A Trial of Everolimis in Patients With Advanced Renal Cell Carcinoma.

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01206764
• Collaborator: (none)
• Enrollment: 143
• Locations: 22
• Arm: 1
• Actual Duration (Months): 91.6
• Patients Per Site: 6.5
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

Renal cell carcinoma (RCC) accounts for more than 200,000 new cases of cancer and over 100,000 cancer deaths annually in the World (Ferlay, et al., 2004). It is estimated that there were about 15,000 new cases of RCC in the region that excludes the Americas, European Union and Japan. Renal cell carcinomas arise from the proximal tubal epithelium are more common in males than in females with an overall lifetime risk of 1 in 75 and a median age of diagnosis of 65 years.

Everolimus (Certican®) has been approved since 2003 in more than 60 countries for the prevention of organ rejection in patients with renal and cardiac transplantation. Everolimus (RAD001) is a derivative of rapamycin, which acts as a signal transduction inhibitor. It targets mTOR, a key protein kinase regulating cell growth, proliferation, and survival. The mTOR pathway activity is modulated by the phosphatidylinositol-3-kinase (PI3K)/protein kinase B AKT (AKT) pathway, a pathway known to be deregulated in numerous human cancers. RAD001 (Afinitor®) has been investigated as an anticancer agent based on its potential to act:

• directly on the tumor cells by inhibiting tumor cell growth and proliferation;

• indirectly by inhibiting angiogenesis leading to reduced tumor vascularity (via potent inhibition of tumor cell hypoxia-inducible factor 1 (HIF-1) activity, VEGF production, and VEGF-induced proliferation of endothelial cells).

Primary: To evaluate the PFS rate over time.

Secondary:

• To evaluate the disease control rate (stable disease [SD] + partial response [PR] + complete response [CR]);

• To evaluate the objective response rate (ORR; where ORR = CR + PR) and duration;

• To describe the safety profile of RAD001.

Condition or Disease	Intervention/Treatment	Phase
Renal Cell Carcinoma	Drug: RAD001	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 143 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-label, Multi-center Phase 2 Study to Evaluate Everolimus as Monotherapy Treatment for Patients With Metastatic Recurrent and/or Unresectable Renal Cell Carcinoma (EVERMORE).
• Actual Study Start Date: Nov 11, 2009
• Actual Primary Completion Date: Jun 6, 2017
• Actual Study Completion Date: Jul 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: RAD001	Drug: RAD001; Other Names: Everolimus

Outcome Measures

Primary Outcome Measures

1. PFS (Progression-Free Survival) [Approximately 4 years]

   the time from the date of the start of RAD001 treatment to the date of the first documented disease progression or death due to any cause

Secondary Outcome Measures

1. Disease Control Rate (Stable Disease [SD] + Partial Response [PR] + Complete Response [CR]); [Approximately 4 years]

   The disease control rate was based on the data as per local radiological review following the RECIST criteria. The disease control rate is defined as the proportion of patients with CR, PR, or SD and was summarized in terms of percentage with 95% exact Clopper-Pearson CIs

2. Objective Response Rate (ORR; Where ORR = CR + PR) [Approximately 4 years]

   The overall tumor response was based on the data as per local radiological review, following RECIST criteria. The ORR is defined as the proportion of patients with CR or PR and was summarized in terms of percentage with 95% exact Clopper-Pearson CIs

3. Duration of Response (DOR) [Approximately 4 years]

   The DOR analysis applied only to patients whose overall response was CR or PR and was defined as the time from onset of response (CR/PR) to progression or death from any cause

4. Overall Survival [Approximately 4 years]

   Overall survival is defined as the time from date of start of treatment to date of death due to any cause. If a patient is not known to have died, survival will be censored at the date of last contact.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria: Patients may be entered in the study only if they meet all of the following criteria:

• Age ≥18 years old;

• Patients with advanced renal cell carcinoma with confirmed clear or non-clear cell histology, with or without nephrectomy, and with any MSKCC prognosis;

• Prior cytokine therapy is permitted;

• Patients with at least one measurable lesion at baseline as per the Response Evaluation Criteria in Solid Tumors (RECIST) criteria. If skin lesions are reported as target lesions, they must be documented (at baseline and at every physical exam) using color photography and a measuring device (such as a caliper) in clear focus to allow the size of the lesion(s) to be determined from the photograph;

• Life expectancy ≥3 months. Life expectancy should be judged in relation to other determining patient eligibility factors such as laboratory results, Karnofsky Performance Status, etc.;

• Patients with a Karnofsky Performance Status ≥70%;

• Adequate bone marrow function as shown by: absolute neutrophil count (ANC) ≥1.5 x 109/L, platelets ≥100 x 109/L, hemoglobin (Hb) >9 g/dL;

• Adequate liver function: serum bilirubin ≤1.5 x upper limit of normal (ULN), alanine transaminase (ALT), and aspartate transaminase (AST) ≤2.5 x ULN;

• Adequate renal function: serum creatinine ≤1.5 x ULN;

• Females of childbearing potential must have had a negative serum or urine pregnancy test 7 days prior to the administration of the study treatment start;

• Patients who give a written informed consent obtained according to local guidelines.

