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Personalized AZithromycin/metronidAZole Therapy in Pediatric Crohn's Disease (CD) (PAZAZ)

Primary Purpose

Crohn Disease, Pediatric Crohns Disease

Status

Recruiting

Phase

Phase 2

Locations

International

Study Type

Interventional

Intervention

Azithromycin

Metronidazole

Standard of Care

About this trial

This is an interventional treatment trial for Crohn Disease focused on measuring Microbiome

Eligibility Criteria

3 Years - 17 Years (Child)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Provision of signed and dated informed consent form (and assent form, as applicable);
Stated willingness to comply with all study procedures and availability for the duration of the study;
Male or female, aged 3 to 17 years;
Diagnosed with CD according to standard clinical and histological criteria, within 36 months of week 0;
Exhibiting mild to moderate symptoms of active disease, as determined by a PCDAI score >10 (or > 7.5 excluding the height item) and ≤37.5;
Fecal calprotectin level >=250 µg/g within 30 days prior to week 0 visit based on local measurement, if available, or to be arranged with lead site if an endoscopy is not performed within 30 days prior to week 0 visit.

Exclusion Criteria:

Current or previous use of biologic therapy;
Presence of stricturing, penetrating (intestinal or perianal) and/or fistulizing CD;
Pregnancy or lactation;
Have undergone intestinal resection;
Positive Clostridium Difficile toxin;
Treatment with another investigational drug or other intervention within 30 days before week 0;
Risk factors for arrhythmia including history of prolonged corrected QT interval (QTc), hypokalemia or hypomagnesemia, resting bradycardia, or concurrent treatment with other drugs with potential for QT prolongation;
History of cockayne syndrome;
Prior diagnosis of any hematologic condition/blood dyscrasia which may result in leukopenia (even if leukocyte count is normal at screening);
Known allergy or intolerance to azithromycin or metronidazole;
Subjects who received intravenous anti-infective within 35 days prior to week 0 visit or anti-infectives within 14 days prior to the week 0 visit;
Subject on oral aminosalicylates who has not been on stable doses for greater than, or discontinued within, at least 14 days prior to week 0;
Subject on cyclosporine, tacrolimus or mycophenolate mofetil. Stable doses (no change within 14 days prior to week 0) of azathioprine, 6-mercaptopurine or methotrexate (MTX) are not a reason for exclusion;
Subject who received fecal microbial transplantation within 35 days prior to week 0 visit;
Screening laboratory and other analyses show any of the following abnormal results:
- aspartate transaminase (AST), alanine transaminase (ALT) > 2 X upper limit of the reference range,
- White blood cell (WBC) count < 3.0 X 109/L,
- Total bilirubin >= 20 micromol/liter (1.17 mg/dL); except for subjects with isolated elevation of indirect bilirubin relating to Gilbert syndrome,
- Estimated glomerular filtration rate (GFR) by simplified 4-variable Modification of Diet in Renal Disease (MDRD) formula of < 30 mL/min/1.73 m²,
- Hemoglobin < 80 gram/liter,
- Platelets < 100,000/µL.

Sites / Locations

UCSF Benioff Children's Hospital
University of Pittsburgh Medical Center, Children's Hospital of Pittsburgh
IWK Health Centre
Wolfson Medical Centre
Amsterdam UMCRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Other

Experimental

Arm Label

Standard of Care

Standard of Care + Antibiotics

Arm Description

SOC induction (nutritional therapy) for up to 12 weeks, as assigned by the treating gastroenterologist prior to study entry.

