Clinical Trials List
Protocol NumberDAP-PEDOST-11-03
NCT Number(ClinicalTrials.gov Identfier)NCT01922011
2015-12-01 - 2016-12-30
Phase III
Terminated5
ICD-9730.07
Acute osteomyelitis, ankle and foot
A Multicenter, Randomized, Double-Blinded Comparative Study to Evaluate the Efficacy, Safety, and Pharmacokinetics of Daptomycin Versus Active Comparator in Pediatric Subjects with Acute Hematogenous Osteomyelitis Due to Gram-Positive Organisms
-
Trial Applicant
-
Sponsor
Cubist Pharmaceuticals, Inc.
-
Trial scale
Multi-Regional Multi-Center
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Update
2025/08/20
Investigators and Locations
Co-Principal Investigator
- Daniel Tsung-Ning Huang Division of Pediatrics
- 黃競瑩 Division of Pediatrics
- Nan-Chang Chiu Division of Pediatrics
The Actual Total Number of Participants Enrolled
0 Stop recruiting
Co-Principal Investigator
- 潘蕙嫻 Division of Pediatrics
- FANG-LIANG HUANG Division of Pediatrics
The Actual Total Number of Participants Enrolled
0 Stop recruiting
Principal Investigator
Co-Principal Investigator
- 黃冠穎 Division of Pediatrics
- Chi-Long Chen Division of Pediatrics
- 郭貞孍 Division of Pediatrics
- Yhu-Chering Huang Division of Pediatrics
- Hsuan-Kai Kao Division of Pediatrics
- 謝育嘉 Division of Pediatrics
- Cheng-Hsun Chiu Division of Pediatrics
The Actual Total Number of Participants Enrolled
0 Stop recruiting
Audit
None
Co-Principal Investigator
- 楊宗儒 Division of Pediatrics
- Luan-Yin Chang Division of Pediatrics
- Chun-yi Lu Division of Pediatrics
- 林谷龍 Division of Pediatrics
The Actual Total Number of Participants Enrolled
0 Stop recruiting
Audit
None
Co-Principal Investigator
- 黃競瑩 Division of Pediatrics
- Nan-Chang Chiu Division of Pediatrics
- Daniel Tsung-Ning Huang Division of Pediatrics
The Actual Total Number of Participants Enrolled
0 Stop recruiting
Condition/Disease
Acute Hematogenous Osteomyelitis
Objectives
PrimaryThe primary objective is:To demonstrate the noninferiority of daptomycin compared with vancomycin (or equivalent) or nafcillin(or β-lactam equivalent) in pediatric subjects with AHO with respect to improvement in the generalcategories of Pain, Inflammation, and Limb Function on or before Study Day 5 in the MITT Analysis Set.If the primary objective is met then the following will be evaluated:Testing for superiority of daptomycin with respect to comparator in time to improvement in the generalcategories of Pain, Inflammation, and Limb Function in the MITT Analysis Set. If this is successful, testingfor superiority of daptomycin with respect to comparator in the primary endpoint will also be performed.
