Clinical Trials Register

Summary
EudraCT Number:	2015-003278-34
Sponsor's Protocol Code Number:	IRFMN-HIV-6986
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2021-06-04
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

Italy - Italian Medicines Agency

A.2

EudraCT number

2015-003278-34

A.3

Full title of the trial

A RANDOMIZED, CROSS-OVER, BIOEQUIVALENCE STUDY OF EFAVIRENZ TABLETS 600 mg OF MYLAN SpA AND SUSTIVA® (EFAVIRENZ) TABLETS 600 mg OF BRISTOL MYERS SQUIBB AT STEADY STATE IN PATIENTS WITH HIV-1

STUDIO RANDOMIZZATO, CROSS-OVER, PER LA VALUTAZIONE DELLA BIOEQUIVALENZA TRA EFAVIRENZ COMPRESSE 600 MG (MYLAN SPA) E SUSTIVA® (EFAVIRENZ) COMPRESSE 600 MG (BRISTOL MYERS SQUIBB) ALLO STEADY STATE IN PAZIENTI CON HIV-1

A.3.1

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

A RANDOMIZED BIOEQUIVALENCE STUDY OF EFAVIRENZ GENERIC DRUG AND SUSTIVA® (TABLETS 600 mg) IN PATIENTS WITH HIV-1

STUDIO RANDOMIZZATO PER LA VALUTAZIONE DELLA BIOEQUIVALENZA TRA EFAVIRENZ GENERICO E SUSTIVA® ENTRAMBI IN COMPRESSE DA 600 MG IN PAZIENTI CON HIV-1

A.3.2

Name or abbreviated title of the trial where available

EFAVIRENZ

A.4.1

Sponsor's protocol code number

IRFMN-HIV-6986

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	IRCCS- ISTITUTO DI RICERCHE FARMACOLOGICHE MARIO NEGRI
B.1.3.4	Country	Italy
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	Mylan S.p.A.
B.4.2	Country	Italy
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri"
B.5.2	Functional name of contact point	Laboratorio di Ricerca Clinica
B.5.3	Address:
B.5.3.1	Street Address	Via Privata Giuseppe La Masa 19
B.5.3.2	Town/ city	Milano
B.5.3.3	Post code	20156
B.5.3.4	Country	Italy
B.5.4	Telephone number	0239014637
B.5.5	Fax number	0233200231
B.5.6	E-mail	federica.chiappa@marionegri.it

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	EFAVIRENZ MYLAN - 600 MG COMPRESSE RIVESTITE CON FILM 30 COMPRESSE IN BLISTER PVC/PVDC/AL
D.2.1.1.2	Name of the Marketing Authorisation holder	MYLAN S.P.A.
D.2.1.2	Country which granted the Marketing Authorisation	Italy
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.3.1	Product name	Efavirenz
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	EFAVIRENZ
D.3.9.1	CAS number	154598-52-4
D.3.9.2	Current sponsor code	non applicabile
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	600
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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
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	Comparator
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	SUSTIVA - 600 MG COMPRESSE FILM RIVESTITE 30 COMPRESSE IN BLISTER USO ORALE
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	Italy
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.3.1	Product name	SUSTIVA
D.3.2	Product code	non applicabile
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	EFAVIRENZ
D.3.9.1	CAS number	154598-52-4
D.3.9.2	Current sponsor code	non applicabile
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	600
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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
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

Patients with HIV-1

Pazienti affetti da HIV-1

E.1.1.1

Medical condition in easily understood language

Patients with HIV-1

Pazienti affetti da HIV-1

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	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10020192
E.1.2	Term	HIV-1
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

The primary objective of the study is to assess the bioequivalence at steady state, in line with clinical practice, of Efavirenz (Mylan) tablets 600 mg and Sustiva® 600 mg tablets in patients with HIV-1.

L’obiettivo primario dello studio è quello di valutare la bioequivalenza allo steady state, in condizioni di normale pratica clinica, di Efavirenz (Mylan) in compresse da 600mg e Sustiva® in compresse da 600mg in pazienti affetti da HIV-1.

E.2.2

Secondary objectives of the trial

To monitor the safety and tolerability profile of Efavirenz and Sustiva®.

