Trial Review

Did you know?

The ANZCTR now automatically displays published trial results and simplifies the addition of trial documents such as unpublished protocols and statistical analysis plans.

These enhancements will offer a more comprehensive view of trials, regardless of whether their results are positive, negative, or inconclusive.

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers
Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT04338399




Registration number
NCT04338399
Ethics application status
Date submitted
18/03/2020
Date registered
8/04/2020
Date last updated
2/11/2023

Titles & IDs
Public title
The BURAN Study of Buparlisib in Patients With Recurrent or Metastatic HNSCC
Scientific title
The BURAN Study of Buparlisib (AN2025) In Combination With Paclitaxel Compared to Paclitaxel Alone, in Patients With Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma
Secondary ID [1] 0 0
AN2025H0301
Universal Trial Number (UTN)
Trial acronym
BURAN
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Head and Neck Cancer 0 0
Condition category
Condition code
Cancer 0 0 0 0
Head and neck

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Buparlisib & Paclitaxel

Experimental: Buparlisib & Weekly Paclitaxel - Drug: Patients will receive 100 mg (2 x 50 mg) buparlisib hard gel capsule administered orally, once daily starting on Day 1 of Treatment Cycle 1, Drug: Paclitaxel (80 mg/m2) administered intravenously (IV) on Days 1, 8, and 15 of a 21-day treatment cycle.

Treatment will continue until disease progression, unacceptable toxicity, death or discontinuation for any other reason.

Active comparator: Weekly Paclitaxel - Patients will receive weekly paclitaxel (80 mg/m2) administered intravenously (IV) on Days 1, 8, and 15 of a 21-day treatment cycle. Treatment will continue until disease progression, unacceptable toxicity, death or discontinuation for any other reason.


Treatment: Drugs: Buparlisib & Paclitaxel
Investigation drug plus paclitaxel
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Overall Survival (OS)
Timepoint [1] 0 0
Overall survival will be measured from time of randomization until death from any cause. The analysis will occur when all patients have been randomized and followed for 12 months.
Secondary outcome [1] 0 0
Progression free survival
Timepoint [1] 0 0
PFS will be assessed up to 24 months after all patients are randomized
Secondary outcome [2] 0 0
Overall Response Rate
Timepoint [2] 0 0
ORR will be assessed for all patients 6 months after randomization is complete.
Secondary outcome [3] 0 0
Health Related Quality of Life (QoL): Time to Definitive deterioration of Quality of Life as assessed by EORTC C30 questionnaire
Timepoint [3] 0 0
Assessments will be made from randomization until treatment discontinuation
Secondary outcome [4] 0 0
Safety and Tolerability of Buparlisib in combination with Paclitaxel compared with Paclitaxel alone as Measured by Number of Participants Experiencing Adverse Events (AEs).
Timepoint [4] 0 0
From screening until 4 weeks following treatment discontinuation
Secondary outcome [5] 0 0
Pharmacokinetics of Buparlisib: plasma concentration-time profile of Buparlisib during 15 days of treatment
Timepoint [5] 0 0
Day 0 to Day 15 sparse sampling

Eligibility
Key inclusion criteria
1. Aged =18 years old.
2. Able to provide informed consent obtained before any trial related activities and according to local guidelines.
3. Patient has histologically and/or cytologically-confirmed HNSCC.
4. Patient has archival or new tumor tissue for the analysis of biomarkers and confirmation of HPV status (if unknown). One tumor block (preferred) or a recommended minimum of 5 unstained slides for patients with known HPV status (for tumor DNA characterization) or a recommended minimum of 10 slides for patients whose HPV status is unknown (5 slides for HPV testing plus 5 slides needed for biomarker testing). Enrollment in the study is contingent on confirmation of the availability of an adequate amount of tumor tissue, except in rare special circumstances, which must be reviewed and approved by the sponsor.
5. Patient has either progressive or recurrent disease after treatment with PDL1/PD1 based therapy for recurrent or metastatic disease:

1. PDLl/PD1 therapy alone for metastatic (monotherapy) disease
2. PDL1/PD1 in combination with chemotherapy for metastatic and recurrent disease
3. PDL1/PD1 used for metastatic disease, after or prior to receiving a platinum agent for locally advanced or metastatic disease.
6. 6. Patient has received no more than two prior lines of systemic treatment for HNSCC (single agent chemotherapy used as a radiosensitizer is not counted as a prior line of therapy).
7. Patient has measurable disease as determined per RECIST version 1.1. If the only site of measurable disease is a previously irradiated lesion, documented progression of disease and a four-week period since radiotherapy completion is required.
8. Patient has adequate bone marrow function and organ function as shown by the following:

1. Absolute neutrophil count (ANC) =1.5 x 109/L.
2. Hemoglobin =9 g/dL (which may be reached by transfusion).
3. Platelets =100 x 109/L (which may be reached by transfusion).
4. International normalized ratio (INR) =1.5.
5. Calcium (corrected for serum albumin) within normal limits (WNL) or = grade 1 severity according to NCI-CTCAE version 5.0 if judged clinically not significant by the Investigator.

Patients concomitantly taking bisphosphonates or denosumab for calcium correction are eligible.
6. Normal potassium and magnesium levels.
7. Alanine aminotransferase (AST) and aspartate aminotransferase (ALT) = 1.5 x upper limit of normal (ULN) or < 3.0 x ULN if liver metastases are present.
8. Total serum bilirubin = ULN or = 1.5 x ULN if liver metastases are present; or total bilirubin = 3.0 x ULN with direct bilirubin below or within normal range in patients with well documented Gilbert's Syndrome. Gilbert's syndrome is defined as presence of episodes of unconjugated hyperbilirubinemia with normal results from cells blood count (including normal reticulocyte count and blood smear), normal liver function test results, and absence of other contributing disease processes at the time of diagnosis.
9. Serum creatinine = 1.5 x ULN or calculated and directly measured creatinine clearance (CrCL) > 30 mL/min.
10. Haemoglobin A1c (glycosylated hemoglobin; HbA1c) =8%.
9. Patient has Eastern Cooperative Oncology Group (ECOG) performance status =1.
10. Patient is able to swallow and retain oral medication. Patients able to swallow oral medication but mostly self-nourished through gastric or jejunal feeding tube are eligible.
11. Patients must apply highly effective contraception during and throughout the study, as well after the final dose of study treatment
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Patients meeting any of the following criteria will not be eligible for participation in the study:

1. Patient has received previous treatment with any protein kinase B (PKB/AKT), mammalian target of rapamycin (mTOR) inhibitors, or phosphatidylinositol 3 kinase (PI3K) pathway inhibitors.
2. Patient received treatment with a taxane as part of prior treatment for metastatic disease.
3. Patient has symptomatic central nervous system (CNS) metastases. Patients with asymptomatic CNS metastases may participate in this study. Patient must have completed any prior local treatment for CNS metastases = 28 days prior to the start of study treatment (including radiotherapy) and must be on a stable low dose of corticosteroid therapy. Radiosurgery must have been completed at least 14 days prior to start of study treatment.
4. Patient has received wide field radiotherapy = 4 weeks or limited field radiation for palliation = 2 weeks prior to starting study treatment or who have adverse events which have not recovered to grade 1 or better from previous chemotherapy treatment (except alopecia, autoimmune endocrine events must be stable and controlled).
5. Patient has grade = 2 neuropathy, colitis, pneumonitis, , and uncontrolled endocrinopathies (e.g., hypothyroidism, diabetes with hemoglobin A1c > 8%) from previous treatment
6. Patient has had major surgery within 14 days prior to starting study treatment or has not recovered from major side effects.
7. Patient is currently receiving increasing or chronic treatment (>5 days) with corticosteroids or another immunosuppressive agent. The following uses of corticosteroids are permitted: single doses; standard premedication for paclitaxel, topical applications (e.g., rash), inhaled sprays (e.g., obstructive airways diseases), eye drops, or local injections (e.g., intra-articular), or < 10 mg prednisolone or equivalent.
8. Patient is being treated at start of study treatment with any of the following drugs:

1. Drugs known to be strong or moderate inhibitors or inducers of isoenzyme cytochrome P450 3A4 (CYP3A4) including herbal medications (see Table 16).
2. Drugs with a known risk of inducing Torsades de Pointes. Note: The patient must have discontinued strong inducers for at least one week and must have discontinued strong inhibitors before the treatment is initiated. Switching to a different medication prior to starting study treatment is allowed.
9. Patient is currently receiving warfarin or other coumarin-derived anti-coagulant, for treatment, prophylaxis, or otherwise. Therapy with heparin, low molecular weight heparin (LMWH), fondaparinux or new oral anticoagulants (NOACs) is allowed.
10. Patient has a known hypersensitivity and/or contraindication to paclitaxel, standard premedication for paclitaxel, or other products containing Cremophor®.
11. Patient has other concurrent severe and/or uncontrolled medical conditions that would, in the Investigator's judgment, contraindicate patient participation in the clinical study (e.g., active or uncontrolled severe infection, chronic active hepatitis, immunocompromised, acute or chronic pancreatitis, uncontrolled high blood pressure, interstitial lung disease, etc).
12. Patient has a known history of human immunodeficiency virus (HIV) infection (testing not mandatory).
13. Patient has any of the following cardiac abnormalities:

1. Symptomatic congestive heart failure within 12 months of the screening period.
2. History of documented congestive heart failure (New York Heart Association functional classification III-IV) or documented cardiomyopathy and left ventricular ejection fraction (LVEF) <50% as determined by multiple gated acquisition (MUGA) scan or echocardiogram (ECHO).
3. Myocardial infarction =six months prior to enrollment.
4. Unstable angina pectoris.
5. Serious uncontrolled cardiac arrhythmia.
6. Symptomatic pericarditis.
7. QT interval corrected according to the formula of Fridericia (QTcF) > 450 msec for males and > 470 msec for females, on the screening electrocardiogram (ECG).
8. Currently receiving treatment with medication that has a known risk to prolong the QT interval or inducing Torsades de Pointes, and the treatment cannot be discontinued or switched to a different medication prior to starting study treatment.
14. Patient has impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of study treatment (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection).
15. Patient has a medically documented history of or active major depressive episode, bipolar disorder (I or II), obsessive-compulsive disorder, schizophrenia, a history of suicidal attempt or ideation, or homicidal ideation (e.g., risk of doing harm to self or others), or active severe personality disorders (defined according to the Diagnostic and Statistical Manual of Mental Disorders Fifth Edition [DSM-V]) are not eligible. Note: For patients with psychotropic treatments ongoing at baseline, the dose and the schedule should not be modified within the previous six weeks prior to start of study treatment.
16. Patient has other prior or concurrent malignancy except for the following: adequately treated basal cell or squamous cell skin cancer, or other adequately treated in situ cancer, early gastric or GI cancer resected completely by endoscopy procedures or any other cancer from which the patient has been disease free for = 3years.
17. Patient has a history of non-compliance to any medical regimen or inability to grant consent.
18. Patient is concurrently using or has used another approved or investigational cancer agent within 4 weeks of randomization.
19. Patient is pregnant or nursing (lactating). Patients with elevated human chorionic gonadotrophin (hCG) at baseline that is judged to be related to the tumor are eligible if hCG levels do not show the expected doubling when repeated five to seven days later, or pregnancy has been ruled out by vaginal ultrasound.
20. Patient has received a live vaccine within 30 days of planned start of study therapy. Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (eg, Flu-Mist®) are live attenuated vaccines, and are not allowed. Non-live COVID vaccinations or boosters should not occur within 30 days of study start.

