Author: druginteractionchecker_lgaiz4

CLINICAL STUDIES

14 14.1 Clinical Efficacy in Adults with HIV-1 Infection Treatment-Naïve Adult Patients Study 903 Data through 144 weeks are reported for Study 903, a double-blind, active-controlled multicenter trial comparing VIREAD (300 mg once daily) administered in combination with lamivudine and efavirenz versus stavudine (d4T), lamivudine, and efavirenz in 600 antiretroviral-naïve subjects.

Subjects had a mean age of 36 years (range 18–64), 74% were male, 64% were Caucasian and 20% were Black.

The mean baseline CD4 cell count was 279 cells/mm (range 3–956) and median baseline plasma HIV-1 RNA was 77,600 copies/mL (range 417–5,130,000).

Subjects were stratified by baseline HIV-1 RNA and CD4 cell count.

Forty-three percent of subjects had baseline viral loads >100,000 copies/mL and 39% had CD4 cell counts <200 cells/mm .

Treatment outcomes through 48 and 144 weeks are presented in Table 17.

+ 3 + + 3 Table 17 Outcomes of Randomized Treatment at Week 48 and 144 (Study 903) At Week 48 At Week 144 Outcomes VIREAD+3TC +EFV (N=299) d4T+3TC +EFV (N=301) VIREAD+3TC +EFV (N=299) d4T+3TC +EFV (N=301) Responder Subjects achieved and maintained confirmed HIV-1 RNA <400 copies/mL through Week 48 and 144.

79% 82% 68% 62% Virologic failure Includes confirmed viral rebound and failure to achieve confirmed <400 copies/mL through Week 48 and 144.

6% 4% 10% 8% Rebound 5% 3% 8% 7% Never suppressed 0% 1% 0% 0% Added an antiretroviral agent 1% 1% 2% 1% Death <1% 1% <1% 2% Discontinued due to adverse event 6% 6% 8% 13% Discontinued for other reasons Includes lost to follow-up, subject's withdrawal, noncompliance, protocol violation and other reasons.

8% 7% 14% 15% Achievement of plasma HIV-1 RNA concentrations of less than 400 copies/mL at Week 144 was similar between the two treatment groups for the population stratified at baseline on the basis of HIV-1 RNA concentration (> or ≤100,000 copies/mL) and CD4 cell count (< or ≥200 cells/mm ).

Through 144 weeks of therapy, 62% and 58% of subjects in the VIREAD and stavudine arms, respectively achieved and maintained confirmed HIV-1 RNA <50 copies/mL.

The mean increase from baseline in CD4 cell count was 263 cells/mm for the VIREAD arm and 283 cells/mm for the stavudine arm.

+ 3 + 3 3 Through 144 weeks, 11 subjects in the VIREAD group and 9 subjects in the stavudine group experienced a new CDC Class C event.

Study 934 Data through 144 weeks are reported for Study 934, a randomized, open-label, active-controlled multicenter trial comparing emtricitabine + VIREAD administered in combination with efavirenz versus zidovudine/lamivudine fixed-dose combination administered in combination with efavirenz in 511 antiretroviral-naïve subjects.

From Weeks 96 to 144 of the trial, subjects received a fixed-dose combination of emtricitabine and tenofovir DF with efavirenz in place of emtricitabine + VIREAD with efavirenz.

Subjects had a mean age of 38 years (range 18–80), 86% were male, 59% were Caucasian and 23% were Black.

The mean baseline CD4 cell count was 245 cells/mm (range 2–1191) and median baseline plasma HIV-1 RNA was 5.01 log copies/mL (range 3.56–6.54).

Subjects were stratified by baseline CD4 cell count (< or ≥200 cells/mm ); 41% had CD4 cell counts 100,000 copies/mL.

Treatment outcomes through 48 and 144 weeks for those subjects who did not have efavirenz resistance at baseline are presented in Table 18.

+ 3 10 + 3 + 3 Table 18 Outcomes of Randomized Treatment at Week 48 and 144 (Study 934) Outcomes At Week 48 At Week 144 FTC +VIREAD +EFV (N=244) AZT/3TC +EFV (N=243) FTC +VIREAD +EFV (N=227) Subjects who were responders at Week 48 or Week 96 (HIV-1 RNA <400 copies/mL) but did not consent to continue the trial after Week 48 or Week 96 were excluded from analysis.

AZT/3TC +EFV (N=229) Responder Subjects achieved and maintained confirmed HIV-1 RNA <400 copies/mL through Weeks 48 and 144.

84% 73% 71% 58% Virologic failure Includes confirmed viral rebound and failure to achieve confirmed <400 copies/mL through Weeks 48 and 144.

2% 4% 3% 6% Rebound 1% 3% 2% 5% Never suppressed 0% 0% 0% 0% Change in antiretroviral regimen 1% 1% 1% 1% Death <1% 1% 1% 1% Discontinued due to adverse event 4% 9% 5% 12% Discontinued for other reasons Includes lost to follow-up, subject withdrawal, noncompliance, protocol violation and other reasons.

10% 14% 20% 22% Through Week 48, 84% and 73% of subjects in the emtricitabine + VIREAD group and the zidovudine/lamivudine group, respectively, achieved and maintained HIV-1 RNA <400 copies/mL (71% and 58% through Week 144).

The difference in the proportion of subjects who achieved and maintained HIV-1 RNA <400 copies/mL through 48 weeks largely results from the higher number of discontinuations due to adverse events and other reasons in the zidovudine/lamivudine group in this open-label trial.

In addition, 80% and 70% of subjects in the emtricitabine + VIREAD group and the zidovudine/lamivudine group, respectively, achieved and maintained HIV-1 RNA <50 copies/mL through Week 48 (64% and 56% through Week 144).

The mean increase from baseline in CD4 cell count was 190 cells/mm in the EMTRIVA + VIREAD group and 158 cells/mm in the zidovudine/lamivudine group at Week 48 (312 and 271 cells/mm at Week 144).

+ 3 3 3 Through 48 weeks, 7 subjects in the emtricitabine + VIREAD group and 5 subjects in the zidovudine/lamivudine group experienced a new CDC Class C event (10 and 6 subjects through 144 weeks).

Treatment-Experienced Adult Patients Study 907 Study 907 was a 24-week, double-blind placebo-controlled multicenter trial of VIREAD added to a stable background regimen of antiretroviral agents in 550 treatment-experienced subjects.

After 24 weeks of blinded trial treatment, all subjects continuing on trial were offered open-label VIREAD for an additional 24 weeks.

Subjects had a mean baseline CD4 cell count of 427 cells/mm (range 23–1385), median baseline plasma HIV-1 RNA of 2340 (range 50–75,000) copies/mL, and mean duration of prior HIV-1 treatment was 5.4 years.

Mean age of the subjects was 42 years, 85% were male and 69% were Caucasian, 17% Black and 12% Hispanic.

+ 3 The percent of subjects with HIV-1 RNA <400 copies/mL and outcomes of subjects through 48 weeks are summarized in Table 19.

Table 19 Outcomes of Randomized Treatment (Study 907) Outcomes 0–24 weeks 0–48 weeks 24–48 weeks VIREAD (N=368) Placebo (N=182) VIREAD (N=368) Placebo Crossover to VIREAD (N=170) HIV-1 RNA <400 copies/mL Subjects with HIV-1 RNA <400 copies/mL and no prior study drug discontinuation at Week 24 and 48 respectively.

40% 11% 28% 30% Virologic failure Subjects with HIV-1 RNA ≥400 copies/mL efficacy failure or missing HIV-1 RNA at Week 24 and 48 respectively.

53% 84% 61% 64% Discontinued due to adverse event 3% 3% 5% 5% Discontinued for other reasons Includes lost to follow-up, subject withdrawal, noncompliance, protocol violation and other reasons.

3% 3% 5% 1% At 24 weeks of therapy, there was a higher proportion of subjects in the VIREAD arm compared to the placebo arm with HIV-1 RNA <50 copies/mL (19% and 1%, respectively).

Mean change in absolute CD4 cell counts by Week 24 was +11 cells/mm for the VIREAD group and -5 cells/mm for the placebo group.

