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Neurofibromatosis 1Phase 2NCT00076102

Pirfenidone in Children and Young Adults With Neurofibromatosis Type I and Progressive Plexiform Neurofibromas

A Phase 2 study testing Pirfenidone in people with Neurofibromatosis 1 and Neurofibroma, Plexiform, run by National Cancer Institute (NCI) at 15 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

Background: Neurofibromatosis Type 1 (NF1) is an autosomal dominant, progressive genetic disorder characterized by diverse clinical manifestations. Patients with NF1 have an increased risk of developing tumors of the central and peripheral nervous system including plexiform neurofibromas, which are benign nerve sheath… Read more about this study

Who is it for?
Ages 3 to 21 years
Conditions the study is for
Neurofibromatosis 1, Neurofibroma, Plexiform
What is being tested?
Pirfenidone
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
36 participants
Where
15 sitesUnited States
Study dates
21 Jul 2004to 1 Apr 2010
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 3 to 21 years
  • All sexes
  • No healthy volunteers
  • Child, Adult

Who may be able to join

  • Age: greater than or equal to 3 years and Less than or equal to 21 years of age. Required body surface area (BSA): greater than or equal to 0.31 m^2.
  • Diagnosis: Patients with NF1 and progressive plexiform neurofibromas that have the potential to cause significant morbidity, such as (but not limited to) head and neck lesions that could compromise the airway or great vessels, brachial or lumbar plexus lesions that could cause nerve compression and loss of function, lesions that could result in major deformity (e.g., orbital lesions) or significant cosmetic problems, lesions of the extremity that cause limb hypertrophy or loss of function, and painful lesions. Histologic confirmation of tumor is not necessary in the presence of consistent clinical and radiographic findings, but should be considered if malignant degeneration of a plexiform neurofibroma is clinically suspected. In addition to plexiform neurofibroma(s), all study subjects must have at least one other diagnostic criteria for NF1 listed below (National Institutes of Health (NIH) Consensus Conference):
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  • Six or more cafe-au-lait spots (greater than or equal to 0.5 cm in prepubertal subjects or greater than or equal to 1.5 cm in postpubertal subjects)
  • Freckling in the axilla or groin
  • Optic glioma
Show all 32Show fewer
  • Two or more Lisch nodules
  • A distinctive bony lesion (dysplasia of the sphenoid bone or dysplasia or thinning of long bone cortex)
  • A first-degree relative with NF1
  • In this study a plexiform neurofibroma is defined as a neurofibroma that has grown along the length of a nerve and may involve multiple fascicles and branches. A spinal plexiform neurofibroma involves two or more levels with connection between the levels or extending laterally along the nerve.
  • 3. Measurable disease: Patients must have measurable plexiform neurofibroma(s). For the purpose of this study a measurable lesion will be defined as a lesion of at least 3 cm measured in one dimension. There must be evidence of recurrent or progressive disease as documented by an increase in size or the presence of new plexiform neurofibromas on MRI. Progression at the time of study entry is defined as:
  • A measurable increase of the plexiform neurofibroma (greater than or equal to 20% increase in the volume, or a greater than or equal to 13% increase in the product of the two longest perpendicular diameters, or a greater than or equal to 6% increase in the longest diameter) over the last two consecutive scans (magnetic resonance imaging (MRI) or computed tomography (CT), or over the time period of approximately one year prior to evaluation for this study.
  • Patients who underwent surgery for a progressive plexiform neurofibroma will be eligible to enter the study after the surgery, provided the plexiform neurofibroma was incompletely resected and is measurable.
  • 4. Prior therapy: Patients with NFI are eligible at the time of recurrence or progression of an inoperable plexiform neurofibroma. Patients will only be eligible if complete tumor resection is not feasible, or if a patient with a surgical option refuses surgery.
