- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02054156
OPTIMIZing Treatment for Early Pseudomonas Aeruginosa Infection in Cystic Fibrosis (OPTIMIZE)
OPTIMIZing Treatment for Early Pseudomonas Aeruginosa Infection in Cystic Fibrosis: The OPTIMIZE Multicenter, Placebo-Controlled, Double-Blind, Randomized Trial
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
Cystic fibrosis (CF) lung disease begins in the first few months of life and follows a course of recurrent lower airway bacterial infection and inflammation and progression of disease over years and decades at a variable pace. With the development of chronic lung infection, obstructive disease progressively worsens, ultimately leading to respiratory failure. Pseudomonas aeruginosa (Pa) is the most important pathogen infecting the CF lower airways, and its acquisition early in life is associated with a pro-inflammatory effect, lower lung function, poor nutritional outcomes, and decreased survival.
Pseudomonas aeruginosa (Pa) infection of the cystic fibrosis (CF) airway typically proceeds from early infection to chronic infection. Although some studies have shown that a minority of individuals with CF spontaneously clear early Pseudomonas aeruginosa (Pa) infection, data from multiple studies suggest that antibiotics are superior to no treatment in clearing Pseudomonas aeruginosa (Pa) from respiratory cultures. Understanding the transition period from early to chronic Pseudomonas aeruginosa (Pa) infection is thus of critical importance in identifying strategies to prevent this progression.
The study will assess the clinical and microbiologic efficacy and safety of azithromycin given three times weekly in combination with standardized tobramycin solution for inhalation (TIS) therapy among children with early Pseudomonas aeruginosa (Pa). TIS therapy is defined as an initial eradication treatment with 1-2 courses of 28 days TIS and subsequent 28 day treatments only at times a quarterly respiratory culture is positive for Pseudomonas aeruginosa (Pa). Eligible participants will be randomized within one month of their Pseudomonas aeruginosa (Pa) positive culture to receive one of the following two treatment strategies for 18 months: (1) oral placebo in addition to standardized TIS therapy, or (2) oral azithromycin in addition to standardized TIS therapy.
At the first study visit, participants will undergo a physical examination and a review of their medical history. Lung function will be measured via spirometry (in children greater than four years of age who are able to perform spirometry), electrocardiogram (ECG) testing will be conducted, and hearing ability will be measured via audiometry. Blood will be drawn for laboratory tests and a specimen will be obtained for a respiratory culture before randomization and study drug dispensing occurs. Subsequent study visits will take place at Day 21, Weeks 13, 26, 39, 52, 65, and 78. At each visit, participants will undergo a physical examination, a spirometry test (as appropriate), a respiratory specimen for Pseudomonas aeruginosa (Pa) culture will be collected and study drug will be dispensed (except at Week 78). Participants will complete self-report or parent-completed respiratory symptom questionnaires and signs and symptoms evaluations will be performed at all visits. Repeat hearing and laboratory tests will be performed at Weeks 39 and 78 and ECG testing will be repeated at Day 21 and Week 78. Participants will be required to maintain a medication diary throughout the study.
Study Type
Enrollment (Actual)
Phase
- Phase 3
Contacts and Locations
Study Locations
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Alaska
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Anchorage, Alaska, United States, 99519-6604
- CFF Affiliate Program Providence Medical Center
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Arizona
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Tucson, Arizona, United States, 85724
- CFF Care Center Arizona Health Science Center
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Arkansas
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Little Rock, Arkansas, United States, 72202
- CFF Care Center & Pediatric Program Arkansas Children's Hospital
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California
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Los Angeles, California, United States, 90027
- Childrens Hospital Los Angeles
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Palo Alto, California, United States, 94304
- CFF Care Center & Pediatric Program Stanford University
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Colorado
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Aurora, Colorado, United States, 80045
- CFF Care Center & Pediatric Program Children's Hospital Colorado
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Connecticut
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New Haven, Connecticut, United States, 06520
- CFF Care Center & Pediatric Program Yale University
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Florida
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Jacksonville, Florida, United States, 32207
- CFF Care Center & Pediatric Program Nemours Children's Clinic - Jacksonville
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Saint Petersburg, Florida, United States, 33701
- CFF Care Center & Pediatric Program All Children's Hospital
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Georgia
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Atlanta, Georgia, United States, 30324
- CFF Care Center & Pediatric Program Emory University
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Atlanta, Georgia, United States, 30342
- CFF Affiliate Program Children's Healthcare of Atlanta
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Idaho
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Boise, Idaho, United States, 83712
- CFF Care Center St. Luke's CF Clinic
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Illinois
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Chicago, Illinois, United States, 60611-2605
- CFF Care Center & Pediatric Program Ann & Robert H. Lurie Children's Hospital of Chicago
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Indiana
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Indianapolis, Indiana, United States, 46202-5271
- CFF Care Center & Pediatric Program Riley Hospital for Children
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Iowa
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Iowa City, Iowa, United States, 52242
- CFF Care Center & Pediatric Program University of Iowa
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Maine
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Portland, Maine, United States, 04102
- CFF Care Center & Pediatric Program Maine Medical Center
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Massachusetts
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Boston, Massachusetts, United States, 02115
- CFF Care Center & Pediatric Program Children's Hospital Boston
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Michigan
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Ann Arbor, Michigan, United States, 48109-5212
- CFF Care Center & Pediatric Program University of Michigan
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Detroit, Michigan, United States, 48201
