Trial Outcomes & Findings for Phase II Safety and Acceptability of an Investigational Injectable Product, TMC278LA, for Pre-Exposure Prophylaxis (NCT NCT02165202)

Last Updated: 2018-08-27

Results Overview

Number of participants experiencing any Grade 2 or higher clinical and laboratory AEs to evaluate the safety of the injectable product, TMC278 LA (1200 mg dose administered at Weeks 4, 12, 20, 28, 36 and 44), through 48 weeks after initial injection (at Week 52) in women in SSA and the US.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

136 participants

Primary outcome timeframe

Up to 52 weeks

Results posted on

2018-08-27

Participant Flow

Participants will be randomized to either the active product regimen or the placebo arm at enrollment. Participants randomized to active and placebo product will first be prescribed oral TMC278 (rilpivirine) 25 mg capsule and oral placebo capsule, once daily for four weeks as an oral run-in and then will receive IM injections at week 4.

Participant milestones

Participant milestones
Measure	Rilpivirine Arm 1: Participants randomized to the active arm will receive rilpivirine 25 mg capsules once daily for four weeks to be taken orally with a meal. Participants will then receive IM injections of TMC278 LA, 1200 mg dose, at eight week intervals (at Weeks 4, 12, 20, 28, 36 and 44). On each dosing occasion 1200 mg of TMC278 LA will be delivered in two, 2 mL injections, one in each gluteus maximus muscle. All participants will receive a total of six doses (12 IM injections). Rilpivirine: Rilpivirine (TMC278), a non-nucleoside reverse transcriptase inhibitor (NNRTI) is a substituted diaryl-pyrimidine (DAPY) derivative with potent antiviral activity against HIV. It is approved by the US FDA for once daily oral administration and is effective as part of treatment for ARV-na'ive HIV-infected patients as rilpivirine 25 mg capsules. It is also co-formulated with TDF and FTC for use as a once- daily single fixed-dose combination (Complera™).	Placebo Arm 2: Participants randomized to the placebo arm will receive placebo capsules once daily for four weeks to be taken orally with a meal. Participants will then receive IM injections of saline (0.9% NaCI) at eight week intervals (at Weeks 4, 12, 20, 28, 36 and 44). On each dosing occasion placebo will be delivered in two, 2 mL injections, one in each gluteus maximus muscle. All participants will receive a total of six doses (12 IM injections). Placebo: Participants randomized to the placebo arm will receive oral placebo capsules prior to injection of saline solution (0.9%NaCI). Participants will be observed while taking the study product by site staff on approximately six occasions during the first two weeks of the oral run-in at Week 0 (Enrollment), at Week 2 (Oral Run-in Safety Visit), and on four separate DOT visits between Weeks 0 and 2. Cervicovaginal and rectal fluid will be collected for PK studies at a single follow-up visit.
Oral Phase STARTED	91	45
Oral Phase COMPLETED	80	42
Oral Phase NOT COMPLETED	11	3
Injection Phase STARTED	80	42
Injection Phase COMPLETED	70	36
Injection Phase NOT COMPLETED	10	6

