TROPICS 3: A Study of Tenecteplase for Restoration of Function in Dysfunctional Hemodialysis Catheters

• Sponsor: Genentech, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00396032
• Collaborator: (none)
• Enrollment: 150
• Arms: 2

Study Details

Study Description

Brief Summary

This was a Phase III, randomized, double-blind, placebo-controlled study conducted at 37 centers in the United States. 150 subjects ≥ 16 years of age who required hemodialysis (HD) and had a dysfunctional HD catheter were enrolled in the study.

Condition or Disease	Intervention/Treatment	Phase
Dysfunctional Hemodialysis Catheters	Drug: placebo; Drug: tenecteplase	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 150 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Phase III, Randomized, Double-Blind, Placebo-Controlled Study of Tenecteplase for Restoration of Function in Dysfunctional Hemodialysis Catheters
• Study Start Date: Oct 1, 2006
• Actual Primary Completion Date: Dec 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 1	Drug: tenecteplase; For the initial treatment, 2 mL of reconstituted lyophilized tenecteplase instilled into each lumen of the HD catheter; subsequent treatments were 2 mL of open-label tenecteplase
Placebo Comparator: 2	Drug: placebo; For the initial treatment, 2 mL of placebo instilled into each lumen of the HD catheter; subsequent treatments were 2 mL of open-label tenecteplase

Outcome Measures

Primary Outcome Measures

1. Percentage of Subjects Who Had Treatment Success With Respect to Blood Flow Rate (BFR) at Visit 1 [Visit 1 of HD treatment]

   Treatment success is defined as BFR of ≥300 mL/min and an increase from baseline BFR of ≥25 mL/min at an associated target arterial pressure in the range of 0 to -280 mmHg 30 (±10) minutes prior to the end of HD and at the end of HD.

2. Incidence of Targeted Adverse Events (AEs) From Initial Study Drug Administration Through the Start of Visit 2 [Visits 1 and 2 of consecutive HD treatments]

   Targeted AEs were intracranial hemorrhages (ICHs), major bleeding, embolic events, thrombosis, catheter-related bloodstream infections (CRBSIs), and catheter related complications

Secondary Outcome Measures

1. Change in BFR From Baseline to the End of HD at Visit 1 [Visit 1 of HD treatment]

   BFR is measured in mL/minute.

2. Percentage of Subjects Who Had Treatment Success With Respect to BFR at Visit 2 (MITT Population With Extended Dwell Tenecteplase at Visit 1) [Visit 2 of consecutive HD treatments]

   Treatment success is defined as BFR of ≥300 mL/min and an increase from baseline BFR of ≥25 mL/min at an associated target arterial pressure in the range of 0 to -280 mmHg 30 (±10) minutes prior to the end of HD and at the end of HD.

3. Percentage of Subjects Who Had Treatment Success With Respect to BFR at Visit 2 (MITT Population With Open-label Tenecteplase at Visit 2) [Visit 2 of consecutive HD treatments]

   Treatment success is defined as BFR of ≥300 mL/min and an increase from baseline BFR of ≥25 mL/min at an associated target arterial pressure in the range of 0 to -280 mmHg 30 (±10) minutes prior to the end of HD and at the end of HD.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 16 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Clinically stable, in the opinion of the investigator

• Use of a cuffed, tunneled HD catheter

• HD prescribed at a BFR of ≥300 mL/min

• Baseline BFR (at any time during the first 60 minutes of HD) of <300 mL/min at an associated pre-pump negative arterial pressure in the range between and including -240 mmHg and -280 mmHg

• Baseline BFR (at any time during the first 60 minutes of HD) at least 25 mL/min below the prescribed BFR

• Demonstrated BFR of ≥300 mL/min (using catheter lines in the customary direction) at an arterial pressure in the range of 0 to -280 mmHg in at least one HD session in the 14 days prior to Visit 1

• Anticipated use of the same catheter for at least four consecutive HD sessions, on the same type and model of HD apparatus

• Able to have fluids infused at the volume necessary to instill study drug into the HD catheter

Exclusion Criteria:

• HD catheter with sustainable BFR of ≥300 mL/min following subject repositioning

• HD catheter inserted <2 days prior to screening

• Evidence of a mechanical, non-thrombotic cause of HD catheter dysfunction (e.g., kink in the catheter or suture constricting the catheter) or dysfunction caused by known fibrin sheath

• Use of an implantable port

• HD catheter that is internally coated with any therapeutic agent (e.g., the Decathlon™ Gold catheter)

• Anticipated use of catheter for any other type of diagnostic or therapeutic procedure (i.e., other than HD) during study drug treatment

