Comparative Safety Study of Two Vaginal Applicators With Tenofovir

Comparative Safety Study of Pre-Filled Plastic and User-Filled Paper Vaginal Applicators With Candidate Microbicide, Tenofovir

Status

Completed

Phases

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01283555

Enrollment

Registered

2011-01-26

Start date

2011-01-31

Completion date

2011-06-30

Last updated

2012-07-16

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Microbicide Applicator

Keywords

Microbicide, Applicator, Safety

Brief summary

The primary objective of this study is to compare the effect of two vaginal applicators, delivering the candidate microbicide Tenofovir, on symptoms and signs of irritation of the external genitalia, cervix and vagina as seen on colposcopy after seven days of twice daily use. The secondary objectives are to: 1. Evaluate and compare the dosing accuracy and precision of the user-filled applicator and pre-filled applicator with the candidate microbicide, Tenofovir. 2. Compare the acceptability of the user-filled applicator with the pre-filled applicator.

Interventions

DRUGTenofovir

Delivered using prefilled and user-filled applicator

Study design

Allocation

RANDOMIZED

Intervention model

CROSSOVER

Primary purpose

PREVENTION

Masking

NONE

Eligibility

Sex/Gender

FEMALE

Age

18 Years to 50 Years

Healthy volunteers

Yes

Inclusion criteria

* Female * Age 18 to 50, inclusive * Pre-menopausal * In good health as reported by individual * Have regular menstrual cycles (24 to 35 days) * Low risk for sexually transmitted infections (only one sexual partner in the last three months) * Not pregnant or at risk of pregnancy (must either have had a tubal ligation, or currently be using a hormonal method of contraception) * Negative on a urine pregnancy test * Willing to abstain from sexual intercourse and masturbation during two 7-day periods when applicators are being used * Willing to abstain from use of vaginal products during course of study (including douching, use of vaginal applicators for medication, lubrication, sex toys, other) * Willing to follow procedural requirements of study * Willing and able to provide informed consent for study participation * Willing to provide investigator with phone number or address where she can be reached during the study

Exclusion criteria

* History of hysterectomy * Pregnancy or within two months of last pregnancy outcome (delivery, spontaneous or induced abortion, medical or surgical management of ectopic pregnancy) * Post-menopausal * Breastfeeding * Use of an intra-uterine device (IUD), cervical caps or diaphragm for contraceptive purposes * Diagnosis or treatment for a sexually transmitted disease within the past 30 days; * More than one sexual partner in the last 3 months * Has had surgery on the external genitalia, vagina, or cervix within the past 3 months; * Current or past use of any anti-retroviral therapies including but not limited to systemic Tenofovir (Viread®) * Current or anticipated use of drugs on a daily basis that may reduce renal function (e.g. acyclovir or ibuprofen) or liver function (e.g. Tylenol) * HIV positive at time of screening * Hepatitis B surface antigen (HBsAg) positive at time of screening * Positive test results for Neisseria gonorrhea, Chlamydia trachomatis, or Trichomonas vaginalis at time of screening. * At baseline colposcopic exam (Visit 2), findings involving disruption of epithelium with disruption of blood vessels or deep disruption of epithelium alone. Any area of epithelium with bleeding will be considered deeply disrupted. * Any abnormal finding on colposcopic exams which in the opinion of the investigator, precludes participation in the study * At baseline exams, clinical symptoms or signs of vaginitis or vulvitis confirmed by a wet mount exam of the discharge. Note: If vaginitis or vulvitis is present at either baseline exam (visits 2 or 10), volunteer will be treated and rescheduled for new baseline exam one week after application of last treatment dose. If signs or symptoms are still present at the rescheduled baseline exam for Visit 2, the volunteer will not be enrolled into study. If signs or symptoms are still present at the rescheduled baseline exam for Visit 10, the volunteer will be discontinued from the study. * Serum chemistry (glucose, creatinine, bilirubin, AST \[aspartate aminotransferase\] and ALT \[alanine transaminase\]) not within normal expected levels according to the specifications of the local laboratory. * Hemoglobin, hematocrit and total white blood cell not within 15 % of lower and upper limit normal levels according to the specifications of the local laboratory. * Participation in any other research study in the 30 days prior to screening and/or plans to participate in any other research study during the entire study duration.

