Clostridium difficile Vaccine

Adjusted GMCs and 2-sided 95% confidence intervals (CIs) of toxin A and toxin B specific neutralizing antibody levels were calculated by exponentiating the least square (LS) means and the corresponding CIs based on analysis of logarithmically transformed concentrations using a linear regression model with terms of baseline concentration (log scale) and vaccine group. EIP at Month 7 (EI7): all enrolled participants who received all 3 doses of investigational product; had blood drawn for assay testing within 28 to 47 days after visit 4; had valid and determinate assay results for either toxin A or B for the specified analysis at Month 7; had no major protocol deviations.

Seroresponse was defined as at least a 4-fold rise from the baseline neutralizing antibody level following vaccination. 95% CI was based on Clopper-Pearson method. EI7: all enrolled participants who received all 3 doses of investigational product; had blood drawn for assay testing within 28 to 47 days after visit 4; had valid and determinate assay results for either toxin A or B for the specified analysis at Month 7; had no major protocol deviations.

Local reactions included pain at injection site, redness and swelling. These were recorded by participants in an electronic diary (e-diary). Redness and swelling were measured and recorded in measuring device units, where 1 measuring device unit= 0.5 centimeter (cm). Redness and swelling were graded as mild: 2.5-5.0 cm, moderate: greater than (\>) 5.0-10.0 cm, severe: \>10.0 cm, potentially life threatening: necrosis or exfoliative dermatitis for redness, or necrosis for swelling. Pain at injection site was graded as mild: did not interfere with daily activity, moderate: interfered with daily activity, severe: prevented daily activity, potentially life threatening: emergency room visit or hospitalization. The maximum severity was defined as highest grading of each local reaction through 7 days of vaccination.

Local reactions included pain at injection site, redness and swelling. These were recorded by participants in an e-diary. Redness and swelling were measured and recorded in measuring device units, where 1 measuring device unit= 0.5 cm. Redness and swelling were graded as mild: 2.5-5.0 cm, moderate: \>5.0-10.0 cm, severe: \>10.0 cm, potentially life threatening: necrosis or exfoliative dermatitis for redness, or necrosis for swelling. Pain at injection site was graded as mild: did not interfere with daily activity, moderate: interfered with daily activity, severe: prevented daily activity, potentially life threatening: emergency room visit or hospitalization. The maximum severity was defined as highest grading of each local reaction through 7 days of vaccination.

Local reactions included pain at injection site, redness and swelling. These were recorded by participants in an e-diary. Redness and swelling were measured and recorded in measuring device units, where 1 measuring device unit= 0.5 cm. Redness and swelling were graded as mild: 2.5-5.0 cm, moderate: \>5.0-10.0 cm, severe: \>10.0 cm, potentially life threatening: necrosis or exfoliative dermatitis for redness, or necrosis for swelling. Pain at injection site was graded as mild: did not interfere with daily activity, moderate: interfered with daily activity, severe: prevented daily activity, potentially life threatening: emergency room visit or hospitalization. The maximum severity was defined as highest grading of each local reaction through 7 days of vaccination.

Systemic events included fever, fatigue, headache, joint pain, muscle pain and vomiting. These were recorded by participants in an e-diary. Fever was categorized as: mild (38.0 to 38.4 degree \[deg\] Celsius \[C\]), moderate (38.5 to 38.9 deg C), severe (39.0 to 40.0 deg C) and potentially life threatening (\>40.0 deg C). Fatigue, headache, muscle pain and joint pain were graded as mild: did not interfere with activity, moderate: some interference with activity, severe: prevented daily routine activity and potentially life threatening: emergency room visit or hospitalization. Vomiting was graded as mild: 1 to 2 times in 24 hours(h), moderate: \>2 times in 24h, severe: required intravenous hydration and potentially life threatening: emergency room visit or hospitalization for hypotensive shock. The maximum severity was defined as highest grading of each systemic event through 7 days of vaccination.

Systemic events included fever, fatigue, headache, joint pain, muscle pain and vomiting. These were recorded by participants in an e-diary. Fever was categorized as: mild (38.0 to 38.4 deg C), moderate (38.5 to 38.9 deg C), severe (39.0 to 40.0 deg C) and potentially life threatening (\>40.0 deg C). Fatigue, headache, muscle pain and joint pain were graded as mild: did not interfere with activity, moderate: some interference with activity, severe: prevented daily routine activity and potentially life threatening: emergency room visit or hospitalization. Vomiting was graded as mild: 1 to 2 times in 24h, moderate: \>2 times in 24h, severe: required intravenous hydration and potentially life threatening: emergency room visit or hospitalization for hypotensive shock. The maximum severity was defined as highest grading of each systemic event through 7 days of vaccination.

