Mycoplasma Genitalium Antibiotic Susceptibility and Treatment (MEGA)

• Sponsor: University of Washington (Other)
• Overall Status: Completed
• CT.gov ID: NCT00358462
• Collaborator: National Institute of Allergy and Infectious Diseases (NIAID) (NIH)
• Enrollment: 606
• Location: 1
• Arms: 2
• Duration (Months): 58
• Patients Per Site Per Month: 10.5

Study Details

Study Description

Brief Summary

The purpose of this study is to find out which of 2 different antibiotics, doxycycline or azithromycin, works best against germs that may cause nongonococcal urethritis.

Study participants will include approximately 1200 men, 16 years of age or older, attending a sexually transmitted diseases clinic in Seattle, Washington with clinical signs of urethral inflammation (>=5PMNs/HPF on a Gram-stained slide prepared from urethral exudates and/or a visible urethral discharge upon examination).

Urine specimens will be collected and tested for Mycoplasma genitalium and Ureaplasmas. Each participant will receive a blinded packet of study medication. Participants will answer an enrollment questionnaire and will also receive a log to complete between visits to record information about treatment adherence, side effects, symptoms, and sexual activity. All subjects will be asked to return for evaluation 3 weeks after the initial clinic visit. Subjects who test positive for M. genitalium and/or Ureaplasmas at the initial clinic visit will also be asked to return for a third study visit, 6 weeks following the initial clinic visit. During follow-up visits, participants will answer a follow-up questionnaire and will be re-evaluated for signs of urethritis. Those who were initially positive for M. genitalium and/or Ureaplasmas will be re-tested for these organisms.

Study participants with signs and/or symptoms of urethritis or who test positive for M. genitalium or Ureaplasmas at the follow-up study visit will receive another blinded treatment packet containing the alternate medication. Those who require additional treatment at the 6-week visit will be asked to return for a fourth follow-up study visit at 9-10 weeks. Study participants who did not test positive for M. genitalium or Ureaplasmas at the initial clinic visit, but who continue to demonstrate signs and/or symptoms of infection at their single follow-up study visit will treated according to clinic standard of care (after the study clinician unblinds their randomly-assigned treatment regimen).

Condition or Disease	Intervention/Treatment	Phase
Urethritis	Drug: Azithromycin; Drug: Doxycycline	Phase 3

Detailed Description

OBJECTIVES

The primary objective of this study is to determine the relative effectiveness of azithromycin and doxycycline in eradicating Mycoplasma genitalium and Ureaplasmas among men with nongonococcal urethritis (NGU).

Secondary objectives of this study are to:

• determine the sensitivity of persisting organisms to azithromycin and doxycycline by performing minimum inhibitory concentration (MIC) testing

• determine the relationship between persistence/recurrence of clinical signs and persistent/recurrent detection of M. genitalium and Ureaplasmas among men with NGU treated with azithromycin or doxycycline, measured by follow-up clinical exams and repeated assays performed on specimens collected at follow-up study visits

STUDY DESCRIPTION

1200 men with NGU, ages 16 and older, will be enrolled in a randomized double-blinded treatment trial. Urine samples, oral swabs, and urethral swabs will be obtained from each subject at the initial clinic visit. Urine specimens will be tested for M. genitalium and Ureaplasma. Study participants will be randomly assigned to receive one of two pre-packaged treatments: active doxycycline plus placebo azithromycin or active azithromycin plus placebo doxycycline. Subjects will complete a questionnaire, and will be given a simple standardized log in which they will be asked to keep track of adherence to the study drug, record solicited adverse events, note when symptoms disappear and/or reappear, and document sexual activity between study visits.

Subjects who test positive for M. genitalium or Ureaplasmas at the initial clinic visit will be asked to return for at least two follow-up study visits: at approximately 3 and 6 weeks following the initial clinic visit. During follow-up visits, participants will answer a follow-up questionnaire and will be re-evaluated for signs of urethritis and re-tested for M. genitalium and Ureaplasmas. Study participants with signs and/or symptoms of urethritis or who test positive for M. genitalium or Ureaplasmas at the follow-up study visits will receive a blinded treatment packet containing the alternate medication, or will be offered open-label moxifloxacin if the alternate treatment regimen was administered at the prior follow-up study visit. If additional treatment is administered at the 6-week follow-up study visit, a fourth study visit will be scheduled to occur approximately 9 or 10 weeks following the initial clinic visit.

Study participants who were negative for M. genitalium and Ureaplasma at enrollment will be asked to return for evaluation for a single follow-up study visit, approximately 3 weeks after the initial clinic visit. At this visit they will complete the follow-up questionnaire and provide specimens for future testing.