Design outcomes

Primary

Measure	Time frame	Description
Number of Colposcopic Findings (Baseline and After One Week of Product Use)	7 days	Comparison of colposcopic findings between baseline visits and after one week of twice-daily application of Tenofovir 1% gel with either a user-filled or prefilled applicator

Secondary

Measure	Time frame	Description
Filling Precision (5% Range)	3 dose delivery measurements during 1 week of product use	A 5% range was calculated around the average filled volumes to determine how many applicators were filled within this range (+/-5% of average volume)
Filling Precision (10% Range)	3 dose delivery measurements during 1 week of product use	A 10% range was calculated around the average filled volumes to determine how many applicators were filled within this range (+/-10% of average volume)
Filling Accuracy (% of Target Dose)	3 dose delivery measurements during 1 week of product use	The target dose for Tenofovir gel in this study was 4.0ml, which is the volume of Tenofovir being used in current microbicide clinical trials. The filled volume for each applicator was compared with the intended target dose of 4.0ml.
Dosing Volume (Expressed Volume)	3 dose delivery measurements during 1 week of product use	At each dose delivery visit, the applicator was weighed prior to vaginal insertion and after use. The volume of gel expressed was measured using the following data: weight of filled applicator, weight of emptied applicator, the average weight of an empty applicator, and gel density.
Dosing Precision, 5% (Expressed Volume)	3 dose delivery measurements during 1 week of product use	A 5% range was calculated around the average expressed volume of 3.83ml to determine how many applicators delivered a dose within this range (+/-5% of average volume)
Dosing Precision, 10% (Expressed Volume)	3 dose delivery measurements during 1 week of product use	A 10% range was calculated around the average expressed volume of 3.83ml to determine how many applicators delivered a dose within this range (+/-10% of average volume)
Dosing Accuracy (% of Target Dose Delivered)	3 dose delivery measurements during 1 week of product use	The target dose for Tenofovir gel in this study was 4.0ml, which is the volume of Tenofovir being used in current microbicide clinical trials. The average dose delivered for each applicator was compared with the intended target dose of 4.0ml.
Number of Participants Reporting Applicator Easy to Fill	Final study visit (after completing both study arms)	Participants were asked to describe the process of filling the user-filled applicator. Response categories included easy, moderately difficult, and difficult. Since ease of filling only applies to the user-filled applicator, this question was not applicable for the prefilled applicator.
Number of Respondents Reporting Confidence With Filling the User-filled Applicator	Final study visit (after completing both study arms)	Participants were asked when using the user-filled applicator, how confident did they feel that they at inserted the correct amount of gel into the applicator. Response categories included very confident, confident, and not confident. (Note: this question does not apply to the prefilled applicator.)
Reasons Given by Participants for Knowing When the Applicator Was Filled Correctly	Final study visit (after completing both study arms)	Participants were asked how did they know when the applicator was filled correctly (that is, with the right amount of gel). More than one answer was allowed. Response categories included plunger automatically stopped, the 'FULL' line was reached, and other. Note: this question does not apply to the prefilled applicator.
Filled Volume	3 dose delivery measurements during 1 week of product use	At each dose delivery visit, the applicator was weighed, prior to vaginal insertion. For the user-filled applicator, the participant handed the applicator to the investigator after filling with gel from the multidose tube. The applicator was then weighed and returned to the participant for insertion. For the prefilled applicator, the participant inserted the plunger into the barrel, and then handed the applicator to the investigator for weighing.
Number of Participants Reporting That the Gel Was Easy to Dispense	Final study visit (after completing both study arms)	Participants were asked to describe the dispensing of the gel into the vagina with each applicator (user-filled and prefilled). Response categories included easy, moderately difficult, and difficult.
Number of Participants Reporting Applicator Preference (User-filled or Prefilled) Across a Variety of Factors	Final study visit (after completing both study arms)	Participants were asked about their preference for either the user-filled or prefilled applicator with regard to several use factors as well as in relation to disposal, storage, and overall comfort and preference. Response categories included user-filled, prefilled, and same.
Number of Participants Reporting That Applicator Was Comfortable to Use	Final study visit (after completing both study arms)	Participants were asked to describe the comfort of use for each applicator type(user-filled and prefilled). Response categories included comfortable, neutral, and uncomfortable.
Number of Participants Reporting Suggestions Regarding Ease of Use or Comfort	Final study visit (after completing both study arms)	Participants were asked if they could suggest ways that would make each applicator easier or more comfortable to use. Response categories were yes and no. If yes, participants were asked to describe how they would make the applicator easier and/or more comfortable to use.
Number of Participants Reporting That the Instructions for Use Were Helpful	Final study visit (after completing both study arms)	For each applicator type, participants were asked if the instructions were helpful to you. Response categories were yes and no.
Number of Participants Reporting That Both Applicators Were Acceptable	Final study visit (after completing both study arms)	Participants were asked if both applicators were acceptable to them. Responses were either yes or no.
Number of Participants Reporting That the Cost of the Applicator Would Influence Their Choice of Applicator	Final study visit (after completing both study arms)	Participants were asked if the cost of the applicator would influence their choice of applicator. Response categories were yes, no, and maybe.
Number of Participants Reporting That They Would Use the User-filled Applicator in the Future if it Came With a Gel for HIV Prevention	Final study visit (after completing both study arms)	Participants were asked if they would use the user-filled applicator in the future if it came with a gel that helped prevent HIV infection. Response categories included yes, no, and in some circumstances.
Number of Participants Reporting That They Would Not Want to Use the User-filled Applicator in the Future if it Came With a Gel for HIV Prevention	Final study visit (after completing both study arms)	Participants were asked if there were any reasons that they would not want to use this user-filled applicator in the future if it came with a gel that helped prevent HIV infection. Response categories included yes, no, and in some circumstances.
Number of Participants Reporting That They Would Recommend the User-filled Applicator for HIV Prevention	Final study visit (after completing both study arms)	Participants were asked if they would recommend the user-filled applicator to other women if it came with a gel that helped prevent HIV infection. Response categories included yes, no, and in some circumstances.
Number of Participants Reporting Applicator Easy to Insert	Final study visit (after completing both study arms)	Participants were asked to describe the insertion of the applicator into the vagina for each applicator (user-filled and prefilled). Response categories included easy, moderately difficult, and difficult.

