Determine the Tolerability and Safety of Atovaquone-proguanil (ATV-PG) Co-administered With Amodiaquine (AQ)

NCT04002687 | Completed Phase 1 DMC

• 1 other identifier: APM/18/1702001
• Study Type: interventional
• Target: 44
• Locations: 1 country
• Sites: 1

Brief Summary

The aim of the study is to determine the tolerability and safety of ATV-PG + AQ, ATV-PG + AQ placebo, ATV-PG placebo + AQ, and ATV-PG placebo + AQ placebo administered once daily for 3 days to healthy adult male and female subjects.This study in healthy adults is the first step towards establishing the tolerability and safety of the approved doses of ATV-PG and AQ when co-administered. If considered acceptable based on the findings of this study, the tolerability, safety and PE will subsequently be assessed, within the target geographical areas.

Conditions

Malaria

Outcome Measures

Primary Outcomes (1)

• Treatment-emergent adverse events (TEAEs) will be assessed of the approved dose of ATV-PG and the adult equivalent of the approved SMC dose of AQ when administered alone and in combination and in combination, in comparison with placebo.

  TEAEs will include clinical signs, nausea, vomiting and diarrhea, proportion of subjects with clinically relevant changes in laboratory safety tests (hematology, chemistry (in particular ALT, AST and bilirubin increases) and urinalysis), proportion of subjects with morphological and/or rhythm abnormalities on electrocardiogram (ECG), proportion of subjects with clinically significant changes in ECG time intervals (PR, QRS, QT and QTc intervals) and proportion of subjects with clinically significant changes in vital signs (systolic blood pressure, diastolic blood pressure and pulse rate).

  Day 1 to Day 29 post dose, (Day 36 +/- 1 day including follow up)

Secondary Outcomes (6)

• To measure the the maximum observed plasma concentration (Cmax) of atovaquone (ATV), proguanil (PG) and cycloguanil (CG), and amodiaquine (AQ) and desethyl-amodiaquine (DEAQ) following administration of ATV-PG and AQ alone and in combination.

  Day 1 to Day 22

• To measure the maximum plasma concentration (tmax) of atovaquone (ATV), proguanil (PG) and cycloguanil (CG), and amodiaquine (AQ) and desethyl-amodiaquine (DEAQ) following administration of ATV-PG and AQ alone and in combination.

  Day 1 to Day 22

• To measure the area under the plasma concentration-time curve from time zero to last detectable plasma concentration (AUC0-t) of atovaquone, proguanil and cycloguanil, and amodiaquine and desethyl-amodiaquine (DEAQ) following administration.

  Day 1 to Day 22

• To measure the area under the plasma concentration-time curve from time zero extrapolated to infinity (AUC0-inf) of atovaquone (ATV), proguanil (PG) and cycloguanil (CG), and amodiaquine (AQ) and desethyl-amodiaquine (DEAQ) following administr

  Day 1 to Day 22

• To measure the terminal elimination rate constant (λz) of atovaquone (ATV), proguanil (PG) and cycloguanil (CG), and amodiaquine (AQ) and desethyl-amodiaquine (DEAQ) following administr

  Day 1 to Day 22

Study Arms (4)

ATV-PG 1000-400 mg + AQ 612 mg

EXPERIMENTAL

T1 (n=16) - Atovaquone (ATV),Proguanil (PG) 1000-400 mg + Amodiaquine (AQ) 612 mg on days 1,2, 3.

Drug: ATV-PG 1000-400 mg + AQ 612 mg

ATV-PG 1000-400 mg + AQ unmatched placebo

ACTIVE COMPARATOR

T 2 (n=12) - Atovaquone (ATV)-Proguanil (PG) 1000-400 mg + Amodiaquine (AQ) unmatched placebo on days 1,2, 3.

Drug: ATV-PG 1000-400 mg + AQ 612 mg

ATV-PG unmatched placebo + AQ 612 mg

ACTIVE COMPARATOR

T 3 (n=12) - Atovaquone (ATV)-Proguanil (PG) unmatched placebo + Amodiaquine (AQ) 612 mg on days 1,2, 3.

Drug: ATV-PG 1000-400 mg + AQ 612 mg

ATV-PG unmatched placebo + AQ unmatched placebo

PLACEBO COMPARATOR

T 4 (n=12) - Atovaquone (ATV)-Proguanil (PG) unmatched placebo + AQ unmatched placebo on days 1,2, 3.

Drug: ATV-PG 1000-400 mg + AQ 612 mg

Interventions

ATV-PG 1000-400 mg + AQ 612 mg DRUG

The dosing will be carried out by an unblinded member of the investigator's staff. Dosing will take place behind a curtain and during IMP administration the subjects will be blindfolded. ATV-PG (or placebo) will always be given first, then AQ (or placebo).