  • Since there is no standard effective chemotherapy for patients with NF1 and progressive plexiform neurofibromas, patients may be treated on this trial without having received prior medical therapy.
  • Patients who received prior medical treatment for their plexiform neurofibroma(s) must have recovered from the toxic effects of all prior therapy before entering this study. The Cancer Therapy Evaluation Program Common Terminology Criteria for Adverse Events (CTCAE-3) Version 3.0 will be used for toxicity assessment. A copy of the CTCAE version 3.0 can be downloaded from the CTEP home page (http:// ctep.cancer.gov). Recovery is defined as a toxicity grade less than 2, unless otherwise specified in the Inclusion and Exclusion Criteria.
  • Patients must have had their last dose of radiation therapy at least six weeks prior to study entry, and their last dose of chemotherapy at least four weeks prior to study entry. Patients who received G-CSF after the prior cycle of chemotherapy must be off G-CSF for at least one week prior to entering this study.
  • 5. Performance Status: Performance Status: Patients should have a life expectancy of at least 12 months. Patients greater than 10 years must have a Karnofsky performance level greater than or equal to 50, and children less than or equal to 10 years must have a Lansky performance level greater than or equal to 50. Patients who are wheelchair bound because of paralysis should be considered ambulatory when they are up in their wheel chair.
  • 6. Hematologic Function: Patients must have an absolute granulocyte count greater than or equal to 1,500/uL, a hemoglobin greater than or equal to 9.0 gm/dl, and a platelet count greater than or equal to 150,000/microliter at study entry (all transfusion independent).
  • 7. Hepatic Function: Patients must have a bilirubin within normal limits and serum glutamic pyruvic transaminase (SGPT) less then or equal to 2x upper limit of normal. Patients with Gilbert syndrome are excluded from the requirement of a normal bilirubin. (Gilbert syndrome is found in 3-10% of the general population, and is characterized by mild, chronic unconjugated hyperbilirubinemia in the absence of liver disease or overt hemolysis).
  • 8. Renal Function: Patients must have an age-adjusted normal serum creatinine (see table below) OR a creatinine clearance greater than or equal to 70 mL/min/1.73 m^2.
  • Age Maximum Serum Creatinine
  • (years) (mg/dl)
  • less than or equal to 5 0.8
  • 5 less than age less than or equal to 10 1.0
  • 10 less than age less than or equal to 15 1.2
  • greater than 15 1.5
  • 9. Informed Consent: All patients or their legal guardians (if the patients is less than 18 years old) must sign an Institutional Review Board (IRB) approved document of informed consent (screening protocol) prior to performing studies to determine patient eligibility. After confirmation of patient eligibility all patients or their legal guardians must sign the protocol specific informed consent to document their understanding of the investigational nature and the risks of this study before any protocol related studies are performed (other than the studies which were performed to determine patient eligibility). When appropriate, pediatric patients will be included in all discussions. Age appropriate assent forms for children from 7 through 12 years, and for children from 13 through 17 years have been developed and will be signed by the pediatric patients, when appropriate, in order to obtain written assent.
  • 10. Durable Power of Attorney (DPA): All patients greater than or equal to 18 years of age will be offered the opportunity to assign DPA so that another person can make decisions about their medical care if they become incapacitated or cognitively impaired.
  • 11. Patients must be able to take pirfenidone by mouth. Capsules can be opened and content mixed with food for easier consumption in small children.
  • 12. Patients (both male and female) must be willing to practice birth control (including abstinence) during and for two months after treatment, if of a child-bearing age. For purposes of the protocol, all patients greater than 9 years of age or those showing pubertal development will be considered of childbearing age.
  • 13. Ability to undergo magnetic resonance imaging (MRI) and no contraindication for MRI examinations following the MRI protocol outlined.

