A Study of the Drugs Selumetinib vs. Carboplatin and Vincristine in Patients With Low-Grade Glioma

Low Grade Glioma Clinical Trial

Official title:

A Phase 3 Randomized Non-Inferiority Study of Carboplatin and Vincristine Versus Selumetinib (NSC# 748727) in Newly Diagnosed or Previously Untreated Low-Grade Glioma (LGG) Not Associated With BRAFV600E Mutations or Systemic Neurofibromatosis Type 1 (NF1)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04166409
• Other study ID #: NCI-2019-07600
• Secondary ID: NCI-2019-07600AC
• Status: Recruiting
• Phase: Phase 3
• Start date: January 31, 2020
• Est. completion date: December 31, 2026

Study information

• Verified date: March 2024
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This phase III trial compares the effect of selumetinib versus the standard of care treatment with carboplatin and vincristine (CV) in treating patients with newly diagnosed or previously untreated low-grade glioma (LGG) that does not have a genetic abnormality called BRAFV600E mutation and is not associated with systemic neurofibromatosis type 1. Selumetinib works by blocking some of the enzymes needed for cell growth and may kill tumor cells. Carboplatin and vincristine are chemotherapy drugs that work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. The overall goal of this study is to see if selumetinib works just as well as the standard treatment of CV for patients with LGG. Another goal of this study is to compare the effects of selumetinib versus CV in subjects with LGG to find out which is better. Additionally, this trial will also examine if treatment with selumetinib improves the quality of life for subjects who take it.

Description:

PRIMARY OBJECTIVE: I. To demonstrate that the efficacy of treatment with selumetinib as measured by event-free survival (EFS) is non-inferior compared to treatment with carboplatin/vincristine (CV) in previously-untreated low-grade glioma (LGG) not associated with BRAFV600E mutations or systemic neurofibromatosis type 1 (NF1). SECONDARY OBJECTIVES: I. To estimate tumor response rates to each regimen of chemotherapy. II. To evaluate visual acuity (VA) outcomes utilizing Teller Acuity Cards (TAC) and HOTV letter acuity testing in previously-untreated optic pathway gliomas (OPGs). III. To describe the improvement in motor function as measured by the Vineland Scale in children with previously-untreated LGG that have motor deficits at enrollment. IV. To estimate the difference in EFS and tumor response rate between BRAF rearranged and non-BRAF rearranged patients treated on each chemotherapy regimen. V. To prospectively evaluate the quality of life of children with LGG not associated with BRAFV600E or systemic NF1 treated with either CV or selumetinib. VI. To prospectively evaluate the cognitive, social, emotional, and behavioral functioning of children with LGG not associated with BRAFV600E or systemic NF1 treated with either CV or selumetinib. EXPLORATORY OBJECTIVE: I. To obtain paired blood and tumor specimens for future biology studies, including studies to correlate genomic drivers to response. OUTLINE: Patients are randomized to 1 of 2 arms. ARM I: INDUCTION: Patients receive vincristine sulfate intravenously (IV) over 1 minute on days 1, 8, 15, 22, 29, 36, 43, 50, 57, and 64, and carboplatin IV over 60 minutes on days 1, 8, 15, 22, 43, 50, 57, and 64 in the absence of disease progression or unacceptable toxicity. Patients also undergo collection of blood and magnetic resonance imaging (MRI) at baseline and end of induction. MAINTENANCE: Patients receive vincristine sulfate IV over 1 minute on days 1, 8, and 15, and carboplatin IV over 60 minutes on days 1, 8, 15, and 22. Treatment repeats every 42 days for up to 8 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo collection of blood and undergo MRI at baseline, throughout the trial, and during follow up. ARM II: Patients receive selumetinib sulfate orally (PO) twice daily (BID) on days 1-28. Treatment repeats every 28 days for up to 27 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo collection of blood and undergo MRI at baseline, throughout the trial, and during follow up. After completion of study treatment, patients are followed up every 3 months for year 1, every 6 months for years 2-3, and then annually for years 4-10.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 220
• Est. completion date: December 31, 2026
• Est. primary completion date: December 31, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 2 Years to 21 Years

