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CompletedNCT01519414Updated Sep 12, 2018Results posted

Tivantinib in Treating Patients With Metastatic Prostate Cancer

A Phase 2 interventional study of Laboratory Biomarker Analysis and Placebo in Hormone-Resistant Prostate Cancer, Prostate Adenocarcinoma and Recurrent Prostate Carcinoma, sponsored by National Cancer Institute (NCI). Completed at 20 sites in United States. Open to male participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2018-09-12.

Sponsored by National Cancer Institute (NCI) · Phase 2, Interventional, and Treatment

Phase
Phase 2
Study type
Interventional
Enrollment
78
Allocation
Randomized
Ages
18 Years and older
Sex
Male
01

Study summary

This randomized phase II trial studies how well tivantinib works compared to placebo in treating patients with metastatic prostate cancer. Tivantinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Read the detailed description

PRIMARY OBJECTIVES:

I. To determine progression-free survival (PFS) in men with minimally symptomatic or asymptomatic metastatic, castrate-resistant, chemotherapy-naïve prostate cancer treated with ARQ 197 (tivantinib).

SECONDARY OBJECTIVES:

I. To determine the prostate-specific antigen (PSA) response rate at 12 weeks in men with metastatic, castrate-resistant, chemotherapy-naïve prostate cancer treated with ARQ 197.

II. To determine the radiographic response rate at 12 weeks based on Response Evaluation Criteria in Solid Tumors (RECIST) criteria on computed tomography (CT) scans and stability of bone lesions on bone scan in castrate-resistant, chemotherapy-naïve prostate cancer treated with ARQ 197.

III. To determine the proportion of patients who are progression-free at 12 weeks.

IV. To assess safety and tolerability in patients treated with ARQ 197 using the National Institute of Cancer (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 grading of toxicities.

TERTIARY OBJECTIVES:

I. Evaluate markers of bone turnover. (Exploratory)

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

Arm I: Patients receive tivantinib orally (PO) twice daily (BID) on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Arm II: Patients receive placebo PO BID on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients with disease progression may crossover to Arm I.

After completion of study treatment, patients are followed up every 3 months for 6 months.

02

Conditions studied

  • Hormone-Resistant Prostate Cancer
  • Prostate Adenocarcinoma
  • Recurrent Prostate Carcinoma
  • Stage IV Prostate Cancer

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03

In context

Prostatic Neoplasms

6,370 studies on the registry are indexed under Prostatic Neoplasms; 1,400 are open to participants now.

This study's enrollment of 78 is above the median of 58 across 4,822 interventional studies indexed under Prostatic Neoplasms.

Browse Prostatic Neoplasms studies →

Lead sponsor

National Cancer Institute (NCI) is the lead sponsor of 3,506 studies on the registry; 334 are open to participants now.

Of its 402 completed or terminated interventional studies of FDA-regulated products, 365 (91%) have results posted.

Counted across the registry records on this site, refreshed daily.

04

Who can participate

Ages eligible
18 Years and older
Sexes eligible
Male
Accepts healthy volunteers
No

Inclusion criteria

  • Patients must have histologically documented adenocarcinoma of the prostate with progressive systemic disease (either rising PSA or progression of disease on CT scan or magnetic resonance imaging [MRI] or bone scan) despite castrate levels of testosterone due to orchiectomy or luteinizing hormone-releasing hormone (LHRH) agonist or antagonist; castrate levels of testosterone must be maintained throughout the study
  • Evidence of metastatic disease on CT or bone imaging
  • Patients must have demonstrated evidence of progressive disease since the most recent change in therapy; progressive disease is defined as any one of the following (measurable disease, bone scan, or PSA progression):

