Tivicay PD (Page 8 of 9)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Two-year carcinogenicity studies in mice and rats were conducted with dolutegravir. Mice were administered doses of up to 500 mg per kg, and rats were administered doses of up to 50 mg per kg. In mice, no significant increases in the incidence of drug-related neoplasms were observed at the highest doses tested, resulting in dolutegravir AUC exposures approximately 14 times higher than those in humans at the maximum recommended dose. In rats, no increases in the incidence of drug-related neoplasms were observed at the highest dose tested, resulting in dolutegravir AUC exposures 10 times and 15 times higher in males and females, respectively, than those in humans at the maximum recommended dose.

Mutagenesis

Dolutegravir was not genotoxic in the bacterial reverse mutation assay, mouse lymphoma assay, or in the in vivo rodent micronucleus assay.

Impairment of Fertility

In a study conducted in rats, there were no effects on mating or fertility with dolutegravir up to 1,000 mg per kg per day. This dose is associated with an exposure that is approximately 24 times higher than the exposure in humans at the maximum recommended dose.

14 CLINICAL STUDIES

14.1 Description of Clinical Studies

The efficacy and safety of TIVICAY or TIVICAY PD were evaluated in the studies summarized in Table 15.

Table 15. Trials Conducted with TIVICAY or TIVICAY PD in HIV-1–Infected Subjects
NRTI = nucleoside reverse transcriptase inhibitor; BR = Background regimen; INSTI = integrase strand transfer inhibitor; OBT = Optimized background therapy; CAR = Current antiretroviral regimen.

Population

Trial

Trial Arms

Timepoint (Week)

Adults:

Treatment-naïve

SPRING-2 (ING113086)(NCT01227824)

TIVICAY + 2 NRTIs (n = 403)

Raltegravir + 2 NRTIs (n = 405)

96

SINGLE (ING114467)(NCT01263015)

TIVICAY + EPZICOM (n = 414)

ATRIPLA (n = 419)

144

FLAMINGO (ING114915)(NCT01449929)

TIVICAY + NRTI BR (n = 243)

Darunavir/ritonavir + NRTI BR (n = 242)

96

Treatment-experienced, INSTI-naïve

SAILING (ING111762)(NCT01231516)

TIVICAY + BR (n = 354)

Raltegravir + BR (n = 361)

48

INSTI-experienced

VIKING-3 (ING112574)

(NCT01328041)

TIVICAY + OBT (n = 183)

48

Virologically suppressed

SWORD-1 (NCT02429791)

SWORD-2 (NCT02422797)

Pooled presentation

TIVICAY + Rilpivirine (n = 513)

CAR (n = 511)

48

Pediatrics:

4 weeks and older and weighing at least 3 kg without INSTI resistance

IMPAACT P1093 (NCT01302847)

TIVICAY or TIVICAY PD + BR (n = 75)

24

14.2 Adult Subjects

Treatment-Naïve Subjects

In SPRING-2, 822 subjects were randomized and received at least 1 dose of either TIVICAY 50 mg once daily or raltegravir 400 mg twice daily, both in combination with fixed-dose dual NRTI treatment (either abacavir sulfate and lamivudine [EPZICOM] or emtricitabine/tenofovir [TRUVADA]). There were 808 subjects included in the efficacy and safety analyses. At baseline, the median age of subjects was 36 years, 13% female, 15% non-white, 11% had hepatitis B and/or C virus co-infection, 2% were CDC Class C (AIDS), 28% had HIV-1 RNA greater than 100,000 copies per mL, 48% had CD4+ cell count less than 350 cells per mm3 , and 39% received EPZICOM; these characteristics were similar between treatment groups.

In SINGLE, 833 subjects were randomized and received at least 1 dose of either TIVICAY 50 mg once daily with fixed-dose abacavir sulfate and lamivudine (EPZICOM) or fixed-dose efavirenz/emtricitabine/tenofovir (ATRIPLA). At baseline, the median age of subjects was 35 years, 16% female, 32% non-white, 7% had hepatitis C co-infection (hepatitis B virus co-infection was excluded), 4% were CDC Class C (AIDS), 32% had HIV-1 RNA greater than 100,000 copies per mL, and 53% had CD4+ cell count less than 350 cells per mm3 ; these characteristics were similar between treatment groups.

