PK of Efavirenz & Lopinavir Nano-formulations in Healthy Volunteers

NCT02631473 | Suspended Phase 1 DMC

• 1 other identifier: SSAT 055
• Study Type: interventional
• Target: 50
• Locations: 1 country
• Sites: 1

Brief Summary

This study is an open-label, prospective pharmacokinetic study investigating two antiretroviral agents in parallel and employing an adaptive design with two stages, whereby the results obtained in the primary stage inform the doses selected for investigation in the secondary stage

Conditions

HIV

Outcome Measures

Primary Outcomes (5)

• The pharmacokinetics of a new pharmaceutical formulation of efavirenz (NANOefavirenz) and lopinavir (NANOlopinavir) in HIV negative healthy volunteers, as measured by Ctrough

  Trough concentration (Ctrough) is defined as the concentration at 24 hours after the observed drug dose.

  Assessed from baseline visit (day 1) to : 1) Day 31 (Primary Stage Group A); 2) Day 30 (Primary Stage Group B); 3) Day 80 (Secondary Stage Group A); 4) Day 30 (Secondary Stage Group B)

• The pharmacokinetics of a new pharmaceutical formulation of efavirenz (NANOefavirenz) and lopinavir (NANOlopinavir) in HIV negative healthy volunteers, as measured by Cmax

  Cmax is defined as the maximum observed plasma concentration

  Assessed from baseline visit (day 1) to : 1) Day 31 (Primary Stage Group A); 2) Day 30 (Primary Stage Group B); 3) Day 80 (Secondary Stage Group A); 4) Day 30 (Secondary Stage Group B)

• The pharmacokinetics of a new pharmaceutical formulation of efavirenz (NANOefavirenz) and lopinavir (NANOlopinavir) in HIV negative healthy volunteers, as measured by t1/2

  t1/2 is defined as the elimination half-life

  Assessed from baseline visit (day 1) to : 1) Day 31 (Primary Stage Group A); 2) Day 30 (Primary Stage Group B); 3) Day 80 (Secondary Stage Group A); 4) Day 30 (Secondary Stage Group B)

• The pharmacokinetics of a new pharmaceutical formulation of efavirenz (NANOefavirenz) and lopinavir (NANOlopinavir) in HIV negative healthy volunteers, as measured by Tmax

  Tmax is defined as the time point at Cmax (Tmax)

  Assessed from baseline visit (day 1) to : 1) Day 31 (Primary Stage Group A); 2) Day 30 (Primary Stage Group B); 3) Day 80 (Secondary Stage Group A); 4) Day 30 (Secondary Stage Group B)

• The pharmacokinetics of a new pharmaceutical formulation of efavirenz (NANOefavirenz) and lopinavir (NANOlopinavir) in HIV negative healthy volunteers, as measured by total drug exposure

  Total drug exposure will be expressed as the area under the plasma concentration-time curve (AUC): from 0-12 (AUC0-12h) and 0-56 hours (AUC0-56h) for lopinavir; or 0-24 (AUC0-24h) and 0-228 hours (AUC0-24h) for efavirenz.

  Assessed from baseline visit (day 1) to : 1) Day 31 (Primary Stage Group A); 2) Day 30 (Primary Stage Group B); 3) Day 80 (Secondary Stage Group A); 4) Day 30 (Secondary Stage Group B)

Secondary Outcomes (11)

• Safety and tolerability of NANOefavirenz and NANOlopinavir in HIV negative healthy volunteers, as measured by concomitant medication check

  1) From screening visit to day 45 (Primary Stage Group A); 2) From screening visit to day 44 (Primary Stage Group B); 3) From screening visit to day 94 (Secondary Stage Group A); 4) From screening visit to day 44 (Secondary Stage Group B)

• Safety and tolerability of NANOefavirenz and NANOlopinavir in HIV negative healthy volunteers, as measured by Adverse Events

  1) From screening visit to day 45 (Primary Stage Group A); 2) From screening visit to day 44 (Primary Stage Group B); 3) From screening visit to day 94 (Secondary Stage Group A); 4) From screening visit to day 44 (Secondary Stage Group B)