Systemic events included fever, fatigue, headache, joint pain, muscle pain and vomiting. These were recorded by participants in an e-diary. Fever was categorized as: mild (38.0 to 38.4 deg C), moderate (38.5 to 38.9 deg C), severe (39.0 to 40.0 deg C) and potentially life threatening (\>40.0 deg C). Fatigue, headache, muscle pain and joint pain were graded as mild: did not interfere with activity, moderate: some interference with activity, severe: prevented daily routine activity and potentially life threatening: emergency room visit or hospitalization. Vomiting was graded as mild: 1 to 2 times in 24h, moderate: \>2 times in 24h, severe: required intravenous hydration and potentially life threatening: emergency room visit or hospitalization for hypotensive shock. The maximum severity was defined as highest grading of each systemic event through 7 days of vaccination.

An AE was any untoward medical occurrence in a participant who received investigational product without regard to possibility of causal relationship. Percentage of participants with any AEs (both serious and all non-serious AEs) and non-serious AEs through 1 month after last study vaccination were reported in this outcome measure. Only AEs and non-SAEs collected by non-systematic assessment (i.e., excluding local reactions and systemic events) were reported in this outcome measure.

SAE was any untoward medical occurrence that at any dose resulted in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly.

GMC was calculated as the mean of the assay results after making the logarithm transformation and then back transformation to its original scale. Confidence intervals (CIs) were back transformations of CIs based on the Student t distribution for the mean logarithm of the concentrations. Clostridium difficile toxin A and toxin B were inactivated by a combination of genetic mutations to decrease toxin activity and chemical treatments were done prior to final purification and formulation of the drug substance.

Local reactions included pain at injection site, redness and swelling. These were recorded by participants in an electronic diary (e-diary). Pain at injection site was graded as mild: did not interfere with daily activity, moderate: interfered with daily activity, severe: prevented daily activity, grade 4: emergency room visit or hospitalization. Redness and swelling were measured and recorded in measuring device units. One measuring device unit= 0.5 centimeter (cm) and graded as mild: 2.5 to 5.0 cm, moderate: greater than (\>) 5.0 to 10.0 cm, severe: \>10.0 cm, Grade 4 indicated necrosis or exfoliative dermatitis for redness and necrosis for swelling. The maximum severity was defined as highest grading of each local reaction within 7 days of vaccination. Events were classified as Grade 4 based on study investigator's judgement.

Local reactions included pain at injection site, redness and swelling. These were recorded by participants in an e-diary. Pain at injection site was graded as mild: did not interfere with daily activity, moderate: interfered with daily activity, severe: prevented daily activity, grade 4: emergency room visit or hospitalization. Redness and swelling were measured and recorded in measuring device units. One measuring device unit= 0.5 cm and graded as mild: 2.5 to 5.0 cm, moderate: \> 5.0 to 10.0 cm, severe: \>10.0 cm, Grade 4 indicated necrosis or exfoliative dermatitis for redness and necrosis for swelling. The maximum severity was defined as highest grading of each local reaction within 7 days of vaccination. Events were classified as Grade 4 based on study investigator's judgement.

Local reactions included pain at injection site, redness and swelling. These were recorded by participants in an e-diary. Pain at injection site was graded as mild: did not interfere with daily activity, moderate: interfered with daily activity, severe: prevented daily activity, grade 4: emergency room visit or hospitalization. Redness and swelling were measured and recorded in measuring device units. One measuring device unit= 0.5 cm and graded as mild: 2.5 to 5.0 cm, moderate: \> 5.0 to 10.0 cm, severe: \>10.0 cm, Grade 4 indicated necrosis or exfoliative dermatitis for redness and necrosis for swelling. The maximum severity was defined as highest grading of each local reaction within 7 days of vaccination. Events were classified as Grade 4 based on study investigator's judgement.

Systemic events included fever, fatigue, headache, joint pain, muscle pain and vomiting. These were recorded by participants in an e-diary. Fever was categorized as: mild: (38.0 to 38.4 degree Celsius \[deg C\]), moderate: (38.5 to 38.9 deg C), severe (39.0 to 40.0 deg C), grade 4: \>40 deg C. Fatigue, headache, joint pain and muscle pain were graded as mild: did not interfere with activity, moderate: some interference with activity, severe: prevented daily activity, grade 4: emergency room visit or hospitalization. Vomiting was graded as mild: 1 to 2 times in 24 hours, moderate: \>2 times in 24 hours, severe: required intravenous hydration, grade 4: emergency room visit or hospitalization for hypotensive shock. The maximum severity was defined as highest grading of each systemic event within 7 days of vaccination. Events were classified as Grade 4 based on study investigator's judgement.

