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Tecovirimat for Clade I MPXV Infection in the Democratic Republic of Congo. BACKGROUND: Tecovirimat is available for the treatment of mpox (formerly known as monkeypox) in Europe and the United States, on the basis of findings from efficacy studies in animals and safety evaluations in healthy humans. Evidence from randomized, controlled trials of safety and efficacy in patients with mpox is lacking. METHODS: We conducted a double-blind, randomized, placebo-controlled trial of tecovirimat in patients with mpox in the Democratic Republic of Congo (DRC). Patients with at least one mpox skin lesion and positive polymerase-chain-reaction results for clade I MPXV were assigned in a 1:1 ratio to receive tecovirimat or placebo. All patients received supportive care. The primary end point was resolution of mpox lesions, measured in number of days after randomization. Safety was also assessed. RESULTS: From October 7, 2022, through July 9, 2024, a total of 597 patients underwent randomization - 295 to receive tecovirimat and 302 to receive placebo. The median time from randomization to lesion resolution was 7 days with tecovirimat and 8 days with placebo; the competing-risks hazard ratio for lesion resolution was 1.13 (95% confidence interval [CI], 0.97 to 1.31; P = 0.14). Results were similar whether patients began the trial regimen within 7 days after the reported onset of symptoms (competing-risks hazard ratio, 1.16; 95% CI, 0.98 to 1.37) or more than 7 days after onset (competing-risks hazard ratio, 1.00; 95% CI, 0.71 to 1.40). Overall mortality was 1.7%, which was lower than the case fatality rate of 4.6% reported in the DRC in 2023. At 14 days, the percentages of patients who had blood, lesion, and oropharyngeal samples negative for MPXV by PCR were similar in the two groups. Adverse events occurred in 72.9% of the patients in the tecovirimat group and 70.5% of those in the placebo group, and serious adverse events were reported in 5.1% and 5.0%, respectively. CONCLUSIONS: Tecovirimat did not reduce the number of days to lesion resolution in patients with mpox caused by clade I MPXV. No safety concerns were identified. (Funded by the National Institute of Allergy and Infectious Diseases and others; PALM007 ClinicalTrials.gov number, NCT05559099.).

PALM007 was a double-blind, randomized controlled trial comparing 14 days of oral tecovirimat to placebo for mpox treatment. Patients with ≥1 mpox skin lesion and a positive MPXV-PCR from blood, oropharynx, or skin lesion sample were eligible, including all ages and pregnant women. Patients were excluded if they weighed <3 kg, had severe anemia (hemoglobin <7 g/dL), or were currently using (or planning to use) meglitinide or midazolam. All patients provided written informed consent. Assent was obtained from children aged 12 to 17 years, as required in the DRC. Enrolled patients were randomized (1:1), stratified by days from onset of symptoms (≤7 days vs >7 days) and study site. Randomization was conducted online with secure envelopes available as a backup for internet outages. Unblinded pharmacists performed randomization and prepared medications in a restricted-access pharmacy and had no contact with patients. Days to resolution of mpox lesions, defined as the first day all skin lesions were scabbed or desquamated (i.e., “resolved”), was the primary endpoint based on analyses of data from Pittman et al.12 Mucosal lesions were not included in the primary endpoint. All patients were hospitalized for 14 days of tecovirimat period, regardless of lesion status, and then discharged when lesions resolved and two consecutive blood MPXV-PCRs were negative. Patients attended a follow-up visit at 28 days with an optional visit at 58 days. Full details of study design can be seen in the protocol at nejm.org.

