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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT04456699




Registration number
NCT04456699
Ethics application status
Date submitted
1/07/2020
Date registered
2/07/2020

Titles & IDs
Public title
Efficacy and Safety of Olaparib (MK-7339) With or Without Bevacizumab Compared to Bevacizumab With a Fluoropyrimidine in Unresectable or Metastatic Colorectal Cancer (CRC) (MK-7339-003/LYNK-003)
Scientific title
A Phase 3 Randomized, Open-label Study to Evaluate the Efficacy and Safety of Olaparib Alone or in Combination With Bevacizumab Compared to Bevacizumab With a Fluoropyrimidine in Participants With Unresectable or Metastatic Colorectal Cancer Who Have Not Progressed Following First-line Induction (LYNK-003)
Secondary ID [1] 0 0
MK-7339-003
Secondary ID [2] 0 0
7339-003
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Metastatic Colorectal Cancer 0 0
Condition category
Condition code
Cancer 0 0 0 0
Bowel - Back passage (rectum) or large bowel (colon)

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Olaparib
Treatment: Drugs - 5-FU
Treatment: Drugs - Bevacizumab
Treatment: Drugs - Capecitabine
Treatment: Drugs - Leucovorin/ levoleucovorin

Experimental: Olaparib + bevacizumab - Participants will receive olaparib (300 mg twice daily \[BID\] oral) + Bevacizumab (5 mg/kg intravenous \[IV\] once every 2 weeks \[Q2W\]) until progressive disease or end of study.

Experimental: Olaparib - Participants will receive olaparib (300 mg BID) oral, until progressive disease or end of study.

Active comparator: Bevacizumab + chemotherapy - Participants will receive investigator's choice of either bevacizumab (7.5 mg/kg IV once every three weeks (Q3W)) + capecitabine (1000 mg/m\^2 BID for 14 days, then 7 days off, Q3W) or bevacizumab (5 mg/kg IV Q2W) + 5-FU (2400 mg/m2 IV over 46 to 48 hours Q2W; bolus 5-FU (400 mg/m2) can be added prior to infusional 5-FU, per local standards and at the investigator's discretion). Leucovorin or levoleucovorin 400 mg/m\^2 (leucovorin) or 200 mg/m\^2 (levoleucovorin) Q2W IV infusion may be added per investigator's discretion. Treatment will continue until progressive disease or end of study.


Treatment: Drugs: Olaparib
300 mg BID, oral until progressive disease or end of study

Treatment: Drugs: 5-FU
2400 mg/m\^2 over 46 to 48 hours Q2W IV infusion until disease progression or end of study; bolus 5-FU (400mg/m2) can be added prior to infusional 5-FU, per local standards and at the investigator's discretion

Treatment: Drugs: Bevacizumab
5 mg/kg or 7.5 mg/kg Q2W or Q3W IV infusion until progressive disease or end of study

Treatment: Drugs: Capecitabine
1000 mg/m\^2 oral capsule BID for 14 days, then 7 days off, Q3W) until progressive disease or end of study

Treatment: Drugs: Leucovorin/ levoleucovorin
400 mg/m\^2 (leucovorin) or 200 mg/m\^2 (levoleucovorin) may be added to Bevacizumab + 5-FU per investigator's discretion Q2W IV infusion until progressive disease or end of study
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Progression Free Survival (PFS) Using Response Evaluation Criteria in Solid Tumors Version (RECIST) 1.1 as Assessed by Blinded Independent Central Review (BICR).
Timepoint [1] 0 0
Up to approximately 30 months
Secondary outcome [1] 0 0
Overall Survival (OS)
Timepoint [1] 0 0
Up to approximately 30 months
Secondary outcome [2] 0 0
Objective Response Rate (ORR) Per RECIST 1.1 as Assessed by BICR
Timepoint [2] 0 0
Up to approximately 30 months
Secondary outcome [3] 0 0
Number of Participants With One or More Adverse Events (AE)
Timepoint [3] 0 0
Up to approximately 30 months
Secondary outcome [4] 0 0
Number of Participants Discontinuing Study Intervention Due to an AE
Timepoint [4] 0 0
Up to approximately 30 months

Eligibility
Key inclusion criteria
1. Has a histologically-confirmed metastatic or unresectable (Stage IV as defined by American Joint Committee on Cancer (AJCC eighth edition) colorectal adenocarcinoma (National Comprehensive Cancer Network [NCCN] 2018).
2. Has not progressed (ie, achieved a stable disease [SD], partial response [PR], or complete response [CR]) after a first-line induction course of at least 6 cycles of FOLFOX + bevacizumab or 4 cycles of CAPOX + bevacizumab as first-line therapy.