    • Measurable disease progression: objective evidence of increase > 20% in the sum of the longest diameters (LD) of target lesions from the time of maximal regression or the appearance of one or more new lesions
    • Bone scan progression: appearance of two or more new lesions on bone scan attributable to prostate cancer will constitute progression
    • PSA progression: two successive rises from baseline PSA separated at least by one week with the last value >= 2 ng/mL
  • Asymptomatic or minimally symptomatic from prostate cancer - no symptoms attributed to prostate cancer greater than grade I using NCI CTCAE version 4.0 grading of toxicities
  • Secondary hormonal therapies (e.g., abiraterone acetate, flutamide, estrogen) must be discontinued for at least 4 weeks prior to study enrollment unless the duration of the therapy was less than 8 weeks and there was no demonstrated decrease in PSA
  • Secondary hormonal therapies with bicalutamide or nilutamide must be discontinued for 6 weeks unless duration of therapy was less than 8 weeks and there was no demonstrated PSA decrease
  • Prior abiraterone (or investigational anti-androgen) use is allowed; these too will need to be discontinued at least 4 weeks prior to study enrollment
  • PSA prior to treatment must be >= 2 ng/ml
  • Castrate testosterone level (\< 50 ng/dL)
  • Eastern Cooperative Oncology Group (ECOG) performance status =\< 2 (Karnofsky >= 60%)
  • No prior chemotherapy unless utilized in neoadjuvant/adjuvant setting and must have completed > 6 months prior to enrollment
  • Four weeks since major surgery or radiation therapy
  • Absolute neutrophil count >= 1,500/mcL
  • Platelets >= 100,000/mcL
  • Total bilirubin within normal institutional limits
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =\< 2.0 X institutional upper limit of normal
  • Creatinine within normal institutional limits OR creatinine clearance >= 40 mL/min/1.73 m\^2 for patients with creatinine levels above institutional normal
  • Patients must have signed an informed consent document stating that they understand the investigational nature of the proposed treatment
  • Men and any female partners of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control) prior to study entry and for the duration of study participation and for additional 2 months after finishing therapy; should a patient's sexual partner become pregnant or suspect she is pregnant while patient is participating in this study, he should inform the treating physician immediately
  • Bisphosphonate or denosumab therapy is permitted provided patients began therapy prior to registration and that they continue them as per the manufacturer's guidelines and/or per institutional practice; patients not taking ongoing bisphosphonate or denosumab therapy will not be permitted to start such therapy until they have completed 12 weeks of study treatment
  • Patients must be able to swallow pills to participate in the study

Exclusion criteria

Exclusion Criteria:

  • Patients who have radiotherapy within 4 weeks or chemotherapy prior to entering the study or those who have not recovered (resolution to grade 1) from adverse events due to agents administered more than 4 weeks earlier; neoadjuvant/adjuvant chemotherapy for local disease is allowed if greater than 6 months have elapsed
  • Previous hepatocyte growth factor receptor (C-MET) inhibitor treatment (either monoclonal antibody to C-MET or human growth factor [HGF] or small molecule inhibitory to C-MET)
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition ARQ 197
  • Caution should be used with patients receiving inhibitors of cytochrome P450 family 2, subfamily C, polypeptide 19 (CYP2C19) and strong inhibitors of cytochrome P450 family 3, subfamily A, polypeptide4 (CYP3A4); additional hematologic testing will be advised if the medication cannot be substituted
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or known psychiatric illness/social situations that would limit compliance with study requirements
  • Known brain metastasis
  • Current, recent (within 4 weeks of the first study drug administration), or concurrent planned participation in another investigational therapeutic study
  • Patients with a "currently active" second malignancy other than non-melanoma skin cancers are not to be registered; patients are not considered to have a "currently active" malignancy if they have completed therapy and are now considered to be at less than 30% risk for relapse (by their physician)
  • Patients may continue on a daily multi-vitamin and calcium/vitamin D supplements; all other herbal, alternative, and food supplements (i.e., PC-SPES, Saw Palmetto, St. John wort, etc.) must be discontinued before registration
  • New York Heart Association (NYHA) class III or greater congestive heart failure
  • History of myocardial infarction or unstable angina within 6 months prior to initial treatment
  • History of severely impaired lung function
  • Baseline electrocardiogram (ECG) abnormalities including first degree (PR interval > 210 ms), second degree, or third degree heart block (exception: patients with pacemakers may be enrolled); QRS prolongation or bundle branch block (QRS >= 120 ms), or QT prolongation (per institutional standard of care: Fridericia corrected QT interval [QTcF] or Bazett corrected QT interval [QTcB] >= 470 ms); other ECG abnormalities will need consideration by the treating investigator and enrollment is up to his/her discretion
  • Presence of non-healing wound, active ulcer, or untreated bone fracture
  • Known diabetics that have poorly controlled diabetes mellitus (glycated hemoglobin [HbA1c] >= 8.0%) or fasting glucose level >= 189 mg/dL (diabetic patient); patients may be potentially eligible once anti-diabetic agent(s) are either added or titrated to control their diabetes mellitus
  • Active liver disease (AST or ALT >= 2.0 times the upper limit of normal [ULN] or total bilirubin >= institutional ULN) or gallbladder disease; patients with known liver cirrhosis or severe hepatic impairment (Child-Pugh Class C) will also be excluded
  • A known history of human immunodeficiency virus (HIV) seropositivity
  • Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of ARQ 197 (e.g., uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or significant small bowel resection)
  • Patients with an active bleeding diathesis
05

