Clarithromycin (Page 8 of 9)
14.2 Otitis Media
Otitis Media Trial of clarithromycin tablets vs. Oral Cephalosporin
In a controlled clinical trial of pediatric patients with acute otitis media performed in the United States, where significant rates of beta-lactamase producing organisms were found, clarithromycin tablets was compared to an oral cephalosporin. In this trial, strict evaluability criteria were used to determine clinical response. For the 223 patients who were evaluated for clinical efficacy, the clinical success rate (i.e., cure plus improvement) at the post-therapy visit was 88% for clarithromycin tablets and 91% for the cephalosporin.
In a smaller number of patients, microbiologic determinations were made at the pre-treatment visit. The presumptive bacterial eradication/clinical cure outcomes (i.e., clinical success) are shown in Table 16.
| Pathogen | Clinical Success Rates | |
| Clarithromycin Tablets | Oral Cephalosporin | |
| S. pneumoniae | 13/15 (87%) | 4/5 |
| H. influenzaea | 10/14 (71%) | 3/4 |
| M. catarrhalis | 4/5 | 1/1 |
| S. pyogenes | 3/3 | 0/1 |
| All Pathogens Combined | 30/37 (81%) | 8/11 (73%) |
| a None of the H. influenzae isolated pre-treatment was resistant to clarithromycin tablets; 6% were resistant to the control agent. | ||
Otitis Media Trials of Clarithromycin Tablets vs. Antimicrobial/Beta-lactamase Inhibitor
In two other controlled clinical trials of acute otitis media performed in the United States, where significant rates of beta-lactamase producing organisms were found, clarithromycin tablets was compared to an oral antimicrobial agent that contained a specific beta-lactamase inhibitor. In these trials, strict evaluability criteria were used to determine the clinical responses. In the 233 patients who were evaluated for clinical efficacy, the combined clinical success rate (i.e., cure and improvement) at the post-therapy visit was 91% for both clarithromycin tablets and the control.
For the patients who had microbiologic determinations at the pre-treatment visit, the presumptive bacterial eradication/clinical cure outcomes (i.e., clinical success) are shown in Table 17.
| Clinical Success Rates | ||
| PATHOGEN | Clarithromycin Tablets | Antimicrobial/ Beta-lactamase Inhibitor |
| S. pneumoniae | 43/51 (84%) | 55/56 (98%) |
| H. influenzae a | 36/45 (80%) | 31/33 (94%) |
| M. catarrhalis | 9/10 (90%) | 6/6 |
| S. pyogenes | 3/3 | 5/5 |
| All Pathogens Combined | 91/109 (83%) | 97/100 (97%) |
| a Of the H. influenzae isolated pre-treatment, 3% were resistant to clarithromycin tablets and 10% were resistant to the control agent. | ||
14.3 H. pylori Eradication to Decrease the Risk of Duodenal Ulcer Recurrence
Clarithromycin tablets + Lansoprazole and Amoxicillin
Two U.S. randomized, double-blind clinical trials (trial 6 and trial 7) in patients with H. pylori and duodenal ulcer disease (defined as an active ulcer or history of an active ulcer within one year) evaluated the efficacy of clarithromycin tablets 500 mg twice daily in combination with lansoprazole 30 mg twice daily and amoxicillin 1 gm twice daily as 14-day triple therapy for eradication of H. pylori.
H. pylori eradication was defined as two negative tests (culture and histology) at 4 weeks to 6 weeks following the end of treatment.
The combination of clarithromycin tablets plus lansoprazole and amoxicillin as triple therapy was effective in eradication of H. pylori (see results in Table 18). Eradication of H. pylori has been shown to reduce the risk of duodenal ulcer recurrence.
A randomized, double-blind clinical trial (trial 8) performed in the U.S. in patients with H. pylori and duodenal ulcer disease (defined as an active ulcer or history of an ulcer within one year) compared the efficacy of clarithromycin tablets in combination with lansoprazole and amoxicillin as triple therapy for 10 days and 14 days. This trial established that the 10-day triple therapy was equivalent to the 14-day triple therapy in eradicating H. pylori (see results in Table 18).