Systemic events included fever, fatigue, headache, joint pain, muscle pain and vomiting. These were recorded by participants in an e-diary. Fever was categorized as: mild: (38.0 to 38.4 deg C), moderate: (38.5 to 38.9 deg C), severe (39.0 to 40.0 deg C), grade 4: \>40 deg C. Fatigue, headache, joint pain and muscle pain were graded as mild: did not interfere with activity, moderate: some interference with activity, severe: prevented daily activity, grade 4: emergency room visit or hospitalization. Vomiting was graded as mild: 1 to 2 times in 24 hours, moderate: \>2 times in 24 hours, severe: required intravenous hydration, grade 4: emergency room visit or hospitalization for hypotensive shock. The maximum severity was defined as highest grading of each systemic event within 7 days of vaccination. Events were classified as Grade 4 based on study investigator's judgement.

Systemic events included fever, fatigue, headache, joint pain, muscle pain and vomiting. These were recorded by participants in an e-diary. Fever was categorized as: mild: (38.0 to 38.4 deg C), moderate: (38.5 to 38.9 deg C), severe (39.0 to 40.0 deg C), grade 4: \>40 deg C. Fatigue, headache, joint pain and muscle pain were graded as mild: did not interfere with activity, moderate: some interference with activity, severe: prevented daily activity, grade 4: emergency room visit or hospitalization. Vomiting was graded as mild: 1 to 2 times in 24 hours, moderate: \>2 times in 24 hours, severe: required intravenous hydration, grade 4: emergency room visit or hospitalization for hypotensive shock. The maximum severity was defined as highest grading of each systemic event within 7 days of vaccination. Events were classified as Grade 4 based on study investigator's judgement.

An AE was defined as any untoward medical occurrence in a participant who received investigational product without regard to possibility of causal relationship. AEs included both serious and all non-serious adverse events (NSAEs). Only AEs and NSAEs collected by non-systematic assessment (i.e., excluding local reactions and systemic events) were reported in this outcome measure.

An SAE was defined as any untoward medical occurrence at any dose that resulted in any of the following outcomes: death; life-threatening (immediate risk of death); required inpatient hospitalization or prolongation of existing hospitalization; persistent or significant disability/incapacity (substantial disruption of the ability to conduct normal life functions); congenital anomaly/birth defect; or that was considered as an important medical event.

CDI definition 1 for a primary episode of CDI (no previous CDI onset in the prior 8 weeks) was defined as either a) presence of diarrhea, defined as passage of 3 or more unformed stools (Bristol stool chart types 5-7) in 24 or fewer consecutive hours, and stool sample that was positive for the toxin B gene (by polymerase chain reaction \[PCR)\] and positive for toxin A and/or toxin B, as measured in the central laboratory; or b) Pseudomembranous colitis diagnosed at colonoscopy, at surgery, or histopathologically; and corresponding stool sample that was positive for the toxin B gene (via PCR) as measured in the central laboratory. End of surveillance period was defined as accumulation of at least 40 CDI cases.

CDI definition 1 for a primary episode of CDI (no previous CDI onset in the prior 8 weeks) was defined as either a) presence of diarrhea, defined as passage of 3 or more unformed stools (Bristol stool chart types 5-7) in 24 or fewer consecutive hours, and stool sample that was positive for the toxin B gene (by PCR) and positive for toxin A and/or toxin B, as measured in the central laboratory; or b) Pseudomembranous colitis diagnosed at colonoscopy, at surgery, or histopathologically; and corresponding stool sample that was positive for the toxin B gene (via PCR) as measured in the central laboratory. End of surveillance period was defined as accumulation of at least 40 CDI cases.

Local reactions included redness, swelling and pain at injection site. These were recorded by participants in an electronic diary (e-diary). Redness and swelling were measured and recorded in measuring device units. One measuring device unit= 0.5 centimeter (cm) and graded as mild: 2.5 to 5.0 cm, moderate: greater than (\>) 5.0 to 10.0 cm, severe: \>10.0 cm. Grade 4 indicated necrosis or exfoliative dermatitis for redness and necrosis for swelling Pain at injection site was graded as mild: did not interfere with daily activity, moderate: interfered with daily activity, severe: prevented daily activity. Grade 4 indicated emergency room visit or hospitalization.

Local reactions included redness, swelling and pain at injection site. These were recorded by participants in an e-diary. Redness and swelling were measured and recorded in measuring device units. One measuring device unit= 0.5 cm and graded as mild: 2.5 to 5.0 cm, moderate: \> 5.0 to 10.0 cm, severe: \>10.0 cm. Grade 4 indicated necrosis or exfoliative dermatitis for redness and necrosis for swelling. Pain at injection site was graded as mild: did not interfere with daily activity, moderate: interfered with daily activity, severe: prevented daily activity. Grade 4 indicated emergency room visit or hospitalization.