Mean change in absolute CD4 cell counts by Week 48 was +4 cells/mm for the VIREAD group.

+ 3 3 + 3 Through Week 24, one subject in the VIREAD group and no subjects in the placebo arm experienced a new CDC Class C event.

14.2 Clinical Efficacy in Adults with Chronic Hepatitis B HBeAg-Negative Chronic Hepatitis B Study 0102 was a Phase 3, randomized, double-blind, active-controlled trial of VIREAD 300 mg compared to HEPSERA 10 mg in 375 HBeAg- (anti-HBe+) subjects with compensated liver function, the majority of whom were nucleoside-naïve.

The mean age of subjects was 44 years, 77% were male, 25% were Asian, 65% were Caucasian, 17% had previously received alpha-interferon therapy and 18% were nucleoside-experienced (16% had prior lamivudine experience).

At baseline, subjects had a mean Knodell necroinflammatory score of 7.8; mean plasma HBV DNA was 6.9 log copies/mL; and mean serum ALT was 140 U/L.

10 HBeAg-Positive Chronic Hepatitis B Study 0103 was a Phase 3, randomized, double-blind, active-controlled trial of VIREAD 300 mg compared to HEPSERA 10 mg in 266 HBeAg+ nucleoside-naïve subjects with compensated liver function.

The mean age of subjects was 34 years, 69% were male, 36% were Asian, 52% were Caucasian, 16% had previously received alpha-interferon therapy, and <5% were nucleoside experienced.

At baseline, subjects had a mean Knodell necroinflammatory score of 8.4; mean plasma HBV DNA was 8.7 log copies /mL; and mean serum ALT was 147 U/L.

10 The primary data analysis was conducted after all subjects reached 48 weeks of treatment and results are summarized below.

The primary efficacy endpoint in both trials was complete response to treatment defined as HBV DNA <400 copies/mL (69 IU/mL) and Knodell necroinflammatory score improvement of at least 2 points, without worsening in Knodell fibrosis at Week 48 (Table 20).

Table 20 Histological, Virological, Biochemical, and Serological Response at Week 48 0102 (HBeAg-) 0103 (HBeAg+) VIREAD (N=250) HEPSERA (N=125) VIREAD (N=176) HEPSERA (N=90) Complete Response 71% 49% 67% 12% Histology Histological Response Knodell necroinflammatory score improvement of at least 2 points without worsening in Knodell fibrosis.

72% 69% 74% 68% <400 copies/mL (<69 IU/mL) HBV DNA 93% 63% 76% 13% Normalized ALT ALT The population used for analysis of ALT normalization included only subjects with ALT above ULN at baseline.

76% 77% 68% 54% HBeAg Loss/Seroconversion Serology NA NA = Not Applicable NA 20%/19% 16%/16% HBsAg Loss/Seroconversion 0/0 0/0 3%/1% 0/0 Treatment Beyond 48 Weeks In Studies 0102 (HBeAg-negative) and 0103 (HBeAg-positive), subjects who completed double-blind treatment (389 and 196 subjects who were originally randomized to VIREAD and HEPSERA, respectively) were eligible to roll over to open-label VIREAD with no interruption in treatment.

In Study 0102, 266 of 347 subjects who entered the open-label period (77%) continued in the study through Week 384.

Among subjects randomized to VIREAD followed by open-label treatment with VIREAD, 73% had HBV DNA <400 copies/ml (69 IU/ml), and 63% had ALT normalization at Week 384.

Among subjects randomized to HEPSERA followed by open-label treatment with VIREAD, 80% had HBV DNA <400 copies/mL (69 IU/mL) and 70% had ALT normalization through Week 384.

At Week 384, both HBsAg loss and seroconversion were approximately 1% in both treatment groups.

In Study 0103, 146 of 238 subjects who entered the open-label period (61%) continued in the study through Week 384.

Among subjects randomized to VIREAD, 49% had HBV DNA <400 copies/mL (69 IU/mL), 42% had ALT normalization, and 20% had HBeAg loss (13% seroconversion to anti-HBe antibody) through Week 384.

Among subjects randomized to HEPSERA followed by open-label treatment with VIREAD, 56% had HBV DNA <400 copies/mL (69 IU/mL), 50% had ALT normalization, and 28% had HBeAg loss (19% seroconversion to anti-HBe antibody) through Week 384.

At Week 384, HBsAg loss and seroconversion were 11% and 8% respectively, in subjects initially randomized to VIREAD and 12% and 10%, respectively, in subjects initially randomized to HEPSERA.

Of the originally randomized and treated 641 subjects in the two studies, liver biopsy data from 328 subjects who received continuing open-label treatment with VIREAD monotherapy were available for analysis at baseline, Week 48 and Week 240.

There were no apparent differences between the subset of subjects who had liver biopsy data at Week 240 and those subjects remaining on open-label VIREAD without biopsy data that would be expected to affect histological outcomes at Week 240.

Among the 328 subjects evaluated, the observed histological response rates were 80% and 88% at Week 48 and Week 240, respectively.

In the subjects without cirrhosis at baseline (Ishak fibrosis score 0-4), 92% (216/235) and 95% (223/235) had either improvement or no change in Ishak fibrosis score at Week 48 and Week 240, respectively.

In subjects with cirrhosis at baseline (Ishak fibrosis score 5-6), 97% (90/93) and 99% (92/93) had either improvement or no change in Ishak fibrosis score at Week 48 and Week 240, respectively.

Twenty-nine percent (27/93) and 72% (67/93) of subjects with cirrhosis at baseline experienced regression of cirrhosis by Week 48 and Week 240, respectively, with a reduction in Ishak fibrosis score of at least 2 points.

No definitive conclusions can be established about the remaining study population who were not part of this subset analysis.

Patients with Lamivudine-Resistant Chronic Hepatitis B Study 121 was a randomized, double-blind, active-controlled trial evaluating the safety and efficacy of VIREAD compared to an unapproved antiviral regimen in subjects with chronic hepatitis B, persistent viremia (HBV DNA ≥ 1,000 IU/mL), and genotypic evidence of lamivudine resistance (rtM204I/V +/- rtL180M).

One hundred forty-one adult subjects were randomized to the VIREAD treatment arm.

The mean age of subjects randomized to VIREAD was 47 years (range 18–73), 74% were male, 59% were Caucasian, and 37% were Asian.

At baseline, 54% of subjects were HBeAg-negative, 46% were HBeAg-positive, and 56% had abnormal ALT.

Subjects had a mean HBV DNA of 6.4 log copies/mL and mean serum ALT of 71 U/L at baseline.

10 After 96 weeks of treatment, 126 of 141 subjects (89%) randomized to VIREAD had HBV DNA < 400 copies/mL (69 IU/mL), and 49 of 79 subjects (62%) with abnormal ALT at baseline had ALT normalization.

Among the HBeAg-positive subjects randomized to VIREAD, 10 of 65 subjects (15%) experienced HBeAg loss, and 7 of 65 subjects (11%) experienced anti-HBe seroconversion through Week 96.

The proportion of subjects with HBV DNA concentrations below 400 copies/mL (69 IU/mL) at Week 96 was similar between the VIREAD monotherapy and the comparator arms.

Across the combined chronic hepatitis B treatment trials, the number of subjects with adefovir-resistance associated substitutions at baseline was too small to establish efficacy in this subgroup.

Patients with Chronic Hepatitis B and Decompensated Liver Disease VIREAD was studied in a small randomized, double-blind, active-controlled trial evaluating the safety of VIREAD compared to other antiviral drugs in subjects with chronic hepatitis B and decompensated liver disease through 48 weeks (Study 0108).

Forty-five adult subjects (37 males and 8 females) were randomized to the VIREAD treatment arm.

At baseline, 69% subjects were HBeAg-negative, and 31% were HBeAg-positive.

Subjects had a mean Child-Pugh score of 7, a mean MELD score of 12, mean HBV DNA of 5.8 log copies/mL and mean serum ALT of 61 U/L at baseline.

Trial endpoints were discontinuation due to an adverse event and confirmed increase in serum creatinine ≥ 0.5 mg/dL or confirmed serum phosphorus of < 2 mg/dL .