Test Drug
daptomycin (CUBICIN)
Active Ingredient
Daptomycin
Dosage Form
Injection
Dosage
500 mg /vial
Endpoints
主要療效結果測量：
主要療效結果測量為在 MITT 分析組中，試驗第 5 天以前一般類別症狀 疼痛、發炎及肢體功能的
臨床改善。
臨床改善的判定將會以試驗主持人對各項一般類別症狀 疼痛、發炎、肢體功能的整體評估為準。
以這些評估為準，將會根據下列定義認定受試者達到臨床改善的標準：
若基期時顯示具有 3 項一般性類別的症狀：至少 2 項一般性類別項目達到至少 1 分的改善(亦
即重度至中度、中度至輕度、輕度至無症狀)，且第 3 項類別無惡化
若基期時顯示具有 2 項一般性類別的症狀：至少 1 項一般性類別項目達到至少 2 分的改善(亦
即重度至輕度、中度至無症狀)，且另外 2 項類別無惡化或新發現，或此 2 項類別達到至少 1
分的改善，且第 3 項類別無新發現
若基期時顯示具有 1 項一般性類別的症狀：該類別達到至少 2 分的改善(亦即重度至輕度、中
度至無症狀)，且另外 2 項類別無新發現
次要結果測量－療效：
在 MITT 分析組中，一般類別症狀(疼痛、發炎及肢體功能)、過去 24 小時間體溫≤ 38°C (100.4°F)
及試驗第 5 天以前 CRP (以 4 至 7 天內的追蹤 CRP 確認)較基期降低至少 30%等臨床改善的複合
評估指標
在 MITT 及 CE 分析組中，EOIV、EOT 和 TOC 時各受試者的臨床結果
在 mMITT 及 ME 分析組中，TOC 時各基期病原組的臨床結果
在 mMITT 及 ME 分析組中，TOC 時各受試者的微生物學結果
在 mMITT 及 ME 分析組中，TOC 時各基期病原組的微生物學結果
在 MITT 分析組中，EOT 和 TOC 時達到持續臨床改善
次要結果測量－安全性：
安全性評估將會在安全性分析組中進行，評估內容包括：
不良事件(AE)：AE、嚴重不良事件(SAE)、死亡及因 AE 退出試驗
臨床：生命徵象(脈搏、血壓、呼吸速率、體溫)及重點神經學檢查
實驗室檢測：全血球計數和分類計數，以及生化檢查
外部的獨立資料安全監督委員將會定期審核本試驗得到的安全性資料，以確保所有納入受試者的
安全。
次要結果測量－藥動學：
藥動學(PK)結果測量將包括 daptomycin 的血漿濃度。
主要療效結果測量為在 MITT 分析組中，試驗第 5 天以前一般類別症狀 疼痛、發炎及肢體功能的
臨床改善。
臨床改善的判定將會以試驗主持人對各項一般類別症狀 疼痛、發炎、肢體功能的整體評估為準。
以這些評估為準，將會根據下列定義認定受試者達到臨床改善的標準：
若基期時顯示具有 3 項一般性類別的症狀：至少 2 項一般性類別項目達到至少 1 分的改善(亦
即重度至中度、中度至輕度、輕度至無症狀)，且第 3 項類別無惡化
若基期時顯示具有 2 項一般性類別的症狀：至少 1 項一般性類別項目達到至少 2 分的改善(亦
即重度至輕度、中度至無症狀)，且另外 2 項類別無惡化或新發現，或此 2 項類別達到至少 1
分的改善，且第 3 項類別無新發現
若基期時顯示具有 1 項一般性類別的症狀：該類別達到至少 2 分的改善(亦即重度至輕度、中
度至無症狀)，且另外 2 項類別無新發現
次要結果測量－療效：
在 MITT 分析組中，一般類別症狀(疼痛、發炎及肢體功能)、過去 24 小時間體溫≤ 38°C (100.4°F)
及試驗第 5 天以前 CRP (以 4 至 7 天內的追蹤 CRP 確認)較基期降低至少 30%等臨床改善的複合
評估指標
在 MITT 及 CE 分析組中，EOIV、EOT 和 TOC 時各受試者的臨床結果
在 mMITT 及 ME 分析組中，TOC 時各基期病原組的臨床結果
在 mMITT 及 ME 分析組中，TOC 時各受試者的微生物學結果
在 mMITT 及 ME 分析組中，TOC 時各基期病原組的微生物學結果
在 MITT 分析組中，EOT 和 TOC 時達到持續臨床改善
次要結果測量－安全性：
安全性評估將會在安全性分析組中進行，評估內容包括：
不良事件(AE)：AE、嚴重不良事件(SAE)、死亡及因 AE 退出試驗
臨床：生命徵象(脈搏、血壓、呼吸速率、體溫)及重點神經學檢查
實驗室檢測：全血球計數和分類計數，以及生化檢查
外部的獨立資料安全監督委員將會定期審核本試驗得到的安全性資料，以確保所有納入受試者的
安全。
次要結果測量－藥動學：
藥動學(PK)結果測量將包括 daptomycin 的血漿濃度。
Inclution Criteria
Inclusion Criteria:
Subjects are required to meet ALL of the following inclusion criteria:
1. Informed consent in writing from parent(s) or legally-acceptable representative(s) and, informed assent
from subject (if age appropriate according to local requirements)
2. Male or female, 1 year to < 18 years old (subject must be randomized before 18th birthday). A
stepwise approach will be implemented to gate enrollment as follows: enrollment will begin with
children aged 2-17 years; after an external Drug Safety Monitoring Board (DSMB) review,
enrollment will be broadened to 1-17 years.