Local reactions included redness, swelling and pain at injection site. These were recorded by participants in an e-diary. Redness and swelling were measured and recorded in measuring device units. One measuring device unit= 0.5 cm and graded as mild: 2.5 to 5.0 cm, moderate: \> 5.0 to 10.0 cm, severe: \>10.0 cm. Grade 4 indicated necrosis or exfoliative dermatitis for redness and necrosis for swelling. Pain at injection site was graded as mild: did not interfere with daily activity, moderate: interfered with daily activity, severe: prevented daily activity. Grade 4 indicated emergency room visit or hospitalization.

Systemic events included fever, fatigue, headache, joint pain, muscle pain and vomiting. These were recorded by participants in an e-diary. Fever was categorized as: mild: (38.0 to 38.4 degree Celsius \[deg C\]), moderate: (38.5 to 38.9 deg C), severe (39.0 to 40.0 deg C), potentially life threatening (\> 40.0 deg C). Fatigue, headache, joint pain and muscle pain were graded as mild: did not interfere with activity, moderate: some interference with activity, severe: prevented daily activity, grade 4: emergency room visit or hospitalization. Vomiting was graded as mild: 1 to 2 times in 24 hours, moderate: \>2 times in 24 hours, severe: required intravenous hydration, grade 4: emergency room visit or hospitalization for hypotensive shock.

Systemic events included fever, fatigue, headache, joint pain, muscle pain and vomiting. These were recorded by participants in an e-diary. Fever was categorized as: mild: (38.0 to 38.4 deg C), moderate: (38.5 to 38.9 deg C), severe (39.0 to 40.0 deg C), potentially life threatening (\> 40.0 deg C). Fatigue, headache, joint pain and muscle pain were graded as mild: did not interfere with activity, moderate: some interference with activity, severe: prevented daily activity, grade 4: emergency room visit or hospitalization. Vomiting was graded as mild: 1 to 2 times in 24 hours, moderate: \>2 times in 24 hours, severe: required intravenous hydration, grade 4: emergency room visit or hospitalization for hypotensive shock.

Systemic events included fever, fatigue, headache, joint pain, muscle pain and vomiting. These were recorded by participants in an e-diary. Fever was categorized as: mild: (38.0 to 38.4 deg C), moderate: (38.5 to 38.9 deg C), severe (39.0 to 40.0 deg C), potentially life threatening (\> 40.0 deg C). Fatigue, headache, joint pain and muscle pain were graded as mild: did not interfere with activity, moderate: some interference with activity, severe: prevented daily activity, grade 4: emergency room visit or hospitalization. Vomiting was graded as mild: 1 to 2 times in 24 hours, moderate: \>2 times in 24 hours, severe: required intravenous hydration, grade 4: emergency room visit or hospitalization for hypotensive shock.

An AE was defined as any untoward medical occurrence in a participant who received investigational product without regard to possibility of causal relationship. AEs included both serious and all non-serious adverse events. An SAE was defined as any untoward medical occurrence at any dose that resulted in any of the following outcomes: death; life-threatening (immediate risk of death); required inpatient hospitalization or prolongation of existing hospitalization; persistent or significant disability/incapacity (substantial disruption of the ability to conduct normal life functions); congenital anomaly/birth defect; or that was considered as an important medical event. AEs included both SAEs and all Non-SAEs (except local and systemic events).

An SAE was defined as any untoward medical occurrence at any dose that resulted in any of the following outcomes: death; life-threatening (immediate risk of death); required inpatient hospitalization or prolongation of existing hospitalization; persistent or significant disability/incapacity (substantial disruption of the ability to conduct normal life functions); congenital anomaly/birth defect; or that was considered as an important medical event.

Toxin A antibodies (threshold \>= 219 neutralization units/mL) were measured using neutralization assay.

Toxin A antibodies (threshold \>= 219 neutralization units/mL) were measured using neutralization assay.

Toxin B antibodies (threshold \>= 2586 neutralization units/mL) were measured using neutralization assay.

Toxin B antibodies (threshold \>= 2586 neutralization units/mL) were measured using neutralization assay.

Toxin A and B antibodies (threshold \>= 219 and 2586 neutralization units/mL) were measured using neutralization assay.

Toxin A and B antibodies (threshold \>= 219 and 2586 neutralization units/mL) were measured using neutralization assay.

Local reactions included pain at injection site, swelling and redness collected by using an electronic diary (e-diary). Pain was graded as: mild (grade 1) (did not interfere with activity), moderate (grade 2)(interfered with activity), severe (grade 3) (prevented daily activity) and grade 4 (emergency room visit or hospitalization). Redness and swelling were graded as: mild (2.5-5.0 centimeter \[cm\]), moderate (\>5.0 to 10.0 cm), severe (\>10.0 cm) and grade 4 (necrosis).

