Pelvic Inflammatory Disease
Conditions
Keywords
PID, Pelvic Inflammatory Disease
Brief summary
This study is a randomized placebo-controlled trial comparing two antibiotic treatment regimens for acute PID. Women with acute PID will be randomized to one of two treatment regimens: 1) a single intramuscular dose of ceftriaxone 250 mg, doxycycline 100 mg orally twice a day for 14 days, along with placebo tablets orally twice a day for 14 days or 2) same doses of ceftriaxone and doxycycline, and metronidazole 500 mg orally twice a day for 14 days. The primary objective is to compare the eradication of anaerobic organisms from the upper genital tract between women who receive standard outpatient antibiotic treatment to those who receive standard outpatient treatment along with a two-week course of metronidazole.
Detailed description
This study is a randomized placebo-controlled trial comparing two antibiotic treatment regimens for acute PID. Women with acute PID will be randomized to one of two treatment regimens. One group of women will receive a single intramuscular dose of ceftriaxone 250 mg, doxycycline 100 mg orally twice a day for 14 days, along with placebo tablets orally twice a day for 14 days. The second group of women will receive the same doses of ceftriaxone and doxycycline, and metronidazole 500 mg orally twice a day for 14 days. The primary objective is to compare the eradication of anaerobic organisms from the upper genital tract in women with acute PID who receive standard outpatient antibiotic treatment to the eradication of these organisms from the upper genital tract in women who receive standard outpatient treatment along with a two-week course of metronidazole. Women will be followed for one month for clinical outcomes, and will undergo assessment for clearance of microorganisms from the upper genital tract. Our hypothesis is that an antibiotic treatment regimen that includes anaerobic coverage will more effectively clear anaerobic organisms from the endometrium in women with acute PID compared to a standard antibiotic treatment regimen lacking effective antibiotic coverage against anaerobes.
Interventions
DRUGCeftriaxone
ceftrixone 250mg IM single dose
DRUGDoxycycline
Doxycycline 100 mg PO bid x 14 days
DRUGMetronidazole
metronidazole 500 mg PO bid x 14 days
DRUGPlacebo Oral Capsule
placebo oral capsule PO bid x 14 days
Sponsors
National Institute of Allergy and Infectious Diseases (NIAID)
Harold Wiesenfeld
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
15 Years to 40 Years
Healthy volunteers
No
Inclusion criteria
Women must meet all of the following inclusion criteria: 1. Age 15-40 at the time of enrollment (Note: Participants between the ages of 15-17 will require written informed consent from parent/legal guardian. Written assent will also be obtained from the minor) 2. Acute PID, defined by symptoms and signs guided by current CDC guidelines:50 1. Current symptoms of lower abdominal or pelvic pain (present for ≤30 days) AND 2. Cervical motion tenderness AND/OR uterine tenderness AND/OR adnexal tenderness on pelvic examination 3. Ability to provide written informed consent
Exclusion criteria
Women with any of the following will be ineligible to participate: 1. Pregnant or nursing a baby (Note: a urine pregnancy test will be done at enrollment. Result must be negative to participate in the study.) 2. Uterine procedure (e.g. dilation and curettage, abortion) or miscarriage within the past 6 weeks. 3. Allergy to any of the study medications (cephalosporins, doxycycline, or metronidazole) or Type 1 hypersensitivity allergic reaction to penicillin for those with unknown tolerance to cephalosporins. 4. Systemic or vaginal antibiotic therapy in the preceding 7 days 5. Requires inpatient PID therapy (per the current CDC guidelines)50 6. Inability to obtain an endometrial biopsy at enrollment 7. Known inability to comply with the follow-up visits 8. Prior hysterectomy 9. Menopause (including natural menopause defined as lack of menses for 12 consecutive months \[in the absence of pregnancy\] and surgical menopause defined as a woman who has had both ovaries removed) 10. Inability to swallow pills 11. Not willing to refrain from alcohol during the two week treatment period (and two additional days following completion of study medication) 12. Other condition present at enrollment that requires additional antibiotic treatment 13. Current use of any of the following medications: * Anticoagulants, coumarin- or indandione-derivative: warfarin * cimetidine (Tagamet) * Disulfiram * Seizure medications including: phenytoin (Dilantin), carbamezapine (Tegretol), barbiturates (i.e. Phenobarbital) * Lithium * Immunosuppressive drugs including: cyclosporine, amprenavir * Antacids, minerals or bismuth subsalicylate (Pepto Bismol) 14. Any condition, in the opinion of the investigator that would interfere with the participant's safety or with study outcomes 15. Participation in any study involving an investigational product in the past 30 days or anticipation of participation in any study using an investigational product in the next 30 days 16. Previous participation in this study 17. Evidence of a tuboovarian abscess