* Participants must not have received an investigational agent during their induction course.
* Determination of best overall response (SD/PR/CR) will be made by the investigator.
* Non-PD will be verified by BICR prior to randomization based on the images submitted to imaging contract research organization (iCRO) as described in inclusion criterion 4.
* "First-line therapy" is defined as the first systemic chemotherapy regimen given for the diagnosis of unresectable or metastatic CRC. Participants may have received prior adjuvant/neoadjuvant chemotherapy for CRC, as long as it was completed at least 6 months prior to initiation of first-line CAPOX + bevacizumab or FOLFOX + bevacizumab induction treatment.
3. Has experienced unacceptable toxicity to oxaliplatin that, in the opinion of the treating physician, requires/required the discontinuation of oxaliplatin. Note: As an example, unacceptable toxicity may include (but is not limited to) severe or prolonged neurotoxicity.

• Participants must be randomized within a minimum of 2 weeks and a maximum of 6 weeks after their last dose of CAPOX + bevacizumab or FOLFOX + bevacizumab (last dose is the day of the last infusion that contained oxaliplatin).
4. Has provided to the iCRO 1 set of baseline radiographic images taken before or during the CAPOX + bevacizumab or FOLFOX + bevacizumab induction period and at least 42 days prior to the imaging performed during Screening. Tumor imaging at Screening must be performed within 28 days prior to the date of randomization.
5. Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 within 10 days prior to randomization.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Has known hypersensitivity to the components and/or excipients in bevacizumab, 5-FU, capecitabine, or olaparib.
2. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable (ie, without evidence of progression for at least 28 days by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable and without requirement of steroid intervention for at least 14 days prior to first dose of study intervention.
3. Has an active infection requiring systemic therapy.
4. Has a known history of human immunodeficiency virus (HIV) infection. No HIV testing is required unless mandated by local health authority.
5. Has a known history of or is positive for hepatitis B surface antigen (HBsAg reactive) or hepatitis C ribonucleic acid (HCV RNA [qualitative]) is detected). Note: No testing for hepatitis B and hepatitis C is required unless mandated by local health authority.
6. Has a known psychiatric or substance abuse disorder that would interfere with the participant's ability to cooperate with the requirements of the study.
7. Has myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) or with features suggestive of MDS/AML.
8. Has hemoptysis or hematemesis within 28 days prior to randomization.
9. Has evidence of bleeding diathesis or significant coagulopathy (in the absence of anticoagulation).
10. Has clinically significant bleeding within 28 days prior to randomization.
11. Is considered a poor medical risk due to a serious, uncontrolled medical disorder, nonmalignant systemic disease or active, uncontrolled infection. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial infarction, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, extensive interstitial bilateral lung disease on high-resolution computed tomography (HRCT) scan or any psychiatric disorder that prohibits obtaining informed consent.
12. Has 1 or more conditions that, in the opinion of the treating physician, make the participant ineligible for treatment with bevacizumab. These conditions may include:

* Uncontrolled hypertension (systolic blood pressure [SBP] >150 mm Hg or diastolic blood pressure [DBP] >100 mm Hg) or a history of hypertensive crisis or hypertensive encephalopathy
* Arterial thromboembolic events (eg, myocardial infarction, cerebral infarction)
* History of nephrotic syndrome or moderate proteinuria
* History of gastrointestinal perforation
* History of non-gastrointestinal fistula formation
* History of possible reversible encephalopathy syndrome (RPLS)
13. Has received prior systemic anticancer therapy (other than CAPOX + bevacizumab or FOLFOX + bevacizumab induction) including investigational agents within 28 days prior to randomization. Note: Participants must have recovered from all AEs due to previous therapies to =Grade 1 or baseline. Participants with persistent alopecia or Grade =3 neuropathy are eligible.
14. Has received prior therapy with olaparib or with any other polyadenosine 5'-diphosphoribose polymerase (PARP) inhibitor.
15. Is currently receiving either strong (eg, itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate (eg, ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil) inhibitors of cytochrome P450 3A4 (CYP3A4) that cannot be discontinued for the duration of the study. The required washout period prior to randomization is 2 weeks.
16. Is currently receiving either strong (phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's Wort) or moderate (eg. bosentan, efavirenz, modafinil) inducers of CYP3A4 that cannot be discontinued for the duration of the study. The required washout period prior to randomization is 5 weeks for phenobarbital and 3 weeks for other agents.
17. Has undergone major surgery within 2 weeks of randomization or has not recovered adequately from toxicities and/or complications from any major surgery prior to randomization.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
19/08/2020
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
6/11/2023
Sample size
Target
Accrual to date
Final
335
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,VIC
Recruitment hospital [1] 0 0
St George Hospital ( Site 0052) - Kogarah
Recruitment hospital [2] 0 0
Liverpool Hospital ( Site 0055) - Liverpool
Recruitment hospital [3] 0 0
Royal Brisbane and Women s Hospital ( Site 0054) - Herston
Recruitment hospital [4] 0 0
Queen Elizabeth Hospital ( Site 0053) - Woodville South
Recruitment hospital [5] 0 0
Monash Health ( Site 0050) - Clayton
Recruitment hospital [6] 0 0
Peninsula Health Frankston Hospital ( Site 0056) - Frankston
Recruitment postcode(s) [1] 0 0
2217 - Kogarah
Recruitment postcode(s) [2] 0 0
2170 - Liverpool
Recruitment postcode(s) [3] 0 0
4029 - Herston
Recruitment postcode(s) [4] 0 0
5011 - Woodville South
Recruitment postcode(s) [5] 0 0
3168 - Clayton
Recruitment postcode(s) [6] 0 0
3199 - Frankston
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
California
Country [2] 0 0
United States of America
State/province [2] 0 0
Colorado
Country [3] 0 0
United States of America
State/province [3] 0 0
Georgia
Country [4] 0 0
United States of America
State/province [4] 0 0
Illinois
Country [5] 0 0
United States of America
State/province [5] 0 0
Kentucky
Country [6] 0 0
United States of America
State/province [6] 0 0
Louisiana
Country [7] 0 0
United States of America
State/province [7] 0 0
Maine
Country [8] 0 0
United States of America
State/province [8] 0 0
Michigan
Country [9] 0 0
United States of America
State/province [9] 0 0
Mississippi
Country [10] 0 0
United States of America
State/province [10] 0 0
Missouri
Country [11] 0 0
United States of America
State/province [11] 0 0
Montana
Country [12] 0 0
United States of America
State/province [12] 0 0
Nebraska
Country [13] 0 0
United States of America
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Oregon
Country [14] 0 0
United States of America
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Pennsylvania
Country [15] 0 0
United States of America
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Tennessee
Country [16] 0 0
United States of America
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Texas
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United States of America
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Virginia
Country [18] 0 0
Belgium
State/province [18] 0 0
Antwerpen
Country [19] 0 0
Belgium
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Bruxelles-Capitale, Region De
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Belgium
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Oost-Vlaanderen
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Belgium
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Vlaams-Brabant
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Belgium
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West-Vlaanderen
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Canada
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New Brunswick
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Canada
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Ontario
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Canada
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Quebec
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Chile
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Araucania
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Chile
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Region M. De Santiago
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Colombia
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Cesar
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Colombia
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Cordoba
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Colombia
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Distrito Capital De Bogota
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Colombia
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Risaralda
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Colombia
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Santander
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Colombia