Eligibility

Inclusion Criteria:

• Patients must be >= 2 years and =< 21 years at the time of enrollment
• Patients must have a body surface area (BSA) of >= 0.5 m^2 at enrollment
• Patients must have non-neurofibromatosis type 1 (non-NF1) low-grade glioma (LGG) without a BRAFV600E mutation as confirmed by Rapid Central Pathology and Molecular Screening Reviews performed on APEC14B1 (NCT02402244) and that has not been treated with any modality besides surgery. Note: Patients may be newly-diagnosed OR previously diagnosed, and there is no required time frame between biopsy/surgery and treatment initiation.
• Patients with residual tumor after resection or progressive tumor after initial diagnosis (with or without surgery) who have not received treatment (chemotherapy and/or radiation) are eligible
• Patients must have two-dimensional measurable tumor >= 1 cm^2 to be eligible
• Eligible histologies will include all tumors considered low-grade glioma or low-grade astrocytoma (World Health Organization [WHO] grade I and II) by 5th edition WHO classification of central nervous system (CNS) tumors with the exception of subependymal giant cell astrocytoma
• Patients with metastatic disease or multiple independent primary LGG are eligible
• Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2 OR a serum creatinine based on age/gender as follows (performed within

7 days prior to enrollment):

• Age: Maximum Serum Creatinine (mg/dL)
• 2 to < 6 years: 0.8 mg/dL (male); 0.8 mg/dL (female)
• 6 to < 10 years: 1 mg/dL (male); 1 mg/dL (female)
• 10 to < 13 years: 1.2 mg/dL (male); 1.2 mg/dL (female)
• 13 to < 16 years: 1.5 mg/dL (male); 1.4 mg/dL (female)
• >= 16 years: 1.7 mg/dL (male); 1.4 mg/dL (female)
• Total bilirubin =< 1.5 x upper limit of normal (ULN) for age (performed within 7 days prior to enrollment) (children with a diagnosis of Gilbert's syndrome will be allowed on study regardless of their total and indirect [unconjugated] bilirubin levels as long as their direct [conjugated] bilirubin is < 3.1 mg/dL)
• Serum glutamic pyruvic transaminase (SGPT) (alanine aminotransferase [ALT]) =< 135 U/L (performed within 7 days prior to enrollment). For the purpose of this study, the ULN for SGPT is 45 U/L
• Albumin >= 2 g/dL (performed within 7 days prior to enrollment)
• Left ventricular ejection fraction (LVEF) >= 53% (or institutional normal; if the LVEF result is given as a range of values, then the upper value of the range will be used) by echocardiogram (performed within 4 weeks prior to enrollment)
• Corrected QT (QTc) interval =< 450 msec by electrocardiography (EKG) (performed within 4 weeks prior to enrollment)
• Absolute neutrophil count >= 1,000/uL (unsupported) (performed within 7 days prior to enrollment)
• Platelets >= 100,000/uL (unsupported) (performed within 7 days prior to enrollment)
• Hemoglobin >= 8 g/dL (may be supported) (performed within 7 days prior to enrollment)
• Patients with a known seizure disorder should be stable and should not have experienced a significant increase in seizure frequency within 2 weeks prior to enrollment
• Patients 2-17 years of age must have a blood pressure that is =< 95th percentile for age, height, and gender at the time of enrollment (with or without the use of anti-hypertensive medications)
• Patients >= 18 years of age must have a blood pressure =< 130/80 mmHg at the time of enrollment (with or without the use of anti-hypertensive medications)
• Note for patients of all ages: Adequate blood pressure can be achieved using medication for the treatment of hypertension
• All patients must have ophthalmology toxicity assessments performed within 4 weeks prior to enrollment
• For all patients, a magnetic resonance imaging (MRI) of the brain (with orbital cuts for optic pathway tumors) and/or spine (depending on the site(s) of primary disease) with and without contrast must be performed within 4 weeks prior to enrollment
• Patients must have a performance status corresponding to Eastern Cooperative Oncology Group (ECOG) scores of 0, 1, or 2. Use Karnofsky for patients > 16 years of age and Lansky for patients =< 16 years of age
• Patients must have the ability to swallow whole capsules
• All patients have signed an appropriate consent form and Health Insurance Portability and Accountability Act (HIPAA) authorization form (if applicable)
• All patients and/or their parents or legal guardians must sign a written informed consent
• All patients have been consented and enrolled on APEC14B1 (NCT02402244) followed by enrollment on the ACNS1833 Pre-Enrollment Eligibility Screening (Step 0) on the same day to complete the Rapid Central Review
• All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met

