Dolutegravir Interactions With Artemisinin-based Combination Therapies

NCT02242799 | Completed Phase 1 DMC

• 1 other identifier: PK13
• Study Type: interventional
• Target: 46
• Locations: 1 country
• Sites: 1

Brief Summary

Malaria and HIV are found in the same regions of the world and developing countries are most affected by both diseases. For malaria, new drugs have been introduced called ACTs. These drugs are effective against malaria but little is known about how the levels of these drugs in blood relate to how effective these drugs are. For HIV, a new drug has been developed called dolutegravir which has potential to be widely used in developing countries. This proposal will explore how dolutegravir affects the drug levels of these antimalarial drugs and vice versa. In total, 46 healthy volunteers will participate in this study.

Conditions

Malaria; HIV

Keywords

Malaria; HIV; Dolutegravir; Artemisinin; Pharmacokinetics; Interactions

Outcome Measures

Primary Outcomes (5)

• Change in area under time-concentration curve [AUC] of DTG and antimalarial drugs

  When subjects are at steady state (of single drug or combination, as detailed in the study design section) intensive PK sampling will be performed

  At steady state (after 3 days dosing for antimalarials and 7 days for DTG)

• Change in maximum concentration [Cmax] of DTG and antimalarials

  PK sampling will be done when each drug is at presumed 'steady state'

  At steady state (3 days for antimalarials and 7 days for DTG)

• Change in time to maximum concentration [Tmax] for antimalarials and DTG

  Medications will be dosed up to steady state before PK sampling is undertaken

  At steady state (3 days for antimalarials and 7 days for DTG)

• Change in clearance [Cl/F] for antimalarials and DTG

  Medications will be dosed up to steady state prior to PK sampling

  Steady state - 3 days for antimalarials and 7 days for dolutegravir

• Change in trough concentration [Ctrough]) for antimalarial drugs and DTG

  PK sampling will be performed at steady state

  Steady state - 3 days for antimalarials and 7 days for DTG

Secondary Outcomes (1)

• Safety and tolerability of the drug combinations

  Until 2 weeks after all medication has been discontinued at the end of study

Study Arms (4)

Study A Sequence 1

EXPERIMENTAL

Artemether-lumefantrine combination alone for 3 days with PK sampling at steady state, then 21 day washout period followed by Dolutegravir 50mg od dosing to steady state (7 days) with PK sampling then a further 3 days where Artemether-lumefantrine combination and Dolutegravir 50mg od are given together, with PK sampling at steady state.

Drug: Dolutegravir 50mg od; Drug: Artemether-lumefantrine combination

Study A Sequence 2

EXPERIMENTAL

Dolutegravir 50mg od given for 7 days with PK sampling at steady state, followed immediately by a further 3 days where Artemether-lumefantrine combination and Dolutegravir 50mg od are given together, again with PK sampling at steady state. Following a 21 day washout period, the subject will then receive Artemether-lumefantrine combination alone for 3 days, with PK sampling at steady state.

Drug: Dolutegravir 50mg od; Drug: Artemether-lumefantrine combination

Study B Sequence 1

EXPERIMENTAL

Administration of artesunate-amodiaquine for 3 days with PK sampling at steady state

Drug: Artesunate-amodiaquine

Study B Sequence 2

EXPERIMENTAL

Dolutegravir alone for 7 days with PK sampling at steady state, followed immediately by administration of both artesunate-amodiaquine and dolutegravir together for a further 3 days with PK sampling at steady state

Drug: Dolutegravir 50mg od; Drug: Artesunate-amodiaquine

Interventions

Dolutegravir 50mg od DRUG

Dolutegravir 50mg once daily will be given either alone or in combination, as specified

Also known as: Tivicay, ViiV Healthcare, GSK1349572

Study A Sequence 1; Study A Sequence 2; Study B Sequence 2

Artemether-lumefantrine combination DRUG

Artemether-lumefantrine combination will be given both alone and in combination with Dolutegravir 50mg od in order to assess changes in PK