Monitorare il profilo di sicurezza e tollerabilità di Efavirenz e Sustiva®.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Able to understand and willing to sign written informed consent form, obtained before any screening procedure;
2. Male or female, aged 18 years or older;
3. Body Mass Index> 18.5 Kg/m2 to < 30.0 Kg/m2;
4. Patient currently receiving an antiretroviral regimen containing Efavirenz by a period of 6 months before the screening visit;
5. Documented plasma HIV-1 RNA levels <37 copies/mL (or undetectable HIV-1 RNA level according to the local assay being used if the limit of detection is >37 copies/mL, Abbott RT-PCR kit HIV-1) for 6 months preceding the screening visit;
6. Willing and able to comply with protocol requirements;
7. A female subject is eligible to enter the study if it is confirmed that she is:
a. Not pregnant or breastfeeding;
b. With a negative serum pregnancy test at screening visit;
c. Of non-childbearing potential (i.e., women who have had a hysterectomy, have had both ovaries removed or medically documented ovarian failure, or are postmenopausal women> 54 years of age with cessation (for >12 months) of previously occurring menses and appropriate post-menopausal FSH elevation, or
d. Of childbearing potential and agrees to utilize highly effective protocol-specified contraceptive method or be non-heterosexually active or practice sexual abstinence from screening throughout the duration of study treatment and for 30 days following the last study drug dose;
e. utilizes hormonal contraceptive as one of their birth control methods must have used the same method for at least three months prior to study dosing.

1. Consenso informato scritto firmato prima di qualsiasi procedura di screening, in accordo con le linee guida vigenti in Italia.
2. Uomini o donne di età > 18 anni;
3. Indice di Massa Corporea > 18.5 Kg/m2 < 30.0 Kg/m2;
4. Pazienti in regime di trattamento antiretrovirale comprendente Efavirenz da un periodo di almeno 6 mesi precedenti la visita di screening;
5. Documentati livelli plasmatici di HIV-1 RNA < 37 copie/mL (o livelli di HIV-1 RNA non rilevabili secondo il test locale in uso, se il limite di rilevazione è > 37 copie/mL, kit Abbott RT-PCR HIV-1) nei 6 mesi antecedenti la visita di screening;
6. Pazienti disposti e in grado di rispettare i requisiti del protocollo;
7. Pazienti di sesso femminile che abbiano i requisiti per entrare nello studio, se verificato che:
a. non sono in gravidanza o allattamento;
b. presentano un test di gravidanza ematico negativo alla visita di screening;
c. non sono potenzialmente fertili (vale a dire, donne che hanno subito un'isterectomia, hanno subito una rimozione di entrambe le ovaie o con insufficienza ovarica medicalmente documentata, donne in post-menopausa di età superiore a 54 anni e senza ciclo mestruale da più di 12 mesi e con livello di FSH indicativo di menopausa).
d. sono in età fertile, ma che si impegnano a utilizzare un metodo contraccettivo altamente efficace specificato nel protocollo, che non sono eterosessualmente attive o che praticano astinenza sessuale per tutta la durata del trattamento, dallo screening fino a 30 giorni successivi all’ultima dose di trattamento effettuata per lo studio;
e. utilizzano un contraccettivo ormonale come metodo di controllo delle nascite (deve essere usato lo stesso metodo per almeno tre mesi prima della prima dose di farmaco).

E.4

Principal exclusion criteria

1. Evidence of gastro-intestinal diseases influencing drug absorption;
2. Evidence of decompensated cirrhosis (e.g., ascites, encephalopathy, etc.);
3. Evidence of allergy or intolerance to the study drugs or their components or drugs of their class, or a history of drug or other allergy
4. Current alcohol or substance use judged by the Investigator to potentially interfere with subject study compliance;
5. Participation in any clinical trial within last three months;
6. Use of enzyme-modifying drugs within 30 days prior to receiving the first dose of study medication;
7. Presence of significant disease or clinically significant abnormal laboratory values on the laboratory evaluations, medical history or physical examination during the screening;
8. Hepatic transaminases (AST and ALT) >3 × upper limit of normal (ULN)
9. Not adequate renal function in terms of estimated glomerular filtration rate <50 mL/min according to the Cockcroft-Gault formula: Male: (140 – age in years) x (wt in kg) = CLcr (mL/min)72 x (serum creatinine in mg/dL); Female: (140 – age in years) x (wt in kg) x 0.8 = CLcr (mL/min)72 x (serum creatinine in mg/dL).
10. Any change to the antiretroviral combination in the month preceding the first study drug administration

