Clinical Trial Results:
Phase II study of oral PHA-848125AC in patients with thymic carcinoma previously treated with chemotherapy
Summary
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EudraCT number |
2009-014338-79 |
Trial protocol |
FR IT |
Global end of trial date |
17 Dec 2018
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Results information
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Results version number |
v1(current) |
This version publication date |
27 Nov 2019
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First version publication date |
27 Nov 2019
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Other versions |
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Summary report(s) |
Synopsis |
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 |
CDKO-125a-006
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01011439 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
TIZIANA LIFE SCIENCES PLC
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Sponsor organisation address |
3rd Floor, 11-12 St. James’s Square, LONDON, United Kingdom, SW1Y 4LB
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Public contact |
Vaseem Palejwala, TIZIANA LIFE SCIENCES PLC, +1 267 982 Ext. 9784, vpalejwala@tizianalifesciences.com
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Scientific contact |
Cristina Davite, CLinical Organization for Strategies & Solutions S.r.l. - CLIOSS S.r.l., +39 03311482, cristina.davite@clioss.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 |
24 Nov 2017
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
31 May 2017
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Global end of trial reached? |
Yes
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Global end of trial date |
17 Dec 2018
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Was the trial ended prematurely? |
Yes
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General information about the trial
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Main objective of the trial |
Assessment of the antitumor activity of PHA-848125AC as second-line treatment in patients with recurrent or metastatic, unresectable thymic carcinoma previously treated with chemotherapy. Antitumor activity will be evaluated on the basis of the progression-free survival status at 3 months.
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Protection of trial subjects |
Study protocol foresees that therapies considered necessary for the patient's well being might be given at the discretion of the Investigator, i.e., chronic treatments for concomitant medical conditions, as well as agents required for life-threatening medical problems.
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Background therapy |
None. | ||
Evidence for comparator |
Not applicable. | ||
Actual start date of recruitment |
22 Feb 2010
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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 |
United States: 13
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Country: Number of subjects enrolled |
France: 23
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Country: Number of subjects enrolled |
Italy: 36
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Worldwide total number of subjects |
72
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EEA total number of subjects |
59
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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) |
57
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From 65 to 84 years |
15
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85 years and over |
0
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Recruitment
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Recruitment details |
Eighty two patients were recruited from 22 February 2010 to 05 April 2016. | ||||||||||||||||||
Pre-assignment
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Screening details |
Seventy-two patients were enrolled and treated with milciclib. Ten patients were screening failure due to inclusion /exclusion criteria not sactisfied (8 patients) or other reasons (2 patients). | ||||||||||||||||||
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 |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||||||
Arms
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Arm title
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Arm1 | ||||||||||||||||||
Arm description |
All patients treated with milciclib. | ||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||
Investigational medicinal product name |
Milciclib maleate
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Investigational medicinal product code |
PHA-848125AC
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Other name |
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Pharmaceutical forms |
Capsule, hard
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Routes of administration |
Oral use
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Dosage and administration details |
Milciclib maleate (PHA-848125AC) was administered orally at the dose of 150 mg/day (flat dose) once daily for 7 consecutive days of each treatment cycle. A treatment cycle comprised 7 days of milciclib maleate administration (Day 1 to 7) followed by 7 days of rest for a total of 14 days (2 weeks) period. After an overnight fasting, with free access to water, patients took the study drug with a large glass of plain water without ice. A light breakfast could be served 1.5-2 hours after study drug intake.
Each patient remained on treatment until disease progression, patient refusal, consent withdrawal, or the occurrence of unacceptable toxicity.
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Baseline characteristics reporting groups
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Reporting group title |
Arm1
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Reporting group description |
All patients treated with milciclib. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Arm1
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Reporting group description |
All patients treated with milciclib. | ||
Subject analysis set title |
Evaluable patients
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Subject analysis set type |
Per protocol | ||
Subject analysis set description |
• Patients Evaluable for Efficacy Analysis: This definition included the patient population for the primary efficacy analysis of PFS-3 rate and consisted of all treated patients who had fulfilled the following additional conditions:
- They had received histological confirmation of thymic carcinoma by an Independent Review Committee
- They had received at least 80% of drug in the first two cycles overall.
- They had undergone baseline and >/=1 on-treatment tumor/oncologic assessments or had died before tumor re-assessment.
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Subject analysis set title |
Patients with CR or PR
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Among the evaluable patients whose showing CR or PR.
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End point title |
Progression-free survival rate at 3 months (PFS-3 rate). [1] | ||||||||||
End point description |
The PFS-3 rate was calculated as the proportion of evaluable patients known to be alive and progression-free at ≥ 3 months since study treatment start, out of the total number of evaluable patients.
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End point type |
Primary
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End point timeframe |
From baseline to 3 months after the patient started the study treatment.
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Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: A PFS-3 rate of at least 33% was obtained, as expected. The p-value given by the exact binomial test (<.001) lead the rejection of the null hyphotesis (p=0.17) in favour of the althernative one (p=0.33). |
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No statistical analyses for this end point |
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End point title |
Objective Response Rate | ||||||||||
End point description |
Confirmed Objective Response Rate (CR, completed response + PR, partial response) according to RECIST guideline (version 1.1). Point and 95% confidence interval estimates was to be calculated for the objective tumor response rate (confirmed CRs or PRs). The analysis was to be performed in the evaluable populations.
