Treatment of Gardnerella Vaginalis Vaginal Colonization With Amoxicillin

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT03211156
• Collaborator: (none)
• Enrollment: 97
• Locations: 2
• Arms: 2
• Actual Duration (Months): 23.3
• Patients Per Site: 48.5
• Patients Per Site Per Month: 2.1

Study Details

Study Description

Brief Summary

This is a randomized, double-blind, placebo-controlled Phase 2 study designed to determine if amoxicillin will eradicate vaginal colonization/infection with Gardnerella vaginalis (GV) when administered to women who are colonized/infected with GV but have no clinical evidence of Bacterial Vaginosis (BV). The study will be conducted at 2 clinics in the United States: University of Alabama at Birmingham and Wake Forest University Health Sciences. Entire study duration is approximately 24 months and subject participation duration is approximately 22 days. Approximately 245 healthy adult females, 18 to 45 years of age will be screened to enroll approximately 98 participants to achieve 82 evaluable participants at the test of cure (ToC) visit. Participants will be enrolled and randomized to one of two groups, either amoxicillin (2 x 250 mg capsules by mouth twice daily for 7 days) or placebo. Women who are enrolled will be asked to return for one further visit, Visit 2 (Day 15 - 21), where a ToC will be completed. For those not enrolled, participation will end at their post screening follow up phone call. Women will be asked to use condoms during their participation. The primary objective is to determine if treatment with amoxicillin eradicates GV in women who are colonized/infected with GV but have no clinical evidence of BV.

Condition or Disease	Intervention/Treatment	Phase
Vaginitis Gardnerella	Drug: Amoxicillin; Other: Placebo	Phase 2

Detailed Description

This is a randomized, double-blind, placebo-controlled Phase 2 study designed to determine if amoxicillin will eradicate vaginal colonization/infection with Gardnerella vaginalis (GV) when administered to women who are colonized/infected with GV but have no clinical evidence of Bacterial Vaginosis (BV). The study will be conducted at 2 clinics in the United States: University of Alabama at Birmingham and Wake Forest University Health Sciences. Entire study duration is approximately 24 months and subject participation duration is approximately 22 days. Approximately 245 healthy adult females, 18 to 45 years of age will be screened to enroll approximately 98 participants to achieve 82 evaluable participants at the test of cure (ToC) visit. Women who consent to screening participation will undergo pelvic examination on entry and vaginal specimens collected for pH, whiff test and wet prep microscopy (Amsel criteria with the exception of evaluation of vaginal discharge), Nugent score, nucleic acid amplification test (NAAT) for trichomonas, quantitative NAAT for GV, and microbiome analysis. At Visit 1 (Enrollment - Day 1), women who tested positive for GV by NAAT, negative for BV by Nugent, and negative for trichomonas by NAAT will be enrolled and randomized to one of two groups, either amoxicillin (2 x 250 mg capsules by mouth twice daily for 7 days) or placebo. Women who are enrolled will be asked to return for one further visit, Visit 2 (Day 15 - 21), where a ToC will be completed (a pelvic exam completed with the same specimens taken as those at baseline with the exception of the trichomonas NAAT). For those not enrolled, participation will end at their post screening follow up phone call. Women will be asked to use condoms during their participation. The primary objective is to determine if treatment with amoxicillin eradicates GV in women who are colonized/infected with GV but have no clinical evidence of BV. The secondary objective is to evaluate the safety and tolerability of amoxicillin compared to placebo.

Study Design

• Study Type: Interventional
• Actual Enrollment: 97 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-Blind, Placebo Controlled, Phase 2 Study to Assess Treatment of Gardnerella Vaginalis Vaginal Colonization With Amoxicillin
• Actual Study Start Date: Sep 11, 2017
• Actual Primary Completion Date: Aug 22, 2019
• Actual Study Completion Date: Aug 22, 2019

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo arm Placebo 2 capsules PO twice a day for 7 days, n=49	Other: Placebo; Placebo
Experimental: Treatment arm Amoxicillin 2 x 250 mg capsules PO twice a day for 7 days, n=49	Drug: Amoxicillin; Amoxicillin is an aminopenicillin antibiotic

Outcome Measures

Primary Outcome Measures

1. The Proportion of Participants With Eradication of Gardnerella Vaginalis (GV) in Each Study Arm at Visit 2 (Day 15-21) as Assessed by Nucleic Acid Amplification Test (NAAT). [Day 15 to 21]

   Eradication of GV is defined by a negative NAAT result for GV at Visit 2. Participants who have a missing GV NAAT result at the test of cure (TOC) visit were classified as treatment failures. The denominator for proportions is based on the number of subjects who were randomized to the specified treatment group.