10 [See ] Adverse Reactions (6.1) At 48 weeks, 31/44 (70%) and 12/26 (46%) Viread-treated subjects achieved an HBV DNA < 400 copies/mL (69 IU/mL), and normalized ALT, respectively.

The trial was not designed to evaluate treatment impact on clinical endpoints such as progression of liver disease, need for liver transplantation, or death.

CLINICAL STUDIES

14 The use of lamivudine is based on the results of clinical trials in HIV-1-infected subjects in combination regimens with other antiretroviral agents.

Information from trials with clinical endpoints or a combination of CD4+ cell counts and HIV-1 RNA measurements is included below as documentation of the contribution of lamivudine to a combination regimen in controlled trials.

14.1 Adult Subjects Clinical Endpoint Trial NUCB3007 (CAESAR) was a multicenter, double-blind, placebo-controlled trial comparing continued current therapy (zidovudine alone [62% of subjects] or zidovudine with didanosine or zalcitabine [38% of subjects]) to the addition of lamivudine or lamivudine plus an investigational non-nucleoside reverse transcriptase inhibitor (NNRTI), randomized 1:2:1.

A total of 1,816 HIV-1-infected adults with 25 to 250 CD4+ cells per mm 3 (median = 122 cells per mm 3 ) at baseline were enrolled: median age was 36 years, 87% were male, 84% were nucleoside-experienced, and 16% were therapy-naive.

The median duration on trial was 12 months.

Results are summarized in Table 9.

Table 9.

Number of Subjects (%) with at Least One HIV-1 Disease Progression Event or Death a An investigational non-nucleoside reverse transcriptase inhibitor not approved in the United States.

Endpoint Current Therapy (n = 460) Lamivudine plus Current Therapy (n = 896) Lamivudine plus an NNRTI a plus Current Therapy (n = 460) HIV-1 progression or death 90 (19.6%) 86 (9.6%) 41 (8.9%) Death 27 (5.9%) 23 (2.6%) 14 (3.0%) Surrogate Endpoint Trials Dual Nucleoside Analogue Trials: Principal clinical trials in the initial development of lamivudine compared lamivudine/zidovudine combinations with zidovudine monotherapy or with zidovudine plus zalcitabine.

These trials demonstrated the antiviral effect of lamivudine in a 2-drug combination.

More recent uses of lamivudine in treatment of HIV-1 infection incorporate it into multiple-drug regimens containing at least 3 antiretroviral drugs for enhanced viral suppression.

Dose Regimen Comparison Surrogate Endpoint Trials in Therapy-Naive Adults: EPV20001 was a multicenter, double-blind, controlled trial in which subjects were randomized 1:1 to receive lamivudine 300 mg once daily or lamivudine 150 mg twice daily, in combination with zidovudine 300 mg twice daily and efavirenz 600 mg once daily.

A total of 554 antiretroviral treatment-naive HIV-1-infected adults enrolled: male (79%), white (50%), median age of 35 years, baseline CD4+ cell counts of 69 to 1,089 cells per mm 3 (median = 362 cells per mm 3 ), and median baseline plasma HIV-1 RNA of 4.66 log 10 copies per mL.

Outcomes of treatment through 48 weeks are summarized in Figure 1 and Table 10.

Figure 1.

Virologic Response through Week 48, EPV20001 a,b (Intent-to-Treat) a Roche AMPLICOR HIV-1 MONITOR.

b Responders at each visit are subjects who had achieved and maintained HIV-1 RNA less than 400 copies per mL without discontinuation by that visit.

Table 10.

Outcomes of Randomized Treatment through 48 Weeks (Intent-to-Treat) a Achieved confirmed plasma HIV-1 RNA less than 400 copies per mL and maintained through 48 weeks.

b Achieved suppression but rebounded by Week 48, discontinued due to virologic failure, insufficient viral response according to the investigator, or never suppressed through Week 48.

c Includes consent withdrawn, lost to follow-up, protocol violation, data outside the trial-defined schedule, and randomized but never initiated treatment.

Outcome Lamivudine 300 mg Once Daily plus RETROVIR plus Efavirenz (n = 278) Lamivudine 150 mg Twice Daily plus RETROVIR plus Efavirenz (n = 276) Responder a 67% 65% Virologic failure b 8% 8% Discontinued due to clinical progression <1% 0% Discontinued due to adverse events 6% 12% Discontinued due to other reasons c 18% 14% The proportions of subjects with HIV-1 RNA less than 50 copies per mL (via Roche Ultrasensitive assay) through Week 48 were 61% for subjects receiving lamivudine 300 mg once daily and 63% for subjects receiving lamivudine 150 mg twice daily.

Median increases in CD4+ cell counts were 144 cells per mm 3 at Week 48 in subjects receiving lamivudine 300 mg once daily and 146 cells per mm 3 for subjects receiving lamivudine 150 mg twice daily.

A small, randomized, open-label pilot trial, EPV40001, was conducted in Thailand.

A total of 159 treatment-naive adult subjects (male 32%, Asian 100%, median age 30 years, baseline median CD4+ cell count 380 cells per mm 3 , median plasma HIV-1 RNA 4.8 log 10 copies per mL) were enrolled.

Two of the treatment arms in this trial provided a comparison between lamivudine 300 mg once daily (n = 54) and lamivudine 150 mg twice daily (n = 52), each in combination with zidovudine 300 mg twice daily and abacavir 300 mg twice daily.

In intent-to-treat analyses of 48-week data, the proportions of subjects with HIV-1 RNA below 400 copies per mL were 61% (33 of 54) in the group randomized to once-daily lamivudine and 75% (39 of 52) in the group randomized to receive all 3 drugs twice daily; the proportions with HIV-1 RNA below 50 copies per mL were 54% (29 of 54) in the once-daily lamivudine group and 67% (35 of 52) in the all-twice-daily group; and the median increases in CD4+ cell counts were 166 cells per mm 3 in the once-daily lamivudine group and 216 cells per mm 3 in the all-twice-daily group.

Figure 1 14.2 Pediatric Subjects Clinical Endpoint Trial ACTG300 was a multicenter, randomized, double-blind trial that provided for comparison of lamivudine plus RETROVIR (zidovudine) with didanosine monotherapy.

A total of 471 symptomatic, HIV-1-infected therapy-naive (less than or equal to 56 days of antiretroviral therapy) pediatric subjects were enrolled in these 2 treatment arms.

The median age was 2.7 years (range: 6 weeks to 14 years), 58% were female, and 86% were non-white.

The mean baseline CD4+ cell count was 868 cells per mm 3 (mean: 1,060 cells per mm 3 and range: 0 to 4,650 cells per mm 3 for subjects aged less than or equal to 5 years; mean: 419 cells per mm 3 and range: 0 to 1,555 cells per mm 3 for subjects aged over 5 years) and the mean baseline plasma HIV-1 RNA was 5.0 log 10 copies per mL.

The median duration on trial was 10.1 months for the subjects receiving lamivudine plus RETROVIR and 9.2 months for subjects receiving didanosine monotherapy.

Results are summarized in Table 11.

Table 11.

Number of Subjects (%) Reaching a Primary Clinical Endpoint (Disease Progression or Death) Endpoint Lamivudine plus RETROVIR (n = 236) Didanosine (n = 235) HIV-1 disease progression or death (total) 15 (6.4%) 37 (15.7%) Physical growth failure 7 (3.0%) 6 (2.6%) Central nervous system deterioration 4 (1.7%) 12 (5.1%) CDC Clinical Category C 2 (0.8%) 8 (3.4%) Death 2 (0.8%) 11 (4.7%) Once-Daily Dosing ARROW (COL105677) was a 5-year randomized, multicenter trial which evaluated multiple aspects of clinical management of HIV-1 infection in pediatric subjects.

HIV-1-infected, treatment-naïve subjects aged 3 months to 17 years were enrolled and treated with a first-line regimen containing lamivudine and abacavir, dosed twice daily according to World Health Organization recommendations.

After a minimum of 36 weeks on treatment, subjects were given the option to participate in Randomization 3 of the ARROW trial, comparing the safety and efficacy of once-daily dosing with twice-daily dosing of lamivudine and abacavir, in combination with a third antiretroviral drug, for an additional 96 weeks.

