A Multicenter, Randomized, Double-Blind, Comparative Study to Evaluate the Safety, Tolerability, and Efficacy of 2 Dosing Regimens of an Antifungal Drug in the Treatment of Fungal Infections in Adults (0991-801)(COMPLETED)

• Sponsor: Merck Sharp & Dohme LLC (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00250432
• Collaborator: (none)
• Enrollment: 204
• Arms: 2
• Duration (Months): 26

Study Details

Study Description

Brief Summary

Comparison of the safety and effectiveness of standard drug dosing versus a daily dose 3 times higher than the standard dose in patients with invasive candidiasis (bloodstream and/or systemic yeast infections)

Condition or Disease	Intervention/Treatment	Phase
Invasive Candidiasis	Drug: caspofungin acetate	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 204 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Multicenter, Randomized, Double-Blind, Comparative Study to Evaluate the Safety, Tolerability, and Efficacy of 2 Dosing Regimens of Caspofungin in the Treatment of Invasive Candidiasis in Adults
• Study Start Date: Jan 1, 2006
• Actual Primary Completion Date: Jan 1, 2008
• Actual Study Completion Date: Mar 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: 1 50 mg intravenous (IV) infusion (diluted with 9% saline) administered daily (following a 70-mg IV loading dose on Day 1), over the course of ~2 hrs. all patients should be treated with antifungal therapy for at least 14 days following both the improvement in clinical and radiographic signs of disease and the eradication of Candida from culture samples obtained from the invasive site of infection.	Drug: caspofungin acetate; Caspofungin acetate 50 mg IV infusion (diluted with 9% saline) (following a 70-mg IV loading dose on Day 1); Caspofungin acetate 150 mg IV infusion (diluted with 9% saline) administered daily, over the course of ~2 hrs. Duration of Treatment - 14-90 days.
Experimental: 2 150 mg intravenous (IV) infusion (diluted with 9% saline) administered daily, over the course of ~2 hrs. all patients should be treated with antifungal therapy for at least 14 days following both the improvement in clinical and radiographic signs of disease and the eradication of Candida from culture samples obtained from the invasive site of infection.	Drug: caspofungin acetate; Caspofungin acetate 50 mg IV infusion (diluted with 9% saline) (following a 70-mg IV loading dose on Day 1); Caspofungin acetate 150 mg IV infusion (diluted with 9% saline) administered daily, over the course of ~2 hrs. Duration of Treatment - 14-90 days.

Outcome Measures

Primary Outcome Measures

1. Number of Patients Who Develop Significant Drug-related Adverse Events. [90 Days]

   Number of patients with at least 1 significant drug-related adverse event (serious drug-related or drug-related adverse events leading to caspofungin discontinuation) while on caspofungin study therapy or during the immediate 14-day post-caspofungin therapy period.

Secondary Outcome Measures

1. Number of Patients With a Favorable Overall Response. [90 Days]

   Number of patients with a favorable overall response, defined as a clinical response of "cure" or "apparent cure" along with a microbiological response of "eradication" or "presumptive eradication" at the End of Caspofungin Therapy.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Clinical and Laboratory evidence of blood stream &/or systemic candida infections

Exclusion Criteria:

• Possible candida contamination

• Candida colonization (non invasive infection), urine, cardiac, bone or brain and prosthetic device infections

• Acute or moderately severe liver disease

• Abnormal liver function tests

• Abnormal blood clotting for patients on blood thinners

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Merck Sharp & Dohme LLC

Investigators

• Study Director: Medical Monitor, Merck Sharp & Dohme LLC

Study Documents (Full-Text)

None provided.

More Information

Publications

• Betts RF, Nucci M, Talwar D, Gareca M, Queiroz-Telles F, Bedimo RJ, Herbrecht R, Ruiz-Palacios G, Young JA, Baddley JW, Strohmaier KM, Tucker KA, Taylor AF, Kartsonis NA; Caspofungin High-Dose Study Group. A Multicenter, double-blind trial of a high-dose caspofungin treatment regimen versus a standard caspofungin treatment regimen for adult patients with invasive candidiasis. Clin Infect Dis. 2009 Jun 15;48(12):1676-84. doi: 10.1086/598933.