Reasons for withdrawal

Reasons for withdrawal
Measure	Rilpivirine Arm 1: Participants randomized to the active arm will receive rilpivirine 25 mg capsules once daily for four weeks to be taken orally with a meal. Participants will then receive IM injections of TMC278 LA, 1200 mg dose, at eight week intervals (at Weeks 4, 12, 20, 28, 36 and 44). On each dosing occasion 1200 mg of TMC278 LA will be delivered in two, 2 mL injections, one in each gluteus maximus muscle. All participants will receive a total of six doses (12 IM injections). Rilpivirine: Rilpivirine (TMC278), a non-nucleoside reverse transcriptase inhibitor (NNRTI) is a substituted diaryl-pyrimidine (DAPY) derivative with potent antiviral activity against HIV. It is approved by the US FDA for once daily oral administration and is effective as part of treatment for ARV-na'ive HIV-infected patients as rilpivirine 25 mg capsules. It is also co-formulated with TDF and FTC for use as a once- daily single fixed-dose combination (Complera™).	Placebo Arm 2: Participants randomized to the placebo arm will receive placebo capsules once daily for four weeks to be taken orally with a meal. Participants will then receive IM injections of saline (0.9% NaCI) at eight week intervals (at Weeks 4, 12, 20, 28, 36 and 44). On each dosing occasion placebo will be delivered in two, 2 mL injections, one in each gluteus maximus muscle. All participants will receive a total of six doses (12 IM injections). Placebo: Participants randomized to the placebo arm will receive oral placebo capsules prior to injection of saline solution (0.9%NaCI). Participants will be observed while taking the study product by site staff on approximately six occasions during the first two weeks of the oral run-in at Week 0 (Enrollment), at Week 2 (Oral Run-in Safety Visit), and on four separate DOT visits between Weeks 0 and 2. Cervicovaginal and rectal fluid will be collected for PK studies at a single follow-up visit.
Oral Phase Refused further participation	5	1
Oral Phase Study product Related Toxicity	1	0
Oral Phase Unable to contact Participant	1	1
Oral Phase Clinical reasons	1	0
Oral Phase QTcF>500 ms or increase of>60 ms	1	0
Oral Phase CMC advised termination	1	0
Oral Phase Relocated, no follow-up planned	1	0
Oral Phase Abnormal EKG	0	1
Injection Phase Abnormal Lab Value	5	1
Injection Phase Reactive HIV or HIV Suspected	0	2
Injection Phase Unable to attend within Visit Window	1	0
Injection Phase QTcF>500 ms or increase of>60 ms	0	1
Injection Phase End of Study	2	1
Injection Phase Study Product related Toxicity	1	0
Injection Phase No longer interested	0	1
Injection Phase Participant unwilling to comply	1	0

