ABC/3TC/ZDV ABC PBO/3TC/ZDV

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1 The study listed may include approved and non-approved uses, formulations or treatment regimens. The results reported in any single study may not reflect the overall results obtained on studies of a product. Before prescribing any product mentioned in this Register, healthcare professionals should consult prescribing information for the product approved in their country. Study No: CAB33 Title: A Randomized, Double-Blind, Parallel-Group, Multicenter Trial to Evaluate the Safety and Efficacy of 1592U89 in Combination with Lamivudine (3TC) and Zidovudine (ZDV) versus 3TC/ZDV in HIV-1 Infected Antiretroviral Therapy Naive Subjects with CD4+ cell counts 1 cells/mm³ Rationale: Progress in the understanding of the pathogenesis of Human Immunodeficiency Virus (HIV-1) disease has led to a re-evaluation of antiretroviral therapy (ART) strategies. Monotherapy with approved nucleoside reverse transcriptase inhibitors (NRTIs) is insufficient in maintaining long-term suppression of HIV-1 replication. Limitations of approved monotherapies have included inability to completely suppress viral replication, development of mutations within the HIV-1 reverse transcriptase resulting in drug resistance, and cumulative toxicity over extended treatment periods. Clinical benefit observed with combination therapies in clinical trials support the initial use of at least two antiretroviral agents. In order to evaluate abacavir (ABC) in combination with other antiretroviral agents, this phase III trial was designed to compare the safety and efficacy of ABC in combination with lamivudine (3TC) and zidovudine (ZDV) versus 3TC/ZDV in HIV-1 infected ART naive subjects with CD4+ cell counts 1 cells/mm³. Phase: III Study Period: 6 May 97 to 1 December 98 Study Design: Subjects were randomized into two treatment groups, either or ABC placebo (PBO)/3TC/ZDV, and were given the option at Week 16, if they met the switch criterion of two consecutive HIV-1 R PCR measurements of >5 copies/ml, to remain on randomized therapy, discontinue study drug, or receive openlabel ABC in combination with other ARTs. Following an amendment to the protocol which reduced the sample size in the randomized cohort from to 14, a second cohort was added () that allowed subjects to enroll into an open-label arm in which subjects received open-label. This amendment also changed the switch criterion from >5 copies/ml to >4 copies/ml. Subjects enrolled into the study were eligible to remain in the study until the study reached completion, defined as weeks after the last subject recruited received study drug. Centres: 23 centres: in the United States, 1 in Belgium, 6 in Spain, and 4 in United Kingdom. Indication: Human Immunodeficiency Virus Treatment: The subjects in were randomized to one of two treatment arms in three strata according to their screening plasma HIV-1 R level (<1, copies/ml; 1, - 1, copies/ml; or >1, copies/ml). The subjects enrolled into received open-label ABC (3mg twice daily (BID)) + 3TC (15mg BID) + ZDV (3mg BID). Study Drugs Week Study Study Drug : Randomized Therapy : Open Label ABC Therapy Dose BID Total Daily Dose BID Total Daily Dose BID Dose Dose ABC 3mg 6mg 3mg 6mg 3mg 6mg ZDV 3mg 6mg 15mg 3mg 3mg 6mg 3TC 15mg 3mg 3mg 6mg 15mg 3mg ABC PBO Duration Minimum of weeks Minimum of weeks Total Daily Dose Objectives: The primary objectives of the week study were: to compare antiviral activity following 16 weeks treatment with versus 3TC/ZDV as demonstrated by the proportion of subjects with plasma HIV-1 R levels 4 copies/ml, plasma HIV-1 R profiles, and CD4+ lymphocyte profiles; to compare safety and tolerance following 16 weeks of treatment with versus 3TC/ZDV; and to assess safety and tolerance following weeks treatment with. Primary Outcome Variable(s): The primary efficacy variable was assessed by evaluation of plasma HIV-1 R and CD4+ cell count. Secondary Outcome Variable(s): The secondary efficacy endpoints of this study included HIV-1 phenotype and genotype (for a subset of subjects), progression of disease as defined by occurrence of Acquired Immunodeficiency Disorder Syndrome-defining indicator diseases and secondary infections and mortality. 1

