Trial Outcomes & Findings for PK Study of Rifampicin Interactions With DMPA and Efavirenz in TB (NCT NCT02412436)

NCT ID: NCT02412436

Last Updated: 2019-07-01

Results Overview

The percent of participants with plasma DMPA concentrations below 0.1 ng/mL was calculated with an exact Clopper-Pearson 95% confidence interval. Suppression of ovulation generally occurs as long as the DMPA level is =\> 0.1 ng/mL.

• Recruitment status: COMPLETED
• Study phase: PHASE2
• Target enrollment: 62 participants
• Primary outcome timeframe: Week 12
• Results posted on: 2019-07-01

Participant Flow

Study participants were recruited at five ACTG Clinical Research Sites in four countries (two sites from South Africa and one site from each of Botswana, Kenya, and Zimbabwe) between November 2015 and March 2017.

Of the 85 women screened, 62 were deemed eligible and enrolled into this single-arm study.

Participant milestones

Measure	Arm A: Depot Medroxyprogesterone Acetate At study entry/week 0, participants received depot medroxyprogesterone acetate (DMPA) 150 mg administered intramuscularly as a single dose and co-administered with rifampicin (RIF) and efavirenz (EFV).
Overall Study STARTED	62
Overall Study COMPLETED	44
Overall Study NOT COMPLETED	18

Reasons for withdrawal

Measure	Arm A: Depot Medroxyprogesterone Acetate At study entry/week 0, participants received depot medroxyprogesterone acetate (DMPA) 150 mg administered intramuscularly as a single dose and co-administered with rifampicin (RIF) and efavirenz (EFV).
Overall Study Protocol-mandated Discontinuation	7
Overall Study Lost to Follow-up	6
Overall Study Unable to get to clinic	3
Overall Study Death	1
Overall Study Not Willing to Adhere to Requirements	1

Baseline Characteristics

One participant was missing HIV RNA at baseline due to specimen issues.

Baseline characteristics by cohort

Measure	Arm A: Depot Medroxyprogesterone Acetate n=62 Participants At study entry/week 0, participants received depot medroxyprogesterone acetate (DMPA) 150 mg administered intramuscularly as a single dose and co-administered with rifampicin (RIF) and efavirenz (EFV).
Age, Continuous	32 years n=62 Participants
Age, Customized 20-29 years	24 Participants n=62 Participants
Age, Customized 30-39 years	25 Participants n=62 Participants
Age, Customized 40-49 years	13 Participants n=62 Participants
Sex: Female, Male Female	62 Participants n=62 Participants
Sex: Female, Male Male	0 Participants n=62 Participants
Race/Ethnicity, Customized Black African	62 Participants n=62 Participants
Region of Enrollment Botswana	7 Participants n=62 Participants
Region of Enrollment Zimbabwe	8 Participants n=62 Participants
Region of Enrollment Kenya	12 Participants n=62 Participants
Region of Enrollment South Africa	35 Participants n=62 Participants
Body Mass Index (BMI)	20.8 kg/m^2 n=62 Participants
HIV Antiretroviral Therapy EFV + two NRTIs	62 Participants n=62 Participants
HIV Antiretroviral Therapy EFV + more than two NRTIs	0 Participants n=62 Participants
HIV RNA < 400 copies/mL	52 Participants n=61 Participants • One participant was missing HIV RNA at baseline due to specimen issues.
HIV RNA => 400 copies/mL	9 Participants n=61 Participants • One participant was missing HIV RNA at baseline due to specimen issues.
CD4+ Cell Count	407 cells/mm^3 n=62 Participants
TB Treatment RIF and INH	52 Participants n=62 Participants
TB Treatment RIF, INH, and ethambutol	10 Participants n=62 Participants

PRIMARY outcome

Timeframe: Week 12

Population: Participants who did not have DMPA concentrations at weeks 10 and 12 were excluded from the analysis

The percent of participants with plasma DMPA concentrations below 0.1 ng/mL was calculated with an exact Clopper-Pearson 95% confidence interval. Suppression of ovulation generally occurs as long as the DMPA level is => 0.1 ng/mL.