SOC induction (nutritional therapy) for up to 12 weeks, as assigned by the treating gastroenterologist prior to study entry. Azithromycin (weeks 4-12) Metronidazole (weeks 4-12)

Outcomes

Primary Outcome Measures

Percent of Subjects with Sustained Remission

Subjects without need for re-induction for clinical flare (new course of nutritional therapy, need to restart steroids), steroid dependence, biologic (e.g. anti-TNF) use, and/or intestinal surgery

Feasibility of multinational microbiome-randomized trial

Proportion of subjects that are successfully randomized in randomization procedure, proportion of patients per treatment arm, proportion of subjects that complete 1 year endpoint

Secondary Outcome Measures

Change in Pediatric Crohn's Disease Activity Index (PCDAI) Score over Baseline to Week 52

Pediatric Crohn's Disease Activity Index (PCDAI) is an index used to measure disease activity of pediatric patients with Crohn's Disease assessing abdominal pain, stool frequency, patient functioning, hematocrit, erythrocyte sedimentation rate, albumin, weight, height, examination of abdomen, perirectal disease, and extraintestinal manifestations. Scores range from 0 to 100, with higher scores indicating greater disease activity.

Change in Fecal Calprotectin Levels in Stool over Baseline to Week 52

Fecal calprotectin is a non-invasive surrogate protein marker for bowel inflammation.

Change in C-Reactive Protein (CRP) Levels in Blood over Baseline to Week 52

CRP is a blood protein marker of inflammation. CRP levels are classified as 'normal/low' or 'elevated/high' based on standard laboratory reference ranges.

Change in IMPACT-III Score over Baseline to Week 52

The IMPACT III questionnaire is a 35-item assessment of health-related quality of life in patients with inflammatory bowel disease (Crohn's disease [CD] or ulcerative colitis). In this study, subjects aged 9 and older will complete this questionnaire at week 0, 12, 24, and 52. Subjects mark an option from 1 to 5 for each item.The total scores range from 35 to 175, with higher scores representing a better quality of life.

Full Information

NCT ID

NCT04186247

First Posted

December 2, 2019

Last Updated

October 2, 2023

Sponsor

University of North Carolina, Chapel Hill

Collaborators

Crohn's and Colitis Foundation, University of Amsterdam

1. Study Identification

Unique Protocol Identification Number

NCT04186247

Brief Title

Personalized AZithromycin/metronidAZole Therapy in Pediatric Crohn's Disease (CD)

Acronym

PAZAZ

Official Title

Personalized AZithromycin/metronidAZole, in Combination With Standard Induction Therapy, to Achieve a Fecal Microbiome Community Structure and Metagenome Changes Associated With Sustained Remission in Pediatric Crohn's Disease (CD): a Pilot Study

Study Type

Interventional

2. Study Status

Record Verification Date

May 2023

Overall Recruitment Status

Recruiting

Study Start Date

August 13, 2021 (Actual)

Primary Completion Date

December 2023 (Anticipated)

Study Completion Date

December 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

University of North Carolina, Chapel Hill

Collaborators

Crohn's and Colitis Foundation, University of Amsterdam

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

This is a multi-center, randomized, controlled open-label add-on design trial pilot study to evaluate the efficacy of personalized adjunctive antibiotic (azithromycin + metronidazole) therapy in pediatric subjects with mild to moderate Crohn's disease (CD) who have a microbiome profile associated with increased risk of early relapse. This an add-on design trial for subjects already receiving standard of care therapy to induce remission; there will be no placebos.

Detailed Description

The study hypothesis is that adjunctive antibiotic therapy will improve clinical response to standard of care (SOC) induction therapy in a subgroup of CD patients with a relapse-associated microbiome profile. Prior to starting SOC induction therapy at week 0, subjects will provide a baseline stool sample that will be screened for microbiome profiles associated with risk of relapse according to an established statistical model. At week 4, subjects with a relapse-associated microbiome will be randomized into either a control arm that will continue to receive SOC induction therapy for an additional 8 weeks, or a treatment arm that will receive adjunctive antibiotic therapy in addition to continuing to receive SOC induction therapy for an additional 8 weeks. Subjects who do not have a relapse-associated microbiome will enter a separate control arm that will continue to receive SOC induction therapy and will have data collected for exploratory objectives. Subjects who are not in clinical remission by week 4 will receive antibiotic therapy regardless of microbiome signature at baseline. Subjects will be monitored for an additional 40 weeks after the treatment period (52 weeks total).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Crohn Disease, Pediatric Crohns Disease

Keywords

Microbiome

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

20 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Standard of Care

Arm Type

Other

Arm Description

SOC induction (nutritional therapy) for up to 12 weeks, as assigned by the treating gastroenterologist prior to study entry.