Secondary Outcome Measures

1. The Proportion of Participants Reporting Related Adverse Events (AEs and SAEs) in Each Study Arm Following the First Dose of Study Product Through Visit 2. [Day 1 through Day 15 to 21]

   AEs were defined as any untoward medical occurrence in a participant administered a pharmaceutical product. SAEs included any untoward medical occurrence that resulted in death; was life threatening; was a persistent/significant disability/incapacity; required inpatient hospitalization or prolongation or a congenital anomaly/birth defect. AEs and SAEs were collected from participants following the first dose of treatment through Visit 2 (Day 15-21). Events are included if deemed by the investigator to be related to the study product.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 45 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

1. Women ages 18-45, inclusive.

2. No evidence of vaginitis (yeast, trichomonas, and BV/abnormal vaginal flora) or other vaginal conditions which in the opinion of the investigator could be confounders*.

*These causes will initially be detected by wet mount microscopy with trichomonas during the screening procedures and later confirmed by NAAT and BV/abnormal vaginal flora confirmed by Nugent scoring (Nugent score of 4-10).

1. Presence of GV detected by NAAT*.

*Results of NAAT testing will be available prior to return for Enrollment visit.

1. Willing to use condoms during vaginal intercourse while participating in the study.

2. Not currently menstruating at screening visit.

3. Willing and able to provide written informed consent.

4. Negative urine pregnancy test on all participants of childbearing potential at study screening.

5. Participant must be of non-childbearing potential* or must be using highly effective birth control** to avoid becoming pregnant.

*Non-childbearing potential is defined as being post-menopausal for at least 1 year, status after bilateral tubal ligation, or status after bilateral oophorectomy or status after hysterectomy.

**In addition to the required use of condoms by the male partner during study participation, participants must agree to avoid becoming pregnant by using one of the following acceptable method of birth control for 30 days prior to screening and for the duration of the study:

• Intrauterine contraceptive device; OR

• Oral contraceptives; OR

• Hormonal injections; OR

• Hormonal implants; OR

• Contraceptive patches; OR

• Monogamous relationship with vasectomized partner; OR

• Exclusively same-sex relationships; OR

• Abstinence

1. Participant is not planning on taking antibiotics or using any intravaginal microbicides from the Screening visit through the Visit 2 Follow-up (TOC).

2. Participant is willing and able to cooperate to the extent and degree required by this protocol at the discretion of the investigator.

Exclusion Criteria:

1. Pregnant or nursing.

2. Allergic to penicillin, amoxicillin, cephalosporins, or other ß-lactam antibiotic.

3. Use of antibiotics in the past 14 days prior to screening visit.

4. HIV infected.

5. Women taking immunosuppressive agents.

6. History of renal impairment. 8. Use of any investigational drug within the past 30 days prior to screening. 9. Any other condition that, in the opinion of the investigator, would interfere with participation in the study.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama at Birmingham School of Medicine - Infectious Disease	Birmingham	Alabama	United States	35205
2	Guilford County Health Department - Greensboro - STD Clinic	Winston-Salem	North Carolina	United States	27157

Sponsors and Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID)

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - May 23, 2019
• Statistical Analysis Plan - Feb 27, 2019

More Information

Publications

None provided.

• Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
• ClinicalTrials.gov Identifier: NCT03211156
• Other Study ID Numbers: 16-0073
• First Posted: Jul 7, 2017
• Last Update Posted: Aug 28, 2020
• Last Verified: Jun 28, 2017

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No
• Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID): Amoxicillin; Gardnerella vaginalis; Vaginal Colonization
• Additional relevant MeSH terms: Vaginosis, Bacterial; Vaginitis; Amoxicillin

Study Results

Participant Flow

Recruitment Details	Participants were recruited from women who were colonized/infected with Gardnerella vaginalis but have no clinical evidence of Bacterial Vaginosis. Enrollment occurred between 21SEP2017 and 08AUG2019.

Arm/Group Title	Placebo	Amoxicillin
Arm/Group Description	Participants received Amoxicillin placebo 2 capsules orally twice a day for 7 days, n=49 Placebo: Placebo	Participants received Amoxicillin 2 x 250 mg capsules orally twice a day for 7 days, n=48 Amoxicillin: Amoxicillin is an aminopenicillin antibiotic
Period Title: Overall Study
STARTED	49	48
Received Study Drug	47	45
COMPLETED	47	45
NOT COMPLETED	2	3

Baseline Characteristics

Arm/Group Title	Placebo	Amoxicillin	Total
Arm/Group Description	Participants received Amoxicillin placebo 2 capsules orally twice a day for 7 days, n=49 Placebo: Placebo	Participants received Amoxicillin 2 x 250 mg capsules orally twice a day for 7 days, n=48 Amoxicillin: Amoxicillin is an aminopenicillin antibiotic	Total of all reporting groups
Overall Participants	49	48	97
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	30.5 (7.8)	29.0 (7.3)	29.8 (7.5)
Sex: Female, Male (Count of Participants)
Female	49 100%	48 100%	97 100%
Male	0 0%	0 0%	0 0%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	3 6.1%	4 8.3%	7 7.2%
Not Hispanic or Latino	46 93.9%	44 91.7%	90 92.8%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 2%	0 0%	1 1%
Asian	0 0%	2 4.2%	2 2.1%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	33 67.3%	29 60.4%	62 63.9%
White	15 30.6%	13 27.1%	28 28.9%
More than one race	0 0%	2 4.2%	2 2.1%
Unknown or Not Reported	0 0%	2 4.2%	2 2.1%
Region of Enrollment (participants) [Number]
United States	49 100%	48 100%	97 100%