Study Design

• Study Type: Interventional
• Actual Enrollment: 606 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Mycoplasma Genitalium Antibiotic Susceptibility and Treatment: A Randomized Double-blind Trial of the Efficacy of Azithromycin and Doxycycline for Clinical and Microbiological Cure of M. Genitalium in Men With Nongonococcal Urethritis
• Study Start Date: Jan 1, 2007
• Actual Primary Completion Date: Nov 1, 2011
• Actual Study Completion Date: Nov 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Active azithromycin+placebo doxycycline Active azithromycin (1g) and placebo doxycycline	Drug: Azithromycin; two 500mg tablets or four 250mg tablets administered as a single dose; Other Names: Zithromax Zmax
Active Comparator: Active doxycycline+placebo azithromycin Active doxycycline and placebo azithromycin	Drug: Doxycycline; one 100mg capsule administered twice daily for seven days; Other Names: Doryx Doxychel Monodox Oracea Periostat Vibra-Tabs Vibramycin

Outcome Measures

Primary Outcome Measures

1. mITT Analysis of Eradication of M. Genitalium at First Follow-up Study Visit [approximately 3 weeks after initial study visit (allowable window is 2-5 weeks after initial study visit)]

   Microbiologic cure of M. genitalium at first follow-up visit (defined as a negative in-house PCR test performed on urine)

2. mITT Analysis of Eradication of U. Urealyticum at First Follow-up Visit [3 weeks (allowable window 2-5)]

   Microbiologic cure, defined as negative PCR for U. urealyticum (if cultured), or negative culture at first follow-up visit

Secondary Outcome Measures

1. Clinical Cure Among Case Subjects Who Were Positive for M. Genitalium at the Initial Study Visit [approximately 3 weeks after initial study visit (allowable window is 2-5 weeks after initial study visit)]

   Proportion of men with M. genitalium at the initial study visit who had clinical cure, defined as <5 PMNs/HPF (with or without urethral symptoms) on a urethral Gram stain and absence of urethral discharge at follow-up.

2. Clinical Cure Among Case Subjects Who Were Positive for Ureaplasmas at the Initial Study Visit [approximately 3 weeks after initial study visit (allowable window is 2-5 weeks after initial study visit)]

   Proportion of men with Ureaplasma urealyticum at the initial study visit who had clinical cure, defined as <5 PMNs/HPF (with or without urethral symptoms) on a urethral Gram stain and absence of urethral discharge at follow-up.

3. Minimum Inhibitory Concentrations (MIC) of M. Genitalium for Azithromycin [baseline]

   In vitro susceptibiities of M. genitalium to azithromycin

4. Minimum Inhibitory Concentrations (MIC) of M. Genitalium for Doxycycline [baseline]

   In vitro susceptibilities of M. genitalium to doxycycline

5. Minimum Inhibitory Concentrations (MIC) of U. Ureaplasma Biovar 2 [baseline]

   In vitro susceptibilities of U. urealyticum biovar 2

6. Minimum Inhibitory Concentrations (MIC) of U. Parvum [baseline]

   In vitro susceptibilities of U. parvum

Eligibility Criteria

Criteria

• Ages Eligible for Study: 16 Years and Older
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Has a visible urethral discharge or greater than or equal to 5 polymorphonuclear leukocytes (PMNs) per high power field on a Gram-stained slide of a urethral swab sample

• Possesses and is willing to disclose valid contact information for follow-up

• English-speaking

• Gives informed consent

• Exhibits understanding of study procedures

• Exhibits ability to comply with study procedures for the entire length of the study

Exclusion Criteria:

• Has previously participated in this study

• Has taken antibiotics within the prior month

• Has known allergies to tetracyclines or azithromycin

• Is being treated with any of the following: warfarin, ergot derivatives, pimozide (Orap), propafenone (Rytmonorm, Rythmol), disopyramide (Norpace, Rythmodan), rifampin, digoxin, isotretinoin, or methotrexate

• Has received a kidney, heart, or lung transplant.

• Is undertaking concomitant systemic steroid therapy

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Public Health -- Seattle & King County Sexually Transmitted Diseases Clinic located at Harborview Medical Center	Seattle	Washington	United States	98104

Sponsors and Collaborators

• University of Washington
• National Institute of Allergy and Infectious Diseases (NIAID)

Investigators

• Principal Investigator: Lisa E Manhart, PhD, University of Washington

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Lisa Manhart, Study Principal Investigator, University of Washington
• ClinicalTrials.gov Identifier: NCT00358462
• Other Study ID Numbers: 26995; 05-0143 (protocol number); U19AI031448; R01AI072728
• First Posted: Jul 31, 2006
• Last Update Posted: Aug 15, 2018
• Last Verified: Jul 1, 2018