ospitalized for 14 days of tecovirimat period, regardless of lesion status, and then discharged when lesions resolved and two consecutive blood MPXV-PCRs were negative. Patients attended a follow-up visit at 28 days with an optional visit at 58 days. Full details of study design can be seen in the protocol at nejm.org. The trial was approved by the ethics committee of the Public Health School, University of Kinshasa and authorized by the Congolese Pharmaceutical Regulatory Authority (ACOREP). An independent data and safety monitoring board oversaw the study. The protocol was conducted in compliance with ICH GCP-E6. The study was conducted at Tunda and Kole General Reference Hospitals in Maniema and Sankuru Provinces. Local staff were trained, with oversight provided by INRB. Kinshasa-based staff rotated between sites regularly, with two-month site rotations and interim rest periods, to ensure across-site standardization. Patients were evaluated daily throughout hospitalization for mpox-related signs and symptoms, complications, and laboratory abnormalities by site clinicians. Malnutrition status (severe acute, moderate acute, or none) was assessed at baseline and managed daily throughout hospitalization (Table S2) by site clinicians and nutritionists.

aluated daily throughout hospitalization for mpox-related signs and symptoms, complications, and laboratory abnormalities by site clinicians. Malnutrition status (severe acute, moderate acute, or none) was assessed at baseline and managed daily throughout hospitalization (Table S2) by site clinicians and nutritionists. All patients received supportive care including symptom relief, nutritional support, skin care, and oropharyngeal care. When indicated, intravenous fluid, correction of hypoglycemia and electrolyte abnormalities, blood transfusion, antimalarials, broad spectrum antibiotics and antifungal treatment was provided. All participants not requiring treatment with broader antibiotics received prophylactic treatment with cloxacillin. Tecovirimat dosing was weight-based per investigator brochure (see Protocol). Patients weighing <13kg required fractional capsule dosing not covered under approved labeling. Patients received 3 meals/day and were evaluated daily by a study nutritionists to ensure caloric intake of ≥600 calories of high-fat food before product administration. Psychological support was provided to all participants throughout the study. A social mobilization and communication team engaged local communities to raise awareness about mpox, clinical research, and address rumors. Lesions were assessed daily by a dermatologist or trained clinician until resolution. Whole-body unresolved lesion counts were performed at baseline and classified according to a modified WHO lesion-count score (Table S1)13.

Psychological support was provided to all participants throughout the study. A social mobilization and communication team engaged local communities to raise awareness about mpox, clinical research, and address rumors. Lesions were assessed daily by a dermatologist or trained clinician until resolution. Whole-body unresolved lesion counts were performed at baseline and classified according to a modified WHO lesion-count score (Table S1)13. During the study, some patients developed new lesions after initial resolution. An optional visit was added to capture recrudescent disease, with “confirmed” recrudescence defined as, “new skin lesions consistent with mpox and MPXV PCR-positive skin swab or blood.” Cases without confirmatory skin or blood PCR were deemed probable recrudescent cases. A blinded primary endpoint adjudication committee determined status. Real-time PCR testing for MPXV in blood and oropharyngeal samples occurred every-other day until two consecutive-negative results or discharge. Lesion PCR was performed every-other day until lesion resolution. At each site, MPXV nucleic acid was detected using the RADI platform (KH Medical) MPOX Detection Kit with specific fluorescent channels for Clade I, Clade II, and generic orthopoxvirus. RT-PCR cycle threshold values ≤40 defined positive results, per manufacturer guidelines. Samples were stored for MPXV sequencing.

ion. At each site, MPXV nucleic acid was detected using the RADI platform (KH Medical) MPOX Detection Kit with specific fluorescent channels for Clade I, Clade II, and generic orthopoxvirus. RT-PCR cycle threshold values ≤40 defined positive results, per manufacturer guidelines. Samples were stored for MPXV sequencing. Details about point-of-care clinical laboratory testing and pharmacokinetic (PK) processing are provided in the supplement. Rapid-diagnostic testing for malaria was conducted at baseline. Pregnancy status was determined in all females of childbearing age. HIV-1 serologic testing was performed retrospectively. Prior to dosing on visit-day 7, PK analyses were obtained to capture steady-state concentration using a validated HPLC-MS/MS method14. The target effect threshold of ≥169 ng/mL was based on non-human primate studies15. Adverse events (AEs) were assessed daily from enrollment through discharge and at follow-up visits. See protocol for grading criteria. All pregnancy outcomes were documented.

