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    Summary
    EudraCT Number:2007-006448-23
    Sponsor's Protocol Code Number:PIVOT
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2008-02-22
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedUK - MHRA
    A.2EudraCT number2007-006448-23
    A.3Full title of the trial
    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
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    PIVOT
    A.3.2Name or abbreviated title of the trial where available
    Protease Inhibitor monotherapy Vs Ongoing Triple-therapy (PIVOT)
    A.4.1Sponsor's protocol code numberPIVOT
    A.5.1ISRCTN (International Standard Randomised Controlled Trial) NumberISRCTN04857074
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT01230580
    A.7Trial is part of a Paediatric Investigation Plan Information not present in EudraCT
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorMedical Research Council
    B.1.3.4CountryUnited Kingdom
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    B.5.2Functional name of contact point
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Information not present in EudraCT
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameProtease Inhibitors (all licenced PIs allowed per the protocol)
    D.3.2Product code PI
    D.3.4Pharmaceutical form
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    HIV
    E.1.1.1Medical condition in easily understood language
    HIV
    E.1.1.2Therapeutic area Diseases [C] - Virus Diseases [C02]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 16.0
    E.1.2Level PT
    E.1.2Classification code 10020161
    E.1.2Term HIV infection
    E.1.2System Organ Class 10021881 - Infections and infestations
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To determine whether a strategy of switching to PI monotherapy is as good as continuing triple drug therapy (the standard of care) in terms of the proportion of patients who maintain all possible drug treatment options after at least 3 years of follow-up.
    E.2.2Secondary objectives of the trial
    To compare the two treatment strategies for :
    • Serious drug or disease-related complications
    • Adverse events
    • Virological rebound
    • CD4+ count change
    • Health-related Quality of life change
    • Neurocognitive function change
    • Cardiovascular risk change
    • Health care costs
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    INCLUSION CRITERIA
    1. Documented HIV infection on ELISA and confirmatory test.

    2. Male or female patients, aged 18 years or more.

    3. Receiving combination ART for at least 24 weeks with a regimen comprising 2 NRTIs and either an NNRTI or a PI (boosted or un-boosted).

    4. No change in ART drugs in the 12 weeks prior to screening.

    5. Plasma VL <50 copies/ml at screening and 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 24 weeks prior to screening). A patient who has had one VL “blip” to <200 copies/ml in the 24 weeks prior to screening may be included, provided that the 2 VL tests that immediately preceded the blip and all the VL tests(of which there must be at least 1 prior to screening) that immediately followed the blip all gave results <50 copies/ml.

    6. CD4+ count >100 cells/mm3 at screening.
    (This criterion is included because immune reconstitution is a priority in patients with very low CD4+ counts, and there is currently insufficient data to assess whether PI monotherapy will lead to equivalent rates of CD4+ recovery as standard-of-care treatment.)

    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.

    E.4Principal exclusion criteria
    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. Previous change in ART drug regimen for reasons of unsatisfactory virological response (patients who have changed regimen for prevention or managemnt of toxicity or to improve regimen convenience are permitted to enter the trial).

    3. Previous allergic reaction to a PI.

    4. 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.

    5. Patient requiring treatment with radiotherapy, cytotoxic chemotherapy, or is anticipated to need these during the trial period.

    6. Treatment for acute opportunistic infection within 3 months prior to trial screening.

    7. Pregnant or trying to become pregnant at the time of trial entry.

    8. 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.

    9. History of HIV encephalopathy with current deficit >1 in any domain of the Neuropsychiatric AIDS Rating Scale.

    10. Past or current history of cardiovascular disease, or 10 year absolute coronary heart disease risk of >30%, or risk of >20% if the patient has diabetes or a family history of premature ischaemic heart disease or stroke(based on the Framingham equation and assessed using the Joint British Societies cardiovascular risk prediction charts).

