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

NCT02802501 | Completed Phase 3 Results

• 1 other identifier: 200894
• Study Type: interventional
• Target: 150
• Locations: 1 country
• Sites: 1

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 In Indonesia, chloroquine has been replaced by artemisinin-based combination therapy (i.e. ACTs) due to widespread chloroquine resistance.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

Keywords

Safety; Artemisinin Combination Therapy; Efficacy; Tafenoquine; Superiority; Primaquine; Radical cure; Vivax; ACT; Plasmodium vivax malaria; Dihydroartemisinin-piperaquine

Outcome Measures

Primary Outcomes (1)

• Percentage of Participants With Relapse-free Efficacy at Six Months After Administration of Tafenoquine With DHA-PQP and DHA-PQP Alone

  A participant was considered to have demonstrated relapse-free efficacy at 6 months if: a) Participant had non-zero Plasmodium vivax (P.vivax) asexual parasite count at Baseline (Day 1), b) Participant demonstrated initial clearance of P.vivax parasitemia, c) Participant had no positive asexual P.vivax parasite count at any assessment prior to or on study Day 180 following initial parasite clearance, d) Participants did not take a concomitant medication with anti-malarial activity (excluding study treatment) at any point between Study Day 1 and their last parasite assessment, e) Participant was parasite-free at 6 months. The percentage of participants who were relapse-free at 6 months post dose has been presented.

  6 months post-dose

Secondary Outcomes (21)

• Percentage of Participants With Relapse-free Efficacy at Six Months After Administration of Tafenoquine With DHA-PQP and Primaquine+DHA-PQP

  6 months post-dose

• Percentage of Participants With Relapse-free Efficacy at Six Months After Administration of Primaquine With DHA-PQP and DHA-PQP Alone

  6 months post-dose

• Percentage of Participants With Relapse-free Efficacy at Four Months After Administration of Tafenoquine With DHA-PQP and DHA-PQP Alone

  4 months post-dose

• Time to Relapse of P. Vivax Malaria

  Up to Day 180

• Time to Fever Clearance

  Up to Day 7

Study Arms (3)

DHA-PQP plus tafenoquine 300 mg single dose

EXPERIMENTAL

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.

Drug: Tafenoquine; Drug: Matched-Placebo for Primaquine; Drug: Dihydroartemisinin-piperaquine (DHA-PQP); Drug: ACT plus PQ (Rescue medication); Drug: PQ (End of study treatment)

DHA-PQP plus primaquine 15 mg for 14 days

ACTIVE COMPARATOR

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.

Drug: Matched-Placebo for Tafenoquine; Drug: Primaquine; Drug: Dihydroartemisinin-piperaquine (DHA-PQP); Drug: ACT plus PQ (Rescue medication); Drug: PQ (End of study treatment)

DHA-PQP alone (placebo arm)

PLACEBO COMPARATOR

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.

Drug: Matched-Placebo for Tafenoquine; Drug: Matched-Placebo for Primaquine; Drug: Dihydroartemisinin-piperaquine (DHA-PQP); Drug: ACT plus PQ (Rescue medication); Drug: PQ (End of study treatment)

Interventions

Tafenoquine 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.

DHA-PQP plus tafenoquine 300 mg single dose

Matched-Placebo for Tafenoquine 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.

DHA-PQP alone (placebo arm); DHA-PQP plus primaquine 15 mg for 14 days

Primaquine 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).

DHA-PQP plus primaquine 15 mg for 14 days

Matched-Placebo for Primaquine 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).

DHA-PQP alone (placebo arm); DHA-PQP plus tafenoquine 300 mg single dose

Dihydroartemisinin-piperaquine (DHA-PQP) 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.

DHA-PQP alone (placebo arm); DHA-PQP plus primaquine 15 mg for 14 days; DHA-PQP plus tafenoquine 300 mg single dose

ACT plus PQ (Rescue medication) 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.

DHA-PQP alone (placebo arm); DHA-PQP plus primaquine 15 mg for 14 days; DHA-PQP plus tafenoquine 300 mg single dose

PQ (End of study treatment) 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); DHA-PQP plus primaquine 15 mg for 14 days; DHA-PQP plus tafenoquine 300 mg single dose

Eligibility Criteria

• Age: 18 Years+
• Sex: male
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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).

Sponsors & Collaborators

• GlaxoSmithKline: lead
• Medicines for Malaria Venture: collaborator

Study Sites (1)

GSK Investigational Site

Jakarta, 10430, Indonesia

Location

Related Publications (1)

• 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.

  PMID: 37236221 DERIVED

MeSH Terms

Conditions

Malaria, Vivax

Interventions

tafenoquine; Primaquine

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Aminoquinolines; Quinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

GSKClinicalSupportHD@gsk.com

866-435-7343

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 26, 2016
• First Posted: June 16, 2016
• Study Start: April 8, 2018
• Primary Completion: August 19, 2019
• Study Completion: August 19, 2019
• Last Updated: July 24, 2020
• Results First Posted: July 24, 2020

Record last verified: 2020-06

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: IPD will be made available within 6 months of publishing the results of the primary endpoints of the study.
• Access Criteria: Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted, when justified, for up to another 12 months.

Locations

ID (1)