• Responsible Party: Merck Sharp & Dohme LLC
• ClinicalTrials.gov Identifier: NCT00250432
• Other Study ID Numbers: 0991-801; 2005_085
• First Posted: Nov 8, 2005
• Last Update Posted: Mar 24, 2017
• Last Verified: Feb 1, 2017

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Additional relevant MeSH terms: Candidiasis; Candidiasis, Invasive; Caspofungin

Study Results

Participant Flow

Recruitment Details	This was a Phase III study. The first patient was enrolled (FPE) on 13-Jan-2006. The last patient's last visit (LPLV) was on 13-Mar-2008. A total of 38 inpatient centers were involved in the recruitment worldwide (14 in the United States, 13 in the European Union, 7 in Central or South America, and 4 in Asia)

Arm/Group Title	Caspofungin 70/50 mg	Caspofungin 150 mg
Arm/Group Description	Caspofungin 50 mg IV daily (following a 70-mg IV loading dose on Day 1)	Caspofungin 150 mg IV daily
Period Title: Overall Study
STARTED	104	100
COMPLETED	59	53
NOT COMPLETED	45	47

Baseline Characteristics

Arm/Group Title	Caspofungin 70/50 mg	Caspofungin 150 mg	Total
Arm/Group Description	Caspofungin 50 mg IV daily (following a 70-mg IV loading dose on Day 1)	Caspofungin 150 mg IV daily	Total of all reporting groups
Overall Participants	104	100	204
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	56.0	57.8	56.9
Sex: Female, Male (Count of Participants)
Female	50 48.1%	40 40%	90 44.1%
Male	54 51.9%	60 60%	114 55.9%
Race/Ethnicity, Customized (participants) [Number]
Caucasian	70 67.3%	65 65%	135 66.2%
Black	11 10.6%	12 12%	23 11.3%
Asian	17 16.3%	16 16%	33 16.2%
Hispanic	4 3.8%	5 5%	9 4.4%
Other	2 1.9%	2 2%	4 2%
Site Of Invasive Candida Infection (Number) [Number]
Abscess(involving an intra-abdominal site)	0 0%	2 2%	2 1%
Abscess (involving a non-abdominal site)	0 0%	1 1%	1 0.5%
Acute disseminated candidiasis or multiple sites	6 5.8%	7 7%	13 6.4%
Blood (candidemia)	91 87.5%	81 81%	172 84.3%
Chronic disseminated candidiasis (hepatosplenic)	1 1%	0 0%	1 0.5%
Fungemia (non Candida)	0 0%	2 2%	2 1%
Kidney (Pyelonephritis)	0 0%	1 1%	1 0.5%
Lung (Pneumonia)	1 1%	1 1%	2 1%
Peritoneal fluid (Peritonitis)	4 3.8%	5 5%	9 4.4%
Pleural fluid (Empyema)	1 1%	0 0%	1 0.5%
APACHE II Score (at Study Entry) (Units on a Scale) [Mean (Full Range) ]
Mean (Full Range) [Units on a Scale]	16.5	17.0	16.8

Outcome Measures

1. Primary Outcome

Title	Number of Patients Who Develop Significant Drug-related Adverse Events.
Description	Number of patients with at least 1 significant drug-related adverse event (serious drug-related or drug-related adverse events leading to caspofungin discontinuation) while on caspofungin study therapy or during the immediate 14-day post-caspofungin therapy period.
Time Frame	90 Days