Also known as: Co-artem

Study A Sequence 1; Study A Sequence 2

Artesunate-amodiaquine DRUG

Artesunate-amodiaquine will be given alone or in combination with Dolutegravir 50mg od (in a parallel study design) in order to assess the potential interaction causing changes in PK parameters

Also known as: Coarsucam

Study B Sequence 1; Study B Sequence 2

Eligibility Criteria

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

You may qualify if:

• Evidence of a personally signed and dated informed consent document indicating that the participant has been informed of all pertinent aspects of the study.
• Participants who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
• Men and women aged 18 years and above
• Weight ≥40 kg
• HIV antibody negative at screening.
• Malaria blood film negative at screening
• Willing to use mosquito bednets routinely for the duration of the study
• Women of childbearing potential must be willing to use an effective barrier contraception method for the duration of the study.

You may not qualify if:

• Significant disease affecting cardiac, respiratory, gastrointestinal or neurological symptoms which in the clinician's medical judgment could be worsened by participating in this study or the presence of medical or surgical conditions which could prevent the subject from complying with study procedures.
• Serum alanine transaminase (ALT) levels above 3x upper limit of normal
• Serum creatinine levels above 2x upper limit of normal
• Hepatitis B surface antigen positive
• Use of medications which are known inducers/inhibitors of CYP or glucuronyl transferase UGT1A1 within past 2 months (e.g. anticonvulsants, TB medications, HIV agents for prophylaxis, azole antifungals)
• Evidence of QT prolongation on electrocardiogram (ECG) QTc (Rate adjusted QT interval) \>450ms (men) or \>470ms (women)
• Pregnant women or female subjects who are unwilling to use a suitable contraceptive method for the duration of the study (condom, diaphragm, IUD or contraceptive implant)
• Likely to be poorly adherent based on clinician's medical judgement
• Known to be current injection drug user

Sponsors & Collaborators

• University of Liverpool: lead
• ViiV Healthcare: collaborator
• Makerere University: collaborator

Study Sites (1)

Infectious Diseases Institute

Kampala, Uganda

Location

Related Publications (1)

• Walimbwa SI, Lamorde M, Waitt C, Kaboggoza J, Else L, Byakika-Kibwika P, Amara A, Gini J, Winterberg M, Chiong J, Tarning J, Khoo SH. Drug Interactions between Dolutegravir and Artemether-Lumefantrine or Artesunate-Amodiaquine. Antimicrob Agents Chemother. 2019 Jan 29;63(2):e01310-18. doi: 10.1128/AAC.01310-18. Print 2019 Feb.

  PMID: 30420479 DERIVED

Related Links

• Dolutegravir product information

MeSH Terms

Conditions

Malaria

Interventions

dolutegravir; Artemether, Lumefantrine Drug Combination; amodiaquine, artesunate drug combination

Condition Hierarchy (Ancestors)

Protozoan Infections; Parasitic Diseases; Infections; Mosquito-Borne Diseases; Vector Borne Diseases

Intervention Hierarchy (Ancestors)

Artemether; Artemisinins; Reactive Oxygen Species; Free Radicals; Inorganic Chemicals; Organic Chemicals; Lumefantrine; Fluorenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Sesquiterpenes; Terpenes; Polycyclic Compounds; Drug Combinations; Pharmaceutical Preparations

Study Officials

• Mohammed Lamorde, PhD, MBChB

  Infectious Diseases Institute

  STUDY DIRECTOR

• Saye H Khoo, FRCP, PhD

  University of Liverpool

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Site sub-investigator

Study Record Dates

• First Submitted: September 13, 2014
• First Posted: September 17, 2014
• Study Start: June 1, 2015
• Primary Completion: September 1, 2016
• Study Completion: September 1, 2016
• Last Updated: October 5, 2016

Record last verified: 2016-10

Locations

UG (1)