Prior to dosing on visit-day 7, PK analyses were obtained to capture steady-state concentration using a validated HPLC-MS/MS method14. The target effect threshold of ≥169 ng/mL was based on non-human primate studies15. Adverse events (AEs) were assessed daily from enrollment through discharge and at follow-up visits. See protocol for grading criteria. All pregnancy outcomes were documented. The primary analysis was based on the intent-to-treat population, evaluating differences in days to lesion resolution, based on Gray’s test of the competing-risk (“subdistribution”) hazard ratio (crHR)16 to account for death as a competing event, stratified by onset of symptoms (≤7 vs >7 days). Given the low mortality, results from the Fine-Gray and Cox proportional hazards models (with deaths censored at 28 days) are similar.17 Cox models and Kaplan-Meier estimates are additionally reported for the primary analysis (and exclusively reported for others). When applicable, censoring was applied on the confirmed recrudescence day. Longitudinal analyses of virologic results included last-observation-carried-forward and imputation of skin-lesion PCR values as negative after lesion resolution when PCR-testing stopped.

e primary analysis (and exclusively reported for others). When applicable, censoring was applied on the confirmed recrudescence day. Longitudinal analyses of virologic results included last-observation-carried-forward and imputation of skin-lesion PCR values as negative after lesion resolution when PCR-testing stopped. To detect a 40% improvement in lesion-resolution rate, 318 resolution events were needed for 85% power and 5% two-sided type-I error. As a result of the unexpectedly high influx of patients, the sample size was increased to 550 resolution events, without knowledge of interim data. See Supplement for statistical analysis plans, which includes pre-specified secondary and subgroup analyses, and interim monitoring procedures. A post-hoc analysis adjusted for site-specific imbalances in disease severity and treatment assignment. (Supplement)

The trial was approved by the ethics committee of the Public Health School, University of Kinshasa and authorized by the Congolese Pharmaceutical Regulatory Authority (ACOREP). An independent data and safety monitoring board oversaw the study. The protocol was conducted in compliance with ICH GCP-E6. The study was conducted at Tunda and Kole General Reference Hospitals in Maniema and Sankuru Provinces. Local staff were trained, with oversight provided by INRB. Kinshasa-based staff rotated between sites regularly, with two-month site rotations and interim rest periods, to ensure across-site standardization.

Patients were evaluated daily throughout hospitalization for mpox-related signs and symptoms, complications, and laboratory abnormalities by site clinicians. Malnutrition status (severe acute, moderate acute, or none) was assessed at baseline and managed daily throughout hospitalization (Table S2) by site clinicians and nutritionists. All patients received supportive care including symptom relief, nutritional support, skin care, and oropharyngeal care. When indicated, intravenous fluid, correction of hypoglycemia and electrolyte abnormalities, blood transfusion, antimalarials, broad spectrum antibiotics and antifungal treatment was provided. All participants not requiring treatment with broader antibiotics received prophylactic treatment with cloxacillin. Tecovirimat dosing was weight-based per investigator brochure (see Protocol). Patients weighing <13kg required fractional capsule dosing not covered under approved labeling. Patients received 3 meals/day and were evaluated daily by a study nutritionists to ensure caloric intake of ≥600 calories of high-fat food before product administration. Psychological support was provided to all participants throughout the study. A social mobilization and communication team engaged local communities to raise awareness about mpox, clinical research, and address rumors.

Lesions were assessed daily by a dermatologist or trained clinician until resolution. Whole-body unresolved lesion counts were performed at baseline and classified according to a modified WHO lesion-count score (Table S1)13. During the study, some patients developed new lesions after initial resolution. An optional visit was added to capture recrudescent disease, with “confirmed” recrudescence defined as, “new skin lesions consistent with mpox and MPXV PCR-positive skin swab or blood.” Cases without confirmatory skin or blood PCR were deemed probable recrudescent cases. A blinded primary endpoint adjudication committee determined status. Real-time PCR testing for MPXV in blood and oropharyngeal samples occurred every-other day until two consecutive-negative results or discharge. Lesion PCR was performed every-other day until lesion resolution. At each site, MPXV nucleic acid was detected using the RADI platform (KH Medical) MPOX Detection Kit with specific fluorescent channels for Clade I, Clade II, and generic orthopoxvirus. RT-PCR cycle threshold values ≤40 defined positive results, per manufacturer guidelines. Samples were stored for MPXV sequencing. Details about point-of-care clinical laboratory testing and pharmacokinetic (PK) processing are provided in the supplement. Rapid-diagnostic testing for malaria was conducted at baseline. Pregnancy status was determined in all females of childbearing age. HIV-1 serologic testing was performed retrospectively.