Outcome measures

Measure	Arm A: Depot Medroxyprogesterone Acetate n=42 Participants At study entry/week 0, participants received depot medroxyprogesterone acetate (DMPA) 150 mg administered intramuscularly as a single dose and co-administered with rifampicin (RIF) and efavirenz (EFV).
Percent of Participants With DMPA Concentrations Below 0.1 ng/mL at Week 12	11.9 percentage of participants Interval 4.0 to 25.6

PRIMARY outcome

Timeframe: Week 12

Population: Participants who did not have progesterone concentrations at weeks 10 and 12 were excluded from the analysis.

The percent of participants with plasma progesterone levels above 1 ng/mL was calculated with an exact Clopper-Pearson 95% confidence interval. Ovulation generally occurs when the progesterone level is > 5 ng/mL. If there were participants with plasma progesterone levels > 1 ng/mL, then the percent of participants with plasma progesterone levels > 5 ng/mL would have been calculated by study week.

Outcome measures

Measure	Arm A: Depot Medroxyprogesterone Acetate n=42 Participants At study entry/week 0, participants received depot medroxyprogesterone acetate (DMPA) 150 mg administered intramuscularly as a single dose and co-administered with rifampicin (RIF) and efavirenz (EFV).
Percent of Participants With Progesterone Levels Above 1 ng/mL at Week 12	0.0 percentage of participants Interval 0.0 to 8.4

SECONDARY outcome

Timeframe: Weeks 2, 4, 6, 8, and 10

Population: Participants who did not have a DMPA concentration at the analysis week of interest were excluded from each analysis as appropriate. For example, participants missing a DMPA concentration at week 4 were excluded from the week 4 analysis.

The percents of participants with plasma DMPA concentrations below 0.1 ng/mL at weeks 2, 4, 6, 8, and 10 were calculated with exact Clopper-Pearson 95% confidence intervals. Suppression of ovulation generally occurs as long as the DMPA level is => 0.1 ng/mL.

Outcome measures

Measure	Arm A: Depot Medroxyprogesterone Acetate n=42 Participants At study entry/week 0, participants received depot medroxyprogesterone acetate (DMPA) 150 mg administered intramuscularly as a single dose and co-administered with rifampicin (RIF) and efavirenz (EFV).
Percent of Participants With DMPA Concentrations Below 0.1 ng/mL at Weeks 2, 4, 6, 8, and 10 Week 2 DMPA < 0.1 ng/mL	0.0 percentage of participants Interval 0.0 to 8.8
Percent of Participants With DMPA Concentrations Below 0.1 ng/mL at Weeks 2, 4, 6, 8, and 10 Week 4 DMPA < 0.1 ng/mL	0.0 percentage of participants Interval 0.0 to 8.8
Percent of Participants With DMPA Concentrations Below 0.1 ng/mL at Weeks 2, 4, 6, 8, and 10 Week 6 DMPA < 0.1 ng/mL	0.0 percentage of participants Interval 0.0 to 8.6
Percent of Participants With DMPA Concentrations Below 0.1 ng/mL at Weeks 2, 4, 6, 8, and 10 Week 8 DMPA < 0.1 ng/mL	0.0 percentage of participants Interval 0.0 to 8.4
Percent of Participants With DMPA Concentrations Below 0.1 ng/mL at Weeks 2, 4, 6, 8, and 10 Week 10 DMPA < 0.1 ng/mL	2.4 percentage of participants Interval 0.1 to 12.6

SECONDARY outcome

Timeframe: Weeks 0, 2, 4, 6, 8, 10, and 12

Population: Participants who did not have DMPA concentrations at weeks 10 and 12 were excluded from the analysis.

The cumulative percentage of participants having a DMPA concentration less than 0.1 ng/mL at week 12 was calculated using a Kaplan-Meier estimator with an associated standard error. The confidence interval was calculated using a log-log transformation. Suppression of ovulation generally occurs as long as the DMPA level is => 0.1 ng/mL.