Arm Title

Standard of Care + Antibiotics

Arm Type

Experimental

Arm Description

SOC induction (nutritional therapy) for up to 12 weeks, as assigned by the treating gastroenterologist prior to study entry. Azithromycin (weeks 4-12) Metronidazole (weeks 4-12)

Intervention Type

Drug

Intervention Name(s)

Azithromycin

Other Intervention Name(s)

Zithromax, Zmax

Intervention Description

Weeks 4-12: 7.5 mg/kg azithromycin once daily (500 mg/day maximum) for five consecutive days/ week for 4 weeks, and 3 times a week for the following 4 weeks

Intervention Type

Drug

Intervention Name(s)

Metronidazole

Other Intervention Name(s)

Flagyl

Intervention Description

Weeks 4-12: 20 mg/kg/day of metronidazole (10 mg/kg twice daily to a maximum of 1000 mg/day) for 8 weeks

Intervention Type

Other

Intervention Name(s)

Standard of Care

Intervention Description

SOC induction therapy is nutritional therapy (Crohn's disease exclusion diet + partial enteral nutrition) for up to 12 weeks. Induction therapy is as assigned by the treating gastroenterologist prior to study entry.

Primary Outcome Measure Information:

Title

Percent of Subjects with Sustained Remission

Description

Subjects without need for re-induction for clinical flare (new course of nutritional therapy, need to restart steroids), steroid dependence, biologic (e.g. anti-TNF) use, and/or intestinal surgery

Time Frame

Week 52

Title

Feasibility of multinational microbiome-randomized trial

Description

Proportion of subjects that are successfully randomized in randomization procedure, proportion of patients per treatment arm, proportion of subjects that complete 1 year endpoint

Time Frame

week 52

Secondary Outcome Measure Information:

Title

Change in Pediatric Crohn's Disease Activity Index (PCDAI) Score over Baseline to Week 52

Description

Time Frame

Baseline to Week 52

Title

Change in Fecal Calprotectin Levels in Stool over Baseline to Week 52

Description

Fecal calprotectin is a non-invasive surrogate protein marker for bowel inflammation.

Time Frame

Baseline to Week 52

Title

Change in C-Reactive Protein (CRP) Levels in Blood over Baseline to Week 52

Description

CRP is a blood protein marker of inflammation. CRP levels are classified as 'normal/low' or 'elevated/high' based on standard laboratory reference ranges.