Study design

Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomized
Intervention model
Crossover assignment
Masking
Double (Participant, Investigator)
Enrollment
78 participants (actual)

Study arms

  • Experimental
    Arm I (tivantinib)

    Patients receive tivantinib PO BID on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

    Other: Laboratory Biomarker Analysis · Drug: Tivantinib

  • Placebo comparator
    Arm II (placebo)

    Patients receive placebo PO BID on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients with disease progression may crossover to Arm I.

    Other: Laboratory Biomarker Analysis · Other: Placebo

Interventions

  • OtherLaboratory Biomarker Analysis

    Optional correlative studies

  • OtherPlacebo

    Given PO

    Also known as: placebo therapy, PLCB, sham therapy

  • DrugTivantinib

    Given PO

    Also known as: ARQ 197, ARQ-197, c-Met Inhibitor ARQ 197

06

What researchers measure

Primary outcomes

  1. Progression-free Survival (PFS) Based on the RECIST Criteria

    The progression-free survival distributions between the two arms will be compared using log-rank tests. Progression-free survival curves will be constructed using the Kaplan-Meier product limit method, and additional analyses will be done using the Cox proportional hazards model.

    Time frame: Time from study entry to the date of documented progression and/or death, assessed up to 6 months

Secondary outcomes

  1. Changes in PSA Levels

    Evaluated and patterns graphically explored through waterfall plots.

    Time frame: Baseline to 12 weeks

  2. Proportion of Patients Who Respond

    An assumed binomial distribution used. Summarized with their corresponding 95% binomial confidence intervals and compared in an exploratory manner between the two treatment arms. Dichotomized outcomes of response will be descriptively summarized and graphically evaluated using bar graphs.

    Time frame: At 12 weeks

  3. PSA Response Rate

    Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.

    Time frame: up to 12 weeks

  4. Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0

    Fisher's exact tests will be used to quantitatively compare the incidence of severe as well as specific toxicities of interest between the treatment arms and graphically assessed differences in maximum grades observed for toxicities between the arms.

    Time frame: Up to 1 year

Other outcomes

  1. Radiographic Response Rate Based on RECIST Criteria

    Summarized with their corresponding 95% binomial confidence intervals and compared in an exploratory manner between the two treatment arms. Dichotomized outcomes of response will be descriptively summarized and graphically evaluated using bar graphs.