Outcomes for SPRING-2 (Week 96 analysis) and SINGLE (Week 144 open-label phase analysis which followed the Week 96 double-blind phase) are provided in Table 16. Side-by-side tabulation is to simplify presentation; direct comparisons across trials should not be made due to differing trial designs.

Table 16. Virologic Outcomes of Randomized Treatment in SPRING-2 at Week 96 and SINGLE at Week 144 (Snapshot Algorithm)
NRTI = Nucleoside reverse transcriptase inhibitor.
a Adjusted for pre-specified stratification factors.b The primary endpoint was assessed at Week 48 and the virologic success rate was 88% in the group receiving TIVICAY and 86% in the raltegravir group, with a treatment difference of 2.6% and 95% CI of (-1.9%, 7.2%).c The primary endpoint was assessed at Week 48 and the virologic success rate was 88% in the group receiving TIVICAY and 81% in the ATRIPLA group, with a treatment difference of 7.4% and 95% CI of (2.5%, 12.3%). d Includes subjects who discontinued due to an adverse event or death at any time point if this resulted in no virologic data on treatment during the analysis window.e Other includes reasons such as withdrew consent, loss to follow-up, moved, and protocol deviation.

SPRING-2 Week 96

SINGLE Week 144

TIVICAY 50 mg Once Daily + 2 NRTIs (n = 403)

Raltegravir 400 mg Twice Daily + 2 NRTIs (n = 405)

TIVICAY 50 mg + EPZICOM Once Daily (n = 414)

ATRIPLA Once Daily (n = 419)

HIV-1 RNA <50 copies/mL

82%

78%

71%

63%

Treatment differencea

4.9% (95% CI: -0.6%, 10.3%)b

8.3% (95% CI: 2.0%, 14.6%)c

Virologic nonresponse

5%

10%

10%

7%

Data in window not <50 copies/mL

1%

3%

4%

<1%

Discontinued for lack of efficacy

2%

3%

3%

3%

Discontinued for other reasons while not suppressed

<1%

3%

3%

4%

Change in ART regimen

<1%

<1%

0

0

No virologic data

12%

12%

18%

30%

Reasons

Discontinued study/study drug due to adverse event or deathd

2%

2%

4%

14%

Discontinued study/study drug for other reasonse

8%

9%

12%

13%

Missing data during window but on study

2%

<1%

2%

3%

Proportion (%) of Subjects with HIV-1 RNA <50 copies/mL by Baseline Category

Plasma viral load (copies/mL)

≤100,000

84%

83%

73%

64%

>100,000

79%

63%

69%

61%

Gender

Male

84%

79%

72%

66%

Female

70%

68%

69%

48%

Race

White

83%

78%

72%

71%

African-American/African Heritage/Other

77%

75%

71%

47%

SPRING-2: Virologic outcomes were also comparable across baseline characteristics including CD4+ cell count, age, and use of EPZICOM or TRUVADA as NRTI background regimen. The median change in CD4+ cell counts from baseline was 276 cells per mm3 in the group receiving TIVICAY and 264 cells per mm3 for the raltegravir group at 96 weeks.

There was no treatment-emergent resistance to dolutegravir or to the NRTI background.

SINGLE: Treatment differences were maintained across baseline characteristics including baseline viral load, CD4+ cell count, age, gender, and race.

The adjusted mean changes in CD4+ cell counts from baseline were 378 cells per mm3 in the group receiving TIVICAY + EPZICOM and 332 cells per mm3 for the ATRIPLA group at 144 weeks. The adjusted difference between treatment arms and 95% CI was 46.9 cells per mm3 (15.6 cells per mm3 , 78.2 cells per mm3) (adjusted for pre-specified stratification factors: baseline HIV-1 RNA, and baseline CD4+ cell count).

There was no treatment-emergent resistance to dolutegravir, abacavir, or lamivudine.

