A Phase 4 interventional study of Amoxicillin/clavulanate and Clindamycin in Focal Infection, Dental, sponsored by GlaxoSmithKline. Completed at 15 sites in 4 countries. Open to participants aged 18 Years to 75 Years. Per ClinicalTrials.gov, last updated 2017-09-25.
Sponsored by GlaxoSmithKline · Phase 4, Interventional, and Treatment
In clinical practice, amoxicillin + clavulanic acid is widely used in the treatment of odontogenic infection. Therefore, this study is designed to generate data to support its use by demonstrating efficacy, safety and tolerability in comparison with clindamycin in subjects with acute odontogenic infections with or without abscess. This will be a two-arm, parallel, comparative, observer blind, randomised study to assess efficacy, safety and tolerability of amoxicillin + clavulanic acid (875mg/125mg) in comparison with clindamycin (150mg) administered for 5-7 days in subjects with acute odontogenic infections with or without abscess. The study will be performed in adult subjects both male and female ≥18 years of age who present with acute odontogenic infections. A total of 472 subjects will be randomized in 1:1 ratio, i.e. 236 subjects in each treatment arm. The treatment duration of the study will be at least 5 days or maximum 7 days depending upon the treatment response. Subjects will be assessed on Day 5 and if Investigator feels the need of continuing the treatment at Day 5 then treatment will be continued till Day 7. For subjects who do not show treatment response on Day 5, assessments will be performed on Day 7.
This two-arm, parallel, comparative, observer blind, randomised study will be performed in adult subjects both male and female ≥18 years of age who present with acute odontogenic infection with or without abscess. A total of 472 subjects will be randomised in 1:1 ratio to get 205 evaluable subjects in each study arm. After obtaining informed consent, subject will undergo surgical intervention including surgical incisions, drainages, removal of the involved tooth, debridement, puncture lavage or trephination, if deemed necessary by the Investigator. These surgical interventions will be performed before the start of study treatment. On Day 0 after confirming the eligibility, subjects will be randomised to either of the study arms. The treatment duration of the study will be at least 5 days which may increase to 7 days, if Investigator feels the need of continuing the treatment at Day 5. In such cases clinical assessment will be done again at Day 7. Thus the efficacy evaluation will be performed at baseline (Day 0) prior to study drug administration and on Day 5 and/ or 7. Safety laboratory evaluations will be performed at Screening Visit and will be repeated at end of study treatment i.e. either on Day 5 or Day 7. On Baseline, Day 2, Day 5 and/ or Day 7, Visual Analogue Scale (VAS) will be used to measure amount of pain and swelling that a subject will experience. This scale has numerical ratings from 0 to 10. Zero would mean "No pain" and 10 would mean "Worst possible pain". The subject will be asked to choose the most appropriate score on VAS which best describes his/her pain status over last 24 hours. While using VAS for swelling, zero would mean "No swelling" and 10 would mean "Maximum possible swelling". The Investigator will choose the most appropriate score on VAS which best describes subject's swelling.
Sample for microbiological culture will be obtained at the discretion of Investigator while performing the surgical procedure. When microbiological culture is indicated and feasible, two sets (each consisting of aerobic and anaerobic media) will be obtained. This sampling will be done in approximately 80 subjects randomly who will provide consent at Screening. The sample will be collected and dispatched in appropriate transport medium to the central laboratory for culture and antibiotic susceptibility.
Protocol waivers or exemptions will not be allowed.
The total duration of each subject's participation will be 6-9 days including Screening period of 0-1 day (Day -1 to Day 0) and Treatment period of 5-7 days (Day 0 to Day 5-7).
