Cervix Cancer, Cervix Intraepithelial Neoplasia Grade 3, Cervix; Intraepithelial Neoplasia, Grade I, Cervix; Intraepithelial Neoplasia, Grade II
Conditions
Keywords
Artesunate, dihydroartemisinin, pharmacokinetics
Brief summary
This study investigates the pharmacokinetics of Artesunate (AS) and dihydroartemisinin (DHA), the active metabolite of Artesunate, following intravaginal use at the dosing and frequency being studied for cervical precancer treatment. A secondary objective is to investigate safety among study participants.
Detailed description
Due to lack of access to primary and secondary prevention, women living in low-and middle-income countries bear a disproportionate burden of cervical cancer, accounting for 90% of new cases and 85% of deaths globally. Cervical cancer can be prevented through vaccination against Human papillomavirus (HPV), whose infection is required to develop cervical cancer. Among unvaccinated women, screening for HPV or cervical precancer allows identification of precancerous lesions - primarily cervical intraepithelial neoplasia grade 2 or 3 (CIN2/3), that can be treated and cured, to prevent progression to cancer. Most CIN2/3 lesions that are left untreated will progress to invasive cervical cancer. Current treatments for CIN2/3 in both high- and low-resource countries (LMICs) require trained health care providers, who are often out of reach for many women, particularly in rural areas in LMICs. Lack of access to precancer treatment following screening in LMICs in part accounts for the high burden of incident cervical cancer. Preclinical data have demonstrated pro-apoptotic effects of Artesunate (AS), a commonly available drug with an excellent safety profile in oral, rectal and intravenous routes primarily used to treat malaria in LMICs. This led to a recent Phase I study in the United States that demonstrated that self-administered vaginal artesunate inserts (pessaries) are safe, well-tolerated, and demonstrate efficacy for treatment of CIN2/3. Based on the mechanism of action, the clinical safety profile, and widespread availability as a generic drug on the World Health Organization (WHO) List of Essential Medications, vaginal artesunate inserts (pessaries), if backed by data from randomized trials, may offer patient-controlled and access cervical precancer treatment method for women in LMICs who face the greatest burden of cervical cancer and have difficulty accessing skilled providers for precancer treatment. However, given that artesunate is a well-known drug used in malaria treatment, it is critical to ensure that vaginal application of the drug will not promote resistance for use in malaria treatment.
Interventions
Subjects will use the study pessaries, placed in the vagina every day for 5 consecutive days.
DIAGNOSTIC_TESTblood draws for pharmacokinetics of the study drug
On day 5, all participants will have their blood draws before they use the pessary, and at 15 min, 30 mins, 1 hour, 2 hours, 4 hours, 6 hours, and 8 hours after inserting the pessary. Blood samples will be tested for the pharmacokinetics of the study drug.
Sponsors
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
UNC Lineberger Comprehensive Cancer Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
1. Age 18 years or older 2. Negative pregnancy test at screening 3. Willingness to use contraception (hormonal or barrier) during the 5-day study dosing phase if of childbearing age (less than 50 years of age) 4. Ability and willingness to provide informed consent.
Exclusion criteria
1. Current pregnancy or breastfeeding status 2. History of total hysterectomy 3. Known allergy to Artesunate. 4. Have a medical comorbidity that in the opinion of the investigator would interfere with study participation. 5. Currently receiving artemisinin-based agents for malaria treatment or completed artemisinin-based treatment within the previous 3 days.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| To Determine the Area Under the Plasma Concentration Versus Time Curve (AUC) of Dihydroartemisinin | Day 5 | To determine the area under the plasma concentration versus time curve (AUC) of dihydroartemisinin (DHA) following five consecutive days of self-administration of 200mg Artesunate vaginal inserts (pessaries). Mean DHA AUC will be submitted. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| To Determine the Maximum Concentration of Artesunate (AS) | Day 5 | To determine the maximum concentration of Artesunate (AS) (Cmax) following five consecutive days of self-administration of 200mg Artesunate vaginal inserts (pessaries) among healthy women. Mean artesunate Cmax (ng/ml) value will be submitted. |