Local reactions included pain at injection site, swelling and redness collected by using an electronic diary (e-diary). Pain was graded as: mild (did not interfere with activity), moderate (interfered with activity), severe (prevented daily activity) and grade 4 (emergency room visit or hospitalization). Redness and swelling were graded as: mild (2.5-5.0 cm), moderate (\>5.0 to 10.0 cm), severe (\>10.0 cm) and grade 4 (necrosis).

Local reactions included pain at injection site, swelling and redness collected by using an electronic diary (e-diary). Pain was graded as: mild (did not interfere with activity), moderate (interfered with activity), severe (prevented daily activity) and grade 4 (emergency room visit or hospitalization). Redness and swelling were graded as: mild (2.5-5.0 cm), moderate (\>5.0 to 10.0 cm), severe (\>10.0 cm) and grade 4 (necrosis).

Local reactions included pain at injection site, swelling and redness collected by using an electronic diary (e-diary). Pain was graded as: mild (did not interfere with activity), moderate (interfered with activity), severe (prevented daily activity) and grade 4 (emergency room visit or hospitalization). Redness and swelling were graded as: mild (2.5-5.0 cm), moderate (\>5.0 to 10.0 cm), severe (\>10.0 cm) and grade 4 (necrosis).

Local reactions included pain at injection site, swelling and redness collected by using an electronic diary (e-diary). Pain was graded as: mild (did not interfere with activity), moderate (interfered with activity), severe (prevented daily activity) and grade 4 (emergency room visit or hospitalization). Redness and swelling were graded as: mild (2.5-5.0 cm), moderate (\>5.0 to 10.0 cm), severe (\>10.0 cm) and grade 4 (necrosis).

Local reactions included pain at injection site, swelling and redness collected by using an electronic diary (e-diary). Pain was graded as: mild (did not interfere with activity), moderate (interfered with activity), severe (prevented daily activity) and grade 4 (emergency room visit or hospitalization). Redness and swelling were graded as: mild (2.5-5.0 cm), moderate (\>5.0 to 10.0 cm), severe (\>10.0 cm) and grade 4 (necrosis).

Systemic events included fever, vomiting, diarrhea, headache, fatigue, new or worsening muscle pain, new or worsening joint pain and were recorded by using an e-diary. Fever was graded as mild (38.0 to 38.4 degree Celsius (C)), moderate (38.5 to 38.9 degree C), severe (39.0 to 40.0 degree C), grade 4 (\>40.0 degree C). Vomiting was graded as mild (1-2 times in 24 hours), moderate (\>2 times in 24 hours), severe (required intravenous hydration) and grade 4 (hospitalization for hypotensive shock). Diarrhea was graded as mild (2-3 loose stools in 24 hours), moderate (4-5 loose stools in 24 hours), severe (\>=6 stools in 24 hours) and grade 4 (hospitalization). Headache, fatigue, new or worsening muscle pain and new or worsening joint pain was graded as mild (no interference with activity), moderate (some interference with activity), severe (prevents daily activity) and grade 4 (hospitalization).

Systemic events included fever, vomiting, diarrhea, headache, fatigue, new or worsening muscle pain, new or worsening joint pain and were recorded by using an e-diary. Fever was graded as mild (38.0 to 38.4 C), moderate (38.5 to 38.9 degree C), severe (39.0 to 40.0 degree C), grade 4 (\>40.0 degree C). Vomiting was graded as mild (1-2 times in 24 hours), moderate (\>2 times in 24 hours), severe (required intravenous hydration) and grade 4 (hospitalization for hypotensive shock). Diarrhea was graded as mild (2-3 loose stools in 24 hours), moderate (4-5 loose stools in 24 hours), severe (\>=6 stools in 24 hours) and grade 4 (hospitalization). Headache, fatigue, new or worsening muscle pain and new or worsening joint pain was graded as mild (no interference with activity), moderate (some interference with activity), severe (prevents daily activity) and grade 4 (hospitalization).

Systemic events included fever, vomiting, diarrhea, headache, fatigue, new or worsening muscle pain, new or worsening joint pain and were recorded by using an e-diary. Fever was graded as mild (38.0 to 38.4 C), moderate (38.5 to 38.9 degree C), severe (39.0 to 40.0 degree C), grade 4 (\>40.0 degree C). Vomiting was graded as mild (1-2 times in 24 hours), moderate (\>2 times in 24 hours), severe (required intravenous hydration) and grade 4 (hospitalization for hypotensive shock). Diarrhea was graded as mild (2-3 loose stools in 24 hours), moderate (4-5 loose stools in 24 hours), severe (\>=6 stools in 24 hours) and grade 4 (hospitalization). Headache, fatigue, new or worsening muscle pain and new or worsening joint pain was graded as mild (no interference with activity), moderate (some interference with activity), severe (prevents daily activity) and grade 4 (hospitalization).