• Safety and tolerability of NANOefavirenz and NANOlopinavir in HIV negative healthy volunteers, as measured by symptom directed physical exam

  1) From screening visit to day 45 (Primary Stage Group A); 2) From screening visit to day 44 (Primary Stage Group B); 3) From screening visit to day 94 (Secondary Stage Group A); 4) From screening visit to day 44 (Secondary Stage Group B)

• Safety and tolerability of NANOefavirenz and NANOlopinavir in HIV negative healthy volunteers, as measured by vital signs

  1) From screening visit to day 45 (Primary Stage Group A); 2) From screening visit to day 44 (Primary Stage Group B); 3) From screening visit to day 94 (Secondary Stage Group A); 4) From screening visit to day 44 (Secondary Stage Group B)

• Safety and tolerability of NANOefavirenz and NANOlopinavir in HIV negative healthy volunteers, as measured by ECG

  1) From screening visit to day 21 (Primary Stage Group A); 2) From screening visit to day 28 (Primary Stage Group B); 3) From screening visit to day 70 (Secondary Stage Group A); 4) From screening visit to day 28 (Secondary Stage Group B)

Study Arms (6)

1st Stage-Group A

ACTIVE COMPARATOR

1. Day 1: 50 mg NANO-efavirenz single dose 2. Days 4-21: 50 mg NANO-efavirenz OD (once daily)

Drug: 50mg NANO-efavirenz

1st Stage-Group B

ACTIVE COMPARATOR

1. Days 1-7: 400mg NANO-lopinavir BID (twice daily) 2. Days 8-21: Wash-out period 3. Days: 22-28: 200mg NANO-lopinavir BID plus 100mg Ritonavir (Norvir) BID

Drug: 400mg NANO-Lopinavir; Drug: 200mg NANO-Lopinavir; Drug: 100mg Ritonavir

2nd Stage-Group A-Group 1-Dose level 1

ACTIVE COMPARATOR

1. 21 Days: 300mg NANO-efavirenz OD 2. 4 weeks: Wash-out period 3. 21 days: 600mg Sustiva OD

Drug: 300mg NANO-Efavirenz; Drug: 600mg Sustiva

2nd Stage-Group A-Group 2-Dose level 2

ACTIVE COMPARATOR

1. 21 Days: 200mg NANO-efavirenz OD 2. 4 weeks: Wash-out period 3. 21 days: 400mg Sustiva OD

Drug: 200mg NANO-Efavirenz; Drug: 400mg Sustiva

2nd Stage-Group B-Arm 1

ACTIVE COMPARATOR

1. 7 days: Kaletra® (lopinavir400mg/ritonavir100mg) BD 2. 2 weeks: Wash-out period 3. 7 days: NANO-lopinavir (200mg +/- ritonavir®)

Drug: Kaletra® (lopinavir 400mg/ritonavir 100mg); Drug: +/- 200mg NANO-Lopinavir; Drug: +/- 200mg ritonavir NORVIR

2nd Stage-Group B-Arm 2

ACTIVE COMPARATOR

1. 7 days: NANO-lopinavir (200mg +/- ritonavir Norvir) 2. 2 weeks: Wash-out period 3. 7 days: Kaletra® (lopinavir400mg/ritonavir100mg) BD

Drug: Kaletra® (lopinavir 400mg/ritonavir 100mg); Drug: +/- 200mg NANO-Lopinavir; Drug: +/- 200mg ritonavir NORVIR