FLAMINGO: In FLAMINGO, 485 subjects were randomized and received at least 1 dose of either TIVICAY 50 mg once daily (n = 243) or darunavir + ritonavir 800 mg/100 mg once daily (n = 242), both in combination with investigator-selected NRTI background regimen (either fixed-dose abacavir and lamivudine [EPZICOM] or fixed-dose emtricitabine/tenofovir disoproxil fumarate [TRUVADA]). There were 484 subjects included in the efficacy and safety analyses. At baseline, the median age of subjects was 34 years, 15% female, 28% non-white, 10% had hepatitis B and/or C virus co-infection, 3% were CDC Class C (AIDS), 25% had HIV‑1 RNA greater than 100,000 copies per mL, and 35% had CD4+ cell count less than 350 cells per mm3 ; these characteristics were similar between treatment groups. Overall response rates by Snapshot algorithm through Week 96 were 80% for TIVICAY and 68% for darunavir/ritonavir. The proportion of subjects who were non-responders (HIV-1 RNA greater than or equal to 50 copies per mL) at Week 96 was 8% and 12% in the arms receiving TIVICAY and darunavir + ritonavir, respectively; no virologic data were available for 12% and 21% for subjects treated with TIVICAY and darunavir + ritonavir, respectively. The adjusted overall response rate difference in proportion and 95% CI was 12.4% (4.7%, 20.2%). No treatment-emergent primary resistance substitutions were observed in either treatment group.

Treatment-Experienced, Integrase Strand Transfer Inhibitor-Naïve Subjects

In the international, multicenter, double-blind trial (SAILING), 719 HIV‑1–infected, antiretroviral treatment-experienced adults were randomized and received either TIVICAY 50 mg once daily or raltegravir 400 mg twice daily with investigator-selected background regimen consisting of up to 2 agents, including at least 1 fully active agent. There were 715 subjects included in the efficacy and safety analyses. At baseline, the median age was 43 years, 32% were female, 50% non-white, 16% had hepatitis B and/or C virus co-infection, 46% were CDC Class C (AIDS), 20% had HIV-1 RNA greater than 100,000 copies per mL, and 72% had CD4+ cell count less than 350 cells per mm3 ; these characteristics were similar between treatment groups. All subjects had at least 2-class antiretroviral treatment resistance, and 49% of subjects had at least 3-class antiretroviral treatment resistance at baseline. Week 48 outcomes for SAILING are shown in Table 17.

Table 17. Virologic Outcomes of Randomized Treatment in SAILING at 48 Weeks (Snapshot Algorithm)
a BR = Background regimen. Background regimen was restricted to less than or equal to 2 antiretroviral treatments with at least 1 fully active agent.b Adjusted for pre-specified stratification factors. c Other includes reasons such as withdrew consent, loss to follow-up, moved, and protocol deviation.

TIVICAY 50 mg Once Daily + BRa

(n = 354)

Raltegravir 400 mg Twice Daily + BRa

(n = 361)

HIV-1 RNA <50 copies/mL

71%

64%

Adjustedb treatment difference

7.4% (95% CI: 0.7%, 14.2%)

Virologic nonresponse

20%

28%

No virologic data

9%

9%

Reasons

Discontinued study/study drug due to adverse event or death

3%

4%

Discontinued study/study drug for other reasonsc

5%

4%

Missing data during window but on study

2%

1%

Proportion (%) with HIV-1 RNA <50 copies/mL by Baseline Category

Plasma viral load (copies/mL)

≤50,000 copies/mL

75%

71%

>50,000 copies/mL

62%

47%

Background regimen

No darunavir use

67%

60%

Darunavir use with primary PI substitutions

85%

67%

Darunavir use without primary PI substitutions

69%

70%

Gender

Male

70%

66%

Female

74%

60%

Race

White

75%

71%

African-American/African Heritage/Other

67%

57%

Treatment differences were maintained across the baseline characteristics including CD4+ cell count and age.

The mean changes in CD4+ cell counts from baseline were 162 cells per mm3 in the group receiving TIVICAY and 153 cells per mm3 in the raltegravir group.

Treatment-Experienced, Integrase Strand Transfer Inhibitor-Experienced Subjects

VIKING-3 examined the effect of TIVICAY 50 mg twice daily over 7 days of functional monotherapy, followed by OBT with continued treatment of TIVICAY 50 mg twice daily.

In the multicenter, open-label, single-arm VIKING-3 trial, 183 HIV‑1–infected, antiretroviral treatment-experienced adults with virological failure and current or historical evidence of raltegravir and/or elvitegravir resistance received TIVICAY 50 mg twice daily with the current failing background regimen for 7 days, then received TIVICAY with OBT from Day 8. A total of 183 subjects enrolled: 133 subjects with INSTI resistance at screening and 50 subjects with only historical evidence of resistance (and not at screening). At baseline, median age of subjects was 48 years; 23% were female, 29% non-white, and 20% had hepatitis B and/or C virus co-infection. Median baseline CD4+ cell count was 140 cells per mm3 , median duration of prior antiretroviral treatment was 13 years, and 56% were CDC Class C. Subjects showed multiple-class antiretroviral treatment resistance at baseline: 79% had greater than or equal to 2 NRTI, 75% greater than or equal to 1 NNRTI, and 71% greater than or equal to 2 PI major substitutions; 62% had non-R5 virus.