Who cannot join

  • Pregnant or breast feeding females are excluded, because the toxic effects and pharmacology of pirfenidone in the fetus and newborn are unknown.
  • Clinically significant unrelated systemic illness (serious infections or significant cardiac, pulmonary, hepatic or other organ dysfunction), which in the judgment of the Principal or Associate Investigator would compromise the patient's ability to tolerate pirfenidone or are likely to interfere with the study procedures or results.
  • An investigational agent within the past 30 days.
  • Ongoing radiation therapy, chemotherapy, hormonal therapy directed at the tumor, immunotherapy, or biologic therapy (for example interferon).
  • Inability to return for follow-up visits or obtain follow-up studies required to assess toxicity and response to therapy.
  • Prior treatment with pirfenidone.
  • Evidence of an optic glioma, malignant glioma, malignant peripheral nerve sheath tumor, or other cancer requiring treatment with chemotherapy or radiation therapy

Trial locations and contacts

15 sites in 1 country.

15 sites in 1 country

United States15 sites
  • Johns Hopkins Oncology Center

    Baltimore, Maryland, 21287

  • National Institutes of Health Clinical Center, 9000 Rockville Pike

    Bethesda, Maryland, 20892

  • University of Alabama

    Birmingham, Alabama, 35233

  • Childrens Hospital, Dana-Farber Cancer Institute

    Boston, Massachusetts, 02115

  • Childrens Memorial Hospital, Chicago

    Chicago, Illinois, 60614

  • Cleveland Clinic

    Cleveland, Ohio, 44195

  • Texas Children's Hospital

    Houston, Texas, 77030

  • Beth Israel Medical Center

    New York, New York, 10003

  • Childrens Hospital, Philadelphia

    Philadelphia, Pennsylvania, 19104

  • Childrens Hospital, Pittsburgh

    Pittsburgh, Pennsylvania, 15213

  • Oregon Health Sciences University

    Portland, Oregon, 97201-3098

  • Mayo Clinic, Rochester

    Rochester, Minnesota, 55905

  • St. Louis Children's Hospital

    St Louis, Missouri, 63110

  • SUNY Upstate Medical University

    Syracuse, New York, 13210

  • Childrens National Medical Center

    Washington D.C., District of Columbia, 20010

Other trials in United States

About this study

Official title: Phase II Trial of Pirfenidone in Children, Adolescents, and Young Adults With Neurofibromatosis Type 1 and Progressive Plexiform Neurofibromas

Background:

Neurofibromatosis Type 1 (NF1) is an autosomal dominant, progressive genetic disorder characterized by diverse clinical manifestations. Patients with NF1 have an increased risk of developing tumors of the central and peripheral nervous system including plexiform neurofibromas, which are benign nerve sheath tumors that may cause severe morbidity and possible mortality. The histopathology of these tumors suggests that events connected with formation of fibroblasts might constitute a point of molecular vulnerability. Gene profile analysis demonstrates overexpression of fibroblast growth factor, epidermal growth factor, and platelet-derived growth factor in plexiform neurofibromas in patients with NF1. Pirfenidone is a novel antifibrotic agent that inhibits these and other growth factors. Clinical experience in adults has demonstrated that pirfenidone is effective in a variety of fibrosing conditions and pirfenidone is presently under study in a phase II trial for adults with progressive plexiform neurofibromas. A phase I trial of pirfenidone in children and young adults with NF1 and plexiform neurofibromas was completed, and has established the phase II dose (the dose resulting in a mean drug exposure [AUC] not more than 1 standard deviation below the mean drug exposure [AUC] in adults who received pirfenidone at the dose level demonstrating activity in fibrosing conditions). Pirfenidone has been well tolerated.

Read more

Objectives:

To determine whether pirfenidone increases the time to disease progression based on volumetric measurements in children and young adults with NF1 and growing plexiform neurofibromas.

To define the objective response rate to pirfenidone in NF1-related plexiform neurofibromas.

To describe and define the toxicities of pirfenidone.

Eligibility:

Individuals (greater than or equal to 3 years to less than or equal to 21 years of age) with a clinical diagnosis of NF1 and inoperable, measurable, and progressive plexiform neurofibromas that have the potential to cause substantial morbidity.

Design:

The phase II dose will be used in a single stage, single arm phase II trial The natural history of the growth of plexiform neurofibromas is unknown. For this reason, time to disease progression on the placebo arm of an ongoing National Cancer Institute (NCI) Pediatric Oncology Branch (POB) placebo-controlled, double-blind, cross-over phase II trial of the farnesyltransferase inhibitor R115777 for children and young adults with NF1 and progressive plexiform neurofibromas.

Funding source - Food and Drug Administration (FDA) Office of Orphan Products Development (OOPD)

Read the detailed description

Background:

Neurofibromatosis Type 1 (NF1) is an autosomal dominant, progressive genetic disorder characterized by diverse clinical manifestations. Patients with NF1 have an increased risk of developing tumors of the central and peripheral nervous system including plexiform neurofibromas, which are benign nerve sheath tumors that may cause severe morbidity and possible mortality. The histopathology of these tumors suggests that events connected with formation of fibroblasts might constitute a point of molecular vulnerability. Gene profile analysis demonstrates overexpression of fibroblast growth factor, epidermal growth factor, and platelet-derived growth factor in plexiform neurofibromas in patients with NF1. Pirfenidone is a novel antifibrotic agent that inhibits these and other growth factors. Clinical experience in adults has demonstrated that pirfenidone is effective in a variety of fibrosing conditions and pirfenidone is presently under study in a phase II trial for adults with progressive plexiform neurofibromas. A phase I trial of pirfenidone in children and young adults with NF1 and plexiform neurofibromas was completed, and has established the phase II dose (the dose resulting in a mean drug exposure [AUC] not more than 1 standard deviation below the mean drug exposure [AUC] in adults who received pirfenidone at the dose level demonstrating activity in fibrosing conditions). Pirfenidone has been well tolerated.

Objectives:

To determine whether pirfenidone increases the time to disease progression based on volumetric measurements in children and young adults with NF1 and growing plexiform neurofibromas.