Baseline Characteristics

1 participant was missing weight measurement

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Rilpivirine n=91 Participants Arm 1: Participants randomized to the active arm will receive rilpivirine 25 mg capsules once daily for four weeks to be taken orally with a meal. Participants will then receive IM injections of TMC278 LA, 1200 mg dose, at eight week intervals (at Weeks 4, 12, 20, 28, 36 and 44). On each dosing occasion 1200 mg of TMC278 LA will be delivered in two, 2 mL injections, one in each gluteus maximus muscle. All participants will receive a total of six doses (12 IM injections). Rilpivirine: Rilpivirine (TMC278), a non-nucleoside reverse transcriptase inhibitor (NNRTI) is a substituted diaryl-pyrimidine (DAPY) derivative with potent antiviral activity against HIV. It is approved by the US FDA for once daily oral administration and is effective as part of treatment for ARV-na'ive HIV-infected patients as rilpivirine 25 mg capsules. It is also co-formulated with TDF and FTC for use as a once- daily single fixed-dose combination (Complera™).	Placebo n=45 Participants Arm 2: Participants randomized to the placebo arm will receive placebo capsules once daily for four weeks to be taken orally with a meal. Participants will then receive IM injections of saline (0.9% NaCI) at eight week intervals (at Weeks 4, 12, 20, 28, 36 and 44). On each dosing occasion placebo will be delivered in two, 2 mL injections, one in each gluteus maximus muscle. All participants will receive a total of six doses (12 IM injections). Placebo: Participants randomized to the placebo arm will receive oral placebo capsules prior to injection of saline solution (0.9%NaCI). Participants will be observed while taking the study product by site staff on approximately six occasions during the first two weeks of the oral run-in at Week 0 (Enrollment), at Week 2 (Oral Run-in Safety Visit), and on four separate DOT visits between Weeks 0 and 2. Cervicovaginal and rectal fluid will be collected for PK studies at a single follow-up visit.	Total n=136 Participants Total of all reporting groups
Age, Continuous	31 years n=91 Participants	30 years n=45 Participants	31 years n=136 Participants
Sex: Female, Male Female	91 Participants n=91 Participants	45 Participants n=45 Participants	136 Participants n=136 Participants
Sex: Female, Male Male	0 Participants n=91 Participants	0 Participants n=45 Participants	0 Participants n=136 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	6 Participants n=91 Participants	3 Participants n=45 Participants	9 Participants n=136 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	85 Participants n=91 Participants	42 Participants n=45 Participants	127 Participants n=136 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=91 Participants	0 Participants n=45 Participants	0 Participants n=136 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=91 Participants	0 Participants n=45 Participants	0 Participants n=136 Participants
Race (NIH/OMB) Asian	1 Participants n=91 Participants	0 Participants n=45 Participants	1 Participants n=136 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=91 Participants	0 Participants n=45 Participants	0 Participants n=136 Participants
Race (NIH/OMB) Black or African American	86 Participants n=91 Participants	42 Participants n=45 Participants	128 Participants n=136 Participants
Race (NIH/OMB) White	3 Participants n=91 Participants	0 Participants n=45 Participants	3 Participants n=136 Participants
Race (NIH/OMB) More than one race	0 Participants n=91 Participants	1 Participants n=45 Participants	1 Participants n=136 Participants
Race (NIH/OMB) Unknown or Not Reported	1 Participants n=91 Participants	2 Participants n=45 Participants	3 Participants n=136 Participants
Region of Enrollment United States	24 Participants n=91 Participants	12 Participants n=45 Participants	36 Participants n=136 Participants
Region of Enrollment Zimbabwe	35 Participants n=91 Participants	17 Participants n=45 Participants	52 Participants n=136 Participants
Region of Enrollment South Africa	32 Participants n=91 Participants	16 Participants n=45 Participants	48 Participants n=136 Participants
Age, Categorical 18-25	22 Participants n=91 Participants	14 Participants n=45 Participants	36 Participants n=136 Participants
Age, Categorical 26-35	45 Participants n=91 Participants	14 Participants n=45 Participants	59 Participants n=136 Participants
Age, Categorical 36-45	24 Participants n=91 Participants	17 Participants n=45 Participants	41 Participants n=136 Participants
Height	159 cm n=91 Participants	158 cm n=45 Participants	158 cm n=136 Participants
Weight	76 kg n=90 Participants • 1 participant was missing weight measurement	73 kg n=45 Participants • 1 participant was missing weight measurement	75 kg n=135 Participants • 1 participant was missing weight measurement
BMI	31 kg/m^2 n=90 Participants • 1 participant was missing BMI	29 kg/m^2 n=45 Participants • 1 participant was missing BMI	30 kg/m^2 n=135 Participants • 1 participant was missing BMI
Marital Status Married/civil union/legal partnership	45 Participants n=91 Participants	18 Participants n=45 Participants	63 Participants n=136 Participants
Marital Status Living with primary or main partner	5 Participants n=91 Participants	2 Participants n=45 Participants	7 Participants n=136 Participants
Marital Status Have primary or main partner, not living	15 Participants n=91 Participants	6 Participants n=45 Participants	21 Participants n=136 Participants
Marital Status Single/divorced/widowed	26 Participants n=91 Participants	19 Participants n=45 Participants	45 Participants n=136 Participants
Marital Status Other	0 Participants n=91 Participants	0 Participants n=45 Participants	0 Participants n=136 Participants
Employment Status Not employed	60 Participants n=91 Participants	22 Participants n=45 Participants	82 Participants n=136 Participants
Employment Status Part-time employment	17 Participants n=91 Participants	14 Participants n=45 Participants	31 Participants n=136 Participants
Employment Status Full-time employment	14 Participants n=91 Participants	9 Participants n=45 Participants	23 Participants n=136 Participants
Education No schooling	0 Participants n=91 Participants	0 Participants n=45 Participants	0 Participants n=136 Participants
Education Primary school, not complete	16 Participants n=91 Participants	11 Participants n=45 Participants	27 Participants n=136 Participants
Education Primary school, complete	58 Participants n=91 Participants	27 Participants n=45 Participants	85 Participants n=136 Participants
Education Secondary school, not complete	7 Participants n=91 Participants	3 Participants n=45 Participants	10 Participants n=136 Participants
Education Secondary school, complete	10 Participants n=91 Participants	4 Participants n=45 Participants	14 Participants n=136 Participants
Education Technical training, not complete	0 Participants n=91 Participants	0 Participants n=45 Participants	0 Participants n=136 Participants
Education Technical training, complete	0 Participants n=91 Participants	0 Participants n=45 Participants	0 Participants n=136 Participants
Education College or university, not complete	0 Participants n=91 Participants	0 Participants n=45 Participants	0 Participants n=136 Participants
Education College or university, complete	0 Participants n=91 Participants	0 Participants n=45 Participants	0 Participants n=136 Participants

PRIMARY outcome

Timeframe: Up to 52 weeks

Population: Participants who received at least one injection and were followed up to 52 weeks are included in this analysis.