Real-time PCR testing for MPXV in blood and oropharyngeal samples occurred every-other day until two consecutive-negative results or discharge. Lesion PCR was performed every-other day until lesion resolution. At each site, MPXV nucleic acid was detected using the RADI platform (KH Medical) MPOX Detection Kit with specific fluorescent channels for Clade I, Clade II, and generic orthopoxvirus. RT-PCR cycle threshold values ≤40 defined positive results, per manufacturer guidelines. Samples were stored for MPXV sequencing. Details about point-of-care clinical laboratory testing and pharmacokinetic (PK) processing are provided in the supplement. Rapid-diagnostic testing for malaria was conducted at baseline. Pregnancy status was determined in all females of childbearing age. HIV-1 serologic testing was performed retrospectively. Prior to dosing on visit-day 7, PK analyses were obtained to capture steady-state concentration using a validated HPLC-MS/MS method14. The target effect threshold of ≥169 ng/mL was based on non-human primate studies15.

The primary analysis was based on the intent-to-treat population, evaluating differences in days to lesion resolution, based on Gray’s test of the competing-risk (“subdistribution”) hazard ratio (crHR)16 to account for death as a competing event, stratified by onset of symptoms (≤7 vs >7 days). Given the low mortality, results from the Fine-Gray and Cox proportional hazards models (with deaths censored at 28 days) are similar.17 Cox models and Kaplan-Meier estimates are additionally reported for the primary analysis (and exclusively reported for others). When applicable, censoring was applied on the confirmed recrudescence day. Longitudinal analyses of virologic results included last-observation-carried-forward and imputation of skin-lesion PCR values as negative after lesion resolution when PCR-testing stopped. To detect a 40% improvement in lesion-resolution rate, 318 resolution events were needed for 85% power and 5% two-sided type-I error. As a result of the unexpectedly high influx of patients, the sample size was increased to 550 resolution events, without knowledge of interim data. See Supplement for statistical analysis plans, which includes pre-specified secondary and subgroup analyses, and interim monitoring procedures. A post-hoc analysis adjusted for site-specific imbalances in disease severity and treatment assignment. (Supplement)

From October 7, 2022 through July 9, 2024, 793 patients were screened, 616 were clade I MPXV-positive, and 597 were randomized: 295 to tecovirimat and 302 to placebo. (Table 1; Figure S1) At baseline, most patients were <18 years old (64.3%); 48.9% were female. Most (79.2%) presented≤7 days of reported symptom onset. Most (65%) presented with severe or grave disease (i.e., >100 lesions). Mean lesion count was 487 (SD:994; median:185; range:1,10264). Baseline MPXV-PCR was positive in 96.5%, 87.2%, and 54.0% of lesion, oropharynx, and blood samples, respectively. Malaria was diagnosed in 19.6% of patients (and treated). Moderate or severe malnutrition was recorded in 18.6% of cases. Four patients (0.7%) were seropositive for HIV-1 infection (and referred for care). Pregnancies were observed in 16 patients. Baseline characteristics were similar across arms, although the tecovirimat arm had slightly more patients with severe or grave lesion counts compared to placebo (67.5% vs 62.6%). (Table 1) The stratified crHR for days to lesion resolution was 1.13 (95% confidence interval [CI] 0.97 to 1.31; p=0.14), with an estimated one-day improvement in median day of resolution (7 versus 8 for tecovirimat and placebo, respectively). Results were similar within strata: crHRs for onset ≤7 days and >7 days were 1.16 (95% CI:0.98, 1.37) and 1.00 (95% CI:0.71, 1.40), respectively. (Table 2, Figure 1) Ten (1.7%) deaths, 5 in each arm, occurred within 58 days. Seven (43.8%) of 16 pregnancies ended in intrauterine fetal demise, with no differences by treatment arm (Table 2).