The primary objective of the study is to compare clinical efficacy (cure and improvement) of both the treatment arms which uses VAS for assessment of pain and swelling. Since the clinical efficacy parameters are subjective, it is mandatory to keep the observer/Investigator blinded during the study assessment. In addition, designing blinded study is challenging owing to different dosage regimen and formulation of study drugs. The study design of double blind double dummy is not recommended in view of increased pill burden which in turn can have an impact on treatment compliance. The possibility of over-encapsulation is ruled out due to large pill size of amoxicillin + clavulanic acid. Therefore to maintain blinding of Investigators, the study is designed as observer blind with Investigator remaining blinded throughout the study period. An unblinded study team member will be appointed for each site who will be involved in dispensing of the study drugs to subjects. The unblinded study team member will remain present during subject assessment for all study visits and will ensure that Investigator remains blinded to treatment assignment.
Study treatment includes amoxicillin + clavulanic acid (875mg/125mg) two times daily or clindamycin (150mg) four times daily for 5-7 days both administered orally with meal. Augmentin™ (amoxicillin + clavulanic acid) from GSK and Dalacin-C (clindamycin) from Pfizer will be used as study treatments. The contents of the label will be in accordance with all applicable regulatory requirements.
Patients can receive additional medical therapy such as analgesics or anti-inflammatory drugs. However, opioid analgesics and any other antibiotic apart from study drugs will not be permitted during entire study period.
This study will be conducted in accordance with ICH GCP, all applicable subject privacy requirements, and the ethical principles that are outlined in the Declaration of Helsinki 2008, including IRB/ IEC review and approval of study protocol and any subsequent amendments, subject informed consent and Investigator reporting requirements.
6,687 studies on the registry are indexed under Infections; 807 are open to participants now.
This study's enrollment of 472 is above the median of 120 across 4,200 interventional studies indexed under Infections.
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Inclusion Criteria:
Inclusion Criterion:
Exclusion Criteria:
Amoxicillin/ clavulanate 1 g bd for for at least 5 days upto seven days depending on treament response
Drug: Amoxicillin/clavulanate
Clindamycin 150 mg qid for at least 5 days or maximum 7 days depending upon treatment response
Drug: Clindamycin
Amoxicillin/clavulanate 1 g bd for at least 5 days or maximum 7 days depending upon the treatment response.
Clindamycin 150 mg qid for at least 5 days or maximum 7 days depending upon the treatment response.
Percentage of Participants Achieving Clinical Success (Cure or Improvement) Considering Clinical Judgment of the Investigator at the End of Treatment (Day 5 or Day 7)
Clinical success is defined as the achievement of cure or improvement in signs and symptoms of odontogenic infections. Cure is defined as the complete resolution of signs and symptoms of infection present at baseline, such that no additional antimicrobial therapy is required. Improvement is defined as the resolution of fever (if present at baseline), \>70% reduction in swelling and pain and improvement in other signs and symptoms such that no additional antimicrobial therapy is required. Visual Analogue Scale (VAS) is used to measure the amount of pain and swelling that a participant experiences. This scale has numerical ratings from 0 to 10. Zero indicates no pain and 10 indicates worst possible pain.
Time frame: Day 5 or Day 7 [End of treatment]
Number of Participants Achieving Clinical Success (Cure or Improvement) Considering Clinical Judgment of the Investigator at Day 5
Clinical success is defined as the achievement of cure or improvement in signs and symptoms of odontogenic infections. Cure is defined as the complete resolution of signs and symptoms of infection present at baseline, such that no additional antimicrobial therapy is required. Improvement is defined as the resolution of fever (if present at baseline), \>70% reduction in swelling and pain and improvement in other signs and symptoms such that no additional antimicrobial therapy is required. Visual Analogue Scale (VAS) is used to measure the amount of pain and swelling that a participant experiences. This scale has numerical ratings from 0 to 10. Zero indicates no pain and 10 indicates worst possible pain.
