Topical Metronidazole and Miconazole Co-formulated Vaginal Suppositories for Preventing Vaginal Infections in HIV-seronegative Women

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT01230814
• Collaborator: (none)
• Enrollment: 234
• Locations: 4
• Arms: 2
• Duration (Months): 28
• Patients Per Site: 58.5
• Patients Per Site Per Month: 2.1

Study Details

Study Description

Brief Summary

This research study is about vaginal infections such as bacterial vaginosis, yeast infections, and trichomoniasis. Usually, these infections can be treated with medication, but sometimes they come back after treatment. Researchers want to know if using vaginal suppositories can decrease the risk of vaginal infections. Participants will include 234 women who are sexually active (greater than or equal to 4 episodes of sex with men during the past month), HIV-negative, 18 to 45 years old, with bacterial infection [vaginosis and/or vulvovaginal candidiasis (VVC) and/or Trichomonas vaginalis] detected by laboratory testing at a screening visit. Women will receive vaginal suppositories containing drug or inactive ingredients (placebo). Participation in the study will be about 12 months. Study procedures include: urine and blood tests, physical exams, and questionnaires.

Condition or Disease	Intervention/Treatment	Phase
Bacterial Vaginosis; Candidiasis; Trichomoniasis	Drug: Neo-Penotran® Forte (active ingredient Metronidazole & Miconazole Nitrate); Drug: Placebo	Phase 2

Detailed Description

Vaginal infections including bacterial vaginosis (BV), vulvovaginal candidiasis (VVC), and Trichomonas (T.) vaginalis are common and have been associated with increased risk of HIV and other sexually transmitted infections (STIs) in multiple prospective studies. Effective interventions for prevention of vaginal infections could substantially reduce the risk of HIV and other STIs in women. A recently completed trial has demonstrated that monthly periodic presumptive treatment (PPT) can reduce vaginal infections and promote Lactobacillus colonization. However, the oral regimen of metronidazole 2 grams plus fluconazole 150 mg was not sufficiently effective to warrant moving to Phase III HIV/STI prevention trials using this intervention. The identification of more efficacious regimens for reducing vaginal infections is a crucial step towards the development of inexpensive, female-controlled, non-coitally dependent HIV/STI risk reduction interventions for women. There is growing evidence that higher doses and longer courses may be more effective for treatment of vaginal infections than single-dose therapy. The overall goal of this protocol is to conduct a randomized, double-blind, placebo-controlled trial to test the efficacy of monthly PPT with topical metronidazole 750 mg plus miconazole 200 mg (co-formulated suppositories) versus matching placebo suppositories nightly for five nights each month for reducing the rates of BV and VVC among HIV-seronegative women. This regimen could produce sufficient reductions in vaginal infections to support its use in Phase III HIV and STI prevention trials. The study participants will include 234 women who are sexually active (greater than or equal to 4 episodes of heterosexual intercourse during the past month), HIV-seronegative, 18 to 45 years old, with BV and/or VVC and/or T. vaginalis detected by laboratory testing at a screening visit. There will be two study arms. The treatment arm (117 subjects) will receive PPT with intravaginal metronidazole 750 mg plus miconazole 200 mg (co-formulated suppositories) for five consecutive nights each month. The placebo arm (117 subjects) will receive PPT with identical placebo intravaginal suppositories for five consecutive nights each month. Individual participants will be in the study for one year.

