Clostridium Difficile Vaccine Efficacy Trial

Study Overview
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Brief Summary
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The Clover trial is evaluating an investigational vaccine that may help to prevent Clostridium difficile infection. Participants in the study are adults 50 years of age and older, who are at risk of developing Clostridium difficile infection. The study will assess whether the vaccine prevents the disease, and whether it is safe and well tolerated. Each subject will receive 3 doses of Clostridium difficile vaccine or placebo and be followed for up to 3 years after vaccination for potential Clostridium difficile infection.

Official Title
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A PHASE 3, PLACEBO-CONTROLLED, RANDOMIZED, OBSERVER-BLINDED STUDY TO EVALUATE THE EFFICACY, SAFETY, AND TOLERABILITY OF A CLOSTRIDIUM DIFFICILE VACCINE IN ADULTS 50 YEARS OF AGE AND OLDER

Conditions
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Clostridium Difficile Infection

Intervention / Treatment
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* Biological: Clostridium difficile vaccine
* Biological: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Evidence of a personally signed and dated informed consent document. Willing and able to comply with study procedures. Subjects with an increased risk of future contact with healthcare systems or subjects who have received systemic antibiotics in the previous 12 weeks. Ability to be contacted by telephone during study participation. Negative urine pregnancy test for female subjects of childbearing potential. Exclusion Criteria: Investigator site staff members directly involved in the conduct of the study and their family members, site staff members otherwise supervised by the investigator, or subjects who are Pfizer employees, including their family members, directly involved in the conduct of the study. Participation in other studies involving investigational drug(s)/vaccine(s) within 28 days prior to study entry until 1 month after the third vaccination. Previous administration of an investigational C difficile vaccine or C difficile mAb therapy. Prior episode of CDI.. Receipt of blood products or immunoglobulins within 6 months before enrollment. Subjects who may be unable to respond to vaccination due to: Metastatic malignancy; or End-stage renal disease; or Any serious medical disorder likely to be fatal within the next 12 months; or Congenital or acquired immunodeficiency; or Receipt of high dose systemic corticosteroids for 14 days within 28 days of enrollment; or Receipt of chronic systemic treatment with other known immunosuppressant medications, or radiotherapy, within 6 months of enrollment. Known infection with human immunodeficiency virus (HIV). Any bleeding disorder or anticoagulant therapy that would contraindicate intramuscular injection. Any contraindication to vaccination or vaccine components, including previous anaphylactic reaction to any vaccine or vaccine-related components. Prior small- or large-bowel resection. Any condition or treatment resulting in frequent diarrhea. Other acute or chronic condition or abnormality that may increase the risk associated with study participation or IP administration or may interfere with interpretation of study results Pregnant or breastfeeding female subjects; male subjects and female subjects who are sexually active and at risk for pregnancy and will not/cannot use 2 methods of contraception