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
Active, not recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
12/12/2020
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
30/06/2026
Actual
Sample size
Target
483
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
Recruitment hospital [1] 0 0
Princess Alexandra Hospital - Brisbane
Recruitment postcode(s) [1] 0 0
4102 - Brisbane
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
Connecticut
Country [3] 0 0
United States of America
State/province [3] 0 0
Florida
Country [4] 0 0
United States of America
State/province [4] 0 0
Georgia
Country [5] 0 0
United States of America
State/province [5] 0 0
Illinois
Country [6] 0 0
United States of America
State/province [6] 0 0
Kentucky
Country [7] 0 0
United States of America
State/province [7] 0 0
Michigan
Country [8] 0 0
United States of America
State/province [8] 0 0
Missouri
Country [9] 0 0
United States of America
State/province [9] 0 0
New York
Country [10] 0 0
United States of America
State/province [10] 0 0
North Carolina
Country [11] 0 0
United States of America
State/province [11] 0 0
Ohio
Country [12] 0 0
United States of America
State/province [12] 0 0
Pennsylvania
Country [13] 0 0
United States of America
State/province [13] 0 0
South Carolina
Country [14] 0 0
United States of America
State/province [14] 0 0
Tennessee
Country [15] 0 0
United States of America
State/province [15] 0 0
Texas
Country [16] 0 0
Argentina
State/province [16] 0 0
Buenos Aires
Country [17] 0 0
Argentina
State/province [17] 0 0
Ciudad Autonoma de Buenos Aire
Country [18] 0 0
Argentina
State/province [18] 0 0
Córdoba
Country [19] 0 0
Argentina
State/province [19] 0 0
La Rioja
Country [20] 0 0
Argentina
State/province [20] 0 0
Tucuman
Country [21] 0 0
Belgium
State/province [21] 0 0
Ghent
Country [22] 0 0
Belgium
State/province [22] 0 0
Jette
Country [23] 0 0
Belgium
State/province [23] 0 0
Liege
Country [24] 0 0
Belgium
State/province [24] 0 0
Ottignies
Country [25] 0 0
Canada
State/province [25] 0 0
Montreal
Country [26] 0 0
Canada
State/province [26] 0 0
Winnipeg
Country [27] 0 0
China
State/province [27] 0 0
Beijing
Country [28] 0 0
China
State/province [28] 0 0
Bengbu
Country [29] 0 0
China
State/province [29] 0 0
Changsha
Country [30] 0 0
China
State/province [30] 0 0
Chengdu
Country [31] 0 0
China
State/province [31] 0 0
Chongqing
Country [32] 0 0
China
State/province [32] 0 0
Guangzhou
Country [33] 0 0
China
State/province [33] 0 0
Hangzhou
Country [34] 0 0
China
State/province [34] 0 0
Hefei
Country [35] 0 0
China
State/province [35] 0 0
Jinan
Country [36] 0 0
China
State/province [36] 0 0
Kunming
Country [37] 0 0
China
State/province [37] 0 0
Naning
Country [38] 0 0
China
State/province [38] 0 0
Shanghai
Country [39] 0 0
China
State/province [39] 0 0
Tianjin
Country [40] 0 0
China
State/province [40] 0 0
Zhengzhou
Country [41] 0 0
China
State/province [41] 0 0
Zhuhai
Country [42] 0 0
France
State/province [42] 0 0
Bordeaux
Country [43] 0 0
France
State/province [43] 0 0
Caen
Country [44] 0 0
France
State/province [44] 0 0
Lyon
Country [45] 0 0
France
