Clinical Trial Results:
NGR019: Randomized double-blind phase II study of NGR-hTNF versus placebo as maintenance treatment in advanced malignant pleural mesothelioma (MPM)
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Summary
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EudraCT number |
2010-023614-31 |
Trial protocol |
IT DE |
Global end of trial date |
02 Oct 2018
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Results information
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Results version number |
v1(current) |
This version publication date |
01 Jan 2020
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First version publication date |
01 Jan 2020
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
NGR019
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
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WHO universal trial number (UTN) |
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Sponsors
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Sponsor organisation name |
MolMed S.p.A.
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Sponsor organisation address |
Via Olgettina, 58, Milan, Italy, 20132
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Public contact |
Clinical Operations, MolMed S.p.A., 0039 02212771, clinical.operations@molmed.com
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Scientific contact |
Clinical Operations, MolMed S.p.A., 0039 02212771, clinical.operations@molmed.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
31 Oct 2019
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
02 Oct 2018
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Global end of trial reached? |
Yes
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Global end of trial date |
02 Oct 2018
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
To compare progression-free survival (PFS) in patients randomized to NGR-hTNF versus patients randomized to placebo
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Protection of trial subjects |
The study was conducted in accordance with the ethical principles that have their origins in the Declaration of Helsinki. The study was performed in compliance with Good Clinical Practice (CPMP/ICH/135/95), and the essential documents are archived as required by the applicable regulatory requirements. The study and any amendments were reviewed by an Independent Ethics Committees or Institutional Review Boards.
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Background therapy |
Where applicable and as appropriate according to the Institutional clinical practice and literature guidelines, patients in both arms should receive Best Supportive Care (BSC). All concomitant medication(s) must be reported in the Case Report Form (CRF). - BSC includes antibiotics, analgesics, antiemetics, thoracentesis, pleurodesis, blood transfusions, nutritional support, and focal external-beam radiation for control of pain, cough, dyspnea, or hemoptysis. - BSC excludes surgery, immunotherapy, anticancer therapy, and radiotherapy (except palliative). | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
18 May 2011
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Italy: 135
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Country: Number of subjects enrolled |
Russian Federation: 2
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Worldwide total number of subjects |
137
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EEA total number of subjects |
135
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
27
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From 65 to 84 years |
110
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85 years and over |
0
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Recruitment
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Recruitment details |
The study was performed in a total of 12 investigational study sites in total (11 in Italy and 1 in Russia). Other sites were opened in Italy (1 site) and in Germany (2 sites), but no patients were enrolled in these sites. Department of Medical Oncology and Haematology, Istituto Clinico Humanitas, Rozzano (Milan), Italy, was the Coordinator Centre | ||||||||||||||||||||||||||||||
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Pre-assignment
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Screening details |
137 patients were enrolled: 69 in arm A, and 68 in arm B. 3 patients in arm A were not treated due to progression of disease (n=1), informed consent withdrawal (n=1) and physician decision (n=1). | ||||||||||||||||||||||||||||||
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Period 1
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Period 1 title |
Overall trial (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | ||||||||||||||||||||||||||||||
Roles blinded |
Subject, Investigator | ||||||||||||||||||||||||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Arm A (experimental group = NGR-hTNF + BSC) | ||||||||||||||||||||||||||||||
Arm description |
• NGR-hTNF: 0.8 μg/m² as 60-minute intravenous infusion every week until confirmed evidence of disease progression or unacceptable toxicity occurs. • Best Supportive Care (BSC): where applicable and as appropriate according to Institutional clinical practice and literature guidelines. It included antibiotics, analgesics, antiemetics, thoracentesis, pleurodesis, blood transfusions, nutritional support, and focal external-beam radiation for control of pain, cough, dyspnea, or hemoptysis. All concomitant medication(s) had to be reported in the Case Report Form (CRF). | ||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||
Investigational medicinal product name |
NGR-hTNF
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Concentrate for solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
The patients will receive NGR-hTNF/placebo administration every week by 60-minute intravenous infusion at 0.8 μg/m² until progressive disease.
Acetaminophen/paracetamol 1000 mg p.o. or i.v. is recommended as prophylaxis 30 to 60 minutes prior starting each infusion of NGR-hTNF/placebo.
No concomitant hydration is allowed during the NGR-hTNF/placebo infusion period.
No corticosteroid therapy is allowed during NGR-hTNF infusion and for two subsequent hours.