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Valle Del Cauca
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France
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Bas-Rhin
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France
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Bretagne
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France
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Doubs
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France
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Gironde
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France
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Herault
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France
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Rhone-Alpes
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France
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Paris
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Germany
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Baden-Wurttemberg
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Germany
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Nordrhein-Westfalen
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Germany
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Berlin
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Germany
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Hamburg
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Hungary
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Bekes
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Hungary
State/province [46] 0 0
Borsod-Abauj-Zemplen
Country [47] 0 0
Hungary
State/province [47] 0 0
Hajdu-Bihar
Country [48] 0 0
Hungary
State/province [48] 0 0
Jasz-Nagykun-Szolnok
Country [49] 0 0
Hungary
State/province [49] 0 0
Zala
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Hungary
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Budapest
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Japan
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Aichi
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Japan
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Chiba
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Japan
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Ehime
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Japan
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Kanagawa
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Japan
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Saitama
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Japan
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Shizuoka
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Japan
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Fukuoka
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Japan
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Tokyo
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Korea, Republic of
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Seoul
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Korea, Republic of
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Taegu-Kwangyokshi
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Latvia
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Daugavpils
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Latvia
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Riga
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Lithuania
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Kaunas
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Lithuania
State/province [64] 0 0
Vilnius
Country [65] 0 0
Russian Federation
State/province [65] 0 0
Arkhangel Skaya Oblast
Country [66] 0 0
Russian Federation
State/province [66] 0 0
Baskortostan, Respublika
Country [67] 0 0
Russian Federation
State/province [67] 0 0
Krasnoyarskiy Kray
Country [68] 0 0
Russian Federation
State/province [68] 0 0
Moskovskaya Oblast
Country [69] 0 0
Russian Federation
State/province [69] 0 0
Moskva
Country [70] 0 0
Russian Federation
State/province [70] 0 0
Sankt-Peterburg
Country [71] 0 0
South Africa
State/province [71] 0 0
Gauteng
Country [72] 0 0
South Africa
State/province [72] 0 0
Limpopo
Country [73] 0 0
South Africa
State/province [73] 0 0
Western Cape
Country [74] 0 0
Spain
State/province [74] 0 0
Alicante
Country [75] 0 0
Spain
State/province [75] 0 0
Asturias
Country [76] 0 0
Spain
State/province [76] 0 0
Barcelona
Country [77] 0 0
Spain
State/province [77] 0 0
Madrid
Country [78] 0 0
Turkey
State/province [78] 0 0
Adana
Country [79] 0 0
Turkey
State/province [79] 0 0
Ankara
Country [80] 0 0
Turkey
State/province [80] 0 0
Edirne
Country [81] 0 0
Turkey
State/province [81] 0 0
Istanbul
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Turkey
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Izmir
Country [83] 0 0
Turkey
State/province [83] 0 0
Konya
Country [84] 0 0
Ukraine
State/province [84] 0 0
Dnipropetrovska Oblast
Country [85] 0 0
Ukraine
State/province [85] 0 0
Kharkivska Oblast
Country [86] 0 0
Ukraine
State/province [86] 0 0
Kyivska Oblast
Country [87] 0 0
Ukraine
State/province [87] 0 0
Zaporizka Oblast
Country [88] 0 0
Ukraine
State/province [88] 0 0
Kyiv

Funding & Sponsors
Primary sponsor type
Commercial sector/industry
Name
Merck Sharp & Dohme LLC
Address
Country
Other collaborator category [1] 0 0
Commercial sector/industry
Name [1] 0 0
AstraZeneca
Address [1] 0 0
Country [1] 0 0

Ethics approval
Ethics application status

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Medical Director
Address 0 0
Merck Sharp & Dohme LLC
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
When will data be available (start and end dates)?
Available to whom?
Available for what types of analyses?
How or where can data be obtained?
IPD available at link: http://engagezone.msd.com/ds_documentation.php


What supporting documents are/will be available?




Results publications and other study-related documents

TypeCitations or Other Details
Journal Takashima A, Garcia-Alfonso P, Manneh R, Besen AA,... [More Details]


Results not provided in https://clinicaltrials.gov/study/NCT04456699