    Time frame: Up to 12 weeks

  2. Change in Bone Specific Alkaline Phosphatase (BSAP) in Serum

    BSAP will first be descriptively summarized by treatment group and also evaluated using graphical analyses to assess potential patterns over time and see if changes in bone resorption differ between those who are progression-free at 12 weeks vs. not after treatment with tivantinib. The potential impact of early changes in these markers on PFS using Cox regression models will be also explored.

    Time frame: Baseline to up to 6 months

  3. Change in Markers of Bone Turnover in Urine

    NTx and CTX will first be descriptively summarized by treatment group and also evaluated using graphical analyses to assess potential patterns over time and see if changes in bone resorption differ between those who are progression-free at 12 weeks vs. not after treatment with tivantinib. The potential impact of early changes in these markers on PFS using Cox regression models will be also explored.

    Time frame: Baseline to up to 6 months

07

Results

Posted Sep 12, 2018

Participant flow

Pre Cross-over
Participant flow — Pre Cross-over
MilestoneArm I (Tivantinib)Arm II (Placebo)Crossover From Placebo to Tivantinib
Started52260
Completed52260
Not completed000
Post Cross-over
Participant flow — Post Cross-over
MilestoneArm I (Tivantinib)Arm II (Placebo)Crossover From Placebo to Tivantinib
Started521412
Completed521412
Not completed000

Outcome measures

PrimaryProgression-free Survival (PFS) Based on the RECIST Criteria

The progression-free survival distributions between the two arms will be compared using log-rank tests. Progression-free survival curves will be constructed using the Kaplan-Meier product limit method, and additional analyses will be done using the Cox proportional hazards model.

Time frame:
Time from study entry to the date of documented progression and/or death, assessed up to 6 months
Reported as:
Median · months
Progression-free Survival (PFS) Based on the RECIST Criteria
monthsArm I (Tivantinib)Arm II (Placebo)
Progression-free Survival (PFS) Based on the RECIST Criteria5.5 (3.2 to 8.0)3.7 (2.7 to 5.4)
Statistical analysis
  • Arm I (Tivantinib) vs Arm II (Placebo) · Log Rank · p = 0.02
SecondaryChanges in PSA Levels

Evaluated and patterns graphically explored through waterfall plots.

Time frame:
Baseline to 12 weeks
Reported as:
Median · percentage change from baseline
Changes in PSA Levels
percentage change from baselineArm I (Tivantinib)Arm II (Placebo)
Changes in PSA Levels140.1 (-9.0 to 5768.1)301.5 (-3.3 to 3254.4)
SecondaryProportion of Patients Who Respond

An assumed binomial distribution used. Summarized with their corresponding 95% binomial confidence intervals and compared in an exploratory manner between the two treatment arms. Dichotomized outcomes of response will be descriptively summarized and graphically evaluated using bar graphs.

Time frame:
At 12 weeks
Reported as:
Number · percentage of patients
Proportion of Patients Who Respond
percentage of patientsArm I (Tivantinib)Arm II (Placebo)Crossover From Placebo to Tivantinib
Proportion of Patients Who Respond1.9 (0.05 to 10.26)0 (0 to 0)8.3 (0.2 to 38.5)
SecondaryPSA Response Rate

Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.

Time frame:
up to 12 weeks
Reported as:
Number · percentage of patients
PSA Response Rate
percentage of patientsArm I (Tivantinib)Arm II (Placebo)Crossover From Placebo to Tivantinib
PSA Response Rate1.9 (0.05 to 10.26)0 (0 to 0)8.3 (0.2 to 38.5)
SecondaryIncidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0

Fisher's exact tests will be used to quantitatively compare the incidence of severe as well as specific toxicities of interest between the treatment arms and graphically assessed differences in maximum grades observed for toxicities between the arms.

