Open Label Pharmacokinetic Study of OZ439 and Piperaquine on Administration of OZ439+TPGS Granules for Oral Suspension Alone or With Either Piperaquine Phosphate Tablets or Granules for Oral Solution in Healthy Volunteers

• ClinicalTrials.gov Identifier: NCT01958619
• Recruitment Status: Completed
• First Posted: October 9, 2013
• Results First Posted: April 21, 2015
• Last Update Posted: May 8, 2015
• Sponsor: Medicines for Malaria Venture
• Collaborator: Richmond Pharmacology Limited
• Information provided by (Responsible Party): Medicines for Malaria Venture

Study Description

Brief Summary:

A healthy volunteer study to characterise the exposure of the two study medications, following administration of OZ439 + TPGS granules with piperaquine phosphate granules (intended for children) and with piperaquine phosphate tablets (intended for adults). Ideally, to confirm the exposure demonstrated in an earlier bioavailability study.

Condition or disease	Intervention/treatment	Phase
Malaria	Drug: 1440mg PQP tablets; Drug: 960mg PQP tablets; Drug: 800mg OZ439 + TPGS; Drug: 960mg PQP granules	Phase 1

Detailed Description:

A Phase 1 open label parallel group, four arm study conducted in healthy male and female subject aged 18 to 55 years of age. Subjects will receive either treatment A, B, C or D as described below:

• Treatment A: 1440 mg PQP tablets and 800 mg OZ439 + TPGS granules for oral suspension
• Treatment B: 960 mg PQP tablets and 800 mg OZ439 + TPGS granules for oral suspension
• Treatment C: 960 mg PQP granules for oral solution and 800 mg OZ439 + TPGS granules for oral suspension
• Treatment D: 800 mg OZ439 + TPGS granules for oral suspension

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 55 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Open Label Pharmacokinetic Study of OZ439 and Piperaquine Following Administration of OZ439+TPGS Granules for Oral Suspension Alone or With Either Piperaquine Phosphate Tablets or Granules for Oral Solution in the Fasted State in Healthy Volunteers
• Study Start Date: October 2013
• Actual Primary Completion Date: January 2014
• Actual Study Completion Date: January 2014

Arms and Interventions

Arm	Intervention/treatment
Experimental: Treatment A: 1440mg PQP tablets & 800mg OZ439 + TPGS; Piperaquine phosphate tablets (1440mg) and OZ439 (800mg) + TPGS granules for oral suspension under fasted conditions.	Drug: 1440mg PQP tablets; Piperaquine phosphate tablets (1440mg); Drug: 800mg OZ439 + TPGS; OZ439 (800mg) + TPGS granules for oral suspension
Experimental: Treatment B: 960mg PQP tablets & 800mg OZ439 + TPGS; Piperaquine phosphate tablets (960mg) and OZ439 (800mg) + TPGS granules for oral suspension under fasted conditions.	Drug: 960mg PQP tablets; Piperaquine phosphate tablets (960mg); Drug: 800mg OZ439 + TPGS; OZ439 (800mg) + TPGS granules for oral suspension
Experimental: Treatment C: 960mg PQP granules & 800mg OZ439 + TPGS; Piperaquine phosphate granules for oral solution (960mg) and OZ439 (800mg) + TPGS granules for oral suspension under fasted conditions.	Drug: 800mg OZ439 + TPGS; OZ439 (800mg) + TPGS granules for oral suspension; Drug: 960mg PQP granules; Piperaquine phosphate granules for oral solution (960mg)
Experimental: Treatment D: 800mg OZ439 + TPGS; OZ439 (800mg) + TPGS granules for oral suspension under fasted conditions.	Drug: 800mg OZ439 + TPGS; OZ439 (800mg) + TPGS granules for oral suspension

Outcome Measures

Primary Outcome Measures :