Time frame: Day 5
Number of Participants (Par.) Achieving Clinical Success (CS) (Cure or Improvement [Imp] in Signs [s] and Symptoms [sx] [s/sx]) Without Considering Clinical (cl) Judgment (Jdg) of the Investigator (Inv) at Day 5
CS is defined as cure or imp in s/sx of odontogenic infections. Cure is defined as the complete resolution of s/sx of infection present at Baseline (BL) and imp is defined as resolution of fever (if present at BL), \>70% reduction in swelling and pain and imp in other s/sx such that no additional antimicrobial (ant) therapy is required. In event of cure or imp with complete resolution of fever and \>70% reduction in swelling and pain, but 'no change' or 'worsening from BL' in other s/sx (like increased leucocyte count/tooth mobility), the inv's opinion was sought on whether additional ant therapy was required. Par. that required no additional ant therapy were considered a 'success' while those requiring additional ant therapy were deemed a 'failure'. For a sensitivity analysis, all such par. with 'no change' or 'worsening from BL' in these other s/sx were considered as cl failures and termed 'Without Considering Cl Jdg of Inv', even though main s/sx are 'cured' or 'improved'. .
Time frame: Day 5
Change From Baseline in the Visual Analogue Scale Assessment of Pain Score at Days 2, 5 and 7
Visual Analogue Scale (VAS) is used to measure the amount of pain that the participant experiences. This scale has numerical ratings from 0 to 10. Zero indicates no pain and 10 indicates worst possible pain. Change in Pain/Swelling is calculated as VAS score at Baseline minus the score at a later time point (Day 2, 5 or 7).
Time frame: Baseline, Days 2, 5 and 7
Change From Baseline in Visual Analogue Scale Assessment of Swelling at Days 2, 5 and 7
Visual Analogue Scale (VAS) is used to measure the amount of swelling that the participant experiences. This scale has numerical ratings from 0 to 10. Zero indicates no swelling and 10 indicates worst possible swelling. Change in Pain/Swelling is calculated as VAS score at Baseline minus the score at a later time point (Day 2, 5 or 7).
Time frame: Baseline, Days 2, 5 and 7
A total of 510 participants (par.) were screened; 472 were randomized to receive one of the two study treatments. Of the 472 par.; 235 par. were randomized to the amoxicillin + clavulanic acid (amx+clv) arm and 237 par. to the clindamycin (clin) arm.
| Milestone | Amoxicillin 875 mg + Clavulanic Acid 125 mg | Clindamycin 150 mg |
|---|---|---|
| Started | 234 | 237 |
| Itt population-randomized treatment arm | 234 | 237 |
| Itt population-actual treatment received | 236 | 235 |
| Completed | 223 | 229 |
| Not completed | 11 | 8 |
| Withdrew: Adverse event | 1 | 2 |
| Withdrew: Protocol violation | 1 | 4 |
| Withdrew: Withdrawal by subject | 6 | 0 |
| Withdrew: Lost to follow-up | 1 | 1 |
| Withdrew: Physician decision | 1 | 0 |
| Withdrew: Surgical intervention | 1 | 1 |
Clinical success is defined as the achievement of cure or improvement in signs and symptoms of odontogenic infections. Cure is defined as the complete resolution of signs and symptoms of infection present at baseline, such that no additional antimicrobial therapy is required. Improvement is defined as the resolution of fever (if present at baseline), \>70% reduction in swelling and pain and improvement in other signs and symptoms such that no additional antimicrobial therapy is required. Visual Analogue Scale (VAS) is used to measure the amount of pain and swelling that a participant experiences. This scale has numerical ratings from 0 to 10. Zero indicates no pain and 10 indicates worst possible pain.
| Percentage of participants | Amoxicillin 875 mg + Clavulanic Acid 125 mg | Clindamycin 150 mg |
|---|---|---|
| Percentage of Participants Achieving Clinical Success (Cure or Improvement) Considering Clinical Judgment of the Investigator at the End of Treatment (Day 5 or Day 7) | 88.2 | 89.7 |
Clinical success is defined as the achievement of cure or improvement in signs and symptoms of odontogenic infections. Cure is defined as the complete resolution of signs and symptoms of infection present at baseline, such that no additional antimicrobial therapy is required. Improvement is defined as the resolution of fever (if present at baseline), \>70% reduction in swelling and pain and improvement in other signs and symptoms such that no additional antimicrobial therapy is required. Visual Analogue Scale (VAS) is used to measure the amount of pain and swelling that a participant experiences. This scale has numerical ratings from 0 to 10. Zero indicates no pain and 10 indicates worst possible pain.
