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This multi-center open label clinical trial aims to identify predictors of low antibody titers to vaccine antigens in children with ALL who completed chemotherapy in the prior 6 months, and to determine the immunogenicity and safety of diphtheria-tetanus-acellular pertussis-inactivated poliomyelitis-Haemophilus influenzae type b (DTaP-IPV-Hib) and 13-valent pneumococcal conjugate vaccine (PCV13) booster immunization administered 6 months post-chemotherapy, followed by 23-valent pneumococcal polysaccharide vaccination (PPV23) 2 months later. The results will support the development of clinical practice guidelines for this population.
Rationale and Aims: Children with acute lymphoblastic leukemia (ALL) have evidence of persistent immunosuppression following chemotherapy and may experience waning of immunity to vaccines received prior to treatment. There is no standard of care in Canada regarding immunologic evaluation or booster immunization of children with ALL after chemotherapy. This study aims to identify predictors of low baseline immunity to vaccine antigens in children with ALL and to evaluate the immunogenicity and safety of a standard immunization regimen: DTaP-IPV-Hib and PCV13 booster immunization administered 6 months post-chemotherapy, followed by PPV23.
Study Design: This will be a multi-center open-label clinical trial in which children who were diagnosed with ALL at ≥1 year of age, and have not received immunizations other than influenza since completing chemotherapy will undergo immunologic evaluation and serologic testing for pneumococcus, tetanus, pertussis and varicella. They will then be immunized with PCV13, DTaP-IPV-Hib, regardless of immunization history [unless PPV23 was received within the prior 12 months]. Other routine vaccines required as per provincial and centre-specific immunization policies will also be administered. PPV23 will be administered 8 weeks after PCV13. Repeat serologic testing will be conducted at 2 months and 12-15 months after DTaP-IPV-Hib and PCV13 immunization to assess short and long-term immune responses.
Adverse events following immunization (AEFI) will be captured through standardized telephone interviews on days 8-10 and 30-33 post-immunization that will capture local and systemic AEFI.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Experimental | Active Comparator | Children who were diagnosed with ALL at ≥1 year of age, and are within 6-8 months of completing chemotherapy will receive 1 dose each of: Prevnar®13 and Pediacel® vaccines, followed by 1 dose of Pneumovax® 23 given 2 months after PCV13. |
|
| Healthy Control | No Intervention | Children 3-18 years of age who are not immunocompromised age-matched to cases from Group 1. |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Prevnar®13 | Biological | A single dose of Prevnar®13 will be administered to subjects with ALL who are 6-12 months post-completion of chemotherapy. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Percentage of Participants With Protective Titres to PCV13 Serotypes Post-immunization With PCV13+PPV23 | The percentage of participants with protective titres (with protective level defined as ≥0.35 ug/ml, as per World Health Organization criteria) to PCV13 serotypes will be assessed at 2 months and 12-15 months post PCV13+PPV23 and compared to baseline levels. | Pre-vaccination Baseline, 2 months and 12-15 months |
| Measure | Description | Time Frame |
|---|---|---|
| Number of Participants With Protective Titres to PCV7 Serotypes at Baseline | The number of participants with protective titres (≥0.35 ug/ml) to PCV7 serotypes at baseline will be compared to age-matched controls. | Day 0 |
| Baseline Pneumococcal Antibody Titres in Subjects With ALL Versus Controls |
| Measure | Description | Time Frame |
|---|---|---|
| Number of Participants With Adverse Events Following Immunization Requiring Healthcare Visit or Leading to >=1 Day of Disability | Adverse Events Following Immunization requiring healthcare visit or leading to >=1 day of disability will be captured through structured telephone interviews on days 8-10 and 30-33 after each immunization | days 8-10 and 30-33 |
Cases with ALL:
Inclusion Criteria:
Exclusion Criteria:
Controls:
Inclusion criteria
Exclusion criteria
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| Name | Affiliation | Role |
|---|---|---|
| Karina Top, MD, MS | Dalhousie University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| IWK Health Centre | Halifax | Nova Scotia | B3K 6R8 | Canada |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 32067048 | Derived | Top KA, Vaudry W, Morris SK, Pham-Huy A, Pernica JM, Tapiero B, Gantt S, Price VE, Rassekh SR, Sung L, McConnell A, Rubin E, Chawla R, Halperin SA. Waning Vaccine Immunity and Vaccination Responses in Children Treated for Acute Lymphoblastic Leukemia: A Canadian Immunization Research Network Study. Clin Infect Dis. 2020 Dec 3;71(9):e439-e448. doi: 10.1093/cid/ciaa163. |
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155 of the 156 participants recruited met inclusion criteria. Of the 78 participants with ALL recruited, 1 did not meet inclusion criteria and 3 withdrew consent prior to study start. All of the 78 control participants met inclusion criteria.