Systemic events included fever, vomiting, diarrhea, headache, fatigue, new or worsening muscle pain, new or worsening joint pain and were recorded by using an e-diary. Fever was graded as mild (38.0 to 38.4 C), moderate (38.5 to 38.9 degree C), severe (39.0 to 40.0 degree C), grade 4 (\>40.0 degree C). Vomiting was graded as mild (1-2 times in 24 hours), moderate (\>2 times in 24 hours), severe (required intravenous hydration) and grade 4 (hospitalization for hypotensive shock). Diarrhea was graded as mild (2-3 loose stools in 24 hours), moderate (4-5 loose stools in 24 hours), severe (\>=6 stools in 24 hours) and grade 4 (hospitalization). Headache, fatigue, new or worsening muscle pain and new or worsening joint pain was graded as mild (no interference with activity), moderate (some interference with activity), severe (prevents daily activity) and grade 4 (hospitalization).

Systemic events included fever, vomiting, diarrhea, headache, fatigue, new or worsening muscle pain, new or worsening joint pain and were recorded by using an e-diary. Fever was graded as mild (38.0 to 38.4 C), moderate (38.5 to 38.9 degree C), severe (39.0 to 40.0 degree C), grade 4 (\>40.0 degree C). Vomiting was graded as mild (1-2 times in 24 hours), moderate (\>2 times in 24 hours), severe (required intravenous hydration) and grade 4 (hospitalization for hypotensive shock). Diarrhea was graded as mild (2-3 loose stools in 24 hours), moderate (4-5 loose stools in 24 hours), severe (\>=6 stools in 24 hours) and grade 4 (hospitalization). Headache, fatigue, new or worsening muscle pain and new or worsening joint pain was graded as mild (no interference with activity), moderate (some interference with activity), severe (prevents daily activity) and grade 4 (hospitalization).

Systemic events included fever, vomiting, diarrhea, headache, fatigue, new or worsening muscle pain, new or worsening joint pain and were recorded by using an e-diary. Fever was graded as mild (38.0 to 38.4 C), moderate (38.5 to 38.9 degree C), severe (39.0 to 40.0 degree C), grade 4 (\>40.0 degree C). Vomiting was graded as mild (1-2 times in 24 hours), moderate (\>2 times in 24 hours), severe (required intravenous hydration) and grade 4 (hospitalization for hypotensive shock). Diarrhea was graded as mild (2-3 loose stools in 24 hours), moderate (4-5 loose stools in 24 hours), severe (\>=6 stools in 24 hours) and grade 4 (hospitalization). Headache, fatigue, new or worsening muscle pain and new or worsening joint pain was graded as mild (no interference with activity), moderate (some interference with activity), severe (prevents daily activity) and grade 4 (hospitalization).

An AE was any untoward medical occurrence in a participant who received investigational product without regard to possibility of causal relationship. Treatment-emergent are events between first dose of study drug and up to 28 days after last dose of study drug that were absent before treatment or that worsened relative to pretreatment state.

An AE was any untoward medical occurrence in a participant who received investigational product without regard to possibility of causal relationship. Treatment-emergent are events between first dose of study drug and up to 28 days after last dose of study drug that were absent before treatment or that worsened relative to pretreatment state.

An AE was any untoward medical occurrence in a participant who received investigational product without regard to possibility of causal relationship. SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly; lack of efficacy in an approved indication. Treatment-emergent serious adverse events are events between first dose of study drug and up to 6 months after last dose of study drug that were absent before treatment or that worsened relative to pretreatment state.

An AE was any untoward medical occurrence in a participant who received investigational product without regard to possibility of causal relationship. SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly; lack of efficacy in an approved indication. Treatment-emergent serious adverse events are events between first dose of study drug and up to 6 months after last dose of study drug that were absent before treatment or that worsened relative to pretreatment state.

Pain at injection site: mild=does not interfere with activity; moderate=interferes with activity; severe=prevents daily activity; Grade 4=emergency department visit or hospitalization. Redness/swelling: Mild=2.5 to 5.0 cm; moderate= \>5.0 to 10.0 cm; severe= \>10 cm; Grade 4=necrosis or exfoliative dermatitis for redness category and only necrosis for swelling category. Any local reaction=any pain at the injection site, any swelling, or any redness.