| Percentage of participants | Amoxicillin 875 mg + Clavulanic Acid 125 mg | Clindamycin 150 mg |
|---|---|---|
| Percentage of Participants Achieving Clinical Success (Cure or Improvement) Considering Clinical Judgment of the Investigator at the End of Treatment (Day 5 or Day 7) | 85.5 | 86.4 |
Clinical success is defined as the achievement of cure or improvement in signs and symptoms of odontogenic infections. Cure is defined as the complete resolution of signs and symptoms of infection present at baseline, such that no additional antimicrobial therapy is required. Improvement is defined as the resolution of fever (if present at baseline), \>70% reduction in swelling and pain and improvement in other signs and symptoms such that no additional antimicrobial therapy is required. Visual Analogue Scale (VAS) is used to measure the amount of pain and swelling that a participant experiences. This scale has numerical ratings from 0 to 10. Zero indicates no pain and 10 indicates worst possible pain.
| Percentage of participants | Amoxicillin 875 mg + Clavulanic Acid 125 mg | Clindamycin 150 mg |
|---|---|---|
| Percentage of Participants Achieving Clinical Success (Cure or Improvement) Considering Clinical Judgment of the Investigator at the End of Treatment (Day 5 or Day 7) | 83.3 | 85.7 |
Clinical success is defined as the achievement of cure or improvement in signs and symptoms of odontogenic infections. Cure is defined as the complete resolution of signs and symptoms of infection present at baseline, such that no additional antimicrobial therapy is required. Improvement is defined as the resolution of fever (if present at baseline), \>70% reduction in swelling and pain and improvement in other signs and symptoms such that no additional antimicrobial therapy is required. Visual Analogue Scale (VAS) is used to measure the amount of pain and swelling that a participant experiences. This scale has numerical ratings from 0 to 10. Zero indicates no pain and 10 indicates worst possible pain.
| Participants | Amoxicillin 875 mg + Clavulanic Acid 125 mg | Clindamycin 150 mg |
|---|---|---|
| Number of Participants Achieving Clinical Success (Cure or Improvement) Considering Clinical Judgment of the Investigator at Day 5 | 169 | 159 |
CS is defined as cure or imp in s/sx of odontogenic infections. Cure is defined as the complete resolution of s/sx of infection present at Baseline (BL) and imp is defined as resolution of fever (if present at BL), \>70% reduction in swelling and pain and imp in other s/sx such that no additional antimicrobial (ant) therapy is required. In event of cure or imp with complete resolution of fever and \>70% reduction in swelling and pain, but 'no change' or 'worsening from BL' in other s/sx (like increased leucocyte count/tooth mobility), the inv's opinion was sought on whether additional ant therapy was required. Par. that required no additional ant therapy were considered a 'success' while those requiring additional ant therapy were deemed a 'failure'. For a sensitivity analysis, all such par. with 'no change' or 'worsening from BL' in these other s/sx were considered as cl failures and termed 'Without Considering Cl Jdg of Inv', even though main s/sx are 'cured' or 'improved'. .
| Participants | Amoxicillin 875 mg + Clavulanic Acid 125 mg | Clindamycin 150 mg |
|---|---|---|
| Number of Participants (Par.) Achieving Clinical Success (CS) (Cure or Improvement [Imp] in Signs [s] and Symptoms [sx] [s/sx]) Without Considering Clinical (cl) Judgment (Jdg) of the Investigator (Inv) at Day 5 | 158 | 150 |
Visual Analogue Scale (VAS) is used to measure the amount of pain that the participant experiences. This scale has numerical ratings from 0 to 10. Zero indicates no pain and 10 indicates worst possible pain. Change in Pain/Swelling is calculated as VAS score at Baseline minus the score at a later time point (Day 2, 5 or 7).
