Efficacy and Safety Study of Tafenoquine (TQ) Co-administered With Dihydroartemisinin-piperaquine (DHA-PQP) for the Radical Cure of Plasmodium Vivax (P. Vivax) Malaria

NCT ID: NCT02802501

Last Updated: 2020-07-24

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 150 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-04-08
• Study Completion Date: 2019-08-19

Brief Summary

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 In Indonesia, chloroquine has been replaced by artemisinin-based combination therapy (i.e. ACTs) due to widespread chloroquine resistance.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.

Conditions

Malaria, Vivax

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

DHA-PQP plus tafenoquine 300 mg single dose

Subjects will receive open label DHA-PQP, 3 or 4 tablets per day (according to the body weight) from Day 1 to Day 3. They will receive double-blind 300 mg single dose of tafenoquine (TQ) on Day 1 and matched-placebo for primaquine (PQ) from Day 1 to Day 14.

Group Type: EXPERIMENTAL

Tafenoquine

Intervention Type: DRUG

This intervention is provided as tablet containing 150 mg of tafenoquine. Two tablets of this formulation will be administered orally with water as a single dose after a meal. Dose will be taken at least 3 hours after DHA-PQP.

Matched-Placebo for Primaquine

Intervention Type: DRUG

This intervention contains primaquine matched-placebo. One capsule of this formulation will be administered orally with water as a single dose after a meal for 14 days. Dose will be taken at least 3 hours after DHA-PQP (Days 1, 2 and 3).

Dihydroartemisinin-piperaquine (DHA-PQP)

Intervention Type: DRUG

This formulation is provided as tablet containing 320 mg of piperaquine tetrasphosphate (as the tetrahydrate; PQP) and 40 mg dihydroartemisinin (DHA). This tablet will be administered orally as single dose for 3 days. For subjects weighing \<75 kg, 3 tablets will be administered per day. For subjects weighing \>=75 kg, 4 tablets will be administered per day. Dose will be taken at least 3 hours after last food intake. No food will be allowed for at least 3 hours after dosing.

ACT plus PQ (Rescue medication)

Intervention Type: DRUG

Subjects with relapse during the 180 day follow up period will be given an ACT plus PQ 0.5 mg/kg for 14 days as rescue medication.

PQ (End of study treatment)

Intervention Type: DRUG

Subjects who do not relapse during the study will receive PQ 0.5mg/kg for 14 days at the end of the study.

DHA-PQP plus primaquine 15 mg for 14 days

Subjects will receive open label DHA-PQP, 3 or 4 tablets per day (according to body weight) from Day 1 to Day 3. They will receive double-blind 15 mg primaquine (PQ) from Day 1 to Day 14 and matched-placebo for tafenoquine (TQ) on Day 1.

Group Type: ACTIVE_COMPARATOR

Matched-Placebo for Tafenoquine

Intervention Type: DRUG

This intervention contains tafenoquine matched-placebo. Two tablets of this formulation will be administered orally with water as a single dose after a meal. Dose will be taken at least 3 hours after DHA-PQP.

Primaquine

Intervention Type: DRUG

This intervention is provided as over-encapsulated tablet containing 15 mg of primaquine. One capsule of this formulation will be administered orally with water as a single dose after a meal for 14 days. Dose will be taken at least 3 hours after DHA-PQP (Days 1, 2 and 3).

Dihydroartemisinin-piperaquine (DHA-PQP)

Intervention Type: DRUG

This formulation is provided as tablet containing 320 mg of piperaquine tetrasphosphate (as the tetrahydrate; PQP) and 40 mg dihydroartemisinin (DHA). This tablet will be administered orally as single dose for 3 days. For subjects weighing \<75 kg, 3 tablets will be administered per day. For subjects weighing \>=75 kg, 4 tablets will be administered per day. Dose will be taken at least 3 hours after last food intake. No food will be allowed for at least 3 hours after dosing.

ACT plus PQ (Rescue medication)

Intervention Type: DRUG

Subjects with relapse during the 180 day follow up period will be given an ACT plus PQ 0.5 mg/kg for 14 days as rescue medication.

PQ (End of study treatment)

Intervention Type: DRUG

Subjects who do not relapse during the study will receive PQ 0.5mg/kg for 14 days at the end of the study.

DHA-PQP alone (placebo arm)

Subjects will receive open label DHA-PQP, 3 or 4 tablets per day (according to body weight) from Day 1 to Day 3. They will receive double-blind matched-placebo for tafenoquine (TQ) on Day 1 and matched-placebo for primaquine (PQ) from Day 1 to Day 14.

Group Type: PLACEBO_COMPARATOR

Matched-Placebo for Tafenoquine

Intervention Type: DRUG

This intervention contains tafenoquine matched-placebo. Two tablets of this formulation will be administered orally with water as a single dose after a meal. Dose will be taken at least 3 hours after DHA-PQP.