Outcome Measure Data

Analysis Population Description

All patients as treated population

Arm/Group Title	Caspofungin 70/50 mg	Caspofungin 150 mg
Arm/Group Description	Caspofungin 50 mg IV daily (following a 70-mg IV loading dose on Day 1)	Caspofungin 150 mg IV daily
Measure Participants	104	100
Number [Participants]	2 1.9%	3 3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Caspofungin 70/50 mg, Caspofungin 150 mg
	Comments	A significant drug-related adverse event was defined as either a drug-related serious adverse event or a drug-related adverse event leading to discontinuation of caspofungin therapy. Comparison between the 2 caspofungin groups was based on upper bound of the 95% confidence interval for the difference.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Safety with caspofungin 150 mg daily will be non-inferior to that of caspofungin 70/50 mg. Non-inferiority was defined as upper limit of the 2-sided, 95% confidence interval for the difference (150-mg group - 70/50-mg group) must be less than 0.15 (15 percentage points).
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Rate Difference
	Estimated Value	1.1
	Confidence Interval	() 95%; -4.1 to 6.8
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 5.6
	Estimation Comments	The confidence interval computation was based on the method by Miettinen and Nurminen.

2. Secondary Outcome

Title	Number of Patients With a Favorable Overall Response.
Description	Number of patients with a favorable overall response, defined as a clinical response of "cure" or "apparent cure" along with a microbiological response of "eradication" or "presumptive eradication" at the End of Caspofungin Therapy.
Time Frame	90 Days

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS): Included those patients who received at least 1 full dose of caspofungin study therapy and had a documented diagnosis of invasive candidiasis from a sterile, invasive body site, as defined in the protocol.

Arm/Group Title	Caspofungin 70/50 mg	Caspofungin 150 mg
Arm/Group Description	Caspofungin 50 mg IV daily (following a 70-mg IV loading dose on Day 1)	Caspofungin 150 mg IV daily
Measure Participants	102	95
Number [Participants]	73 70.2%	74 74%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Caspofungin 70/50 mg, Caspofungin 150 mg
	Comments	There was no formal hypothesis testing for efficacy in this study. The main efficacy analysis was the number (percentage) of patients with a favorable overall response at the end of caspofungin study therapy, together with the within treatment 95% exact binomial confidence intervals, and the estimated treatment difference, and its 95% confidence interval.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Rate Difference
	Estimated Value	6.3
	Confidence Interval	() 95%; -5.9 to 18.4
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 12.1
	Estimation Comments	The 95% confidence interval on the difference will be based on the method of Miettinen and Nurminen.

