Nongonococcal urethritis (NGU) remains one of the most common sexually transmitted disease syndromes observed in men with Chlamydia trachomatis being the causative agent in 35% to 50% of cases.1 Complications include acute epididymitis, acute conjunctivitis, and Reiter's syndrome. Importantly, the failure to identify and treat NGU places female partners at risk for infection, with resultant mucopurulent cervicitis (MPC), pelvic inflammatory disease, chronic pelvic pain, ectopic pregnancy and tubal factor infertility. C. trachomatis infections have also been associated with the transmission of human immunodeficiency virus (HIV) in both men and women.2 Other potentially causative organisms of NGU include U. urealyticum, M. genitalium, and Trichomonas vaginalis. However, in up to 50% of cases, no causative organism is identified.3
The current STD Treatment Guidelines from the Centers For Disease Control recommend azithromycin 1 g given orally as a single-dose or doxycycline 100 mg twice a day orally for seven days as empirical treatment for NGU.4 These regimens are effective, but persistent or recurrent chlamydial infection occurs within three months in up to 15% to 20% of men and clinical cure rates are often only 65% to 75% at four weeks posttreatment.5,6 Thus, safe and effective alternative drugs, preferably administered by single-dose, are needed. However, there have not been any new drugs approved for the treatment of urethritis since the registration of Zithromax® in 1996.
Rifalazil is an orally active second-generation rifamycin that exerts its antimicrobial action by inhibiting bacterial DNA-dependent RNA polymerase.7 It is bactericidal against C. trachomatis in McCoy cells culture with a MIC90 of 0.00025 μg/mL.8 Rifalazil also achieves high intracellular concentrations and its elimination half-life is approximately 100 hours.9,10 Before this study, 213 individuals had received single and multiple doses of rifalazil from 2.5 to 275 mg with an acceptable safety profile.
Given the above, we hypothesized that single-dose rifalazil would be as effective as single-dose azithromycin in the treatment of acute chlamydial NGU and potentially nonchlamydial NGU. We thus undertook this double-blind, multicenter study comparing the efficacy of three escalating doses of rifalazil versus azithromycin in men with acute NGU.
Male outpatients, between the ages of 18 and 45 years inclusive, who presented with symptoms of NGU (urethral discharge, dysuria, and urethral pruritis) of no more than 14 days duration were eligible for study. Participants were required to have a history of urethral discharge or observable urethral discharge at examination, a urethral Gram stain with five or more polymorphonuclear leukocytes (PMN) per oil immersion field on at least three fields, and no microscopic evidence of gonococcal infection. Participants were enrolled in 11 centers across the USA, mostly in sexually transmitted disease or public health clinics, between July 2003 and May 2004.
Patients were excluded from study participation if they had subsequent laboratory evidence of gonococcal infection; a sexual partner known to have a current gonococcal infection; history of persistent or recurrent (≥three episodes) NGU or C. trachomatis infection within the last six months; signs/symptoms of epididymitis, prostatitis, or Reiter's syndrome; HIV, acquired immune deficiency syndrome or syphilis infection; other significant systemic disease; possible or known active tuberculosis; allergy to rifampin, rifapentine, rifabutin, ceftriaxone or other cephalosporins, azithromycin, erythromycin, or any macrolide; systemic antimicrobial agent or investigational drug in the preceding 30 days; or a gastrointestinal condition that would likely affect drug absorption.
All participating patients signed written voluntary informed consent forms approved by the appropriate local institutional review board. Patients underwent a medical history and a physical examination and had urethral swabs obtained for Gram stain to enumerate PMN and to detect Gram-negative diplococci consistent with Neisseria gonorrhoeae and for culture for U. urealyticum.11,12 The first 10 to 20 ml of voided urine was collected for target capture transcription-mediated amplification testing with the GEN-PROBE® APTIMA® Combo 2 assay (APTIMA) for C. trachomatis and N. gonorrhoeae, for polymerase chain reaction testing for M. genitalium13 and for culture with InPouch™ TV test for T. vaginalis. Blood specimens were obtained for a complete blood count, chemistry panel, C-reactive protein, rapid plasma reagin for syphilis, and for identification of hepatitis B surface antigen, hepatitis C virus antibody, and human immunodeficiency virus. Patients were advised to abstain from all sexual activity or use condoms during the study period.
Randomization, Treatment and Follow-Up
Patients were randomly assigned in blocks of four by numbered kits to receive either rifalazil 2.5 mg, 12.5 mg or 25 mg or azithromycin 1 g, with a 1:1:1:1 ratio. Subjects in the rifalazil groups received the single-dose as one active capsule and three placebo capsules, all overencapsulated; patients in the azithromycin group received the single-dose as four active 250 mg capsules, all overencapsulated. The medication was taken under direct observation in the clinic. Neither the investigator nor the patient nor any of the clinic staff was aware of the medication assignment.