2 Statistical Methods: The primary analyses were to assess the durability of the plasma HIV-1 R response over time as measured by the time from first dose to a plasma HIV-1 R measurement (HIV R) in excess of 4 copies/ml at or after 8 weeks OR the occurrence of a CDC Class C event. The distribution of time to event was estimated using Kaplan-Meier product-limit estimates and presented graphically. The null hypothesis of no treatment effect was evaluated using permutation based log-rank test controlling from randomization strata. Average Area Under the Curve Minus Baseline (AAUCMB) was calculated to assess the treatment effect on absolute CD4+ results and log1 HIV-1 R levels. The AAUCMB was calculated using the trapezoidal rule divided by the total time followed on study minus the baseline value. Opportunistic infections were categorized according to the CDC Classification System for HIV infection. A disease progression event occurred at the time of a confirmed new or recurrent Class B/C event or death. Tabulations of the number and type of disease progression were prepared Data (HIV-1 R and CD4+ cell count) were presented with summary statistics by scheduled assessment within treatment group. The comparison of the proportion of subjects with plasma HIV-1 R 4 copies/ml or <5 copies/ml were tested. The proportions were estimated overall by treatment group and by treatment group with randomization strata. Statistical comparisons between treatment groups were made using Cochran Mantel Haenszel test controlling for randomization strata. The primary population for analyses of clinical efficacy was the Intent to Treat (ITT) population. The ITT population was defined as all subjects with data who were enrolled into the study as randomized, regardless of what treatment was received and the eventual outcome of study participation. An additional ITT population, referred to as the "ITT Exposed" population, was utilized for the plasma HIV-1 R analyses. The ITT exposed population excluded subjects who never initiated treatment with the study drugs. The evaluation of safety included all subjects who initiated treatment with at least one dose of study medication (defined as the Safety population). Two analysis strategies were utilized when evaluating the plasma HIV-1 R response in the ITT populations. These included the "Switch=Failure" and the "Switch Included" analyses. For the "Switch=Failure" analyses, subjects who switched ART were considered a failure after the time of switch. The "Switch Included" analyses included all subjects who switched ART regimens or discontinued therapy prior to Week. Study Population: Male or female subjects, 13 years of age or older (or years of age or older in some countries in accordance with local regulatory requirements), with documented HIV-1 infection and who were ART naive were eligible for enrollment. Subjects were to have CD4+ cell counts 1 c/mm³. Subjects were not eligible if they had laboratory assessments out of range defined for the study, had active or ongoing opportunistic infections or had recently received immunomodulating agents or HIV therapeutic vaccines. Number of Subjects: Planned, N Randomized, N Randomized but never started treatment, N 4 5 Completed week study, 66 (76) 62 (72) (62) Total Number Subjects Withdrawn, N (%) (24) 24 (28) 28 (38) Withdrawn due to Adverse Events, 4 (5) 8 (9) (26) Withdrawn due to (insufficient viral response) Lack of Efficacy, 2 (2) 2 (2) 1 (1) Withdrawn for other reasons, 15 () 14 (16) 8 (11) Completed weeks of randomized treatment, n(%) 62 (71) 8 (9)* Total Number Subjects Discontinued Treatment, N(%) 25 (29) 78 (91) Discontinued due to Adverse Events, n(%) 6 (24) 2 (3) Discontinued due to (insufficient viral response) lack of 1 (4) efficacy, n(%) Discontinued due to other reasons, n(%) (72) 76 (97) *Fifty four subjects completed the study but not on their originally assigned 2-drug regimen (i.e. added open-label ABC plus/minus other ART Demographics: N Females: Males 16:71 25:61 :53 Mean Age in years (sd) 34 (8.4) 35 (7.4) 35 (7.7) White, (56) 44 (51) 39 (53) 2

