PFIZER INC. Study Initiation Date and Primary Completion or Completion Dates: March 1991 to August 1991

Transcription

1 PFIZER INC. These results are supplied for informational purposes only. Prescribing decisions should be made based on the approved package insert. For publications based on this study, see associated bibliography. PROPRIETARY DRUG NAME /GENERIC DRUG NAME: Fasigyn /Tinidazole PROTOCOL NO.: TND-II PROTOCOL TITLE: A Randomized Assesser-blind, Parallel-group Comparison of Fasigyn DS Tablets (1 BD for 3 days) and Entamizole Forte Tablets (1 TID for 5 days) in Intestinal Amebiasis with Colonic symptoms. Study Centre: One centre in India Study Initiation Date and Primary Completion or Completion Dates: March 1991 to August 1991 Phase of Development: Phase 3 Study Objective(s): To compare the efficacy and tolerability of Fasigyn DS (1 tablet BD for 3 days) and of Entamizole (1 tablet TID for 5 days) in subjects with intestinal amebiasis and colonic symptoms. METHODS Study Design: This was a randomised, assessor-blind, parallel-group trial to compare the efficacy and tolerability of Fasigyn DS and Entamizole in subjects having colonic symptoms and Entamoeba histolytica (trophozoites, cysts, or both) in their stools. The study was carried out between March and August The subjects were required to make at least 3 visits. The first study visit was to collect information on subject history and symptoms, to examine the stools and for the subject to collect the study drug. The second visit (one week later) was for reporting compliance and adverse events (if any). The third visit (3 weeks later), was the final assessment of symptoms and stool examination. In all the visits, the microscopist was unaware of the treatment given to the subject. Number of Subjects (Planned and Analyzed): In total, 100 subjects were screened and enrolled in the study. Diagnosis and Main Criteria for Inclusion: The study included subjects of either sex, aged years, with intestinal amebiasis that was diagnosed by microscopic examination of stools by formol-ether concentration method for trophozoites, cysts, or both, of E histolytica, and symptoms referable to the colon. The subjects were not to have taken any amebicidal drug for at least one month before entering the trial and should not have had any history of irritable bowel syndrome (IBS), e.g. repeated episodes of colonic dysfunction with only mucus in stools, and with temporary relief of symptoms after a variety of specific and/or Page 1

2 nonspecific therapy. Subjects were also to have a high likelihood of returning for follow-up after 1 week and 4 weeks. Study Treatment: Overall, 50 subjects were given Fasigyn DS, 1 tablet twice daily for 3 days, after dinner, immediately after the first stool examination. Entamizole was given to the other 50 subjects at a dose of 1 tablet three times daily for 5 days, after meals, immediately after the first stool examination. Allocation of the subjects to the regimens was randomised in blocks of 10 subjects and recorded on each subject s form. Efficacy Evaluations: Primary Efficacy Evaluation: The primary efficacy endpoint was evaluated by stool examination at the third visit. The parasitic response was assessed as cure if the stool was negative for E histolytica and failure if it was positive. Secondary Efficacy Evaluation: The secondary efficacy endpoint was evaluated by assessing the symptomatic relief of the subjects. The clinical response was assessed as relieved or not relieved. Other Miscellaneous Efficacy Evaluation: Compliance was evaluated by assessing the number of subjects missing one or more tablets, and the number of tablets missed by the noncomplying subjects. Non-compliance and its extent were correlated with the parasitic response. Safety Evaluations: Safety was determined by the following assessments: Monitoring adverse events and their outcome. Severity and duration of adverse events, as well as their relationship to the study drug. Statistical Methods: Comparison between groups was done by means of student s t-test for measured variables and chi-square test for attributes. RESULTS Subject Disposition and Demography: In total, 100 subjects were screened and assigned study treatment. In total, 50 subjects received Fasigyn DS, 1 tablet twice daily for 3 days and another 50 subjects received Entamizole 1 tablet thrice daily for 5 days. One subject in the Entamizole group was excluded from the analysis when his symptoms returned on Day 12 after initial relief. The subject s stool was positive for E. histolytica. The subject took clioquinol tablets for 4 days. The subject s stool was negative for E. histolytica on Day 30; however, the subject was still excluded from the analysis so as not to confound the results. Demography characteristics are summarized in Table 1. Page 2