State/province [45] 0 0
Marseille
Country [46] 0 0
France
State/province [46] 0 0
Montpellier
Country [47] 0 0
France
State/province [47] 0 0
Nantes
Country [48] 0 0
France
State/province [48] 0 0
Neuilly Sur Seine
Country [49] 0 0
France
State/province [49] 0 0
Paris
Country [50] 0 0
France
State/province [50] 0 0
Saint-Grégoire
Country [51] 0 0
France
State/province [51] 0 0
Vandœuvre-lès-Nancy
Country [52] 0 0
Germany
State/province [52] 0 0
Aachen
Country [53] 0 0
Germany
State/province [53] 0 0
Bonn
Country [54] 0 0
Germany
State/province [54] 0 0
Essen
Country [55] 0 0
Germany
State/province [55] 0 0
Georgsmarienhütte
Country [56] 0 0
Germany
State/province [56] 0 0
Giessen
Country [57] 0 0
Germany
State/province [57] 0 0
Greifswald
Country [58] 0 0
Germany
State/province [58] 0 0
Hamburg
Country [59] 0 0
Germany
State/province [59] 0 0
Hannover
Country [60] 0 0
Germany
State/province [60] 0 0
Leipzig
Country [61] 0 0
Germany
State/province [61] 0 0
Mainz
Country [62] 0 0
Hong Kong
State/province [62] 0 0
Hong Kong
Country [63] 0 0
Hungary
State/province [63] 0 0
Budapest
Country [64] 0 0
Hungary
State/province [64] 0 0
Pécs
Country [65] 0 0
Hungary
State/province [65] 0 0
Szekszárd
Country [66] 0 0
Italy
State/province [66] 0 0
Bologna
Country [67] 0 0
Italy
State/province [67] 0 0
Brescia
Country [68] 0 0
Italy
State/province [68] 0 0
Candiolo
Country [69] 0 0
Italy
State/province [69] 0 0
Cesena
Country [70] 0 0
Italy
State/province [70] 0 0
Cuneo
Country [71] 0 0
Italy
State/province [71] 0 0
Firenze
Country [72] 0 0
Italy
State/province [72] 0 0
Milano
Country [73] 0 0
Italy
State/province [73] 0 0
Milan
Country [74] 0 0
Italy
State/province [74] 0 0
Napoli
Country [75] 0 0
Italy
State/province [75] 0 0
Novara
Country [76] 0 0
Italy
State/province [76] 0 0
Palermo
Country [77] 0 0
Italy
State/province [77] 0 0
Parma
Country [78] 0 0
Italy
State/province [78] 0 0
Pavia
Country [79] 0 0
Italy
State/province [79] 0 0
Rozzano
Country [80] 0 0
Italy
State/province [80] 0 0
Salerno
Country [81] 0 0
Italy
State/province [81] 0 0
Siena
Country [82] 0 0
Italy
State/province [82] 0 0
Sondrio
Country [83] 0 0
Italy
State/province [83] 0 0
Tricase
Country [84] 0 0
Italy
State/province [84] 0 0
Udine
Country [85] 0 0
Italy
State/province [85] 0 0
Verona
Country [86] 0 0
Japan
State/province [86] 0 0
Akashi-shi
Country [87] 0 0
Japan
State/province [87] 0 0
Chuo Ku
Country [88] 0 0
Japan
State/province [88] 0 0
Fukuoka shi
Country [89] 0 0
Japan
State/province [89] 0 0
Hidaka
Country [90] 0 0
Japan
State/province [90] 0 0
Kita-gun
Country [91] 0 0
Japan
State/province [91] 0 0
Kobe
Country [92] 0 0
Japan
State/province [92] 0 0
Koto-Ku
Country [93] 0 0
Japan
State/province [93] 0 0
Matsuyama
Country [94] 0 0
Japan
State/province [94] 0 0
Nagoya
Country [95] 0 0
Japan
State/province [95] 0 0
Osaka Sayama-shi
Country [96] 0 0
Japan
State/province [96] 0 0
Sapporo
Country [97] 0 0
Japan
State/province [97] 0 0
Sendai
Country [98] 0 0
Japan
State/province [98] 0 0
Shinagawa-Ku
Country [99] 0 0
Japan
State/province [99] 0 0
Shizuoka
Country [100] 0 0
Korea, Republic of
