200056

ViiV Healthcare

980 Great West Road, Brentford, Middlesex, United Kingdom,

GSK Response Center, GlaxoSmithKline, 1 866-435-7343,

GSK Response Center, GlaxoSmithKline, 1 866-435-7343,

No

No

No

Interim

13 Dec 2015

Yes

13 Dec 2015

No

To select an intramuscular dosing regimen of GSK744 LA plus TMC278 LA based on a comparison of the Week 32 antiviral activity, tolerability, and safety of two IM dosing regimens, relative to GSK744 30 mg plus Abacavir/Lamivudine (ABC/3TC) orally once daily.

An IDMC committee will evaluate the efficacy, tolerability, and safety of cabotegravir (CAB) and Rilpivirine (RPV) at the following times: before all eligible subjects have transitioned from the Induction Period to the Maintenance Period; after approximately 45 subjects have reached Week 8 of the Maintenance Period. Futility guidance (e.g., a Bayesian posterior probability approach when 50% of subjects have completed Week 24 of the Maintenance Period) is included to monitor the performance of all treatment arms in order to prevent subjects from continuing on a dosing regimen if existing data indicates that subjects are at unacceptable risk of inadequate maintenance of virologic suppression. A CAB treatment arm should be recommended to stop if there is an indication of any safety signal/effect that would not support continuation of one or more of the CAB treatment groups. This should take into consideration any of the following which are felt to be clinically significant: I. Serious adverse events (e.g. liver event). II. Combinations of non-serious events. III. Treatment-limiting adverse events. IV. Unacceptable number of protocol defined virologic failures with CAB or RPV resistance defined as at least 3 or more virologic failures comprising of ≥ 20% of the treated subjects in an IM treatment arm. V. Mean predose concentrations for the long acting (LA) treatment arm less than 1x protein-adjusted 90% inhibitory concentration (PAIC) 90 (0.166 µg/mL) for CAB and less than 12ng/mL for RPV.

28 Apr 2014

Yes

Yes

Canada: 34

United States: 84

Spain: 104

France: 36

Germany: 52

310

192

0

0

0

0

0

0

310

0

0

Induction Period (20 Weeks)

Non-randomised - controlled

Cabotegravir Oral Tablet

Tablet

Oral use

Cabotegravir (CAB) Oral Tablet was formulated as white to almost white oval shaped film coated 30 mg tablets for oral administration. In IP, participants received CAB 30 mg once daily for 20 weeks

Abacavir/Lamivudine Oral Tablet

Tablet

Oral use

Abacavir/Lamivudine (ABC/3TC)was supplied as fixed dose combination (FDC) oral tablet, which contained 600 mg of ABC (as abacavir sulfate) and 300 mg of 3TC. The tablets were orange, film-coated, modified capsule-shaped and debossed with "GS FC2" on one side with no markings on the reverse side. ABC/3TC was packaged in bottles of 30 tablets. In IP, participants received ABC/3TC 600/300 mg once daily for 20 weeks.

Rilpivirine Oral Tablet

Tablet

Oral use

Rilpivirine (RPV) Oral Tablet was supplied as a 25 mg tablet that was off-white, round, biconvex, film-coated and debossed on one side with “TMC” and the other side with “25”. Participants received RPV 25 mg tablet once daily in last 4 weeks of IP.

Maintenance Period (96 weeks)

Randomised - controlled

Yes

Cabotegravir Injectable Suspension

Suspension for injection

Intramuscular use

CAB Injectable Suspension was a sterile white to slightly colored suspension containing 200 mg/mL of CAB as free acid for administration by intramuscular (IM) injection. The product was packaged in a 3 mL United States Pharmacopeia (USP) Type I glass vial with a 13 mm gray stopper and aluminium seal. Each vial was for single use containing a withdrawable volume of 2.0 mL, and did not require dilution prior to administration. Participants randomized to Q8W regimen arm received following intra muscular (IM) doses: Day 1 only – CAB LA 800 mg (loading dose delivered as two 400 mg IM injections). Week 4 only - CAB LA 600 mg IM. Week 8 - CAB LA 600 mg IM every 8 Weeks (Q8W) for 96 weeks.