1. OZ439 Cmax [ Time Frame: Days 1 pre-dose and post-dose at 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16 and 24 hours (Day 2), and, 48 (Day 3), 72 (Day 4), 96 (Day 5) and 168 (Day 8) hours post-dose. Sampling will also be done on Day 11, 15, 29 and 43. ]
   OZ439 observed maximum drug plasma concentration
2. OZ439 AUC0-∞ [ Time Frame: Days 1 pre-dose and post-dose at 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16 and 24 hours (Day 2), and, 48 (Day 3), 72 (Day 4), 96 (Day 5) and 168 (Day 8) hours post-dose. Sampling will also be done on Day 11, 15, 29 and 43. ]
   OZ439 Area under plasma concentration time curve from time zero extrapolated to infinity.

Secondary Outcome Measures :

1. Piperaquine Cmax [ Time Frame: Days 1 pre-dose and post-dose at 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16 and 24 hours (Day 2), and, 48 (Day 3), 72 (Day 4), 96 (Day 5) and 168 (Day 8) hours post-dose. Sampling will also be done on Day 11, 15, 29 and 43. ]
   Piperaquine Observed maximum drug plasma concentration
2. Piperaquine AUC0-∞ [ Time Frame: Days 1 pre-dose and post-dose at 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16 and 24 hours (Day 2), and, 48 (Day 3), 72 (Day 4), 96 (Day 5) and 168 (Day 8) hours post-dose. Sampling will also be done on Day 11, 15, 29 and 43. ]
   Piperaquine Area under plasma concentration time curve from time zero extrapolated to infinity.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 55 Years (Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

Inclusion Criteria:

• healthy, male or female, any race aged 18-55 years at screening
• body mass index of 18-30kg/m2 inclusive; and a total body weight >50kg and up to 100kg at screening

• Females must have negative pregnancy test at screening, be non-lactating and of non-childbearing potential confirmed by:

  • natural (spontaneous) post-menopausal defined as amenorrheic for 12 months without an alternative medical cause with a screening FSH level >25IU/L for post menopause
  • irreversible surgical sterilisation by bilateral oophorectomy or bilateral salpingectomy but not tubal ligation (with or without hysterectomy) at least six months ago
• Must agree to use acceptable methods of contraception Males must use acceptable methods of contraception if the male subject's partner could become pregnant from the time of the first administration of treatment or study medication until 3 months following administration of the last dose of study medication

One of the following acceptable methods of contraception must be used:

• Condom & occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository)
• Surgical sterilisation (vasectomy with documentation of azoospermia) and a barrier method (condom or occlusive cap [diaphragm or cervical/vault caps] used with spermicidal foam/gel/film/cream/suppository)
• Female partner uses oral contraceptives (combination oestrogen/progesterone pills), injectable progesterone or subdermal implants and a barrier method (as above)
• Female partner uses medically prescribed topically-applied transdermal contraceptive patch and a barrier method (as above)
• Female partner has had documented tubal ligation (sterilization). In addition, a barrier method (as above) must be used
• Female partner has had documented placement of an intrauterine device or system and the use of a barrier method (as above)

• True abstinence: when 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. Abstinent subjects must agree use one of the above-mentioned contraceptive methods, if sexual relationships start during the study or up to 90 days after the last dose of study drug

  • Subjects should not donate egg and sperm from the time of administration of study medication until 3 months after study medication
  • Must be capable of understanding and complying with the requirements of the protocol and must have signed the informed consent form prior to undergoing any study-related procedures

Exclusion Criteria:

• Male subjects with female partner(s) who is (are) pregnant or lactating from the time of the administration of study medication
• Has a clinically significant disease or any condition or disease that might affect drug absorption, distribution or excretion
• History of allergic reaction to artemisinin-based compounds, 4-aminoquinolines such as piperaquine or any other clinically relevant allergy to drugs or food
• Any clinically significant abnormal laboratory, vital signs or other safety findings as determined by medical history, physical examination or other evaluations conducted at screening or on admission
• History or current evidence of any clinically relevant cardiovascular, pulmonary, hepatic, renal, gastrointestinal (excluding appendectomy and cholecystectomy), haematological, endocrinological, immunological, metabolic, neurological, oncological, psychiatric, urological or other disease, or current infection
• History of post-antibiotic colitis
• Electrocardiogram abnormalities in the 12-lead Electrocardiogram (at screening) and/or 24-hour Holter Electrocardiogram (at screening) which in the opinion of the Investigator is clinically relevant or will interfere with the ECG analysis