Time frame:
Up to 1 year
Reported as:
Number · patients
Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0
patientsArm I (Tivantinib)Arm II (Placebo)Crossover From Placebo to Tivantinib
Acute coronary syndrome100
Alkaline phosphatase increased002
Anemia302
Back pain111
Confusion020
Cataract100
Death NOS101
Dehydration021
Dizziness010
Duodenal ulcer100
Dyspnea010
Enterocolitis infectious010
Fall010
Fatigue200
Febrile neutropenia100
Gait disturbance010
Generalized muscle weakness010
Hypertension100
Hypokalemia010
Hyponatremia100
Hypotension010
Hypoxia110
Infections and infestations - Other, specify100
Lymph gland infection100
Lymphocyte count decreased222
Musculoskeletal and connective tissue disorder - O010
Neoplasms benign, malignant and unspecified (incl110
Nervous system disorders - Other, specify010
Neutrophil count decreased202
Platelet count decreased100
Pleural effusion001
Productive cough001
Sinus bradycardia300
Sinus tachycardia010
Syncope020
Thromboembolic event010
Tumor pain100
Upper respiratory infection010
Urinary tract obstruction001
White blood cell decreased202
Other pre-specifiedRadiographic Response Rate Based on RECIST Criteria

Summarized with their corresponding 95% binomial confidence intervals and compared in an exploratory manner between the two treatment arms. Dichotomized outcomes of response will be descriptively summarized and graphically evaluated using bar graphs.

Time frame:
Up to 12 weeks
Reported as:
Number · percentage of patients
Radiographic Response Rate Based on RECIST Criteria
percentage of patientsArm I (Tivantinib)Arm II (Placebo)Crossover From Placebo to Tivantinib
Radiographic Response Rate Based on RECIST Criteria1.9 (0.05 to 10.26)0 (0 to 0)8.3 (0.2 to 38.5)
Other pre-specifiedChange in Bone Specific Alkaline Phosphatase (BSAP) in Serum

BSAP will first be descriptively summarized by treatment group and also evaluated using graphical analyses to assess potential patterns over time and see if changes in bone resorption differ between those who are progression-free at 12 weeks vs. not after treatment with tivantinib. The potential impact of early changes in these markers on PFS using Cox regression models will be also explored.

Time frame:
Baseline to up to 6 months

Results for this outcome have not been posted.

Other pre-specifiedChange in Markers of Bone Turnover in Urine

NTx and CTX will first be descriptively summarized by treatment group and also evaluated using graphical analyses to assess potential patterns over time and see if changes in bone resorption differ between those who are progression-free at 12 weeks vs. not after treatment with tivantinib. The potential impact of early changes in these markers on PFS using Cox regression models will be also explored.

Time frame:
Baseline to up to 6 months

Results for this outcome have not been posted.

Adverse events

Non-serious events are listed at a 0% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
Arm I (Tivantinib)7/52 (13.5%)19/52 (36.5%)52/52 (100%)
Arm II (Placebo)4/26 (15.4%)22/26 (84.6%)26/26 (100%)
Crossover From Placebo to Tivantinib0/12 (0%)5/12 (41.7%)12/12 (100%)
Most frequent serious events
Showing 10 of 36
Most frequent serious events
EventArm I (Tivantinib)Arm II (Placebo)Crossover From Placebo to Tivantinib
Death NOSGeneral disorders1/520/261/12
Edema limbsGeneral disorders1/520/261/12
FatigueGeneral disorders1/520/261/12
Urinary tract obstructionRenal and urinary disorders0/520/261/12
Pleural effusionRespiratory, thoracic and mediastinal disorders0/520/261/12
DehydrationMetabolism and nutrition disorders0/522/260/12
ConfusionPsychiatric disorders0/522/260/12
Thromboembolic eventVascular disorders1/522/260/12
Sinus tachycardiaCardiac disorders0/521/260/12
Abdominal painGastrointestinal disorders0/521/260/12
Most frequent other events
Showing 10 of 155
Most frequent other events
EventArm I (Tivantinib)Arm II (Placebo)Crossover From Placebo to Tivantinib
FatigueGeneral disorders30/5211/267/12
AnemiaBlood and lymphatic system disorders23/5212/266/12
AnorexiaMetabolism and nutrition disorders17/525/266/12
Back painMusculoskeletal and connective tissue disorders9/5213/263/12
Pain in extremityMusculoskeletal and connective tissue disorders13/5211/262/12
Neutrophil count decreasedInvestigations5/520/265/12
White blood cell decreasedInvestigations12/521/265/12
Lymphocyte count decreasedInvestigations11/526/264/12
ConstipationGastrointestinal disorders14/527/263/12
PainGeneral disorders5/527/262/12