Rilpivirine Injectable Suspension

Suspension for injection

Intramuscular use

Rilpivirine Injectable Suspension was a sterile white suspension containing 300 mg/mL of TMC278 as free base for administration by intramuscular (IM) injection. The product was packaged in a 2 mL USP Type I glass vial with a 13 mm grey stopper and aluminium seal. Each vial was for single use containing a nominal fill of 2.0 mL, and did not require dilution prior to administration but required refrigeration. Participants randomized to Q8W regimen arm received following intra muscular (IM) doses: RPV LA 900 mg IM every 8 Weeks (Q8W) for 96 weeks

Cabotegravir Injectable Suspension

Suspension for injection

Intramuscular use

CAB Injectable Suspension was a sterile white to slightly colored suspension containing 200 mg/mL of CAB as free acid for administration by intramuscular (IM) injection. The product was packaged in a 3 mL USP Type I glass vial with a 13 mm gray stopper and aluminium seal. Each vial was for single use containing a withdrawable volume of 2.0 mL, and did not require dilution prior to administration. Participants randomized to Q4W regimen arm received following IM doses: Day 1 only - CAB LA 800 mg (loading dose delivered as two 400 mg IM injections). Week 4 - CAB LA 400 mg IM + every 4 weeks (Q4W) for 96 weeks

Rilpivirine Injectable Suspension

Suspension for injection

Intramuscular use

Rilpivirine Injectable Suspension was a sterile white suspension containing 300 mg/mL of TMC278 as free base for administration by intramuscular (IM) injection. The product was packaged in a 2 mL USP Type I glass vial with a 13 mm grey stopper and aluminium seal. Each vial was for single use containing a nominal fill of 2.0 mL, and did not require dilution prior to administration but required refrigeration. Participants randomized to Q4W regimen arm received following IM doses: RPV LA 600 mg IM every 4 weeks (Q4W) for 96 weeks.

Cabotegravir Oral Tablet

Tablet

Oral use

Cabotegravir (CAB) Oral Tablet was formulated as white to almost white oval shaped film coated 30 mg tablets for oral administration. In the MP, participants randomized in oral regimen arm (CAB 30 mg + ABC/3TC) received 30 mg of CAB once daily for 96 weeks (or 104 weeks if going on to the EP).

Abacavir/Lamivudine Oral Tablet

Tablet

Oral use

Abacavir/Lamivudine (ABC/3TC)was supplied as fixed dose combination (FDC) oral tablet, which contained 600 mg of ABC (as abacavir sulfate) and 300 mg of 3TC. The tablets were orange, film-coated, modified capsule-shaped and debossed with GS FC2 on one side with no markings on the reverse side. ABC/3TC was packaged in bottles of 30 tablets. In the MP, participants randomized in oral regimen arm (CAB 30 mg + ABC/3TC) received ABC/3TC 600/300 mg once daily for 96 weeks (or 104 weeks if going on to the EP).

CAB 30 mg + ABC/3TC once daily

CAB 30 mg + ABC/3TC once daily

CAB LA 600 mg + RPV LA 900 mg IM - Q8W

CAB LA 400 mg + RPV LA 600 mg IM - Q4W

CAB 30 mg + ABC/3TC once daily orally

Percentage of par. with Plasma HIV-1 RNA <50 c/mL at Week (Wk) 32 was assessed using the MSDF, as codified by the FDA "snapshot" algorithm. This algorithm treated all par. without HIV-1 RNA data at Wk 32 as nonresponders, as well as par. who switched their concomitant antiretroviral therapy (ART) prior to Wk 32 as follows: background ART substitutions non-permitted per protocol; background ART substitutions permitted per protocol but prescribed while not suppressed, unless the decision to switch was documented as being before or at the first on-treatment visit where HIV-1 RNA was assessed. Otherwise, virologic success or failure was determined by the last available HIV-1 RNA assessment while the par. was on-treatment within the Wk 32 time window: +/- 2-Wk window, followed by +/- 6-Wk window only if necessary to obtain data in window. ITT-ME Population consisted of all randomized par. who received at least one dose of investigational product during the MP of the study.

Primary

Week 32

CAB LA 600 mg + RPV LA 900 mg IM - Q8W v CAB 30 mg + ABC/3TC once daily orally

171

Pre-specified

3.7

2-sided

CAB LA 400 mg + RPV LA 600 mg IM - Q4W v CAB 30 mg + ABC/3TC once daily orally

171

Pre-specified

2.8

2-sided

Posterior probability that the true difference in response rates (Q8W – Oral CAB) is greater than -10% was calculated according to a Bayesian model assuming Beta(23,2) and Beta(1,1) prior distributions for the Q8W and Oral CAB response rates, respectively. A posterior probability of at least 90% corresponds to substantial evidence of positive outcome and is pre specified as the weight of evidence threshold for concluding that the IM dosing regimen (Q8W) is comparable to the Oral CAB regimen.

CAB LA 600 mg + RPV LA 900 mg IM - Q8W v CAB 30 mg + ABC/3TC once daily orally

171

Pre-specified

Posterior probability that the true difference in response rates (Q4W – Oral CAB) is greater than -10% was calculated according to a Bayesian model assuming Beta(23,2) and Beta(1,1) prior distributions for the Q4W and Oral CAB response rates, respectively. A posterior probability of at least 90% corresponds to substantial evidence of positive outcome and is pre specified as the weight of evidence threshold for concluding that the IM dosing regimen (Q4W) is comparable to the Oral CAB regimen.