Exclusion Criteria:

• Patients must not have received any prior tumor-directed therapy including chemotherapy, radiation therapy, immunotherapy, or bone marrow transplant. Prior surgical intervention is permitted
• Patients with a concurrent malignancy or history of treatment (other than surgery) for another tumor within the last year are ineligible
• Patients with diffuse intrinsic pontine tumors as seen on MRI (> 2/3 of pons involvement on imaging) are not eligible even if biopsy reveals grade I/II histology
• Patients may not be receiving any other investigational agents
• Patients with any serious medical or psychiatric illness/condition, including substance use disorders or ophthalmological conditions, likely in the judgment of the investigator to interfere or limit compliance with study requirements/treatment
• Patients who, in the opinion of the investigator, are not able to comply with the study procedures are not eligible
• Female patients who are pregnant are not eligible since fetal toxicities and teratogenic effects have been noted for several of the study drugs. A pregnancy test is required for female patients of childbearing potential
• Lactating females who plan to breastfeed their infants are not eligible
• Sexually active patients of reproductive potential who have not agreed to use an effective contraceptive method for the duration of their study participation and for 12 weeks after stopping study therapy are not eligible.
• Note: Women of child-bearing potential and males with sexual partners who are pregnant or who could become pregnant (i.e., women of child-bearing potential) should use effective methods of contraception for the duration of the study and for 12 weeks after stopping study therapy to avoid pregnancy and/or potential adverse effects on the developing embryo
• Known genetic disorder that increases risk for coronary artery disease. Note: The presence of dyslipidemia in a family with a history of myocardial infarction is not in itself an exclusion unless there is a known genetic disorder documented
• Symptomatic heart failure
• New York Health Association (NYHA) class II-IV prior or current cardiomyopathy
• Severe valvular heart disease
• History of atrial fibrillation
• Current or past history of central serous retinopathy
• Current or past history of retinal vein occlusion or retinal detachment
• Patients with uncontrolled glaucoma
• If checking pressure is clinically indicated, patients with intraocular pressure (IOP) > 22 mmHg or ULN adjusted by age are not eligible
• Supplementation with vitamin E greater than 100% of the daily recommended dose. Any multivitamin containing vitamin E must be stopped prior to study enrollment even if less than 100% of the daily recommended dosing for vitamin E
• Surgery within 2 weeks prior to enrollment, with the exception of surgical biopsy, placement of a vascular access device or cerebral spinal fluid (CSF) diverting procedure such as endoscopic third ventriculostomy (ETV) and ventriculoperitoneal (VP) shunt.
• Note: Patients must have healed from any prior surgery
• Patients who have an uncontrolled infection are not eligible

Related Conditions & MeSH terms

• Astrocytoma
• Glioma
• Low Grade Astrocytoma
• Low Grade Glioma
• Metastatic Low Grade Astrocytoma
• Metastatic Low Grade Glioma

Intervention

Procedure:
• Biospecimen Collection
Correlative studies

Drug:
• Carboplatin
Given IV

Procedure:
• Magnetic Resonance Imaging
Undergo MRI

Other:
• Quality-of-Life Assessment
Ancillary studies
• Questionnaire Administration
Ancillary studies