3 Table 1. Demographic Characteristics of the Subjects Characteristic Fasigyn (N=50) Entamizole (N=49) Sex Male Female Age (yr) Mean SEM Wt (Kg) Mean SEM N=Total number of subjects; Yr=Year; Wt=Weight; Kg=Kilogram; SEM=Standard error of mean. Prevalence of symptoms and parasites are summarized in Table 2 and Table 3, respectively. Pain in the abdomen was significantly more frequent in the Fasigyn group (100% vs 78%, p<0.01). All subjects had cysts of ameba in the stools, but trophozoites were not found. The other parasites present were A. lumricoides, hookworm and G. lamblia. The Fasigyn group had a significantly lower prevalence of A lumbricoides (32% vs 57%, p<0.01). Table 2. Prevalence of Symptoms Symptom Fasigyn (N=50) Entamizole (N=49) Pain in abdomen 50 (100%) 38 (78%) Diarrhea 33 (66%) 41 (84%) Constipation 41 (82%) 38 (78%) Mucus in stools 36 (72%) 39 (80%) Blood in stool 0 (0%) 3 (6%) Tenderness on liver 0 (0%) 5 (10%) p<0.05 for difference between groups. Table 3. Prevalence of Parasites in Stools Parasite Fasigyn (N=50) Entamizole (N=49) E. histolytica Trophozoites 0 0 Cysts 50 (100%) 49 (100%) A. lumbricoides* 16 (32%) 28 (57%) Hookworm 13 (26%) 12 (24%) G. lamblia 3 (6%) 6 (12%) p<0.01 for difference between groups. Efficacy Results: Primary Efficacy Endpoint: On Day 30, the stools of 46 subjects in the Fasigyn group were free from E. histolytica, which showed that the cure rate was 92% (46/50). In the Entamizole group, E. histolytica was absent from the stools of 38 subjects, which showed that the cure rate was 76% (38/50). The difference of 16% between the groups narrowly failed to reach significance (p=0.08). Analysis of the results in compliers revealed that Fasigyn cured 92% of subjects (46/50), whereas Entamizole cured 85% of subjects (33/39) (Table 4). Page 3

4 Table 4. Parasitic Cure Response Fasigyn Entamizole Cure 46/50 (92%) 38/49 (78%) Failure 4/50 (8%) 11/49 (22%) For difference between groups, p=0.08 In the Fasigyn group, 3 subjects who had giardiasis were cured. However, in the Entamizole group, 2/6 subjects who had giardiasis were cured. Secondary Efficacy Endpoint: The subjects showed symptomatic relief in both groups (Table 5). Relief of pain in the abdomen, constipation, and mucus in the stools was significantly higher in the Fasigyn group (p<0.05). Table 5. Symptomatic Relief Symptom Fasigyn (N=50) Entamizole (N=49) Pain in abdomen 46/50 (92%) 26/38 (68%) Diarrhea 33/33 (100%) 39/41 (95%) Constipation 38/41 (93%) 28/38 (74%) Mucus in stools 36/36 (100%) 30/39 (77%) p<0.05 and p<0.01 for difference between groups. N=total number of subjects Other Miscellaneous Efficacy Endpoint: In the Fasigyn group, subjects took all tablets as prescribed and thus compliance was 100%. In the Entamizole group, 10 subjects (20%) failed to take one or more tablets. The difference in compliance between the two groups was significant (p<0.01). The average number of missed tablets was 3.1 (range: 1 to 6), which represented 20% of the doses (range: 7% to 40%). Out of 10 subjects in the Entamizole group who failed to comply with the prescribed dosage regimen, 5 subjects were cured and 5 failed. Further analysis showed that the average number of tablets missed by those who failed was 4.2 (28% of doses), whereas the average number of tablets missed by those who cured was 2.0 (14% of doses), and the difference narrowly failed to reach significance (p=0.08). Safety Results: The safety results are summarized in Table 6. The most frequent adverse event during the study was altered taste (11 subjects [22%] in the Fasigyn group and 3 subjects [6%] in the Entamizole group). The difference between the treatment groups in the incidence of altered taste was not significant (p=0.08). No subjects in the Fasigyn group defaulted, probably because the treatment was over in just 3 days. Page 4

5 Table 6. Summary of Adverse Experiences Adverse Event Fasigyn (N=50) Entamizole (N=49) Altered taste 11 (22%) 3 (6%) Nausea 2 0 Headache 1 0 Gastritis 1 0 Constipation 0 1 Drowsiness 0 1 p=0.08 for difference between groups. CONCLUSION(S): In cyst-passing subjects of amebiasis with colonic symptoms, Fasigyn 1 g daily for 3 days was as effective as, but operationally more effective than, Entamizole 1 tablet three times daily for 5 days. While the Fasigyn regimen was conducive to good compliance, the Entamizole regimen predisposes to non-compliance to the extent of 20%, which was probably the reason for its lower use-effectiveness as revealed in this study. Page 5