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| A randomised controlled trial of a strategy of switching to boosted protease inhibitor monotherapy versus continuing combination antiretroviral therapy for the long-term management of HIV-1 infected patients who have achieved sustained virological suppression on highly-active antiretroviral therapy |
| Source of record | UK Trials |
| ISRCTN | ISRCTN04857074 |
| Date ISRCTN assigned | 01/02/2008 |
| Local reference number(s) | HTA 06/403/90; MRC ref: PIVOT |
| Public title | A randomised controlled trial of a strategy of switching to boosted protease inhibitor monotherapy versus continuing combination antiretroviral therapy for the long-term management of HIV-1 infected patients who have achieved sustained virological suppression on highly-active antiretroviral therapy |
| Scientific title | |
| Acronym | PIVOT: Protease Inhibitor monotherapy Versus Ongoing Triple-therapy in the long-term management of HIV infection |
| Disease/condition/study domain | HIV infection |
| Study hypothesis | This trial aims to determine whether a strategy of switching to Protease Inhibitor (PI) monotherapy is non-inferior to continuing triple drug therapy, in terms of the proportion of patients who maintain all their available drug treatment options after at least 3 years of follow-up, and to compare clinical events, safety, toxicity and health economic parameters between the two strategies. |
| Design/methodology | Parallel group, open-label, multi-centre, randomised controlled strategic trial. |
| Research ethics review | The protocol will be submitted in February 2008 to a UK REC for approval. |
| Countries of trial | United Kingdom, Ireland and Italy. |
| Participants - inclusion criteria | 1. Documented HIV infection on Enzyme-Linked Immuno-Sorbent Assay (ELISA) and confirmatory test. 2. Male or female patients, aged 18 years or more. 3. Receiving combination AntiRetroviral Therapy (ART) for at least 24 weeks with a regimen comprising 2 Nucleoside Reverse Transcriptase Inhibitor (NRTIs) and either an NonNucleoside Reverse Transcriptase Inhibitors (NNRTI) or a Protease Inhibitor (PI) (boosted or un-boosted). 4. No change in ART drugs in the 12 weeks prior to screening. 5. Plasma viral load <50 copies/ml for at least 24 weeks prior to screening (must have at least 1 documented result <50 copies/ml at more than 24 weeks prior to screening, and at least 1 documented result <50 copies/ml taken within 12 weeks prior to screening). A patient who has had one viral load "blip" to <200 copies/ml in the 24 weeks prior to screening may be included, provided that the 2 viral load tests that immediately preceded the blip and the 2 viral load tests that immediately followed the blip all gave results <50 copies/ml. 6. CD4+ count >100 cells/mm3 at screening. 7. Willing to continue unchanged or to modify, antiretroviral therapy, in accordance with the randomised assignment. 8. Likely to be resident in the UK for the full duration of the trial and willing to comply with trial visit schedule throughout the follow-up period. 9. Willing to provide written informed consent. |
| Participants - exclusion criteria | 1. Known major protease resistance mutation(s) documented on prior resistance testing if performed (prior resistance testing is not mandatory for trial participation). 2. Evidence of previous failure while taking a PI-containing regimen (defined as failure to achieve viral load <50 copies/ml within 24 weeks after starting a PI-containing regimen, or having 2 viral load results >50 copies/ml after having achieved a viral load <50 copies/ml on the PI-containing regimen). 3. Evidence of previous failure on an NNRTI-containing regimen (defined as in 2, above), unless a successful viral sequence (resistance test) was obtained following failure and within 60 days prior to the date of switching to a new fully suppressive regimen. 4. Previous allergic reaction to a PI. 5. Patient currently using or likely to require use of concomitant medication with known interaction with PI s including rifampicin, amiodarone, flecainide, bupropion, clozapine, ergotamine, mexilitine, midazolam, pethidine, pimozide, quinidine, sertindole, sildenafil, voriconazole, zolpidem, St John's Wort. 6. Patient requiring treatment with radiotherapy, cytotoxic chemotherapy, or is anticipated to need these during the trial period. 7. Treatment for acute opportunistic infection within 3 months prior to trial screening. 8. Pregnant or trying to become pregnant at the time of trial entry. 9. History of active substance abuse or psychiatric illness that, in the opinion of the investigator, would preclude compliance with the protocol, dosing schedule or assessments. 10. History of HIV encephalopathy with current deficit >1 in any domain of the Neuropsychiatric AIDS Rating Scale. 11. Past or current history of cardiovascular disease, or 10-year absolute coronary heart disease risk of >30% (calculated from the Framingham equation, and assessed using the Joint British Societies cardiovascular risk prediction charts). 