Interventions

50mg NANO-efavirenz DRUG

OD

1st Stage-Group A

400mg NANO-Lopinavir DRUG

BID

1st Stage-Group B

+/- 200mg NANO-Lopinavir DRUG

BID

2nd Stage-Group B-Arm 1; 2nd Stage-Group B-Arm 2

100mg Ritonavir DRUG

BID

Also known as: Norvir

1st Stage-Group B

300mg NANO-Efavirenz DRUG

OD

2nd Stage-Group A-Group 1-Dose level 1

600mg Sustiva DRUG

OD

Also known as: Efavirenz

2nd Stage-Group A-Group 1-Dose level 1

200mg NANO-Efavirenz DRUG

OD

2nd Stage-Group A-Group 2-Dose level 2

Kaletra® (lopinavir 400mg/ritonavir 100mg) DRUG

BID

Also known as: Lopinavir/Ritonavir

2nd Stage-Group B-Arm 1; 2nd Stage-Group B-Arm 2

+/- 200mg ritonavir NORVIR DRUG

BID

Also known as: Ritonavir

2nd Stage-Group B-Arm 1; 2nd Stage-Group B-Arm 2

400mg Sustiva DRUG

Also known as: Efavirenz

2nd Stage-Group A-Group 2-Dose level 2

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• The ability to understand and sign a written informed consent form, prior to participation in any screening procedures and must be willing to comply with all study requirements
• Male or non-pregnant, non-lactating females
• Between 18 to 65 years, inclusive
• Body Mass Index (BMI) of 18 to 30 kg/m2, inclusive
• Women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study and for a period of at least 12 weeks after the study
• A female may be eligible to enter and participate in the study if she:
• 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,
• is of child-bearing potential with a negative pregnancy test at both Screening and Day 1 and agrees to use one of the following methods of contraception to avoid pregnancy:
• Complete 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;
• 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 protocol appendix 7 for an example listing of approved IUDs);
• Condom and depot medroxyprogesterone acetate ( DMPA) injections
• Male partner sterilization confirmed prior to the female subject's entry into the study, and this male is the sole partner for that subject;
• Any other method with published data showing that the expected failure rate is \<1% per year.
• Any contraception method must be used consistently, in accordance with the approved product label and for at least 2 weeks after discontinuation of IP.

You may not qualify if:

• Any significant acute or chronic medical illness including hypertension (BP persistently \>140/90 mmHg) or hypotension (BP persistently \<90/60 mmHg)
• Prolongation of ECG intervals: PR \> 200 msec or QTcF \> 450 msec.
• Evidence of organ dysfunction or any clinically significant deviation from normal in physical examination, vital signs, ECG or clinical laboratory determinations.
• Liver transaminase (ALT or AST \> 1.25 x the upper limit of the normal range)
• Significant psychiatric history (including severe depression) or history of seizures.
• Positive blood screen for either hepatitis B surface antigen or hepatitis C antibody
• Positive blood screen for HIV-1 and/or 2 antibodies
• Current or recent (within 3 months) gastrointestinal disease
• Clinically relevant alcohol or drug use (positive urine drug screen) or history of alcohol or drug use considered by the Investigator to be sufficient to hinder adherence to treatment, follow-up procedures or evaluation of adverse events. Smoking is permitted, but tobacco intake should remain consistent throughout the study
• Known cardiac disease history of any family history of sudden cardiac death.
• Exposure to any investigational drug or placebo within 3 months of first dose of study drug
• Use of any other drugs (unless approved by the Investigator), including over-the-counter medications and herbal preparations, within two weeks prior to first dose of study drug, unless approved/prescribed by the Principal Investigator as known not to interact with study drugs.
• Females of childbearing potential without the use of effective non-hormonal birth control methods, or not willing to continue practising these birth control methods for at least 12 weeks after the end of the treatment period
• Previous allergy to any of the constituents of the pharmaceuticals administered in this trial
• Rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucosegalactose malabsorption

Sponsors & Collaborators

• St Stephens Aids Trust: lead
• University of Liverpool: collaborator

Study Sites (1)

St Stephen's Centre

London, London, SW10 9NH, United Kingdom

Location

MeSH Terms

Interventions

efavirenz; Ritonavir; lopinavir-ritonavir drug combination; Lopinavir

Intervention Hierarchy (Ancestors)

Thiazoles; Sulfur Compounds; Organic Chemicals; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Pyrimidinones; Pyrimidines

Study Officials

• Marta Boffito

  Chelsea & Westminster Hospital

  PRINCIPAL INVESTIGATOR

• Steve Rannard

  University of Liverpool

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 6, 2015
• First Posted: December 16, 2015
• Study Start: November 1, 2015
• Primary Completion: November 1, 2017
• Last Updated: December 7, 2016

Record last verified: 2016-12

Locations

GB (1)