Roche trials database

Protocol number:

ML21287

Title of Study:

A randomized, open-label study evaluating the antiviral activity and safety of 3 month Fuzeon induction with an optimized background antiretroviral regimen versus OB alone, in Fuzeon-naive HIV-1 infected patients with virological failure.

Sponsor:

Hoffmann-La Roche

Company division:

Pharmaceutical

Product name:

enfuvirtide [Fuzeon]

Generic name:

enfuvirtide

Therapeutic area:

• HIV Infections

Clinical study summary:

This randomized, open-label, multicenter study was designed to evaluate the efficacy and safety of Fuzeon (enfurvirtide; ENF) in combination with optimized background antiretroviral regimen (OB) compared to OB alone, in patients with HIV-1 infection. Patients were randomized to one of two treatment arms; Arm A: Fuzeon + OB, Arm B: OB alone.

Study center(s):

17 centers in France

Phase of development:

II

Objectives:

The primary objective was to evaluate the virological efficacy (plasma HIV-1 RNA viral load < 50 copies/ml) at Week 24 (W24) of two different therapeutic strategies: one with 3-month induction with Fuzeon of an optimized background regimen (OB) including two fully active molecules (Genotype sensitivity score: GSS ≥ 2), the other with OB alone (GSS ≥ 2).

The secondary objectives were as follows:

- To evaluate the immunovirological efficacy of the two therapeutic strategies throughout the study,

- To describe the archiving of resistance mutations in proviral DNA,

- To describe the onset of resistance mutations to antiretroviral therapy on viral “quasispecies” during the plasma viral load decrease phase following the initiation of antiretroviral therapy,

- To describe “the protective effect” of Fuzeon on the combined antiretroviral therapy,

- To describe the causes of virological failure,

- To evaluate the patient’s quality of life in both study arms,

- To evaluate adherence to OB in the OB alone arm and to OB and Fuzeon in the ENF + OB arm,

- To evaluate the safety of the treatment in the two arms

Methodology:

This was a non-comparative, randomized, open-label, multicenter phase II study with two arms, in HIV-infected patients requiring a new optimized background regimen including at least two fully active compounds.

All patients gave their informed consent in writing before any study-specific evaluation or procedure was performed. Investigations during the screening period were performed 4 weeks prior to the enrolment visit. Eligible patients were randomized (1:1):

• In the group receiving optimized antiretroviral background regimen (OB) alone (OB group)
• In the group receiving 3-month induction Fuzeon (ENF) combined to OB (OB + ENF group)

In addition to these scheduled visits, blood samples were collected at several visits in these patients. According to the viral load (VL) at W24, patients were followed differently:

- Virological responder patients (viral load VL < 50 copies/ml at W24) maintaining their VL < 50 copies/ml were followed up every three months until W100, and a follow-up visit was conducted 1 month after the end of the study.

- Virological non-responder patients at W24 and virological responder patients at W24 who presented subsequent virological failure (VL ≥ 50 copies/ml confirmed within no more than 4 weeks) were enrolled in the Rollover study. Rollover patients benefited from 3 months of Fuzeon with initiation of a new optimized treatment. This new OB was chosen after taking into account the results of previous pharmacological assays and viral genotyping. These patients were followed according to the initial schedule of the trial and up to W100 according to the initial inclusion date.

A follow-up visit took place after the end of the study or after the premature discontinuation visit in order to collect serious adverse events.

Number of patients (planned/analyzed):

29 patients randomized and analyzed

Diagnosis and main criteria for inclusion:

Adult patients, ≥18 years of age with HIV-1 infection and on same stable highly active antiretroviral therapy for >4 weeks, with viral load >1000 RNA copies/mL; Fuzeon-naive. Patients for whom there is the possibility of potential effective OB without enfuvirtide (GSS≥2)

Test product, dose and mode of administration or test procedure:

Enfuvirtide 90 mg subcutaneously twice a day,

• during the 14-week induction period (D0 to W14) in combination with an optimized antiretroviral background regimen (OB), in patients randomized in the ENF + OB group,
• during the ROLL-OVER study period in combination with an OB in patients not responding at W24 and in patients responders at W24 but with subsequent virological failure.

Reference therapy, dose and mode of administration or reference procedure:

Optimized antiretroviral background  regimen (OB) alone

Criteria for evaluation (efficacy, safety):

Efficacy

Primary:

The virological efficacy at Week 24 of the two strategies (ENF + OB and OB alone) was evaluated in terms of success and failure. Success was defined by the percentage of randomized patients with a viral load < 50 copies/mL at W24 and who received 14 weeks of Fuzeon in the ENF + OB arm. Otherwise, patients were considered as virological failure.