| Trial | Duration | Triple Therapy Evaluable Analysisa | Triple Therapy Intent-to-Treat Analysisb |
| Trial 6 | 14 days | 92c [80 to 97.7] (n = 48) | 86c [73.3 to 93.5] (n = 55) |
| Trial 7 | 14 days | 86d [75.7 to 93.6] (n = 66) | 83d [72 to 90.8] (n = 70) |
| Trial 8e | 14 days | 85 [77 to 91] (N = 113) | 82 [73.9 to 88.1] (N = 126) |
| 10 days | 84 [76 to 89.8] (N = 123) | 81 [73.9 to 87.6] (N = 135) | |
| a Based on evaluable patients with confirmed duodenal ulcer (active or within one year) and H. pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtest (Delta West LTD., Bentley, Australia), histology, and/or culture. Patients were included in the analysis if they completed the trial. Additionally, if patients were dropped out of the trial due to an adverse reaction related to the drug, they were included in the analysis as evaluable failures of therapy.b Patients were included in the analysis if they had documented H. pylori infection at baseline as defined above and had a confirmed duodenal ulcer (active or within one year). All dropouts were included as failures of therapy.c (p < 0.05) versus clarithromycin tablets/lansoprazole and lansoprazole/amoxicillin dual therapy.d (p < 0.05) versus clarithromycin tablets/amoxicillin dual therapy.e The 95% confidence interval for the difference in eradication rates, 10-day minus 14-day, is (10.5, 8.1) in the evaluable analysis and (-9.7, 9.1) in the intent-to-treat analysis | |||
Clarithromycin tablets + Omeprazole and Amoxicillin Therapy
Three U.S., randomized, double-blind clinical trials in patients with H. pylori infection and duodenal ulcer disease (n = 558) compared clarithromycin tablets plus omeprazole and amoxicillin to clarithromycin tablets plus amoxicillin. Two trials (trials 9 and 10) were conducted in patients with an active duodenal ulcer, and the third trial (trial 11) was conducted in patients with a duodenal ulcer in the past 5 years, but without an ulcer present at the time of enrollment. The dosage regimen in the trials was clarithromycin tablets 500 mg twice a day plus omeprazole 20 mg twice a day plus amoxicillin 1 gram twice a day for 10 days. In trials 9 and 10, patients who took the omeprazole regimen also received an additional 18 days of omeprazole 20 mg once a day. Endpoints studied were eradication of H. pylori and duodenal ulcer healing (trials 9 and 10 only). H. pylori status was determined by CLOtest® , histology, and culture in all three trials. For a given patient, H. pylori was considered eradicated if at least two of these tests were negative, and none was positive. The combination of clarithromycin tablets plus omeprazole and amoxicillin was effective in eradicating H. pylori (see results in Table 19).
| Clarithromycin Tablets + omeprazole + amoxicillin | Clarithromycin Tablets + amoxicillin | |||
| Per-Protocola | Intent-to-Treatb | Per-Protocola | Intent-to-Treatb | |
| Trial 9 | c 77 [64, 86] (n = 64) | 69 [57, 79] (n = 80) | 43 [31, 56] (n = 67) | 37 [27, 48] (n = 84) |
| Trial 10 | c 78 [67, 88] (n = 65) | 73 [61, 82] (n = 77) | 41 [29, 54] (n = 68) | 36 [26, 47] (n = 84) |
| Trial 11 | c 90 [80, 96] (n = 69) | 83 [74, 91] (n = 84) | 33 [24, 44] (n = 93) | 32 [23, 42] (n = 99) |
| a Patients were included in the analysis if they had confirmed duodenal ulcer disease (active ulcer trials 9 and 10; history of ulcer within 5 years, trial 11) and H. pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtest® , histology, and/or culture. Patients were included in the analysis if they completed the trial. Additionally, if patients dropped out of the trial due to an adverse reaction related to the study drug, they were included in the analysis as failures of therapy. The impact of eradication on ulcer recurrence has not been assessed in patients with a past history of ulcer.b Patients were included in the analysis if they had documented H. pylori infection at baseline and had confirmed duodenal ulcer disease. All dropouts were included as failures of therapy. c p < 0.05 versus clarithromycin tablets plus amoxicillin. | ||||
Clarithromycin tablets + Omeprazole Therapy
Four randomized, double-blind, multi-center trials (trials 12, 13, 14, and 15) evaluated clarithromycin tablets 500 mg three times a day plus omeprazole 40 mg once a day for 14 days, followed by omeprazole 20 mg once a day (trials 12, 13, and 15) or by omeprazole 40 mg once a day (trial 14) for an additional 14 days in patients with active duodenal ulcer associated with H. pylori. Trials 12 and 13 were conducted in the U.S. and Canada and enrolled 242 and 256 patients, respectively. H. pylori infection and duodenal ulcer were confirmed in 219 patients in trial 12 and 228 patients in trial 13. These trials compared the combination regimen to omeprazole and clarithromycin tablets monotherapies. Trials 14 and 15were conducted in Europe and enrolled 154 and 215 patients, respectively. H. pylori infection and duodenal ulcer were confirmed in 148 patients in trial 14 and 208 patients in trial 15. These trials compared the combination regimen to omeprazole monotherapy. The results for the efficacy analyses for these trials are described in Tables 20, 21, and 22.