The stratified crHR for days to lesion resolution was 1.13 (95% confidence interval [CI] 0.97 to 1.31; p=0.14), with an estimated one-day improvement in median day of resolution (7 versus 8 for tecovirimat and placebo, respectively). Results were similar within strata: crHRs for onset ≤7 days and >7 days were 1.16 (95% CI:0.98, 1.37) and 1.00 (95% CI:0.71, 1.40), respectively. (Table 2, Figure 1) Ten (1.7%) deaths, 5 in each arm, occurred within 58 days. Seven (43.8%) of 16 pregnancies ended in intrauterine fetal demise, with no differences by treatment arm (Table 2). Most patients became MPXV PCR-negative by 14 days in blood (87.3%; 281/322) and had either achieved lesion resolution or were PCR-negative in skin lesions (90.2%; 515/571). In oropharynx samples, only 53.9% (280/519) were PCR-negative by 14 days. No treatment differences were observed with any sample type (blood, lesion, or oropharynx). (Table 2, Figures 2 and S6)

ays in blood (87.3%; 281/322) and had either achieved lesion resolution or were PCR-negative in skin lesions (90.2%; 515/571). In oropharynx samples, only 53.9% (280/519) were PCR-negative by 14 days. No treatment differences were observed with any sample type (blood, lesion, or oropharynx). (Table 2, Figures 2 and S6) Pre-defined subgroup analyses suggested a treatment-by-site interaction (HR=1.59, 95% CI: 1.15, 2.21,), with a treatment effect in Kole but not Tunda. In Kole, median days to resolution were 7 days (tecovirimat; 95% CI:7 to 8 days) and 9 days (placebo; 95% CI:8 to 10 days) (Figures 3 and S3, Table S13). Overall, lesion severity (severe/grave) was greater in Kole (73.2%) than Tunda (57.5%). (Table S3) However, at baseline, more patients assigned to tecovirimat in Kole had less severe disease relative to placebo, while in Tunda the opposite asymmetry was noted. (Figure S18) Models that adjusted for baseline imbalances in lesion count and blood, OP and skin PCR cycle-thresholds (CT) were explored. With these adjustments, no interaction of treatment effect with site was observed.(Table S21) Site-based analyses of virologic endpoints over time did not demonstrate an independent enhanced rate of negative PCRs (across all sample types) from tecovirimat.(Figure S6) The blinded adjudication committee identified 20 confirmed (n=12) or probable (n=8) recrudescent cases (of 27 evaluated): 55% (11/20) received tecovirimat and 45% (9/20) received placebo. Most cases (95%; 19/20) occurred in Tunda and seven (35%) confirmed cases occurred within 28 days of randomization.

Pre-defined subgroup analyses suggested a treatment-by-site interaction (HR=1.59, 95% CI: 1.15, 2.21,), with a treatment effect in Kole but not Tunda. In Kole, median days to resolution were 7 days (tecovirimat; 95% CI:7 to 8 days) and 9 days (placebo; 95% CI:8 to 10 days) (Figures 3 and S3, Table S13). Overall, lesion severity (severe/grave) was greater in Kole (73.2%) than Tunda (57.5%). (Table S3) However, at baseline, more patients assigned to tecovirimat in Kole had less severe disease relative to placebo, while in Tunda the opposite asymmetry was noted. (Figure S18) Models that adjusted for baseline imbalances in lesion count and blood, OP and skin PCR cycle-thresholds (CT) were explored. With these adjustments, no interaction of treatment effect with site was observed.(Table S21) Site-based analyses of virologic endpoints over time did not demonstrate an independent enhanced rate of negative PCRs (across all sample types) from tecovirimat.(Figure S6) The blinded adjudication committee identified 20 confirmed (n=12) or probable (n=8) recrudescent cases (of 27 evaluated): 55% (11/20) received tecovirimat and 45% (9/20) received placebo. Most cases (95%; 19/20) occurred in Tunda and seven (35%) confirmed cases occurred within 28 days of randomization. Several baseline characteristics were associated with slower lesion resolution, including high lesion count, PCR positivity (yes/no, in oropharyngeal or skin lesions), lower PCR-CT (blood, oropharyngeal, and skin lesions), presence of fever or mouth sores, abnormally high aspartate aminotransferase and white blood cell counts. Notably, age, sex, days from symptom onset, malnutrition status and malaria baseline-positivity were not associated with slower resolution. Adjustments for each characteristic did not alter conclusions about treatment efficacy. (Table S25)