| To Determine the Maximum Concentration of Dihydroartemisinin (DHA) (Cmax) | Day 5 | To determine the maximum concentration of dihydroartemisinin (DHA) (Cmax) following five consecutive days of self-administration of 200mg Artesunate vaginal inserts (pessaries) among healthy women. Mean DHA Cmax (ng/ml) value will be submitted. |
| To Determine the Time to Maximum Concentration (Tmax) of Artesunate (AS) Following Five Consecutive Days | Day 5 | To determine the time to maximum concentration (Tmax) of Artesunate (AS) following five consecutive days of self-administration of 200mg Artesunate vaginal inserts (pessaries) among healthy women. Mean DHA Tmax (hours) value will be submitted. |
| To Determine the Time to Maximum Concentration (Tmax) of Dihydroartemisinin (DHA | Day 5 | To determine the time to maximum concentration (Tmax) of dihydroartemisinin (DHA) following five consecutive days of self-administration of 200mg Artesunate vaginal inserts (pessaries) among healthy women. Mean (Tmax) will be submitted. |
| To Determine the Half-life (t1/2) of Artesunate (AS) | Day 5 | To determine the half-life (t1/2) of Artesunate (AS) following five consecutive days of self-administration of 200mg Artesunate vaginal inserts (pessaries) among healthy women. Mean Artesunate half-life (t1/2) (mins) will be submitted. |
| To Determine the Area Under the Plasma Concentration Versus Time Curve (AUC) of Artesunate (AS) | Day 5 | To determine the area under the plasma concentration versus time curve (AUC) of Artesunate (AS) following five consecutive days of self-administration of 200mg Artesunate vaginal inserts (pessaries). Mean artesunate AUC will be submitted. |
| To Determine the Apparent Clearance (CL/F) of Artesunate (AS) | Day 5 | To determine the apparent clearance (CL/F) of Artesunate (AS) following five consecutive days of self-administration of 200mg Artesunate vaginal inserts (pessaries) among healthy women. Mean Artesunate clearance (L/Kg/hr) will be submitted. |
| To Determine the Apparent Clearance (CL/F) of Dihydroartemisinin (DHA) | Day 5 | To determine the apparent clearance (CL/F) of dihydroartemisinin (DHA) following five consecutive days of self-administration of 200mg Artesunate vaginal inserts (pessaries) among healthy women. Mean DHA clearance (L/Kg/hr) will be submitted. |
| To Determine the Volume of Distribution (V/F) of Artesunate (AS) | Day 5 | To determine the volume of distribution (V/F) of Artesunate (AS) following five consecutive days of self-administration of 200mg Artesunate vaginal inserts (pessaries) among healthy women. Mean Artesunate volume of distribution (L/Kg) will be submitted. |
| To Determine the Volume of Distribution (V/F) of Dihydroartemisinin (DHA) | Day 5 | To determine the volume of distribution (V/F) of dihydroartemisinin (DHA) following five consecutive days of self-administration of 200mg Artesunate vaginal inserts (pessaries) among healthy women. Mean dihydroartemisinin (DHA) of distribution (V/F) will be submitted. |
| Type, Frequency, Severity, and Duration of Adverse Events | Up to day 10 days | To investigate the safety of a 5-day course of self-administered intravaginal artesunate vaginal inserts (pessary) in women. Type, frequency, severity, and duration of reported and observed adverse events (AEs) using the U.S National Cancer Institute Common Terminology Criteria for Adverse Events, v5.0 (CTCAE 5.0) and the Division of AIDS Female Genital Adverse Events Grading Table will be submitted. |
| To Determine the Half-life (t1/2) of Dihydroartemisinin (DHA) | Day 5 | To determine the half-life (t1/2) of dihydroartemisinin (DHA) following five consecutive days of self-administration of 200mg Artesunate vaginal inserts (pessaries) among healthy women. Mean DHA half-life (mins) will be submitted. |
Countries
Kenya
Participant flow
Recruitment details
Participants were recruited in one center in Kenya.
Pre-assignment details
Twelve participants consented and found eligible.
Participants by arm
| Arm | Count |
|---|---|
| Artesunate Vaginal Inserts/ Pessaries Artesunate vaginal inserts/pessaries are used as a treatment for cervical precancerous lesions.