Exclusion Criteria:Patients may not be entered into the study if they meet any of the following criteria:

• Patients within 2 weeks post-minor surgery (e.g., herniorrhaphy), 4 weeks post-major surgery (e.g., intra-thoracic, intra-abdominal, or intra-pelvic) to avoid wound healing complications. Percutaneous biopsies require no waiting time prior to study entry;

• Patients with a recent history of hemoptysis, ≥0.5 teaspoon of red blood;

• Patients who have received prior systemic treatment for their metastatic RCC other than with cytokine therapy;

• Patients who received prior therapy with a VEGF pathway inhibitor, such as sunitinib, sorafenib, and bevacizumab;

• Patients who have previously received mTOR inhibitors (sirolimus, temsirolimus, everolimus, deferolimus);

• History or clinical evidence of central nervous system (CNS) metastases. Note: Subjects who have previously-treated CNS metastases (surgery ± radiotherapy, radiosurgery, or gamma knife) and meet all 3 of the following criteria are eligible:

Are asymptomatic; Have had no evidence of active CNS metastases for ≥6 months prior to enrollment and; Have no requirement for steroids or enzyme-inducing anticonvulsants (EIAC);

• Clinically significant gastrointestinal abnormalities including, but not limited to: Malabsorption syndrome; Major resection of the stomach or small bowel that could affect the absorption of study drug; Active peptic ulcer disease; Inflammatory bowel disease; Ulcerative colitis, or other gastrointestinal conditions with increased risk of perforation; History of abdominal fistula, gastrointestinal perforation, or intra abdominal abscess within 28 days prior to beginning of study treatment;

• Patients receiving chronic systemic treatment with corticosteroids (dose of ≥10 mg/day methylprednisone equivalent) or another immune-suppressive agent. Inhaled and topical steroids are acceptable, as well as opotherapy after bilateral adrenal gland removal;

• Patients with a known history of human immunodeficiency virus seropositivity;

• Patients with autoimmune hepatitis;

• Patients with an active, bleeding diathesis. Patients may use coumadin or heparin preparations;

• Patients who have any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study;

• Patients who have a history of another primary malignancy ≤3 years, with the exception of non-melanoma skin cancer and carcinoma in situ of uterine;

• Female patients who are pregnant or breastfeeding, or adults of reproductive potential who are not using effective birth control methods. If barrier contraceptives are being used, these must be continued throughout the study by both sexes. Oral contraceptives are not acceptable;

• Patients who are using other investigational agents or who had received investigational drugs ≤4 weeks prior to study treatment start; Patients unwilling or unable to comply with the protocol.

Other protocol-defined inclusion/exclusion may apply

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Alger		Algeria	016000
2	Novartis Investigative Site	Oran		Algeria
3	Novartis Investigative Site	Alexandria		Egypt	21131
4	Novartis Investigative Site	Cairo		Egypt
5	Novartis Investigative Site	Mansoura		Egypt
6	Novartis Investigative Site	Indore	Madhya Pradesh	India	452 008
7	Novartis Investigative Site	Pune	Maharashtra	India	411013
8	Novartis Investigative Site	Amman		Jordan	11941
9	Novartis Investigative Site	Ashrafieh		Lebanon	166830
10	Novartis Investigative Site	Moscow		Russian Federation	115478
11	Novartis Investigative Site	Samara		Russian Federation	443031
12	Novartis Investigative Site	Riyadh		Saudi Arabia	11211
13	Novartis Investigative Site	Cape Town		South Africa	7500
14	Novartis Investigative Site	Cape Town		South Africa	7925
15	Novartis Investigative Site	Durban		South Africa	4001
16	Novartis Investigative Site	Parktown		South Africa	2193
17	Novartis Investigative Site	Songkhla	Hat Yai	Thailand	90110
18	Novartis Investigative Site	Bangkok		Thailand	10400
19	Novartis Investigative Site	Chiang Mai		Thailand	50200
20	Novartis Investigative Site	Tunis	Tunisie	Tunisia	1007
21	Novartis Investigative Site	Ariana		Tunisia	2080
22	Novartis Investigative Site	Sousse		Tunisia	4000