h sores, abnormally high aspartate aminotransferase and white blood cell counts. Notably, age, sex, days from symptom onset, malnutrition status and malaria baseline-positivity were not associated with slower resolution. Adjustments for each characteristic did not alter conclusions about treatment efficacy. (Table S25) Fifteen patients (5.1%) receiving tecovirimat experienced 17 serious adverse events (SAEs), while 15 patients (5.0%) receiving placebo experienced 15 SAEs (Tables S6 and S7); 72.9% of tecovirimat recipients experienced an AE compared to 70.5% of placebo patients (Table S8). Malaria occurred more often in placebo patients (18.2%) compared to tecovirimat patients (12.2%). Gastrointestinal AEs occurred in 26.4% and 23.8% of tecovirimat and placebo patients, respectively, with abdominal pain as the most frequently reported symptom. Of 60 pharmacokinetics values, 65.0% had drug concentrations ≥169ng/mL (Table S9). Drug concentrations tended to be higher in those ≥19 years-old (on average, 214ng/mL higher, relative to 6–18-year-olds) and those from Tunda (on average, 236ng/mL) (Table S10, Figure S11). Higher drug concentrations were not associated with faster lesion resolution or PCR results at 7 and 14 days. (Tables S11–S12, Figure S12).

From October 7, 2022 through July 9, 2024, 793 patients were screened, 616 were clade I MPXV-positive, and 597 were randomized: 295 to tecovirimat and 302 to placebo. (Table 1; Figure S1) At baseline, most patients were <18 years old (64.3%); 48.9% were female. Most (79.2%) presented≤7 days of reported symptom onset. Most (65%) presented with severe or grave disease (i.e., >100 lesions). Mean lesion count was 487 (SD:994; median:185; range:1,10264). Baseline MPXV-PCR was positive in 96.5%, 87.2%, and 54.0% of lesion, oropharynx, and blood samples, respectively. Malaria was diagnosed in 19.6% of patients (and treated). Moderate or severe malnutrition was recorded in 18.6% of cases. Four patients (0.7%) were seropositive for HIV-1 infection (and referred for care). Pregnancies were observed in 16 patients. Baseline characteristics were similar across arms, although the tecovirimat arm had slightly more patients with severe or grave lesion counts compared to placebo (67.5% vs 62.6%). (Table 1)

The stratified crHR for days to lesion resolution was 1.13 (95% confidence interval [CI] 0.97 to 1.31; p=0.14), with an estimated one-day improvement in median day of resolution (7 versus 8 for tecovirimat and placebo, respectively). Results were similar within strata: crHRs for onset ≤7 days and >7 days were 1.16 (95% CI:0.98, 1.37) and 1.00 (95% CI:0.71, 1.40), respectively. (Table 2, Figure 1)

