MPOX
Conditions
Keywords
HMPXV
Brief summary
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).
Detailed description
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).
Interventions
* Participants weighing 25 kg to less than 40 kg - Tecovirimat 400 mg every 12 hours for 14 days * Participants weighing 40 kg to less than 120 kg - Tecovirimat 600 mg every 12 hours for 14 days * Participants weighing 120 kg and over - Tecovirimat 600 mg every 8 hours for 14 days
DRUGPlacebo for Tecovirimat
* Participants weighing 25 kg to less than 40 kg - Placebo for Tecovirimat 400 mg every 12 hours for 14 days * Participants weighing 40 kg to less than 120 kg - Placebo for Tecovirimat 600 mg every 12 hours for 14 days * Participants weighing 120 kg and over - Placebo for Tecovirimat 600 mg every 8 hours for 14 days
DRUGTecovirimat Oral Capsule (Open Label)
* Participants weighing \<3 kg - Tecovirimat 33.3 mg every 12 hours for 14 days * Participants weighing 3 kg to less than 6 kg- Tecovirimat 50 mg every 12 hours for 14 days * Participants weighing 6 kg to less than 13 kg - Tecovirimat 100 mg every 12 hours for 14 days * Participants weighing 13 kg to less than 25 kg - Tecovirimat 200 mg every 12 hours for 14 days * Participants weighing 25 kg to less than 40 kg - Tecovirimat 400 mg every 12 hours for 14 days * Participants weighing 40 kg to less than 120 kg - Tecovirimat 600 mg every 12 hours for 14 days * Participants weighing 120 kg and over - Tecovirimat 600 mg every 8 hours for 14 days
Sponsors
National Institute of Allergy and Infectious Diseases (NIAID)
SIGA Technologies
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
Inclusion criteria
(All participants; Arms A, B, and C): 1. Laboratory-confirmed or presumptive human mpox virus (HMPXV) infection. 2. HMPXV illness of \<14 days duration immediately prior to study entry. 3. At least one active (not yet scabbed) skin lesion, mouth lesion, or proctitis with or without visible ulcers. 4. 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. 5. 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. 6. 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. 1. Age \<18 years at the time of study entry. 2. 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.
Exclusion criteria
(All participants; Arms A, B, and C): 1. Prior or concomitant receipt of tecovirimat (e.g., under an alternative access mechanism. 2. 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. 3. Participants who, in the judgement of the investigator, will be at significantly increased risk as a result of participation in the study. 4. Participants who require intravenous dosing of tecovirimat.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cumulative Proportion With Clinical Resolution by Day 29 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Time-weighted Average of Pain Intensity Difference Over 5 Days of Treatment | Through 5 days of treatment (i.e., Treatment Day 6) | Pain was measured on 11-point numerical rating scale (NRS) where 0 = no pain and 10 = worst possible pain. Pain intensity difference at ith day of treatment (i = 2, ..., 6) calculated as NRS pain score at baseline (last available pre-treatment) minus NRS pain score on ith day of treatment Time-weighted average of pain intensity difference over 5 days of treatment was a weighted average of the pain intensity difference from treatment day 2 to treatment day 6, where the weights were calculated as the duration in days between the ith day of treatment and the day of the previous measurement. The lowest possible value that this could have been was -10, which would have indicated an increase in pain by 10 points on average over 5 days of treatment. The highest possible value that this could have been was +10, which would have indicated a decrease in pain by 10 points on average over 5 days of treatment. Includes data from follow-up visits occurring through October 23, 2024. |
| Mean Time-weighted Average of Pain Intensity Difference Over 14 Days of Treatment | Through 14 days of treatment (i.e., Treatment Day 15) | Pain was measured on 11-point numerical rating scale (NRS) where 0 = no pain and 10 = worst possible pain. Pain intensity difference at ith day of treatment (i = 2, ..., 15) calculated as NRS pain score at baseline (last available pre-treatment) minus NRS pain score on ith day of treatment Time-weighted average of pain intensity difference over 14 days of treatment was a weighted average of the pain intensity difference from treatment day 2 to treatment day 15, where the weights were calculated as the duration in days between the ith day of treatment and the day of the previous measurement. The lowest possible value that this could have been was -10, which would have indicated an increase in pain by 10 points on average over 5 days of treatment. The highest possible value that this could have been was +10, which would have indicated a decrease in pain by 10 points on average over 5 days of treatment. Includes data from follow-up visits occurring through October 23, 2024. |