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Clearance of Anaerobic Organisms From the Endometrium | Enrollment to 30 days | Clearance of anaerobic microorganisms from the endometrium at the 30 day follow-up visit among women who had anaerobic microorganisms detected in their endometrial tissue sample at enrollment. Clearance is defined as no anaerobic microorganisms detected in the endometrial tissue biopsy sample collected at the 30-day visit. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Prevalence of M. Genitalium in the Cervix and Endometrium From Women With Acute PID. | enrollment | The number of women who had M. genitalium detected in cervical and endometrial biopsy cultures by nucleic acid amplification tests at enrollment. |
| The Eradication of M. Genitalium From the Lower and Upper Genital Tract Following Antibiotic Therapy for Acute PID. | Enrollment to 30 days | M. genitalium not detected in the cervical and endometrial cultures by nucleic acid amplification testing at the 30 day visit among women who had M. genitalium detected at either anatomical site at the enrollment visit. |
| Resolution of Clinical Signs and Symptoms of Acute PID - Intention to Treat Analysis | Enrollment to 3 day follow up visit | Clinical response to treatment is improvement (reduction) of the McCormack Scale total score from baseline to day 3 follow-up visit. Participants without a 3-day measure were considered treatment failures. |
| Identification of Endometrial Microorganisms Present Obtained From Women With or Without Evidence of Endometritis. | enrollment | Identification of endometrial microorganisms present obtained from women with or without evidence of endometritis using a combination of culture methods, rRna sequencing and whole genomic sequencing. The aim is to identify the etiology of endometritis. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Ceftriaxone, Doxycycline, Placebo ceftrixone 250mg IM single dose plus doxycycline 100 mg PO bid x 14 days plus placebo PO bid x 14 days
ceftriaxone, doxycycline, placebo: ceftrixone 250mg IM single dose plus doxycycline 100 mg PO bid x 14 days plus placebo PO bid x 14 days | 117 |
| Ceftriaxone, Doxycycline, Metronidazole ceftriaxone 250 mg IM single dose plus doxycycline 100 mg PO bid x 14 days plus metronidazole 500 mg PO bid x 14 days
ceftriaxone, doxycycline, metronidazole: ceftriaxone 250 mg IM single dose plus doxycycline 100 mg PO bid x 14 days plus metronidazole 500 mg PO bid x 14 days | 116 |
| Total | 233 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Incarceration | 1 | 0 |
| Overall Study | Physician Decision | 3 | 3 |
| Overall Study | Withdrawal by Subject | 0 | 3 |
Baseline characteristics
| Characteristic | Ceftriaxone, Doxycycline, Placebo | Total | Ceftriaxone, Doxycycline, Metronidazole |
|---|---|---|---|
| Age, Continuous | 23.2 years STANDARD_DEVIATION 4.3 | 24.0 years STANDARD_DEVIATION 4.8 | 24.7 years STANDARD_DEVIATION 5.1 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 11 Participants | 22 Participants | 11 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 106 Participants | 211 Participants | 105 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 76 Participants | 144 Participants | 68 Participants |
| Race (NIH/OMB) More than one race | 10 Participants | 19 Participants | 9 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 4 Participants | 2 Participants |
| Race (NIH/OMB) White | 28 Participants | 63 Participants | 35 Participants |
| Region of Enrollment United States | 117 participants | 233 participants | 116 participants |
| Sex: Female, Male Female | 117 Participants | 233 Participants | 116 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 94 / 117 | 104 / 116 |
| serious Total, serious adverse events | 5 / 117 | 7 / 116 |
Outcome results
Primary
Clearance of Anaerobic Organisms From the Endometrium
Clearance of anaerobic microorganisms from the endometrium at the 30 day follow-up visit among women who had anaerobic microorganisms detected in their endometrial tissue sample at enrollment. Clearance is defined as no anaerobic microorganisms detected in the endometrial tissue biopsy sample collected at the 30-day visit.