Outcome measures

Outcome measures
Measure	Rilpivirine n=80 Participants Arm 1: Participants randomized to the active arm will receive rilpivirine 25 mg capsules once daily for four weeks to be taken orally with a meal. Participants will then receive IM injections of TMC278 LA, 1200 mg dose, at eight week intervals (at Weeks 4, 12, 20, 28, 36 and 44). On each dosing occasion 1200 mg of TMC278 LA will be delivered in two, 2 mL injections, one in each gluteus maximus muscle. All participants will receive a total of six doses (12 IM injections). Rilpivirine: Rilpivirine (TMC278), a non-nucleoside reverse transcriptase inhibitor (NNRTI) is a substituted diaryl-pyrimidine (DAPY) derivative with potent antiviral activity against HIV. It is approved by the US FDA for once daily oral administration and is effective as part of treatment for ARV-na'ive HIV-infected patients as rilpivirine 25 mg capsules. It is also co-formulated with TDF and FTC for use as a once- daily single fixed-dose combination (Complera™).	Placebo n=42 Participants Arm 2: Participants randomized to the placebo arm will receive placebo capsules once daily for four weeks to be taken orally with a meal. Participants will then receive IM injections of saline (0.9% NaCI) at eight week intervals (at Weeks 4, 12, 20, 28, 36 and 44). On each dosing occasion placebo will be delivered in two, 2 mL injections, one in each gluteus maximus muscle. All participants will receive a total of six doses (12 IM injections). Placebo: Participants randomized to the placebo arm will receive oral placebo capsules prior to injection of saline solution (0.9%NaCI). Participants will be observed while taking the study product by site staff on approximately six occasions during the first two weeks of the oral run-in at Week 0 (Enrollment), at Week 2 (Oral Run-in Safety Visit), and on four separate DOT visits between Weeks 0 and 2. Cervicovaginal and rectal fluid will be collected for PK studies at a single follow-up visit.
Number of Participants Experiencing Any Grade 2 or Higher AEs During Injection Phase	59 Participants	31 Participants