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

• Statistical Analysis Plan - Sep 22, 2017
• Study Protocol - May 12, 2010

More Information

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT01206764
• Other Study ID Numbers: CRAD001LIC01
• First Posted: Sep 22, 2010
• Last Update Posted: Jun 24, 2019
• Last Verified: Mar 1, 2019

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Novartis Pharmaceuticals: RCC,; mTOR pathway,; angiogenesis,; PFS,; partial response [PR] + complete response [CR]); metastatic recurrent renal cell carcinoma; metastatic unresectable renal cell carcinoma
• Additional relevant MeSH terms: Carcinoma; Carcinoma, Renal Cell; Everolimus

Study Results

Participant Flow

Arm/Group Title	RAD001
Arm/Group Description	Two 5 mg RAD001 tablets
Period Title: Overall Study
STARTED	142
COMPLETED	4
NOT COMPLETED	138

Baseline Characteristics

Arm/Group Title	RAD001
Arm/Group Description	Two 5 mg RAD001 tablets
Overall Participants	142
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	55.5 (12.63)
Sex: Female, Male (Count of Participants)
Female	55 38.7%
Male	87 61.3%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	42 29.6%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	2 1.4%
White	71 50%
More than one race	0 0%
Unknown or Not Reported	27 19%

Outcome Measures

1. Primary Outcome

Title	PFS (Progression-Free Survival)
Description	the time from the date of the start of RAD001 treatment to the date of the first documented disease progression or death due to any cause
Time Frame	Approximately 4 years

Outcome Measure Data

Analysis Population Description

The Intent-to-Treat population (ITT population) consisted of all patients treated with RAD001.

Arm/Group Title	RAD001
Arm/Group Description	Two 5 mg RAD001 tablets
Measure Participants	142
Median (95% Confidence Interval) [Weeks]	27.71

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	RAD001
	Comments	Single arm open label study
	Type of Statistical Test	Other
	Comments	Kaplan Meier
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Net)
	Estimated Value	27.71
	Confidence Interval	(2-Sided) 95%; 21.86 to 35.29
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Disease Control Rate (Stable Disease [SD] + Partial Response [PR] + Complete Response [CR]);
Description	The disease control rate was based on the data as per local radiological review following the RECIST criteria. The disease control rate is defined as the proportion of patients with CR, PR, or SD and was summarized in terms of percentage with 95% exact Clopper-Pearson CIs
Time Frame	Approximately 4 years

Outcome Measure Data

Analysis Population Description

The Intent-to-Treat population (ITT population) consisted of all patients treated with RAD001.

Arm/Group Title	RAD001
Arm/Group Description	Two 5 mg RAD001 tablets
Measure Participants	142
Number (95% Confidence Interval) [Percentage of Participants]	74.6 52.5%

3. Secondary Outcome

Title	Objective Response Rate (ORR; Where ORR = CR + PR)
Description	The overall tumor response was based on the data as per local radiological review, following RECIST criteria. The ORR is defined as the proportion of patients with CR or PR and was summarized in terms of percentage with 95% exact Clopper-Pearson CIs
Time Frame	Approximately 4 years

Outcome Measure Data

Analysis Population Description

The Intent-to-Treat population (ITT population) consisted of all patients treated with RAD001.

Arm/Group Title	RAD001
Arm/Group Description	Two 5 mg RAD001 tablets
Measure Participants	142
Number (95% Confidence Interval) [Percentage of participants]	17 12%

4. Secondary Outcome

Title	Duration of Response (DOR)
Description	The DOR analysis applied only to patients whose overall response was CR or PR and was defined as the time from onset of response (CR/PR) to progression or death from any cause
Time Frame	Approximately 4 years

Outcome Measure Data

Analysis Population Description

The Intent-to-Treat population (ITT population) consisted of all patients treated with RAD001.

Arm/Group Title	RAD001
Arm/Group Description	Two 5 mg RAD001 tablets
Measure Participants	142
Median (95% Confidence Interval) [Weeks]	169

5. Secondary Outcome

Title	Overall Survival
Description	Overall survival is defined as the time from date of start of treatment to date of death due to any cause. If a patient is not known to have died, survival will be censored at the date of last contact.
Time Frame	Approximately 4 years

Outcome Measure Data

Analysis Population Description

The Intent-to-Treat population (ITT population) consisted of all patients treated with RAD001.

