E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Virus Diseases [C02] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10020160 |
E.1.2 | Term | HIV disease |
E.1.2 | System Organ Class | 100000004862 |
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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 evaluate the virological efficacy at week 48 of once daily doravirine plus raltegravir dual therapy in HIV-1-infected patients suppressed on ART
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E.2.2 | Secondary objectives of the trial |
• Virological efficacy of the doravirine plus raltegravir dual therapy • To assess the proportion of patients in therapeutic success up to week 48 and week 96 • Resistance profile in case of virological failure • Evolution of CD4 and CD8 T-cells, and CD4/CD8 ratio • Clinical and biological tolerability of the doravirine plus raltegravir dual therapy • Quality of life questionnaire • Observance questionnaire • Evolution of HIV-reservoir (Whole blood will be collected at D0, W48 and W96) • Evolution of the inflammation markers (on frozen plasma/serum samples at D0, W48 and W96 (analysis not yet funded)
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Seminal sub-study dated 16/01/2020 version 1.0 This sub-study will be proposed to 30 patients in order to evaluate at D0 and W48 the potential suppressive effect of the dual DOR/RAL regimen on the HIV-RNA seminal viral load and the minimal free and total concentrations (Cmin) of RAL and DOR in seminal and blood plasma. It is known that semen-to-plasma ratio of raltegravir concentrations > 1 indicate a good penetration of raltegravir in the seminal compartment (ANRS-163 ETRAL, Lê MP, and co. Pharmacotherapy 2019). No data were available for doravirine but the modest protein binding (approximately 76 %) is in favour of the good penetration of doravirine in anatomical compartments. Total sperm samples will be collected at home the day of the patient visit using the dedicated container delivered by the investigator during the previous visit and then transferred to the participating site within the 6 hours following sample collection.
Cerebrospinal fluid sub-study dated 16/01/2020 version 1.0 The aim of this sub study is to evaluate the maintenance of HIV viral suppression as well as changes in neuronal injury and inflammatory markers in cerebrospinal fluid (CSF) in a group of patients receiving a 3 drug-regimen and after switching to a Doravirine+Raltegravir. CSF will be taken at D0 and week 48. HIV-1 RNA in plasma and CSF will be determined by real-time PCR (LOQ < 40 copies/mL). Neuronal damage marker Neurofilament light chain (NFL) as well as inflammatory markers (STREM2 and YKL40) will be measured in CSF at baseline and week 48.
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E.3 | Principal inclusion criteria |
• Age ≥ 18 years • Patients with HIV-1 documented infection • CD4 ≥ 200/mm3 • On stable combined ART regimen with at least 2 drugs for at least 6 months • HIV-RNA plasma VL ≤ 50 copies/mL during the last 12 months prior to screening visit (W-6/W-4), documented by at least 2 time-points with no more than one blip (defined as one HIV-RNA plasma VL between 51 and 200 copies/mL followed by one HIV-RNA plasma VL ≤ 50 copies/mL) • Naive to doravirine • Absence of resistance to doravirine* and/or raltegravir**(see list mutations below) - on all HIV-genotypes with available RT and integrase gene sequences allowing resistance interpretation in case of previous virological failure - or on DNA genotype performed at screening if HIV genotype is not available in case of prior virological failure. • Signed informed consent form. • Patient affiliated to a social insurance regimen. For French patients only: subject enrolled in or a beneficiary of a Social Security programme (State Medical Aid or AME is not a Social Security programme).
*Mutations associated to doravirine resistance are: V106A/M, Y188L, G190E/S, M230L, F227C, at least 2 among: A98G, L100I, K101E, V106I, E138K, Y181C/V, G190A or H221Y . **Mutations associated to raltegravir resistance are: T66A/K, E92Q, G118R, F121Y, G140A/S Y143A/C/G/H/R/S, Q148E/G/H/K/R, V151L, N155H/S/T, E157Q, S230R, R263K, L74 F/I + V75I.
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E.4 | Principal exclusion criteria |
• Absence of RT and INI HIV sequence available (past genotypes or failure of amplification of DNA at screening) • HBV co-infection • Hemoglobin <9 g/dL • Platelets <80,000/mm3 • Creatinine clearance <60 mL/min (MDRD) • AST or ALT ≥5N • Concomitant DAA for anti-HCV therapy • Any severe concomitant illness • Any drug with potential drug-drug interaction with doravirine • Concomitant treatment using interferon, interleukins or any other immune-therapy or chemotherapy • Concomitant prophylactic or curative treatment for an opportunistic infection • All conditions (use of alcohol, drugs, etc.) judged by the investigator to possibly interfere with trial protocol compliance, adherence and/or trial treatment tolerance • Subjects under "sauvegarde de justice" (judicial protection due to temporarily and slightly diminished mental or physical faculties), or under legal guardianship • Subjects participating in another clinical trial evaluating different therapies and including an exclusion period that is still in force during the screening phase • Pregnant women or breastfeeding women
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E.5 End points |
E.5.1 | Primary end point(s) |
The proportion of patients with virological failure before or at week 48. Protocol virological failure is defined as two pVL>50 copies/mL two weeks apart. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
• Proportion of patients maintaining viral suppression (pVL <50 copies/mL, Snapshot approach) • Evolution of CD4 and CD8 T-cells, and CD4/CD8 ratio • Proportion of patients with virological blips (HIV-RNA pVL>50 copies/mL followed by a second measurement <50 copies/mL) • Resistance profile in case of protocol defined virological failure (PDVF) • Proportion of patients with acquired resistance mutation among those with PDVF • Frequency of grade 3 and 4 events • Quality of life assessed by self-questionnaire at screening, D0, W24, W48, W72, W96 • Observance assessed by self-questionnaire at D0, W24, W48, W96 • Evolution of total cell HIV-DNA in PBMC from D0 to W48 and W96 • Evolution of inflammation markers from D0 to W48 and W96 (not yet funded) • To assess HIV-RNA viral load and Cmin (Minimal Drug Concentration) of doravirine/raltegravir at D0 and W48 in human male genital compartment (Seminal sub-study, 30 patients) • Evaluate the maintenance of HIV viral suppression as well as changes in neuronal injury and inflammatory markers in cerebrospinal fluid (CSF) at D0 and W48 (CSF sub-study, 15 patients included in the Spanish centers) (sub-study not yet funded)
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
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.8.2.4 | Number of treatment arms in the trial | 2 |
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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 2 |
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 | No |
E.8.7 | Trial 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
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LVLS All patients who discontinue trial medication will be followed up and requested to attend for trial visits up until week 96, even if they stop taking trial medication.
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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 | |
E.8.9.1 | In the Member State concerned months | 36 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial months | 36 |