Outcome measures

Measure	Arm A: Depot Medroxyprogesterone Acetate n=42 Participants At study entry/week 0, participants received depot medroxyprogesterone acetate (DMPA) 150 mg administered intramuscularly as a single dose and co-administered with rifampicin (RIF) and efavirenz (EFV).
Cumulative Percentage of Participants With DMPA < 0.1 ng/mL	11.9 cumulative percentage of participants Interval 5.1 to 26.3

SECONDARY outcome

Timeframe: Weeks 0, 2, 4, 6, 8, 10, and 12

Population: Participants who did not have DMPA concentrations at weeks 10 and 12 were excluded from the analysis.

Describe the DMPA plasma area under the curve (AUC) between 0 and 12 weeks, where AUC(0-12wks) was calculated using non-compartmental methods.The Week 0 time point was drawn prior to DMPA injection.

Outcome measures

Measure	Arm A: Depot Medroxyprogesterone Acetate n=42 Participants At study entry/week 0, participants received depot medroxyprogesterone acetate (DMPA) 150 mg administered intramuscularly as a single dose and co-administered with rifampicin (RIF) and efavirenz (EFV).
DMPA AUC	7.63 ng*week/mL Interval 5.39 to 11.42

SECONDARY outcome

Timeframe: Weeks 0, 2, 4, 6, 8, 10, and 12

Population: Participants who did not have DMPA concentrations at weeks 10 and 12 were excluded from the analysis.

Describe the DMPA minimum observed concentration (Cmin) between 0 and 12 weeks. The Week 0 time point was drawn prior to DMPA injection.

Outcome measures

Measure	Arm A: Depot Medroxyprogesterone Acetate n=42 Participants At study entry/week 0, participants received depot medroxyprogesterone acetate (DMPA) 150 mg administered intramuscularly as a single dose and co-administered with rifampicin (RIF) and efavirenz (EFV).
DMPA Cmin	0.33 ng/mL Interval 0.21 to 0.49

SECONDARY outcome

Timeframe: Weeks 0, 2, 4, 6, 8, 10, and 12

Population: Participants who did not have DMPA concentrations at weeks 10 and 12 were excluded from the analysis.

Describe the DMPA maximum observed concentration (Cmax) between 0 and 12 weeks. The Week 0 time point was drawn prior to DMPA injection.

Outcome measures

Measure	Arm A: Depot Medroxyprogesterone Acetate n=42 Participants At study entry/week 0, participants received depot medroxyprogesterone acetate (DMPA) 150 mg administered intramuscularly as a single dose and co-administered with rifampicin (RIF) and efavirenz (EFV).
DMPA Cmax	1.04 ng/mL Interval 0.67 to 1.66

SECONDARY outcome

Timeframe: Weeks 0, 2, 4, 6, 8, 10, and 12

Population: Participants who did not have DMPA concentrations at weeks 10 and 12 were excluded from the analysis.

Describe the apparent DMPA clearance (CL/F) between 0 and 12 weeks. The Week 0 time point was drawn prior to DMPA injection.

Outcome measures

Measure	Arm A: Depot Medroxyprogesterone Acetate n=42 Participants At study entry/week 0, participants received depot medroxyprogesterone acetate (DMPA) 150 mg administered intramuscularly as a single dose and co-administered with rifampicin (RIF) and efavirenz (EFV).
DMPA CL/F	19681 L/week Interval 13139.0 to 27845.0

SECONDARY outcome

Timeframe: Weeks 2, 4, 6, 8, 10, and 12

Population: All enrolled participants were included in the analysis.

The percent of participants who experienced a grade 3 (severe) or higher sign/symptom or laboratory abnormality were calculated with an exact Clopper-Pearson 95% confidence interval. Events were graded (1=mild, 2=moderate, 3=severe, 4=life-threatening, 5=death) according to the DAIDS AE Grading Table (V1.0).