Mean reduction from baseline in HIV-1 RNA at Day 8 (primary endpoint) was 1.4 log10 (95% CI: 1.3 log10 , 1.5 log10 ). Response at Week 48 was affected by baseline INSTI substitutions [see Microbiology (12.4)].

After the functional monotherapy phase, subjects had the opportunity to re-optimize their background regimen when possible. Week 48 virologic outcomes for VIKING-3 are shown in Table 18.

Table 18. Virologic Outcomes of Treatment of VIKING-3 at 48 Weeks (Snapshot Algorithm)
OBT = Optimized Background Therapy.

TIVICAY 50 mg Twice Daily + OBT

(n = 183)

HIV-1 RNA <50 copies/mL

63%

Virologic nonresponse

32%

No virologic data

Reasons

Discontinued study/study drug due to adverse event or death

3%

Proportion (%) with HIV-1 RNA <50 copies/mL by Baseline Category

Gender

Male

63%

Female

64%

Race

White

63%

African-American/African Heritage/Other

64%

Subjects harboring virus with Q148 and with additional Q148-associated secondary substitutions also had a reduced response at Week 48 in a stepwise fashion [see Microbiology (12.4)].

The median change in CD4+ cell count from baseline was 80 cells per mm3 at Week 48.

Virologically Suppressed Subjects

SWORD-1 and SWORD-2 are identical 148-week, Phase 3, randomized, multicenter, parallel-group, non-inferiority trials. A total of 1,024 adult HIV-1–infected subjects who were on a stable suppressive antiretroviral regimen (containing 2 NRTIs plus either an INSTI, an NNRTI, or a PI) for at least 6 months (HIV-1 RNA less than 50 copies per mL), with no history of treatment failure and no known substitutions associated with resistance to dolutegravir or rilpivirine received treatment in the trials. Subjects were randomized 1:1 to continue their current antiretroviral regimen (n°= 511) or be switched to TIVICAY 50 mg plus rilpivirine 25 mg administered once daily (n = 513). Subjects originally assigned to continue their current antiretroviral regimen and who remained virologically suppressed at Week 48 switched to TIVICAY plus rilpivirine at Week 52 (n = 477).

The primary efficacy endpoint for the SWORD trial was the proportion of subjects with plasma HIV-1 RNA less than 50 copies per mL at Week 48. The proportion of subjects with HIV-1 RNA less than 50 copies per mL at Week 48 was 95% for both treatment groups; treatment difference and 95% CI was -0.2% (-3.0%, 2.5%). The proportion of subjects with HIV‑1 RNA greater than or equal to 50 copies per mL (virologic failure) at Week 48 was 0.6% and 1.2% for the dolutegravir plus rilpivirine treatment group and the current antiretroviral regimen treatment groups, respectively; treatment difference and 95% CI was -0.6% (-1.7%, 0.6%). At Week 148 in the pooled SWORD-1 and SWORD-2 trials, 84% of subjects who received TIVICAY plus rilpivirine from study start had plasma HIV-1 RNA less than 50 copies/mL (Snapshot algorithm). In subjects who initially remained on their current antiretroviral regimen and switched to TIVICAY plus rilpivirine at Week 52, 90% had plasma HIV-1 RNA less than 50 copies/mL at Week 148 (Snapshot algorithm), which was comparable to the response rate (89%) observed at Week 100 (similar exposure duration) in subjects receiving TIVICAY plus rilpivirine from study start.

Refer to the prescribing information for JULUCA (dolutegravir and rilpivirine) tablet for complete virologic outcome information.

All MedLibrary.org resources are included in as near-original form as possible, meaning that the information from the original provider has been rendered here with only typographical or stylistic modifications and not with any substantive alterations of content, meaning or intent.

This site is provided for educational and informational purposes only, in accordance with our Terms of Use, and is not intended as a substitute for the advice of a medical doctor, nurse, nurse practitioner or other qualified health professional.

Privacy Policy | Copyright © 2022. All Rights Reserved.