Study Design

• Study Type: Interventional
• Actual Enrollment: 234 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Prevention
• Official Title: A Double-Blind, Randomized Trial of Monthly Treatment With Topical Metronidazole and Miconazole Co-formulated Vaginal Suppositories Versus Placebo for Preventing Vaginal Infections in HIV-seronegative Women
• Study Start Date: Apr 1, 2011
• Actual Primary Completion Date: Aug 1, 2013
• Actual Study Completion Date: Aug 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm 1 Intravaginal metronidazole 750 mg plus miconazole 200 mg (co-formulated suppositories) nightly for 5 consecutive nights each month; 117 Subjects.	Drug: Neo-Penotran® Forte (active ingredient Metronidazole & Miconazole Nitrate); Neo-Penotran® Forte (active ingredient Metronidazole & Miconazole Nitrate), co-formulated vaginal suppositories containing metronidazole 750 mg with miconazole 200 mg and excipients (Witepsol S 55). Witepsol S 55 is a hard fat suppository base. Such bases consist mainly of triglyceride esters of the higher saturated fatty acids along with varying proportions of mono- and diglycerides. 117 subjects receive nightly for 5 consecutive night each month.
Placebo Comparator: Arm 2 Placebo suppositories nightly for five consecutive nights each month; 117 Subjects.	Drug: Placebo; Placebo vaginal suppositories, identical in appearance to the active product; contains Witepsol S 55, Titanium Dioxide and D+C yellow #10 with no metronidazole or miconazole.117 subjects receive nightly for 5 consecutive nights each month.

Outcome Measures

Primary Outcome Measures

1. Efficacy of Monthly Periodic Presumptive Treatment (PPT) Using Metronidazole With Miconazole Intravaginal Suppositories Versus Matching Placebo Nightly for Five Nights Each Month for Preventing Vulvovaginal Candidiasis (VVC). [Months 2, 4, 6, 8, 10, and 12.]

   Percentage of follow-up visits (Months 2, 4, 6, 8, 10, 12) positive for VVC based on the presence of fungal elements (pseudohyphae, blastoconidia, or both) on vaginal saline wet mount plus a positive culture showing yeast on Sabouraud's agar.

2. Efficacy of Monthly Periodic Presumptive Treatment (PPT) Using Metronidazole With Miconazole Intravaginal Suppositories Versus Matching Placebo Nightly for Five Nights Each Month for Preventing Bacterial Vaginosis (BV). [Months 2, 4, 6, 8, 10, and 12.]

   Percentage of follow-up visits (Months 2, 4, 6, 8, 10, 12) positive for BV as determined by applying standard microscopic scoring criteria (Nugent's criteria) to vaginal Gram stained slides. BV is diagnosed when the score is greater than or equal to 7.

Secondary Outcome Measures

1. Efficacy of Monthly Periodic Presumptive Treatment (PPT) Using Metronidazole With Miconazole Intravaginal Suppositories Versus Placebo for Preventing Any Vaginal Infection (a Combined Endpoint Including BV, VVC, and Trichomonas Vaginalis Infection). [Months 2, 4, 6, 8, 10, and 12.]

   Percentage of follow-up visits (Months 2, 4, 6, 8, 10, 12) positive for any of three vaginal infections (BV, VVC, Trichomonas vaginalis infection).

2. Efficacy of Monthly Periodic Presumptive Treatment (PPT) Using Metronidazole With Miconazole Intravaginal Suppositories Versus Matching Placebo Nightly for Five Nights Each Month for Preventing BV by Clinical Criteria (Amsel's Criteria). [Months 2, 4, 6, 8, 10, and 12.]

   Percentage of follow-up visits (Months 2, 4, 6, 8, 10, 12) positive for BV by clinical criteria (Amsel's criteria).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 45 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Informed consent obtained and informed consent form (ICF) signed.

• Female, aged 18-45 years.

• Sexually active with greater than or equal to 4 episodes of sex with a male partner during the past month.

• Human immunodeficiency virus (HIV)-seronegative on both HIV tests in parallel screening.

• Presence of bacterial vaginosis (BV) and/or vulvovaginal candidiasis (VVC) and/or T. vaginalis infection at screening:

1. BV: Microscopic criteria (Nugent's score greater than or equal to 7)

2. VVC: Fungal elements (pseudohyphae, blastoconidia, or both) on vaginal saline wet mount plus a positive culture showing yeast on Sabouraud's agar.