Duodenal Ulcer Healing
The combination of clarithromycin tablets and omeprazole was as effective as omeprazole alone for healing duodenal ulcer (see Table 20).
| Trial | Clarithromycin Tablets + Omeprazole | Omeprazole | Clarithromycin Tablets |
| U.S. Trials | |||
| Trial 13 | 94% (58/62)a | 88% (60/68) | 71% (49/69) |
| Trial 12 | 88% (56/64)a | 85% (55/65) | 64% (44/69) |
| Non-U.S. Trials | |||
| Trial 15 | 99% (84/85) | 95% (82/86) | N/A |
| Trial 14b | 100% (64/64) | 99% (71/72) | N/A |
| a p < 0.05 for clarithromycin tablets + omeprazole versus clarithromycin tablets monotherapy.b In trial 14 patients received omeprazole 40 mg daily for days 15 to 28. | |||
Eradication of H. pylori Associated with Duodenal Ulcer
The combination of clarithromycin tablets and omeprazole was effective in eradicating H. pylori (see Table 21). H. pylori eradication was defined as no positive test (culture or histology) at 4 weeks following the end of treatment, and two negative tests were required to be considered eradicated. In the per-protocol analysis, the following patients were excluded: dropouts, patients with major protocol violations, patients with missing H. pylori tests post-treatment, and patients that were not assessed for H. pylori eradication at 4 weeks after the end of treatment because they were found to have an unhealed ulcer at the end of treatment.
| Trial | Clarithromycin Tablets + Omeprazole | Omeprazole | Clarithromycin Tablets |
| U.S. Trials | |||
| Trial 13 | 64% (39/61)a,b | 0% (0/59) | 39% (17/44) |
| Trial 12 | 74% (39/53)a,b | 0% (0/54) | 31% (13/42) |
| Non-U.S. Trials | |||
| Trial 15 | 74% (64/86)b | 1% (1/90) | N/A |
| Trial 14 | 83% (50/60)b | 1% (1/74) | N/A |
| a Statistically significantly higher than clarithromycin tablets monotherapy (p < 0.05). b Statistically significantly higher than omeprazole monotherapy (p < 0.05). | |||
Ulcer recurrence at 6-months and at 12 months following the end of treatment was assessed for patients in whom ulcers were healed post-treatment (see the results in Table 22). Thus, in patients with duodenal ulcer associated with H. pylori infection, eradication of H. pylori reduced ulcer recurrence.
| H. pylori Negative at 4 to 6 Weeks | H. pylori Positive at 4 to 6 Weeks | |
| U.S. Trials Recurrence at 6 Months | ||
| Trial 100 | ||
| Clarithromycin tablets + Omeprazole | 6% (2/34) | 56% (9/16) |
| Omeprazole | (0/0) | 71% (35/49) |
| Clarithromycin tablets | 12% (2/17) | 32% (7/22) |
| Trial 067 | ||
| Clarithromycin tablets + Omeprazole | 38% (11/29) | 50% (6/12) |
| Omeprazole | (0/0) | 67% (31/46) |
| Clarithromycin tablets | 18% (2/11) | 52% (14/27) |
| Non-U.S. Trials Recurrence at 6 Months | ||
| Trial 058 | ||
| Clarithromycin tablets + Omeprazole | 6% (3/53) | 24% (4/17) |
| Omeprazole | 0% (0/3) | 55% (39/71) |
| Trial 812b | ||
| Clarithromycin tablets + Omeprazole | 5% (2/42) | 0% (0/7) |
| Omeprazole | 0% (0/1) | 54% (32/59) |
| Non-U.S. Trials Recurrence at 12-Months in Trial 14 | ||
| Clarithromycin tablets + Omeprazole | 3% (1/40) | 0% (0/6) |
| Omeprazole | 0% (0/1) | 67% (29/43) |
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