3 Primary Efficacy Results: Proportion of Subjects Plasma HIV-1 R Event Free through Weeks % Event Free (95% CI) 74 (65, 84) 31 (, ) 78 (68, 88) P-value (unstratified log rank) <.1 Not Available () P-value (log rank, adjusting for baseline plasma HIV-1 R) <.1 Proportion of Subjects With Plasma HIV-1 R <4 copies/ml at Week ITT, Switch=Failure ITT, Switch Included ITT Exposed, Switch=Failure ITT Exposed, Switch Included Proportion of Subjects With Plasma HIV-1 R <5 copies/ml at Week ITT, Switch=Failure N= 13 (62) 34 (71) 6 (33) 53 (61) 13 (62) 35 () 7 (39) 55 (63) 13 (68) 34 (72) 6 (35) 53 (64) 13 (68) 35 (74) 7 (41) 55 (66) 1 () 24 (5) 4 (22) N= 3 (15) 2 (4) 5 (6) (6) 3 (61) 5 (29) (55) 3 (16) 2 (4) 5 (6) (63) 3 (67) 5 (29) (58) 2 (1) 1 (2) 1 (53) () 3 (25) 32 (44) (63) 23 (55) 4 (33) 39 (53) 5 (26) 11 (26) 1 (8) 3

4 ITT, Switch Included ITT Exposed, Switch=Failure ITT Exposed, Switch Included CD4+ AAUCMB over weeks (cells/cubic mm) (ITT Switch Included) 38 (44) 1 () 25 (52) 5 (28) 4 (46) 1 (53) 24 (51) 4 (24) 38 (46) 1 (53) 25 (53) 5 (29) 4 () 3 (3) 7 (35) (37) 3 () 28 (33) 2 (11) 1 (2) 3 (4) 7 (37) (4) 3 () 28 (35) (23) 5 (26) 13 (31) 2 () (27) Median CD4+ Cell Counts Change from Baseline (cells/cubic mm) at Week (ITT Switch Included)

5 Secondary Outcome Results Summary of Number and Type of Clinical Disease Progressions through Week (ITT) Number of Events Number of Confirmed Class C Events 2 Type of Progression: A to B A to B A to B A to B A to B A to B A to B A to B -- A to B A to B -- A to B A to C -- A to C B to C -- C to New C Safety Results:. Any condition that was clearly related to HIV-l disease was excluded from the definition of adverse events (AEs) and serious AEs (SAEs).. Lymphomas and invasive cervical carcinoma were required to be reported even if they were considered to be HIV-related. Fatal HIV-related events were not part of this exemption; if a fatal event occurred, it was to be recorded and reported according to the criteria for SAEs. Most Frequent Adverse Events through week On-Therapy (Safety Population): ABC+3TC+ZDV PBO+3TC+ZDV Subjects with any AE(s) 82 (99) 7 () Nausea 41 () 34 () Malaise and Fatigue 33 (4) 22 (27) Headache 32 (39) () Diarrhea 16 () 14 () Nausea and Vomiting 16 () 9 (11) Musculoskeletal Pain 14 () 7 (9) Cough 13 (16) 7 (9) Sleep Disorders 11 (13) 4 (5) Feeding Problems 1 () 9 (11) Abnormal Enzyme Levels 1 () 6 (7) Ear, Nose and Throat Infection 8 (1) 9 (11) Temperature Regulation Disturbance 7 (8) 8 (1) Nasal Signs and Symptoms 8 (1) 7 (9) Sleep disorders 11(13) 4(5) Serious Adverse Events (SAEs) On-Therapy, [n considered by the investigator to be related to study medication]: Subjects with any SAEs, -Includes both fatal and non-fatal events ABC+3TC+ZDV (23) 8 (1) PBO+3TC+ZDV [related] Abnormal Enzyme Levels 6 (7) [1] 4 (5) [2] Hyperglycemia 1 (1) [] Decreased White Blood Cells 4 (5) [4] 1 (1) [] Anemia 1 (1) [1] 1 (1) [1] Fracture 2 (2) [] [related] Medicinal Substance Non-specific Effects (overdose) 1 (1) [Not Specified (NS)] Soft Tissue Injuries 1 (1) [] Lung Disorders 2 (2) [NS] 1 (1) [] Pleura Disorders Pneumonia 1 (1) [1] 5