3. Presence of suspected or confirmed AHO warranting hospitalization and IV antibacterial therapy
4. Confirmed (I, II and III) or suspected (I and III) presence of AHO meeting the following criteria:
I. Acute onset or worsening ≤21 days before randomization of at least 2 of the following 7 clinical
symptom parameters (organized into 3 general categories; Appendix - 4), such that at least 1 category
(Pain, Inflammation or Limb Function) will be present and if only 1 category is present it needs to be
of at least moderate severity.
Pain
Localized pain
Point tenderness (on palpation)
Inflammation
Localized warmth in the affected area
Localized swelling in the affected area
Area of induration
Limb Function
Difficulty bearing weight on affected limb
Motion restriction and/or loss of function in affected limb
AND
II. At least 1 of the following:
Radiologic imaging (magnetic resonance imaging [MRI], bone scan, x-ray, or computed
tomography [CT] scan) consistent with osteomyelitis (per guidance in Appendix - 1) performed
within 7 days before randomization (or planned to occur within 7 days after randomization). If a
qualifying radiologic imaging study is inconclusive, follow-up radiologic imaging must be done
to confirm the diagnosis of AHO.
OR
A positive microbiological culture from a bone biopsy or bone aspirate (if available), or blood, or
presumptive evidence of gram-positive infection by Gram-stain of specimen, or positive PCR (or
other rapid detection method) testing.
AND
III. Presence of at least 1 of the following:
CRP > 5 mg/dL
Erythrocyte sedimentation rate (ESR) > 20 mm/hour
Leukocytosis (> 12,000 white blood cells [WBC]/mm3
), leukopenia (< 4000 WBC/mm3
), or
immature neutrophils [bands] (> 10% regardless of total peripheral WBC)
Fever > 38°C (100.4ºF) or hypothermia < 36°C (96.8ºF)
Note: Subjects enrolled with suspected AHO (I and III) will need radiologic or microbiologic
confirmation post-randomization for inclusion in MITT population.
5. Female subjects who have reached menarche must have a negative serum or urine pregnancy test
6. Female subjects who have reached menarche and are sexually active must be willing to practice
sexual abstinence or dual methods of birth control (e.g., condom or diaphragm with spermicidal foam
or gel) during treatment and for at least 28 days after the last dose of IV study drug (if no PO switch)
or PO therapy
Subjects are required to meet ALL of the following inclusion criteria:
1. Informed consent in writing from parent(s) or legally-acceptable representative(s) and, informed assent
from subject (if age appropriate according to local requirements)
2. Male or female, 1 year to < 18 years old (subject must be randomized before 18th birthday). A
stepwise approach will be implemented to gate enrollment as follows: enrollment will begin with
children aged 2-17 years; after an external Drug Safety Monitoring Board (DSMB) review,
enrollment will be broadened to 1-17 years.
3. Presence of suspected or confirmed AHO warranting hospitalization and IV antibacterial therapy
4. Confirmed (I, II and III) or suspected (I and III) presence of AHO meeting the following criteria:
I. Acute onset or worsening ≤21 days before randomization of at least 2 of the following 7 clinical
symptom parameters (organized into 3 general categories; Appendix - 4), such that at least 1 category
(Pain, Inflammation or Limb Function) will be present and if only 1 category is present it needs to be
of at least moderate severity.
Pain
Localized pain
Point tenderness (on palpation)
Inflammation
Localized warmth in the affected area
Localized swelling in the affected area
Area of induration
Limb Function
Difficulty bearing weight on affected limb
Motion restriction and/or loss of function in affected limb
AND
II. At least 1 of the following:
Radiologic imaging (magnetic resonance imaging [MRI], bone scan, x-ray, or computed
tomography [CT] scan) consistent with osteomyelitis (per guidance in Appendix - 1) performed
within 7 days before randomization (or planned to occur within 7 days after randomization). If a
qualifying radiologic imaging study is inconclusive, follow-up radiologic imaging must be done
to confirm the diagnosis of AHO.
OR
A positive microbiological culture from a bone biopsy or bone aspirate (if available), or blood, or
presumptive evidence of gram-positive infection by Gram-stain of specimen, or positive PCR (or
other rapid detection method) testing.