Artesunate pessary: Subjects will use the study pessaries, placed in the vagina every day for 5 consecutive days. | 12 |
| Total | 12 |
Baseline characteristics
| Characteristic | Artesunate Vaginal Inserts/ Pessaries |
|---|---|
| Age, Continuous | 23.3 years STANDARD_DEVIATION 5.1 |
| Current or prior alcohol use No | 3 Participants |
| Current or prior alcohol use Yes | 9 Participants |
| Current or prior tobacco use No | 10 Participants |
| Current or prior tobacco use yes | 2 Participants |
| Electricity available no | 1 Participants |
| Electricity available yes | 11 Participants |
| Level of education College or higher | 2 Participants |
| Level of education Completed Secondary | 10 Participants |
| Marital Status Married | 0 Participants |
| Marital Status Single/Never Married | 12 Participants |
| Occupation other | 1 Participants |
| Occupation Salaried work | 1 Participants |
| Occupation student | 10 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 12 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 0 Participants |
| Region of Enrollment Kenya | 12 participants |
| Sex: Female, Male Female | 12 Participants |
| Sex: Female, Male Male | 0 Participants |
| Tap water available No | 2 Participants |
| Tap water available yes | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 12 |
| other Total, other adverse events | 8 / 12 |
| serious Total, serious adverse events | 0 / 12 |
Outcome results
Primary
To Determine the Area Under the Plasma Concentration Versus Time Curve (AUC) of Dihydroartemisinin
To determine the area under the plasma concentration versus time curve (AUC) of dihydroartemisinin (DHA) following five consecutive days of self-administration of 200mg Artesunate vaginal inserts (pessaries). Mean DHA AUC will be submitted.
Time frame: Day 5
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Artesunate Vaginal Inserts/ Pessaries | To Determine the Area Under the Plasma Concentration Versus Time Curve (AUC) of Dihydroartemisinin | 464.90 ng/mL-h | Standard Deviation 228.7 |
Secondary
To Determine the Apparent Clearance (CL/F) of Artesunate (AS)
To determine the apparent clearance (CL/F) of Artesunate (AS) following five consecutive days of self-administration of 200mg Artesunate vaginal inserts (pessaries) among healthy women. Mean Artesunate clearance (L/Kg/hr) will be submitted.
Time frame: Day 5
Population: The plasma apparent clearance (CL/F) of Artesunate could not be estimated because the concentration versus time profiles of both forms did not reach an elimination phase (i.e., the concentration versus time profile did not decrease) from 0 to 8h post administration of intravaginal artesunate.
Secondary
To Determine the Apparent Clearance (CL/F) of Dihydroartemisinin (DHA)
To determine the apparent clearance (CL/F) of dihydroartemisinin (DHA) following five consecutive days of self-administration of 200mg Artesunate vaginal inserts (pessaries) among healthy women. Mean DHA clearance (L/Kg/hr) will be submitted.
Time frame: Day 5
Population: The plasma apparent clearance (CL/F) of dihydroartemisinin (DHA) could not be estimated because the concentration versus time profiles of both forms did not reach an elimination phase (i.e., the concentration versus time profile did not decrease) from 0 to 8h post administration.
Secondary
To Determine the Area Under the Plasma Concentration Versus Time Curve (AUC) of Artesunate (AS)
To determine the area under the plasma concentration versus time curve (AUC) of Artesunate (AS) following five consecutive days of self-administration of 200mg Artesunate vaginal inserts (pessaries). Mean artesunate AUC will be submitted.
Time frame: Day 5
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Artesunate Vaginal Inserts/ Pessaries | To Determine the Area Under the Plasma Concentration Versus Time Curve (AUC) of Artesunate (AS) | 504.21 ng/mL-h | Standard Deviation 281.11 |
Secondary
To Determine the Half-life (t1/2) of Artesunate (AS)
To determine the half-life (t1/2) of Artesunate (AS) following five consecutive days of self-administration of 200mg Artesunate vaginal inserts (pessaries) among healthy women. Mean Artesunate half-life (t1/2) (mins) will be submitted.
Time frame: Day 5
Population: The plasma half-life of Artesunate could not be estimated because the concentration versus time profiles did not reach an elimination phase (i.e., the concentration versus time profile did not decrease) from 0 to 8h post administration of intravaginal artesunate.
Secondary
To Determine the Half-life (t1/2) of Dihydroartemisinin (DHA)
To determine the half-life (t1/2) of dihydroartemisinin (DHA) following five consecutive days of self-administration of 200mg Artesunate vaginal inserts (pessaries) among healthy women. Mean DHA half-life (mins) will be submitted.
Time frame: Day 5
Population: The plasma half-life of dihydroartemisinin (DHA) could not be estimated because the concentration versus time profiles did not reach an elimination phase (i.e., the concentration versus time profile did not decrease) from 0 to 8h post administration.
Secondary
To Determine the Maximum Concentration of Artesunate (AS)
To determine the maximum concentration of Artesunate (AS) (Cmax) following five consecutive days of self-administration of 200mg Artesunate vaginal inserts (pessaries) among healthy women. Mean artesunate Cmax (ng/ml) value will be submitted.