6 Abnormal Liver Function Tests 1 (1) [1] 1 (1) [} Intracranial Hemorrhage 1 (1) [] Muscle Disorder 1 (1) [1] Viral Neurological Infection 1 (1) [] Protozoan Infection 1 (1) [] Depressive Disorders 1 (1) [] Suicide and Attempted Suicide 1 (1) [] Subjects with fatal SAEs, 1 (1) [related] [related] Lymphoma 1 (1) [] Most Frequent Adverse Events On Therapy (Safety Population): Subjects with any AE(s) 68 (93) Nausea 35 () Malaise and Fatigue 27 (37) Diarrhea 22 (3) Headache (25) Cough 15 () Feeding Problems 11 (15) Decreased White Blood Cells 11 (15) Sleep Disorders 1 (14) Ear, Nose and Throat Infection 9 () Depressive Disorders 9 () Serious Adverse Events (SAEs) On Therapy, [n considered by the investigator to be related to study medication]: Subjects with any SAEs, -Includes both fatal and non-fatal events 15 () Abnormal Enzyme Levels 4 (5) [] Decreased White Blood Cells 3 (4) [2] Anemia 2 (3) [2] Hepatitis 2 (3) [1] Disorders of Lipid Metabolism 1 (1) [] Abnormal Liver Function Tests 1 (1) [] Viral Hepatobiliary and Pancreatic Infection 1 (1) [] Death 1 (1) [] Edema and Swelling 1 (1) [] Temperature Regulation Disturbance 1 (1) [1] Diarrhea 1 (1) [1] Nausea 1 (1) [1] Bronchitis 1 (1) [] Musculoskeletal Pain 1 (1) [1] Convulsions 1 (1) [] Mood Disorders 1 (1) [] Abnormal Menstrual Cycle 1 (1) [] Female Reproductive Neoplasia of Uncertain Behavior 1 (1) [] Pyelitis 1 (1) [] Subjects with fatal SAEs, 1 (1) [related] Death (Substance Abuse) 1 (1) [] Drug Proportion of isolates predicted as having reduced Genotypes at viral rebound 6

7 susceptibility 3TC 1% (/) M4V ± any other ABC % (2/) L74V + M4V and Y115F + M4V ZDV/d4T 8% (1/) M41L + M4V + C/S5Y ddi 8% (1/) L74V + M4V PIs None No PI associated mutations NNRTIs None No NNRTI associated mutations Conclusion: See publication below Publications: Mutations in HIV-1 reverse transcriptase during therapy with abacavir, lamivudine and zidovudine in HIV-1-infected adults with no prior antiretroviral therapy M Ait-Khaled, A Rakik, P Griffin, A Cutrell, MA Fischl, N Clumeck, SB Greenberg, R Rubio, BS Peters, F Pulido, J Gould, G Pearce, W Spreen, M Tisdale & S Lafon for the C33 International Study Team Antiviral Therapy 2; 1: FISCHL M, GREENBERG S, CLUMECK N, PETERS B, RUBIO R, GOULD J, BOONE G, WEST M, SPREEN B, and LAFON S. Ziagen (Abacavir, ABC, 1592) Combined with 3TC & ZDV is Highly Effective and Durable Through Weeks in HIV-1 Infected Antiretroviral-Therapy-Naive Subjects (CA33). 6th CROI 31 Jan- 4 Feb 99. M AIT-KHALED, A RAKIK, P GRIFFIN, J GOULD, A CUTRELL, M FISCHL and the C33 International study group. Viral rebound during weeks of ABC/3TC/ ZDV combination therapy in antiretroviral naïve subjects is infrequent with emergent virus showing a limited number of NRTI resistance mutations. Abstracts of the 3rd International Workshop on HIV Drug Resistance and Treatment Strategies, San Diego USA, (Poster 76) Date Updated: 28-Oct-5 7