Also known as: ATV-PG 1000-400 mg + AQ unmatched placebo, ATV-PG unmatched placebo + AQ 612 mg

ATV-PG 1000-400 mg + AQ 612 mg; ATV-PG 1000-400 mg + AQ unmatched placebo; ATV-PG unmatched placebo + AQ 612 mg; ATV-PG unmatched placebo + AQ unmatched placebo

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• \) Male or female, of sub-Saharan African origin (both parents born in sub-Saharan Africa), aged ≥18 to ≤45 years at the date of signing informed consent which is defined as the beginning of the Screening Period.
• \. Female subjects of childbearing potential and male subjects with female partners of childbearing potential must be willing to follow the following contraception requirements. Contraception must start one complete menstrual cycle prior to the first day of dosing and continue until at least 90 days after the end of the systemic exposure of the study drug (90 days after the last study drug administration).
• Female subjects who are documented as being of non-childbearing potential are exempt from contraception requirements. Documentation of non-childbearing potential must include at least one of the following criteria:
• Postmenopausal - evidence of menopause based on a combination of amenorrhea for at least one year and increased serum follicle-stimulating hormone (FSH) level (\> 30 IU/L), or
• Surgical sterilization - evidence of hysterectomy and/or bilateral oophorectomy.
• All female subjects of childbearing potential and all male subjects with female partnersof childbearing potential, who are pregnant or breastfeeding must practice highly effective or acceptable methods of contraception (defined below) when having heterosexual intercourse.
• Sexual abstinence, defined as refraining from heterosexual intercourse during the entire period of risk associated with the study drug treatment can be considered a highly effective method of contraception for female and male subjects. Reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical study and the preferred and usual lifestyle of the subject.
• Contraception methods for female subjects in this study:
• Hormonal contraception:
• Combined i.e. oestrogen- and progestogen-containing (oral, intravaginal or transdermal)
• Progestogen-only (oral, injectable or implantable)
• Intrauterine hormone-releasing system (IUS)
• Intrauterine device (IUD) or
• Bilateral tubal occlusion
• Male partner vasectomised (with documented evidence of azoospermia if possible)

You may not qualify if:

• Current or recurrent disease (e.g., cardiovascular, haematological, neurological,endocrine, immunological, renal, hepatic or gastrointestinal or other conditions) that could affect the action, absorption, or disposition of ATV-PG or AQ, or could affect clinical assessments or clinical laboratory evaluations.
• Any significant history of seizures or epilepsy.
• Current or relevant history of physical or psychiatric illness that may require treatment or make the subject unlikely to fully comply with the requirements or complete the study, or any condition that presents undue risk from the investigational product or study procedures.
• Any other significant disease or disorder which, in the opinion of the Investigator, may either put the subject at risk because of participation in the study may influence the result of the study, or the subject's ability to participate in the study.
• Documented retinopathy.
• History of photosensitivity.
• History of malaria.
• Subjects have travelled to malaria endemic regions for more than a total of 4 weeks within the past 12 months (as per Global Malaria Risk: https://www.malariasite.com/malaria-risk/ \[20\]-)
• The history or presence of any of the following cardiac conditions: known structural cardiac abnormalities; family history of long QT syndrome; cardiac syncope or recurrent, idiopathic syncope; exercise related clinically significant cardiac events.
• Any clinically significant abnormalities in rhythm, conduction or morphology of resting ECG or clinically important abnormalities that may interfere with the interpretation of QTc interval changes. This includes subjects with any of the following (at screening or Day -1):
• Sinus node dysfunction.
• Clinically significant PR (PQ) interval prolongation.
• Intermittent second or third degree AV block.
• Complete bundle branch block.
• Sustained cardiac arrhythmia's including (but not limited to) atrial fibrillation or supraventricular tachycardia; any symptomatic arrhythmia with the exception of isolated extra systoles.

Sponsors & Collaborators

• Medicines for Malaria Venture: lead
• Richmond Pharmacology Limited: collaborator

Study Sites (1)

Richmond Pharmacology Ltd.

Croydon, London, CR7 7YE, United Kingdom

Location

MeSH Terms

Conditions

Malaria

Condition Hierarchy (Ancestors)

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

Study Officials

• Ulrike Lorch, MD FRCA FFPM

  Richmond Pharmacology Limited

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: This study will be conducted in a double-blind fashion whereby subjects and clinical study site staff are blinded. Because the placebo tablets are not an exact match for the active treatment, tablets will be administered by an un-blinded member of clinical study staff, who will protect the blinding from both subjects and all other site staff. Dosing will take place behind a curtain and during IMP administration the subjects will be blindfolded. The pharmacy staff preparing the investigational products will not be blinded to study drug assignment. During the study, the individual randomisation codes will be kept in the site's clinical trials pharmacy, accessible to the pharmacy personnel only. Upon completion of the study, after the database lock and after the blind is revealed, the randomisation list will be filed in the Trial Master File. Sponsor staff involved in clinical decision-making (such as those involved in SRC decisions) will be blinded to study drug assignment.
• Purpose: PREVENTION
• Intervention Model: FACTORIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Fifty-two subjects will be enrolled and randomized to one of the four treatment (Cohorts 1 to 4) in a ratio of 4:3:3:3 as described below: * Treatment 1 (n=16) - ATV-PG 1000-400 mg + AQ 612 mg; * Treatment 2 (n=12) - ATV-PG 1000-400 mg + AQ unmatched placebo; * Treatment 3 (n=12) - ATV-PG unmatched placebo + AQ 612 mg; * Treatment 4 (n=12) - ATV-PG unmatched placebo + AQ unmatched placebo.

Study Record Dates

• First Submitted: June 17, 2019
• First Posted: June 28, 2019
• Study Start: April 4, 2019
• Primary Completion: October 29, 2019
• Study Completion: October 29, 2019
• Last Updated: March 19, 2020

Record last verified: 2020-03

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL
• Time Frame: Data will be available within 6 months after study completion.
• Access Criteria: Requestors will be required to sign a Data Access Agreement.

Locations

GB (1)