Ten (1.7%) deaths, 5 in each arm, occurred within 58 days. Seven (43.8%) of 16 pregnancies ended in intrauterine fetal demise, with no differences by treatment arm (Table 2). Most patients became MPXV PCR-negative by 14 days in blood (87.3%; 281/322) and had either achieved lesion resolution or were PCR-negative in skin lesions (90.2%; 515/571). In oropharynx samples, only 53.9% (280/519) were PCR-negative by 14 days. No treatment differences were observed with any sample type (blood, lesion, or oropharynx). (Table 2, Figures 2 and S6) Pre-defined subgroup analyses suggested a treatment-by-site interaction (HR=1.59, 95% CI: 1.15, 2.21,), with a treatment effect in Kole but not Tunda. In Kole, median days to resolution were 7 days (tecovirimat; 95% CI:7 to 8 days) and 9 days (placebo; 95% CI:8 to 10 days) (Figures 3 and S3, Table S13). Overall, lesion severity (severe/grave) was greater in Kole (73.2%) than Tunda (57.5%). (Table S3) However, at baseline, more patients assigned to tecovirimat in Kole had less severe disease relative to placebo, while in Tunda the opposite asymmetry was noted. (Figure S18) Models that adjusted for baseline imbalances in lesion count and blood, OP and skin PCR cycle-thresholds (CT) were explored. With these adjustments, no interaction of treatment effect with site was observed.(Table S21) Site-based analyses of virologic endpoints over time did not demonstrate an independent enhanced rate of negative PCRs (across all sample types) from tecovirimat.(Figure S6)

OP and skin PCR cycle-thresholds (CT) were explored. With these adjustments, no interaction of treatment effect with site was observed.(Table S21) Site-based analyses of virologic endpoints over time did not demonstrate an independent enhanced rate of negative PCRs (across all sample types) from tecovirimat.(Figure S6) The blinded adjudication committee identified 20 confirmed (n=12) or probable (n=8) recrudescent cases (of 27 evaluated): 55% (11/20) received tecovirimat and 45% (9/20) received placebo. Most cases (95%; 19/20) occurred in Tunda and seven (35%) confirmed cases occurred within 28 days of randomization.

Several baseline characteristics were associated with slower lesion resolution, including high lesion count, PCR positivity (yes/no, in oropharyngeal or skin lesions), lower PCR-CT (blood, oropharyngeal, and skin lesions), presence of fever or mouth sores, abnormally high aspartate aminotransferase and white blood cell counts. Notably, age, sex, days from symptom onset, malnutrition status and malaria baseline-positivity were not associated with slower resolution. Adjustments for each characteristic did not alter conclusions about treatment efficacy. (Table S25)

Fifteen patients (5.1%) receiving tecovirimat experienced 17 serious adverse events (SAEs), while 15 patients (5.0%) receiving placebo experienced 15 SAEs (Tables S6 and S7); 72.9% of tecovirimat recipients experienced an AE compared to 70.5% of placebo patients (Table S8). Malaria occurred more often in placebo patients (18.2%) compared to tecovirimat patients (12.2%). Gastrointestinal AEs occurred in 26.4% and 23.8% of tecovirimat and placebo patients, respectively, with abdominal pain as the most frequently reported symptom.

Of 60 pharmacokinetics values, 65.0% had drug concentrations ≥169ng/mL (Table S9). Drug concentrations tended to be higher in those ≥19 years-old (on average, 214ng/mL higher, relative to 6–18-year-olds) and those from Tunda (on average, 236ng/mL) (Table S10, Figure S11). Higher drug concentrations were not associated with faster lesion resolution or PCR results at 7 and 14 days. (Tables S11–S12, Figure S12).

The current study, conducted in the setting of endemic mpox with clade I MPXV, failed to show any differences between placebo and tecovirimat groups regarding time to lesion resolution or declines in viremia. No safety concerns were observed with tecovirimat use. In a pre-specified subgroup analysis, there was evidence of faster lesion resolution in Kole patients on tecovirimat. Exploratory analyses revealed site-level asymmetries in baseline severity by arm that may have exaggerated the estimate of tecovirimat efficacy in Kole but simultaneously underestimated it in Tunda. Models that adjusted for these imbalances reduced site-level differences in treatment effect and provided statistical evidence that was consistent with no effect. Notably, virologic outcomes did not support the site-by-treatment interaction. Other analyses (e.g., alternative clinical endpoints, longitudinal changes in quantitative PCR, viral sequencing) may further elucidate observed site differences and may point to a hypothesis for further testing. All-cause mortality at 58-days (1.7%) was lower than the 4.6% case-fatality rate reported from recent DRC surveillance data9 and may highlight the importance of standardized, aggressive supportive care. While the level of care provided in PALM007 likely improved outcomes, it may not be easily provided in resource-limited and outpatient settings.