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End point type |
Secondary
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End point timeframe |
During all study period.
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No statistical analyses for this end point |
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End point title |
Progression-free survival | ||||||||||
End point description |
The time from the date of treatment start to the date of first documentation of objective progression or of death due to any cause, whichever came first.
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End point type |
Secondary
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End point timeframe |
During all study period.
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No statistical analyses for this end point |
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End point title |
Duration of Response | ||||||||
End point description |
Duration of Response was defined, for the subset of patients with CR or PR, as the time for when criteria for response were first met until the first date that recurrent or progressive disease had been objectively documented (taking as reference for progressive disease the smallest measurements recorded on study).
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End point type |
Secondary
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End point timeframe |
During all study period.
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No statistical analyses for this end point |
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End point title |
Overall Survival | ||||||||
End point description |
Overall Survival (OS) was defined as the time from the date of treatment start to the date of death from any cause
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End point type |
Secondary
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End point timeframe |
During all study period.
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No statistical analyses for this end point |
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Adverse events information
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Timeframe for reporting adverse events |
From signature of informed consent until to 28 days after the last milciclib intake. However, if the patient started a new anticancer therapy before 28 days after last milciclib intake , the AE reporting period ended when the new treatment started.
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Adverse event reporting additional description |
AE follow up after the end of reporting period was done for: 1) All SAE with outcome "not recovered" or "unknown" at the end of reporting period and 2) non-serious related AEs with outcome "not recovered " at the end of reporting period. These events were followed until resolution or when they were considered "chronic or stable".
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
20.1
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Reporting groups
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Reporting group title |
Arm1
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Reporting group description |
All patients treated wit milciclib maleate. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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? Yes | |||
Date |
Amendment |
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21 Jan 2011 |
• To specifically state in inclusion criterion #2 (IC #2) that patients with histologically or cytologically proven diagnosis of unresectable B3 thymoma or thymic carcinoma, as per the World Health Organization (WHO) classification of tumours of the thymus, can be included in the study.
• To specify the time window in days for performing the oncologic assessment at 3 months, i.e. between days 92 and 98 after first drug administration.
• To add the possibility to investigate the baseline status of additional biomarkers related to the mechanism of action for the compound PHA-848125AC in tumor biopsies.
• To delete the reference to an expert pathologist reviewing the tumor tissue slides used for biomarkers analyses.
• To notify changes in Sponsor Study Management Personnel and Sponsor Additional Trial Personnel. |
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13 Dec 2011 |
• To change IC No. 10, by adding calculated creatinine clearance (CrCl) as a parameter to evaluate patients' renal function at study entry;
• To add the recommendation to monitor patients for events indicative of, or suggestive of, TMA/HUS (Thrombotic Microangiopathy/Hemolytic Uremic Syndrome) and in case of such events to temporarily hold study drug administration and to perform specific analyses to determine whether the events are compatible with TMA/HUS.
• To add information related to a new IMP (Investigational Medicinal Product) packaging and labeling.
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27 Jun 2014 |
• To reduce the frequency of visits at the site for patients who had already received 6 treatment cycles and remain on treatment for a longer period of time (more than 6 cycles).
• To reconsider study protocol indications on time points of oncological assessment at 3 months, as per protocol required between 92 to 98 days from first drug administration. In some instances, this requirement cannot be fulfilled by centers because of technical and logistical reasons thus causing oncologic assessment to be made beyond the 98th day. For the purpose of the analysis, the assessments performed before the next scheduled one, i.e. on day 135 (42 days after the 3rd month assessment) in the evaluation of the main endpoint was to be accounted with the outcome they had, regardless of the timing of measurement.
• To better clarify the definition of “patients evaluable for efficacy analysis” since it was misleading in the study protocol.
• To update the shelf life of the 50 mg and 100 mg capsules and to delete the 10 mg capsules since not used in the current study.
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09 Mar 2017 |
• To notify study discontinuation. Enrollment was completed on April 2016 and since sufficient data were already collected and the primary efficacy endpoint of the study was already achieved (i.e., the progression free survival status at 3 months was obtained in 24 out of the 52 evaluable patients (46.2%) i.e., more than the 14 successes required by protocol), a data cut-off on 31 May 2017 was planned, in order to proceed with clinical database closure and the preparation of the Clinical Study Report. The Sponsor continued to guarantee the supply of the investigational compound until the patients still on treatment would have benefit from the therapy. After the cut-off date, all the assessments data pertaining to the patients still on treatment were no longer collected in the Case Report Form, but only in the patient’s medical notes. Safety was to be followed up for Serious Adverse Events only: SAEs were to be notified to CLIOSS Pharmacovigilance up to 28 days after the last patient had taken his/her milciclib maleate last dose. The intention with this data cut-off of 31 May 2017 was to bring the study schedule more closely aligned to standard clinical practice.
• End of study definition. End of study can only occur when the last patient had discontinued study therapy, and a follow up period would have no longer performed.
• Administrative changes: Tiziana Life Sciences PLC entered as new Sponsor for CDKO-125a-006 trial. With this amendment the name of Nerviano Medical Sciences (NMS) has been replaced with Tiziana Life Sciences, PLC (Tiziana) throughout the whole documents.
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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. | |||
NA |