| Number of Participants Who Developed Severe HMPXV Disease | From study entry through 56 days of follow-up (i.e., Day 57) | Severe HMPXV disease was defined as 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, or lesions that required surgical intervention including debridement, urinary catheterization, or sigmoidoscopy, or extended below the dermis. |
| Number of Participants With HMPXV DNA Below Limit of Detection in Skin Lesions | Baseline, Days 8, 15, 22, 29, and 57 | HMPXV DNA was measured as detected or below limit of detection. Includes data from follow-up visits occurring through October 23, 2024. |
| Number of Participants With HMPXV DNA Below Limit of Detection in Oropharynx | Baseline, Days 8, 15, 22, 29, and 57 | HMPXV DNA was measured as detected or below limit of detection. Includes data from follow-up visits occurring through October 23, 2024. |
| Number of Participants With HMPXV DNA Below Limit of Detection in Rectum | Baseline, Days 8, 15, 22, 29, and 57 | HMPXV DNA was measured as detected or below limit of detection. Includes data from follow-up visits occurring through October 23, 2024. |
| Number of Participants With HMPXV DNA Below Limit of Detection in Blood | Baseline, Days 8, 15, 22, 29, and 57 | HMPXV DNA measured as detected or below limit of detection. Includes data from follow-up visits occurring through October 23, 2024. |
| Number of Participants With HMPXV DNA Below Limit of Detection in Vaginal Swabs | Baseline, Days 8, 15, 22, 29, and 57 | HMPXV DNA measured as detected or below limit of detection. Includes data from follow-up visits occurring through October 23, 2024. |
| Cumulative Proportion With Complete Lesion Healing by Day 29 | From study entry through 28 days of follow-up (i.e., Day 29) | Complete lesion healing was defined as all lesions re-epithelialized. The cumulative incidence of complete lesion healing 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. |
| Number of Participants With no Missed Doses (of Last Three Prescribed Doses) | Days 8 and 15 | Since the adherence assessment was removed from protocol version 3.0, the number of participants with adherence data was expected to be small and no formal statistical comparison between treatment arms was done. Includes data from follow-up visits occurring through October 23, 2024. |
| Median Change From Baseline in EuroQol (EQ) Visual Analogue Scale (VAS) Score | Days 8, 15, and 29 | Participants' self-rated health measured on a visual analogue scale (VAS) where 0 = "The worst health you can imagine" and 100 = "The best health you can imagine." Change in EQ VAS score at each timepoint calculated as absolute change from baseline (last available pre-treatment). Includes data from follow-up visits occurring through October 23, 2024. |
| Number of Participants Who Reported Each Level of Response on Mobility Dimension of EuroQol EQ-5D-5L Questionnaire | Baseline, Days 8, 15, and 29 | Participants' self-reported health state within mobility dimension of the five-dimension EuroQol EQ-5D-5L questionnaire. Participants were asked to indicate their health state by selecting the most appropriate response level for them from five ordinal response levels: no problems (1), slight problems (2), moderate problems (3), severe problems (4), and extreme problems (5). Results were dichotomized into no problems (level 1) and any problems (levels 2, 3, 4, and 5 combined) for reporting and analysis. Includes data from follow-up visits occurring through October 23, 2024. |
| 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 | Participants' self-reported health state within self-care dimension of five-dimension EuroQol EQ-5D-5L questionnaire. Participants were asked to indicate their health state by selecting the most appropriate response level for them from five ordinal response levels: no problems (1), slight problems (2), moderate problems (3), severe problems (4), and extreme problems (5). Results were dichotomized into no problems (level 1) and any problems (levels 2, 3, 4, and 5 combined) for reporting and analysis. Includes data from follow-up visits occurring through October 23, 2024. |
| 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 | Participants' self-reported health state within usual activities dimension of five-dimension EuroQol EQ-5D-5L questionnaire. Participants were asked to indicate their health state by selecting the most appropriate response level for them from five ordinal response levels: no problems (1), slight problems (2), moderate problems (3), severe problems (4), and extreme problems (5). Results were dichotomized into no problems (level 1) and any problems (levels 2, 3, 4, and 5 combined) for reporting and analysis. Includes data from follow-up visits occurring through October 23, 2024. |
| 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 | Participants' self-reported health state within pain/discomfort dimension of five-dimension EuroQol EQ-5D-5L questionnaire. Participants were asked to indicate their health state by selecting the most appropriate response level for them from five ordinal response levels: no problems (1), slight problems (2), moderate problems (3), severe problems (4), and extreme problems (5). Results were dichotomized into no problems (level 1) and any problems (levels 2, 3, 4, and 5 combined) for reporting and analysis. Includes data from follow-up visits occurring through October 23, 2024. |