Ages Eligible for Study
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Minimum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Clostridium difficile vaccine<br> | Biological: Clostridium difficile vaccine<br>* Toxoid-based Clostridium difficile vaccine<br>|
| Placebo Comparator: Placebo<br> | Biological: Placebo<br>* Normal saline solution (0.9% sodium chloride)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of First Primary Episodes of Clostridium Difficile Infection (CDI) (Definition 1) Follow-up After Dose 3 | 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. | From 14 days after Dose 3 to the end of the surveillance period (mean follow-up after dose 3 was 34.2 months) | 
| Number of First Primary Episodes of Clostridium Difficile Infection (CDI) (Definition 1) Follow-up After Dose 2 | 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. | From 14 days after Dose 2 to the end of the surveillance period (mean follow-up after dose 2 was 36 months) | 
| Percentage of Participants Reporting Local Reactions Within 7 Days After Dose 1 | 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. | Within 7 days after Dose 1 at Month 0 | 
| Percentage of Participants Reporting Local Reactions Within 7 Days After Dose 2 | 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. | Within 7 days after Dose 2 at Month 1 | 
| Percentage of Participants Reporting Local Reactions Within 7 Days After Dose 3 | 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. | Within 7 days after Dose 3 at Month 6 | 
| Percentage of Participants Reporting Systemic Events Within 7 Days After Dose 1 | 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. | Within 7 days after Dose 1 at Month 0 | 
| Percentage of Participants Reporting Systemic Events Within 7 Days After Dose 2 | 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. | Within 7 days after Dose 2 at Month 1 | 
| Percentage of Participants Reporting Systemic Events Within 7 Days After Dose 3 | 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. | Within 7 days after Dose 3 at Month 6 | 
| Number of Participants Reporting Adverse Events (AEs) | 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). | From Day 1 of Dose 1 to 1 Month after Dose 3 (7 Months) | 
| Number of Participants Reporting Serious Adverse Events (SAEs) | 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. | From Day 1 of Dose 1 up to 6 months after Dose 3 (up to Month 12) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of All Episodes of CDI (Definition 1 and 2) After Dose 3 | CDI definition 1 for primary episode of CDI (no previous CDI onset in prior 8 weeks) and CDI definition 2 for recurrent episode (episode occurred 8 weeks or less after onset of previous episode [provided symptoms of previous episode resolved]) were both defined as either a) presence of diarrhea, (passage of 3 or more unformed stools [Bristol stool chart types 5-7]) in 24 or fewer consecutive hours, stool sample positive for toxin B gene (by PCR),positive for toxin A and/or toxin B, as measured in central laboratory; or b) Pseudomembranous colitis diagnosed at colonoscopy, surgery, histopathologically; and corresponding stool sample positive for toxin B gene (via PCR) as measured in central laboratory. End of surveillance period was defined as accumulation of at least 40 CDI cases. | From 14 days after Dose 3 to the end of the surveillance period (mean follow-up after dose 3 was 34.2 months) | 
| Time to Resolution for Participants With First Primary Episodes of CDI (Definition 1) After Dose 3 | Resolution of the event was the last day on which the event was recorded in the e-diary or the date the event ends if it was unresolved during the participant diary-recording period (end date collected on the case report form [CRF]). 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. | From 14 days after Dose 3 to the end of the surveillance period (mean follow-up after dose 3 was 34.2 months) | 
| Proportion of Participants Who Required Medical Attention During First Primary Episode of CDI (Definition 1) After Dose 3 | 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. | From 14 days after Dose 3 to the end of the surveillance period (mean follow-up after dose 3 was 34.2 months) | 
| Number of Participants With Recurrent Episodes of CDI (Definition 2) After Dose 3 | CDI definition 2 for a recurrent episode (an episode of CDI that occurred 8 weeks or less after the onset of a previous CDI episode [provided the symptoms of the previous episode had resolved]), 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 (by PCR) as measured in the central laboratory. End of surveillance period was defined as accumulation of at least 40 CDI cases. | From 14 days after Dose 3 to the end of the surveillance period (mean follow-up after dose 3 was 34.2 months) | 
| Number of All Episodes of CDI (Definition 1 and 2) After Dose 2 | CDI definition 1 for primary episode of CDI (no previous CDI onset in prior 8 weeks) and CDI definition 2 for recurrent episode (episode occurred 8 weeks or less after onset of previous episode [provided symptoms of previous episode resolved]) were both defined as either a) presence of diarrhea, (passage of 3 or more unformed stools [Bristol stool chart types 5-7]) in 24 or fewer consecutive hours, stool sample positive for toxin B gene (by PCR),positive for toxin A and/or toxin B, as measured in central laboratory; or b) Pseudomembranous colitis diagnosed at colonoscopy, surgery, histopathologically; and corresponding stool sample positive for toxin B gene (via PCR) as measured in central laboratory. End of surveillance period was defined as accumulation of at least 40 CDI cases. | From 14 days after Dose 2 to the end of the surveillance period (mean follow-up after dose 2 was 36 months) | 
| Number of Participants With Recurrent Episodes of CDI (Definition 2) After Dose 2 | CDI definition 2 for a recurrent episode (an episode of CDI that occurred 8 weeks or less after the onset of a previous CDI episode [provided the symptoms of the previous episode had resolved]), 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 (by PCR) as measured in the central laboratory. End of surveillance period was defined as accumulation of at least 40 CDI cases. | From 14 days after Dose 2 to the end of the surveillance period (mean follow-up after dose 2 was 36 months) | 
| Number of First Primary Episode of CDI (Definition 1) After Dose 2 and Before Dose 3 | 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. | From 14 days after Dose 2 to Dose 3 or the day the third vaccination was expected (168 days after Dose 2) for participants who received only 2 doses | 
| Number of Participants With Recurrent Episode of CDI (Definition 2) After Dose 2 and Before Dose 3 | CDI definition 2 for a recurrent episode (an episode of CDI that occurred 8 weeks or less after the onset of a previous CDI episode [provided the symptoms of the previous episode had resolved]), 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 (by PCR) as measured in the central laboratory. End of surveillance period was defined as accumulation of at least 40 CDI cases. | From 14 days after Dose 2 to Dose 3 or the day the third vaccination was expected (168 days after Dose 2) for participants who received only 2 doses |