CAB LA 400 mg + RPV LA 600 mg IM - Q4W v CAB 30 mg + ABC/3TC once daily orally

171

Pre-specified

Virologic failure is defined as any of the following: Non-response as indicated by a less than a 1.0 log10 copies/milliliter (c/mL) decrease in plasma HIV-1 RNA after 4 weeks of starting the IP (subsequently confirmed, unless the plasma HIV-1 RNA is <400 c/mL). Rebound as indicated by two consecutive plasma HIV-1 RNA levels >=200 c/mL after prior suppression to < 200 c/mL. Rebound as indicated by two consecutive plasma HIV-1 RNA that are > 0.5 log10 c/mL increase in plasma HIV-1 RNA from the nadir value on study, where the lowest HIV-1 RNA value is >=200 c/mL.

Primary

From the start of study treatment in the Maintenance Period up to Week 32

An AE is defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. A SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect, important medical events which may require medical or surgical intervention, drug-induced liver injury with hyperbilirubinaemia. This includes all post-baseline IP and MP AEs,as well as LTFP AEs for participants not entering the extension period that occur within 35/63 days of last IM injection (Q4W/Q8W) up to and including the start date of LTFP antiretroviral therapy. Safety Maintenance Population consisted of all participants who entered the MP and received at least one dose of investigational product.

Primary

From the start of the investigational product up to an average of 59 weeks

An AE is defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. This includes all post-baseline IP and MP AEs,as well as LTFP AEs for participants not entering the extension period that occur within 35/63 days of last MP IM injection (Q4W/Q8W) up to and including the start date of LTFP antiretroviral therapy. Adverse events that occurred during the study were evaluated by the Investigator and graded according to the 2004 version of the Division of AIDS (DAIDS) grading criteria, where Grade 1-mild, Grade 2-moderate, Grade 3-severe, Grade 4-potentially life-threatening.

Primary

From the start of the investigational product up to an average of 59 weeks

Clinical chemistry parameters aspartate amino transferase (AST), alanine amino transferase (ALT), alkaline phosphatase (ALP), carbon dioxide(CO2) content/bicarbonate (HCO3), cholesterol, creatine kinase (CK), glucose, low density lipoprotein (LDL) cholesterol, lipase, potassium, and sodium, total bilirubin (TBIL) and triglycerides were evaluated throughout the study. Toxicity was assessed for all laboratory parameters and was automatically graded by the central lab according to the 2004 version of the DAIDS grading criteria, where Grade 1-mild, Grade 2-moderate, Grade 3-severe, Grade 4-potentially life-threatening. This includes all post-baseline treatment emergent IP and MP toxicities, as well as LTFP toxicities for participants not entering the extension period that occur within 35/63 days of last IM injection (Q4W/Q8W) up to and including the start date of LTFP antiretroviral therapy.

Primary

From the start of the investigational product up to an average of 59 weeks

Clinical chemistry parameters, hemoglobin, platelet count, total neutrophils (total ANC – total absolute neutrophil) and white blood cell count were evaluated throughout the study. Toxicity was assessed for all laboratory parameters and was automatically graded by the central lab according to the 2004 version of the DAIDS grading criteria, where Grade 1-mild, Grade 2-moderate, Grade 3-severe, Grade 4-potentially life-threatening. This includes all post-baseline treatment emergent IP and MP toxicities, as well as LTFP toxicities for participants not entering the extension period that occur within 35/63 days of last IM injection (Q4W/Q8W) up to and including the start date of LTFP antiretroviral therapy.

Primary

From the start of the investigational product up to an average of 59 weeks

Urinalysis dipstick included urine occult blood, urine glucose, urine ketones, urine nitrite, urine protein and urine leukocyte esterase test for detecting white blood cells. Dipstick results were categorized as: Traces, 1+, 2+, 3+ or Positive. Only those participants available at the specified time points were analyzed (represented by n=X, X, X in the category titles).

Primary

From the start of the investigational product up to an average of 59 weeks

Post-baseline serious adverse events (SAEs) and non-serious adverse events (AEs), defined as those events collected from the start of study treatment and until the follow up contact (up to an average of 59 weeks).

SAEs and non-serious AEs were reported for members of the Safety Maintenance population consisted of all participants who entered the MP and received at least one dose of investigational product.

18.1

CAB LA 600 mg + RPV LA 900 mg IM - Q8W

CAB LA 400 mg + RPV LA 600 mg IM - Q4W

CAB 30 mg + ABC/3TC once daily