Participants were recruited based on physician referral across 10 pediatric centres. Controls were recruited at 3 centres. Participants were enrolled between November 2015 to September 2017.
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| ID | Title | Description |
|---|---|---|
| FG000 | Experimental | Children who were diagnosed with ALL at ≥1 year of age, and are within 6-8 months of completing chemotherapy will receive 1 dose each of: Prevnar®13 and Pediacel® vaccines, followed by 1 dose of Pneumovax® 23 given 2 months after PCV13. Prevnar®13: A single dose of Prevnar®13 will be administered to subjects with ALL who are 6-12 months post-completion of chemotherapy. Pneumovax® 23: A single dose of Pneumovax® 23 will be administered to subjects approximately 2 months after Prevnar®13 Pediacel®: A single dose of Pediacel® will be administered to subjects with ALL who are 6-12 months post-completion of chemotherapy. |
| FG001 | Healthy Control | Children 3-18 years of age who are not immunocompromised age-matched to cases from Group 1. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Experimental | Children who were diagnosed with ALL at ≥1 year of age, and are within 6-8 months of completing chemotherapy will receive 1 dose each of: Prevnar®13 and Pediacel® vaccines, followed by 1 dose of Pneumovax® 23 given 2 months after PCV13. Prevnar®13: A single dose of Prevnar®13 will be administered to subjects with ALL who are 6-12 months post-completion of chemotherapy. Pneumovax® 23: A single dose of Pneumovax® 23 will be administered to subjects approximately 2 months after Prevnar®13 Pediacel®: A single dose of Pediacel® will be administered to subjects with ALL who are 6-12 months post-completion of chemotherapy. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Percentage of Participants With Protective Titres to PCV13 Serotypes Post-immunization With PCV13+PPV23 | The percentage of participants with protective titres (with protective level defined as ≥0.35 ug/ml, as per World Health Organization criteria) to PCV13 serotypes will be assessed at 2 months and 12-15 months post PCV13+PPV23 and compared to baseline levels. | Participants analyzed equaled the overall number of ALL participants that completed the study and had analyzable serology collected at 2 months and 12-15 months post-vaccination. | Posted | Count of Participants | Participants | Pre-vaccination Baseline, 2 months and 12-15 months |
|
AEFI was captured through structured telephone interviews on days 8-10 and 30-33 after each immunization
Any untoward or unfavorable medical occurrence in a participant, including any abnormal sign (for example, abnormal physical exam or laboratory finding), symptom, or disease, temporally associated with the participant's participation in the research, whether or not considered related to the participant's participation in the research. Adverse Events were not monitored for Healthy Controls as they did not receive the interventions, they provided baseline data only.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | DTaP-IPV-HiB+PCV13 | DTaP-IPV-Hib: diphtheria-tetanus-acellular pertussis-inactivated polio-H. influenzae type b vaccine PCV13: 13-valent pneumococcal conjugate vaccine |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Pain/erythema/swelling at injection site | Skin and subcutaneous tissue disorders | Systematic Assessment |
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Karina Top | IWK Health Centre | 902-470-6343 | karina.top@dal.ca |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Jun 14, 2017 | Oct 6, 2020 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D054198 | Precursor Cell Lymphoblastic Leukemia-Lymphoma |
| ID | Term |
|---|---|
| D007945 | Leukemia, Lymphoid |
| D007938 | Leukemia |
| D009370 | Neoplasms by Histologic Type |
| D009369 | Neoplasms |
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| ID | Term |
|---|---|
| C414006 | 23-valent pneumococcal capsular polysaccharide vaccine |
| C541234 | diphtheria-tetanus-five component acellular pertussis-inactivated poliomyelitis -Haemophilus influenzae type b conjugate vaccine |