State/province [100] 0 0
Busan
Country [101] 0 0
Korea, Republic of
State/province [101] 0 0
Incheon
Country [102] 0 0
Korea, Republic of
State/province [102] 0 0
Seongnam-si
Country [103] 0 0
Korea, Republic of
State/province [103] 0 0
Seoul
Country [104] 0 0
Korea, Republic of
State/province [104] 0 0
Suwon-si
Country [105] 0 0
Poland
State/province [105] 0 0
Gliwice
Country [106] 0 0
Poland
State/province [106] 0 0
Warszawa
Country [107] 0 0
Spain
State/province [107] 0 0
A Coruña
Country [108] 0 0
Spain
State/province [108] 0 0
Badalona
Country [109] 0 0
Spain
State/province [109] 0 0
Barcelona
Country [110] 0 0
Spain
State/province [110] 0 0
Burgos
Country [111] 0 0
Spain
State/province [111] 0 0
Córdoba
Country [112] 0 0
Spain
State/province [112] 0 0
Hospitalet de Llobregat
Country [113] 0 0
Spain
State/province [113] 0 0
Jaén
Country [114] 0 0
Spain
State/province [114] 0 0
Leganés
Country [115] 0 0
Spain
State/province [115] 0 0
Lugo
Country [116] 0 0
Spain
State/province [116] 0 0
Madrid
Country [117] 0 0
Spain
State/province [117] 0 0
Majadahonda
Country [118] 0 0
Spain
State/province [118] 0 0
Málaga
Country [119] 0 0
Spain
State/province [119] 0 0
Pamplona
Country [120] 0 0
Spain
State/province [120] 0 0
Santander
Country [121] 0 0
Spain
State/province [121] 0 0
Santiago De Compostela
Country [122] 0 0
Spain
State/province [122] 0 0
Sevilla
Country [123] 0 0
Spain
State/province [123] 0 0
Valencia
Country [124] 0 0
Spain
State/province [124] 0 0
Zaragoza
Country [125] 0 0
Taiwan
State/province [125] 0 0
Changhua
Country [126] 0 0
Taiwan
State/province [126] 0 0
Kaohsiung
Country [127] 0 0
Taiwan
State/province [127] 0 0
Taichung
Country [128] 0 0
Taiwan
State/province [128] 0 0
Tainan
Country [129] 0 0
Taiwan
State/province [129] 0 0
Taipei
Country [130] 0 0
Taiwan
State/province [130] 0 0
Taoyuan
Country [131] 0 0
United Kingdom
State/province [131] 0 0
Edinburgh
Country [132] 0 0
United Kingdom
State/province [132] 0 0
Glasgow
Country [133] 0 0
United Kingdom
State/province [133] 0 0
London
Country [134] 0 0
United Kingdom
State/province [134] 0 0
Sutton

Funding & Sponsors
Primary sponsor type
Commercial sector/industry
Name
Adlai Nortye Biopharma Co., Ltd.
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
The BURAN study is a randomized, open-label phase III study to assess the treatment effect of once-daily buparlisib in combination with weekly paclitaxel compared to weekly paclitaxel alone in patients with refractory, recurrent, or metastatic head and neck squamous cell carcinoma (HNSCC) that have progressed after prior anti PD 1/anti PD L1 monotherapy; prior anti PD 1/anti PD L1 therapy in combination with platinum-based therapy; or after sequential treatment of anti PD 1/anti PD L1 therapy, either prior to or post, platinum-based therapy.
Trial website
https://clinicaltrials.gov/study/NCT04338399
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Senior Director, Global Operations
Address 0 0
Adlai Nortye USA Inc.
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



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/study/NCT04338399