E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
malaria prophylaxis in HIV patients |
|
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 8.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10025494 |
E.1.2 | Term | Malaria prophylaxis |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To determine the effect of antiretroviral agents (low-dose ritonavir + lopinavir, low dose ritonavir + atazanavir, efavirenz) on the pharmacokinetics of single dose atovaquone determined by intersubject comparison. |
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E.2.2 | Secondary objectives of the trial |
-To determine the effect of antiretroviral agents (low-dose ritonavir + lopinavir, low dose ritonavir + atazanavir, efavirenz) on the pharmacokinetics of single dose proguanil determined by intersubject comparison.
-To evaluate the safety of combined use of single dose atovaquone/proguanil and lopinavir/ritonavir, atazanavir/ritonavir and efavirenz. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Healthy volunteers: 1.Subject is at least 18 and not older than 65 years of age on the day of dosing of atovaquone/proguanil. 2.Subject does not smoke more than 10 cigarettes, 2 cigars, or 2 pipes per day for at least 3 months prior to the first dosing. 3.Subject has a Quetelet Index (Body Mass Index) of 18 to 30 kg/m2, extremes included. 4.Subject is able and willing to sign the Informed Consent Form prior to screening evaluations. 5.Subject is in good age-appropriate health condition as established by medical history, physical examination, results of biochemistry, haematol-ogy and urinalysis testing within 4 weeks prior to the first dose.Results of biochemistry, haematology and urinalysis testing should be within the laboratory's reference ranges (see Appendix A of study protocol). If not, the subject is included on condition that the Investigator judges that the deviations are not clinically relevant. This should be clearly recorded. 6.Subject has a normal blood pressure and pulse rate, according to the In-vestigator's judgement.
HIV patients: 1.HIV-infected as documented by positive HIV antibody test and confirmed by Western Blot. 2.CD4+ > 200 * 106 /L. 3.Subject is at least 18 and not older than 65 years of age at the day of dosing of atovaquone/proguanil. 4.Subject has a Quetelet Index (Body Mass Index) of 18 to 30 kg/m2, extremes included. 5.Subject is able and willing to sign the Informed Consent Form prior to screening evaluations. 6.Use of lopinavir/ritonavir, atazanavir/ritonavir or efavirenz for at least 1 month in a dose of 400/100mg bid, 300/100 mg QD, or 600 mg QD respectively. |
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E.4 | Principal exclusion criteria |
Healthy volunteers: 1.History of sensitivity/idiosyncrasy to atovaquone/proguanil or chemically related compounds or excipients. 2.Positive HIV test. 3.Positive HbsAg test (hepatitis B) or positive hepatitis C test. 4.Therapy with any drug (for two weeks preceding dosing), except for paracetamol. 5.Creatinine clearance < 60 mL/min (calculated from serum creatinine). 6.Current diarrhoea. 7.Relevant history or current condition that might interfere with drug absorption, distribution, metabolism or excretion. 8.History of or current abuse of drugs, alcohol or solvents. 9.Inability to understand the nature and extent of the trial and the procedures required. 10.Participation in a drug trial within 60 days prior to the first dose. 11.Donation of blood within 60 days prior to the first dose. 12.Pregnant female (as confirmed by an HCG test performed less than 3 weeks before the first dose) or breast-feeding female. 13.Abnormal serum transminases, determined as levels being > 3 times upper limit of normal (see Appendix A for normal ranges of clinical laboratory values). 14.Febrile illness within 3 days before the first dose
HIV infected patients: 1.History of sensitivity/idiosyncrasy to atovaquone/proguanil or chemically related compounds or excipients. 2.Suspicion of non-adherence to the HIV medication. 3.Current diarrhoea. 4.Relevant history or current condition that might interfere with drug absorp-tion, distribution, metabolism or excretion. 5.Inability to understand the nature and extent of the trial and the procedures required. 6.Pregnant female (as confirmed by an HCG test performed less than 3 weeks before the first dose) or breast-feeding female. 7.Abnormal serum transminases determined as levels being > 3 times upper limit of normal (see Appendix A for normal ranges of clinical laboratory values). 8.Creatinine clearance < 60 mL/min (calculated from serum creatinine). 9.Any change in antiretroviral medication within 1 month immediately preceding the dose of atovaquone/proguanil. 10.Concomitant use of medications that interfere with atovaquone or proguanil pharmacokinetics: anti-coagulants, aurothioglucose, chloroquine, cimetidine, fluoxetine, fluvoxamine, metoclopramide, omeprazole, magnesiumtrisilicate, rifabutin, rifampin, tetracycline, thyphoid vaccine, topiramate. 11.Use of a HAART regime containing both lopinavir/ritonavir and an other protease inhibitor or an NNRTI. 12.Use of a HAART regime containing both atazanavir/ritonavir and an other protease inhibitor or an NNRTI. 13.Use of a HAART regime containing both efavirenz and one or more prote-ase inhibitors or nevirapine. 14.Active hepatobiliary or hepatic disease 15.Alcohol abuse |
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E.5 End points |
E.5.1 | Primary end point(s) |
The effect of lopinavir/ritonavir, atazanavir/ritonavir and efavirenz on atovaquone pharmacokinetics (AUC, Cmax). |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | Yes |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
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.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 6 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.7 | Trial has a data monitoring committee | No |
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 last visit of the last subject undergoing the trial |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 1 |