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Arm title
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Arm B (control group = Placebo + BSC) | ||||||||||||||||||||||||||||||
Arm description |
• Placebo: 0.8 μg/m² as 60-minute intravenous infusion every week until confirmed evidence of disease progression or unacceptable toxicity occurs. • Best Supportive Care: where applicable and as appropriate according to Institutional clinical practice and literature guidelines. It included antibiotics, analgesics, antiemetics, thoracentesis, pleurodesis, blood transfusions, nutritional support, and focal external-beam radiation for control of pain, cough, dyspnea, or hemoptysis. All concomitant medication(s) had to be reported in the Case Report Form (CRF). | ||||||||||||||||||||||||||||||
Arm type |
Placebo | ||||||||||||||||||||||||||||||
Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Concentrate for solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
0.8 µg/m² as 60-minute iv infusion every week until confirmed evidence of disease progression or unacceptable toxicity occurred.
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| Notes [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same. Justification: The analysis were performed on treated patients. |
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Baseline characteristics reporting groups
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Reporting group title |
Arm A (experimental group = NGR-hTNF + BSC)
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Reporting group description |
• NGR-hTNF: 0.8 μg/m² as 60-minute intravenous infusion every week until confirmed evidence of disease progression or unacceptable toxicity occurs. • Best Supportive Care (BSC): where applicable and as appropriate according to Institutional clinical practice and literature guidelines. It included antibiotics, analgesics, antiemetics, thoracentesis, pleurodesis, blood transfusions, nutritional support, and focal external-beam radiation for control of pain, cough, dyspnea, or hemoptysis. All concomitant medication(s) had to be reported in the Case Report Form (CRF). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Arm B (control group = Placebo + BSC)
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Reporting group description |
• Placebo: 0.8 μg/m² as 60-minute intravenous infusion every week until confirmed evidence of disease progression or unacceptable toxicity occurs. • Best Supportive Care: where applicable and as appropriate according to Institutional clinical practice and literature guidelines. It included antibiotics, analgesics, antiemetics, thoracentesis, pleurodesis, blood transfusions, nutritional support, and focal external-beam radiation for control of pain, cough, dyspnea, or hemoptysis. All concomitant medication(s) had to be reported in the Case Report Form (CRF). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Arm A (experimental group = NGR-hTNF + BSC)
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Reporting group description |
• NGR-hTNF: 0.8 μg/m² as 60-minute intravenous infusion every week until confirmed evidence of disease progression or unacceptable toxicity occurs. • Best Supportive Care (BSC): where applicable and as appropriate according to Institutional clinical practice and literature guidelines. It included antibiotics, analgesics, antiemetics, thoracentesis, pleurodesis, blood transfusions, nutritional support, and focal external-beam radiation for control of pain, cough, dyspnea, or hemoptysis. All concomitant medication(s) had to be reported in the Case Report Form (CRF). | ||
Reporting group title |
Arm B (control group = Placebo + BSC)
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Reporting group description |
• Placebo: 0.8 μg/m² as 60-minute intravenous infusion every week until confirmed evidence of disease progression or unacceptable toxicity occurs. • Best Supportive Care: where applicable and as appropriate according to Institutional clinical practice and literature guidelines. It included antibiotics, analgesics, antiemetics, thoracentesis, pleurodesis, blood transfusions, nutritional support, and focal external-beam radiation for control of pain, cough, dyspnea, or hemoptysis. All concomitant medication(s) had to be reported in the Case Report Form (CRF). | ||
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End point title |
Progression-free survival (PFS), defined as the time from the date of randomization until disease progression, or death due to any cause. | ||||||||||||
End point description |
Defined as the time from the date of randomization until disease progression, or death due to any cause.
Progression is defined using Response Evaluation Criteria In Solid Tumors (RECIST), as a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to relative increase of 20% the sum must also demonstrate an absolute increase of at least 5 mm. In addition the appearance of one or more new lesions was also considered progression.
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End point type |
Primary
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End point timeframe |
Assessed every 6 weeks, up to the last treatment cycle.
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Statistical analysis title |
Progression-free survival (PFS) | ||||||||||||
Statistical analysis description |
The median PFS was 3.3 months (95% CI: 2.7-4.2 months) in arm A and 4.0 months (95% CI: 2.8-5.3 months) in arm B. Two (3.0%) patients in arm A and 5 (7.4%) in arm B were censored, while events (i.e. failures) were reported in 64 (97%) patients in arm A and in 63 (92.6%) in arm B. The comparison between arms in the log rank model did not show statistically significant differences (p = 0.505).
