• The percentage (%) of planned rIL-2 taken during the first rIL-2 dosing cycle while participating in this substudy
  
• rIL-2 uptake will be assessed at day 1 (day 1 of the dosing cycle of rIL-2)
  
• day 5
  
• and day 10 by means of adherence assessment and patient diaries
  

• Mean amount of rIL-2 taken during the cycle in million international units (MIU)
  
• Number of cycles initiated during the 6 month period
  
• Patterns of rIL-2 cycling frequency in the six months after randomisation into the substudy
  
• Percentage of planned rIL-2 taken during the cycles after the first cycle
  
• 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
  
• Mean time between receipt of rIL-2 on this substudy and the last dosing cycle of rIL-2 prior to entry into the substudy
  
• Number of patients with dose modifications during the cycle due to toxicity
  
• Percentage of patients completing any cycle initiated
  
• Number of patients with grade 1-4 gastrointestinal (GI) toxicities
  
• Number of patients with grade 1-4 constitutional upset (defined as any or all of the following: flu-like illness/fever/myalgia/arthralgia/headache)
  
• Number of patients with grade 1-4 oedema and/or other clinical manifestations of capillary leak syndrome, eg pulmonary oedema
  
• Number of patients with >= 10% weight gain during rIL-2 dosing
  
• Grade 1-4 creatinine changes during and after rIL-2 dosing
  
• Grade 1-4 serum sodium changes during and after rIL-2 dosing
  
• Changes in quality of life during and after rIL-2
  
• Patterns of use of breakthrough adjunctive therapies
  
• Safety of adjunctive agents as measured by grade 1-4 toxicity attributed to any of the adjunctive agents
  
• Incidence of serious adverse events (SAEs) (considered rIL-2-related or related to one of the adjunctive agents) and grade 4 clinical events during and within 8 weeks of the rIL-2 dosing cycle
  
• CD4+ T-cell count change
  
• Number of patients indicating willingness to receive further rIL-2 following first rIL-2 cycle
  
• The study visits are screening, baseline (day 1 of the rIL-2 dosing cycle), day 5 of the rIL-2 dosing cycle, day 10 of the rIL-2 dosing cycle and day 60 of the rIL-2 dosing cycle.
  

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.