12. History of insulin-dependent diabetes mellitus. 13. Patient currently receiving interferon therapy for Hepatitis C virus infection or considered likely to need such therapy during the course of the trial. 14. Co-infection with hepatitis B, defined as Hepatitis BsAg positive at screening or at any time since HIV diagnosis. 15. Any other active clinically significant condition, or findings during screening medical history or examination that would, in the opinion of the investigator, compromise the patient's safety or outcome in the trial. 16. Anaemia (haemoglobin <9.5g/dl), neutropenia (absolute neutrophil count <1,000/mm3) or thrombocytopenia (platelet count <50,000mm3) at trial screening. 17. ALanine aminoTransferase (ALT) or alkaline phosphatase greater than 3 times the upper limit of normal at trial screening. 18. Fasting plasma glucose >7.0mmol/L at trial screening. 19. Fasting plasma triglyceride level >3mmol/L at trial screening despite the use of lipid lowering drugs. 20. Fasting plasma total cholesterol >6.2mmol/L at trial screening despite the use of lipid lowering drugs. |
| Patient information material | Not available in web format, please use the contact details below to request a patient information sheet |
| Anticipated start date | 01/04/2008 |
| Anticipated end date | 01/04/2013 |
| Status of trial | Ongoing |
| Target number of participants | 400 |
| Interventions | Patients randomised to the PI monotherapy group will stop other ART drugs and start/continue only on ritonavir-boosted PI monotherapy (selection of drug at discretion of physician or patient). Those who do not maintain complete virological suppression or who are unable to tolerate the PI (substitution for toxicity is allowed), will switch promptly back to their previous triple therapy. Patients randomised to the control group will continue their current regimen. Duration of interventions: 5 years |
| Primary outcome measure(s) | Loss of future drug options, defined as the first occurrence of intermediate to high level resistance to any one or more of the standard antiretroviral drugs (limited to licensed drugs in contemporary use) to which the patient's virus was considered to be sensitive at study entry (i.e. excluding drug resistance that was known to be present on previous resistance testing). Duration of follow-up: 5 years |
| Secondary outcome measure(s) | 1. Serious drug or disease-related complication, defined as the first occurrence of one of the following in any individual patient: 1.1. Death from any cause 1.2. Serious AIDS-defining illness 1.3. Serious non-AIDS defining illness: a. Acute myocardial infarction b. Coronary artery disease requiring invasive procedures c. Cirrhosis d. Acute liver failure e. End-stage renal disease f. Stroke g. Clinical acute pancreatitis h. Severe lactic acidaemia i. Severe facial lipoatrophy j. Severe peripheral neuropathy k. Non-AIDS malignancy 2. Adverse events, defined as the total number of Grade III and IV adverse events. 3. Virological rebound, defined in two ways using the "Time to Loss Of Virologic Response" (TLOVR) algorithm: 3.1. Two consecutive tests, taken at least 4 weeks apart, with a viral load more than 50 copies/ml (the first test must also be confirmed by re-testing the same blood sample). Patients who have virological rebound in the PI monotherapy arm, but re-suppress viral load to <50 copies/ml with re-introduction of NRTIs, will not count as failures; OR 3.2. As above, with at least one of the samples giving a viral load result more than 400 copies/ml. 4. CD4+ count change, defined as change from baseline in absolute CD4+ count. 5. Health-related Quality of Life change, defined as change from baseline in the mental and physical health summary scores. 6. Neurocognitive function change, defined as change from baseline in the neurocognitive function summary score. 7. Cardiovascular risk change, defined as change from baseline in the risk of cardiovascular disease calculated from the Framingham equation. 8. Health care costs, defined as the total cost of health care resources utilised per patient year. Duration of follow-up: 5 years |
| Sources of funding | NIHR Health Technology Assessment Programme - HTA (UK) |
| Sponsor name | Medical Research Council (UK) |
| Sponsor details | MRC Clinical Trials Unit 222 Euston Road London United Kingdom NW1 2DA |
| Sponsor telephone | +44 (0)207 6704808 |
| Sponsor fax | +44 (0)207 6704817 |
| Sponsor email | nick.paton@ctu.mrc.ac.uk |
| Sponsor website | http://www.ctu.mrc.ac.uk |
| Contact name | Dr Nicholas Paton |
| Contact details | Medical Research Council Clinical Trials Unit 222 Euston Road London United Kingdom NW1 2DA |
| Contact telephone | +44 (0)207 6704808 |
| Contact fax | +44 (0)207 6704817 |
| Contact email | nick.paton@ctu.mrc.ac.uk |
| More information | For more up-to-date information please go to the ISRCTN link below. |
| Link to record in ISRCTN Register | ISRCTN04857074 |
| Date last extracted from ISRCTN register | 17/04/2008 |
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