Outcome Measures

1. Primary Outcome

Title	The Proportion of Participants With Eradication of Gardnerella Vaginalis (GV) in Each Study Arm at Visit 2 (Day 15-21) as Assessed by Nucleic Acid Amplification Test (NAAT).
Description	Eradication of GV is defined by a negative NAAT result for GV at Visit 2. Participants who have a missing GV NAAT result at the test of cure (TOC) visit were classified as treatment failures. The denominator for proportions is based on the number of subjects who were randomized to the specified treatment group.
Time Frame	Day 15 to 21

Outcome Measure Data

Analysis Population Description

Participants included in the ITT population are those who randomized, regardless of whether they received study treatment or were compliant with the administration procedures or schedule.

Arm/Group Title	Placebo	Amoxicillin
Arm/Group Description	Participants received Amoxicillin placebo 2 capsules orally twice a day for 7 days, n=49 Placebo: Placebo	Participants received Amoxicillin 2 x 250 mg capsules orally twice a day for 7 days, n=48 Amoxicillin: Amoxicillin is an aminopenicillin antibiotic
Measure Participants	49	48
Number (95% Confidence Interval) [proportion of participants]	0.16 0.3%	0.21 0.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Amoxicillin
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.757
	Comments
	Method	Chi-squared, Corrected
	Comments

2. Secondary Outcome

Title	The Proportion of Participants Reporting Related Adverse Events (AEs and SAEs) in Each Study Arm Following the First Dose of Study Product Through Visit 2.
Description	AEs were defined as any untoward medical occurrence in a participant administered a pharmaceutical product. SAEs included any untoward medical occurrence that resulted in death; was life threatening; was a persistent/significant disability/incapacity; required inpatient hospitalization or prolongation or a congenital anomaly/birth defect. AEs and SAEs were collected from participants following the first dose of treatment through Visit 2 (Day 15-21). Events are included if deemed by the investigator to be related to the study product.
Time Frame	Day 1 through Day 15 to 21

Outcome Measure Data

Analysis Population Description

Participants included in the safety population are those who randomized and received at least one dose of treatment.

Arm/Group Title	Placebo	Amoxicillin
Arm/Group Description	Participants received Amoxicillin placebo 2 capsules orally twice a day for 7 days, n=49 Placebo: Placebo	Participants received Amoxicillin 2 x 250 mg capsules orally twice a day for 7 days, n=48 Amoxicillin: Amoxicillin is an aminopenicillin antibiotic
Measure Participants	47	45
Number (95% Confidence Interval) [proportion of participants]	0.04 0.1%	0.18 0.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Amoxicillin
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.048
	Comments
	Method	Fisher Exact
	Comments

Adverse Events

Time Frame	Unsolicited non-serious AEs and SAE were collected through Visit 2 (Day 15-21) after the first dose of treatment.
Adverse Event Reporting Description	The safety data collection was targeted to collect serious and non-serious adverse events and congenital anomalies / birth defects as applicable that occurred after the first dose of treatment through Visit 2 (Day 15-21). Adverse events were captured by subject report/interview and clinical assessments, including clinician-conducted pelvic examination.
Arm/Group Title	Placebo		Amoxicillin
Arm/Group Description	Participants received Amoxicillin placebo 2 capsules orally twice a day for 7 days, n=49 Placebo: Placebo		Participants received Amoxicillin 2 x 250 mg capsules orally twice a day for 7 days, n=48 Amoxicillin: Amoxicillin is an aminopenicillin antibiotic
All Cause Mortality
	Placebo		Amoxicillin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/47 (0%)		0/45 (0%)
Serious Adverse Events
	Placebo		Amoxicillin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/47 (0%)		0/45 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		Amoxicillin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/47 (6.4%)		10/45 (22.2%)
Gastrointestinal disorders
Abdominal pain upper	0/47 (0%)	0	1/45 (2.2%)	1
Nausea	1/47 (2.1%)	1	1/45 (2.2%)	1
Immune system disorders
Allergic reaction to excipient	0/47 (0%)	0	1/45 (2.2%)	1
Infections and infestations
Atypical pneumonia	0/47 (0%)	0	1/45 (2.2%)	1
Bacterial vaginosis	0/47 (0%)	0	1/45 (2.2%)	1
Vulvovaginal candidiasis	1/47 (2.1%)	1	2/45 (4.4%)	2
Investigations
Potassium hydroxide preparation positive	0/47 (0%)	0	1/45 (2.2%)	1
Musculoskeletal and connective tissue disorders
Back pain	1/47 (2.1%)	1	0/45 (0%)	0
Renal and urinary disorders
Urine odour abnormal	0/47 (0%)	0	1/45 (2.2%)	1
Reproductive system and breast disorders
Vaginal discharge	0/47 (0%)	0	1/45 (2.2%)	1
Vulvovaginal pruritus	0/47 (0%)	0	1/45 (2.2%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.