Secondary:

• CD4 count at W2, W4, W8, W12, W18, W24, W40, W52, W64, W76, W88, W100, and in case of premature withdrawal,
• Number of virological responders with plasma viral load < 50 copies/mL at W2, W4, W8, W12, W18, W24, W52, W76 and W100,
• Evolution of plasma HIV-1 RNA value (copies/ml and log₁₀) between baseline and W2, W4, W8, W12, W18, W24, W52, W76 and W100
• Proportion of patients presenting a decrease of the plasma viral load ≥1 log, and an increase in CD4 count ≥ 50 cells/mm³, at W12 in the OB+Fuzeon arm
• Proportion of patients presenting a viral load < 50 copies/ml at W52 and W100 after having obtained a viral load < 50 copies/ml at W24
• Time to virological failure (VL > 50 copies/ml) for the patients who gained a viral load < 50 copies/ml at Week 24
• Number of “sequences” (3 months) of Fuzeon per patient
• Quantification of proviral DNA at baseline, W12, W24, W100 and in the case of premature treatment discontinuation
• Incidence of resistance mutations to the OB drugs (depending on the available data for drugs from new classes) based on plasma HIV-1 RNA and proviral DNA for patients with virological failure
• Plasma bank for documentation of causes of failure.
• Evaluation of compliance with Fuzeon by counting treatment units returned versus supplied during the period of Fuzeon administration (at W4, W8, W12, W14) and in case of premature study withdrawal.
• Pharmacological dosage at W2 of Fuzeon in the OB + Fuzeon arm and the optimized treatment molecules whatever the randomization arm is. If C_min < lower limit at W2, a new dosage was performed at W8 after controlling adherence or changing ARV doses at W4.
• Description of quality of life and compliance at inclusion (D0), W12, W24 and W52 and in case of premature study-withdrawal using a complete quality of life (MOS-HIV) and compliance questionnaire.

Safety

Adverse events and AIDS classifying events, injection site reactions, laboratory parameters, vital signs

Statistical methods:

The primary endpoint was the proportion of patients with a plasma HIV-1 RNA VL < 50 copies/ml at W24 in the two treatment arms. The analysis was performed in each of the two groups according to the one-stage Fleming method. The expected percentage of non-evaluable patients was approximately 10%. Therefore, 84 patients had to be included in this study. The type 1 error (a) was set at 5% two-sided for all analyses. Quantitative variables were described by the number of values for which information was provided, number of missing data, mean, standard deviation, median, first and third quartiles, minimum and maximum.

Qualitative variables were described by the number of values for which information was provided, number of missing values, frequency and percentage by modality.

The primary criterion was the proportion of patients with a plasma VL<50 copies/ml at W24 in the two treatment groups. The virological efficacy at W24 was evaluated in terms of success and failure: Success was defined by the proportion of randomized patients presenting a plasma VL<50 copies/ml at W24, otherwise failure.

The analysis was performed in each of the two groups according to the one-stage Fleming method. Considered threshold for the number of success (R) was calculated using the equation given by the Fleming method. The 95% two-sided confidence interval of the virological response was given for the two treatment groups. No statistical test was conducted to compare the two groups but a comparison of the confidence intervals could be discussed. This analysis was applied to the ITT population.

Summary (efficacy, safety, other results):

Demographics

A total of 29 patients were included and randomized (ITT population): 15 in the group receiving optimized antiretroviral background regimen (OB alone) and 14 in the group receiving OB + Fuzeon for 3 months.

The ITT population included 69% of men and 31% of women, aged from 25 to 73 years old with a median age of 42 years old. Main baseline characteristics were mostly similar between the two groups of randomization. There were more women in the OB + Fuzeon group (43% versus 20%) and mean weight was slightly higher (71 kg versus 64 kg).

The median time from diagnosis was 15 years, ranging from 4 to 25 years. HIV was mainly transmitted through sexual contact (86%). At selection time as well as at inclusion, most patients had a history of AIDS-defining event (stage C):

53% in the OB group, 43% in the OB + Fuzeon group.

At inclusion, median VL was 19200 copies/ml (4.3 log₁₀) in the OB + Fuzeon group and 10800 copies/ml (4.0 log₁₀) in the OB group. Median CD4 cells count was 346 cells/mm³ (294 cells/mm³ in the OB group and 376 cells/mm³ in the OB + Fuzeon group). Median value of proviral DNA was high: 5.1 log₁₀ / 10⁶ PBMC, similar in both groups.

First ARV treatment had been started between 2 and 18 years, mean (± SD) of 12 (±4) years, without difference between the two treatment groups. Previous therapy included 4 to 14 ARV treatments, with a median of 10 treatments: median of 6 NRTI, 1 NNRTI and 3 PI.

The median (range) duration of current ARV treatment at selection was 3 (1 - 9) years in the OB group and 2 (0 – 8) years in the OB + Fuzeon group. Most patients (93%) received a NRTI, 86% received a PI and 17% received a NNRTI.

