A Randomized, Placebo-Controlled, Double-Blinded Trial of the Safety and Efficacy of Tecovirimat for the Treatment of Human Mpox Virus Disease
试验速览
- 阶段
- 3 期
- 状态
- 终止
- 入组人数
- 719
- 试验地点
- 108
- 主要终点
- Cumulative Proportion With Clinical Resolution by Day 29
研究概览
简要总结
The purpose of this study was to see if tecovirimat is safe and successful at treating mpox. The main questions were whether tecovirimat reduced time to lesion resolution and pain compared to placebo (no treatment).
详细描述
This phase 3, randomized, placebo-controlled, double-blind clinical trial evaluated the efficacy of tecovirimat for the treatment of mpox. Participants who had or were at higher risk for severe disease because of their age or medical history, were pregnant or breastfeeding, or were taking medications that could have decreased their exposure to tecovirimat were assigned to receive open-label tecovirimat for 14 days. All other participants were randomized 2:1 to receive either tecovirimat or placebo for 14 days.
Randomized participants who reported severe pain 5 days after randomization (on Day 6) or later or progressed to severe disease stopped blinded study treatment and started a 14-day course of open-label tecovirimat.
Participants self-monitored lesions daily through 28 days (Day 29) or resolution, whichever came first, and completed a daily pain scale and symptom diary. Study visits occurred weekly through 28 days (Day 29) and included safety and skin assessments and specimen collections. A final study visit occurred at 56 days (Day 57) to assess for recrudescence of infection (development of new lesions after initial resolution of disease).
Version 3 of the protocol gave participants the option to enroll and complete study visits remotely. Participants did not provide specimens at remote visits.
On November 26, 2024, the Data and Safety Monitoring Board (DSMB) recommended that the study close due to statistical futility. The study team and sponsor agreed with the DSMB's recommendation and the study closed to accrual on November 27, 2024. The primary analysis report forming the basis of the primary manuscript used data from follow-up visits occurring through October 23, 2024, the data cutoff for the November 2024 DSMB review (the primary completion date). Outcome measures submitted to clinicaltrials.gov were also based on data from follow-up visits occurring through October 23, 2024, and summaries of participant flow, baseline characteristics, and adverse events submitted to clinicaltrials.gov were based on data from follow-up visits occurring through February 22, 2025 (the study completion date).
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
- Double (Participant, Investigator)
入排标准
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •(All participants; Arms A, B, and C):
- •Laboratory-confirmed or presumptive human mpox virus (HMPXV) infection.
- •HMPXV illness of <14 days duration immediately prior to study entry.
- •At least one active (not yet scabbed) skin lesion, mouth lesion, or proctitis with or without visible ulcers.
- •Non-pregnant people of reproductive potential must agree to use at least one effective means of contraception when engaging in sexual activities that can result in pregnancy, from the time of enrollment through the end of study participation.
- •Ability to provide informed consent (for those above the legal age of consent and those providing consent for minors) and assent (for those who have reached the age of assent, but not the legal age of consent), as allowed by local ethics committees.
- •For participants to be enrolled/followed remotely, ability and willingness to participate in remote telehealth assessments (i.e., video visits).
- •Additional Inclusion Criteria for Arms A and B:
- •1. Age ≥18 years at the time of study entry.
- •Additional Inclusion Criteria for Arm C:
- •Participants who meet the above entry criteria who also meet any of the following criteria will be registered to Arm C.
- •Age <18 years at the time of study entry.
- •Those with severe HMPXV disease defined as having one or more of the following conditions:
- •Suspected or confirmed ocular involvement
- •Facial lesions on the malar, nose, or eyelid region
- •Confluent facial lesions
- •Hospitalization due to HMPXV infection or its complications
- •Lesions that require surgical intervention including debridement, urinary catheterization or sigmoidoscopy, or lesions extending below the dermis.
- •Those with or without severe disease and with one or more of the following:
- •Severe immunosuppression
- •Active skin conditions placing the person at higher risk for disseminated infection
- •Breastfeeding
- •Pregnancy
- •Receipt of potent inducers
- •Current or planned use of another investigational drug at any point during tecovirimat/placebo dosing that would be predicted to have a significant drug-drug interaction with tecovirimat therapeutics.
排除标准
- •(All participants; Arms A, B, and C):
- •Prior or concomitant receipt of tecovirimat (e.g., under an alternative access mechanism.
