Last updated: 07/17/2024 17:04:45
Efficacy and safety study of tafenoquine (TQ) co-administered with dihydroartemisinin-piperaquine (DHA-PQP) for the radical cure of Plasmodium vivax (P. vivax) malaria
EudraCT ID
Not applicable
EU CT Number
Not applicable
Trial status
Completed
Completed
Trial overview
Official title: Study 200894: A double-blind, double-dummy, randomized, parallel group, placebo-controlled superiority study to evaluate the efficacy and safety of tafenoquine (SB-252263, WR238605) co-administered with dihydroartemisinin-piperaquine (DHA-PQP) for the radical cure of Plasmodium vivax malaria
Trial description: Tafenoquine (TQ) is an 8-aminoquinoline anti-malarial drug which is in development as a single-dose treatment for the radical cure of P.vivax malaria when given with standard doses of chloroquine. Currently, the only available drug for radical cure is primaquine (PQ) which requires administration over 14 days, resulting in poor compliance. In Indonesia, chloroquine has been replaced by artemisinin-based combination therapy (i.e. ACTs) due to widespread chloroquine resistance. This study will evaluate the efficacy and safety of a single dose of tafenoquine when co-administered with an ACT (i.e. DHA-PQP). This single-center, double-blind, double-dummy, randomized study will test the superiority of DHA-PQP plus TQ against DHA-PQP alone in the prevention of P. vivax malaria relapse at 6 months. The study will be conducted in male Indonesian soldiers diagnosed with P.vivax malaria on return from deployment to a malarious region of Indonesia. A PQ plus DHA-PQP comparator arm is included to provide an informal comparison against the standard 14 day treatment for P.vivax malaria in Indonesia. Subjects who are glucose-6-phosphate dehydrogenase deficient (G6PD deficient) will be excluded due to the risk of acute hemolysis following dosing with 8-aminoquinolines drugs. Subjects who have a recurrence of P.vivax malaria during the study will be treated with an ACT plus PQ (0.5mg/kg for 14 days), in line with local treatment guidelines. At the end of the 6 month follow up period, any subject who has not relapsed will be given open label PQ (0.5mg/kg daily for 14 days) to minimize the likelihood of relapse after the study. Approximately 200 subjects will be screened to achieve 150 randomized subjects. The total duration of study for each subject will be 180-195 days. This study is being carried out to support registration of TQ in Indonesia and other countries where ACTs are first line therapy.
Primary purpose:
Treatment
Trial design:
Parallel Assignment
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Allocation:
Randomized
Primary outcomes:
Subjects with relapse-free efficacy six months post-dosing (that is clearance of initial infection without subsequent microscopically confirmed recurrence during the 6 month follow up)
Timeframe: Up to Day 180
Secondary outcomes:
Subjects with relapse-free efficacy four months post-dosing.
Timeframe: Up to Day 120
Time to relapse
Timeframe: Up to Day 180
Time to fever clearance (in subjects with fever at baseline)
Timeframe: Up to Day 180
Time to parasite clearance
Timeframe: Up to Day 180
Percentage of subjects with recrudescence (blood stage treatment failure) on or before Day 14
Timeframe: Up to Day 14
Safety as assessed by adverse events (AE) and serious adverse events (SAE)
Timeframe: Up to Day 195
Safety as assessed by number of subjects with abnormal hematology parameters
Timeframe: Up to Day 120
Safety assessed by clinical chemistry
Timeframe: Up to Day 120
Safety as assessed by Electrocardiogram (ECG)
Timeframe: Up to Day 28
Safety as assessed by body temperature
Timeframe: Up to Day 180
Safety as assessed by systolic and diastolic blood pressure
Timeframe: Up to Day 180
Safety as assessed by pulse rate assessment
Timeframe: Up to Day 180
Safety as assessed by respiratory rate
Timeframe: Up to Day 180
Safety as assessed by Gastrointestinal (GI) tolerability
Timeframe: Up to Day 180
Safety as assessed by change from baseline in methemoglobin
Timeframe: Baseline and up to Day 60
Safety as assessed by change from baseline in QTc
Timeframe: Baseline and Day 28
Safety as assessed by incidence of protocol-defined SAEs (that is a decrease in hemoglobin of >=30% or >3 g/dL from baseline; or, a drop in absolute hemoglobin to <7.0 g/dL, in the first 15 days)
Timeframe: Baseline and up to 15 Days
Assessment of oral clearance (CL/F) of tafenoquine when co-administered with DHA-PQP
Timeframe: Up to Day 60
Assessment of volume of distribution (V/F) of tafenoquine when co-administered with DHA-PQP
Timeframe: Up to Day 60
Interventions:
Drug: Tafenoquine
Drug: Matched-Placebo for Tafenoquine
Drug: Primaquine
Drug: Matched-Placebo for Primaquine
Drug: Dihydroartemisinin-piperaquine (DHA-PQP)
Drug: ACT plus PQ (Rescue medication)
Drug: PQ (End of study treatment)
Enrollment:
150
Observational study model:
Not applicable
Primary completion date:
2019-19-08
Time perspective:
Not applicable
Clinical publications:
Inge Sutanto, Amin Soebandrio, Lenny L Ekawati, Krisin Chand, Rintis Noviyanti, Ari Winasti Satyagraha, Decy Subekti, Yulia Widya Santy, Chelzie Crenna-Darusallam, Instiaty Instiaty, Waras Budiman, Catur Bidik Prasetya, Soroy Lardo, Iqbal Elyazar, Stephan Duparc, Eve Cedar, Katie Rolfe, Disala Fernando, Alessandro Berni, Siôn Jones, Jörg-Peter Kleim, Kim Fletcher, Hema Sharma, Ana Martin, Maxine Taylor, Navin Goyal, Justin A Green, Lionel K Tan, J Kevin Baird. Tafenoquine co-administered with dihydroartemisinin-piperaquine for the radical cure of Plasmodium vivax malaria (INSPECTOR): a randomised, placebo-controlled, efficacy and safety study.. The Lancet. Infectious diseases. 2023-May-23;
DOI :10.1016/S1473-3099(23)00213-X
PMID: 37236221
Medical condition
Malaria, Vivax
Product
GSK2579962, artenimol, artenimol/GSK2579962, primaquine, tafenoquine
Collaborators
Medicines for Malaria Venture
Study date(s)
April 2018 to August 2019
Type
Interventional
Phase
3
Participation criteria
Sex
Male
Age
18+ years
Accepts healthy volunteers
No
- Male subjects >=18 years at the time of signing the informed consent.