The most frequent associations of treatment at selection were two NRTI and one PI boosted with ritonavir (64%) and two NRTI and one NNRTI (11%).

For the OB regimen at inclusion, most patients (86%) received an association of 3 to 4 ARV treatments. About half of the patients received 2 NRTI while a third of the patients did not receive any NRTI. Nearly 52% of the patients received one NNRTI and 86% of the patients received one PI. The PI was boosted with ritonavir in all cases. One integrase inhibitor was part of the OB for 12 patients (80%) in the OB group and 9 patients (64%) in the OB + Fuzeon group.

Most patients (86%) had at least one new molecule (etravirine, raltegravir, maraviroc or darunavir) among the OB regimen. In particular, raltegravir was part of the OB for 21 patients (72%). A total of 17 patients (59%) received darunavir and 12 patients (41%) received etravirine, with no imbalance between groups. Two patients in the OB group received maraviroc. Only one patient in the OB group (7%) and three patients in the OB +Fuzeon group (21%) did not receive one of these new molecules.

The most frequent associations of treatments chosen for the OB regimen were one PI boosted with ritonavir associated to one integrase inhibitor and one NRTI (8 patients, 28%) or two NRTI (7 patients, 24%). GSS was ≥ 2 for all patients except one and GSS was ≥ 3 for 62% of the patients. At inclusion, patients harbored viruses with a median total number of resistance mutations of 14, including a median of 4 NRTI-associated resistance mutations, 1 NNRTI-associated resistance mutation and 9 PI-associated resistance mutations (with a median of 3 major PI-associated resistance mutations), with no difference between treatment groups.

Compliance

Among the 14 patients who received Fuzeon, none had a dose adjustment. The median total dose received was 18270 mg, ranging from 15300 mg to 26640 mg.

Among the 29 patients of the ITT population, 5 (17%) had at least one change in the dose of OB, one patient (3%) had at least one temporary stop and 4 patients (14%) had at least one treatment definitively stopped.

Efficacy

Primary criterion: percentage of patients with VL < 50 copies/ml at Week 24

In the ITT population, at Week 24, 14 patients (93.3% - 95%CI[80.7%-100%]) in the group receiving OB alone and 11 patients (78.6% - 95%CI[78.6%-100%]) in the group receiving Fuzeon + OB were considered as virologic responders when taking into account the duration of treatment with Fuzeon (no more than 14 weeks). According to Fleming’s method, both treatments were considered to be effective as more than 10 patients in the OB group and 11 patients in the OB + Fuzeon group were responders.

When the virologic success was defined as a plasma viral load < 50 copies/mL at W24 in both groups, without taking into account the duration of treatment with Fuzeon, only two patients (one in each group) were considered in failure. In that case, the rate of virologic success was 93% in both groups. The patient of the OB group with virologic failure was treated with etravirine, raltegravir and KIVEXA (abacavir, lamivudine). The patient of the OB + Fuzeon group with virologic failure was treated with emtricitabine, tenofovir, atazanavir, ritonavir boost, raltegravir and Fuzeon for 14 weeks.

CD4 count

At baseline, median CD4 cells count was 294 cells/mm³ (range 41 – 984) in the OB group and 364 cells/mm³ (128 – 884) in the OB + Fuzeon group. Median CD4 count increased over time in both groups, the increase being slightly more important in the group receiving OB + Fuzeon during the induction phase (median increase of +53 cells/mm³ at Week 12 and +97 cells/mm³ at Week 18 compared to +33 and +45 cells/mm³ respectively in the OB group). Median CD4 cells count was similar in both groups at Week 24: 520 and 521 cells/mm³. At Week 100, increase from baseline in CD4 cells was 211 cells/mm³ in the OB group and 201 cells/mm³ in the OB + Fuzeon group.

Virologic responders at each visit

At Week 12, the rate of virologic responders (with plasma HIV RNA < 50 copies/ml) was 87% in the OB group and 79% in the OB + Fuzeon group. From Week 18 to Week 100, the rate of virologic responders was ≥ 90% in both groups.

Viral load

Median viral load was < 50 copies/ml (< 1.6 log₁₀) in both groups from Week 4.

Reduction in plasma VL ≥ 1 log, and increase in CD4 count ≥ 50 cells/mm³

Among the 14 patients receiving OB + Fuzeon, 13 (93%) had a reduction in plasma VL ≥ 1 log₁₀ between inclusion/selection and Week 12 and 7 (50%) had a reduction in plasma VL ≥ 1 log₁₀ and an increase in CD4 count ≥ 50 cells/mm³.

Proportion of patients with a plasma VL < 50 copies/ml at W52 and W100

Among the patients who were responders at Week 24 (plasma VL < 50 copies/ml), plasma VL was also less than 50 copies/ml for 96% of them (100% in OB group and 91% in OB + Fuzeon group) at Week 52 and 91% (92% and 90% respectively) at Week 100.

