| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | 10000808 |
| E.1.2 | Term | Acute human immunodeficiency virus type I infection |
| E.1.2 | System Organ Class | 100000004862 |
|
| 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 compare efficacy of DTG/RPV combined tablet versus continued antiretroviral treatment regimen at 48 weeks in individuals with the K103N resistance mutation. |
| Comparer les résultats en termes de charge virale avec le schéma DTG/RPV à dose fixe (bras expérimental) aux résultats avec la poursuite du traitement antirétroviral (bras témoin) à 48 semaines, mesurés par un ARN du VIH-1 confirmé comme inférieur ou supérieur à 50 copies/ml. |
| Vergelijk de resultaten in termen van virale belasting met het vaste dosis-DTG / RPV-regime (experimentele arm) met de resultaten met voortgezette antiretrovirale behandeling (controle-arm) na 48 weken, zoals gemeten met HIV-1-RNA bevestigd als lager of hoger bij 50 kopieën / ml. |
|
| E.2.2 | Secondary objectives of the trial |
To investigate whether switching patients to DTG/RPV FDC is associated with improvement of lipid profile, patient satisfaction, quality of life and potential for drug-drug interactions, investigated over time through 96 weeks with evaluation (and comparison to control arm) at week 24, 48 and 96.
To evaluate DTG & RPV concentrations in blood.
To evaluate changes in cell associated virus. |
1. Déterminer si le switch des patients à DTG/RPV à dose fixe est associé à une amélioration du profil lipidique, de la satisfaction du patient, de sa qualité de vie et du potentiel d’interactions médicamenteuses. Investigation pendant 96 semaines avec évaluation aux semaines 24, 48 et 96.
2. Évaluer les concentrations minimales de DTG et de RPV
3. Changements au niveau du virus associé aux cellules (cellules mononucléaires du sang périphérique) |
1. Bepaal of de overstap van DTG / VRS-patiënten met vaste dosis gepaard gaat met een verbetering van het lipidenprofiel, patiënttevredenheid, kwaliteit van leven en het potentieel voor geneesmiddelinteracties. Onderzoek gedurende 96 weken met evaluatie op week 24, 48 en 96.
2. Evalueer de minimale concentraties van DTG en VPN
3. Veranderingen in het virus geassocieerd met cellen (perifere mononucleaire bloedcellen) |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Is male or female aged 18 years or over.
2. Has documented HIV-1 infection
3. Is capable of giving informed consent, or if appropriate, subjects having an acceptable individual capable of giving
consent on the subject’s behalf.
4. Is willing to comply with the protocol requirements
5. Virologically suppressed (plasma HIV-RNA <50 copies/mL for >24 weeks) and on a stable regimen.
6. Subjects are required to have a history of the K103N mutation. Subjects who at any time have had the mutations
100I, 101E/P, 106A/M, 138K/G/Q, 181C/I/V, 188L, 190A/S/E/Q, 230L mutations are to be excluded. Other NNRTI region
variants can be included. Study sites may ask the coordinating centre for advice as required.
7. Subjects must have never failed INSTI (2 x VL >200 >2 weeks apart) but current regimen can include INSTI.
8. A female, may be eligible to enter and participate in the study if she:
a. is of non-child-bearing potential defined as either post-menopausal (12 months of spontaneous amenorrhea and ≥
45 years of age) or physically incapable of becoming pregnant with documented tubal ligation, hysterectomy or
bilateral oophorectomy or,
b. is of child-bearing potential with a negative pregnancy test at Screening (& baseline visit) and agrees to use one of
the following methods of contraception to avoid pregnancy:
• True abstinence from penile-vaginal intercourse from 2 weeks prior to administration of IP, throughout the study, and
for at least 2 weeks after discontinuation of all study medications (When this is in line with the preferred and usual
lifestyle of the subject.) (Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods), and
withdrawal are not acceptable methods of contraception].
• Double barrier method (male condom/spermicide, male condom/diaphragm, diaphragm/spermicide);
• Any intrauterine device (IUD) with published data showing that the expected failure rate is <1% per year (not all IUDs
meet this criterion, see Appendix 3 for an example listing of approved IUDs);
• Male partner sterilization confirmed prior to the female subject’s entry into the study, and this male is the sole partner
for that subject;
• Approved hormonal contraception (see appendix 4 for a listing of examples of approved hormonal contraception);
• Any other method with published data showing that the expected failure rate is <1% per year.
• Any contraceptive method must be used consistently and for at least 2 weeks after discontinuation of IP
9. If a heterosexually active male, he is using effective birth control methods and is willing to continue practising these birth control methods during the trial and until follow-up visit
10. Subjects currently receiving DTG or RPV, but not both, can be included. |
|
| E.4 | Principal exclusion criteria |
1. Infected with HIV-2
2. Detectable HIV-1 RNA at screening (HIV-1 RNA measurement >=50 c/mL).
3. Subjects requiring regular dosing doing with H2 or PPI antacid medications or a history of achlorhidria or drug
known to interact with RPV or DTG.
4. Use of medications which are associated with Torsades de Pointes
5. Corrected QT interval (QTc [Bazett]) >450 milliseconds or QTc (Bazett) >480 milliseconds for participants with bundle
branch block. The QTc is the QT interval corrected for heart rate according to Bazett's formula (QTcB).
6. Unstable health conditions (i.e. opportunistic infections, cancers, unstable liver disease etc).
7. Any evidence of an active Centers for Disease Control and Prevention Category C disease. Exceptions include
cutaneous Kaposi's sarcoma not requiring systemic therapy and historic CD4+ lymphocyte counts of <200
cells/millimeter^3.
