UMIN-CTR Clinical Trial

Public title

Optimizing Short-term Antibiotic Treatment in Acute Cholangitis: rationale and study protocol for an open-label randomized controlled trial - The BOLT-P3 Trial (Biliary Optimal Limited Treatment - Phase 3)

Acronym

BOLT-P3

Scientific Title

Optimizing Short-term Antibiotic Treatment in Acute Cholangitis: rationale and study protocol for an open-label randomized controlled trial - The BOLT-P3 Trial (Biliary Optimal Limited Treatment - Phase 3)

Scientific Title:Acronym

BOLT-P3

Region

Japan

Condition

Acute cholangitis

Classification by specialty

Hepato-biliary-pancreatic medicine

Classification by malignancy

Others

Genomic information

NO

Narrative objectives1

The recommended duration of antibiotics for acute cholangitis globally is based largely on retrospective studies. In recent years, there has been an increase in retrospective studies suggesting the possibility of shortening the administration period. Concurrently, research on the emergence of resistant bacteria due to long-term administration and the adverse effects of antibiotics themselves has advanced. Therefore, it is presumed that short-course treatments are not inferior to current standard treatments based on evidence could lead to a reduction in the emergence of resistant bacteria, adverse antibiotic events, hospital stay durations, and medical costs.

Basic objectives2

Efficacy

Basic objectives -Others

Trial characteristics_1

Confirmatory

Trial characteristics_2

Developmental phase

Phase III

Primary outcomes

The primary outcome is defined as the rate of cases that achieve clinical cure within 14 days and survive without recurrence.

Key secondary outcomes

The secondary outcomes are as follows:

Recurrence rate within 30 days.
Mortality rate within 30 days.
Total days of antibiotics required for both groups within 30 days.
Total days of hospitalization required for both groups within 30 days.
Clinical cure rates by severity.
Clinical cure rates by fever presence or absence at the end of antibiotic treatment.
Clinical cure rates in patients aged 75 and older.
Clinical cure rates based on blood culture results.
Clinical cure rates based on bile culture results.
Clinical cure rates by antibiotic susceptibility prior to ERCP.
Clinical cure rates based on antibiotic duration prior to ERCP.
Clinical cure rates based on time from admission to ERCP.
Clinical cure rates based on the etiology of acute cholangitis (AC).
Treatment costs.
Incidence of adverse events within 14 days:
(a) Rash
(b) Diarrhea (three or more loose stools daily)
(c) C. difficile enteritis: confirmed by diarrhea (three or more formless stools within 24 hours) and detection of C. difficile toxin A/B in stool or positive stool antigen, culture, or specific genes.
(d) Drug-induced liver injury: any of the following:
ALT elevation >5 times upper limit of normal (ULN)
ALP elevation >2 times ULN
ALT >3 times ULN with total bilirubin >2 times ULN Additionally, recurrence is indicated if imaging shows no worsening biliary duct dilation or if hepatic/biliary enzyme levels re-elevate after initially decreasing.
(e) Acute kidney injury: if any of the following occur within 48 hours:
Increase in serum creatinine by 0.3 mg/dL or more within 48 hours from initial antibiotic administration.
Increase in serum creatinine to 1.5 times baseline from initial antibiotic administration until treatment ends.
Serum creatinine results will be included from this period, even if measured on non-scheduled days. Baseline is defined as the creatinine value within one year before the trial. If unknown, the lowest value within 7 days before the end of treatment will be used.

Study type

Interventional

Basic design

Parallel

Randomization

Randomized

Randomization unit

Individual

Blinding

Open -no one is blinded

Control

Active

Stratification

YES

Dynamic allocation

Institution consideration

Blocking

Concealment

No. of arms

2

Purpose of intervention

Treatment

Type of intervention

Medicine

Interventions/Control_1

This study aims to verify that the efficacy of antibiotic treatment for acute cholangitis following biliary drainage in the trial treatment group, lasting 24-72 hours, is not inferior to that in the standard treatment group, which lasts 96-168 hours.

For the trial treatment group (method and type of antibiotic administration):
Antibiotics are principally administered intravenously. The administration period is 24-72 hours after sufficient biliary drainage has been achieved. To clarify the difference from the standard treatment group, the antibiotic administration duration is specifically set to 24-72 hours. Similar to the standard treatment group, following the recommendations of TG18, a choice is made from aminoglycosides, carbapenems, cephalosporins, fluoroquinolones, sulfonamides, and penicillins. The specific choice of medication is not strictly defined but may be altered based on allergies, local protocols, and previous culture results.