Of the 1,206 original ARROW subjects, 669 participated in Randomization 3.

Virologic suppression was not a requirement for participation: at baseline for Randomization 3 (following a minimum of 36 weeks of twice-daily treatment), 75% of subjects in the twice-daily cohort were virologically suppressed, compared with 71% of subjects in the once-daily cohort.

The proportion of subjects with HIV-1 RNA of less than 80 copies per mL through 96 weeks is shown in Table 12.

The differences between virologic responses in the two treatment arms were comparable across baseline characteristics for gender and age.

Table 12.

Virologic Outcome of Randomized Treatment at Week 96 a (ARROW Randomization 3) Outcome Lamivudine plus Abacavir Twice-Daily Dosing (n = 333) Lamivudine plus Abacavir Once-Daily Dosing (n = 336) HIV-1 RNA <80 copies/mL b 70% 67% HIV-1 RNA ≥80 copies/mL c No virologic data 28% 31% Discontinued due to adverse event or death 1% <1% Discontinued study for other reasons d 0% <1% Missing data during window but on study 1% 1% a Analyses were based on the last observed viral load data within the Week 96 window.

b Predicted difference (95% CI) of response rate is -4.5% (-11% to 2%) at Week 96.

c Includes subjects who discontinued due to lack or loss of efficacy or for reasons other than an adverse event or death, and had a viral load value of greater than or equal to 80 copies per mL, or subjects who had a switch in background regimen that was not permitted by the protocol.

d Other includes reasons such as withdrew consent, loss to follow-up, etc.

and the last available HIV-1 RNA less than 80 copies per mL (or missing).

Analyses by formulation demonstrated the proportion of subjects with HIV-1 RNA of less than 80 copies per mL at randomization and Week 96 was higher in subjects who had received tablet formulations of lamivudine and abacavir (75% [458/610] and 72% [434/601]) than in those who had received solution formulation(s) (with lamivudine solution given at weight band-based doses approximating 8 mg per kg per day) at any time (52% [29/56] and 54% [30/56]), respectively [see Warnings and Precautions (5.5) ] .

These differences were observed in each different age group evaluated.

CLINICAL STUDIES

14 14.1 Neuropathic Pain Associated with Diabetic Peripheral Neuropathy The efficacy of the maximum recommended dose of LYRICA for the management of neuropathic pain associated with diabetic peripheral neuropathy was established in three double-blind, placebo-controlled, multicenter studies with three times a day dosing, two of which studied the maximum recommended dose.

Patients were enrolled with either Type 1 or Type 2 diabetes mellitus and a diagnosis of painful distal symmetrical sensorimotor polyneuropathy for 1 to 5 years.

A total of 89% of patients completed Studies DPN 1 and DPN 2.

The patients had a minimum mean baseline pain score of greater than or equal to 4 on an 11-point numerical pain rating scale ranging from 0 (no pain) to 10 (worst possible pain).

The baseline mean pain scores across the two studies ranged from 6.1 to 6.7.

Patients were permitted up to 4 grams of acetaminophen per day as needed for pain, in addition to pregabalin.

Patients recorded their pain daily in a diary.

Study DPN 1: This 5-week study compared LYRICA 25, 100, or 200 mg three times a day with placebo.

Treatment with LYRICA 100 and 200 mg three times a day statistically significantly improved the endpoint mean pain score and increased the proportion of patients with at least a 50% reduction in pain score from baseline.

There was no evidence of a greater effect on pain scores of the 200 mg three times a day dose than the 100 mg three times a day dose, but there was evidence of dose dependent adverse reactions [see Adverse Reactions (6.1) ] .

For a range of levels of improvement in pain intensity from baseline to study endpoint, Figure 1 shows the fraction of patients achieving that level of improvement.

The figure is cumulative, so that patients whose change from baseline is, for example, 50%, are also included at every level of improvement below 50%.

Patients who did not complete the study were assigned 0% improvement.

Some patients experienced a decrease in pain as early as Week 1, which persisted throughout the study.

Figure 1: Patients Achieving Various Levels of Improvement in Pain Intensity – Study DPN 1 Figure 1 Study DPN 2: This 8-week study compared LYRICA 100 mg three times a day with placebo.

Treatment with LYRICA 100 mg three times a day statistically significantly improved the endpoint mean pain score and increased the proportion of patients with at least a 50% reduction in pain score from baseline.

For various levels of improvement in pain intensity from baseline to study endpoint, Figure 2 shows the fraction of patients achieving that level of improvement.

The figure is cumulative, so that patients whose change from baseline is, for example, 50%, are also included at every level of improvement below 50%.

Patients who did not complete the study were assigned 0% improvement.

Some patients experienced a decrease in pain as early as Week 1, which persisted throughout the study.

Figure 2: Patients Achieving Various Levels of Improvement in Pain Intensity– Study DPN 2 Figure 2 14.2 Postherpetic Neuralgia The efficacy of LYRICA for the management of postherpetic neuralgia was established in three double-blind, placebo-controlled, multicenter studies.

These studies enrolled patients with neuralgia persisting for at least 3 months following healing of herpes zoster rash and a minimum baseline score of greater than or equal to 4 on an 11-point numerical pain rating scale ranging from 0 (no pain) to 10 (worst possible pain).

Seventy-three percent of patients completed the studies.

The baseline mean pain scores across the 3 studies ranged from 6 to 7.

Patients were permitted up to 4 grams of acetaminophen per day as needed for pain, in addition to pregabalin.

Patients recorded their pain daily in a diary.

Study PHN 1: This 13-week study compared LYRICA 75, 150, and 300 mg twice daily with placebo.

Patients with creatinine clearance (CLcr) between 30 to 60 mL/min were randomized to 75 mg, 150 mg, or placebo twice daily.

Patients with creatinine clearance greater than 60 mL/min were randomized to 75 mg, 150 mg, 300 mg or placebo twice daily.

In patients with creatinine clearance greater than 60 mL/min treatment with all doses of LYRICA statistically significantly improved the endpoint mean pain score and increased the proportion of patients with at least a 50% reduction in pain score from baseline.

Despite differences in dosing based on renal function, patients with creatinine clearance between 30 to 60 mL/min tolerated LYRICA less well than patients with creatinine clearance greater than 60 mL/min as evidenced by higher rates of discontinuation due to adverse reactions.

For various levels of improvement in pain intensity from baseline to study endpoint, Figure 3 shows the fraction of patients achieving that level of improvement.

The figure is cumulative, so that patients whose change from baseline is, for example, 50%, are also included at every level of improvement below 50%.

Patients who did not complete the study were assigned 0% improvement.

Some patients experienced a decrease in pain as early as Week 1, which persisted throughout the study.

Figure 3: Patients Achieving Various Levels of Improvement in Pain Intensity– Study PHN 1 Figure 3 Study PHN 2: This 8-week study compared LYRICA 100 or 200 mg three times a day with placebo, with doses assigned based on creatinine clearance.

Patients with creatinine clearance between 30 to 60 mL/min were treated with 100 mg three times a day, and patients with creatinine clearance greater than 60 mL/min were treated with 200 mg three times daily.

Treatment with LYRICA statistically significantly improved the endpoint mean pain score and increased the proportion of patients with at least a 50% reduction in pain score from baseline.

For various levels of improvement in pain intensity from baseline to study endpoint, Figure 4 shows the fraction of patients achieving those levels of improvement.

The figure is cumulative, so that patients whose change from baseline is, for example, 50%, are also included at every level of improvement below 50%.

Patients who did not complete the study were assigned 0% improvement.

Some patients experienced a decrease in pain as early as Week 1, which persisted throughout the study.

Figure 4: Patients Achieving Various Levels of Improvement in Pain Intensity – Study PHN 2 Figure 4 Study PHN 3: This 8-week study compared LYRICA 50 or 100 mg three times a day with placebo with doses assigned regardless of creatinine clearance.

Treatment with LYRICA 50 and 100 mg three times a day statistically significantly improved the endpoint mean pain score and increased the proportion of patients with at least a 50% reduction in pain score from baseline.