Adverse Events

Arm/Group Title	Caspofungin 70/50 mg		Caspofungin 150 mg
Arm/Group Description	Caspofungin 50 mg IV daily (following a 70-mg IV loading dose on Day 1)		Caspofungin 150 mg IV daily
All Cause Mortality
	Caspofungin 70/50 mg		Caspofungin 150 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Caspofungin 70/50 mg		Caspofungin 150 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	46/ (NaN)		44/ (NaN)
Blood and lymphatic system disorders
Leukopenia	0/104 (0%)		1/100 (1%)
Cardiac disorders
Acute Myocardial Infarction	1/104 (1%)		0/100 (0%)
Arrhythmia	0/104 (0%)		1/100 (1%)
Atrioventricular Block	0/104 (0%)		1/100 (1%)
Atrioventricular Block Complete	1/104 (1%)		0/100 (0%)
Bradycardia	0/104 (0%)		1/100 (1%)
Cardiac Arrest	1/104 (1%)		1/100 (1%)
Cardiac Failure Congestive	0/104 (0%)		1/100 (1%)
Cardio-Respiratory Arrest	2/104 (1.9%)		0/100 (0%)
Electromechanical Disorder	1/104 (1%)		0/100 (0%)
Gastrointestinal disorders
Gastrointestinal Haemorrhage	1/104 (1%)		1/100 (1%)
Gastrointestinal Ulcer Perforation	0/104 (0%)		1/100 (1%)
Haematemesis	1/104 (1%)		0/100 (0%)
Intestinal Obstruction	0/104 (0%)		1/100 (1%)
Intra-Abdominal Haemorrhage	0/104 (0%)		1/100 (1%)
Lower Gastrointestinal Haemorrhage	1/104 (1%)		0/100 (0%)
Peritoneal Haemorrhage	0/104 (0%)		1/100 (1%)
Vomiting	1/104 (1%)		0/100 (0%)
General disorders
Brain Death	1/104 (1%)		0/100 (0%)
Death	2/104 (1.9%)		0/100 (0%)
General Physical Health Deterioration	1/104 (1%)		0/100 (0%)
Multi-Organ Failure	5/104 (4.8%)		4/100 (4%)
Non-Cardiac Chest Pain	1/104 (1%)		0/100 (0%)
Pyrexia	1/104 (1%)		0/100 (0%)
Systemic Inflammatory Response Syndrome	0/104 (0%)		1/100 (1%)
Hepatobiliary disorders
Hepatitis Toxic	0/104 (0%)		1/100 (1%)
Hyperbilirubinaemia	0/104 (0%)		1/100 (1%)
Jaundice Cholestatic	1/104 (1%)		0/100 (0%)
Infections and infestations
Abdominal Sepsis	0/104 (0%)		2/100 (2%)
Bacteraemia	2/104 (1.9%)		0/100 (0%)
Cellulitis	2/104 (1.9%)		0/100 (0%)
Cholecystitis Infective	0/104 (0%)		1/100 (1%)
Clostridial Infection	1/104 (1%)		0/100 (0%)
Enterococcal Bacteraemia	0/104 (0%)		2/100 (2%)
Fungaemia	2/104 (1.9%)		0/100 (0%)
Fungal Sepsis	0/104 (0%)		1/100 (1%)
Klebsiella Bacteraemia	0/104 (0%)		1/100 (1%)
Lower Respiratory Tract Infection	0/104 (0%)		1/100 (1%)
Meningitis Aseptic	1/104 (1%)		0/100 (0%)
Pneumonia	3/104 (2.9%)		4/100 (4%)
Pneumonia Staphylococcal	1/104 (1%)		0/100 (0%)
Pseudomonal Bacteraemia	0/104 (0%)		1/100 (1%)
Sepsis	5/104 (4.8%)		6/100 (6%)
Septic Shock	12/104 (11.5%)		13/100 (13%)
Stenotrophomonas Infection	0/104 (0%)		1/100 (1%)
Systemic Candida	1/104 (1%)		1/100 (1%)
Urosepsis	0/104 (0%)		1/100 (1%)
Wound Infection	1/104 (1%)		0/100 (0%)
Injury, poisoning and procedural complications
Accidental Overdose	0/104 (0%)		1/100 (1%)
Tracheal Obstruction	0/104 (0%)		1/100 (1%)
Musculoskeletal and connective tissue disorders