• Previously treated in this study or any tenecteplase catheter clearance trial

• Use of any investigational drug or therapy (defined as any drug or therapy that is not FDA approved) within 28 days prior to screening

• Use of a fibrinolytic agent (e.g., alteplase, tenecteplase, reteplase, or urokinase) within 7 days prior to Visit 1

• Known to be pregnant or breastfeeding at screening or at Visit 1

• Known bacteremia or known or suspected infection in the HD catheter

• Known history of any of the following: intracranial hemorrhage (within the previous 3 years), intracranial aneurysm, or arteriovenous malformation

• Use of heparin (unfractionated or low molecular weight) or other anticoagulants (e.g., for the treatment of heparin-induced thrombocytopenia) within 24 hours prior to Visit 1, except for heparin used only during HD or for prophylaxis (e.g., heparin lock or deep vein thrombosis prophylaxis)

• Subjects treated with warfarin only: international normalized ratio (INR) >3.0 within 7 days prior to Visit 1, or a target INR range that allows for an INR >3.0 A laboratory test to confirm the INR must have been performed within 7 days prior to Visit 1.

• Initiation of or increase in dose of Plavix® (clopidogrel bisulfate) within 7 days prior to Visit 1

• Hemoglobin ≥12.0 g/dL if on an erythropoiesis-stimulating agent (e.g., darbepoetin or erythropoietin) and the dose of the erythropoiesis-stimulating agent has not been held or reduced per institutional policy

• At high risk for bleeding events or embolic complications (i.e., recent pulmonary embolus, deep vein thrombosis, endarterectomy, or clinically significant right-to-left shunt) in the opinion of the investigator, or with known condition for which bleeding constitutes a significant hazard

• BFR of <300 mL/min because of symptomatic hypotension

• Uncontrolled hypertension in the opinion of the investigator

• Known hypersensitivity to tenecteplase or any component of the formulation

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Genentech, Inc.

Investigators

• Study Director: Barbara Gillespie, M.D., FASN,

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• ClinicalTrials.gov Identifier: NCT00396032
• Other Study ID Numbers: N3700g
• First Posted: Nov 6, 2006
• Last Update Posted: Jun 3, 2010
• Last Verified: May 1, 2010

• Keywords provided by , ,: HD; Hemodialysis; Catheter clearance; TNKase; Renal Insufficiency
• Additional relevant MeSH terms: Tenecteplase

Study Results

Participant Flow

Pre-assignment Detail	One participant was randomized but not treated, therefore the modified intent-to-treat (MITT) analysis population was 149.

Arm/Group Title	Tenecteplase	Placebo
Arm/Group Description	For the initial treatment, 2 mL of reconsituted lyophilized tenecteplase instilled into each lumen of the HD catheter; subsequent treatments were 2 mL of open-label tenecteplase	For the initial treatment, 2 mL of placebo instilled into each lumen of the HD catheter; subsequent treatments were 2 mL of open-label tenecteplase
Period Title: Overall Study
STARTED	74	76
COMPLETED	70	71
NOT COMPLETED	4	5

Baseline Characteristics

Arm/Group Title	Tenecteplase	Placebo	Total
Arm/Group Description	For the initial treatment, 2 mL of reconsituted lyophilized tenecteplase instilled into each lumen of the HD catheter; subsequent treatments were 2 mL of open-label tenecteplase	For the initial treatment, 2 mL of placebo instilled into each lumen of the HD catheter; subsequent treatments were 2 mL of open-label tenecteplase	Total of all reporting groups
Overall Participants	74	75	149
Age, Customized (participants) [Number]
< 17 years	0 0%	0 0%	0 0%
>= 17 years to < 65 years	44 59.5%	51 68%	95 63.8%
>= 65 years	30 40.5%	24 32%	54 36.2%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	60.8 (14.1)	57.8 (16.5)	59.3 (15.3)
Sex: Female, Male (Count of Participants)
Female	38 51.4%	37 49.3%	75 50.3%
Male	36 48.6%	38 50.7%	74 49.7%

Outcome Measures

1. Primary Outcome

Title	Percentage of Subjects Who Had Treatment Success With Respect to Blood Flow Rate (BFR) at Visit 1
Description	Treatment success is defined as BFR of ≥300 mL/min and an increase from baseline BFR of ≥25 mL/min at an associated target arterial pressure in the range of 0 to -280 mmHg 30 (±10) minutes prior to the end of HD and at the end of HD.
Time Frame	Visit 1 of HD treatment