3. 1. vaginalis infection: Identification of motile trichomonads on vaginal saline wet preparation.

• Able and willing to comply with study visit schedule and procedures during the 12-month period of follow-up.

• Able and willing to abstain from sex or to use non-latex condoms (provided) for 24 hours following insertion of each vaginal suppository.

• Willing to abstain from alcohol during, and for 48 hours after, treatment.

• Plan to remain in study area for the next year.

• Agree to not participate in other research studies involving drugs, medical devices, or vaginal products for the duration of study.

Exclusion Criteria:

• Currently pregnant (positive urine Beta-Human Chorionic Gonadotropin (hCG) or planning to conceive during the next 12 months (by self-report).

• Currently breastfeeding.

• Within first 3 months post-partum.

• Current menstruation - women who are currently menstruating may be enrolled following the completion of menses.

• History of 4 or more episodes of treatment for any vaginal infection in the past 12 months. This would be a cumulative total, including any treatment for bacterial vaginosis (BV) and/or vulvovaginal candidiasis (VVC) and/or Trichomonas vaginalis (TV) and/or syndromic.

• History of medical condition that would contraindicate use of the study product

1. Porphyria

2. Epilepsy

3. Serious liver disease or signs and symptoms consistent with serious liver disease including jaundice, ascites, esophageal varices, encephalopathy, and bleeding disorders.

4. Renal failure

• History of adverse reaction to the study medications (intravaginal metronidazole or miconazole).

• Current use of medication that may interact with the study drug (due to vaginal absorption of study drug)

1. Warfarin

2. Phenytoin

3. Phenobarbital

4. Disulfiram

5. Cimetidine

6. Lithium

7. Astemizole

8. Terfenadine

• Current use of oral or intravaginal antifungal medication.

• Current use of oral or intravaginal metronidazole, tinidazole, or clindamycin.

• Current use of latex diaphragm.

• As determined by the investigator, a medical condition or situation exists such that study participation would not be advisable.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama at Birmingham Medical Center	Birmingham	Alabama	United States	35294-0007
2	Women's Health Project - Ganjoni Municipal Clinic	Mombasa	Coast	Kenya
3	University of Nairobi - Center for STD/HIV Research & Training	Nairobi		Kenya
4	University of Nairobi - Kenya AIDS Vaccine Initiative	Nairobi		Kenya

Sponsors and Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID)

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
• ClinicalTrials.gov Identifier: NCT01230814
• Other Study ID Numbers: 09-0070; DMID STI CTG 09-0070 PVI
• First Posted: Oct 29, 2010
• Last Update Posted: Oct 6, 2014
• Last Verified: Sep 1, 2014

• Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID): Bacterial vaginosis, metronidazole, miconazole, vulvovaginal candidiasis, trichomonas vaginalis, women, Kenya
• Additional relevant MeSH terms: Candidiasis; Vaginosis, Bacterial; Trichomonas Infections; Vaginal Diseases; Metronidazole; Miconazole; Clotrimazole

Study Results

Participant Flow

Arm/Group Title	Arm 1: Metronidazole Plus Miconazole	Arm 2: Placebo
Arm/Group Description	Intravaginal metronidazole 750 mg plus miconazole 200 mg (co-formulated suppositories) nightly for 5 consecutive nights each month.	Placebo suppositories nightly for five consecutive nights each month.
Period Title: Overall Study
STARTED	118	116
COMPLETED	105	112
NOT COMPLETED	13	4