• Keywords provided by Lisa Manhart, Study Principal Investigator, University of Washington: NGU, M genitalium, Ureaplasma, azithromycin, doxycycline
• Additional relevant MeSH terms: Urethritis; Azithromycin; Doxycycline

Study Results

Participant Flow

Recruitment Details	Men were recruited from a sexually transmitted diseases clinic in Seattle, Washington from January 2007 to July 2011

Arm/Group Title	Active Azithromycin + Placebo Doxycycline	Active Doxycycline + Placebo Azithromycin
Arm/Group Description	Azithromycin : two 500mg tablets or four 250mg tablets administered as a single dose	Doxycycline : one 100mg capsule administered twice daily for seven days
Period Title: Overall Study
STARTED	304	302
COMPLETED	245	238
NOT COMPLETED	59	64

Baseline Characteristics

Arm/Group Title	Active Azithromycin + Placebo Doxycycline	Active Doxycycline + Placebo Azithromycin	Total
Arm/Group Description	Azithromycin : two 500mg tablets or four 250mg tablets administered as a single dose	Doxycycline : one 100mg capsule administered twice daily for seven days	Total of all reporting groups
Overall Participants	304	302	606
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	34.1 (9.8)	33.3 (10.1)	33.7 (10.0)
Sex: Female, Male (Count of Participants)
Female	0 0%	0 0%	0 0%
Male	304 100%	302 100%	606 100%
Region of Enrollment (participants) [Number]
United States	304 100%	302 100%	606 100%

Outcome Measures

1. Primary Outcome

Title	mITT Analysis of Eradication of M. Genitalium at First Follow-up Study Visit
Description	Microbiologic cure of M. genitalium at first follow-up visit (defined as a negative in-house PCR test performed on urine)
Time Frame	approximately 3 weeks after initial study visit (allowable window is 2-5 weeks after initial study visit)

Outcome Measure Data

Analysis Population Description

mITT population (defined as urethral symptoms or visible discharge plus >=5PMNs/HPF at baseline) who tested positive for M. genitalium at baseline

Arm/Group Title	Active Azithromycin + Placebo Doxycycline	Active Doxycycline + Placebo Azithromycin
Arm/Group Description	Azithromycin : two 500mg tablets or four 250mg tablets administered as a single dose	Doxycycline : one 100mg capsule administered twice daily for seven days
Measure Participants	38	27
Number [participants]	15 4.9%	8 2.6%

2. Primary Outcome

Title	mITT Analysis of Eradication of U. Urealyticum at First Follow-up Visit
Description	Microbiologic cure, defined as negative PCR for U. urealyticum (if cultured), or negative culture at first follow-up visit
Time Frame	3 weeks (allowable window 2-5)

Outcome Measure Data

Analysis Population Description

mITT population (defined as urethral symptoms or visible discharge plus >=5PMNs/HPF at baseline) who tested positive for U. urealyticum at baseline

Arm/Group Title	Active Azithromycin + Placebo Doxycycline	Active Doxycycline + Placebo Azithromycin
Arm/Group Description	Azithromycin : two 500mg tablets or four 250mg tablets administered as a single dose	Doxycycline : one 100mg capsule administered twice daily for seven days
Measure Participants	52	55
Number [participants]	39 12.8%	38 12.6%

3. Secondary Outcome

Title	Clinical Cure Among Case Subjects Who Were Positive for M. Genitalium at the Initial Study Visit
Description	Proportion of men with M. genitalium at the initial study visit who had clinical cure, defined as <5 PMNs/HPF (with or without urethral symptoms) on a urethral Gram stain and absence of urethral discharge at follow-up.
Time Frame	approximately 3 weeks after initial study visit (allowable window is 2-5 weeks after initial study visit)

Outcome Measure Data

Analysis Population Description

mITT population

Arm/Group Title	Active Azithromycin+Placebo Doxycycline	Active Doxycycline+Placebo Azithromycin
Arm/Group Description	Active azithromycin (1g) and placebo doxycycline Azithromycin: two 500mg tablets or four 250mg tablets administered as a single dose	Active doxycycline and placebo azithromycin Doxycycline: one 100mg capsule administered twice daily for seven days
Measure Participants	38	27
Number [participants]	24 7.9%	13 4.3%

4. Secondary Outcome

Title	Clinical Cure Among Case Subjects Who Were Positive for Ureaplasmas at the Initial Study Visit
Description	Proportion of men with Ureaplasma urealyticum at the initial study visit who had clinical cure, defined as <5 PMNs/HPF (with or without urethral symptoms) on a urethral Gram stain and absence of urethral discharge at follow-up.
Time Frame	approximately 3 weeks after initial study visit (allowable window is 2-5 weeks after initial study visit)