Outcome measures

Measure	Arm A: Depot Medroxyprogesterone Acetate n=62 Participants At study entry/week 0, participants received depot medroxyprogesterone acetate (DMPA) 150 mg administered intramuscularly as a single dose and co-administered with rifampicin (RIF) and efavirenz (EFV).
Percent of Participants Who Experienced a Grade 3 or Higher Sign/Symptom or Laboratory Abnormality	12.9 percentage of participants Interval 5.7 to 23.9

SECONDARY outcome

Timeframe: Weeks 0, 2, 4, 6, 8, 10, and 12

Population: Participants who did not have DMPA concentrations at weeks 10 and 12 were excluded from the analysis.

Describe the terminal elimination half-life of DMPA (t½) between 0 and 12 weeks, where t½ was calculated using nonlinear mixed-effects (NLME) modelling. The Week 0 time point was drawn prior to DMPA injection.

Outcome measures

Measure	Arm A: Depot Medroxyprogesterone Acetate n=42 Participants At study entry/week 0, participants received depot medroxyprogesterone acetate (DMPA) 150 mg administered intramuscularly as a single dose and co-administered with rifampicin (RIF) and efavirenz (EFV).
DMPA Half-life	55 hours Interval 23.0 to 83.0

SECONDARY outcome

Timeframe: Weeks 0, 2, 4, 6, 8, 10, and 12

Population: Participants who did not have DMPA concentrations at weeks 10 and 12 were excluded from the analysis.

Describe the time at which DMPA levels drop below the threshold of 0.1 ng/mL, based on participant-specific estimated elimination slopes from nonlinear mixed-effects (NLME) models. The Week 0 time point was drawn prior to DMPA injection.

Outcome measures

Measure	Arm A: Depot Medroxyprogesterone Acetate n=42 Participants At study entry/week 0, participants received depot medroxyprogesterone acetate (DMPA) 150 mg administered intramuscularly as a single dose and co-administered with rifampicin (RIF) and efavirenz (EFV).
Time at Which Participant-specific Estimated Elimination Slopes for DMPA Level Cross the Threshold of 0.1 ng/mL	74.2 days Interval 70.1 to 77.6

Adverse Events

Arm A: Depot Medroxyprogesterone Acetate

Serious events: 1 serious events

Other events: 6 other events

Deaths: 1 deaths

Serious adverse events

Measure

Arm A: Depot Medroxyprogesterone Acetate n=62 participants at risk At study entry/week 0, participants received depot medroxyprogesterone acetate (DMPA) 150 mg administered intramuscularly as a single dose and co-administered with rifampicin (RIF) and efavirenz (EFV).

Blood and lymphatic system disorders Bicytopenia

1.6% 1/62 • Week 0 to either premature study discontinuation or Week 12 The study protocol required reporting of all new diagnoses; all new signs and symptoms Grade 3 (severe) or higher; all new all Grade 3 or higher laboratory values; and all signs, symptoms, and laboratory values that led to a change in treatment, regardless of grade. Events were graded (1=mild, 2=moderate, 3=severe, 4=life-threatening, 5=death) according to the DAIDS AE Grading Table (V1.0) and reported per the EAE Manual (V2.0). All enrolled participants were included.

Other adverse events

Measure

Arm A: Depot Medroxyprogesterone Acetate n=62 participants at risk At study entry/week 0, participants received depot medroxyprogesterone acetate (DMPA) 150 mg administered intramuscularly as a single dose and co-administered with rifampicin (RIF) and efavirenz (EFV).

Investigations Neutrophil count decreased

9.7% 6/62 • Week 0 to either premature study discontinuation or Week 12 The study protocol required reporting of all new diagnoses; all new signs and symptoms Grade 3 (severe) or higher; all new all Grade 3 or higher laboratory values; and all signs, symptoms, and laboratory values that led to a change in treatment, regardless of grade. Events were graded (1=mild, 2=moderate, 3=severe, 4=life-threatening, 5=death) according to the DAIDS AE Grading Table (V1.0) and reported per the EAE Manual (V2.0). All enrolled participants were included.

Additional Information

ACTG Clinicaltrials.gov Coordinator

ACTG Network Coordinating Center, Social and Scientific Systems, Inc.

Phone: (301) 628-3313

Email: ACTGCT.Gov@s-3.com

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place