Patients with creatinine clearance between 30 to 60 mL/min tolerated LYRICA less well than patients with creatinine clearance greater than 60 mL/min as evidenced by markedly higher rates of discontinuation due to adverse reactions.

For various levels of improvement in pain intensity from baseline to study endpoint, Figure 5 shows the fraction of patients achieving that level of improvement.

The figure is cumulative, so that patients whose change from baseline is, for example, 50%, are also included at every level of improvement below 50%.

Patients who did not complete the study were assigned 0% improvement.

Some patients experienced a decrease in pain as early as Week 1, which persisted throughout the study.

Figure 5: Patients Achieving Various Levels of Improvement in Pain Intensity– Study PHN 3 Figure 5 14.3 Adjunctive Therapy for Partial Onset Seizures in Patients 4 Years of Age and Older Adjunctive Therapy for Partial Onset Seizures in Adult Patients The efficacy of LYRICA as adjunctive therapy for partial onset seizures in adult patients was established in three 12-week, randomized, double-blind, placebo-controlled, multicenter studies.

Patients were enrolled who had partial onset seizures with or without secondary generalization and were not adequately controlled with 1 to 3 concomitant antiepileptic drugs (AEDs).

Patients taking gabapentin were required to discontinue gabapentin treatment 1 week prior to entering baseline.

During an 8-week baseline period, patients had to experience at least 6 partial onset seizures with no seizure-free period exceeding 4 weeks.

The mean duration of epilepsy was 25 years in these 3 studies and the mean and median baseline seizure frequencies were 22.5 and 10 seizures per month, respectively.

Approximately half of the patients were taking 2 concurrent AEDs at baseline.

Among the LYRICA-treated patients, 80% completed the double-blind phase of the studies.

Table 10 shows median baseline seizure rates and median percent reduction in seizure frequency by dose.

Table 10.

Seizure Response in Controlled, Add-On Epilepsy Studies in Adults Daily Dose of Pregabalin Dosing Regimen N Baseline Seizure Frequency/mo Median % Change from Baseline p-value, vs.

placebo Study E1 Placebo BID 100 9.5 0 50 mg/day BID 88 10.3 -9 0.4230 150 mg/day BID 86 8.8 -35 0.0001 300 mg/day BID 90 9.8 -37 0.0001 600 mg/day BID 89 9.0 -51 0.0001 Study E2 Placebo TID 96 9.3 1 150 mg/day TID 99 11.5 -17 0.0007 600 mg/day TID 92 12.3 -43 0.0001 Study E3 Placebo BID/TID 98 11 -1 600 mg/day BID 103 9.5 -36 0.0001 600 mg/day TID 111 10 -48 0.0001 In the first study (E1), there was evidence of a dose-response relationship for total daily doses of Lyrica between 150 and 600 mg/day; a dose of 50 mg/day was not effective.

In the first study (E1), each daily dose was divided into two equal doses (twice a day dosing).

In the second study (E2), each daily dose was divided into three equal doses (three times a day dosing).

In the third study (E3), the same total daily dose was divided into two equal doses for one group (twice a day dosing) and three equal doses for another group (three times a day dosing).

While the three times a day dosing group in Study E3 performed numerically better than the twice a day dosing group, this difference was small and not statistically significant.

A secondary outcome measure included the responder rate (proportion of patients with greater than or equal to 50% reduction from baseline in partial seizure frequency).

The following figure displays responder rate by dose for two of the studies.

Figure 6: Responder rate by add-on epilepsy study Figure 7: Seizure Reduction by Dose (All Partial Onset Seizures) for Studies E1, E2, and E3 Subset evaluations of the antiseizure efficacy of LYRICA showed no clinically important differences as a function of age, gender, or race.

Figure 6 Figure 7 Adjunctive Therapy for Partial Onset Seizures in Pediatric Patients 4 to Less Than 17 Years of Age The efficacy of LYRICA as adjunctive therapy in partial onset seizures was established in a 12-week, randomized, double-blind, placebo-controlled, multicenter study in pediatric patients 4 years to less than 17 years of age with partial onset seizures with or without secondary generalization.

During an 8-week baseline period, patients had to experience at least 6 partial onset seizures with no seizure-free period exceeding 4 weeks.

The mean duration of epilepsy was 6 years and the mean and median baseline seizure frequencies were 57 and 18 seizures per month, respectively.

Approximately 74% of the patients were taking 2 to 3 concurrent AEDs at baseline.

Among the LYRICA-treated patients, 87% completed the double-blind phase of the study.

In this study, LYRICA 2.5 mg/kg/day (maximum 150 mg/day) and 10 mg/kg/day (maximum 600 mg/day) were compared to placebo.

Administration of each daily dose was divided into two equal doses (twice a day dosing).

Because of higher weight-normalized clearance in patients with body weight less than 30 kg [see Clinical Pharmacology (12.3) ] , the LYRICA dose was increased by 40% to 3.5 mg/kg/day for patients weighing less than 30 kg randomized to the 2.5 mg/kg/day group or to 14 mg/kg/day for patients randomized to the 10 mg/kg/day group.

Table 11 shows median baseline seizure rates, median percent change from baseline in seizure rates, and percent difference relative to placebo (derived from the primary analysis model) by dose.

Table 11.

Seizure Response in Controlled Add-On Partial Onset Seizure Study in Pediatric Patients 4 to Less Than 17 Years of Age Daily Dose of LYRICA N Median Baseline Seizure Frequency/28 days Median % Change from Baseline % Difference Relative to Placebo p-value, versus placebo Abbreviations: BID=twice daily; N=number.

Placebo 93 16.5 -16.9 Not applicable 2.5 mg/kg/day (BID) 2.5 mg/kg/day: Maximum dose 150 mg/day.

Includes patients less than 30 kg for whom dose was adjusted to 3.5 mg/kg/day.

104 23.8 -27.3 -10.5 0.2577 10 mg/kg/day (BID) 10 mg/kg/day: Maximum dose 600 mg/day.

Includes patients less than 30 kg for whom dose was adjusted to 14 mg/kg/day.

97 17.5 -37.1 -21.0 0.0185 There was evidence of a dose-response relationship for total daily doses of LYRICA between 2.5 mg/kg/day and 10 mg/kg/day.

A significant improvement in seizure rate was observed for LYRICA 10 mg/kg/day group compared with placebo.

While the 2.5 mg/kg/day group performed numerically better than placebo, this difference was not statistically significant.

A key secondary efficacy measure, the responder rate (proportion of patients with greater than or equal to 50% reduction from baseline in partial seizure frequency) showed improvements for LYRICA groups compared with placebo.

The following figure displays responder rate by dose: Figure 8: Responder Rate (Greater than or Equal to 50% Reduction) Figure 8 14.4 Management of Fibromyalgia The efficacy of LYRICA for management of fibromyalgia was established in one 14-week, double-blind, placebo-controlled, multicenter study (F1) and one six-month, randomized withdrawal study (F2).

Studies F1 and F2 enrolled patients with a diagnosis of fibromyalgia using the American College of Rheumatology (ACR) criteria (history of widespread pain for 3 months, and pain present at 11 or more of the 18 specific tender point sites).

The studies showed a reduction in pain by visual analog scale.

In addition, improvement was demonstrated based on a patient global assessment (PGIC), and on the Fibromyalgia Impact Questionnaire (FIQ).

Study F1 : This 14-week study compared LYRICA total daily doses of 300 mg, 450 mg and 600 mg with placebo.

Patients were enrolled with a minimum mean baseline pain score of greater than or equal to 4 on an 11-point numeric pain rating scale and a score of greater than or equal to 40 mm on the 100 mm pain visual analog scale (VAS).

The baseline mean pain score in this trial was 6.7.

Responders to placebo in an initial one-week run-in phase were not randomized into subsequent phases of the study.

A total of 64% of patients randomized to LYRICA completed the study.

There was no evidence of a greater effect on pain scores of the 600 mg daily dose than the 450 mg daily dose, but there was evidence of dose-dependent adverse reactions [see Adverse Reactions (6.1) ] .