Outcome Measure Data

Analysis Population Description

mITT population

Arm/Group Title	Active Azithromycin+Placebo Doxycycline	Active Doxycycline+Placebo Azithromycin
Arm/Group Description	Active azithromycin (1g) and placebo doxycycline Azithromycin: two 500mg tablets or four 250mg tablets administered as a single dose	Active doxycycline and placebo azithromycin Doxycycline: one 100mg capsule administered twice daily for seven days
Measure Participants	52	55
Number [participants]	43 14.1%	40 13.2%

5. Secondary Outcome

Title	Minimum Inhibitory Concentrations (MIC) of M. Genitalium for Azithromycin
Description	In vitro susceptibiities of M. genitalium to azithromycin
Time Frame	baseline

Outcome Measure Data

Analysis Population Description

Participants with recovered isolates that successfully underwent in vitro assessment of antibiotic susceptibilities

Arm/Group Title	Cultivated Isolates
Arm/Group Description	Azithromycin MIC's
Measure Participants	56
MIC range <=0.001 - 0.004 ug/ml	31 10.2%
MIC range >8 ug/ml	25 8.2%

6. Secondary Outcome

Title	Minimum Inhibitory Concentrations (MIC) of M. Genitalium for Doxycycline
Description	In vitro susceptibilities of M. genitalium to doxycycline
Time Frame	baseline

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cultivated Isolates
Arm/Group Description	Cultivated M. genitalium isolates that successfully underwent in vitro MICs for doxycycline
Measure Participants	61
Median (Full Range) [MIC (ug/mL)]	0.5

7. Secondary Outcome

Title	Minimum Inhibitory Concentrations (MIC) of U. Ureaplasma Biovar 2
Description	In vitro susceptibilities of U. urealyticum biovar 2
Time Frame	baseline

Outcome Measure Data

Analysis Population Description

isolates

Arm/Group Title	Azithromycin	Doxycycline	Moxifloxacin
Arm/Group Description	Cultivated U. urealyticum biovar 2 isolates that successfully underwent in vitro MICs for azithromycin	Cultivated U. urealyticum biovar 2 isolates that successfully underwent in vitro MICs for doxycycliine	Cultivated U. urealyticum biovar 2 isolates that successfully underwent in vitro MICs for moxifloxacin
Measure Participants	22	22	22
Median (Full Range) [MIC (ug/mL)]	1.00	0.5	0.5

8. Secondary Outcome

Title	Minimum Inhibitory Concentrations (MIC) of U. Parvum
Description	In vitro susceptibilities of U. parvum
Time Frame	baseline

Outcome Measure Data

Analysis Population Description

isolates

Arm/Group Title	Azithromycin	Doxycycline	Moxifloxacin
Arm/Group Description	Cultivated U. parvum isolates that successfully underwent in vitro MICs for azithromycin	Cultivated U. parvum isolates that successfully underwent in vitro MICs for doxycycline	Cultivated U. parvum isolates that successfully underwent in vitro MICs for moxifloxacin
Measure Participants	8	8	8
Median (Full Range) [MIC (ug/mL)]	0.5	0.25	0.25

Adverse Events

Arm/Group Title	Active Azithromycin + Placebo Doxycycline		Active Doxycycline + Placebo Azithromycin
Arm/Group Description	Azithromycin : two 500mg tablets or four 250mg tablets administered as a single dose		Doxycycline : one 100mg capsule administered twice daily for seven days
All Cause Mortality
	Active Azithromycin + Placebo Doxycycline		Active Doxycycline + Placebo Azithromycin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Active Azithromycin + Placebo Doxycycline		Active Doxycycline + Placebo Azithromycin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/304 (0.3%)		3/302 (1%)
Eye disorders
Optic neuritis	0/304 (0%)	0	1/302 (0.3%)	1
Injury, poisoning and procedural complications
Gun shot wound	0/304 (0%)	0	1/302 (0.3%)	1
Broken leg	0/304 (0%)	0	1/302 (0.3%)	1
Psychiatric disorders
Unstable mental status	1/304 (0.3%)	1	0/302 (0%)	0
Other (Not Including Serious) Adverse Events
	Active Azithromycin + Placebo Doxycycline		Active Doxycycline + Placebo Azithromycin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	53/304 (17.4%)		56/302 (18.5%)
Gastrointestinal disorders
Nausea	28/304 (9.2%)	73	36/302 (11.9%)	68
Diarrhea	31/304 (10.2%)	74	35/302 (11.6%)	47
Other	12/304 (3.9%)	32	17/302 (5.6%)	32
General disorders
Vomiting	6/304 (2%)	7	7/302 (2.3%)	7
Rash	6/304 (2%)	7	7/302 (2.3%)	7

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.