| Scores on a scale | Amoxicillin 875 mg + Clavulanic Acid 125 mg | Clindamycin 150 mg |
|---|---|---|
| Day 2, n=227, 233 | 3.34 (3.08 to 3.61) | 3.07 (2.81 to 3.33) |
| Day 5, n=219, 228 | 5.49 (5.27 to 5.71) | 5.38 (5.16 to 5.60) |
| Day 7, n=57, 71 | 6.38 (6.02 to 6.74) | 6.34 (6.02 to 6.66) |
Visual Analogue Scale (VAS) is used to measure the amount of swelling that the participant experiences. This scale has numerical ratings from 0 to 10. Zero indicates no swelling and 10 indicates worst possible swelling. Change in Pain/Swelling is calculated as VAS score at Baseline minus the score at a later time point (Day 2, 5 or 7).
| Scores on a scale | Amoxicillin 875 mg + Clavulanic Acid 125 mg | Clindamycin 150 mg |
|---|---|---|
| Day 2, n=219, 225 | 1.92 (1.72 to 2.11) | 1.61 (1.42 to 1.80) |
| Day 5, n=214, 223 | 3.68 (3.51 to 3.85) | 3.60 (3.43 to 3.76) |
| Day 7, n=55, 68 | 4.21 (3.94 to 4.49) | 4.61 (4.36 to 4.86) |
Collected over Serious adverse events (SAEs) and non-serious AEs were collected from the Baseline (Day 0) until the last dose of study drug (Day 7) or early withdrawal (average of Day 5.88).. Non-serious events are listed at a 3% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Amoxicillin 875 mg + Clavulanic Acid 125 mg | — | 0/236 (0%) | 99/236 (41.9%) |
| Clindamycin 150 mg | — | 0/235 (0%) | 93/235 (39.6%) |
| Event | Amoxicillin 875 mg + Clavulanic Acid 125 mg | Clindamycin 150 mg |
|---|---|---|
| DiarrhoeaGastrointestinal disorders | 19/236 | 28/235 |
| Alanine aminotransferase increasedInvestigations | 26/236 | 24/235 |
| Aspartate aminotransferase increasedInvestigations | 24/236 | 20/235 |
| Increased appetiteMetabolism and nutrition disorders | 20/236 | 15/235 |
| SomnolenceNervous system disorders | 19/236 | 17/235 |
| DizzinessNervous system disorders | 18/236 | 14/235 |
| HeadacheNervous system disorders | 8/236 | 14/235 |
| Blood bilirubin increasedInvestigations | 12/236 | 13/235 |
| Abdominal discomfortGastrointestinal disorders | 11/236 | 7/235 |
| Aspartate aminotransferase decreasedInvestigations | 8/236 | 2/235 |
| Age, Continuous(Years) | Amoxicillin 875 mg + Clavulanic Acid 125 mg | Clindamycin 150 mg | Total |
|---|---|---|---|
| Mean | 33.1 ± 12.8 | 32.6 ± 12.0 | 32.9 ± 12.4 |
| Sex: Female, Male(Participants) | Amoxicillin 875 mg + Clavulanic Acid 125 mg | Clindamycin 150 mg | Total |
|---|---|---|---|
| Female | 135 | 143 | 278 |
| Male | 99 | 94 | 193 |
| Race/Ethnicity, Customized(Participants) | Amoxicillin 875 mg + Clavulanic Acid 125 mg | Clindamycin 150 mg | Total |
|---|---|---|---|
| Asian-Central/South Asian Heritage | 0 | 1 | 1 |
| Asian-East Asian Heritage | 1 | 4 | 5 |
| Asian-South East Asian Heritage | 233 | 232 | 465 |
Plan to share: Yes — Patient-level data for this study will be made available through www.clinicalstudydatarequest.com following the timelines and process described on this site.
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