Baseline Characteristics

Arm/Group Title	Arm 1: Metronidazole Plus Miconazole	Arm 2: Placebo	Total
Arm/Group Description	Intravaginal metronidazole 750 mg plus miconazole 200 mg (co-formulated suppositories) nightly for 5 consecutive nights each month.	Placebo suppositories nightly for five consecutive nights each month.	Total of all reporting groups
Overall Participants	118	116	234
Age (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	29	29	29
Age (Count of Participants)
<=18 years	1 0.8%	1 0.9%	2 0.9%
Between 18 and 65 years	117 99.2%	115 99.1%	232 99.1%
>=65 years	0 0%	0 0%	0 0%
Sex: Female, Male (Count of Participants)
Female	118 100%	116 100%	234 100%
Male	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	118 100%	111 95.7%	229 97.9%
White	0 0%	4 3.4%	4 1.7%
More than one race	0 0%	1 0.9%	1 0.4%
Unknown or Not Reported	0 0%	0 0%	0 0%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	1 0.9%	1 0.4%
Not Hispanic or Latino	118 100%	115 99.1%	233 99.6%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	29 24.6%	29 25%	58 24.8%
Kenya	89 75.4%	87 75%	176 75.2%

Outcome Measures

1. Primary Outcome

Title	Efficacy of Monthly Periodic Presumptive Treatment (PPT) Using Metronidazole With Miconazole Intravaginal Suppositories Versus Matching Placebo Nightly for Five Nights Each Month for Preventing Vulvovaginal Candidiasis (VVC).
Description	Percentage of follow-up visits (Months 2, 4, 6, 8, 10, 12) positive for VVC based on the presence of fungal elements (pseudohyphae, blastoconidia, or both) on vaginal saline wet mount plus a positive culture showing yeast on Sabouraud's agar.
Time Frame	Months 2, 4, 6, 8, 10, and 12.

Outcome Measure Data

Analysis Population Description

Intention to treat population which consisted of all women who were randomized and had at least one follow-up visit. Two women in the metronidazole with miconazole arm did not return after enrollment.

Arm/Group Title	Arm 1: Metronidazole Plus Miconazole	Arm 2: Placebo
Arm/Group Description	Intravaginal metronidazole 750 mg plus miconazole 200 mg (co-formulated suppositories) nightly for 5 consecutive nights each month.	Placebo suppositories nightly for five consecutive nights each month.
Measure Participants	116	116
Measure Follow-up visits	645	665
Number (95% Confidence Interval) [percentage of follow-up visits]	10.4	11.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm 1: Metronidazole Plus Miconazole, Arm 2: Placebo
	Comments	Each participant within a study arm was considered a cluster, with observations at a maximum of 6 visits. The percentage of visits at which VVC was detected was compared between metronidazole plus miconazole arm versus placebo arm using a chi-squared statistic adjusted for clustering using the method of Donner and Klar (2000).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.690
	Comments	The a priori threshold for statistical significance for VVC was p<0.020 (two-sided).
	Method	Clustered chi-squared statistic
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	0.92
	Confidence Interval	(2-Sided) 95%; 0.62 to 1.37
	Parameter Dispersion	Type: Value:
	Estimation Comments	For the relative risk estimate, the metronidazole plus miconazole arm represented the numerator and the placebo arm represented the denominator such that a relative risk <1 indicates a lower percentage of positive test visits in the treated arm.

2. Primary Outcome

Title	Efficacy of Monthly Periodic Presumptive Treatment (PPT) Using Metronidazole With Miconazole Intravaginal Suppositories Versus Matching Placebo Nightly for Five Nights Each Month for Preventing Bacterial Vaginosis (BV).
Description	Percentage of follow-up visits (Months 2, 4, 6, 8, 10, 12) positive for BV as determined by applying standard microscopic scoring criteria (Nugent's criteria) to vaginal Gram stained slides. BV is diagnosed when the score is greater than or equal to 7.
Time Frame	Months 2, 4, 6, 8, 10, and 12.

Outcome Measure Data

Analysis Population Description

Intention to treat population which consisted of all women who were randomized and had at least one follow-up visit. Two women in the metronidazole with miconazole arm did not return after enrollment.