Drug:
• Selumetinib Sulfate
Given PO
• Vincristine Sulfate
Given IV

Locations

Country	Name	City	State
Canada	IWK Health Centre	Halifax	Nova Scotia
Canada	Centre Hospitalier Universitaire Sainte-Justine	Montreal	Quebec
Canada	The Montreal Children's Hospital of the MUHC	Montreal	Quebec
Canada	CHU de Quebec-Centre Hospitalier de l'Universite Laval (CHUL)	Quebec
Canada	Janeway Child Health Centre	Saint John's	Newfoundland and Labrador
Canada	Centre Hospitalier Universitaire de Sherbrooke-Fleurimont	Sherbrooke	Quebec
Puerto Rico	HIMA San Pablo Oncologic Hospital	Caguas
United States	Children's Hospital Medical Center of Akron	Akron	Ohio
United States	Albany Medical Center	Albany	New York
United States	C S Mott Children's Hospital	Ann Arbor	Michigan
United States	Children's Healthcare of Atlanta - Egleston	Atlanta	Georgia
United States	Children's Hospital Colorado	Aurora	Colorado
United States	Dell Children's Medical Center of Central Texas	Austin	Texas
United States	Johns Hopkins University/Sidney Kimmel Cancer Center	Baltimore	Maryland
United States	Eastern Maine Medical Center	Bangor	Maine
United States	Walter Reed National Military Medical Center	Bethesda	Maryland
United States	Children's Hospital of Alabama	Birmingham	Alabama
United States	Saint Luke's Cancer Institute - Boise	Boise	Idaho
United States	Dana-Farber Cancer Institute	Boston	Massachusetts
United States	Massachusetts General Hospital Cancer Center	Boston	Massachusetts
United States	Roswell Park Cancer Institute	Buffalo	New York
United States	University of Vermont and State Agricultural College	Burlington	Vermont
United States	UNC Lineberger Comprehensive Cancer Center	Chapel Hill	North Carolina
United States	Medical University of South Carolina	Charleston	South Carolina
United States	Carolinas Medical Center/Levine Cancer Institute	Charlotte	North Carolina
United States	Lurie Children's Hospital-Chicago	Chicago	Illinois
United States	University of Chicago Comprehensive Cancer Center	Chicago	Illinois
United States	University of Illinois	Chicago	Illinois
United States	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio
United States	Rainbow Babies and Childrens Hospital	Cleveland	Ohio
United States	Prisma Health Richland Hospital	Columbia	South Carolina
United States	Nationwide Children's Hospital	Columbus	Ohio
United States	UT Southwestern/Simmons Cancer Center-Dallas	Dallas	Texas
United States	Geisinger Medical Center	Danville	Pennsylvania
United States	Dayton Children's Hospital	Dayton	Ohio
United States	Blank Children's Hospital	Des Moines	Iowa
United States	Children's Hospital of Michigan	Detroit	Michigan
United States	Duke University Medical Center	Durham	North Carolina
United States	El Paso Children's Hospital	El Paso	Texas
United States	Sanford Broadway Medical Center	Fargo	North Dakota
United States	Cook Children's Medical Center	Fort Worth	Texas
United States	University of Florida Health Science Center - Gainesville	Gainesville	Florida
United States	Helen DeVos Children's Hospital at Spectrum Health	Grand Rapids	Michigan
United States	BI-LO Charities Children's Cancer Center	Greenville	South Carolina
United States	East Carolina University	Greenville	North Carolina
United States	Connecticut Children's Medical Center	Hartford	Connecticut
United States	Penn State Children's Hospital	Hershey	Pennsylvania
United States	Memorial Regional Hospital/Joe DiMaggio Children's Hospital	Hollywood	Florida
United States	Kapiolani Medical Center for Women and Children	Honolulu	Hawaii
United States	Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center	Houston	Texas
United States	M D Anderson Cancer Center	Houston	Texas
United States	Ascension Saint Vincent Indianapolis Hospital	Indianapolis	Indiana
United States	Riley Hospital for Children	Indianapolis	Indiana
United States	University of Iowa/Holden Comprehensive Cancer Center	Iowa City	Iowa
United States	University of Mississippi Medical Center	Jackson	Mississippi
United States	Nemours Children's Clinic-Jacksonville	Jacksonville	Florida
United States	Children's Mercy Hospitals and Clinics	Kansas City	Missouri
United States	East Tennessee Childrens Hospital	Knoxville	Tennessee
United States	University of Kentucky/Markey Cancer Center	Lexington	Kentucky
United States	Arkansas Children's Hospital	Little Rock	Arkansas
United States	Loma Linda University Medical Center	Loma Linda	California
United States	Cedars Sinai Medical Center	Los Angeles	California