Joint Swelling	0/104 (0%)		1/100 (1%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma	0/104 (0%)		1/100 (1%)
Chronic Myeloid Leukaemia	1/104 (1%)		0/100 (0%)
Colon Cancer Metastatic	0/104 (0%)		1/100 (1%)
Metastases To Lung	1/104 (1%)		0/100 (0%)
Pituitary Cancer Metastatic	1/104 (1%)		0/100 (0%)
Tumour Necrosis	1/104 (1%)		0/100 (0%)
Nervous system disorders
Cerebral Haematoma	1/104 (1%)		0/100 (0%)
Convulsion	2/104 (1.9%)		0/100 (0%)
Myasthenia Gravis	0/104 (0%)		1/100 (1%)
Partial Seizures	0/104 (0%)		1/100 (1%)
Renal and urinary disorders
Oliguria	0/104 (0%)		1/100 (1%)
Renal Failure Acute	2/104 (1.9%)		2/100 (2%)
Respiratory, thoracic and mediastinal disorders
Acute Pulmonary Oedema	1/104 (1%)		0/100 (0%)
Acute Respiratory Distress Syndrome	2/104 (1.9%)		3/100 (3%)
Acute Respiratory Failure	1/104 (1%)		1/100 (1%)
Hypercapnia	1/104 (1%)		0/100 (0%)
Lung Infiltration	0/104 (0%)		1/100 (1%)
Pleural Effusion	0/104 (0%)		1/100 (1%)
Pneumonia Aspiration	1/104 (1%)		0/100 (0%)
Pulmonary Embolism	1/104 (1%)		1/100 (1%)
Pulmonary Oedema	0/104 (0%)		1/100 (1%)
Respiratory Arrest	2/104 (1.9%)		1/100 (1%)
Respiratory Disorder	0/104 (0%)		1/100 (1%)
Respiratory Failure	6/104 (5.8%)		1/100 (1%)
Vascular disorders
Haemodynamic Instability	0/104 (0%)		1/100 (1%)
Peripheral Vascular Disorder	0/104 (0%)		1/100 (1%)
Shock Haemorrhage	0/104 (0%)		1/100 (1%)
Venous Thrombosis Limb	1/104 (1%)		0/100 (0%)
Other (Not Including Serious) Adverse Events
	Caspofungin 70/50 mg		Caspofungin 150 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	69/ (NaN)		70/ (NaN)
Blood and lymphatic system disorders
Anaemia	3/104 (2.9%)		4/100 (4%)
Cardiac disorders
Atrial Fibrillation	0/104 (0%)		3/100 (3%)
Bradycardia	2/104 (1.9%)		2/100 (2%)
Tachycardia	1/104 (1%)		2/100 (2%)
Ventricular Tachycardia	3/104 (2.9%)		2/100 (2%)
Endocrine disorders
Adrenal Insufficiency	0/104 (0%)		2/100 (2%)
Gastrointestinal disorders
Abdominal Pain	3/104 (2.9%)		0/100 (0%)
Abdominal Pain Upper	2/104 (1.9%)		3/100 (3%)
Constipation	3/104 (2.9%)		3/100 (3%)
Diarrhea	6/104 (5.8%)		7/100 (7%)
Gastrointestinal Hemorrhage	1/104 (1%)		2/100 (2%)
Haematemesis	0/104 (0%)		2/100 (2%)
Ileus	3/104 (2.9%)		1/100 (1%)
Nausea	5/104 (4.8%)		7/100 (7%)
Vomiting	10/104 (9.6%)		6/100 (6%)
General disorders
Asthenia	2/104 (1.9%)		3/100 (3%)
Chest Pain	1/104 (1%)		2/100 (2%)
Generalised Oedema	3/104 (2.9%)		0/100 (0%)
Hypothermia	2/104 (1.9%)		2/100 (2%)
Injection Site Erythema	0/104 (0%)		2/100 (2%)
Injection Site Phlebitis	4/104 (3.8%)		2/100 (2%)
Injection Site Swelling	1/104 (1%)		2/100 (2%)
Oedema	1/104 (1%)		2/100 (2%)
Oedema Peripheral	4/104 (3.8%)		2/100 (2%)
Pyrexia	5/104 (4.8%)		6/100 (6%)
Hepatobiliary disorders
Jaundice	0/104 (0%)		2/100 (2%)
Infections and infestations
Bacteraemia	3/104 (2.9%)		2/100 (2%)
Empyema	1/104 (1%)		2/100 (2%)
Pneumonia	2/104 (1.9%)		4/100 (4%)
Staphylococcal Bacteraemia	3/104 (2.9%)		4/100 (4%)