Arm/Group Title	Arm 1: Metronidazole Plus Miconazole	Arm 2: Placebo
Arm/Group Description	Intravaginal metronidazole 750 mg plus miconazole 200 mg (co-formulated suppositories) nightly for 5 consecutive nights each month.	Placebo suppositories nightly for five consecutive nights each month.
Measure Participants	116	116
Measure Follow-up Visits	645	665
Number (95% Confidence Interval) [percentage of follow-up visits]	21.2	32.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm 1: Metronidazole Plus Miconazole, Arm 2: Placebo
	Comments	Each participant within a study arm was considered a cluster, with observations at a maximum of 6 visits. The percentage of visits at which BV was detected was compared between metronidazole plus miconazole arm versus placebo arm using a chi-squared statistic adjusted for clustering using the method of Donner and Klar (2000).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.005
	Comments	The a priori threshold for statistical significance for BV was p<0.030 (two-sided).
	Method	clutstered chi-squared statistic
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	0.65
	Confidence Interval	(2-Sided) 95%; 0.48 to 0.87
	Parameter Dispersion	Type: Value:
	Estimation Comments	For the relative risk estimate, the metronidazole plus miconazole arm represented the numerator and the placebo arm represented the denominator such that a relative risk <1 indicates a lower percentage of test visits in the treated arm.

3. Secondary Outcome

Title	Efficacy of Monthly Periodic Presumptive Treatment (PPT) Using Metronidazole With Miconazole Intravaginal Suppositories Versus Placebo for Preventing Any Vaginal Infection (a Combined Endpoint Including BV, VVC, and Trichomonas Vaginalis Infection).
Description	Percentage of follow-up visits (Months 2, 4, 6, 8, 10, 12) positive for any of three vaginal infections (BV, VVC, Trichomonas vaginalis infection).
Time Frame	Months 2, 4, 6, 8, 10, and 12.

Outcome Measure Data

Analysis Population Description

Intention to treat population which consisted of all women who were randomized and had at least one follow-up visit. Two women in the metronidazole with miconazole arm did not return after enrollment.

Arm/Group Title	Arm 1: Metronidazole Plus Miconazole	Arm 2: Placebo
Arm/Group Description	Intravaginal metronidazole 750 mg plus miconazole 200 mg (co-formulated suppositories) nightly for 5 consecutive nights each month.	Placebo suppositories nightly for five consecutive nights each month.
Measure Participants	116	116
Measure Follow-up visits	645	665
Number (95% Confidence Interval) [percentage of follow-up visits]	32.6	46.5

4. Secondary Outcome

Title	Efficacy of Monthly Periodic Presumptive Treatment (PPT) Using Metronidazole With Miconazole Intravaginal Suppositories Versus Matching Placebo Nightly for Five Nights Each Month for Preventing BV by Clinical Criteria (Amsel's Criteria).
Description	Percentage of follow-up visits (Months 2, 4, 6, 8, 10, 12) positive for BV by clinical criteria (Amsel's criteria).
Time Frame	Months 2, 4, 6, 8, 10, and 12.

Outcome Measure Data

Analysis Population Description

Intention to treat population which consisted of all women who were randomized and had at least one follow-up visit. Two women in the metronidazole with miconazole arm did not return after enrollment.

Arm/Group Title	Arm 1: Metronidazole Plus Miconazole	Arm 2: Placebo
Arm/Group Description	Intravaginal metronidazole 750 mg plus miconazole 200 mg (co-formulated suppositories) nightly for 5 consecutive nights each month.	Placebo suppositories nightly for five consecutive nights each month.
Measure Participants	116	116
Measure Follow-up visits	645	665
Number (95% Confidence Interval) [percentage of follow-up visits]	14.4	18.2