AND
III. Presence of at least 1 of the following:
CRP > 5 mg/dL
Erythrocyte sedimentation rate (ESR) > 20 mm/hour
Leukocytosis (> 12,000 white blood cells [WBC]/mm3
), leukopenia (< 4000 WBC/mm3
), or
immature neutrophils [bands] (> 10% regardless of total peripheral WBC)
Fever > 38°C (100.4ºF) or hypothermia < 36°C (96.8ºF)
Note: Subjects enrolled with suspected AHO (I and III) will need radiologic or microbiologic
confirmation post-randomization for inclusion in MITT population.
5. Female subjects who have reached menarche must have a negative serum or urine pregnancy test
6. Female subjects who have reached menarche and are sexually active must be willing to practice
sexual abstinence or dual methods of birth control (e.g., condom or diaphragm with spermicidal foam
or gel) during treatment and for at least 28 days after the last dose of IV study drug (if no PO switch)
or PO therapy
Exclusion Criteria
Exclusion Criteria:
Subjects must NOT meet any of the following exclusion criteria:
1. Documented history of any hypersensitivity or allergic reaction to daptomycin
2. Septic arthritis only (without AHO)
3. AHO of the spine
4. Chronic osteomyelitis (i.e. symptoms of osteomyelitis > 21 days) or osteomyelitis with complications
requiring non-routine surgical treatment (i.e. sequestration)
5. Major trauma, penetrating trauma (including a puncture wound of the foot), postoperative
osteomyelitis, foreign body in or adjacent to affected bone or joint, or other iatrogenic bone or joint
infections present at the site of infection
6. AHO due to a proven gram-negative organism
7. Presence of transient tenosynovitis, juvenile rheumatoid arthritis (JRA), reactive arthritis, bony tumors,
and other osteoarticular diseases suspected to be due to a nonbacterial (e.g., fungal or mycobacterial)
etiology
8. More than 24 hours of effective IV antibacterial therapy for AHO within 96 hours before
randomization. Exceptions: a) microbiological or clinical treatment failure with nonstudy IV
antibacterial therapy that was administered for at least 48 hours. Failure must be confirmed by either
microbiological laboratory report or documented worsening or no improvement of clinical signs or
symptoms; b) low-dose tetracycline derivative for acne (e.g., doxycycline 50 mg q12h); c) Prior
treatment with oral antibiotics if subject has worsening or no improvement of clinical signs and
symptoms
9. Requirement for any potentially effective concomitant systemic antibacterial therapy for gram-positive
infections
10. History of seizures, with the exception of well-documented febrile seizure of childhood; peripheral
neuropathy
11. History of rhabdomyolysis (with the exception of muscle injury due to trauma)
12. Sickle cell anemia
13. Subjects in whom clinical assessments of AHO (e.g., localized pain, point tenderness, localized
warmth, localized swelling, induration, difficulty bearing weight, motion restriction and/or loss of
function) may not be possible (e.g., due to a surgical procedure resulting in non-removable cast or
splint placement) during the first several days post randomization
14. Any condition (e.g., cystic fibrosis, current septic shock) that would make the subject, in the opinion
of the Investigator, unsuitable for the study (e.g., would place a subject at risk or compromise the
quality of the data), or evidence of immediately life-threatening disease, progressively fatal disease, or
life expectancy of 6 months or less
15. Creatinine clearance (CrCl) < 50 mL/min/1.73 m2
as calculated using the updated Schwartz “bedside”
formula:
16. Evidence of significant hepatic, hematologic, or immunologic dysfunction as defined by the
following:
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 5 times the upper
limit of normal (× ULN) or bilirubin level > 2 × ULN
Neutropenia (< 500 neutrophils/mm3
)
Thrombocytopenia (< 50,000 platelets/mm3
)
If human immunodeficiency virus (HIV) positive, CD4 count < 200 cells/mm3
at the last
measurement, history of AIDS-defining illness within the last year, or at risk for HIV if child
is < 18 months of age
Bone marrow or solid organ recipients who have had an episode of graft versus host disease
or acute rejection episode, respectively, within the last 6 months; and/or bone marrow
ablative therapy, including bone marrow transplantation, within the last 12 months
Diagnosis of any primary immunodeficiency disorders
17. Creatine kinase (CK) elevation ≥ 10 × ULN (upper limit of normal) without symptoms or ≥ 5 × ULN
with symptoms
18. Females who are currently pregnant or breastfeeding
19. Participation in any study involving administration of an investigational agent or device within
30 days before the start of first dose of IV study drug or previously participated in the current study or
in another study of daptomycin (in which an active agent was received)
20. Unable or unwilling to adhere to the study-specified procedures and restrictions
21. Has suspected or confirmed pneumonia, empyema, meningitis, or endocarditis. Note: septic emboli
in the lung is not an exclusion if clear evidence of source of infection is other than lungs.