- The subject has a positive Giemsa smear for P. vivax (mixed infection with P.falciparum is acceptable).
- Severe P.vivax malaria as defined by World Health Organization (WHO) criteria.
- Severe vomiting (no food or inability to take food during the previous 8 hours).
Inclusion and exclusion criteria
Inclusion criteria:
- Male subjects >=18 years at the time of signing the informed consent.
- The subject has a positive Giemsa smear for P. vivax (mixed infection with P.falciparum is acceptable).
- The subject has a parasite density of >20 per microliter.
- Glucose-6-phosphate dehydrogenase (G6PD) normal using a suitable qualitative assessment, for example, nicotinamide adenine dinucleotide phosphate (NADPH) qualitative fluorescent spot test (Trinity Biologicals, United States of America).
- The subject has a QTcF of <450 millisecond (msec). Note: Reading based on an average of triplicate ECGs obtained over a brief recording period by machine.
- The subject is willing and able to comply with the study protocol.
- Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the consent form and in the protocol.
Exclusion criteria:
- Severe P.vivax malaria as defined by World Health Organization (WHO) criteria.
- Severe vomiting (no food or inability to take food during the previous 8 hours).
- Screening hemoglobin (Hb) concentration <8 grams per deciliter.
- Liver function test ALT >2 times upper limit of Normal (ULN).
- Any clinically significant concurrent illness (for example, pneumonia, septicemia), significant pre-existing conditions (for example, renal disease, malignancy, Type 1 diabetes), conditions that may affect absorption of study treatment (for example, vomiting, severe diarrhea), or clinical signs and symptoms of severe cardiovascular disease (for example, uncontrolled congestive heart failure, severe coronary artery disease).
- History of hypersensitivity, allergy or adverse reactions to Dihydroartemisinin (DHA) or other artemisinins, piperaquine, tafenoquine or primaquine.
- Subject has previously received treatment with tafenoquine, or has received treatment with any other investigational drug within 30 days of study entry or within 5 half-lives, whichever is longer.
- Subject has taken anti-malarials (for example, ACTs, mefloquine, primaquine, quinacrine) or drugs with anti-malarial activity within the past 30 days.
- Subjects who will likely require the use of medications from the prohibited medications list or have taken them in the past 30 days which include the following medications and medication classes: Drugs with hemolytic potential, Drugs known to prolong the QT corrected (QTc) interval including: Antiarrhythmics; Neuroleptics and antidepressive agents; Certain antimicrobial agents, including agents of the following classes: macrolides, fluroquinolones imidazole and triazole antifungal agents and also pentamidine and saquinavir; Certain non-sedating antihistamines; Cisapride, droperidol, domperidone, bepridil, diphemanil, probucol, levomethadyl, methadone, vinca alkaloids, arsenic trioxide.
- The biguanides: phenformin and buformin (but excluding metformin).
- Drugs that are substrates of the renal transporters organic cation transporter 2 (OCT2), multidrug and toxin extrusion protein 2 (MATE1) and multidrug and toxin extrusion protein 2 (MATE2) and have a narrow therapeutic index (for example, the antiarrhythmic agents: dofetilide, procainamide and pilsicainide).
- Anticipated to be unable to consume daily study treatment under direct supervision by the research team.
- Previous participation in the present clinical trial, that is, subjects experiencing relapse during or after the study period may not be enrolled as a new subject.
- History of illicit drug abuse or heavy alcohol intake, such that full participation in the study could be compromised.
- Any contraindication in the opinion of the Investigator to DHA-PQP or primaquine administration such as: Family history of sudden unexplained death (DHA-PQP); Known congenital QT corrected (QTc) prolongation (DHA-PQP); Known history of a medical condition known to prolong the QT interval: for example, myxoedema, cardiomyopathies, recent myocardial infarction (DHA-PQP); History of symptomatic cardiac arrhythmias or with clinically relevant bradycardia (DHA-PQP); Cardiac illnesses predisposing to arrhythmias for example, severe hypertension, left ventricular hypertrophy, cardiomyopathies, cardiac failure with reduced ejection fraction (DHA-PQP); Presence of an electrolyte disturbance particularly hypokalemia, hypocalcemia, hypomagnesemia (DHA-PQP); Rheumatoid arthritis, lupus erythematosus and other systemic conditions that may cause granulocytopenia (primaquine); History of hemolytic anemia, methemoglobinemia and leucopenia (primaquine).
Trial location(s)
Study documents
Study report synopsis
Available language(s): English
Protocol
Available language(s): English
Protocol and statistical analysis plan
Available language(s): English
If you wish to request for full study report, please contact - [email protected]
Results overview
Results posted on ClinicalTrials.gov
Recruitment status
Completed
Actual primary completion date
2019-19-08
Actual study completion date
2019-19-08
Plain language summaries
Summary of results in plain language
Available language(s): English, Indonesian
To view plain language summaries on trialsummaries.com click here.
Additional information about the trial
Additional information
Not applicable
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