8. History or presence of allergy to the study drugs or their components or drugs of their class;
9. Ongoing malignancy other than cutaneous Kaposi's sarcoma, basal cell carcinoma, or resected, non-invasive
cutaneous squamous cell carcinoma, or cervical intraepithelial neoplasia; other localized malignancies require
agreement between the investigator and the Study medical monitor for inclusion of the subject prior to randomization;
10. Any pre-existing physical or mental condition which, in the opinion of the Investigator, may interfere with the
subject's ability to comply with the dosing schedule and/or protocol evaluations or which may compromise the safety
of the participants. Subjects considered to pose a significant risk of suicide should be excluded.
11. Any condition which, in the opinion of the Investigator, may interfere with the absorption, distribution, metabolism or
excretion of the study drugs or render the subject unable to take oral medication;
12. Using any concomitant therapy disallowed as per the reference safety information and product labelling for the study drugs
13. Has acute viral hepatitis including, but not limited to, A, B, or C
14. Active hepatitis B/ Hep B non-immune subjects who have failed vaccination (antibody concentration < 10
international units). (Note: subjects can be re screened if they receive vaccination and subsequently meet eligibility
criteria)
15. Evidence of Hepatitis B virus (HBV) infection based on the results of testing at Screening for Hepatitis B surface
antigen (HBsAg), Hepatitis B core antibody (anti-HBc), and Hepatitis B surface antibody (HBsAb) as follows:
Participants positive for HBsAg are excluded; Participants positive for anti-HBc (negative HBsAg status) and negative
for HBsAb are excluded. Note: Subject positive for anti-HBc (negative HBsAg status) and positive for HBsAb are
immune to HBV and are not excluded.
16. Participants with an anticipated need for any Hepatitis C virus (HCV) therapy during the Early Switch Phase and for
interferon-based therapy for HCV throughout the entire study period.
17. Any investigational drug within 30 days prior to the trial drug administration
18. Any evidence of viral resistance different to the one described in the inclusion criteria.
19. Dialysis or renal insufficiency (creatinine clearance < 50ml/min)
20. History of decompensated liver disease (Alanine aminotransferase (ALT) ≥ 5 times the upper limit of normal
(ULN), OR ALT ≥3xULN and bilirubin ≥1.5xULN (with >35% direct bilirubin)
21. Unstable liver disease (as defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia,
esophageal or gastric varices, or persistent jaundice), cirrhosis, known biliary abnormalities (with the exception of
Gilbert's syndrome or asymptomatic gallstones)
22. Subjects with severe hepatic impairment (Class C) as determined by Child-Pugh classification (see appendix 4)
23. Opportunistic infection within 4 weeks prior to first dose of DTG plus RPV.
24. Clinical decision that a switch of antiretroviral therapy should be immediate
25. Screening blood result with any grade 3/4 toxicity according to Division of AIDS (DAIDS) grading scale, except:
asymptomatic grade 3 glucose, amylase or lipid elevation or asymptomatic grade 4 triglyceride elevation (re-test
allowed).
26. Any condition (including illicit drug use or alcohol abuse) or laboratory results which, in the investigator’s opinion,
interfere with assessments or completion of the trial.
27. Women planning pregnancy or who are pregnant or breast feeding.
28. Females of childbearing potential and males must be willing to use a highly effective method of contraception (hormonal method of birth control; true abstinence). Contraceptive methods that can achieve a failure rate of less than 1% per year when used consistently and correctly are considered as highly effective birth control methods. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Virological suppression (<50 copies/ml HIV RNA) at week 48 in individuals with previous NNRTIs virological failure and/or baseline
transmitted resistance with the k103N resistance mutation, switching to DTG/RPV FDC. (Analysed in line with FDA snapshot)
2. Virological failure defined by 2 consecutive viral loads >50 copies at least 2 weeks apart, investigated over 96 weeks. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Virological suppression after 48 weeks
Virological failure after 96 weeks |
|
| E.5.2 | Secondary end point(s) |
1a. Proportion of participants with plasma HIV-1 RNA <50 c/mL at week 24, 48 and 96.
b. Changes in laboratory parameter from baseline
c. Changes in renal markers, bone markers, and fasting lipids from baseline, week 24, week 48 and week 96.
d. Resistance in failures (descriptive analysis) and baseline factors associated with failures.
e. Changes in QoL and patient satisfaction from baseline.
f. Number of participants with adverse events (AEs), Severity of AEs, and treatment discontinuations due to AEs.
g. Number of potential DDIs avoided.
h. Virological suppression (<200 copies/ml HIV RNA) at week 24, 48, 96 in individuals with previous NNRTIs
virological failure and/or baseline transmitted resistance with the k103N resistance mutation, switching to DTG/RPV
FDC. Analysed in line with FDA Snapshot method.
i. Pre-dose plasma concentrations of DTG and RPV at week 4 (experimental arm only), 48 (experimental arm only) & 96. Plus pre/post-dose (as appropriate) at early termination visit and /or in the event of virological failure (see section 6.12) a post dose sample will be taken within 20-28 hours.
j. Changes in cell associated virus using PBMC Illumina MiSeq sequencing at week 48 and week 96. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | No |
| E.6.4 | Safety | No |
| 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 | 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
|
| 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 | Yes |
| E.8.2.3.1 | Comparator description |
| Switch immediately or after 48 weeks |
|
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 27 |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 1 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 1 |
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