Some patients experienced a decrease in pain as early as Week 1, which persisted throughout the study.

The results are summarized in Figure 9 and Table 12.

For various levels of improvement in pain intensity from baseline to study endpoint, Figure 9 shows the fraction of patients achieving that level of improvement.

The figure is cumulative.

Patients who did not complete the study were assigned 0% improvement.

Some patients experienced a decrease in pain as early as Week 1, which persisted throughout the study.

Figure 9: Patients Achieving Various Levels of Improvement in Pain Intensity – Fibromyalgia Study F1 Table 12.

Patient Global Response in Fibromyalgia Study F1 Patient Global Impression of Change Treatment Group (mg/day) % Any Improvement 95% CI PGB = Pregabalin Placebo 47.6 (40.0,55.2) PGB 300 68.1 (60.9, 75.3) PGB 450 77.8 (71.5, 84.0) PGB 600 66.1 (59.1, 73.1) Figure 9 Study F2 : This randomized withdrawal study compared LYRICA with placebo.

Patients were titrated during a 6-week open-label dose optimization phase to a total daily dose of 300 mg, 450 mg, or 600 mg.

Patients were considered to be responders if they had both: 1) at least a 50% reduction in pain (VAS) and, 2) rated their overall improvement on the PGIC as “much improved” or “very much improved.” Those who responded to treatment were then randomized in the double-blind treatment phase to either the dose achieved in the open-label phase or to placebo.

Patients were treated for up to 6 months following randomization.

Efficacy was assessed by time to loss of therapeutic response, defined as 1) less than 30% reduction in pain (VAS) from open-label baseline during two consecutive visits of the double-blind phase, or 2) worsening of FM symptoms necessitating an alternative treatment.

Fifty-four percent of patients were able to titrate to an effective and tolerable dose of LYRICA during the 6-week open-label phase.

Of the patients entering the randomized treatment phase assigned to remain on LYRICA, 38% of patients completed 26 weeks of treatment versus 19% of placebo-treated patients.

When considering return of pain or withdrawal due to adverse events as loss of response (LTR), treatment with LYRICA resulted in a longer time to loss of therapeutic response than treatment with placebo.

Fifty-three percent of the pregabalin-treated subjects compared to 33% of placebo patients remained on study drug and maintained a therapeutic response to Week 26 of the study.

Treatment with LYRICA also resulted in a longer time to loss of response based on the FIQ Time to worsening of the FIQ was defined as the time to a 1-point increase from double-blind baseline in each of the subscales, and a 5-point increase from double-blind baseline evaluation for the FIQ total score.

, and longer time to loss of overall assessment of patient status, as measured by the PGIC Time to PGIC lack of improvement was defined as time to PGIC assessments indicating less improvement than “much improvement.” .

Figure 10: Time to Loss of Therapeutic Response, Fibromyalgia Study F2 (Kaplan-Meier Analysis) Figure 10 14.5 Management of Neuropathic Pain Associated with Spinal Cord Injury The efficacy of LYRICA for the management of neuropathic pain associated with spinal cord injury was established in two double-blind, placebo-controlled, multicenter studies.

Patients were enrolled with neuropathic pain associated with spinal cord injury that persisted continuously for at least three months or with relapses and remissions for at least six months.

A total of 63% of patients completed study 1 and 84% completed study 2.

The patients had a minimum mean baseline pain score of greater than or equal to 4 on an 11-point numerical pain rating scale ranging from 0 (no pain) to 10 (worst possible pain).

The baseline mean pain scores across the two studies ranged from 6.5 to 6.7.

Patients were allowed to take opioids, non-opioid analgesics, antiepileptic drugs, muscle relaxants, and antidepressant drugs if the dose was stable for 30 days prior to screening.

Patients were allowed to take acetaminophen and nonsteroidal anti-inflammatory drugs during the studies.

Study SCI 1 : This 12-week, randomized, double-blind, parallel-group, multicenter, flexible dose (150–600 mg/day) study compared pregabalin with placebo.

The 12-week study consisted of a 3-week dose adjustment phase and a 9-week dose maintenance phase.

Treatment with LYRICA 150–600 mg/day statistically significantly improved the endpoint weekly mean pain score, and increased the proportion of patients with at least a 30% and 50% reduction in pain score from baseline.

The fraction of patients achieving various levels of improvement in pain intensity from baseline to Week 12 is presented in Figure 11.

Some patients experienced a decrease in pain as early as week 1, which persisted throughout the study.

Figure 11 : Patients Achieving Various Levels of Improvement in Pain Intensity – Study SCI 1 Figure 11 Study SCI 2 : This 16-week, randomized, double-blind, placebo-controlled, parallel-group, multicenter, flexible dose (150–600 mg/day, in increments of 150 mg) study compared the efficacy, safety and tolerability of pregabalin with placebo.

The 16-week study consisted of a 4-week dose adjustment phase and a 12-week dose maintenance phase.

Treatment with LYRICA statistically significantly improved the endpoint weekly mean pain score, and increased the proportion of patients with at least a 30% and 50% reduction in pain score from baseline.

The fraction of patients achieving various levels of improvement in pain intensity from baseline to Week 16 is presented in Figure 12.

Some patients experienced a decrease in pain as early as week 1, which persisted throughout the study.

Figure 12 : Patients Achieving Various Levels of Improvement in Pain Intensity – Study SCI 2 Figure 12

CLINICAL STUDIES

14 14.1 Epilepsy Monotherapy With LAMICTAL in Adults With Partial Seizures Already Receiving Treatment With Carbamazepine, Phenytoin, Phenobarbital, or Primidone as the Single Antiepileptic Drug: The effectiveness of monotherapy with LAMICTAL was established in a multicenter, double-blind clinical trial enrolling 156 adult outpatients with partial seizures.

The patients experienced at least 4 simple partial, complex partial, and/or secondarily generalized seizures during each of 2 consecutive 4-week periods while receiving carbamazepine or phenytoin monotherapy during baseline.

LAMICTAL (target dose of 500 mg/day) or valproate (1,000 mg/day) was added to either carbamazepine or phenytoin monotherapy over a 4-week period.

Patients were then converted to monotherapy with LAMICTAL or valproate during the next 4 weeks, then continued on monotherapy for an additional 12-week period.

Study endpoints were completion of all weeks of study treatment or meeting an escape criterion.

Criteria for escape relative to baseline were: (1) doubling of average monthly seizure count, (2) doubling of highest consecutive 2-day seizure frequency, (3) emergence of a new seizure type (defined as a seizure that did not occur during the 8-week baseline) that is more severe than seizure types that occur during study treatment, or (4) clinically significant prolongation of generalized tonic-clonic seizures.

The primary efficacy variable was the proportion of patients in each treatment group who met escape criteria.

The percentages of patients who met escape criteria were 42% (32/76) in the group receiving LAMICTAL and 69% (55/80) in the valproate group.

The difference in the percentage of patients meeting escape criteria was statistically significant ( P = 0.0012) in favor of LAMICTAL.

No differences in efficacy based on age, sex, or race were detected.

Patients in the control group were intentionally treated with a relatively low dose of valproate; as such, the sole objective of this study was to demonstrate the effectiveness and safety of monotherapy with LAMICTAL, and cannot be interpreted to imply the superiority of LAMICTAL to an adequate dose of valproate.

Adjunctive Therapy With LAMICTAL in Adults With Partial Seizures: The effectiveness of LAMICTAL as adjunctive therapy (added to other AEDs) was established in 3 multicenter, placebo-controlled, double-blind clinical trials in 355 adults with refractory partial seizures.

The patients had a history of at least 4 partial seizures per month in spite of receiving one or more AEDs at therapeutic concentrations and, in 2 of the studies, were observed on their established AED regimen during baselines that varied between 8 to 12 weeks.

In the third, patients were not observed in a prospective baseline.

In patients continuing to have at least 4 seizures per month during the baseline, LAMICTAL or placebo was then added to the existing therapy.

In all 3 studies, change from baseline in seizure frequency was the primary measure of effectiveness.

The results given below are for all partial seizures in the intent-to-treat population (all patients who received at least one dose of treatment) in each study, unless otherwise indicated.