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| Pneumovax® 23 | Biological | A single dose of Pneumovax® 23 will be administered to subjects approximately 2 months after Prevnar®13 |
|
|
| Pediacel® | Biological | A single dose of Pediacel® will be administered to subjects with ALL who are 6-12 months post-completion of chemotherapy. |
|
|
Baseline geometric mean titers (GMT) and percentage of subjects with protective titres to pneumococcal serotypes in children with ALL versus age-matched controls. |
| Day 0 |
| Immune Responses to Pertussis Toxin Following DTaP-IPV-Hib Booster Vaccination | Baseline, Short-term (baseline - 2 months after vaccination) and long-term (baseline - 12-15 months) vaccine responses to DTaP-IPV-Hib will be measured using GMT ratios. | Prevaccination baseline, 2 months, 12-15 months |
| Baseline Tetanus Toxoid Antibody Titers in Children With ALL Versus Controls | Baseline geometric mean titers (95% confidence intervals) reported as IU/ml in children with ALL versus controls | Day 0 |
| Baseline Pertussis Toxin Titers in Children With ALL Versus Healthy Controls | Baseline geometric mean titers (95% confidence intervals) reported as IU/ml in children with ALL versus controls | Day 0 |
| Baseline Varicella Titers in Children With ALL Versus Controls. | Geometric mean titers (95% confidence interval) in AI (antibody index) | Day 0 |
| Immune Responses to Tetanus Toxoid Following DTaP-IPV-Hib Immunization | Baseline, short-term (baseline to 2 months after vaccination) and long-term (baseline to 12-15 months) vaccine responses to DTaP-IPV-Hib will be measured using GMTs with 95% confidence intervals | baseline, 2 months, 12-15 months |
| Screen Failure |
|
| BG001 | Healthy Control | Children 3-18 years of age who are not immunocompromised age-matched to cases from Group 1. |
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race and Ethnicity Not Collected | Race and Ethnicity were not collected from any participant. | Count of Participants | Participants |
|
| Region of Enrollment | Count of Participants | Participants |
|
| ALL disease risk category | Disease risk category based on patient characteristics at leukemia diagnosis reflects intensity of chemotherapy | Only collected for ALL participants | Count of Participants | Participants |
|
| Treatment Protocol | Only collected for ALL participants | Count of Participants | Participants |
|
| Interval from last chemotherapy to serology | Time in months between last chemotherapy session to baseline blood draw. | Only collected for ALL participants | Median | Full Range | months |
|
| Total white blood cell count at enrollment | Only available for participants with analyzable data | Only collected for participants with AL. Immunological markers not available on all participants with ALL, denominator reflects number of participants with analyzable values for each test. | Median | Inter-Quartile Range | cells x10^9/l |
|
| Total lymphocyte count at enrollment | Only available for participants with analyzable data | Only collected for participants with ALL. Immunological markers not available on all participants with ALL, denominator reflects number of participants with analyzable values for each test. | Median | Inter-Quartile Range | cells x10^9/l |
|
| Lymphocyte subsets at enrollment | Only collected for participants with ALL. Immunological markers not available on all participants with ALL, denominator reflects number of participants with analyzable values for each test. | Median | Inter-Quartile Range | cells x10^9/l |
|
| Total serum IgG at enrollment | Only available for participants with analyzable data | Only collected for participants with ALL. Immunological markers not available on all participants with ALL, denominator reflects number of participants with analyzable values for each test. | Median | Inter-Quartile Range | g/l |
|
| Previous doses of PCV | Count of Participants | Participants |
|
| Previous doses of DTaP or Tdap | Count of Participants | Participants |
|
| Previous doses of varicella vaccine | Count of Participants | Participants |
|