Countries

Dominican Republic

Participant flow

Recruitment details

Recruitment began on 26 January 2011 and ended on 10 March 2011. Recruitment was done at Clinica Profamilia, Santo Domingo, Dominican Republic. Healthy women, 18 to 50 years of age (inclusive), who attended the clinic for health care, who were not at risk for pregnancy, and at low risk of sexually transmitted infection were informed of the study.

Pre-assignment details

25 were enrolled in this study which used a cross-over design. Participants were randomized to order of applicator use.

Participants by arm

Arm	Count
Entire Study Population Includes groups randomized to use the prefilled applicator first and the user-filled applicator first.	25
Total	25

Baseline characteristics

Characteristic	Entire Study Population
Age, Categorical <=18 years	0 Participants
Age, Categorical >=65 years	0 Participants
Age, Categorical Between 18 and 65 years	25 Participants
Age Continuous	33 years STANDARD_DEVIATION 6
Region of Enrollment Dominican Republic	25 participants
Sex: Female, Male Female	25 Participants
Sex: Female, Male Male	0 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	— / —	— / —
other Total, other adverse events	10 / 25	6 / 25
serious Total, serious adverse events	0 / 25	0 / 25

Outcome results

Primary

Number of Colposcopic Findings (Baseline and After One Week of Product Use)

Comparison of colposcopic findings between baseline visits and after one week of twice-daily application of Tenofovir 1% gel with either a user-filled or prefilled applicator

Time frame: 7 days

Population: The number of participants for analysis was determined by counting the number of participants with colposcopic findings and baseline and after one week of product use.

Arm	Measure	Group	Value (NUMBER)
User-Filled Applicator	Number of Colposcopic Findings (Baseline and After One Week of Product Use)	Laceration external genitalia	2 colposcopic findings
User-Filled Applicator	Number of Colposcopic Findings (Baseline and After One Week of Product Use)	Petechiae (iatrogenic)	1 colposcopic findings
User-Filled Applicator	Number of Colposcopic Findings (Baseline and After One Week of Product Use)	Peeling cervic or vagina	1 colposcopic findings
User-Filled Applicator	Number of Colposcopic Findings (Baseline and After One Week of Product Use)	Ecchymosis left lateral vaginal wall (iatrogenic)	1 colposcopic findings
User-Filled Applicator	Number of Colposcopic Findings (Baseline and After One Week of Product Use)	Petechiae	3 colposcopic findings
Prefilled Applicator	Number of Colposcopic Findings (Baseline and After One Week of Product Use)	Ecchymosis left lateral vaginal wall (iatrogenic)	0 colposcopic findings
Prefilled Applicator	Number of Colposcopic Findings (Baseline and After One Week of Product Use)	Petechiae	0 colposcopic findings
Prefilled Applicator	Number of Colposcopic Findings (Baseline and After One Week of Product Use)	Laceration external genitalia	0 colposcopic findings
Prefilled Applicator	Number of Colposcopic Findings (Baseline and After One Week of Product Use)	Peeling cervic or vagina	3 colposcopic findings
Prefilled Applicator	Number of Colposcopic Findings (Baseline and After One Week of Product Use)	Petechiae (iatrogenic)	1 colposcopic findings

Comparison: Fishers exact test was used to compare the frequency of non-iatrogenic colposcopic findings at baseline and follow-up visits (after one week of twice-daily product use).p-value: 0.487Fisher Exact

Secondary

Dosing Accuracy (% of Target Dose Delivered)

The target dose for Tenofovir gel in this study was 4.0ml, which is the volume of Tenofovir being used in current microbicide clinical trials. The average dose delivered for each applicator was compared with the intended target dose of 4.0ml.