Subjects must NOT meet any of the following exclusion criteria:
1. Documented history of any hypersensitivity or allergic reaction to daptomycin
2. Septic arthritis only (without AHO)
3. AHO of the spine
4. Chronic osteomyelitis (i.e. symptoms of osteomyelitis > 21 days) or osteomyelitis with complications
requiring non-routine surgical treatment (i.e. sequestration)
5. Major trauma, penetrating trauma (including a puncture wound of the foot), postoperative
osteomyelitis, foreign body in or adjacent to affected bone or joint, or other iatrogenic bone or joint
infections present at the site of infection
6. AHO due to a proven gram-negative organism
7. Presence of transient tenosynovitis, juvenile rheumatoid arthritis (JRA), reactive arthritis, bony tumors,
and other osteoarticular diseases suspected to be due to a nonbacterial (e.g., fungal or mycobacterial)
etiology
8. More than 24 hours of effective IV antibacterial therapy for AHO within 96 hours before
randomization. Exceptions: a) microbiological or clinical treatment failure with nonstudy IV
antibacterial therapy that was administered for at least 48 hours. Failure must be confirmed by either
microbiological laboratory report or documented worsening or no improvement of clinical signs or
symptoms; b) low-dose tetracycline derivative for acne (e.g., doxycycline 50 mg q12h); c) Prior
treatment with oral antibiotics if subject has worsening or no improvement of clinical signs and
symptoms
9. Requirement for any potentially effective concomitant systemic antibacterial therapy for gram-positive
infections
10. History of seizures, with the exception of well-documented febrile seizure of childhood; peripheral
neuropathy
11. History of rhabdomyolysis (with the exception of muscle injury due to trauma)
12. Sickle cell anemia
13. Subjects in whom clinical assessments of AHO (e.g., localized pain, point tenderness, localized
warmth, localized swelling, induration, difficulty bearing weight, motion restriction and/or loss of
function) may not be possible (e.g., due to a surgical procedure resulting in non-removable cast or
splint placement) during the first several days post randomization
14. Any condition (e.g., cystic fibrosis, current septic shock) that would make the subject, in the opinion
of the Investigator, unsuitable for the study (e.g., would place a subject at risk or compromise the
quality of the data), or evidence of immediately life-threatening disease, progressively fatal disease, or
life expectancy of 6 months or less
15. Creatinine clearance (CrCl) < 50 mL/min/1.73 m2
as calculated using the updated Schwartz “bedside”
formula:
16. Evidence of significant hepatic, hematologic, or immunologic dysfunction as defined by the
following:
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 5 times the upper
limit of normal (× ULN) or bilirubin level > 2 × ULN
Neutropenia (< 500 neutrophils/mm3
)
Thrombocytopenia (< 50,000 platelets/mm3
)
If human immunodeficiency virus (HIV) positive, CD4 count < 200 cells/mm3
at the last
measurement, history of AIDS-defining illness within the last year, or at risk for HIV if child
is < 18 months of age
Bone marrow or solid organ recipients who have had an episode of graft versus host disease
or acute rejection episode, respectively, within the last 6 months; and/or bone marrow
ablative therapy, including bone marrow transplantation, within the last 12 months
Diagnosis of any primary immunodeficiency disorders
17. Creatine kinase (CK) elevation ≥ 10 × ULN (upper limit of normal) without symptoms or ≥ 5 × ULN
with symptoms
18. Females who are currently pregnant or breastfeeding
19. Participation in any study involving administration of an investigational agent or device within
30 days before the start of first dose of IV study drug or previously participated in the current study or
in another study of daptomycin (in which an active agent was received)
20. Unable or unwilling to adhere to the study-specified procedures and restrictions
21. Has suspected or confirmed pneumonia, empyema, meningitis, or endocarditis. Note: septic emboli
in the lung is not an exclusion if clear evidence of source of infection is other than lungs.
The Estimated Number of Participants
-
Taiwan
20 participants
-
Global
144 participants