- •Planned initiation of intramuscular cabotegravir/rilpivirine during study drug administration or for two weeks following completion of study drug administration. Participants who were stable on long-acting intramuscular cabotegravir/rilpivirine were allowed to enroll.
- •Participants who, in the judgement of the investigator, will be at significantly increased risk as a result of participation in the study.
- •Participants who require intravenous dosing of tecovirimat.
研究组 & 干预措施
Tecovirimat (Arm A)
Participants randomized to tecovirimat.
干预措施: Tecovirimat Oral Capsule (Drug)
Placebo (Arm B)
Participants randomized to placebo.
干预措施: Placebo for Tecovirimat (Drug)
Open-Label Tecovirimat (Arm C)
Participants assigned to open-label tecovirimat.
干预措施: Tecovirimat Oral Capsule (Open Label) (Drug)
结局指标
主要结局
Cumulative Proportion With Clinical Resolution by Day 29
时间窗: From study entry through 28 days of follow-up (i.e., Day 29)
Clinical resolution defined as all skin lesions scabbed, desquamated, or healed, and visible mucosal lesions healed. The cumulative proportion with clinical resolution was estimated using the Aalen-Johansen estimator. The treatment effect, i.e., the subdistribution hazard ratio of tecovirimat relative to placebo, was estimated using the Fine and Gray subdistribution proportional hazards model. All-cause death, start of open-label tecovirimat due to disease progression or severe pain, and use of other antivirals with expected activity against mpox were treated as competing events. Follow-up time was censored at last contact. Includes data from follow-up visits occurring through October 23, 2024.
次要结局
- Mean Time-weighted Average of Pain Intensity Difference Over 5 Days of Treatment(Through 5 days of treatment (i.e., Treatment Day 6))
- Mean Time-weighted Average of Pain Intensity Difference Over 14 Days of Treatment(Through 14 days of treatment (i.e., Treatment Day 15))
- Number of Participants Who Developed Severe HMPXV Disease(From study entry through 56 days of follow-up (i.e., Day 57))
- Number of Participants With HMPXV DNA Below Limit of Detection in Skin Lesions(Baseline, Days 8, 15, 22, 29, and 57)
- Number of Participants With HMPXV DNA Below Limit of Detection in Oropharynx(Baseline, Days 8, 15, 22, 29, and 57)
- Number of Participants With HMPXV DNA Below Limit of Detection in Rectum(Baseline, Days 8, 15, 22, 29, and 57)
- Number of Participants With HMPXV DNA Below Limit of Detection in Blood(Baseline, Days 8, 15, 22, 29, and 57)
- Number of Participants With HMPXV DNA Below Limit of Detection in Vaginal Swabs(Baseline, Days 8, 15, 22, 29, and 57)
- Cumulative Proportion With Complete Lesion Healing by Day 29(From study entry through 28 days of follow-up (i.e., Day 29))
- Number of Participants With no Missed Doses (of Last Three Prescribed Doses)(Days 8 and 15)
- Median Change From Baseline in EuroQol (EQ) Visual Analogue Scale (VAS) Score(Days 8, 15, and 29)
- Number of Participants Who Reported Each Level of Response on Mobility Dimension of EuroQol EQ-5D-5L Questionnaire(Baseline, Days 8, 15, and 29)
- Number of Participants Who Reported Each Level of Response on Self-Care Dimension of EuroQol EQ-5D-5L Questionnaire(Baseline, Days 8, 15, and 29)
- Number of Participants Who Reported Each Level of Response on Usual Activities Dimension of EuroQol EQ-5D-5L Questionnaire(Baseline, Days 8, 15, and 29)
- Number of Participants Who Reported Each Level of Response on Pain/Discomfort Dimension of EuroQol EQ-5D-5L Questionnaire(Baseline, Days 8, 15, and 29)
- Number of Participants Who Reported Each Level of Response on Anxiety/Depression Dimension of EuroQol EQ-5D-5L Questionnaire(Baseline, Days 8, 15, and 29)
- Proportion of Participants With Grade 3 or Greater Treatment-emergent Adverse Event(Through 56 days of follow-up (i.e., Day 57))
- Number of Participants Who Died From Any Cause(Through 56 days of follow-up (i.e., Day 57))
- Tecovirimat Concentrations in Children Less Than 18 Years of Age(On Day 8, blood samples were collected pre-dose and at 1, 2, 3, 4, 6, 8, and 10 hours post-dose. On Day 15, a single blood sample was collected within 4 hours of study product administration.)