Three follow-up visits were then scheduled: Day 7 to 11; test-of-cure (Day 15–19; 2-week); and end-of-study (Day 36–40; 5-week). A telephone contact with each patient was attempted on Day 2 or 3. At each follow-up visit, an interval sexual history was obtained, a genitourinary examination was performed, urethral and urine samples were obtained for Gram stain and organism detection, and laboratory blood work was repeated excluding serology. Patients were asked about possible adverse effects at each visit.
Clinical efficacy was assessed at the 2- and 5-week visits using symptoms of urethritis (urethral discharge, dysuria, and urethral pruritis) and signs of urethritis (urethral discharge on exam or PMN on Gram stain) as the criteria for cure. At the 2- and 5-week visits, patients with persistent symptoms and five or more PMN were considered clinical failures. Patients with discordant responses between symptoms and signs were reevaluated within 48 hours, when they had not voided for more than two hours. If these subjects had five or more PMN on Gram stain or persistent urethral discharge regardless of numbers of PMN, they were considered clinical failures. Patients not fulfilling these findings were considered clinical cures. Patients classified as clinical failures at either visit were treated with a nonstudy antibiotic; those who were considered clinical failures at the 2-week visit were carried forward as clinical failures at the 5-week visit.
For a patient to be evaluable for assessment of bacteriologic response to therapy, the organism must have been detected at baseline and follow-up tests must have been obtained. All microbiologic tests were performed at two central laboratories. During the study, bacteriologic results for C. trachomatis and N. gonorrhoeae by APTIMA and or T. vaginalis by InPouch were available to the investigators. Results for M. genitalium and U. urealyticum were made available after the study was completed. At the 2-week visit, responses were classified as eradication (C. trachomatis, U. urealyticum, or M. genitalium that was present at baseline and was no longer present); persistence (organism that was present at baseline was still present); or unevaluable (patient did not return for the visit, refused further testing or could not be evaluated for any other reason). At the 5-week visit, responses were classified as eradication (C. trachomatis, U. urealyticum, or M. genitalium that was present at baseline was no longer present); persistence (organism that was present at baseline and the 2-week visit continued to persist even with alternate therapy; reinfection (organism was absent at the 2-week visit, but was present at the 5-week visit); or unevaluable. At the 2-week visit, failure was defined as microbiologic persistence or unevaluable; at the 5-week visit, failure was defined as persistence, reinfection or unevaluable. All other outcomes were considered to be microbiologic eradications.
In an effort to determine how many patients in each group had both clinical and microbiologic benefits from a study drug, an overall therapeutic outcome was determined at the 2-week visit for the clinically evaluable population. In this analysis, patients were classified as a therapeutic cure (both a clinical cure and microbiologic eradication of C. trachomatis) or a therapeutic failure (either or both the clinical and microbiologic outcomes were failure).
The objectives of this study were to evaluate the safety and clinical cure rates of rifalazil compared with azithromycin in males with NGU; to evaluate the clinical cure rate and microbiologic eradication of C. trachomatis in men treated with rifalazil versus azithromycin; and to evaluate the rifalazil dose response in the treatment of NGU to assist with dose selection for future clinical studies.
Four populations were considered for analysis. The intent-to-treat (ITT) population was defined as all patients who had a diagnosis of NGU and received double-blind study medication and these subjects also constituted the safety population. Patients in the ITT population who had evaluations performed postbaseline, which allowed determination of clinical response to treatment and had no major protocol violations, were included in the clinically evaluable (CE) population. Patients were excluded from the CE population if there were protocol deviations (e.g., the 2-week visit was outside the protocol-defined visit window; the patient failed to return for this visit; they had received an antibiotic before the 2-week visit, unless the antibiotic was administered for clinical failure of NGU before the 2-week visit; a Gram stain was performed within 90 minutes of voiding and there were ≤5 PMN on microscopy; baseline test results received after treatment showed they were positive for N. gonorrhoeae by APTIMA or T. vaginalis by InPouch; they were positive for HIV or syphilis). The microbiologic intent-to-treat population (MITT) was defined as patients in the ITT population who had C. trachomatis, M. genitalium, and/or U. urealyticum at enrollment. The microbiologically evaluable population (ME) was defined as patients who had C. trachomatis, M. genitalium, and/or U. urealyticum at baseline and who were part of the CE or had appropriately timed follow-up evaluations and no protocol violations that could prejudice the assessment of microbiologic eradication or persistence.