    11. History of insulin-dependent diabetes mellitus.

    12. Patient currently receiving interferon therapy for Hepatitis C virus infection or planning to start treatment for Hepatitis C at the time of study entry.

    13. Co-infection with hepatitis B, defined as Hepatitis BsAg positive at screening or at any time since HIV diagnosis, unless the patient has had a documented Hepatitis B DNA measurement of less than 1000 copies/ml taken whilst off Hepatitis B active drug.
    (This criterion is included to avoid the risk of a flare of Hepatitis B with NRTI withdrawal.)

    14. Any other active clinically significant condition, or findings during screening medical history or examination or abnormality on screening laboratory blood tests that would, in the opinion of the investigator, compromise the patient’s safety or outcome in the trial.

    15. Fasting plasma glucose > 7.0mmol/L at trial screening.
    E.5 End points
    E.5.1Primary end point(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 trial entry (i.e. excluding drug resistance that was known to be present on previous resistance testing).
    E.5.2Secondary end point(s)
    (i) Serious drug or disease-related complication. Defined as the first occurrence of one of the following in any individual patient:

    o Death from any cause
    o Serious AIDS-defining illness (see diagnostic criteria, protocol appendix 8)
    o Serious non-AIDS defining illness (see diagnostic criteria, protocol appendix 9)
    -Acute myocardial infarction
    -Coronary artery disease requiring invasive procedures
    -Cirrhosis
    -Acute liver failure
    -End-stage renal disaese
    -Stroke
    -Clinical acute pancreatitis
    -Severe lactic acidaemia
    -Severe facial lipoatrophy
    -Severe peripheral neuropathy
    -Non-AIDS malignancy

    (ii) Adverse events. Defined as the total number of Grade III and IV adverse events.

    (iii) Virological rebound. Defined in two ways using the “Time to loss of virologic response” (TLOVR) algorithm :

    o Two consecutive tests, taken at least 4 weeks apart, with VL 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 VL to <50 copies/ml with re-introduction of NRTIs, will not count as failures; OR

    o As above, with at least one of the samples giving a VL result more than 400 copies/ml.

    (iv) CD4+ count change. Defined as change from baseline in absolute CD4+ count.

    (v) Health-related Quality of Life change. Defined as change from baseline in the mental and physical health summary scores.

    (vi) Neurocognitive function change. Defined as change from baseline in the neurocognitive function summary score.

    (vii) Cardiovascular risk change. Defined as change from baseline in the risk of cardiovascular disease calculated from the Framingham equation.

    (viii) Health care costs. Defined as the total cost of health care resources utilised per patient year.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Information not present in EudraCT
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) Yes
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned44
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    The end of the main part of the PIVOT trial will be LVLS. However, as part of this substantial amendment the trial will be extended for a further 5 years to collect annual routine data. No further visits will be required. This extended phase of the trial will end at the last data collection point in Q1 2019.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years11
    E.8.9.1In the Member State concerned months4
    E.8.9.1In the Member State concerned days1
    E.8.9.2In all countries concerned by the trial years11
    E.8.9.2In all countries concerned by the trial months4
    E.8.9.2In all countries concerned by the trial days1
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1Number of subjects for this age range: 0
    F.1.1.1In Utero No
    F.1.1.1.1Number of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.2.1Number of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F.1.1.3.1Number of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.4.1Number of subjects for this age range: 0
    F.1.1.5Children (2-11years) No
    F.1.1.5.1Number of subjects for this age range: 0
    F.1.1.6Adolescents (12-17 years) No
    F.1.1.6.1Number of subjects for this age range: 0
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 375
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 25
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state400
    F.4.2 For a multinational trial
    F.4.2.2In the whole clinical trial 400
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    The study will use only licensed medication. Thus patients will be able to continue or start PI monotherapy once the research has finished, providing it is judged to be clinically appropriate to do so by their treating physician.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2008-03-19
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2008-12-15
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2018-12-31
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