Outcome Measure Data

Analysis Population Description

Modified intent to treat (MITT) population

Arm/Group Title	Tenecteplase	Placebo
Arm/Group Description	For the initial treatment, 2 mL of reconsituted lyophilized tenecteplase instilled into each lumen of the HD catheter; subsequent treatments were 2 mL of open-label tenecteplase	For the initial treatment, 2 mL of placebo instilled into each lumen of the HD catheter; subsequent treatments were 2 mL of open-label tenecteplase
Measure Participants	74	75
Number [percentage of success]	21.6	5.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tenecteplase, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0044
	Comments	Stratified by baseline BFR: 0-199 mL/min, 200-274 mL/min, and 275-299 mL/min.
	Method	Cochran-Mantel-Haenszel
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Tenecteplase, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0035
	Comments
	Method	Chi-squared
	Comments

2. Primary Outcome

Title	Incidence of Targeted Adverse Events (AEs) From Initial Study Drug Administration Through the Start of Visit 2
Description	Targeted AEs were intracranial hemorrhages (ICHs), major bleeding, embolic events, thrombosis, catheter-related bloodstream infections (CRBSIs), and catheter related complications
Time Frame	Visits 1 and 2 of consecutive HD treatments

Outcome Measure Data

Analysis Population Description

MITT population

Arm/Group Title	Tenecteplase	Placebo
Arm/Group Description	For the initial treatment, 2 mL of reconsituted lyophilized tenecteplase instilled into each lumen of the HD catheter; subsequent treatments were 2 mL of open-label tenecteplase	For the initial treatment, 2 mL of placebo instilled into each lumen of the HD catheter; subsequent treatments were 2 mL of open-label tenecteplase
Measure Participants	74	75
Intracranial hemorrhage	0 0%	0 0%
Major bleeding	0 0%	0 0%
Embolic event	0 0%	0 0%
Thrombosis	0 0%	0 0%
Catheter-related blood stream infection	0 0%	4.0 5.3%
Catheter-related complication	0 0%	0 0%

3. Secondary Outcome

Title	Change in BFR From Baseline to the End of HD at Visit 1
Description	BFR is measured in mL/minute.
Time Frame	Visit 1 of HD treatment

Outcome Measure Data

Analysis Population Description

MITT population

Arm/Group Title	Tenecteplase	Placebo
Arm/Group Description	For the initial treatment, 2 mL of reconsituted lyophilized tenecteplase instilled into each lumen of the HD catheter; subsequent treatments were 2 mL of open-label tenecteplase	For the initial treatment, 2 mL of placebo instilled into each lumen of the HD catheter; subsequent treatments were 2 mL of open-label tenecteplase
Measure Participants	74	75
< 0 mL/min	8.1 (102.97) 10.9%	9.3 (55.98) 12.4%
0-24 mL/min	58.1 78.5%	80.0 106.7%
25-49 mL/min	8.1 10.9%	2.7 3.6%
50-99 mL/min	8.1 10.9%	4.0 5.3%
100-149 mL/min	5.4 7.3%	1.3 1.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tenecteplase, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0396
	Comments	Stratified by baseline BFR: 0-199 mL/min, 200-274 mL/min, and 275-299 mL/min.
	Method	Cochran-Mantel-Haenszel
	Comments

4. Secondary Outcome

Title	Percentage of Subjects Who Had Treatment Success With Respect to BFR at Visit 2 (MITT Population With Extended Dwell Tenecteplase at Visit 1)
Description	Treatment success is defined as BFR of ≥300 mL/min and an increase from baseline BFR of ≥25 mL/min at an associated target arterial pressure in the range of 0 to -280 mmHg 30 (±10) minutes prior to the end of HD and at the end of HD.
Time Frame	Visit 2 of consecutive HD treatments

Outcome Measure Data

Analysis Population Description

MITT population with extended-dwell tenecteplase at Visit 1

Arm/Group Title	Tenecteplase	Placebo
Arm/Group Description	For the initial treatment, 2 mL of reconsituted lyophilized tenecteplase instilled into each lumen of the HD catheter; subsequent treatments were 2 mL of open-label tenecteplase	For the initial treatment, 2 mL of placebo instilled into each lumen of the HD catheter; subsequent treatments were 2 mL of open-label tenecteplase
Measure Participants	24	39
Number [percentage of success]	41.7	38.5

5. Secondary Outcome

Title	Percentage of Subjects Who Had Treatment Success With Respect to BFR at Visit 2 (MITT Population With Open-label Tenecteplase at Visit 2)
Description	Treatment success is defined as BFR of ≥300 mL/min and an increase from baseline BFR of ≥25 mL/min at an associated target arterial pressure in the range of 0 to -280 mmHg 30 (±10) minutes prior to the end of HD and at the end of HD.
Time Frame	Visit 2 of consecutive HD treatments