Two analyses, one using the CE population and one the ME population, were conducted to evaluate the clinical and microbiologic efficacy of rifalazil. The ITT/safety population was used to assess adverse reactions. Response rates were analyzed for dose–response by logistic regression. The exact binomial distribution was used for 95% confidence intervals on response rates for an individual treatment group. The noninferiority analysis of each dose to azithromycin was conducted to more fully understand the data in a set of exploratory Phase 2 analyses.
All adverse effects and laboratory changes were graded in accordance with the National Cancer Institute Common Toxicity Criteria. Maximum grades per patient recorded during the entire period were compared.
A total of 683 patients were screened for eligibility (Fig. 1). Of these, 513 were excluded due to study criteria for patient exclusion. The ITT/safety population consisted of 170 patients with acute NGU who were enrolled at 11 clinical sites throughout the United States. One hundred and twenty-eight (75%) men were randomized to one of the rifalazil regimens and 42 (25%) were randomized to receive azithromycin; the groups were well matched about age, race, microorganisms present at the baseline visit and history of sexually transmitted diseases (Table 1). Eighty-five (66%) rifalazil-treated patients and 26 (62%) azithromycin-treated patients were in the CE population. Reasons for exclusion from the CE were 2-week visit outside of the defined study period Day 15 to 19 (n = 23), lost to follow-up (n = 11), positive APTIMA test for N. gonorrhoeae or InPouch test for T. vaginalis (n = 10), received another antibiotic (n = 8), and test not performed (n = 7). Fifty-one (40%) of the patients in the rifalazil-treated groups and 20 (48%) in the azithromycin-treated group had C. trachomatis infection as determined by APTIMA assay before treatment. Thirty of the fifty-one subjects in the rifalazil-treated groups and 12 in the azithromycin-treated-groups were in the ME population for C. trachomatis. Reasons for exclusion from the ME were 2-week visit outside of the defined study period Day 15 to 19 (n = 13), positive APTIMA test for N. gonorrhoeae or InPouch test for T. vaginalis (n = 7), received another antibiotic (n = 5), lost to follow-up (n = 2), and test not performed (n = 2).
Clinical Response to Treatment
In the CE population, there was a significant dose response for cure in the rifalazil-treated groups at both the 2-week and 5-week visits (P = 0.001 and P = 0.048, respectively) (Fig. 2). At the 2-week visit, 86% of the rifalazil-treated men in the 25 mg group (67–96) and 77% of the azithromycin-treated group (56–91) were clinically cured. At the 5-week visit, the clinical cure rates were 59% (39–78) and 63% (41–81), respectively. It should be noted that the majority of clinical failures in both treatment groups at the 5-week visit were asymptomatic. When patients were stratified by the presence or absence of C. trachomatis at the initial visit, there were also significant dose responses across the rifalazil-treated groups (Fig. 2). At the 2-week visit in those subjects with C. trachomatis, 86% of the rifalazil-treated 25 mg group (57–98) and 75% of the azithromycin-treated group (43–95) were clinically cured, compared with 86% (57–98), and 79% (49–95), respectively, in those subjects who did not have C. trachomatis. At the 5-week visit in those subjects with C. trachomatis, 62% of the rifalazil-treated 25 mg group (32–86) and 45% of the azithromycin-treated group (17–77) were clinically cured, compared with 57% (29–82), and 77% (46–95), respectively, in those subjects who did not have C. trachomatis.
Irrespective of the microorganisms detected at the baseline visit, patients in the rifalazil-treated 2.5 mg group had clinical cure rates under 50% at both the 2-week and 5-week visits (Table 2). Patients in either the rifalazil-treated (25 mg) group or azithromycin-treated group had high clinical cure rates (75–100%) at the 2- week visit regardless of whether the patient had C. trachomatis, U. urealyticum, or M. genitalium detected at initial visit. However, considerably lower clinical cure rates were seen for both of these regimens (40 − 86%) at the 5-week visit. Larger numbers of patients are needed to accurately compare clinical cure rate by etiologic agent.