The median seizure frequency at baseline was 3 per week while the mean at baseline was 6.6 per week for all patients enrolled in efficacy studies.

One study (n = 216) was a double-blind, placebo-controlled, parallel trial consisting of a 24-week treatment period.

Patients could not be on more than 2 other anticonvulsants and valproate was not allowed.

Patients were randomized to receive placebo, a target dose of 300 mg/day of LAMICTAL, or a target dose of 500 mg/day of LAMICTAL.

The median reductions in the frequency of all partial seizures relative to baseline were 8% in patients receiving placebo, 20% in patients receiving 300 mg/day of LAMICTAL, and 36% in patients receiving 500 mg/day of LAMICTAL.

The seizure frequency reduction was statistically significant in the 500-mg/day group compared with the placebo group, but not in the 300-mg/day group.

A second study (n = 98) was a double-blind, placebo-controlled, randomized, crossover trial consisting of two 14-week treatment periods (the last 2 weeks of which consisted of dose tapering) separated by a 4-week washout period.

Patients could not be on more than 2 other anticonvulsants and valproate was not allowed.

The target dose of LAMICTAL was 400 mg/day.

When the first 12 weeks of the treatment periods were analyzed, the median change in seizure frequency was a 25% reduction on LAMICTAL compared with placebo (P <0.001).

The third study (n = 41) was a double-blind, placebo-controlled, crossover trial consisting of two 12-week treatment periods separated by a 4-week washout period.

Patients could not be on more than 2 other anticonvulsants.

Thirteen patients were on concomitant valproate; these patients received 150 mg/day of LAMICTAL.

The 28 other patients had a target dose of 300 mg/day of LAMICTAL.

The median change in seizure frequency was a 26% reduction on LAMICTAL compared with placebo ( P <0.01).

No differences in efficacy based on age, sex, or race, as measured by change in seizure frequency, were detected.

Adjunctive Therapy With LAMICTAL in Pediatric Patients With Partial Seizures: The effectiveness of LAMICTAL as adjunctive therapy in pediatric patients with partial seizures was established in a multicenter, double-blind, placebo-controlled trial in 199 patients 2 to 16 years of age (n = 98 on LAMICTAL, n = 101 on placebo).

Following an 8-week baseline phase, patients were randomized to 18 weeks of treatment with LAMICTAL or placebo added to their current AED regimen of up to 2 drugs.

Patients were dosed based on body weight and valproate use.

Target doses were designed to approximate 5 mg/kg/day for patients taking valproate (maximum dose: 250 mg/day) and 15 mg/kg/day for the patients not taking valproate (maximum dose: 750 mg/day).

The primary efficacy endpoint was percentage change from baseline in all partial seizures.

For the intent-to-treat population, the median reduction of all partial seizures was 36% in patients treated with LAMICTAL and 7% on placebo, a difference that was statistically significant ( P <0.01).

Adjunctive Therapy With LAMICTAL in Pediatric and Adult Patients With Lennox-Gastaut Syndrome: The effectiveness of LAMICTAL as adjunctive therapy in patients with Lennox-Gastaut syndrome was established in a multicenter, double-blind, placebo-controlled trial in 169 patients 3 to 25 years of age (n = 79 on LAMICTAL, n = 90 on placebo).

Following a 4-week single-blind, placebo phase, patients were randomized to 16 weeks of treatment with LAMICTAL or placebo added to their current AED regimen of up to 3 drugs.

Patients were dosed on a fixed-dose regimen based on body weight and valproate use.

Target doses were designed to approximate 5 mg/kg/day for patients taking valproate (maximum dose: 200 mg/day) and 15 mg/kg/day for patients not taking valproate (maximum dose: 400 mg/day).

The primary efficacy endpoint was percentage change from baseline in major motor seizures (atonic, tonic, major myoclonic, and tonic-clonic seizures).

For the intent-to-treat population, the median reduction of major motor seizures was 32% in patients treated with LAMICTAL and 9% on placebo, a difference that was statistically significant ( P <0.05).

Drop attacks were significantly reduced by LAMICTAL (34%) compared with placebo (9%), as were tonic-clonic seizures (36% reduction versus 10% increase for LAMICTAL and placebo, respectively).

Adjunctive Therapy With LAMICTAL in Pediatric and Adult Patients With Primary Generalized Tonic-Clonic Seizures: The effectiveness of LAMICTAL as adjunctive therapy in patients with primary generalized tonic-clonic seizures was established in a multicenter, double-blind, placebo-controlled trial in 117 pediatric and adult patients ≥2 years (n = 58 on LAMICTAL, n = 59 on placebo).

Patients with at least 3 primary generalized tonic-clonic seizures during an 8-week baseline phase were randomized to 19 to 24 weeks of treatment with LAMICTAL or placebo added to their current AED regimen of up to 2 drugs.

Patients were dosed on a fixed-dose regimen, with target doses ranging from 3 mg/kg/day to 12 mg/kg/day for pediatric patients and from 200 mg/day to 400 mg/day for adult patients based on concomitant AED.

The primary efficacy endpoint was percentage change from baseline in primary generalized tonic-clonic seizures.

For the intent-to-treat population, the median percent reduction of primary generalized tonic-clonic seizures was 66% in patients treated with LAMICTAL and 34% on placebo, a difference that was statistically significant ( P = 0.006).

14.2 Bipolar Disorder The effectiveness of LAMICTAL in the maintenance treatment of Bipolar I Disorder was established in 2 multicenter, double-blind, placebo-controlled studies in adult patients who met DSM-IV criteria for Bipolar I Disorder.

Study 1 enrolled patients with a current or recent (within 60 days) depressive episode as defined by DSM-IV and Study 2 included patients with a current or recent (within 60 days) episode of mania or hypomania as defined by DSM-IV.

Both studies included a cohort of patients (30% of 404 patients in Study 1 and 28% of 171 patients in Study 2) with rapid cycling Bipolar Disorder (4 to 6 episodes per year).

In both studies, patients were titrated to a target dose of 200 mg of LAMICTAL, as add-on therapy or as monotherapy, with gradual withdrawal of any psychotropic medications during an 8- to 16-week open-label period.

Overall 81% of 1,305 patients participating in the open-label period were receiving 1 or more other psychotropic medications, including benzodiazepines, selective serotonin reuptake inhibitors (SSRIs), atypical antipsychotics (including olanzapine), valproate, or lithium, during titration of LAMICTAL.

Patients with a CGI-severity score of 3 or less maintained for at least 4 continuous weeks, including at least the final week on monotherapy with LAMICTAL, were randomized to a placebo-controlled, double-blind treatment period for up to 18 months.

The primary endpoint was TIME (time to intervention for a mood episode or one that was emerging, time to discontinuation for either an adverse event that was judged to be related to Bipolar Disorder, or for lack of efficacy).

The mood episode could be depression, mania, hypomania, or a mixed episode.

In Study 1, patients received double-blind monotherapy with LAMICTAL 50 mg/day (n = 50), LAMICTAL 200 mg/day (n = 124), LAMICTAL 400 mg/day (n = 47), or placebo (n = 121).

LAMICTAL (200- and 400-mg/day treatment groups combined) was superior to placebo in delaying the time to occurrence of a mood episode.

Separate analyses of the 200- and 400-mg/day dose groups revealed no added benefit from the higher dose.

In Study 2, patients received double-blind monotherapy with LAMICTAL (100 to 400 mg/day, n = 59), or placebo (n = 70).

LAMICTAL was superior to placebo in delaying time to occurrence of a mood episode.

The mean dose of LAMICTAL was about 211 mg/day.

Although these studies were not designed to separately evaluate time to the occurrence of depression or mania, a combined analysis for the 2 studies revealed a statistically significant benefit for LAMICTAL over placebo in delaying the time to occurrence of both depression and mania, although the finding was more robust for depression.

CLINICAL STUDIES

Clinical Trials In clinical trials, immediate-release oral isosorbide dinitrate has been administered in a variety of regimens, with total daily doses ranging from 30 mg to 480 mg.

Controlled trials of single oral doses of isosorbide dinitrate have demonstrated effective reductions in exercise-related angina for up to 8 hours.