Adverse Events

Rilpivirine

Serious events: 4 serious events

Other events: 80 other events

Deaths: 1 deaths

Placebo

Serious events: 1 serious events

Other events: 40 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Rilpivirine n=80 participants at risk；n=91 participants at risk Arm 1: Participants randomized to the active arm will receive rilpivirine 25 mg capsules once daily for four weeks to be taken orally with a meal. Participants will then receive IM injections of TMC278 LA, 1200 mg dose, at eight week intervals (at Weeks 4, 12, 20, 28, 36 and 44). On each dosing occasion 1200 mg of TMC278 LA will be delivered in two, 2 mL injections, one in each gluteus maximus muscle. All participants will receive a total of six doses (12 IM injections). Rilpivirine: Rilpivirine (TMC278), a non-nucleoside reverse transcriptase inhibitor (NNRTI) is a substituted diaryl-pyrimidine (DAPY) derivative with potent antiviral activity against HIV. It is approved by the US FDA for once daily oral administration and is effective as part of treatment for ARV-na'ive HIV-infected patients as rilpivirine 25 mg capsules. It is also co-formulated with TDF and FTC for use as a once- daily single fixed-dose combination (Complera™).	Placebo n=42 participants at risk；n=45 participants at risk Arm 2: Participants randomized to the placebo arm will receive placebo capsules once daily for four weeks to be taken orally with a meal. Participants will then receive IM injections of saline (0.9% NaCI) at eight week intervals (at Weeks 4, 12, 20, 28, 36 and 44). On each dosing occasion placebo will be delivered in two, 2 mL injections, one in each gluteus maximus muscle. All participants will receive a total of six doses (12 IM injections). Placebo: Participants randomized to the placebo arm will receive oral placebo capsules prior to injection of saline solution (0.9%NaCI). Participants will be observed while taking the study product by site staff on approximately six occasions during the first two weeks of the oral run-in at Week 0 (Enrollment), at Week 2 (Oral Run-in Safety Visit), and on four separate DOT visits between Weeks 0 and 2. Cervicovaginal and rectal fluid will be collected for PK studies at a single follow-up visit.
Infections and infestations Gastroenteritis	1.1% 1/91 • Number of events 1 • Adverse Event data were collected from the time of enrollment to the end of the study. (From enrollment to week 76). Adverse Event data that were collected during injection phase from the time of first injection to week 52 are included in the Report showing list of other AEs excluding Serious AEs. (From week 4 to week 52).	0.00% 0/45 • Adverse Event data were collected from the time of enrollment to the end of the study. (From enrollment to week 76). Adverse Event data that were collected during injection phase from the time of first injection to week 52 are included in the Report showing list of other AEs excluding Serious AEs. (From week 4 to week 52).
Nervous system disorders Haemorrhagic stroke	1.1% 1/91 • Number of events 1 • Adverse Event data were collected from the time of enrollment to the end of the study. (From enrollment to week 76). Adverse Event data that were collected during injection phase from the time of first injection to week 52 are included in the Report showing list of other AEs excluding Serious AEs. (From week 4 to week 52).	0.00% 0/45 • Adverse Event data were collected from the time of enrollment to the end of the study. (From enrollment to week 76). Adverse Event data that were collected during injection phase from the time of first injection to week 52 are included in the Report showing list of other AEs excluding Serious AEs. (From week 4 to week 52).
Injury, poisoning and procedural complications Overdose	1.1% 1/91 • Number of events 1 • Adverse Event data were collected from the time of enrollment to the end of the study. (From enrollment to week 76). Adverse Event data that were collected during injection phase from the time of first injection to week 52 are included in the Report showing list of other AEs excluding Serious AEs. (From week 4 to week 52).	0.00% 0/45 • Adverse Event data were collected from the time of enrollment to the end of the study. (From enrollment to week 76). Adverse Event data that were collected during injection phase from the time of first injection to week 52 are included in the Report showing list of other AEs excluding Serious AEs. (From week 4 to week 52).
Injury, poisoning and procedural complications Radius fracture	1.1% 1/91 • Number of events 1 • Adverse Event data were collected from the time of enrollment to the end of the study. (From enrollment to week 76). Adverse Event data that were collected during injection phase from the time of first injection to week 52 are included in the Report showing list of other AEs excluding Serious AEs. (From week 4 to week 52).	0.00% 0/45 • Adverse Event data were collected from the time of enrollment to the end of the study. (From enrollment to week 76). Adverse Event data that were collected during injection phase from the time of first injection to week 52 are included in the Report showing list of other AEs excluding Serious AEs. (From week 4 to week 52).
Injury, poisoning and procedural complications Pelvic fracture	1.1% 1/91 • Number of events 1 • Adverse Event data were collected from the time of enrollment to the end of the study. (From enrollment to week 76). Adverse Event data that were collected during injection phase from the time of first injection to week 52 are included in the Report showing list of other AEs excluding Serious AEs. (From week 4 to week 52).	0.00% 0/45 • Adverse Event data were collected from the time of enrollment to the end of the study. (From enrollment to week 76). Adverse Event data that were collected during injection phase from the time of first injection to week 52 are included in the Report showing list of other AEs excluding Serious AEs. (From week 4 to week 52).
Gastrointestinal disorders Pancreatitis acute	0.00% 0/91 • Adverse Event data were collected from the time of enrollment to the end of the study. (From enrollment to week 76). Adverse Event data that were collected during injection phase from the time of first injection to week 52 are included in the Report showing list of other AEs excluding Serious AEs. (From week 4 to week 52).	2.2% 1/45 • Number of events 1 • Adverse Event data were collected from the time of enrollment to the end of the study. (From enrollment to week 76). Adverse Event data that were collected during injection phase from the time of first injection to week 52 are included in the Report showing list of other AEs excluding Serious AEs. (From week 4 to week 52).
Gastrointestinal disorders Pancreatitis	0.00% 0/91 • Adverse Event data were collected from the time of enrollment to the end of the study. (From enrollment to week 76). Adverse Event data that were collected during injection phase from the time of first injection to week 52 are included in the Report showing list of other AEs excluding Serious AEs. (From week 4 to week 52).	2.2% 1/45 • Number of events 1 • Adverse Event data were collected from the time of enrollment to the end of the study. (From enrollment to week 76). Adverse Event data that were collected during injection phase from the time of first injection to week 52 are included in the Report showing list of other AEs excluding Serious AEs. (From week 4 to week 52).
Renal and urinary disorders Nephrolithiasis	1.1% 1/91 • Number of events 1 • Adverse Event data were collected from the time of enrollment to the end of the study. (From enrollment to week 76). Adverse Event data that were collected during injection phase from the time of first injection to week 52 are included in the Report showing list of other AEs excluding Serious AEs. (From week 4 to week 52).	0.00% 0/45 • Adverse Event data were collected from the time of enrollment to the end of the study. (From enrollment to week 76). Adverse Event data that were collected during injection phase from the time of first injection to week 52 are included in the Report showing list of other AEs excluding Serious AEs. (From week 4 to week 52).

Other adverse events

Additional Information

Heather Kelly

PATH

Phone: 650-392-2510

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place