Time frame: 3 dose delivery measurements during 1 week of product use

Population: Per protocol all participants were included in the analysis.

Arm	Measure	Value (NUMBER)
User-Filled Applicator	Dosing Accuracy (% of Target Dose Delivered)	96 percent of target dose delivered
Prefilled Applicator	Dosing Accuracy (% of Target Dose Delivered)	NA percent of target dose delivered

Secondary

Dosing Precision, 10% (Expressed Volume)

A 10% range was calculated around the average expressed volume of 3.83ml to determine how many applicators delivered a dose within this range (+/-10% of average volume)

Time frame: 3 dose delivery measurements during 1 week of product use

Population: Per protocol all participants were included in the analysis.

Arm	Measure	Value (NUMBER)
User-Filled Applicator	Dosing Precision, 10% (Expressed Volume)	64 doses
Prefilled Applicator	Dosing Precision, 10% (Expressed Volume)	NA doses

Secondary

Dosing Precision, 5% (Expressed Volume)

A 5% range was calculated around the average expressed volume of 3.83ml to determine how many applicators delivered a dose within this range (+/-5% of average volume)

Time frame: 3 dose delivery measurements during 1 week of product use

Population: Per protocol all participants were included in the analysis.

Arm	Measure	Value (NUMBER)
User-Filled Applicator	Dosing Precision, 5% (Expressed Volume)	48 doses
Prefilled Applicator	Dosing Precision, 5% (Expressed Volume)	NA doses

Secondary

Dosing Volume (Expressed Volume)

At each dose delivery visit, the applicator was weighed prior to vaginal insertion and after use. The volume of gel expressed was measured using the following data: weight of filled applicator, weight of emptied applicator, the average weight of an empty applicator, and gel density.

Time frame: 3 dose delivery measurements during 1 week of product use

Population: Per protocol, all participants were included in the analysis.

Arm	Measure	Value (MEAN)	Dispersion
User-Filled Applicator	Dosing Volume (Expressed Volume)	3.83 ml	Standard Deviation 0.35
Prefilled Applicator	Dosing Volume (Expressed Volume)	NA ml	—

Secondary

Filled Volume

At each dose delivery visit, the applicator was weighed, prior to vaginal insertion. For the user-filled applicator, the participant handed the applicator to the investigator after filling with gel from the multidose tube. The applicator was then weighed and returned to the participant for insertion. For the prefilled applicator, the participant inserted the plunger into the barrel, and then handed the applicator to the investigator for weighing.

Time frame: 3 dose delivery measurements during 1 week of product use

Population: Per protocol all participants were included in the analysis.

Arm	Measure	Value (MEAN)	Dispersion
User-Filled Applicator	Filled Volume	4.22 ml	Standard Deviation 0.24
Prefilled Applicator	Filled Volume	4.11 ml	Standard Deviation 0.07

Secondary

Filling Accuracy (% of Target Dose)

The target dose for Tenofovir gel in this study was 4.0ml, which is the volume of Tenofovir being used in current microbicide clinical trials. The filled volume for each applicator was compared with the intended target dose of 4.0ml.

Time frame: 3 dose delivery measurements during 1 week of product use

Population: Per protocol all participants were included in the analysis.

Arm	Measure	Value (NUMBER)
User-Filled Applicator	Filling Accuracy (% of Target Dose)	105.5 % of target dose filled into applicator
Prefilled Applicator	Filling Accuracy (% of Target Dose)	102.8 % of target dose filled into applicator

Secondary

Filling Precision (10% Range)

A 10% range was calculated around the average filled volumes to determine how many applicators were filled within this range (+/-10% of average volume)

Time frame: 3 dose delivery measurements during 1 week of product use

Population: Per protocol all participants were included in the analysis.

Arm	Measure	Value (NUMBER)
User-Filled Applicator	Filling Precision (10% Range)	74 doses
Prefilled Applicator	Filling Precision (10% Range)	75 doses

Secondary

Filling Precision (5% Range)

A 5% range was calculated around the average filled volumes to determine how many applicators were filled within this range (+/-5% of average volume)

Time frame: 3 dose delivery measurements during 1 week of product use

Population: Per protocol all participants were included in the analysis.

Arm	Measure	Value (NUMBER)
User-Filled Applicator	Filling Precision (5% Range)	69 doses
Prefilled Applicator	Filling Precision (5% Range)	75 doses

Secondary

Number of Participants Reporting Applicator Easy to Fill

Participants were asked to describe the process of filling the user-filled applicator. Response categories included easy, moderately difficult, and difficult. Since ease of filling only applies to the user-filled applicator, this question was not applicable for the prefilled applicator.