- CFF Care Center & Pediatric Program Children's Hospital of Michigan
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Missouri
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Kansas City, Missouri, United States, 64108
- CFF Care Center The Children's Mercy Hospital
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Saint Louis, Missouri, United States, 63104
- CFF Care Center & Pediatric Program Cardinal Glennon Children's Hospital/Saint Louis University
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Saint Louis, Missouri, United States, 63110
- CFF Care Center & Pediatric Program St. Louis Children's Hospital
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Nebraska
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Omaha, Nebraska, United States, 68198
- CFF Care Center & Pediatric Program University of Nebraska Medical Center
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New Jersey
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Long Branch, New Jersey, United States, 07740
- CFF Care Center & Pediatric Program Monmouth Medical Center
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New York
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New York, New York, United States, 10032
- CFF Care Center & Pediatric Program Columbia University
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Syracuse, New York, United States, 13210
- CFF Care Center & Pediatric Program SUNY Upstate Medical University
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Valhalla, New York, United States, 10595
- CFF Care Center New York Medical College
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North Carolina
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Chapel Hill, North Carolina, United States, 27599
- CFF Care Center & Pediatric Program University of North Carolina at Chapel Hill
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Ohio
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Akron, Ohio, United States, 44308
- CFF Care Center & Pediatric Program Akron Children's Hospital
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Cincinnati, Ohio, United States, 45229
- CFF Care Center & Pediatric Program Cincinnati Children's Hospital Medical Center
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Cleveland, Ohio, United States, 44106
- CFF Care Center & Pediatric Program Rainbow Babies and Children's Hospital
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Columbus, Ohio, United States, 43205
- CFF Care Center & Pediatric Program Nationwide Children's Hospital
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Dayton, Ohio, United States, 45404
- CFF Care Center & Pediatric Program The Children's Medical Center
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Oregon
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Portland, Oregon, United States, 97239
- CFF Care Center & Pediatric Program Oregon Health & Sciences University
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Pennsylvania
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Hershey, Pennsylvania, United States, 17033
- CFF Care Center & Pediatric Program Hershey Medical Center
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Pittsburgh, Pennsylvania, United States, 15224
- CFF Care Center & Pediatric Program Children's Hospital of Pittsburgh
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South Dakota
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Sioux Falls, South Dakota, United States, 57117
- CFF Care Center & Pediatric Program Sanford USD Medical Center
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Tennessee
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Memphis, Tennessee, United States, 38103
- CFF Care Center & Pediatric Program University of Tennessee
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Texas
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Austin, Texas, United States, 78723
- CFF Care Center & Pediatric Program Dell Children's Medical Center of Central Texas
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Utah
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Salt Lake City, Utah, United States, 84132
- University of Utah
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Virginia
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Norfolk, Virginia, United States, 23507
- CFF Care Center & Pediatric Program Children's Hospital of the King's Daughters
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Richmond, Virginia, United States, 23298
- CFF Care Center Medical College of Virginia
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Washington
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Seattle, Washington, United States, 98145
- CFF Care Center & Pediatric Program Seattle Children's Hospital
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Wisconsin
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Madison, Wisconsin, United States, 53792
- CFF Care Center & Pediatric Program University of Wisconsin
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Milwaukee, Wisconsin, United States, 53226
- CFF Care Center & Pediatric Program Children's Hospital of Wisconsin
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- Age ≥ 6 months to ≤ 18 years
- Documentation of a CF diagnosis as evidenced by one or more clinical features consistent with the CF phenotype or positive CF Newborn Screening result for immunoreactive trypsinogen (IRT) IRT/DNA or IRT/IRT and one or more of the following criteria:
- sweat chloride ≥ 60 milliequivalent (mEq)/liter by quantitative by pilocarpine iontophoresis test (QPIT)
- two well-characterized mutations in the cystic fibrosis transmembrane conductive regulator (CFTR) gene
- Abnormal nasal potential difference (NPD) (change in NPD in response to a low chloride solution and isoproteronol of less than - 5 mV)
- Documented new positive oropharyngeal, sputum or lower respiratory tract culture for Pa within 30 days of the Baseline Visit (Visit 1), defined as: a) first lifetime documented Pa positive culture; or b) Pa recovered after at least a two-year history of Pa negative respiratory cultures (≥ 1 culture/ year)
- Clinically stable with no evidence of any significant respiratory symptoms at the Baseline Visit that would require administration of intravenous anti- pseudomonal antibiotics, oxygen supplementation, and/or hospitalization as determined by the study physician
- Written informed consent obtained from participant or participant's legal representative (and assent when applicable) and ability for participant to comply with the requirements of the study
Exclusion Criteria:
- Macrolide antibiotic use within 30 days of the Baseline Visit
- Initiation of current course of treatment with TIS >14 days prior to Baseline Visit
- Weight <6.0 kg at the Baseline Visit
- History of aminoglycoside hypersensitivity or adverse reaction to inhaled aminoglycoside
- History of azithromycin hypersensitivity or adverse reaction to azithromycin or allergy to macrolide antibiotics
- History of positive respiratory culture for Non-tuberculous mycobacteria (NTM) or Burkholderia cepacia complex within 2 years of the Baseline Visit
- History of unresolved, abnormal renal function (defined as serum creatinine greater than 1.5 times the upper limit of normal for age).