Time Frame

Baseline to Week 52

Title

Change in IMPACT-III Score over Baseline to Week 52

Description

Time Frame

Baseline to Week 52

10. Eligibility

Sex

All

Minimum Age & Unit of Time

3 Years

Maximum Age & Unit of Time

17 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Provision of signed and dated informed consent form (and assent form, as applicable); Stated willingness to comply with all study procedures and availability for the duration of the study; Male or female, aged 3 to 17 years; Diagnosed with CD according to standard clinical and histological criteria, within 36 months of week 0; Exhibiting mild to moderate symptoms of active disease, as determined by a PCDAI score >10 (or > 7.5 excluding the height item) and ≤37.5; Fecal calprotectin level >=250 µg/g within 30 days prior to week 0 visit based on local measurement, if available, or to be arranged with lead site if an endoscopy is not performed within 30 days prior to week 0 visit. Exclusion Criteria: Current or previous use of biologic therapy; Presence of stricturing, penetrating (intestinal or perianal) and/or fistulizing CD; Pregnancy or lactation; Have undergone intestinal resection; Positive Clostridium Difficile toxin; Treatment with another investigational drug or other intervention within 30 days before week 0; Risk factors for arrhythmia including history of prolonged corrected QT interval (QTc), hypokalemia or hypomagnesemia, resting bradycardia, or concurrent treatment with other drugs with potential for QT prolongation; History of cockayne syndrome; Prior diagnosis of any hematologic condition/blood dyscrasia which may result in leukopenia (even if leukocyte count is normal at screening); Known allergy or intolerance to azithromycin or metronidazole; Subjects who received intravenous anti-infective within 35 days prior to week 0 visit or anti-infectives within 14 days prior to the week 0 visit; Subject on oral aminosalicylates who has not been on stable doses for greater than, or discontinued within, at least 14 days prior to week 0; Subject on cyclosporine, tacrolimus or mycophenolate mofetil. Stable doses (no change within 14 days prior to week 0) of azathioprine, 6-mercaptopurine or methotrexate (MTX) are not a reason for exclusion; Subject who received fecal microbial transplantation within 35 days prior to week 0 visit; Screening laboratory and other analyses show any of the following abnormal results: aspartate transaminase (AST), alanine transaminase (ALT) > 2 X upper limit of the reference range, White blood cell (WBC) count < 3.0 X 109/L, Total bilirubin >= 20 micromol/liter (1.17 mg/dL); except for subjects with isolated elevation of indirect bilirubin relating to Gilbert syndrome, Estimated glomerular filtration rate (GFR) by simplified 4-variable Modification of Diet in Renal Disease (MDRD) formula of < 30 mL/min/1.73 m², Hemoglobin < 80 gram/liter, Platelets < 100,000/µL.

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Johan E Van Limbergen, MD, PhD

Phone

31- 20 566 3053

j.e.vanlimbergen@ansterdamumc.nl

First Name & Middle Initial & Last Name or Official Title & Degree

Charlotte M Verburgt, MD

Phone

0031650063243

c.m.verburgt@amsterdamumc.nl

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Johan E Van Limbergen, MD, PhD

Organizational Affiliation

Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

Arie Levine, MD

Organizational Affiliation

Edith Wolfson Medical Centre, Tel Aviv

Official's Role

Study Chair

First Name & Middle Initial & Last Name & Degree

Francisco Sylvester, MD

Organizational Affiliation

University North Carolina

Official's Role

Study Chair

Facility Information:

Facility Name

UCSF Benioff Children's Hospital

City

San Francisco

State/Province

California

ZIP/Postal Code

94158

Country

United States

Individual Site Status

Not yet recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Melvin Heyman, MD

First Name & Middle Initial & Last Name & Degree

Sofia Verstraete, MD

Facility Name

University of Pittsburgh Medical Center, Children's Hospital of Pittsburgh

City

Pittsburgh

State/Province

Pennsylvania

ZIP/Postal Code

15224

Country

United States

Individual Site Status

Not yet recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Withney Sunseri, MD

whitney.sunseri@chp.edu

Facility Name

IWK Health Centre

City

Halifax

Country

Canada

Individual Site Status

Not yet recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Anthony Otley, MD

Facility Name

Wolfson Medical Centre

City

Tel Aviv

Country

Israel

Individual Site Status

Not yet recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Arie Levine, MD

Facility Name

Amsterdam UMC

City

Amsterdam

Country

Netherlands

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Johan Van Limbergen, MD

First Name & Middle Initial & Last Name & Degree

Tim de Meij, MD

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing Plan Description

Deidentified individual data that supports the results will be shared beginning 9 to 36 months following publication provided the investigator who proposes to use the data has approval from an Institutional Review Board (IRB), Independent Ethics Committee (IEC), or Research Ethics Board (REB), as applicable, and executes a data use/sharing agreement with University of North Carolina.

IPD Sharing Time Frame

Beginning 9 to 36 months following publication

IPD Sharing Access Criteria

IRB, IEC, or REB approval, as applicable, and an executed data use/sharing agreement with University of North Carolina.

Learn more about this trial

Personalized AZithromycin/metronidAZole Therapy in Pediatric Crohn's Disease (CD)

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