Pain at injection site: mild=does not interfere with activity; moderate=interferes with activity; severe=prevents daily activity; Grade 4=emergency department visit or hospitalization. Redness/swelling: Mild=2.5 to 5.0 cm; moderate= \>5.0 to 10.0 cm; severe= \>10 cm; Grade 4=necrosis or exfoliative dermatitis for redness category and only necrosis for swelling category. Any local reaction=any pain at the injection site, any swelling, or any redness.

Pain at injection site: mild=does not interfere with activity; moderate=interferes with activity; severe=prevents daily activity; Grade 4=emergency department visit or hospitalization. Redness/swelling: Mild=2.5 to 5.0 cm; moderate= \>5.0 to 10.0 cm; severe= \>10 cm; Grade 4=necrosis or exfoliative dermatitis for redness category and only necrosis for swelling category. Any local reaction=any pain at the injection site, any swelling, or any redness.

Fever=temperature ≥38.0°C (100.4°C): Mild=38.0°C to 38.4°C (100.4°F-101.1°F); moderate=38.5°C to 38.9°C (101.2°F-102.0°F); severe=39.0°C to 40.0°C (102.1°F-104.0°F); Grade 4= \>40.0°C (\>104.0°F). Vomiting: Mild=1 to 2 times in 24 hours; moderate= \>2 times in 24 hours; severe=requires intravenous hydration; Grade 4=emergency department visit or hospitalization for hypotensive shock. Diarrhea: Mild=2 to 3 loose stools in 24 hours; moderate=4 to 5 loose stools in 24 hours; severe= ≥6 loose stools in 24 hours; Grade 4=emergency department visit or hospitalization. Headache, fatigue, new or worsening joint or muscle pain: Mild=no interference with activity; moderate=some interference with activity; severe=significant interference with activity, prevents daily activity; Grade 4=emergency department visit or hospitalization. Any systemic event: Fever ≥38.0°C, vomiting, diarrhea, headache, fatigue, or new or worsening muscle or joint pain.

Fever=temperature ≥38.0°C (100.4°C): Mild=38.0°C to 38.4°C (100.4°F-101.1°F); moderate=38.5°C to 38.9°C (101.2°F-102.0°F); severe=39.0°C to 40.0°C (102.1°F-104.0°F); Grade 4= \>40.0°C (\>104.0°F). Vomiting: Mild=1 to 2 times in 24 hours; moderate= \>2 times in 24 hours; severe=requires intravenous hydration; Grade 4=emergency department visit or hospitalization for hypotensive shock. Diarrhea: Mild=2 to 3 loose stools in 24 hours; moderate=4 to 5 loose stools in 24 hours; severe= ≥6 loose stools in 24 hours; Grade 4=emergency department visit or hospitalization. Headache, fatigue, new or worsening joint or muscle pain: Mild=no interference with activity; moderate=some interference with activity; severe=significant interference with activity, prevents daily activity; Grade 4=emergency department visit or hospitalization. Any systemic event: Fever ≥38.0°C, vomiting, diarrhea, headache, fatigue, or new or worsening muscle or joint pain.

Fever=temperature ≥38.0°C (100.4°C): Mild=38.0°C to 38.4°C (100.4°F-101.1°F); moderate=38.5°C to 38.9°C (101.2°F-102.0°F); severe=39.0°C to 40.0°C (102.1°F-104.0°F); Grade 4= \>40.0°C (\>104.0°F). Vomiting: Mild=1 to 2 times in 24 hours; moderate= \>2 times in 24 hours; severe=requires intravenous hydration; Grade 4=emergency department visit or hospitalization for hypotensive shock. Diarrhea: Mild=2 to 3 loose stools in 24 hours; moderate=4 to 5 loose stools in 24 hours; severe= ≥6 loose stools in 24 hours; Grade 4=emergency department visit or hospitalization. Headache, fatigue, new or worsening joint or muscle pain: Mild=no interference with activity; moderate=some interference with activity; severe=significant interference with activity, prevents daily activity; Grade 4=emergency department visit or hospitalization. Any systemic event: Fever ≥38.0°C, vomiting, diarrhea, headache, fatigue, or new or worsening muscle or joint pain.

An AE is any untoward medical occurrence in a clinical investigation participant administered a product or medical device; the event need not necessarily have a causal relationship with the treatment or usage. An SAE is any untoward medical occurrence at any dose that results in death, persistent or significant disability/incapacity, or congenital anomaly/birth defect; is life-threatening; or requires or prolongs inpatient hospitalization.

Pain at injection site: mild=does not interfere with activity; moderate=interferes with activity; severe=prevents daily activity; Grade 4=emergency department visit or hospitalization. Redness/swelling: Mild=2.5 to 5.0 cm; moderate= \>5.0 to 10.0 cm; severe= \>10 cm; Grade 4=necrosis or exfoliative dermatitis for redness category and only necrosis for swelling category. Any local reaction=any pain at the injection site, any swelling, or any redness.