Outcome Measure Data

Analysis Population Description

MITT population with open-label tenecteplase at Visit 2

Arm/Group Title	Tenecteplase	Placebo
Arm/Group Description	For the initial treatment, 2 mL of reconsituted lyophilized tenecteplase instilled into each lumen of the HD catheter; subsequent treatments were 2 mL of open-label tenecteplase	For the initial treatment, 2 mL of placebo instilled into each lumen of the HD catheter; subsequent treatments were 2 mL of open-label tenecteplase
Measure Participants	26	23
Number [percentage of success]	11.5	34.8

Adverse Events

Time Frame	The AEs/SAEs were recorded through the completion of Visit 4.
Adverse Event Reporting Description	Safety-evaluable population. SAEs of hypoclycemia and convulsion occurred in the placebo group after treatment with open-label tenecteplase. Note: The incidence of each AE/SAE is reported as the number of participants experiencing the event, not the number of occurrences for each AE/SAE.
Arm/Group Title	Tenecteplase		Placebo
Arm/Group Description	For the initial treatment, 2 mL of reconsituted lyophilized tenecteplase instilled into each lumen of the HD catheter; subsequent treatments were 2 mL of open-label tenecteplase		For the initial treatment, 2 mL of placebo instilled into each lumen of the HD catheter; subsequent treatments were 2 mL of open-label tenecteplase
All Cause Mortality
	Tenecteplase		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Tenecteplase		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/74 (1.4%)		5/75 (6.7%)
Infections and infestations
Bacteraemia	0/74 (0%)		1/75 (1.3%)
Clostridium Difficile Colitis	0/74 (0%)		1/75 (1.3%)
Pneumonia	0/74 (0%)		1/75 (1.3%)
Sepsis	1/74 (1.4%)		0/75 (0%)
Metabolism and nutrition disorders
Hypoglycaemia	0/74 (0%)		1/75 (1.3%)
Nervous system disorders
Convulsion	0/74 (0%)		1/75 (1.3%)
Other (Not Including Serious) Adverse Events
	Tenecteplase		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	12/74 (16.2%)		11/75 (14.7%)
Gastrointestinal disorders
Nausea	1/74 (1.4%)		3/75 (4%)
Vomiting	1/74 (1.4%)		2/75 (2.7%)
Abdominal Pain Upper	1/74 (1.4%)		1/75 (1.3%)
Diarrhoea	1/74 (1.4%)		0/75 (0%)
Stomach Discomfort	0/74 (0%)		1/75 (1.3%)
Gingival Bleeding	1/74 (1.4%)		0/75 (0%)
General disorders
Chills	1/74 (1.4%)		1/75 (1.3%)
Pyrexia	1/74 (1.4%)		1/75 (1.3%)
Catheter Related Complication	1/74 (1.4%)		0/75 (0%)
Catheter Site Pain	1/74 (1.4%)		0/75 (0%)
Catheter Site Pruritus	1/74 (1.4%)		0/75 (0%)
Catheter Thrombosis	0/74 (0%)		1/75 (1.3%)
Chest Pain	1/74 (1.4%)		0/75 (0%)
Feeling Cold	0/74 (0%)		1/75 (1.3%)
Swelling	0/74 (0%)		1/75 (1.3%)
Infections and infestations
Bacteraemia	0/74 (0%)		2/75 (2.7%)
Pyelonephritis	1/74 (1.4%)		0/75 (0%)
Injury, poisoning and procedural complications
Thrombosis in Device	2/74 (2.7%)		1/75 (1.3%)
Musculoskeletal and connective tissue disorders
Muscle Spasms	0/74 (0%)		1/75 (1.3%)
Musculoskeletal Pain	1/74 (1.4%)		0/75 (0%)
Neck Pain	1/74 (1.4%)		0/75 (0%)
Nervous system disorders
Headache	0/74 (0%)		2/75 (2.7%)
Renal and urinary disorders
Dysuria	1/74 (1.4%)		0/75 (0%)
Dyspnoea	0/74 (0%)		1/75 (1.3%)
Respiratory, thoracic and mediastinal disorders
Cough	1/74 (1.4%)		0/75 (0%)
Skin and subcutaneous tissue disorders
Hyperhidrosis	0/74 (0%)		1/75 (1.3%)
Vascular disorders
Hypotension	1/74 (1.4%)		1/75 (1.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.