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Comparison groups |
Arm A (experimental group = NGR-hTNF + BSC) v Arm B (control group = Placebo + BSC)
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Number of subjects included in analysis |
134
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Analysis specification |
Pre-specified
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Analysis type |
other | ||||||||||||
P-value |
= 0.505 | ||||||||||||
Method |
Logrank | ||||||||||||
Confidence interval |
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End point title |
Overall Survival (OS) | ||||||||||||
End point description |
OS was defined as the time from the date of randomization until death due to any cause, or the last date the patient was known to be alive. End point related data are reported as median (95% CI).
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End point type |
Secondary
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End point timeframe |
Assessed every 6 weeks, up to the completion of the last treatment cycle or in case of discontinuation of
the treatment before disease progression. OS was assessed every 12 weeks after the last treatment
cycle up to study completion.
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Statistical analysis title |
Overall survival | ||||||||||||
Statistical analysis description |
The median OS was 14.0 months (95% CI: 10.2-17.2 months) in arm A and 17.4 months (95% CI: 12.4-23.6 months) in arm B. Ten (15.2%) patients in arm A and 15 (22.1%) in arm B were censored, while events (i.e. deaths) were reported in 56 (84.8%) patients in arm A and in 53 (77.9%) in arm B. The comparison between arms in the log rank model did not show statistically significant differences (p = 0.082).
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Comparison groups |
Arm A (experimental group = NGR-hTNF + BSC) v Arm B (control group = Placebo + BSC)
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Number of subjects included in analysis |
134
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Analysis specification |
Pre-specified
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Analysis type |
other | ||||||||||||
P-value |
= 0.082 | ||||||||||||
Method |
Logrank | ||||||||||||
Confidence interval |
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End point title |
Response rate (RR) | |||||||||
End point description |
RR was defined as the percentage of patients who had a best-response rating of complete (CR) or partial response (PR). The tumor thickness perpendicular to the chest wall or mediastinum was assessed
according to modified RECIST criteria for MPM. All other measurable lesions were unidimensionally measured as per the standard RECIST criteria.
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End point type |
Secondary
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End point timeframe |
Assessed every 6 weeks, up to the last treatment cycle or after treatment discontinuation before disease progression.
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| No statistical analyses for this end point | ||||||||||
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End point title |
Quality of life (QoL) | |||||||||
End point description |
QoL was assessed using the modified version for Mesothelioma of Lung Cancer Symptom Scale (LCSS) questionnaire (LCSS-Meso), which consists of eight 100-mm visual analogue scales (VAS), with scores reported from 0 to 100 (0 representing the best score). The 8 individual items of the LCSS questionnaire evaluated were: loss of appetite, fatigue, cough, dyspnoea, pain, symptoms of lung cancer, influence of illness on daily activities and overall quality of life.
Symptomatic progression was defined as a worsening in the average symptom burden index by 25% from baseline.
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End point type |
Secondary
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End point timeframe |
Assessed at the baseline, prior to randomization, and then every 6 weeks up to the last treatment cycle.
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Statistical analysis title |
Time to symptomatic progression | |||||||||
Statistical analysis description |
Symptomatic progression (months) was calculated as: [(Date of symptomatic progression or censoring - Date of randomization) + 1] / 30.4
The median time to symptomatic progression was 24.4 months (95% CI: 2.4-24.4 months) in arm A and 6.4 months (95% CI: 3.0-14.1 months) in arm B.
42 (63.6%) patients in arm A and 42 (61.8%) in arm B were censored, while events (i.e. symptomatic progression) were reported in 24 (36.4%) patients in arm A and in 26 (38.2%) in arm B.
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Comparison groups |
Arm B (control group = Placebo + BSC) v Arm A (experimental group = NGR-hTNF + BSC)
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Number of subjects included in analysis |
134
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Analysis specification |
Pre-specified
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Analysis type |
other | |||||||||
P-value |
= 0.774 | |||||||||
Method |
Logrank | |||||||||
Confidence interval |
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Adverse events information
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Timeframe for reporting adverse events |
Assessed every 3 weeks, up to the completion of the last treatment cycle. After that, unrelated events were registered for the following 28 days; whereas, related serious adverse events were followed indefinitely until resolution or stabilization.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
21.1
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Reporting groups
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Reporting group title |
Arm A (experimental group = NGR-hTNF + BSC)
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Reporting group description |
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Reporting group title |
Arm B (control group = Placebo + BSC)
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Reporting group description |
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? No | |||
Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