United States	Children's Hospital Los Angeles	Los Angeles	California
United States	Mattel Children's Hospital UCLA	Los Angeles	California
United States	Norton Children's Hospital	Louisville	Kentucky
United States	Covenant Children's Hospital	Lubbock	Texas
United States	UMC Cancer Center / UMC Health System	Lubbock	Texas
United States	University of Wisconsin Carbone Cancer Center	Madison	Wisconsin
United States	Saint Jude Children's Research Hospital	Memphis	Tennessee
United States	Banner Children's at Desert	Mesa	Arizona
United States	Nicklaus Children's Hospital	Miami	Florida
United States	University of Miami Miller School of Medicine-Sylvester Cancer Center	Miami	Florida
United States	Children's Hospital of Wisconsin	Milwaukee	Wisconsin
United States	NYU Winthrop Hospital	Mineola	New York
United States	Children's Hospitals and Clinics of Minnesota - Minneapolis	Minneapolis	Minnesota
United States	University of Minnesota/Masonic Cancer Center	Minneapolis	Minnesota
United States	West Virginia University Healthcare	Morgantown	West Virginia
United States	Morristown Medical Center	Morristown	New Jersey
United States	Vanderbilt University/Ingram Cancer Center	Nashville	Tennessee
United States	Yale University	New Haven	Connecticut
United States	The Steven and Alexandra Cohen Children's Medical Center of New York	New Hyde Park	New York
United States	Children's Hospital New Orleans	New Orleans	Louisiana
United States	Laura and Isaac Perlmutter Cancer Center at NYU Langone	New York	New York
United States	Memorial Sloan Kettering Cancer Center	New York	New York
United States	Children's Hospital of The King's Daughters	Norfolk	Virginia
United States	Kaiser Permanente-Oakland	Oakland	California
United States	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma
United States	Children's Hospital and Medical Center of Omaha	Omaha	Nebraska
United States	University of Nebraska Medical Center	Omaha	Nebraska
United States	Children's Hospital of Orange County	Orange	California
United States	AdventHealth Orlando	Orlando	Florida
United States	Arnold Palmer Hospital for Children	Orlando	Florida
United States	Nemours Children's Hospital	Orlando	Florida
United States	Lucile Packard Children's Hospital Stanford University	Palo Alto	California
United States	Sacred Heart Hospital	Pensacola	Florida
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	Phoenix Childrens Hospital	Phoenix	Arizona
United States	Children's Hospital of Pittsburgh of UPMC	Pittsburgh	Pennsylvania
United States	Oregon Health and Science University	Portland	Oregon
United States	Rhode Island Hospital	Providence	Rhode Island
United States	Virginia Commonwealth University/Massey Cancer Center	Richmond	Virginia
United States	Carilion Children's	Roanoke	Virginia
United States	Mayo Clinic in Rochester	Rochester	Minnesota
United States	Beaumont Children's Hospital-Royal Oak	Royal Oak	Michigan
United States	Cardinal Glennon Children's Medical Center	Saint Louis	Missouri
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	Johns Hopkins All Children's Hospital	Saint Petersburg	Florida
United States	Primary Children's Hospital	Salt Lake City	Utah
United States	Children's Hospital of San Antonio	San Antonio	Texas
United States	Methodist Children's Hospital of South Texas	San Antonio	Texas
United States	University of Texas Health Science Center at San Antonio	San Antonio	Texas
United States	Rady Children's Hospital - San Diego	San Diego	California
United States	UCSF Medical Center-Mission Bay	San Francisco	California
United States	Maine Children's Cancer Program	Scarborough	Maine
United States	Seattle Children's Hospital	Seattle	Washington
United States	Providence Sacred Heart Medical Center and Children's Hospital	Spokane	Washington
United States	Southern Illinois University School of Medicine	Springfield	Illinois
United States	State University of New York Upstate Medical University	Syracuse	New York
United States	Madigan Army Medical Center	Tacoma	Washington
United States	Mary Bridge Children's Hospital and Health Center	Tacoma	Washington
United States	New York Medical College	Valhalla	New York
United States	Children's National Medical Center	Washington	District of Columbia
United States	Alfred I duPont Hospital for Children	Wilmington	Delaware
United States	Wake Forest University Health Sciences	Winston-Salem	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Countries where clinical trial is conducted