Adverse Events

Time Frame	Months 2, 4, 6, 8, 10, and 12, and any interim visits.
Adverse Event Reporting Description	Adverse events were followed until resolution even beyond the study-reporting period. Resolution of an adverse event is defined as the return to pretreatment status or stabilization of the condition with the expectation that it will remain chronic.
Arm/Group Title	Arm 1: Metronidazole Plus Miconazole		Arm 2: Placebo
Arm/Group Description	Intravaginal metronidazole 750 mg plus miconazole 200 mg (co-formulated suppositories) nightly for 5 consecutive nights each month.		Placebo suppositories nightly for five consecutive nights each month.
All Cause Mortality
	Arm 1: Metronidazole Plus Miconazole		Arm 2: Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Arm 1: Metronidazole Plus Miconazole		Arm 2: Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/116 (2.6%)		1/116 (0.9%)
Infections and infestations
Malaria	1/116 (0.9%)	1	0/116 (0%)	0
Typhoid fever	1/116 (0.9%)	1	0/116 (0%)	0
Musculoskeletal and connective tissue disorders
Soft tissue injury	1/116 (0.9%)	1	0/116 (0%)	0
Pelvic fracture	0/116 (0%)	0	1/116 (0.9%)	1
Pregnancy, puerperium and perinatal conditions
Ruptured ectopic pregnancy	1/116 (0.9%)	1	0/116 (0%)	0
Other (Not Including Serious) Adverse Events
	Arm 1: Metronidazole Plus Miconazole		Arm 2: Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	109/116 (94%)		111/116 (95.7%)
Cardiac disorders
Chest pain	8/116 (6.9%)	9	7/116 (6%)	8
Gastrointestinal disorders
Abdominal pain	8/116 (6.9%)	10	17/116 (14.7%)	21
Abdominal pain lower	14/116 (12.1%)	17	9/116 (7.8%)	12
Dyspepsia	10/116 (8.6%)	13	13/116 (11.2%)	17
Gastroenteritis	9/116 (7.8%)	10	7/116 (6%)	7
Nausea	5/116 (4.3%)	6	7/116 (6%)	9
Toothache	8/116 (6.9%)	9	8/116 (6.9%)	10
Infections and infestations
Body tinea	8/116 (6.9%)	8	8/116 (6.9%)	10
Malaria	7/116 (6%)	10	9/116 (7.8%)	11
Musculoskeletal and connective tissue disorders
Arthralgia	10/116 (8.6%)	11	9/116 (7.8%)	12
Back pain	21/116 (18.1%)	25	11/116 (9.5%)	13
Myalgia	7/116 (6%)	7	10/116 (8.6%)	15
Soft tissue injury	8/116 (6.9%)	9	4/116 (3.4%)	5
Nervous system disorders
Headache	24/116 (20.7%)	31	36/116 (31%)	53
Hypoaesthesia	12/116 (10.3%)	17	12/116 (10.3%)	19
Renal and urinary disorders
Urinary tract infection	14/116 (12.1%)	24	12/116 (10.3%)	13
Reproductive system and breast disorders
Menorrhagia	9/116 (7.8%)	9	8/116 (6.9%)	8
Nasopharyngitis	6/116 (5.2%)	11	7/116 (6%)	9
Vaginal discharge	27/116 (23.3%)	55	43/116 (37.1%)	67
Vaginal odour	10/116 (8.6%)	19	5/116 (4.3%)	11
Vulvovaginal discomfort	8/116 (6.9%)	13	6/116 (5.2%)	9
Vulvovaginal pruritus	38/116 (32.8%)	62	44/116 (37.9%)	78
Vulvovaginitis	19/116 (16.4%)	23	19/116 (16.4%)	27
Respiratory, thoracic and mediastinal disorders
Cough	6/116 (5.2%)	8	12/116 (10.3%)	16
Pharyngitis	6/116 (5.2%)	7	7/116 (6%)	9
Respiratory tract infection	14/116 (12.1%)	14	18/116 (15.5%)	24
Rhinitis	14/116 (12.1%)	16	10/116 (8.6%)	11
Tonsillitis	9/116 (7.8%)	9	8/116 (6.9%)	9
Upper respiratory tract infection	40/116 (34.5%)	64	36/116 (31%)	54
Skin and subcutaneous tissue disorders
Rash	7/116 (6%)	7	7/116 (6%)	8

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.