Anti-anginal activity is present about 1 hour after dosing.

Most controlled trials of multiple-dose oral ISDN taken every 12 hours (or more frequently) for several weeks have shown statistically significant anti-anginal efficacy for only 2 hours after dosing.

Once-daily regimens, and regimens with one daily dose-free interval of at least 14 hours (e.g., a regimen providing doses at 0800, 1400, and 1800 hours), have shown efficacy after the first dose of each day that was similar to that shown in the single-dose studies cited above.

The effects of the second and later doses have been smaller and shorter-lasting than the effect of the first.

From large, well-controlled studies of other nitrates, it is reasonable to believe that the maximal achievable daily duration of anti-anginal effect from isosorbide dinitrate is about 12 hours.

No dosing regimen for isosorbide dinitrate, however, has ever actually been shown to achieve this duration of effect.

One study of 8 patients, who were administered a pretitrated dose (average 27.5 mg) of immediate-release ISDN at 0800, 1300, and 1800 hours for 2 weeks, revealed that significant anti-anginal effectiveness was discontinuous and totaled about 6 hours in a 24 hour period.

CLINICAL STUDIES

14 Efficacy of clonidine hydrochloride extended-release tablets in the treatment of ADHD was established in children and adolescents (6 to 17 years) in: One short-term, placebo-controlled monotherapy trial (Study 1) One short-term adjunctive therapy to psychostimulants trial (Study 2) One randomized withdrawal trial as monotherapy (Study 3) Short-term Monotherapy and Adjunctive Therapy to Psychostimulant Studies for ADHD The efficacy of clonidine hydrochloride extended-release tablets in the treatment of ADHD was established in 2 (one monotherapy and one adjunctive therapy) placebo-controlled trials in pediatric patients aged 6 to 17, who met DSM-IV criteria of ADHD hyperactive or combined hyperactive/inattentive subtypes.

Signs and symptoms of ADHD were evaluated using the investigator administered and scored ADHD Rating Scale-IV-Parent Version (ADHDRS-IV) total score including hyperactive/impulsivity and inattentive subscales.

Study 1 (CLON-301), was an 8-week randomized, double-blind, placebo-controlled, fixed dose study of children and adolescents aged 6 to 17 (N=236) with a 5-week primary efficacy endpoint.

Patients were randomly assigned to one of the following three treatment groups: clonidine hydrochloride extended-release tablets (CLON) 0.2 mg/day (N=78), clonidine hydrochloride extended-release tablets 0.4 mg/day (N=80), or placebo (N=78).

Dosing for the clonidine hydrochloride extended-release tablets groups started at 0.1 mg/day and was titrated in increments of 0.1 mg/week to their respective dose (as divided doses).

Patients were maintained at their dose for a minimum of 2 weeks before being gradually tapered down to 0.1 mg/day at the last week of treatment.

At both doses, improvements in ADHD symptoms were statistically significantly superior in clonidine hydrochloride extended-release tablets-treated patients compared with placebo-treated patients at the end of 5 weeks as measured by the ADHDRS-IV total score (Table 8).

Study 2 (CLON-302) was an 8-week randomized, double-blind, placebo-controlled, flexible dose study in children and adolescents aged 6 to 17 (N=198) with a 5-week primary efficacy end point.

Patients had been treated with a psychostimulant (methylphenidate or amphetamine) for four weeks with inadequate response.

Patients were randomly assigned to one of two treatment groups: clonidine hydrochloride extended-release tablets adjunct to a psychostimulant (N=102) or psychostimulant alone (N=96).

The clonidine hydrochloride extended-release tablet dose was initiated at 0.1 mg/day and doses were titrated in increments of 0.1 mg/week up to 0.4 mg/day, as divided doses, over a 3-week period based on tolerability and clinical response.

The dose was maintained for a minimum of 2 weeks before being gradually tapered to 0.1 mg/day at the last week of treatment.

ADHD symptoms were statistically significantly improved in clonidine hydrochloride extended-release tablets plus stimulant group compared with the stimulant alone group at the end of 5 weeks as measured by the ADHDRS-IV total score (Table 8).

Table 8 Short-Term Trials Study Number Treatment Group Primary Efficacy Measure: ADHDRS-IV Total Score Mean Baseline Score LS Mean Change from Placebo-subtracted (SD) Baseline (SE) Difference a (95% CI) Study 1 Clonidine Hydrochloride Extended-Release Tablets (0.2 mg/day) 43.8 (7.47) -15.0 (1.38) -8.5 (-12.2, -4.8) Clonidine Hydrochloride Extended-Release Tablets (0.4 mg/day) 44.6 (7.73) -15.6 (1.33) -9.1 (-12.8, -5.5) Placebo 45.0 (8.53) -6.5 (1.35) -­- Study 2 Clonidine Hydrochloride Extended-Release Tablets (0.4 mg/day) + Psychostimulant 38.9 (6.95) -15.8 (1.18) -4.5 (-7.8, -1.1) Psychostimulant alone 39.0 (7.68) -11.3 (1.24) -­- SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval.

a Difference (drug minus placebo) in least-squares mean change from baseline.

Maintenance Monotherapy for ADHD Study 3 (SHN-KAP-401), was a double-blind, placebo-controlled, randomized-withdrawal study in children and adolescents aged 6 to 17 years (n=253) with DSM-IV-TR diagnosis of ADHD.

The study consisted of a 10-week, open-label phase (4 weeks of dose optimization and 6 weeks of dose maintenance), a 26-week double-blind phase, and a 4-week taper-down and follow-up phase.

All patients were initiated at 0.1 mg/day and increased at weekly intervals in increments of 0.1 mg/day until reaching personalized optimal dose (0.1, 0.2, 0.3 or 0.4 mg/day, as divided doses).

Eligible patients had to demonstrate treatment response as defined by ≥30% reduction in ADHD-RS-IV total score and a Clinical Global Impression-Improvement score of 1 or 2 during the open label phase.

Patients who sustained treatment response (n=135) until the end of the open label phase were randomly assigned to one of the two treatment groups, clonidine hydrochloride extended-release tablets (N=68) and Placebo (N=67), to evaluate the long-term efficacy of maintenance dose of clonidine hydrochloride extended-release tablets in the double-blind phase.

The primary efficacy endpoint was the percentage of patients with treatment failure defined as a ≥30% increase(worsening) in ADHD-RS-IV total score and ≥2 points increase (worsening ) in Clinical Global Impression – Severity Scale in 2 consecutive visits or early termination for any reason.

A total of 73 patients experienced treatment failure in the double-blind phase: 31 patients (45.6%) in the clonidine hydrochloride extended-release tablets group and 42 patients (62.7%) in the placebo group, with a statistically significant difference in the primary endpoint favoring clonidine hydrochloride extended-release tablets (Table 9).

The cumulative proportion of patients with treatment failure over time during the double-blind phase is displayed in Figure 2.

Table 9 Treatment Failure: Double-Blind Full Analysis Set (Study 3) Double-Blind Full Analysis Set Study 3 Clonidine Hydrochloride Extended-Release Tablets Placebo Number of subjects 68 67 Number of treatment failures 31 (45.6%) 42 (62.7%) Basis of Treatment Failure Clinical criteria a,b 11 (16.2%) 9 (13.4%) Lack of efficacy c 1 (1.5%) 3 (4.5%) Withdrawal of informed assent/consent 4 (5.9%) 20 (29.9%) Other early termination 15 (22.1%) 10 (14.9%) ADHD-RS-IV = Attention Deficit Hyperactivity Disorder-Rating Scale-4 th edition; CGI-S = Clinical Global Impression-Severity a At the same 2 consecutive visits a (1) 30% or greater reduction in ADHD-RS-IV, and (2) 2-point or more increase in CGI-S.

b Two subjects (1 placebo and 1 Clonidine Hydrochloride Extended-Release Tablets) withdrew consent, but met the clinical criteria for treatment failure.

c Three subjects (all placebo) discontinued the study due to treatment failure, but met only the criterion for ADHD-RS-IV.

Figure 2: Kaplan-Meier Estimation of Cumulative Proportion of Patients with Treatment Failure (Study 3) figure 2