United States,  Canada,  Puerto Rico, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Change in QOL scores over time	QOL scores for each domain of the PedsQL Generic module will be summarized by timepoint (4 timepoints) and treatment arm. Mean QOL scores will be reported with standard deviations. If scores do not follow normal distributions, medians and ranges will be reported instead.	At baseline, 9 months, 30 months, and 60 months after treatment initiation
Other	Change in neurocognitive functioning scores over time	Neurocognitive functioning scores for each index/scale of the Behavior Rating Inventory of Executive Function, Second Edition (BRIEF-2) will be summarized by timepoint (4 timepoints) and treatment arm. Mean scores will be reported with standard deviations. If scores do not follow normal distributions, medians and ranges will be reported instead.	At baseline, 9 months, 30 months, and 60 months after treatment initiation
Primary	Event-free survival (EFS)	The Kaplan-Meier method will be used to estimate EFS which is defined as the interval from randomization to first occurrence of clinical or radiographic disease progression, disease recurrence, second malignant neoplasm, or death from any cause, or to the date of last follow-up. Estimates with 95% confidence intervals will be reported by treatment arm. The hazard ratio with a confidence interval will also be reported to compare treatment arms based on a Cox proportional hazards model stratified by BRAF status, tumor location and size of residual tumor.	Up to 10 years from date of randomization
Secondary	Radiographic tumor response rate	Percentages of patients with responses (complete or partial response) will be reported by treatment arm with 95% confidence intervals. The result of an exact binomial test to test for the difference in response rates between treatment arm will also be reported.	Up to 10 years
Secondary	Overall survival (OS)	The Kaplan-Meier method will be used to estimate OS by treatment arm, defined as the interval from randomization to death from any cause, or to the date of last follow-up. Estimates with confidence intervals will be reported by treatment arm.	Up to 10 years from date of randomization
Secondary	Number of patients who experience an improvement in visual acuity (VA)	Numbers of patients that show improvement in VA after 12 months of treatment will be reported by treatment arm. Patients with at least 1 impaired eye are evaluable. In a patient with a unilateral optic nerve glioma, only the affected eye is considered. In patients with bilateral visual impairment, if VA improves in 1 eye but worsens in the other, the patient will be coded as a treatment failure, whereas if 1 eye improves and the other is at least stable, the patient will be coded as a success.	After the first 12 months of treatment
Secondary	Change in motor function	Motor function is measured using the Vineland-3 Motor Scale. Only patients with motor function deficits at baseline are included. Magnitudes of change for each patient after 48 weeks of therapy from baseline will be calculated and medians (with ranges) by treatment arm will be reported.	After 48 weeks of therapy
Secondary	Change in quality of life (QOL)	QOL will be measured using the PedsQL Total Scale Score as measured from the validated PedsQL Generic Module (for children 2-21 years old). Mean differences in the total scale score between 9 months and baseline will be reported by treatment arm. The results of 2-sample t-test comparing differences in the QOL scores between the 2 arms will also be reported. If change scores do not follow normal distributions, non-parametric alternatives may be employed for analysis.	Baseline and 9 months after treatment initiation
Secondary	Processing speed function	Measured by Wechsler Processing Speed Index (standard score). Scores at 9 months will be summarized by treatment arm and reported as means (with standard deviations) or medians (with ranges) depending on the data distribution.	Up to 9 months post-treatment initiation
Secondary	Change in executive function	Executive function will be measured by the BRIEF-2 Cognitive Regulation Index (CRI). Summary statistics for the differences in scores from baseline to 9 months will be reported by treatment arm.	Baseline and 9-months