Time frame: Enrollment to 30 days
Population: Women who had anaerobic microorganisms detected in their endometrial biopsy sample at enrollment based on standard bacterial culture techniques.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ceftriaxone, Doxycycline, Placebo | Clearance of Anaerobic Organisms From the Endometrium | Clearance of anaerobes | 14 participants |
| Ceftriaxone, Doxycycline, Placebo | Clearance of Anaerobic Organisms From the Endometrium | Anaerobes detected | 7 participants |
| Ceftriaxone, Doxycycline, Metronidazole | Clearance of Anaerobic Organisms From the Endometrium | Clearance of anaerobes | 18 participants |
| Ceftriaxone, Doxycycline, Metronidazole | Clearance of Anaerobic Organisms From the Endometrium | Anaerobes detected | 1 participants |
p-value: 0.046Fisher Exact
Secondary
Identification of Endometrial Microorganisms Present Obtained From Women With or Without Evidence of Endometritis.
Identification of endometrial microorganisms present obtained from women with or without evidence of endometritis using a combination of culture methods, rRna sequencing and whole genomic sequencing. The aim is to identify the etiology of endometritis.
Time frame: enrollment
Population: Women who had an endometrial sample that was sufficient for histologic assessment for endometritis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ceftriaxone, Doxycycline, Placebo | Identification of Endometrial Microorganisms Present Obtained From Women With or Without Evidence of Endometritis. | Neisseria gonorrhoeae | 8 participants |
| Ceftriaxone, Doxycycline, Placebo | Identification of Endometrial Microorganisms Present Obtained From Women With or Without Evidence of Endometritis. | Atopobium vaginae | 7 participants |
| Ceftriaxone, Doxycycline, Placebo | Identification of Endometrial Microorganisms Present Obtained From Women With or Without Evidence of Endometritis. | Haemophilus influenzae | 5 participants |
| Ceftriaxone, Doxycycline, Placebo | Identification of Endometrial Microorganisms Present Obtained From Women With or Without Evidence of Endometritis. | Anaerobic gram negative rods | 8 participants |
| Ceftriaxone, Doxycycline, Placebo | Identification of Endometrial Microorganisms Present Obtained From Women With or Without Evidence of Endometritis. | Mycoplasma genitalium | 12 participants |
| Ceftriaxone, Doxycycline, Placebo | Identification of Endometrial Microorganisms Present Obtained From Women With or Without Evidence of Endometritis. | Anaerobic gram positive cocci | 10 participants |
| Ceftriaxone, Doxycycline, Placebo | Identification of Endometrial Microorganisms Present Obtained From Women With or Without Evidence of Endometritis. | Gardnerella vaginalis | 22 participants |
| Ceftriaxone, Doxycycline, Placebo | Identification of Endometrial Microorganisms Present Obtained From Women With or Without Evidence of Endometritis. | Anaerobic gram positive rods | 4 participants |
| Ceftriaxone, Doxycycline, Placebo | Identification of Endometrial Microorganisms Present Obtained From Women With or Without Evidence of Endometritis. | Chlamydia trachomatis | 17 participants |
| Ceftriaxone, Doxycycline, Metronidazole | Identification of Endometrial Microorganisms Present Obtained From Women With or Without Evidence of Endometritis. | Anaerobic gram positive rods | 11 participants |
| Ceftriaxone, Doxycycline, Metronidazole | Identification of Endometrial Microorganisms Present Obtained From Women With or Without Evidence of Endometritis. | Chlamydia trachomatis | 5 participants |
| Ceftriaxone, Doxycycline, Metronidazole | Identification of Endometrial Microorganisms Present Obtained From Women With or Without Evidence of Endometritis. | Neisseria gonorrhoeae | 2 participants |
| Ceftriaxone, Doxycycline, Metronidazole | Identification of Endometrial Microorganisms Present Obtained From Women With or Without Evidence of Endometritis. | Mycoplasma genitalium | 5 participants |
| Ceftriaxone, Doxycycline, Metronidazole | Identification of Endometrial Microorganisms Present Obtained From Women With or Without Evidence of Endometritis. | Haemophilus influenzae | 1 participants |
| Ceftriaxone, Doxycycline, Metronidazole | Identification of Endometrial Microorganisms Present Obtained From Women With or Without Evidence of Endometritis. | Gardnerella vaginalis | 25 participants |
| Ceftriaxone, Doxycycline, Metronidazole | Identification of Endometrial Microorganisms Present Obtained From Women With or Without Evidence of Endometritis. | Atopobium vaginae | 13 participants |
| Ceftriaxone, Doxycycline, Metronidazole | Identification of Endometrial Microorganisms Present Obtained From Women With or Without Evidence of Endometritis. | Anaerobic gram negative rods | 8 participants |
| Ceftriaxone, Doxycycline, Metronidazole | Identification of Endometrial Microorganisms Present Obtained From Women With or Without Evidence of Endometritis. | Anaerobic gram positive cocci | 11 participants |
Secondary
Resolution of Clinical Signs and Symptoms of Acute PID - Intention to Treat Analysis
Clinical response to treatment is improvement (reduction) of the McCormack Scale total score from baseline to day 3 follow-up visit. Participants without a 3-day measure were considered treatment failures.