Baseline characteristics

Age, Continuous
Age, Continuous(years)Arm I (Tivantinib)Arm II (Placebo)Total
Median67 (43 to 84)66.5 (48 to 85)67 (43 to 85)
Sex: Female, Male
Sex: Female, Male(Participants)Arm I (Tivantinib)Arm II (Placebo)Total
Female000
Male522678
Race (NIH/OMB)
Race (NIH/OMB)(Participants)Arm I (Tivantinib)Arm II (Placebo)Total
American Indian or Alaska Native000
Asian101
Native Hawaiian or Other Pacific Islander000
Black or African American268
White492069
More than one race000
Unknown or Not Reported000
Region of Enrollment
Region of Enrollment(patients)Arm I (Tivantinib)Arm II (Placebo)Total
United States522678
08

Study locations

20 sites
  • MedStar Georgetown University Hospital
    Washington, District of Columbia 20007, United States
  • Moffitt Cancer Center
    Tampa, Florida 33612, United States
  • Northwestern University
    Chicago, Illinois 60611, United States
  • Michael Reese Hospital
    Chicago, Illinois 60616, United States
  • University of Chicago Comprehensive Cancer Center
    Chicago, Illinois 60637, United States
  • Decatur Memorial Hospital
    Decatur, Illinois 62526, United States
  • NorthShore University HealthSystem-Evanston Hospital
    Evanston, Illinois 60201, United States
  • Ingalls Memorial Hospital
    Harvey, Illinois 60426, United States
  • Illinois CancerCare-Peoria
    Peoria, Illinois 61615, United States
  • Southern Illinois University School of Medicine
    Springfield, Illinois 62702, United States
  • Fort Wayne Medical Oncology and Hematology Inc - Jefferson Boulevard
    Fort Wayne, Indiana 46804, United States
  • Indiana University/Melvin and Bren Simon Cancer Center
    Indianapolis, Indiana 46202, United States
  • University of Maryland/Greenebaum Cancer Center
    Baltimore, Maryland 21201, United States
  • University of Maryland Saint Joseph Medical Center
    Towson, Maryland 21204, United States
  • Mercy Hospital Saint Louis
    Saint Louis, Missouri 63141, United States
  • Roswell Park Cancer Institute
    Buffalo, New York 14263, United States
  • Case Western Reserve University
    Cleveland, Ohio 44106, United States
  • Cleveland Clinic Foundation
    Cleveland, Ohio 44195, United States
  • Ohio State University Comprehensive Cancer Center
    Columbus, Ohio 43210, United States
  • University of Wisconsin Hospital and Clinics
    Madison, Wisconsin 53792, United States
09

Updates

Tracking since Sep 25, 2026
No changes since tracking began. The registry record was last updated on Sep 12, 2018, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗
10

Registry details

Key details

Study ID
NCT01519414
Lead sponsor
National Cancer Institute (NCI)
Responsible party
Sponsor
First posted
Jan 27, 2012
Start date
Jan 11, 2012
Primary completion
Aug 18, 2015
Completion
Aug 18, 2015
Results posted
Sep 12, 2018
Last update
Sep 12, 2018

Study contacts

J. Monk
principal investigator · Ohio State University Comprehensive Cancer Center
View the source record on ClinicalTrials.gov ↗

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