• History of clinically significant Electrocardiogram abnormalities, or any of the following abnormalities at screening or on admission:

  • PR >200ms
  • QRS complex >120ms
  • QTcB or QTcF >450ms or shortened QTcB or QTcF less than 340ms for males and females or family history of long QT syndrome or sudden death
  • Any degree of heart block (such as first, second or third degree atrioventricular block, incomplete, full or intermittent bundle branch block)
  • Abnormal T wave morphology / prominent U waves
• Positive results in any of the serology tests for Hepatitis B Surface Antigen, anti Hepatitis core antibody, Hepatitis C antibodies, and HIV 1 and 2 antibodies
• Confirmed positive results from urine drug screen (amphetamines, benzodiazepines, cocaine, cannabinoids, opiates, barbiturates, and methadone) or from the alcohol breath test at screening and admission
• History or clinical evidence of alcohol abuse, or any recreational drug abuse within the 2 years of screening
• Mentally handicapped
• Participation in a drug trial within 90 days of drug administration
• Use of ANY prescription or over the counter medications, within 3 weeks of study medication administration, or vitamins or herbal supplements within 2 weeks of administration of the study drug, unless prior approval is granted. Intermittent use of paracetamol at doses of up to 2g/day is permitted
• Use of moderate/strong inhibitors and/or inducers of CYP450 in 4 weeks of drug administration (or at least 5 half-lives of the compound whichever is the longer)
• Veins unsuitable for intravenous puncture or cannulation on either arm (veins difficult to locate, access or puncture, or veins with a tendency to rupture during or after puncture)
• Transaminases, bilirubin, serum potassium outside normal range at screening or admission
• Haemoglobin < lower limit of normal at screening or admission
• Donation of >500mL blood in 90 days prior to drug administration
• Must be non-smoker for at least three months before screening. "Tobacco use" includes smoking and the use of snuff and chewing tobacco, and other nicotine containing products. May not use any non-nicotine containing smoking cessation aids, e.g. varenicline, for at least three months before screening
• Any consumption of grapefruit, Seville oranges, wild grapes, black mulberries, pomegranates as fruit juice, marmalade or as a raw fruit within 7 days prior to dosing of study drug and throughout the study
• Any circumstances or conditions, which may affect full participation in the trial or compliance with the protocol
• Legal incapacity or limited legal capacity at screening
• Vegetarians, vegans or any dietary restrictions conflicting with the study standardised menus

Contacts and Locations

Locations

United Kingdom

Richmond Pharmacology Ltd.

Croydon, London, United Kingdom, CR7 7YE

Sponsors and Collaborators

Medicines for Malaria Venture

Richmond Pharmacology Limited

Investigators

• Principal Investigator: Ulrike Lorch, MD FRCA FFPM; Richmond Pharmacology Limited

More Information

• Responsible Party: Medicines for Malaria Venture
• ClinicalTrials.gov Identifier: NCT01958619
• Other Study ID Numbers: MMV_OZ439_13_004; 2013-003409-25 ( EudraCT Number )
• First Posted: October 9, 2013
• Results First Posted: April 21, 2015
• Last Update Posted: May 8, 2015
• Last Verified: April 2015

Keywords provided by Medicines for Malaria Venture:

open label; healthy volunteers; pharmacokinetic; parallel group

Additional relevant MeSH terms:

Malaria; Protozoan Infections; Parasitic Diseases; Infections; Vector Borne Diseases; Artefenomel; Antimalarials; Antiprotozoal Agents; Antiparasitic Agents; Anti-Infective Agents