Arm/Group Title	RAD001
Arm/Group Description	Two 5 mg RAD001 tablets
Measure Participants	142
Median (95% Confidence Interval) [Weeks]	NA

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	RAD001
	Comments	The median overall survival was not evaluable, this presents the 25th percentile of overall survival
	Type of Statistical Test	Other
	Comments	Kaplan Meier
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Net)
	Estimated Value	45.71
	Confidence Interval	(2-Sided) 95%; 31.29 to 106.43
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	Approximately 4 years
Adverse Event Reporting Description	AE additional description
Arm/Group Title	RAD001
Arm/Group Description	Two 5 mg RAD001 tablets
All Cause Mortality
	RAD001
	Affected / at Risk (%)	# Events
Total	33/142 (23.2%)
Serious Adverse Events
	RAD001
	Affected / at Risk (%)	# Events
Total	48/142 (33.8%)
Blood and lymphatic system disorders
ANAEMIA	5/142 (3.5%)
FEBRILE NEUTROPENIA	1/142 (0.7%)
HYPOCHROMIC ANAEMIA	1/142 (0.7%)
Cardiac disorders
CARDIO-RESPIRATORY ARREST	2/142 (1.4%)
MYOCARDIAL INFARCTION	1/142 (0.7%)
TACHYCARDIA	1/142 (0.7%)
Endocrine disorders
HYPERCALCAEMIA OF MALIGNANCY	1/142 (0.7%)
Gastrointestinal disorders
ABDOMINAL DISTENSION	1/142 (0.7%)
ABDOMINAL PAIN	2/142 (1.4%)
COLONIC FISTULA	1/142 (0.7%)
CONSTIPATION	1/142 (0.7%)
DIARRHOEA	3/142 (2.1%)
DYSPHAGIA	1/142 (0.7%)
INTESTINAL OBSTRUCTION	2/142 (1.4%)
NAUSEA	1/142 (0.7%)
STOMATITIS	2/142 (1.4%)
UPPER GASTROINTESTINAL HAEMORRHAGE	1/142 (0.7%)
VOMITING	1/142 (0.7%)
General disorders
ASTHENIA	3/142 (2.1%)
FATIGUE	1/142 (0.7%)
MUCOSAL INFLAMMATION	4/142 (2.8%)
MULTI-ORGAN DISORDER	1/142 (0.7%)
PYREXIA	1/142 (0.7%)
Infections and infestations
ABSCESS	1/142 (0.7%)
ANAL ABSCESS	1/142 (0.7%)
BACTERAEMIA	1/142 (0.7%)
DIVERTICULITIS	1/142 (0.7%)
GASTROENTERITIS	1/142 (0.7%)
GENITAL ABSCESS	1/142 (0.7%)
LOWER RESPIRATORY TRACT INFECTION	1/142 (0.7%)
PNEUMONIA	6/142 (4.2%)
SEPSIS	2/142 (1.4%)
TOOTH ABSCESS	1/142 (0.7%)
URINARY TRACT INFECTION	3/142 (2.1%)
Injury, poisoning and procedural complications
FEMUR FRACTURE	1/142 (0.7%)
PROCEDURAL PAIN	1/142 (0.7%)
ROAD TRAFFIC ACCIDENT	1/142 (0.7%)
Investigations
ASPARTATE AMINOTRANSFERASE INCREASED	1/142 (0.7%)
BLOOD CREATININE INCREASED	2/142 (1.4%)
URINE OUTPUT DECREASED	1/142 (0.7%)
Metabolism and nutrition disorders
DECREASED APPETITE	3/142 (2.1%)
DEHYDRATION	3/142 (2.1%)
DIABETES MELLITUS	1/142 (0.7%)
HYPERCALCAEMIA	1/142 (0.7%)
HYPERCHOLESTEROLAEMIA	1/142 (0.7%)
HYPERNATRAEMIA	1/142 (0.7%)
HYPOGLYCAEMIA	1/142 (0.7%)
HYPOKALAEMIA	1/142 (0.7%)
HYPOMAGNESAEMIA	1/142 (0.7%)
HYPOPHOSPHATAEMIA	1/142 (0.7%)
KETOACIDOSIS	1/142 (0.7%)
Musculoskeletal and connective tissue disorders
MUSCULOSKELETAL CHEST PAIN	1/142 (0.7%)
MUSCULOSKELETAL PAIN	2/142 (1.4%)
NECK PAIN	1/142 (0.7%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
BONE CANCER METASTATIC	1/142 (0.7%)