| 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 | Participants' self-reported health state within anxiety/depression dimension of five-dimension EuroQol EQ-5D-5L questionnaire. Participants were asked to indicate their health state by selecting the most appropriate response level for them from five ordinal response levels: no problems (1), slight problems (2), moderate problems (3), severe problems (4), and extreme problems (5). Results were dichotomized into no problems (level 1) and any problems (levels 2, 3, 4, and 5 combined) for reporting and analysis. Includes data from follow-up visits occurring through October 23, 2024. |
| Proportion of Participants With Grade 3 or Greater Treatment-emergent Adverse Event | Through 56 days of follow-up (i.e., Day 57) | Study protocol required reporting of all adverse events (AEs) that (1) led to a change in study treatment regardless of grade, (2) met the serious AE (SAE) or Expedited AE (EAE) reporting requirement, and (3) were Grade 3 or greater. AEs were graded using the DAIDS AE Grading Table (Version 2.1). Severity Grade: 1 = Mild, 2 = Moderate, 3 = Severe, 4 = Life-Threatening, 5 = Death Includes data from follow-up visits occurring through October 23, 2024. |
| Number of Participants Who Died From Any Cause | Through 56 days of follow-up (i.e., Day 57) | Includes data from follow-up visits occurring through October 23, 2024. |
| 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. | Plasma tecovirimat concentrations were quantified using validated liquid chromatography tandem mass spectrometry (LC-MS/MS) methods. The lower limit of quantification was 5.0 ng/mL. |
Countries
Argentina, Brazil, Mexico, Peru, Thailand, United States
Contacts
STUDY_CHAIRTimothy Wilkin, MD, MPH
Cornell
Participant flow
Recruitment details
Participants were enrolled at 58 clinical research sites in 7 countries (United States, Peru, Mexico, Thailand, Argentina, Japan, and Brazil) from September 2022 to November 2024.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 34 years |
| Age, Customized <40 years | 511 Participants |
| Age, Customized >=40 years | 207 Participants |
| Breastfeeding No | 147 Participants |
| Breastfeeding Yes | 0 Participants |
| Days from Symptom Onset, Categorical <=5 days | 40 Participants |
| Days from Symptom Onset, Categorical >5 days | 212 Participants |
| Days from Symptom Onset, Continuous | 8 days |
| Ethnicity (NIH/OMB) Hispanic or Latino | 330 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 143 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 13 Participants |
| HIV Status Living with HIV | 134 Participants |
| HIV Status No test results available | 4 Participants |
| HIV Status Not living with HIV | 100 Participants |
| HIV Status Probably living with HIV, based on best available information | 1 Participants |
| HIV Status Probably not living with HIV, based on best available information | 6 Participants |
| Number of Lesions, Categorical <10 | 43 Participants |
| Number of Lesions, Categorical >100 | 1 Participants |
| Number of Lesions, Categorical 10-100 | 64 Participants |
| Number of Lesions, Continuous | 8 lesions |
| Pain Level, Categorical Mild (0-3) | 60 Participants |
| Pain Level, Categorical Moderate (4-6) | 77 Participants |
| Pain Level, Categorical Severe (7-10) | 287 Participants |
| Pain Level, Continuous | 5 score on a scale |
| Pregnant No | 280 Participants |
| Pregnant Yes | 1 Participants |
| Prior Receipt of Tecovirimat No | 281 Participants |
| Prior Receipt of Tecovirimat Yes | 0 Participants |
| Proctitis No | 188 Participants |
| Proctitis Yes | 102 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 4 Participants |
| Race/Ethnicity, Customized Asian | 47 Participants |
| Race/Ethnicity, Customized Black or African American | 115 Participants |
| Race/Ethnicity, Customized Multiple | 7 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race/Ethnicity, Customized Other | 11 Participants |
| Race/Ethnicity, Customized Unknown | 94 Participants |
| Race/Ethnicity, Customized White | 149 Participants |
| Receipt of >=1 Dose of Smallpox/Mpox Vaccine No | 581 Participants |
| Receipt of >=1 Dose of Smallpox/Mpox Vaccine Yes | 137 Participants |
| Region of Enrollment Argentina | 2 Participants |
| Region of Enrollment Brazil | 0 Participants |
| Region of Enrollment Japan | 2 Participants |
| Region of Enrollment Mexico | 7 Participants |
| Region of Enrollment Peru | 7 Participants |
| Region of Enrollment Thailand | 4 Participants |
| Region of Enrollment United States | 595 Participants |
| Sex: Female, Male Female | 21 Participants |
| Sex: Female, Male Male | 697 Participants |
| Sex/Gender, Customized Cisgender | 141 Participants |
| Sex/Gender, Customized Transgender spectrum | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 267 | 0 / 23 | 0 / 132 | 0 / 13 | 0 / 281 |
| other Total, other adverse events | 7 / 267 | 12 / 23 | 4 / 132 | 9 / 13 | 14 / 281 |
| serious Total, serious adverse events | 4 / 267 | 2 / 23 | 0 / 132 | 2 / 13 | 14 / 281 |
Outcome results
None listed