When considering the patients responders at Week 24 and treated with Fuzeon no longer than 16 weeks, the proportion of these patients (in the OB + Fuzeon group) with VL < 50 copies/ml was 89% at Week 52 and 88% at Week 100.

Virologic failure

Five patients (17%) showed virologic failure (plasma VL≥ 50 copies/ml while the VL was < 50 copies/ml at previous visits): two in the OB group and three in the OB + Fuzeon group.

Proviral DNA

Median value of proviral DNA remained stable between baseline and Week 24: from 5.02 log₁₀/10⁶ PBMC at baseline to 5.01 log₁₀/10⁶ PBMC at Week 24 in the OB group and from 5.05 to 4.88 log₁₀/10⁶ PBMC in the OB + Fuzeon group.

No correlation was found between the value of proviral DNA at baseline and the decrease in VL at W4, W12, W18 or W24.

Roll-Over study

Only one patient of the OB + Fuzeon group entered the roll-over study. This patient entered the roll-over study after Week 40 of the main study, when VL was 1470 copies/ml (3.17 log₁₀). The patient ended the roll-over study after 8 weeks with VL of 4620 copies/ml. This patient was first treated with abacavir, tenofovir, darunavir and boost ritonavir and Fuzeon for 3 months. When entering the roll-over study the patient was treated with abacavir, tenofovir, etravirine and Fuzeon for more than 2 months.

Tropism switches

At inclusion, predominant variant of HIV coreceptor tropism was R5 for 18 patients (64%): and X4 for 10 patients (36%), with no difference between treatment groups. The information was missing for one patient in the OB + Fuzeon group.

At Week 24, tropism switches were observed in six patients: switch from R5 to X4 in five patients (one in the OB group and four in the OB + Fuzeon group), switch from X4 to R5 in one patient in the OB group.

All patients with a switch in HIV coreceptor tropism had a plasma VL ≤ 1.6 log₁₀ copies/ml (50 copies/ml) at week 24 and an increase from baseline in CD4 cells count similar to the patients without tropism switch. Proviral DNA remained similar between inclusion and week 24.

Four out of the five patients with R5 to X4 switch received Fuzeon and none was treated with Maraviroc. They all received an association of several NRTI and one boosted PI.

Quality of life questionnaire

Very few variations from inclusion in the different scores of the MOS-HIV questionnaire were observed in the ITT population during the study. Results are to be analyzed with caution considering the small number of data available, above all in the OB + Fuzeon group.

The median score was already high at baseline and remained high for role and social functioning. A slight increase in median score could be observed for physical function, mental health and health distress in both groups. Pain and cognitive function scores remained stable.

The lowest median scores (<50) were those for general health perception and energy/fatigue and they remained stable during the study. There was only a noticeable increase in general health perception score at W100 (+8 and +15 in OB and OB +Fuzeon group respectively).

Regarding quality of life and health transition score, median variation from baseline remained 0 at all time-points in the OB group while there was an increase (up to a median increase of 25 at Week 100) in the OB + Fuzeon group.

Pharmacokinetics

The pharmacological data for patients with a protocol-defined failure showed that poor adherence to OB regimen was probably not the cause of failure.

Safety

During treatment period, 27 patients (93%) presented with at least one adverse event and a total of 147 adverse events were reported: 86 in the OB group and 61 in the OB + Fuzeon group. For 8 patients of the OB + Fuzeon group (57%), at least one adverse event could be related to Fuzeon and for 14 patients overall (48%) at least one adverse event could be related to OB. AEs related to Fuzeon were only injection site reaction. No AE led to study withdrawal. A total of 8 SAEs were reported for 6 patients (21%): 5 in the OB group (33%) and one in the OB + Fuzeon group. Among these SAEs, none was related to Fuzeon and one was related to OB regimen. During the whole study, 7 patients of the OB + Fuzeon group (50%) experienced at least one injection site reaction. None was considered as a SAE. Mean values of biological parameters as well as vital signs and weight did not change significantly during the study but ranges of values were extended.

Conclusions:

On this limited population of pretreated HIV patients harboring viruses still susceptible to at least 2 ARV (GSS ≥2), a 3-month short-course intensification with Fuzeon did not seem to enhance virological response at Week 24 compared to an already potent OB alone. The increase in CD4 cells was however greater during the intensification period, suggesting a beneficial impact of Fuzeon on immune restoration independently of virological activity. No change in proviral DNA was observed and R5 to X4 tropism switches occurred in five patients despite treatment with Fuzeon for four of them. This study confirmed the good safety profile of Fuzeon. Adverse events related to Fuzeon were only injection site reactions and none was serious.

Date of report:

19.01.2012

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