- History of unresolved, abnormal liver function tests (defined as alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) greater than 4 times the upper limit of normal range) or history of portal hypertension
- History of unresolved, abnormal neutropenia (ANC ≤ 1000)
- Abnormal ECG test at the Baseline Visit defined as a QT interval corrected (QTc) (B) of ≥460 msec or history of ventricular arrhythmia
- History of abnormal hearing sensitivity defined as hearing threshold levels >25 dB HL (decibels Hearing Level) for visual reinforcement audiometry (VRA) at any frequency (500-4000Hz) or >20 Decibels Hearing Level (dBHL) for play or standard audiometry at any two frequencies (500-8000Hz) in either ear, not associated with middle ear disease (including infection) or a flat (Type B) tympanogram
- New initiation of chronic therapy (greater than 21 days) with drugs known to prolong QT interval (refer to Appendix III) within 30 days prior to the Baseline Visit or coadministration of nelfinavir or oral anticoagulants
- Positive serum or urine pregnancy test at the Baseline Visit (to be performed on all females of child-bearing potential) or for females of child bearing potential: pregnant, breastfeeding, or unwilling to use barrier contraception during participation in the study
- Administration of any investigational drug within 30 days prior to the Baseline Visit
- Presence of a condition or abnormality (e.g., pre-existing heart disease) that in the opinion of the site investigator would compromise the safety of the participant or the quality of the data
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Quadruple
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
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Active Comparator: azithromycin and TIS
azithromycin and tobramycin solution for inhalation (TIS) Azithromycin 3 times weekly, oral suspension, 10 mg/kg/dose up to 500 mg, for 18 months Tobramycin solution for inhalation (TIS), 300 mg, twice daily for 28 days when respiratory cultures are found positive for Pa at study visits for 18 months
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3 times weekly, oral suspension, 10 mg/kg/dose up to 500 mg, for 18 months
300 mg, twice daily for 28 days when respiratory cultures are found positive for Pa at study visits for 18 months
Other Names:
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Placebo Comparator: placebo and TIS
placebo and tobramycin solution for inhalation (TIS) Placebo 3 times weekly, oral suspension, volume-matched to azithromycin, for 18 months Tobramycin solution for inhalation (TIS), 300 mg, twice daily for 28 days when respiratory cultures are found positive for Pa at study visits for 18 months
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300 mg, twice daily for 28 days when respiratory cultures are found positive for Pa at study visits for 18 months
Other Names:
3 times weekly, oral suspension, volume-matched to azithromycin, for 18 months
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Time to a Protocol-defined Pulmonary Exacerbation
Time Frame: Over the 18-month study period
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Time to a protocol-defined pulmonary exacerbation requiring oral, inhaled, or intravenous antibiotics, using a prespecified definition available in the study protocol.
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Over the 18-month study period
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Time to Pseudomonas Aeruginosa (Pa) Recurrence
Time Frame: Over the 18-month study period
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Time to Pseudomonas aeruginosa (Pa) recurrence after the first quarter of treatment
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Over the 18-month study period
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Adverse Events (AEs) and Serious Adverse Events (SAEs)
Time Frame: Over the 18-month study period
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The number and percentage of participants with at least one event over the 18-month study period.
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Over the 18-month study period
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Rate of Adverse Events (AEs) and Serious Adverse Events (SAEs)
Time Frame: Over the 18-month study period
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Rate is defined as the number of events per participant follow-up month.
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Over the 18-month study period
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Collaborators and Investigators
Sponsor
Collaborators
Investigators
- Principal Investigator: Bonnie Ramsey, MD, Seattle Children's Center for Clinical and Translational Research, CF Therapeutics Development Network Clinical Coordinating Center
- Principal Investigator: Nicole Hamblett, PhD, Seattle Children's Core for Biomedical Statistics
Publications and helpful links
Study record dates
Study Major Dates
Study Start
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Digestive System Diseases
- Pathologic Processes
- Respiratory Tract Diseases
- Lung Diseases
- Infant, Newborn, Diseases
- Genetic Diseases, Inborn
- Gram-Negative Bacterial Infections
- Bacterial Infections
- Bacterial Infections and Mycoses
- Pancreatic Diseases
- Fibrosis
- Infections
- Cystic Fibrosis
- Pseudomonas Infections
- Anti-Infective Agents
- Anti-Bacterial Agents
- Azithromycin
- Tobramycin
Other Study ID Numbers
- OPTIMIZE-IP-12
- 1U01HL114623-01A1 (U.S. NIH Grant/Contract)
- 1U01HL114589-01A1 (U.S. NIH Grant/Contract)
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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