The microbiologic eradication rate for Chlamydia infected patients who received rifalazil was dose-dependent, ranging from 0% in the 2.5 mg dose to 85% in the 25 mg dose groups (Table 3) (P = 0.005). Microbiologic cure rates for C. trachomatis were comparable in the rifalazil-treated 25 mg and the azithromycin-treated groups. Thus, at the 2-week visit, 11 of the 13 rifalazil-treated patients (85%) demonstrated microbiologic cure of chlamydial infection versus 10 of the 12 azithromycin-treated patients (83%). At the 5-week visit, 10 of 12 rifalazil-treated patients (83%) and 7 of 11 azithromycin-treated patients (64%) demonstrated microbiologic cure of chlamydial infection. Microbiologic cure rates of U. urealyticum were generally low in the rifalazil treated groups (0% to 43%) compared with 71% to 78% in the azithromycin-treated group across both visits at the 5-week visit (P = 0.0069). None of the rifalazil-treated groups demonstrated microbiologic eradication of M. genitalium, while the azithromycin-treated group had 100% eradication and 86% eradication at the 2-week and 5-week visits, respectively, (P <0.0001) (Table 3).
Analysis of Therapeutic Cure
In an effort to evaluate the intersection between clinical cure and microbiologic eradication, therapeutic cure was evaluated for the CE population that was infected with C. trachomatis, M. genitalium, or U. urealyticum. A significant dose response was seen for the rate of therapeutic cure in subjects infected with C. trachomatis among the rifalazil-treated groups (P = 0.002, Table 4). The therapeutic cure rate for C. trachomatis in the azithromycin-treated group, (58%), was lower than in the rifalazil-treated 25 mg group (85%), and rifalazil was noninferior to azithromycin (−0.15 to 0.59) in this analysis. In contrast, no subject with M. genitalium who received rifalazil was a therapeutic cure, while the therapeutic cure for azithromycin in men with M. genitalium was 86% (P <0.0001). Of those subjects with U. urealyticum who received azithromycin, 67% were therapeutic cures compared with 0% to 43% of subjects who received rifalazil.
No deaths, other serious adverse events, or discontinuations due to adverse events occurred during the study. Adverse experiences that were considered at least remotely treatment related occurred in 18% of the rifalazil-treated groups and 19% of the azithromycin related group (ITT population). Gastrointestinal disorders (nausea, abdominal pain, and diarrhea) were the most common side effects reported in the azithromycin-treated group (12% vs. 5% in the rifalazil-treated groups). Headaches were the most common side effect reported by subjects receiving rifalazil (8% overall with 7% rifalazil 2.5 mg; 2% rifalazil 12.5 mg; 14% rifalazil 25 mg) versus 5% in the azithromycin-treated group. Almost all of the adverse effects were mild to moderately severe and did not require intervention. Two subjects in the rifalazil-treated 25 mg group had severe headaches on Day 2 or Day 3 that were thought to be remotely or possibly related to study medication; one of these two subjects also reported severe dizziness. One subject in the azithromycin-treated group had severe crystalluria on Day 4 that was considered possibly related to study medication. Laboratory changes were analyzed separately. Changes in mean laboratory values from baseline to other study visits were unremarkable for any treatment group. One subject receiving rifalazil 2.5 mg exhibited a Grade 3 level in alanine aminotransferase (ALT) (352 U/L; normal 6–43 U/L) on Day 15, with return to normal limits by the end of study. During evaluation of the elevated ALT, he was found to have acute infectious mononucleosis. Three subjects receiving rifalazil 25 mg exhibited Grade 3 levels in absolute neutrophil count (ANC), although two of these subjects had a lower normal or an abnormal value before study enrollment. In the one subject with the ANC at the lower limit of normal (1.96–7.23 × 103/μL) at enrollment, a normal white blood cell count (WBC) and a Grade 3 ANC, 0.95 × 103/μL, were observed at study Day 7, with return to normal by the 2-week visit. The other subject had a Grade 2 ANC, 1.40 × 103/μL, at enrollment with a normal WBC. On Day 7 he had a Grade 3 ANC, 0.63 × 103/μL, with a Grade 1 WBC and then was lost to follow-up. The third subject had a normal ANC at enrollment with a Grade 2 ANC, 1.59 × 103/μL, at the 2-week visit and a Grade 3 ANC, 0.88 × 103/μL, at the 5-week visit with WBC at the lower limit of normal. He was then lost to follow-up. Importantly, none of these laboratory changes were associated with adverse clinical events.
Rifalazil, a new rifamycin compound, is highly active against Chlamydia in cell culture, has a long half-life and achieves high intracellular concentrations, making it a potential candidate for use in the treatment of chlamydial infections.7,9,10,14 Rifampin is also effective against Chlamydia in cell culture and has been used to treat Chlamydia spp. infections. However, the relative ease with which resistance can be selected has prevented its use as monotherapy, and it is seldom employed except in combination regimens. Rifalazil retains in vitro activity even against mutant Chlamydia strains that develop point mutations in the rpoB gene, resulting in resistance to rifampin.8 In addition, rifalazil, unlike rifampin, has not been shown either in vitro or ex vivo to stimulate the cytochrome p-450 system.15–17 We thus undertook this study to assess the safety and effectiveness of a single dose of rifalazil in a dose-ranging Phase 2 trial in men with NGU. We enrolled men with NGU rather than limiting enrollment to Chlamydia NGU since in clinical practice, a causative organism for NGU is generally not identified before treatment. We limited this initial study to men rather than including women with Chlamydia infection since the consequences of inadequately treated infections are more serious in women.
