Toxicity Substudy of Evaluation of Subcutaneous Proleukin in a Randomised International Trial (ESPRIT): TOXIL-2 Substudy

Phase 3TerminatedNCT00147355

Kirby Institute28 enrolled

Overview

This substudy is an open-label, randomised study comparing the uptake of recombinant interleukin-2 (rIL-2) in HIV-1 infected individuals receiving different combinations of antiemetics and analgesic agents during rIL-2 dosing in ESPRIT. The design is a factorial one with 4 arms. All patients will receive regular ibuprofen and paracetamol from days 1-6 of the rIL-2 dosing cycle; in addition, patients will be randomised to receive one of two antiemetic combinations, i.e. ondansetron or metoclopramide with or without low dose codeine phosphate as an additional analgesic agent.

The research is a randomised open-label substudy of ESPRIT. The substudy is exploring whether the amount of rIL-2 taken during a dosing cycle of rIL-2 can be increased through controlling the predictable side-effects of rIL-2 better. This is a four arm study with a factorial design; patients will be randomised to one of four arms. Each arm consists of different combinations of adjunctive agents. Each patient will receive paracetamol and ibuprofen prophylactically throughout the cycle, the other adjunctive agents prescribed will vary according to which arm the patient is randomised to, but the antiemetic used will be either ondansetron or metoclopramide with or without low dose codeine phosphate as an additional analgesic agent. The primary end-point is the percentage of planned rIL-2 actually taken during the cycle. Secondary end-points include safety, side-effects of rIL-2 and the adjunctive agents, CD4+ T-cell changes and quality of life measures.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Interventions

ondansetron, ibuprofen, paracetamolDRUG

ondansetron 4mg bid + Ibuprofen 200mg qds + paracetamol 1g qds days 1-6 inclusive of rIL-2 dosing cycle

Ondansetron, ibuprofen, paracetamolDRUG

Ondansetron 4mg bid + codeine phosphate 15mg tds + Ibuprofen 200mg qds + paracetamol 1g qds days 1-6 inclusive of rIL-2 dosing cycle

metoclopramide, ibuprofen, paracetamolDRUG

metoclopramide 10mg qds + Ibuprofen 200mg qds + paracetamol 1g qds days 1-6 inclusive of rIL-2 dosing cycle

Metoclopramide, codeine phosphate, ibuprofen, paracetamolDRUG

metoclopramide 10mg qds + codeine phosphate 15mg tds + Ibuprofen 200mg qds + paracetamol 1g qds days 1-6 inclusive of rIL-2 dosing cycle

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: Patients participating in ESPRIT and randomised to the rIL-2 arm, who: 1. Are not at CD4+ T-cell target for the protocol 2. Have not received rIL-2 for \> 2 months 3. Have reported both GI upset and constitutional side-effects as one of the reasons for either dose modifying in prior cycles or unwillingness to receive further rIL-2 4. Are considered by the Investigator as medically safe to receive further dosing with rIL-2 5. Are willing to receive further dosing with rIL-2 at the dose specified by the Investigator 6. Are willing to sign informed consent to participate in the substudy Exclusion Criteria: 1. All exclusions for the receipt of rIL-2 on ESPRIT 2. Known allergy to non-steroidal anti-inflammatory drugs (NSAIDs), opiates, 5HT-3 (serotonin-3) inhibitors, anti-dopaminergic antiemetics, or any other components of the proposed adjunct regimens. 3. Use of other NSAIDs (cyclooxygenase-2 \[COX-2\] inhibitors, corticosteroids) or opiate analgesics within two weeks of rIL-2 dosing. Use of low dose aspirin as a cardio-protective agent is allowed.

Locations (16)

Hospital General de Agudos JM Ramos Mejia

Buenos Aires, Buenos Aires, Argentina

FUNCEI

Buenos Aires, Buenos Aires, Argentina

Hospital Italiano de Buenos Aires

Buenos Aires, Buenos Aires, Argentina

Hospital Prof. Alejandro Posadas

Buenos Aires, Argentina

Hospital Interzonal de Agudos San Juan de Dios

La Plata, Argentina

Hospital Interzonal General de Agudos Oscar Alende

Mar del Plata, Argentina

Hospital Central

Mendoza, Argentina

CAICI

Rosario, Argentina

St. Vincent's Hospital

Sydney, New South Wales, Australia

AIDS Medical Unit

Brisbane, Queensland, Australia

...and 6 more locations

Outcomes

Primary Outcomes

percentage of planned rIL-2 taken during the first rIL-2 dosing cycle while participating in this substudy.

we are comparing the percentage of planned rIL-2 taken when randomised to one of the four combinations used as adjunctive therapies to alleviate the known side-effects of rIL-2

Time frame: 6 months

Secondary Outcomes

Patterns of rIL-2 cycling frequency in the six months after randomisation into the substudy

to explore the patterns of rIL-2 and see if the different adjuntive regimens increase tolerability such that more rIL-2 is taken

Time frame: 6 months

Percentage of planned rIL-2 taken during the cycles after the first cycle

this is to assess whether the adjuncts to which the patient was randomised as part of this substudy impact on better tolerability of cycles of rIL-2 beyond the first

Time frame: 6 mths

Mean difference in rIL-2 taken during each cycle in the six-month period following randomisation into this substudy and rIL-2 uptake during the last dosing cycle immediately prior to participation in the substudy

to see if the adjuncts to which the patient is randomised improve amount of rIL-2 taken compared to the cycle taken prior to enrollment in this substudy

Time frame: 6 months

Number of patients with dose modifications during the cycle due to toxicity

to assess whether the adjuncts to which they were randomised reduced the amount of rIL-2 dose modification during the rIL-2 cycle

Time frame: 6 months

Number of patients with grade 1-4 constitutional upset (defined as any or all of the following: flu-like illness/fever/myalgia/arthralgia/headache) and/or GI upset and/or evidence of capillary leak syndromes

to assess the impact of the randomised adjuntive agents on the predictable side-effects of rIL-2

Time frame: 6 months

Grade 1-4 creatinine and sodium changes during and after rIL-2 dosing;

to assess the impact of the randomised adjuntive agents on the predictable effects of rIL-2 in regards to salt and water homeostasis and renal function

Time frame: 6 months

Changes in quality of life during and after rIL-2

to assess whether the use of different adjunctive agents impacted on the tolerability of rIL-2 during the cycle and post as perceived by the patients qOL

Time frame: 6 months

Incidence of SAE and AE

to assess the incidence of SAE and AEs that are rIL-2 (captured for the main study) and adjunctive agents

Time frame: 6 months