-release tablet minus control arm) are given below for the Per Protocol population analysis:

Ciprofloxacin extended-release 1000 mg QD Ciprofloxacin immediate-release 500 mg BID
^ Patients excluded from the Per Protocol population were primarily those with no causative organism(s) at baseline or no organism present at ≥ 105 CFU/mL at baseline, inclusion criteria violation, no valid test-of-cure urine culture within the TOC window, an organism resistant to study drug, premature discontinuation due to an adverse event, lost to follow-up, or non-compliance with dosage regimen (among other criteria).
* n/N = patients with baseline organism(s) eradicated and no new infections or superinfections/total number of patients
** n/N = patients with specified baseline organism eradicated/patients with specified baseline organism
***n/N = patients with clinical success /total number of patients
Randomized Patients 521 521
Per Protocol Patients^ 206 229
cUTI Patients
Bacteriologic Eradication at TOC (n/N)* 148/166 (89.2%) 144/177 (81.4%)
CI [-0.7%, 16.3%]
Bacteriologic Eradication(by organism) at TOC (n/N)**
E. coli 91/94 (96.8%) 90/92 (97.8%)
K. pneumoniae 20/21 (95.2%) 19/23 (82.6%)
E. faecalis 17/17 (100%) 14/21 (66.7%)
P. mirabilis 11/12 (91.6%) 10/10 (100%)
P. aeruginosa 3/3 (100%) 3/3 (100%)
Clinical Cure at TOC (n/N)*** 159/166 (95.8%) 161/177 (91.0%)
CI [-1.1%, 10.8%]
AUP Patients
Bacteriologic Eradication at TOC (n/N)* 35/40 (87.5%) 51/52 (98.1%)
CI [-34.8%, 6.2%]
Bacteriologic Eradication of E. coli at TOC (n/N)** 35/36 (97.2%) 41/41 (100%)
Clinical Cure at TOC (n/N)*** 39/40 (97.5%) 50/52 (96.2%)
CI [-15.3%, 21.1%]

Of the 166 cUTI patients treated with ciprofloxacin extended-release tablets, 148 (89%) had the causative organism(s) eradicated, 8 (5%) had persistence, 5 (3%) patients developed superinfections and 5 (3%) developed new infections. Of the 177 cUTI patients treated in the control arm, 144 (81%) had the causative organism(s) eradicated, 16 (9%) patients had persistence, 3 (2%) developed superinfections and 14 (8%) developed new infections. Of the 40 patients with AUP treated with ciprofloxacin extended-release tablets, 35 (87.5%) had the causative organism(s) eradicated, 2 (5%) patients had persistence and 3 (7.5%) developed new infections. Of the 5 ciprofloxacin extended-release tablet AUP patients without eradication at TOC, 4 were considered clinical cures and did not receive alternative antibiotic therapy. Of the 52 patients with AUP treated in the control arm, 51 (98%) had the causative organism(s) eradicated. One patient (2%) had persistence.

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