Our data demonstrate a striking and statistically significant dose–response for both clinical cure and microbiologic eradication of C. trachomatis with rifalazil. The clinical cure rate with rifalazil 25 mg was similar to that seen with azithromycin at either the 2-week visit (86% vs. 77%, respectively) or the 5-week visit (59% vs. 63%, respectively). Rifalazil 25 mg and azithromycin were equally effective in the microbiologic eradication of C. trachomatis at the 2-week visit (85% vs. 83%, respectively). At the 5-week visit, microbiologic eradication of C. trachomatis appeared higher with rifalazil (83% vs. 64%, respectively), although a larger study would be needed to confirm this. A similar trend was observed in clinical cure rates for subjects at the 5-week visit who had Chlamydia isolated at enrollment (62% rifalazil 25 mg vs. 45% azithromycin). These findings might stem from rifalazil's long tissue half-life and increased in vitro potency as compared with azithromycin, both factors which might produce higher eradication rates.18 Rifalazil might also have an ability to prevent reinfection. In cell culture studies, exposure of monolayers of McCoy cells to single-dose rifalazil conferred 12 days of protection against challenge with Chlamydia versus three days of protection associated with single-dose azithromycin.19 Of note, the clinical and microbiologic cure rates for C. trachomatis infected patients were lower in this study as compared with earlier studies.20 This is most likely attributable to use of a much more sensitive nucleic acid amplification test for chlamydia (APTIMA) than the culture tests used in prior studies as well as a longer follow-up period (5 weeks) than was used in many studies.
C. trachomatis is the principle causative organism in acute NGU, accounting for 35% to 50% of cases.1 In this study, C. trachomatis was isolated from 42% of patients. However, U. urealyticum and more recently M. genitalium are also thought to play an etiological role in NGU and were assessed in our study as well.21 Azithromycin was considerably more effective in eradicating U. urealyticum and M. genitalium than was rifalazil. This is consistent with the observation that members of the Class Mollicutes demonstrate resistance to rifampin based on a specific point mutation in the rpoB gene.22 Although the susceptibility of these bacteria to rifalazil is unknown, such mutations could mediate resistance to rifalazil as well. In fact, M. genitalium was not eradicated from any of the rifalazil treated patients and most of these patients were clinical failures as well. Similarly, U. urealyticum was only eliminated from a small proportion of rifalazil treated patients, but a higher proportion nevertheless demonstrated clinical cure. Thus, some of the patients with M. genitalium and U. urealyticum infections and failure of microbiologic eradication with rifalazil were clinically cured as seen in Table 4. This discordance between microbiologic failure and clinical cure may indicate that M. genitalium and U. urealyticum were not the etiologic agents eliciting symptoms and signs in all cases of NGU in which they were identified. Alternatively, treatment with rifalazil could have transiently reduced the quantity of M. genitalium sufficiently to suppress clinical signs and symptoms followed by subsequent recurrence as was seen at 5 weeks in 3 of the 5 patients with M. genitalium who received 25 mg of rifalazil.
The strengths of our study include a carefully defined study group, detailed criteria for enrollment and outcome, the use of multiple enrollment sites and sensitive molecular tests for defining the infectious agents of most interest. The comparison of clinical and microbiologic outcomes using two very different classes of drugs also provides insights into the roles of these organisms in causing NGU. Limitations of the investigation include the fact that it was a Phase 2 dose ranging study that was not powered to demonstrate significant differences between the four treatment regimens.
However, despite the relatively small number of patients in the trial, the differences in both clinical and microbiologic outcomes by drug regimen and by rifalazil dose and the similarity of the clinical therapeutic outcomes in the azithromycin-treated and 25 mg rifalazil-treated patients were striking. Our findings indicate that rifalazil warrants further investigation for the treatment of STDs, particularly C. trachomatis infection. The drug appears to be safe and well tolerated in men. Larger studies are needed to confirm these studies in men and to evaluate the drug in women with chlamydial infections. Such studies should use microbiologic analysis of the potential etiologic agents of NGU and MPC and correlation of their eradication with clinical response to therapy.
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