Urinary Tract Infection	3/104 (2.9%)		2/100 (2%)
Investigations
Activated Partial Thromboplastin Time Prolonged	0/104 (0%)		2/100 (2%)
Alanine Aminotransferase Increased	4/104 (3.8%)		7/100 (7%)
Aspartate Aminotransferase Increased	6/104 (5.8%)		9/100 (9%)
Blood Albumin Decreased	2/104 (1.9%)		2/100 (2%)
Blood Alkaline Phosphatase Increased	12/104 (11.5%)		9/100 (9%)
Blood Bilirubin Increased	3/104 (2.9%)		2/100 (2%)
Blood Calcium Decreased	1/104 (1%)		2/100 (2%)
Blood Calcium Increased	0/104 (0%)		2/100 (2%)
Blood Chloride Increased	0/104 (0%)		3/100 (3%)
Blood Creatinine Increased	3/104 (2.9%)		3/100 (3%)
Blood Glucose Decreased	3/104 (2.9%)		1/100 (1%)
Blood Glucose Increased	1/104 (1%)		3/100 (3%)
Blood Magnesium Decreased	4/104 (3.8%)		4/100 (4%)
Blood Phosphorus Decreased	2/104 (1.9%)		2/100 (2%)
Blood Potassium Decreased	6/104 (5.8%)		8/100 (8%)
Blood Potassium Increased	2/104 (1.9%)		4/100 (4%)
Blood Sodium Decreased	1/104 (1%)		3/100 (3%)
Blood Sodium Increased	2/104 (1.9%)		4/100 (4%)
Blood Urea Increased	4/104 (3.8%)		1/100 (1%)
Blood Uric Acid Decreased	0/104 (0%)		2/100 (2%)
Carbon Dioxide Decreased	0/104 (0%)		2/100 (2%)
White Blood Cell Count Increased	1/104 (1%)		3/100 (3%)
Hyperglycaemia	2/104 (1.9%)		3/100 (3%)
Hypoglycaemia	1/104 (1%)		3/100 (3%)
Hypokalaemia	2/104 (1.9%)		2/100 (2%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/104 (1%)		3/100 (3%)
Back Pain	1/104 (1%)		2/100 (2%)
Nervous system disorders
Convulsion	3/104 (2.9%)		0/100 (0%)
Headache	5/104 (4.8%)		4/100 (4%)
Psychiatric disorders
Agitation	3/104 (2.9%)		3/100 (3%)
Confusional State	3/104 (2.9%)		2/100 (2%)
Delirium	0/104 (0%)		2/100 (2%)
Depression	3/104 (2.9%)		1/100 (1%)
Insomnia	3/104 (2.9%)		1/100 (1%)
Renal and urinary disorders
Renal Failure	3/104 (2.9%)		2/100 (2%)
Renal Failure Acute	0/104 (0%)		2/100 (2%)
Reproductive system and breast disorders
Vaginal Discharge	3/104 (2.9%)		1/100 (1%)
Respiratory, thoracic and mediastinal disorders
Bronchospasm	1/104 (1%)		2/100 (2%)
Dyspnoea	4/104 (3.8%)		3/100 (3%)
Lung Infiltration	0/104 (0%)		2/100 (2%)
Pleural Effusion	2/104 (1.9%)		2/100 (2%)
Pulmonary Embolism	0/104 (0%)		2/100 (2%)
Pulmonary Oedema	0/104 (0%)		2/100 (2%)
Tachypnoea	3/104 (2.9%)		1/100 (1%)
Skin and subcutaneous tissue disorders
Decubitus Ulcer	3/104 (2.9%)		5/100 (5%)
Pruritus	0/104 (0%)		3/100 (3%)
Rash	5/104 (4.8%)		3/100 (3%)
Vascular disorders
Haematoma	3/104 (2.9%)		0/100 (0%)
Hypertension	5/104 (4.8%)		6/100 (6%)
Hypotension	7/104 (6.7%)		3/100 (3%)
Jugular Vein Thrombosis	0/104 (0%)		2/100 (2%)
Phlebitis	3/104 (2.9%)		1/100 (1%)
Venous Thrombosis Limb	0/104 (0%)		3/100 (3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

Merck agreements may vary with individual investigators, but will not prohibit any investigator from publishing. Merck supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial.