A Phase 2 Study to Evaluate Safety, Tolerability, And Virologic Efficacy of ARN-75039 For the Treatment of Lassa Fever in West Africa
试验速览
- 阶段
- 2 期
- 状态
- 暂停
- 入组人数
- 135
- 试验地点
- 4
- 主要终点
- Incidence of Treatment-Emergent Adverse Events (TEAEs) Grade ≥3
研究概览
简要总结
This multicenter, randomized, open-label Phase 2 clinical trial evaluates the safety, tolerability, and virologic efficacy of ARN-75039, a novel oral antiviral, for treating Lassa fever in hospitalized adults in West Africa. The study is conducted within the INTEGRATE platform and compares two oral dose regimens of ARN-75039 (100 mg BID and 50 mg BID) with intravenous ribavirin, the locally mandated standard of care.
Approximately 135 participants with RT-PCR-confirmed Lassa virus infection will be enrolled and randomized 1:1:1 to receive ARN-75039 high dose, ARN-75039 low dose, or ribavirin for 10 days, followed by safety and efficacy follow-up through Day 28. The primary objectives are to assess safety and tolerability and to evaluate antiviral activity, as measured by the change in slope of Lassa virus RT-PCR cycle threshold (Ct) values from Day 1 to Day 10, in participants with low baseline viral load Ct values. Secondary objectives include additional virologic, pharmacokinetic, and clinical outcome assessments, including time to viral clearance, symptom resolution, organ failure, and mortality.
ARN-75039 is a small-molecule viral entry inhibitor targeting the Lassa virus glycoprotein complex and has demonstrated potent antiviral activity and favorable safety and pharmacokinetic profiles in preclinical models and Phase 1 clinical studies. This study aims to inform dose selection and support further clinical development of ARN-75039 as a potential treatment for Lassa fever.
详细描述
This Phase 2, randomized, open-label, controlled clinical trial, conducted under the INTEGRATE platform, evaluates the safety, tolerability, antiviral activity, and pharmacokinetics of ARN-75039 in adults hospitalized with RT-PCR-confirmed Lassa fever. The trial is conducted at specialized treatment centers in West Africa that have established capacity for Lassa fever diagnosis, inpatient management, and pharmacovigilance. It operates under coordinated African and U.S. regulatory oversight.
Participants are randomized 1:1:1 to receive one of three interventions for a 10-day inpatient treatment period: a high-dose oral regimen of ARN-75039, a low-dose oral regimen of ARN-75039, or intravenous ribavirin administered according to the locally mandated "Irrua regimen." Randomization is stratified by Lassa virus lineage and baseline viral load, as measured by RT-PCR cycle threshold (Ct) values. All participants receive optimized supportive care consistent with INTEGRATE platform standards and local site capabilities.
ARN-75039 is a novel, orally administered small-molecule antiviral that inhibits viral entry by targeting the Lassa virus glycoprotein complex and blocking membrane fusion. The dose regimens evaluated in this study were selected based on preclinical efficacy data, translational pharmacology, and Phase 1 clinical studies demonstrating favorable safety, tolerability, and pharmacokinetic profiles. The study incorporates an initial loading phase followed by tapered twice-daily dosing to rapidly achieve and maintain plasma concentrations associated with antiviral activity while preserving tolerability.
The primary efficacy analysis focuses on the change in slope of Lassa virus RT-PCR Ct values between Day 1 and Day 10 in participants with low baseline Ct values, reflecting viral load dynamics during acute infection. Additional virologic assessments include time to first RT-PCR result below the lower limit of quantification, time to undetectable viral RNA, and longitudinal changes in Ct value across predefined time points. Lineage-specific and baseline viral load-stratified analyses are planned to characterize antiviral effects across circulating Lassa virus variants.
Safety assessments include continuous monitoring of treatment-emergent adverse events, serious adverse events, laboratory abnormalities, vital signs, and clinically significant changes in electrocardiograms and physical examinations. Adverse events are graded using standardized criteria and reviewed by an independent Data and Safety Monitoring Board operating under the INTEGRATE master protocol. Clinical outcome measures include mortality, organ failure, need for intensive care-level support, and time to symptom resolution and hospital discharge.
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
- None
盲法说明
This study is conducted without masking. Participants, care providers, investigators, and some outcomes assessors are aware of the treatment assignments. Viremia and PK assessors will be masked.
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Participants must meet all of the following criteria to be eligible for enrollment:
- •Age ≥ 18 years
- •Hospitalized with clinical disease consistent with Lassa fever
- •Positive plasma Lassa virus RT-PCR at screening
- •Requires hospitalization for Lassa fever per local clinical guidelines
- •Able to provide written informed consent, or consent provided by a legally authorized representative.
排除标准
- •Participants will be excluded if they meet any of the following criteria:
- •Pregnant (confirmed by positive urine pregnancy test in women of childbearing potential)
- •Receipt of specific drug therapy for Lassa fever (e.g., ribavirin, direct antivirals, or host-directed therapies including corticosteroids) within 15 days before enrollment
- •Prior vaccination against Lassa fever
- •History of severe gastrointestinal disease
- •History of chronic generalized pruritus
- •History of severe chronic liver disease
- •History of severe cardiac disorder
- •Sex and Reproductive Criteria
- •Women of childbearing potential must have a negative pregnancy test at screening
- •Breastfeeding is not permitted during the treatment period and early follow-up
- •Participants must agree to comply with protocol-defined contraception requirements
研究组 & 干预措施
Ribavirin intravenous (IV)
Standard of Care "Irrua regimen"
干预措施: Intravenous ribavirin (Drug)
ARN-75039: 100 mg maintenance (high oral dose)
ARN-75039 is an investigational oral antiviral agent administered as tablets. This high dose regimen includes a 300 mg initial dose and 200 second dose on day 1, followed by a 200 mg BID dose on day 2 and 100 mg BID days 3-10.
干预措施: ARN-75039 high (Drug)
ARN-75039: 50 mg maintenance (low oral dose)
ARN-75039 is an investigational oral antiviral agent administered as tablets. This high dose regimen includes a 150 mg initial dose and 100 second dose on day 1, followed by a 100 mg BID dose on day 2 and 50 mg BID days 3-10.
干预措施: ARN-75039 low (Drug)
结局指标
主要结局
Incidence of Treatment-Emergent Adverse Events (TEAEs) Grade ≥3
时间窗: Day 1 through Day 28
Type and frequency of treatment-emergent adverse events of Grade 3 or higher
Change in Viral Load Slope (RT-PCR Ct Values)
时间窗: Day 1 to Day 10
Change in slope of Lassa virus RT-PCR cycle threshold (Ct) values between Day 1 and Day 10 in participants with low baseline Ct values.
次要结局
- Peak C-Reactive Protein (CRP) Level(Day 1 to Day 28)
- Time to First Undetectable Lassa Virus RT-PCR Result(Day 1 to Day 28)
- Pharmacokinetic Outcome: ARN-75039 apparent clearance (CL/F)(Day 1 through Day 10)
- Time to First Organ Failure(Day 1 to Day 28)
- Use of Rescue Medication(Day 1 to Day 28)
- Time to Death(Day 1 to Day 28)
- Change in Viral Load Slope in Participants with Other Baseline Ct Values(Day 1 to Day 10)
- Change in RT-PCR Ct Values at Prespecified Timepoints (Change in Ct values. between Day 1 and Days 2, 3, 4, 6, 8, and 10).(Day 1 to Day 10)
- Time to First RT-PCR Result Below Lower Limit of Quantification (LLOQ)(Day 1 to Day 28)
- All-Cause Mortality(Day 1 to Day 28)
- Proportion of Participants With RT-PCR <LLOQ(Day 1 to Day 28)
- Proportion of Participants With Undetectable RT-PCR(Day 1 to Day 28)
- Estimated Baseline Lassa Virus RT-PCR Cycle Threshold (Ct) Value (Intercept) from Linear Mixed-Effects Model(Day 1)
- Estimated Rate of Change in Lassa Virus RT-PCR Ct Value (Ct Units per Day) from Linear Mixed-Effects Model.(Day 1 to Day 10)
- Change in Ct values stratified by Lassa lineage (Ct <30)(Day 1 to Day 10)
- Pharmacokinetic Outcome: ARN-75039 AUC₀-t(Day 1 through Day 10)
- Pharmacokinetic Outcome: ARN-75039 AUC₀-∞(Day 1 through Day 10)
- Pharmacokinetic Outcome: ARN-75039 Cmax(Day 1 through Day 10)
- Pharmacokinetic Outcome: ARN-75039 Ctrough (Cmin0-24hr)(Day 1 through Day 10)
- Pharmacokinetic Outcome: ARN-75039 Tmax(Day 1 through Day 10)
- Pharmacokinetic Outcome: t½(Day 1 through Day 10)
- Pharmacokinetic Outcome: ARN-75039 apparent volume of distribution (Vz/F)(Day 1 through Day 10)
- Association Between ARN-75039 Plasma Exposure (AUC₀-t) and Change in Lassa Virus RT-PCR Ct Value.(Day 1 to Day 10)
- Time to Resolution of ≥ Grade 2 TEAEs(Day 1 to Day 28)
- Incidence of AEs with Grade ≥3(Day 1 to Day 28)
- Incidence of Serious Adverse Events (SAEs)(Day 1 to Day 28)
- Trial Drug Interruption or Withdrawal(Day 1 to Day 28)
- New Onset Kidney Disease Improving Global Outcomes (KDIGO) Score ≥2(Day 1 to Day 28)
- New Onset Altered Consciousness or Seizure (ACVPU Scale)(Day 1 to Day 28)
- New Onset WHO Bleeding Scale Grade ≥2(Day 1 to Day 28)
- New Onset hemoglobin <8 g/dL(Day 1 to Day 28)
- New Onset AST or ALT ≥3× normal ULN for each(Day 1 to Day 28)
- Receipt of Advanced Supportive Care(Day 1 to Day 28)
- Exploratory Virologic Outcome: Emergence of Resistance-Associated Viral Mutations - Detection of new-onset resistance mutations via viral RNA sequencing.(Day 1 to Day 28)