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

An Open-label, Randomised Study Comparing the Uptake of rIL-2 in HIV-1 Infected Individuals Receiving Different Combinations of Antiemetics and Analgesic Agents During rIL-2 Dosing in ESPRIT: Toxicity Substudy of ESPRIT: TOXIL-2 Substudy

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.

Study Overview

• Status: Terminated
• Conditions: HIV Infections
• Intervention / Treatment: Drug: ondansetron, ibuprofen, paracetamol; Drug: Ondansetron, ibuprofen, paracetamol; Drug: Metoclopramide, codeine phosphate, ibuprofen, paracetamol; Drug: metoclopramide, ibuprofen, paracetamol

Detailed Description

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
• Enrollment (Actual): 28
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina
    • Hospital Italiano de Buenos Aires
  • Buenos Aires, Argentina
    • FUNCEI
  • Buenos Aires, Argentina
    • Hospital Prof. Alejandro Posadas
  • Buenos Aires, Argentina, C221
    • Hospital General de Agudos JM Ramos Mejía
  • La Plata, Argentina
    • Hospital Interzonal de Agudos San Juan de Dios
  • Mar del Plata, Argentina
    • Hospital Interzonal General de Agudos Oscar Alende
  • Mendoza, Argentina
    • Hospital Central
  • Rosario, Argentina
    • CAICI
• Australia
  • New South Wales
    • Sydney, New South Wales, Australia, 2010
      • St. Vincent's Hospital
  • Queensland
    • Brisbane, Queensland, Australia, 4002
      • AIDS Medical Unit
    • Cairns, Queensland, Australia, 4870
      • Cairns Base Hospital
    • Gold Coast, Queensland, Australia, 4220
      • Gold Coast Sexual Health Clinic
    • Nambour, Queensland, Australia, 4560
      • Nambour Hospital
  • Victoria
    • Melbourne, Victoria, Australia, 3000
      • The Alfred Hospital
    • Melbourne, Victoria, Australia, 3000
      • Carlton Clinic
• Israel
  • Rehovot, Israel
    • Kaplan Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: FACTORIAL
• Masking: NONE

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
OTHER: A; Ondansetron 4mg bid + Ibuprofen 200mg qds + paracetamol 1g qds days 1-6 inclusive of rIL-2 dosing cycle	Drug: ondansetron, ibuprofen, paracetamol; ondansetron 4mg bid + Ibuprofen 200mg qds + paracetamol 1g qds days 1-6 inclusive of rIL-2 dosing cycle
OTHER: B; Ondansetron 4mg bid + codeine phosphate 15mg tds + Ibuprofen 200mg qds + paracetamol 1g qds days 1-6 inclusive of rIL-2 dosing cycle	Drug: Ondansetron, ibuprofen, paracetamol; Ondansetron 4mg bid + codeine phosphate 15mg tds + Ibuprofen 200mg qds + paracetamol 1g qds days 1-6 inclusive of rIL-2 dosing cycle
OTHER: D; metoclopramide 10mg qds + codeine phosphate 15mg tds + Ibuprofen 200mg qds + paracetamol 1g qds days 1-6 inclusive of rIL-2 dosing cycle	Drug: Metoclopramide, codeine phosphate, ibuprofen, paracetamol; metoclopramide 10mg qds + codeine phosphate 15mg tds + Ibuprofen 200mg qds + paracetamol 1g qds days 1-6 inclusive of rIL-2 dosing cycle
OTHER: C; metoclopramide 10mg qds + Ibuprofen 200mg qds + paracetamol 1g qds days 1-6 inclusive of rIL-2 dosing cycle	Drug: metoclopramide, ibuprofen, paracetamol; metoclopramide 10mg qds + Ibuprofen 200mg qds + paracetamol 1g qds days 1-6 inclusive of rIL-2 dosing cycle

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	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	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	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	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	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	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	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	6 months

Collaborators and Investigators

• Sponsor: Kirby Institute
• Collaborators: The University of New South Wales
• Investigators: Principal Investigator: Sarah L Pett, M.D, Kirby Institute, Faculty of Medicine, University of New South Wales, Sydney, Australia

Publications and helpful links

Helpful Links

• National Centre in HIV Epidemiology and Clinical Research Homepage

Study record dates

Study Major Dates

• Study Start: November 1, 2005
• Primary Completion (ACTUAL): November 1, 2008
• Study Completion (ACTUAL): December 1, 2008

Study Registration Dates

• First Submitted: September 5, 2005
• First Submitted That Met QC Criteria: September 5, 2005
• First Posted (ESTIMATE): September 7, 2005

Study Record Updates

• Last Update Posted (ESTIMATE): April 12, 2012
• Last Update Submitted That Met QC Criteria: April 11, 2012
• Last Verified: April 1, 2012

More Information

Terms related to this study

• Keywords: HIV; rIL-2-toxicity; interleukin-2 therapy; Toxicity substudy of ESPRIT
• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; HIV Infections; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Autonomic Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Cyclooxygenase Inhibitors; Antipyretics; Antiemetics; Gastrointestinal Agents; Dermatologic Agents; Analgesics, Opioid; Narcotics; Antipsychotic Agents; Tranquilizing Agents; Psychotropic Drugs; Serotonin Agents; Dopamine Agents; Serotonin Antagonists; Dopamine D2 Receptor Antagonists; Dopamine Antagonists; Anti-Anxiety Agents; Respiratory System Agents; Antipruritics; Antitussive Agents; Acetaminophen; Ibuprofen; Ondansetron; Codeine; Metoclopramide
• Other Study ID Numbers: ESPRIT TOXIL-2 UNSW PSO 6361; ACTR012605000407695