Pain at injection site: mild=does not interfere with activity; moderate=interferes with activity; severe=prevents daily activity; Grade 4=emergency department visit or hospitalization. Redness/swelling: Mild=2.5 to 5.0 cm; moderate= \>5.0 to 10.0 cm; severe= \>10 cm; Grade 4=necrosis or exfoliative dermatitis for redness category and only necrosis for swelling category. Any local reaction=any pain at the injection site, any swelling, or any redness.

Pain at injection site: mild=does not interfere with activity; moderate=interferes with activity; severe=prevents daily activity; Grade 4=emergency department visit or hospitalization. Redness/swelling: Mild=2.5 to 5.0 cm; moderate= \>5.0 to 10.0 cm; severe= \>10 cm; Grade 4=necrosis or exfoliative dermatitis for redness category and only necrosis for swelling category. Any local reaction=any pain at the injection site, any swelling, or any redness.

Fever=temperature ≥38.0°C (100.4°C): Mild=38.0°C to 38.4°C (100.4°F-101.1°F); moderate=38.5°C to 38.9°C (101.2°F-102.0°F); severe=39.0°C to 40.0°C (102.1°F-104.0°F); Grade 4= \>40.0°C (\>104.0°F). Vomiting: Mild=1 to 2 times in 24 hours; moderate= \>2 times in 24 hours; severe=requires intravenous hydration; Grade 4=emergency department visit or hospitalization for hypotensive shock. Diarrhea: Mild=2 to 3 loose stools in 24 hours; moderate=4 to 5 loose stools in 24 hours; severe= ≥6 loose stools in 24 hours; Grade 4=emergency department visit or hospitalization. Headache, fatigue, new or worsening joint or muscle pain: Mild=no interference with activity; moderate=some interference with activity; severe=significant interference with activity, prevents daily activity; Grade 4=emergency department visit or hospitalization. Any systemic event: Fever ≥38.0°C, vomiting, diarrhea, headache, fatigue, or new or worsening muscle or joint pain.

Fever=temperature ≥38.0°C (100.4°C): Mild=38.0°C to 38.4°C (100.4°F-101.1°F); moderate=38.5°C to 38.9°C (101.2°F-102.0°F); severe=39.0°C to 40.0°C (102.1°F-104.0°F); Grade 4= \>40.0°C (\>104.0°F). Vomiting: Mild=1 to 2 times in 24 hours; moderate= \>2 times in 24 hours; severe=requires intravenous hydration; Grade 4=emergency department visit or hospitalization for hypotensive shock. Diarrhea: Mild=2 to 3 loose stools in 24 hours; moderate=4 to 5 loose stools in 24 hours; severe= ≥6 loose stools in 24 hours; Grade 4=emergency department visit or hospitalization. Headache, fatigue, new or worsening joint or muscle pain: Mild=no interference with activity; moderate=some interference with activity; severe=significant interference with activity, prevents daily activity; Grade 4=emergency department visit or hospitalization. Any systemic event: Fever ≥38.0°C, vomiting, diarrhea, headache, fatigue, or new or worsening muscle or joint pain.

Fever=temperature ≥38.0°C (100.4°C): Mild=38.0°C to 38.4°C (100.4°F-101.1°F); moderate=38.5°C to 38.9°C (101.2°F-102.0°F); severe=39.0°C to 40.0°C (102.1°F-104.0°F); Grade 4= \>40.0°C (\>104.0°F). Vomiting: Mild=1 to 2 times in 24 hours; moderate= \>2 times in 24 hours; severe=requires intravenous hydration; Grade 4=emergency department visit or hospitalization for hypotensive shock. Diarrhea: Mild=2 to 3 loose stools in 24 hours; moderate=4 to 5 loose stools in 24 hours; severe= ≥6 loose stools in 24 hours; Grade 4=emergency department visit or hospitalization. Headache, fatigue, new or worsening joint or muscle pain: Mild=no interference with activity; moderate=some interference with activity; severe=significant interference with activity, prevents daily activity; Grade 4=emergency department visit or hospitalization. Any systemic event: Fever ≥38.0°C, vomiting, diarrhea, headache, fatigue, or new or worsening muscle or joint pain.

An AE is any untoward medical occurrence in a clinical investigation participant administered a product or medical device; the event need not necessarily have a causal relationship with the treatment or usage. An SAE is any untoward medical occurrence at any dose that results in death, persistent or significant disability/incapacity, or congenital anomaly/birth defect; is life-threatening; or requires or prolongs inpatient hospitalization.