MALIGNANT NEOPLASM PROGRESSION	1/142 (0.7%)
METASTASES TO BONE	1/142 (0.7%)
METASTASES TO LUNG	1/142 (0.7%)
NEOPLASM PROGRESSION	3/142 (2.1%)
Nervous system disorders
DEPRESSED LEVEL OF CONSCIOUSNESS	1/142 (0.7%)
HEMIPARESIS	2/142 (1.4%)
LETHARGY	1/142 (0.7%)
MENTAL IMPAIRMENT	1/142 (0.7%)
NERVOUS SYSTEM DISORDER	1/142 (0.7%)
NEUROPATHY PERIPHERAL	1/142 (0.7%)
Psychiatric disorders
CONFUSIONAL STATE	1/142 (0.7%)
Renal and urinary disorders
HAEMATURIA	1/142 (0.7%)
RENAL FAILURE	2/142 (1.4%)
RENAL FAILURE ACUTE	3/142 (2.1%)
RENAL IMPAIRMENT	1/142 (0.7%)
Respiratory, thoracic and mediastinal disorders
COUGH	1/142 (0.7%)
DYSPNOEA	4/142 (2.8%)
LUNG DISORDER	1/142 (0.7%)
PLEURAL EFFUSION	1/142 (0.7%)
PNEUMONITIS	1/142 (0.7%)
PULMONARY ARTERY THROMBOSIS	2/142 (1.4%)
PULMONARY EMBOLISM	1/142 (0.7%)
RESPIRATORY FAILURE	1/142 (0.7%)
Vascular disorders
ARTERIAL THROMBOSIS LIMB	1/142 (0.7%)
HYPOTENSION	1/142 (0.7%)
THROMBOPHLEBITIS	1/142 (0.7%)
Other (Not Including Serious) Adverse Events
	RAD001
	Affected / at Risk (%)	# Events
Total	125/142 (88%)
Blood and lymphatic system disorders
ANAEMIA	62/142 (43.7%)
LEUKOPENIA	22/142 (15.5%)
NEUTROPENIA	23/142 (16.2%)
THROMBOCYTOPENIA	18/142 (12.7%)
Gastrointestinal disorders
ABDOMINAL PAIN	15/142 (10.6%)
CONSTIPATION	15/142 (10.6%)
DIARRHOEA	18/142 (12.7%)
NAUSEA	15/142 (10.6%)
STOMATITIS	41/142 (28.9%)
VOMITING	9/142 (6.3%)
General disorders
ASTHENIA	22/142 (15.5%)
FATIGUE	30/142 (21.1%)
MUCOSAL INFLAMMATION	24/142 (16.9%)
OEDEMA PERIPHERAL	15/142 (10.6%)
PYREXIA	14/142 (9.9%)
Infections and infestations
URINARY TRACT INFECTION	9/142 (6.3%)
Investigations
ALANINE AMINOTRANSFERASE INCREASED	14/142 (9.9%)
ASPARTATE AMINOTRANSFERASE INCREASED	16/142 (11.3%)
BLOOD ALKALINE PHOSPHATASE INCREASED	11/142 (7.7%)
BLOOD CHOLESTEROL INCREASED	13/142 (9.2%)
BLOOD CREATININE INCREASED	21/142 (14.8%)
BLOOD TRIGLYCERIDES INCREASED	12/142 (8.5%)
GAMMA-GLUTAMYLTRANSFERASE INCREASED	19/142 (13.4%)
PROTHROMBIN TIME PROLONGED	8/142 (5.6%)
Metabolism and nutrition disorders
ABNORMAL LOSS OF WEIGHT	29/142 (20.4%)
DECREASED APPETITE	32/142 (22.5%)
HYPERCHOLESTEROLAEMIA	25/142 (17.6%)
HYPERGLYCAEMIA	37/142 (26.1%)
HYPERMAGNESAEMIA	10/142 (7%)
HYPERTRIGLYCERIDAEMIA	21/142 (14.8%)
HYPERURICAEMIA	10/142 (7%)
HYPOALBUMINAEMIA	11/142 (7.7%)
HYPOCALCAEMIA	18/142 (12.7%)
HYPOKALAEMIA	9/142 (6.3%)
Musculoskeletal and connective tissue disorders
ARTHRALGIA	9/142 (6.3%)
BACK PAIN	12/142 (8.5%)
PAIN IN EXTREMITY	12/142 (8.5%)
Nervous system disorders
DYSGEUSIA	9/142 (6.3%)
HEADACHE	9/142 (6.3%)
Respiratory, thoracic and mediastinal disorders
COUGH	31/142 (21.8%)
DYSPNOEA	20/142 (14.1%)
EPISTAXIS	16/142 (11.3%)
PNEUMONITIS	11/142 (7.7%)
Skin and subcutaneous tissue disorders
PRURITUS	11/142 (7.7%)
RASH	33/142 (23.2%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (i.e., data from all sites) in the clinical trial or disclosure of trial results in their entirety.