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
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 150
- 试验地点
- 1
- 主要终点
- Percentage of Participants With Relapse-free Efficacy at Six Months After Administration of Tafenoquine With DHA-PQP and DHA-PQP Alone
研究概览
简要总结
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 In Indonesia, chloroquine has been replaced by artemisinin-based combination therapy (i.e. ACTs) due to widespread chloroquine resistance.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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- Male
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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).
研究组 & 干预措施
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.
干预措施: Tafenoquine (Drug)
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.
干预措施: Matched-Placebo for Primaquine (Drug)
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.
干预措施: Dihydroartemisinin-piperaquine (DHA-PQP) (Drug)
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.
干预措施: ACT plus PQ (Rescue medication) (Drug)
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.
干预措施: PQ (End of study treatment) (Drug)
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.
干预措施: Matched-Placebo for Tafenoquine (Drug)
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.
干预措施: Primaquine (Drug)
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.
干预措施: Dihydroartemisinin-piperaquine (DHA-PQP) (Drug)
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.
干预措施: ACT plus PQ (Rescue medication) (Drug)
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.
干预措施: PQ (End of study treatment) (Drug)
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.
干预措施: Matched-Placebo for Tafenoquine (Drug)
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.
干预措施: Matched-Placebo for Primaquine (Drug)
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.
干预措施: Dihydroartemisinin-piperaquine (DHA-PQP) (Drug)
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.
干预措施: ACT plus PQ (Rescue medication) (Drug)
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.
干预措施: PQ (End of study treatment) (Drug)
结局指标
主要结局
Percentage of Participants With Relapse-free Efficacy at Six Months After Administration of Tafenoquine With DHA-PQP and DHA-PQP Alone
时间窗: 6 months post-dose
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.
次要结局
- Time to Fever Clearance(Up to Day 7)
- Number of Participants With Hematology Values Outside Clinical Concern Range(Up to Day 120)
- 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)
- Number of Participants With Electrocardiogram (ECG) Values Outside Clinical Concern Range-QT Interval Corrected Using Fredericia's Formula (QTcF)(Up to Day 28)
- Number of Participants With Recrudescence(Up to Day 14)
- Number of Participants With Any Adverse Events (AEs) and Serious Adverse Events (SAEs) During the Double-blind Treatment Phase(Up to Day 180)
- Change From Baseline in QT Interval Corrected by Fridericia's Formula (QTcF)(Baseline (Day 1), Day 3: 4 hours post DHA-PQP dose, Days 7 and 28)
- Change From Baseline in Methemoglobin/ Total Hemoglobin(Baseline (Day 1) and Days 2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,18,20,21,22,24,26,28 and 60)
- Oral Clearance (CL/F) of Tafenoquine When Co-administered With DHA-PQP(Up to Day 60)
- Volume of Distribution (V/F) of Tafenoquine When Co-administered With DHA-PQP(Up to Day 60)
- Time to Parasite Clearance(Up to Day 8)
- Number of Participants With Worst Case Pulse Rate Results Relative to Normal Range Post-Baseline Relative to Baseline(Baseline (Day 1) and up to Day 180)
- Number of Participants With Worst Case Respiratory Rate Results Relative to Normal Range Post-Baseline Relative to Baseline(Baseline (Day 1) and up to Day 180)
- Number of Participants With Gastrointestinal AEs(Up to Day 180)
- Number of Participants With Protocol-defined SAE (Hemoglobin Drop)(Days 3, 5, 7, and 14)
- Number of Participants With Chemistry Values Outside Clinical Concern Range(Up to Day 120)
- Number of Participants With Worst Case Body Temperature Results Relative to Normal Range Post-Baseline Relative to Baseline(Baseline (Day 1) and up to Day 180)
- Number of Participants With Worst Case Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) Results Relative to Normal Range Post-Baseline Relative to Baseline(Baseline (Day 1) and up to Day 180)