Time frame: Enrollment to 3 day follow up visit
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ceftriaxone, Doxycycline, Placebo | Resolution of Clinical Signs and Symptoms of Acute PID - Intention to Treat Analysis | Clinical response | 94 participants |
| Ceftriaxone, Doxycycline, Placebo | Resolution of Clinical Signs and Symptoms of Acute PID - Intention to Treat Analysis | No response | 23 participants |
| Ceftriaxone, Doxycycline, Metronidazole | Resolution of Clinical Signs and Symptoms of Acute PID - Intention to Treat Analysis | Clinical response | 96 participants |
| Ceftriaxone, Doxycycline, Metronidazole | Resolution of Clinical Signs and Symptoms of Acute PID - Intention to Treat Analysis | No response | 20 participants |
p-value: 0.74Fisher Exact
Secondary
The Eradication of M. Genitalium From the Lower and Upper Genital Tract Following Antibiotic Therapy for Acute PID.
M. genitalium not detected in the cervical and endometrial cultures by nucleic acid amplification testing at the 30 day visit among women who had M. genitalium detected at either anatomical site at the enrollment visit.
Time frame: Enrollment to 30 days
Population: There were 34 women who had M. genitalium detected in the cervix or endometrium at enrollment who had test results from the 30-day visit.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ceftriaxone, Doxycycline, Placebo | The Eradication of M. Genitalium From the Lower and Upper Genital Tract Following Antibiotic Therapy for Acute PID. | Not detected in cervix & endometrium | 8 participants |
| Ceftriaxone, Doxycycline, Placebo | The Eradication of M. Genitalium From the Lower and Upper Genital Tract Following Antibiotic Therapy for Acute PID. | Detected in cervix or endometrium | 13 participants |
| Ceftriaxone, Doxycycline, Metronidazole | The Eradication of M. Genitalium From the Lower and Upper Genital Tract Following Antibiotic Therapy for Acute PID. | Not detected in cervix & endometrium | 9 participants |
| Ceftriaxone, Doxycycline, Metronidazole | The Eradication of M. Genitalium From the Lower and Upper Genital Tract Following Antibiotic Therapy for Acute PID. | Detected in cervix or endometrium | 4 participants |
p-value: 0.16Fisher Exact
Secondary
The Prevalence of M. Genitalium in the Cervix and Endometrium From Women With Acute PID.
The number of women who had M. genitalium detected in cervical and endometrial biopsy cultures by nucleic acid amplification tests at enrollment.
Time frame: enrollment
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ceftriaxone, Doxycycline, Placebo | The Prevalence of M. Genitalium in the Cervix and Endometrium From Women With Acute PID. | Detected in cervix only | 16 participants |
| Ceftriaxone, Doxycycline, Placebo | The Prevalence of M. Genitalium in the Cervix and Endometrium From Women With Acute PID. | Detected in cervix and endometrium | 8 participants |
| Ceftriaxone, Doxycycline, Placebo | The Prevalence of M. Genitalium in the Cervix and Endometrium From Women With Acute PID. | Detected in endometrium only | 3 participants |
| Ceftriaxone, Doxycycline, Placebo | The Prevalence of M. Genitalium in the Cervix and Endometrium From Women With Acute PID. | Not detected in cervix and endometrium | 90 participants |
| Ceftriaxone, Doxycycline, Metronidazole | The Prevalence of M. Genitalium in the Cervix and Endometrium From Women With Acute PID. | Not detected in cervix and endometrium | 97 participants |
| Ceftriaxone, Doxycycline, Metronidazole | The Prevalence of M. Genitalium in the Cervix and Endometrium From Women With Acute PID. | Detected in cervix only | 12 participants |
| Ceftriaxone, Doxycycline, Metronidazole | The Prevalence of M. Genitalium in the Cervix and Endometrium From Women With Acute PID. | Detected in endometrium only | 2 participants |
| Ceftriaxone, Doxycycline, Metronidazole | The Prevalence of M. Genitalium in the Cervix and Endometrium From Women With Acute PID. | Detected in cervix and endometrium | 5 participants |