Matched-Placebo for Primaquine

Intervention Type: DRUG

This intervention contains primaquine matched-placebo. One capsule of this formulation will be administered orally with water as a single dose after a meal for 14 days. Dose will be taken at least 3 hours after DHA-PQP (Days 1, 2 and 3).

Dihydroartemisinin-piperaquine (DHA-PQP)

Intervention Type: DRUG

This formulation is provided as tablet containing 320 mg of piperaquine tetrasphosphate (as the tetrahydrate; PQP) and 40 mg dihydroartemisinin (DHA). This tablet will be administered orally as single dose for 3 days. For subjects weighing \<75 kg, 3 tablets will be administered per day. For subjects weighing \>=75 kg, 4 tablets will be administered per day. Dose will be taken at least 3 hours after last food intake. No food will be allowed for at least 3 hours after dosing.

ACT plus PQ (Rescue medication)

Intervention Type: DRUG

Subjects with relapse during the 180 day follow up period will be given an ACT plus PQ 0.5 mg/kg for 14 days as rescue medication.

PQ (End of study treatment)

Intervention Type: DRUG

Subjects who do not relapse during the study will receive PQ 0.5mg/kg for 14 days at the end of the study.

Interventions

Tafenoquine

This intervention is provided as tablet containing 150 mg of tafenoquine. Two tablets of this formulation will be administered orally with water as a single dose after a meal. Dose will be taken at least 3 hours after DHA-PQP.

Intervention Type: DRUG

Matched-Placebo for Tafenoquine

This intervention contains tafenoquine matched-placebo. Two tablets of this formulation will be administered orally with water as a single dose after a meal. Dose will be taken at least 3 hours after DHA-PQP.

Intervention Type: DRUG

Primaquine

This intervention is provided as over-encapsulated tablet containing 15 mg of primaquine. One capsule of this formulation will be administered orally with water as a single dose after a meal for 14 days. Dose will be taken at least 3 hours after DHA-PQP (Days 1, 2 and 3).

Intervention Type: DRUG

Matched-Placebo for Primaquine

This intervention contains primaquine matched-placebo. One capsule of this formulation will be administered orally with water as a single dose after a meal for 14 days. Dose will be taken at least 3 hours after DHA-PQP (Days 1, 2 and 3).

Intervention Type: DRUG

Dihydroartemisinin-piperaquine (DHA-PQP)

This formulation is provided as tablet containing 320 mg of piperaquine tetrasphosphate (as the tetrahydrate; PQP) and 40 mg dihydroartemisinin (DHA). This tablet will be administered orally as single dose for 3 days. For subjects weighing \<75 kg, 3 tablets will be administered per day. For subjects weighing \>=75 kg, 4 tablets will be administered per day. Dose will be taken at least 3 hours after last food intake. No food will be allowed for at least 3 hours after dosing.

Intervention Type: DRUG

ACT plus PQ (Rescue medication)

Subjects with relapse during the 180 day follow up period will be given an ACT plus PQ 0.5 mg/kg for 14 days as rescue medication.

Intervention Type: DRUG

PQ (End of study treatment)

Subjects who do not relapse during the study will receive PQ 0.5mg/kg for 14 days at the end of the study.

Intervention Type: DRUG

Eligibility 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).

• Minimum Eligible Age: 18 Years
• Eligible Sex: MALE
• Accepts Healthy Volunteers: No

Sponsors

Medicines for Malaria Venture

OTHER

Sponsor Role: collaborator

GlaxoSmithKline

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

GSK Clinical Trials

Role: STUDY_DIRECTOR

GlaxoSmithKline

Locations

GSK Investigational Site

Jakarta, , Indonesia

Countries

Indonesia

References

Sutanto I, Soebandrio A, Ekawati LL, Chand K, Noviyanti R, Satyagraha AW, Subekti D, Santy YW, Crenna-Darusallam C, Instiaty I, Budiman W, Prasetya CB, Lardo S, Elyazar I, Duparc S, Cedar E, Rolfe K, Fernando D, Berni A, Jones S, Kleim JP, Fletcher K, Sharma H, Martin A, Taylor M, Goyal N, Green JA, Tan LK, Baird JK. Tafenoquine co-administered with dihydroartemisinin-piperaquine for the radical cure of Plasmodium vivax malaria (INSPECTOR): a randomised, placebo-controlled, efficacy and safety study. Lancet Infect Dis. 2023 Oct;23(10):1153-1163. doi: 10.1016/S1473-3099(23)00213-X. Epub 2023 May 23.

Reference Type: DERIVED

PMID: 37236221 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

200894

Identifier Type: -

Identifier Source: org_study_id