ays (1.7%) was lower than the 4.6% case-fatality rate reported from recent DRC surveillance data9 and may highlight the importance of standardized, aggressive supportive care. While the level of care provided in PALM007 likely improved outcomes, it may not be easily provided in resource-limited and outpatient settings. Approximately 50% of nasopharyngeal MPXV PCRs remained positive at 14 days, raising questions about transmissibility of MPXV after lesion resolution. Viral culture of these positive samples is planned to guide infection control and prevention guidelines.

ays (1.7%) was lower than the 4.6% case-fatality rate reported from recent DRC surveillance data9 and may highlight the importance of standardized, aggressive supportive care. While the level of care provided in PALM007 likely improved outcomes, it may not be easily provided in resource-limited and outpatient settings. Approximately 50% of nasopharyngeal MPXV PCRs remained positive at 14 days, raising questions about transmissibility of MPXV after lesion resolution. Viral culture of these positive samples is planned to guide infection control and prevention guidelines. Current tecovirimat dosing recommendations were established from animal models and concentrations in healthy human volunteers. No human clinical data are available to guide tecovirimat dosing6. In reports from a small group of patients with clade IIb mpox, day-8 tecovirimat exposures were lower than previously reported in healthy volunteers, although all patients exceeded the targeted effective threshold of 169ng/ml18. In our study, 35% of tested samples had concentrations below the minimum-effective concentration despite systematic efforts to ensure adequate caloric intake; 59/60 were above the value that suppressed viral replication in vitro. Drug concentrations on day 7 did not correlate with improved lesion resolution nor with PCR negativity. The reasons for observed differences in drug concentration by site and age are unclear, but include potential differences in comorbidities affecting drug absorption, unknown drug-drug interactions, difficulties achieving adequate food intake, and/or population genetic differences.

on resolution nor with PCR negativity. The reasons for observed differences in drug concentration by site and age are unclear, but include potential differences in comorbidities affecting drug absorption, unknown drug-drug interactions, difficulties achieving adequate food intake, and/or population genetic differences. The PALM007 study has many strengths. The study randomized all patients, regardless of age and pregnancy status, to tecovirimat or placebo. Hospitalization throughout treatment and strong social-mobilization and psychosocial efforts led to low rates of missing data and loss to follow-up. Hospitalization allowed optimization of nutritional support to maximize drug absorption and facilitated SAE/AE monitoring. Staff site-rotations occurred regularly to standardize practice and procedures across sites. Among the limitations is the subjectivity of the primary endpoint. Although training was provided for standardized lesion assessments, inter-observer variability in lesion-resolution day could have attenuated effect estimates. Analysis of a sub-study evaluating inter-observer variability in the field is underway. Lesion stage (e.g., papule, vesicle, pustule, scab) was not evaluated due to increased assessment burden but may be an important marker of disease stage. Lastly, it is important to emphasize that epidemiologic and clinical differences in populations affected by MPXV limit generalization of our results to other populations affected by clade Ia as well as those affected by other MPXV clades.

e to increased assessment burden but may be an important marker of disease stage. Lastly, it is important to emphasize that epidemiologic and clinical differences in populations affected by MPXV limit generalization of our results to other populations affected by clade Ia as well as those affected by other MPXV clades. Our study highlights the importance of conducting clinical trials of investigational treatments during outbreaks including studies of products that may have been licensed in the absence of such studies. Ongoing randomized controlled trials of tecovirimat for mpox caused by clade IIb MPXV, including STOMP, UNITY and EPOXI, will provide needed evidence about tecovirimat efficacy in other populations. Research identifying and evaluating additional treatments for mpox in clade I disease is needed.