To define the objective response rate to pirfenidone in NF1-related plexiform neurofibromas.

To describe and define the toxicities of pirfenidone.

Eligibility:

Individuals (greater than or equal to 3 years to less than or equal to 21 years of age) with a clinical diagnosis of NF1 and inoperable, measurable, and progressive plexiform neurofibromas that have the potential to cause substantial morbidity.

Design:

The phase II dose will be used in a single stage, single arm phase II trial The natural history of the growth of plexiform neurofibromas is unknown. For this reason, time to disease progression on the placebo arm of an ongoing National Cancer Institute (NCI) Pediatric Oncology Branch (POB) placebo-controlled, double-blind, cross-over phase II trial of the farnesyltransferase inhibitor R115777 for children and young adults with NF1 and progressive plexiform neurofibromas will be used as historical control to determine if pirfenidone increases time to disease progression. Eligibility criteria and method of tumor measurements are identical for both trials.

Pirfenidone will be administered orally as capsules at a dose of 500 mg/m^2 three times a day (q8h) for cycles of 28 days with no rest period between cycles based on the results of our pediatric phase I trial.

Being tested
Pirfenidone
Keywords
Side Effect, Oral Administration, Nerve Sheath Tumor, Antifibrotic Agent, Volumetric Tumor Measurement, Plexiform Neurofibroma, Neurofibromatosis Type 1, Volumetric MRI Analysis, Time to Progression, NF1
Medical subject headings
Neurofibromatosis 1, Neurofibroma, Plexiform, Nerve Sheath Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • PirfenidoneDrug

    Also called Esbriet, Deskar

    Pirfenidone orally as capsules three times a day approximately every 8 hours for cycles of 28 days with no rest period between cycles (28 day treatment cycles); 500 mg/m^2 every 8 hours (1500 mg/m2/day).

Study groups in NCT00076102
Study groupRoleWhat they receive
PirfenidoneExperimentalPirfenidone orally as capsules three times a day approximately every 8 hours for cycles of 28 days with no rest period between cycles (28 day treatment cycles); 500 mg/m^2 every 8 hours (1500 mg/m2/day).
Receives: Drug: Pirfenidone

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Median Time to Disease Progression

    Time to progression is defined as greater than or equal to 20% increase in plexiform neurofibromas (PN) volume on magnetic resonance imaging (MRI).

    Measured: 5 years

  2. Number of Participants With Adverse Events

    Here are the number of participants with adverse events. For the detailed list of adverse events see the adverse event module.

    Measured: 5 years

  3. Percentage of Participants Who Had an Objective Response Rate

    Objective response rate is defined as a complete response (CR) or partial response (PR). Complete response is a complete resolution of all measurable or palpable soft tissue tumors for ≥4 weeks and no appearance of new lesions. Partial response is a ≥50% reduction in the sum of the volume of all index lesions for ≥4 weeks.

    Measured: ≥4 weeks

Secondary outcomes (6)
  1. Quality of Life (QOL) Using the Impact of Pediatric Illness (IPI) Scale at Baseline

    Quality of life was assessed by the Impact of Pediatric Illness scale for children 6-18 years of age. The child's primary caregiver completed the proxy Parent Form and children answered either the self-report Child or Adolescent (11-18 years) Form. The parallel IPI Scale forms assess four domains: adaptive behavior, emotional functioning, medical/physical status, and cognitive functioning. Responses to the 43 items are made on a 3-or5-point Likert scale (1 to 5 for Parent and Adolescent Form and 1, 3, 5 for the Child Form) ranging from "not at all" to "a lot". Item scores are transformed to a scale of 0-100, and then mean scores are calculated for the four domains and total scale with higher scores indicating better QOL. Baseline comparisons between child and parent total and domain scores were performed.

    Measured: Baseline

  2. Longitudinal Total Quality of Life Scores Assessed by the Impact of Pediatric Illness Scale

    Quality of life was assessed by the Impact of Pediatric Illness scale for children 6-18 years of age. The child's primary caregiver completed the proxy Parent Form and children answered either the self-report Child or Adolescent (11-18 years) Form prior to cycles 1, 4, 7 and 10. The parallel IPI Scale forms assess four domains: adaptive behavior, emotional functioning, medical/physical status, and cognitive functioning. Responses to the 43 items are made on a 3-or5-point Likert scale (1 to 5 for Parent and Adolescent Form and 1, 3, 5 for the Child Form) ranging from "not at all" to "a lot". Item scores are transformed to a scale of 0-100, and then mean scores are calculated for the four domains and total scale with higher scores indicating better QOL.