Time frame: Day 5
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Artesunate Vaginal Inserts/ Pessaries | To Determine the Maximum Concentration of Artesunate (AS) | 83.74 ng/mL | Standard Deviation 42.73 |
Secondary
To Determine the Maximum Concentration of Dihydroartemisinin (DHA) (Cmax)
To determine the maximum concentration of dihydroartemisinin (DHA) (Cmax) following five consecutive days of self-administration of 200mg Artesunate vaginal inserts (pessaries) among healthy women. Mean DHA Cmax (ng/ml) value will be submitted.
Time frame: Day 5
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Artesunate Vaginal Inserts/ Pessaries | To Determine the Maximum Concentration of Dihydroartemisinin (DHA) (Cmax) | 97.00 ng/mL | Standard Deviation 53.12 |
Secondary
To Determine the Time to Maximum Concentration (Tmax) of Artesunate (AS) Following Five Consecutive Days
To determine the time to maximum concentration (Tmax) of Artesunate (AS) following five consecutive days of self-administration of 200mg Artesunate vaginal inserts (pessaries) among healthy women. Mean DHA Tmax (hours) value will be submitted.
Time frame: Day 5
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Artesunate Vaginal Inserts/ Pessaries | To Determine the Time to Maximum Concentration (Tmax) of Artesunate (AS) Following Five Consecutive Days | 4.17 hours | Standard Deviation 1.59 |
Secondary
To Determine the Time to Maximum Concentration (Tmax) of Dihydroartemisinin (DHA
To determine the time to maximum concentration (Tmax) of dihydroartemisinin (DHA) following five consecutive days of self-administration of 200mg Artesunate vaginal inserts (pessaries) among healthy women. Mean (Tmax) will be submitted.
Time frame: Day 5
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Artesunate Vaginal Inserts/ Pessaries | To Determine the Time to Maximum Concentration (Tmax) of Dihydroartemisinin (DHA | 6.33 hours | Standard Deviation 1.67 |
Secondary
To Determine the Volume of Distribution (V/F) of Artesunate (AS)
To determine the volume of distribution (V/F) of Artesunate (AS) following five consecutive days of self-administration of 200mg Artesunate vaginal inserts (pessaries) among healthy women. Mean Artesunate volume of distribution (L/Kg) will be submitted.
Time frame: Day 5
Population: The plasma volume of distribution (V/F) of Artesunate (AS) could not be estimated because the concentration versus time profiles of both forms did not reach an elimination phase (i.e., the concentration versus time profile did not decrease) from 0 to 8h post administration of intravaginal artesunate.
Secondary
To Determine the Volume of Distribution (V/F) of Dihydroartemisinin (DHA)
To determine the volume of distribution (V/F) of dihydroartemisinin (DHA) following five consecutive days of self-administration of 200mg Artesunate vaginal inserts (pessaries) among healthy women. Mean dihydroartemisinin (DHA) of distribution (V/F) will be submitted.
Time frame: Day 5
Population: The plasma volume of distribution (V/F) of dihydroartemisinin (DHA) could not be estimated because the concentration versus time profiles of both forms did not reach an elimination phase (i.e., the concentration versus time profile did not decrease) from 0 to 8h post administration.
Secondary
Type, Frequency, Severity, and Duration of Adverse Events
To investigate the safety of a 5-day course of self-administered intravaginal artesunate vaginal inserts (pessary) in women. Type, frequency, severity, and duration of reported and observed adverse events (AEs) using the U.S National Cancer Institute Common Terminology Criteria for Adverse Events, v5.0 (CTCAE 5.0) and the Division of AIDS Female Genital Adverse Events Grading Table will be submitted.
Time frame: Up to day 10 days
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Artesunate Vaginal Inserts/ Pessaries | Type, Frequency, Severity, and Duration of Adverse Events | abdominal pain Grade 1 | 3 Participants |
| Artesunate Vaginal Inserts/ Pessaries | Type, Frequency, Severity, and Duration of Adverse Events | vaginal discharge Grade 1 | 8 Participants |
| Artesunate Vaginal Inserts/ Pessaries | Type, Frequency, Severity, and Duration of Adverse Events | Toothache- Grade 1 | 1 Participants |
| Artesunate Vaginal Inserts/ Pessaries | Type, Frequency, Severity, and Duration of Adverse Events | vaginal fistula- Grade 2 | 1 Participants |
| Artesunate Vaginal Inserts/ Pessaries | Type, Frequency, Severity, and Duration of Adverse Events | vaginal pruritis- Grade 1 | 1 Participants |