1. Evidenza di malattie gastrointestinali che possono influire sull’assorbimento del farmaco;
2. Evidenza di cirrosi scompensata (come ascite, encefalopatia, ecc.);
3. Evidenza di allergia o di intolleranza a uno dei farmaci in studio o ai loro componenti, ad altri farmaci della stessa classe, o in generale storia di allergia a farmaci o altre sostanza;
4. Uso attuale di alcool o sostanze che, a giudizio dello sperimentatore, possano interferire con l’aderenza del paziente alle procedure di studio;
5. Partecipazione a qualsiasi altra sperimentazione clinica negli ultimi tre mesi;
6. Utilizzo di farmaci che modifichino l’attività enzimatica
nei 30 giorni antecedenti alla prima somministrazione del farmaco in studio;
7. Presenza di malattie o esami di laboratorio che mostrino variazioni significative dei valori clinicamente rilevanti, anomalie nella storia medica o nell’esame fisico durante lo screening;
8. Valori delle transaminasi epatiche (AST e ALT)> 3 volte il limite superiore della norma (ULN)
9. Non adeguata funzionalità renale in termini di tasso stimato di filtrazione glomerulare <50 mL/min secondo la formula di Cockcroft-Gault: Maschile: (140 - età in anni) x (peso in kg) = CLcr (mL/min) 72 x (creatinina sierica in mg/dl); Femminile: (140 - età in anni) x (peso in kg) x 0,8 = CLcr (mL/min) 72 x (creatinina sierica in mg/dL).
10. Qualsiasi modifica alla combinazione antiretrovirale nel mese precedente alla prima somministrazione del farmaco in studio.

E.5 End points

E.5.1

Primary end point(s)

The following primary pharmacokinetic parameters will be determined: AUC(0-24h) and Cmaxss. Tmaxss and trough levels will also be determined, as secondary pharmacokinetic parameters.

L’indicatore primario dello studio sarà l’area sotto la curva nelle 24 ore (AUC(0-24h)); insieme a questo verrà determinata la concentrazione massima osservata (CmaxSS) allo steady state.
Gli indicatori secondari saranno il tempo corrispondente alla concentrazione massima osservata (Tmaxss) e i livelli minimi di farmaco (Cmin).

E.5.1.1

Timepoint(s) of evaluation of this end point

Endpoint detected after 21 days of drug administration for each treatment period

Endpoint rilevato a 21 giorni di somministrazione di farmaco per ciascun periodo di trattamento

E.5.2

Secondary end point(s)

Safety and tolerability profile of Efavirenz and Sustiva® will be monitored throughout the study for adverse events (all grades), serious adverse events, any adverse events requiring drug interruption or discontinuation, changes in laboratory values, and physical examination findings.

Il profilo di sicurezza e tollerabilità di Efavirenz e Sustiva® verrà monitorato nel corso dello studio attraverso la valutazione degli eventi avversi (tutti i gradi), degli eventi avversi seri, di tutti gli eventi avversi che richiedono l'interruzione o la sospensione del farmaco, delle alterazioni nei valori di laboratorio e dei risultati dell'esame clinico.

E.5.2.1

Timepoint(s) of evaluation of this end point

42 days

42 giorni

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

E.6.4

Safety

Yes

E.6.5

Efficacy

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

Yes

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

Yes

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

Yes

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

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

Yes

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

Yes

E.8.2.3.1

Comparator description

I pazienti riceveranno entrambe le formulazioni di farmaco: Efavirenz generico - Mylan (A) e Sustiva

Subjects will thus receive both drug formulations: Generic Efavirenz -Mylan (A) and Sustiva® (B) wi

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

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

Information not present in EudraCT

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

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

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)

Yes

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)

not applicable

non applicabile

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

2015-12-02

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-10-22

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

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