    Measured: prior to cycles 1, 4, 7 and 10.

  3. Number of Participants With A Response Evaluation Determined by the Comparison of One-Dimensional (1D) Magnetic Resonance Imaging

    Index lesions will be followed for progression by 1D magnetic resonance imaging. Progression is defined as a ≥20% increase in the volume of at least one of the index plexiform neurofibromas compared to the pretreatment volume measured prior to the start of treatment.

    Measured: Prior to cycles 1, 4, 7, and 10 and then every 6 cycles thereafter until progression

  4. Number of Participants With A Response Evaluation Determined by the Comparison of Two-Dimensional (2D) Magnetic Resonance Imaging

    Index lesions will be followed for progression by 2D magnetic resonance imaging. Progression is defined as a ≥20% increase in the volume of at least one of the index plexiform neurofibromas compared to the pretreatment volume measured prior to the start of treatment.

    Measured: Prior to cycles 1, 4, 7, and 10 and then every 6 cycles thereafter until progression

  5. Number of Participants With A Response Evaluation Determined by the Comparison of Three-Dimensional (3D) Magnetic Resonance Imaging

    Index lesions will be followed for progression by 3D magnetic resonance imaging. Compete response is a complete resolution of all measurable or palpable soft tissue tumors for ≥4 weeks and no appearance of new lesions. Partial response is a ≥50% reduction in the sum of the volume of all index lesions for ≥4 weeks. Progression is defined as a ≥20% increase in the volume of at least one of the index plexiform neurofibromas compared to the pretreatment volume measured prior to the start of treatment. Stable disease is a <20% increase, and <25% decrease in the sum of the volume of all index lesions for ≥4 weeks. Minor response is a ≥25% but <50% reduction in the sum of the volume of all index lesions for ≥4 weeks.

    Measured: Prior to cycles 1, 4, 7, and 10 and then every 6 cycles thereafter, approximately 5 years

  6. Number of Participants Who Contributed to the Tissue Bank

    Tumor specimens from patients who undergo tumor surgery or biopsies for clinical reasons.

    Measured: 5 years

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted14 Jan 2004 (estimated)
  2. Study start21 Jul 2004
  3. Primary completion1 Apr 2010
  4. Study completion1 Apr 2010

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
36 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00076102
Sponsor's protocol ID
040080
Other IDs
04-C-0080, FD-R-0002128
Status last verified
Apr 2018
First submitted
13 Jan 2004
Last updated
23 Apr 2018
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No

Publications

  • Cain WC, Stuart RW, Lefkowitz DL, Starnes JD, Margolin S, Lefkowitz SS. Inhibition of tumor necrosis factor and subsequent endotoxin shock by pirfenidone. Int J Immunopharmacol. 1998 Dec;20(12):685-95. doi: 10.1016/s0192-0561(98)00042-3.

    PubMed 9877280
  • DeClue JE, Heffelfinger S, Benvenuto G, Ling B, Li S, Rui W, Vass WC, Viskochil D, Ratner N. Epidermal growth factor receptor expression in neurofibromatosis type 1-related tumors and NF1 animal models. J Clin Invest. 2000 May;105(9):1233-41. doi: 10.1172/JCI7610.

    PubMed 10791998
  • Evans DG, Baser ME, McGaughran J, Sharif S, Howard E, Moran A. Malignant peripheral nerve sheath tumours in neurofibromatosis 1. J Med Genet. 2002 May;39(5):311-4. doi: 10.1136/jmg.39.5.311.

    PubMed 12011145
  • Widemann BC, Babovic-Vuksanovic D, Dombi E, Wolters PL, Goldman S, Martin S, Goodwin A, Goodspeed W, Kieran MW, Cohen B, Blaney SM, King A, Solomon J, Patronas N, Balis FM, Fox E, Steinberg SM, Packer RJ. Phase II trial of pirfenidone in children and young adults with neurofibromatosis type 1 and progressive plexiform neurofibromas. Pediatr Blood Cancer. 2014 Sep;61(9):1598-602. doi: 10.1002/pbc.25041. Epub 2014 Apr 22.

    PubMed 24753394

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Pirfenidone in people with Neurofibromatosis 1 and Neurofibroma, Plexiform, run by National Cancer Institute (NCI) at 15 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 32 inclusion and 7 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 23 Apr 2018. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 15 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 12 Jul 2012). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Median Time to Disease Progression (time frame: 5 years). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00076102, which also lists 4 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 23 Apr 2018.

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