Clinical Trials Register

Summary
EudraCT Number:	2014-004488-19
Sponsor's Protocol Code Number:	UMCN-AKF-14.08
National Competent Authority:	Netherlands - Competent Authority
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2015-01-19
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

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A. Protocol Information

A.1

Member State Concerned

Netherlands - Competent Authority

A.2

EudraCT number

2014-004488-19

A.3

Full title of the trial

Pharmacokinetics, safety and efficacy of atazanavir /dolutegravir/lamivudine regimen as maintenance regimen in pa-tients with intolerance and/or resistance to NRTIs, NNRTIs and RTV: a pilot study (PRADA II study)

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Pilotstudy to asses the pharmacokinetics, the efficacy and safety of the combination of atazanavir, dolutegravir and lamivudine in HIV-1 infected patients who experience side-effects, toxicities or resistance to other anti-HIV drugs.

A.3.2

Name or abbreviated title of the trial where available

PRADA II

A.4.1

Sponsor's protocol code number

UMCN-AKF-14.08

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Radboud University Medical Center
B.1.3.4	Country	Netherlands
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Radboud University Medical Center
B.4.2	Country	Netherlands
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Radboud University Medical Center
B.5.2	Functional name of contact point	David Burger
B.5.3	Address:
B.5.3.1	Street Address	Geert Grooteplein-Zuid 10
B.5.3.2	Town/ city	Nijmegen
B.5.3.3	Post code	6525 GA
B.5.3.4	Country	Netherlands
B.5.4	Telephone number	+31243616405
B.5.5	Fax number	+31243668755
B.5.6	E-mail	david.burger@radboudumc.nl

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Tivicay
D.2.1.1.2	Name of the Marketing Authorisation holder	ViiV Healthcare UK Limited
D.2.1.2	Country which granted the Marketing Authorisation	European Union
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Reyataz
D.2.1.1.2	Name of the Marketing Authorisation holder	BRISTOL-MYERS SQUIBB PHARMA EEIG
D.2.1.2	Country which granted the Marketing Authorisation	European Union
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Capsule
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 3
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	lamivudine
D.2.1.2	Country which granted the Marketing Authorisation	European Union
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

HIV

E.1.1.1

Medical condition in easily understood language

HIV

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	17.1
E.1.2	Level	LLT
E.1.2	Classification code	10068341
E.1.2	Term	HIV-1 infection
E.1.2	System Organ Class	100000004862

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To assess the pharmacokinetics of the alternative maintenance QD regimen combining atazanavir, dolutegravir and lamivudine in HIV infected patients.

E.2.2

Secondary objectives of the trial

To asses short term efficacy of the combination of atazanavir, dolutegravir and lamivudine as maintenance regimen in HIV infected patients.

To evaluate the safety and tolerability of the combination of atazanavir, dolutegravir and lamivudine as maintenance regimen in HIV infected patients.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. HIV-infected as documented by positive HIV antibody test and confirmed by Western Blot.
2. Subject is in need for a switch in maintenance regimen due to adverse effects, toxicities, simplification and/or resistance.
3. Subject is at least 18 years of age at the day of screening.
4. Subject is able and willing to sign the Informed Consent Form prior to screening evaluations.
5. HIV-1 RNA < 40 copies/mL for at least 6 months on antiretroviral therapy prior to inclusion.
6. Subject has no documented resistance mutations to PIs, INSTIs or lamivudine.

E.4

Principal exclusion criteria

1. Documented history of sensitivity/idiosyncrasy to medicinal products or excipients.
2. Relevant history or current condition that might interfere with drug absorption, distribution, me-tabolism or excretion.
3. Inability to understand the nature and extent of the trial and the procedures required.
4. Pregnant female (as confirmed by an HCG test performed less than 3 weeks before the first dose) or breast-feeding female.
5. Abnormal serum transaminases determined as levels being > 5 times upper limit of normal (see Appendix A for normal ranges of clinical laboratory values).
6. Renal failure determined as an estimated Glomerular Filtration Rate (eGFR) < 50 ml/min (MDRD-based).
7. Concomitant use of medications that interfere with atazanavir, dolutegravir or lamivudine pharma-cokinetics: oxcarbamazepine, phenytoin, phenobarbital, carbamazepine, St. John’s wort, rifam-picin, clarithromycin, H2 receptor antagonists, proton pump inhibitors, irinotecan, midazolam, triazolam, co-trimoxazole, other antiretroviral drugs.
8. Concomitant use of medications that are contraindicated for use with atazanavir, dolutegravir or lamivudine: alfuzosin, dofetilide, quetiapine, kinidine, bepridil, simvastatin, atorvastatin, lovastatin, sildenafil (as for use in pulmonary arterial hypertension), cladribine.
9. Active hepatobiliary or hepatic disease (including chronic hepatitis B or C infection).
10. Alcohol abuse.

E.5 End points

E.5.1

Primary end point(s)

Geometric Mean and the 95% classical confidence interval of AUC0-24h, Cmax and C24h for atazanavir and dolutegravir. Median (range) of tmax for atazanavir and dolutegravir. Values will be compared to historical data.

Individual and mean plasma concentrations will be presented. Overlay presentations will be given to illustrate inter-subject variability. Descriptive statistics will be calculated for the plasma concentrations at each sampling time.

E.5.1.1

Timepoint(s) of evaluation of this end point

At week 4 a pharmacokinetic (PK) curve will be recorded for atazanavir and dolutegravir at the following time points: t=0 (pre-dose), 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, 8.0 and 24.0 hours post ingestion.

E.5.2

Secondary end point(s)

HIV-1 RNA and CD4 count will be tabulated per time point. The HIV-1 RNA < 40 copies per mL will be tabulated into a frequency table. Geometric Mean and the 95% classical confidence interval of CD4 count will be calculated and change from baseline will be presented.

Adverse events and serious adverse events will be listed and the incidence (number of subjects with at least one AE) will be presented. Special attention will be given to subjects who discontinued be-cause of AEs.

E.5.2.1

Timepoint(s) of evaluation of this end point

Screening, week 4 and week 12. Safety assessment on every study visit.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

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

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

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

LVLS

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

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

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)

None. Physician and patient will decide together wether the the atazanavir, dolutegravir, lamivudine regimen will be continued or if the patient will switch to another regimen.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2015-01-19

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-07-23

P. End of Trial
P.	End of Trial Status	Prematurely Ended

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