Interventions/Control_2

For the standard treatment group (method and type of antibiotic administration):
Antibiotics are principally administered intravenously. The administration period is 96-168 hours after sufficient biliary drainage has been achieved. To clearly differentiate from the trial treatment group, the antibiotic administration duration in this study is specifically set to 96-168 hours. Following the recommendations of Tokyo Guideline 2018 (TG18), a choice is made from aminoglycosides, carbapenems, cephalosporins, fluoroquinolones, sulfonamides, and penicillins. The specific choice of medication is not strictly defined but may be altered based on allergies, local protocols, and previous culture results.

Interventions/Control_3

Interventions/Control_4

Interventions/Control_5

Interventions/Control_6

Interventions/Control_7

Interventions/Control_8

Interventions/Control_9

Interventions/Control_10

Age-lower limit

18

years-old

<=

Age-upper limit

Not applicable

Gender

Male and Female

Key inclusion criteria

Participants must meet all of the following criteria:
1. Disease: Patients diagnosed with AC in accordance with the TG18, regardless of benign or malignant nature. However, for patients with AC due to dysfunction of distal bile duct stents, inclusion is limited to those who have had a stent in place for more than 30 days.
2. Age: 18 years or older.
3. Previous Treatment: Cases where biliary obstruction has been technically successfully relieved through biliary drainage procedures with ERCP within 48 hours of hospitalization.
4. Consent: Written consent obtained from the patient or their legal representative for participation in this trial.

Key exclusion criteria

Circulatory insufficiency with catecholamines at ERCP time. ICU need. Hypothermia below 35 degrees Celsius. Recurrent cholangitis within 3 months. Biliary stricture >= Bismuth 2 or unclear biliary block. Post-surgery anatomical changes like biliary-jejunal anastomosis. Pancreatitis per International Pancreatic Society/American Pancreatic Association: Upper abdominal pain, serum amylase/lipase >3x ULN, acute pancreatitis imaging. Cholecystitis by TG18: A (Murphy's sign/right upper quadrant issues) + B (fever >37.1 degrees Celsius, CRP >3.0 mg/dL, WBC >10,000 uL) + C (acute cholecystitis imaging). Hepatic abscess. Other infections. Pre-registration continuous antibiotics. Pre-registration ERCP complications (perforation, pancreatitis, bleeding, cholecystitis, sedation-related issues). Immunosuppression: A (>10 mg prednisolone), B (HIV), C (neutrophils <=1500 uL), D (recent hematopoietic stem cell transplantation). Pregnancy. Other exclusions by physician.

Target sample size

210

Name of lead principal investigator

1st name	Sakue
Middle name
Last name	Masuda

Organization

Shonan Kamakura General Hospital

Division name

Gastroenterology medicine center

Zip code

247-8533

Address

Okamoto 1370-1, Kamakura, Kanagawa

TEL

0467-46-1717

Email

sakue.masuda@tokushukai.jp

Name of contact person

1st name	Sakue
Middle name
Last name	Masuda

Organization

Shonan Kamakura General Hospital

Division name

Gastroenterology medicine center

Zip code

247-8533

Address

Okamoto 1370-1, Kamakura, Kanagawa

TEL

0467-46-1717

Homepage URL

Email

sakue.masuda@tokushukai.jp

Institute

Shonan Kamakura General Hospital

Institute

Department

Personal name

Organization

Shonan Kamakura General Hospital

Organization

Division

Category of Funding Organization

Self funding

Nationality of Funding Organization

Co-sponsor

Name of secondary funder(s)

Organization

The Tokushukai Group Ethics Committee

Address

Tokyodo Chiyoda Bldg. 15F, 1-3-1, Kudan-minami, Chiyoda-ku, Tokyo 102-0074, Japan

Tel

03-3263-4801

Email

homepage@tokushukai.jp

Secondary IDs

NO

Study ID_1

Org. issuing International ID_1

Study ID_2

Org. issuing International ID_2

IND to MHLW

Institutions

Date of disclosure of the study information

2024

Year

04

Month

09

Day

URL releasing protocol

Publication of results

Unpublished

URL related to results and publications

Number of participants that the trial has enrolled

Results

Results date posted

Results Delayed

Results Delay Reason

Date of the first journal publication of results

Baseline Characteristics

Participant flow

Adverse events

Outcome measures

Plan to share IPD

IPD sharing Plan description

Recruitment status

Open public recruiting

Date of protocol fixation

2024

Year

03

Month

07

Day

Date of IRB

2024

Year

03

Month

07

Day

Anticipated trial start date

2024

Year

04

Month

15

Day

Last follow-up date

2027

Year

03

Month

31

Day

Date of closure to data entry

Date trial data considered complete

Date analysis concluded

Other related information

Registered date

2024

Year

04

Month

05

Day

Last modified on

2024

Year

11

Month

01

Day

Link to view the page

Value
https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000061735