| Interval from last vaccine to baseline blood draw | Mean | Standard Deviation | years |
|
|
|
| Secondary | Number of Participants With Protective Titres to PCV7 Serotypes at Baseline | The number of participants with protective titres (≥0.35 ug/ml) to PCV7 serotypes at baseline will be compared to age-matched controls. | Posted | Count of Participants | Participants | Day 0 |
|
|
|
| Secondary | Baseline Pneumococcal Antibody Titres in Subjects With ALL Versus Controls | Baseline geometric mean titers (GMT) and percentage of subjects with protective titres to pneumococcal serotypes in children with ALL versus age-matched controls. | Posted | Geometric Mean | 95% Confidence Interval | mg/L | Day 0 |
|
|
|
| Secondary | Immune Responses to Pertussis Toxin Following DTaP-IPV-Hib Booster Vaccination | Baseline, Short-term (baseline - 2 months after vaccination) and long-term (baseline - 12-15 months) vaccine responses to DTaP-IPV-Hib will be measured using GMT ratios. | A total of 73 participants received DTaP-IPV-Hib, 67 provided a follow up sample at 2 months post-vaccination and 66 provided a follow up sample at 12 months post-vaccination. | Posted | Geometric Mean | 95% Confidence Interval | EU/ml | Prevaccination baseline, 2 months, 12-15 months |
|
|
|
| Secondary | Baseline Tetanus Toxoid Antibody Titers in Children With ALL Versus Controls | Baseline geometric mean titers (95% confidence intervals) reported as IU/ml in children with ALL versus controls | Posted | Geometric Mean | 95% Confidence Interval | IU/ml | Day 0 |
|
|
|
| Secondary | Baseline Pertussis Toxin Titers in Children With ALL Versus Healthy Controls | Baseline geometric mean titers (95% confidence intervals) reported as IU/ml in children with ALL versus controls | Posted | Geometric Mean | 95% Confidence Interval | EU/ml | Day 0 |
|
|
|
| Secondary | Baseline Varicella Titers in Children With ALL Versus Controls. | Geometric mean titers (95% confidence interval) in AI (antibody index) | Posted | Geometric Mean | 95% Confidence Interval | Antibody index | Day 0 |
|
|
|
| Secondary | Immune Responses to Tetanus Toxoid Following DTaP-IPV-Hib Immunization | Baseline, short-term (baseline to 2 months after vaccination) and long-term (baseline to 12-15 months) vaccine responses to DTaP-IPV-Hib will be measured using GMTs with 95% confidence intervals | Participants with analyzable data at each timepoint were included | Posted | Geometric Mean | 95% Confidence Interval | IU/ml | baseline, 2 months, 12-15 months |
|
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| Other Pre-specified | Number of Participants With Adverse Events Following Immunization Requiring Healthcare Visit or Leading to >=1 Day of Disability | Adverse Events Following Immunization requiring healthcare visit or leading to >=1 day of disability will be captured through structured telephone interviews on days 8-10 and 30-33 after each immunization | Posted | Count of Participants | Participants | days 8-10 and 30-33 |
|
|
|
| 0 |
| 74 |
| 0 |
| 74 |
| 56 |
| 74 |
| EG001 | PPV23 | PPV23: 23-valent pneumococcal polysaccharide vaccine | 0 | 73 | 0 | 73 | 46 | 73 |
| Systemic symptoms | General disorders | Systematic Assessment | Systemic symptoms included fever, malaise, gastrointestinal symptoms, skin rash, headache, pharyngitis, otitis media |
|
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| D006402 |
| Hematologic Diseases |
| D006425 | Hemic and Lymphatic Diseases |
| D008232 | Lymphoproliferative Disorders |
| D008206 | Lymphatic Diseases |
| D007160 | Immunoproliferative Disorders |
| D007154 | Immune System Diseases |
| Pneumococcal Serotype 4 |
|
| Pneumococcal Serotype 6B |
|
| Pneumococcal Serotype 7F |
|
| Pneumococcal Serotype 9V |
|
| Pneumococcal Serotype 14 |
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| Pneumococcal Serotype 18C |
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| Pneumococcal Serotype 19F |
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| Pneumococcal Serotype 23F |
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| Baseline - 12-15 months post-vaccination |
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