Tapentadol in Chronic Malignant Tumour Related Pain

• Sponsor: Grünenthal GmbH (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT01264887
• Collaborator: (none)
• Enrollment: 31
• Locations: 12
• Arm: 1
• Duration (Months): 38
• Patients Per Site: 2.6
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of this trial is the characterization of the long term safety profile and long-term dose requirements of tapentadol PR (prolonged release) in patients with malignant tumor-related pain. In the United States the prolonged-release formulation is also referred to as the extended-release formulation.

Condition or Disease	Intervention/Treatment	Phase
Cancer; Chronic Pain; Pain	Drug: Tapentadol Prolonged Release	Phase 3

Detailed Description

The prevalence of tumor-related pain is high and the treatment of chronic tumor-related pain remains a challenging therapeutic problem.

Participants directly entering the KF5503/52 trial from the KF5503/15 trial (i.e., within 7 days of Visit 8 of the KF5503/15 trial) is scheduled: a Transfer Visit, an Open-label Treatment Period and a Follow-up Period.

For participants with a gap of more than 7 days and less than 24 weeks, between their full completion of the KF5503/15 trial and entry into the KF5503/52 trial the following is scheduled: an Enrollment Visit, an Entry Visit for assessment of eligibility, an Open-label Treatment Period and a Follow-up Period.

This trial was designed to offer patients with chronic malignant tumor-related pain the option of continuing treatment by receiving tapentadol prolonged release (PR).

The protocol scheduled visits every 28 days during the open-label treatment period. Unscheduled visits (or at least unscheduled telephone calls) were planned when dose adjustment is required. If a visit is not possible at the time of dose change, it could be done up to 7 days later. Unscheduled visits could also be performed whenever considered necessary (i.e., for evaluation of adverse events).

Study Design

• Study Type: Interventional
• Actual Enrollment: 31 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Open-label, Single-arm, Flexible Dosing, Phase III Trial, With Oral Tapentadol Prolonged Release (PR) in Subjects With Chronic Malignant Tumor-related Pain Who Have Completed the Maintenance Period of the KF5503/15 Trial.
• Study Start Date: Mar 1, 2011
• Actual Primary Completion Date: May 1, 2014
• Actual Study Completion Date: May 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Tapentadol Prolonged Release Participants allocated to this treatment arm can be flexibly dosed between 100 to 250 mg tapentadol twice daily (50 and 100 mg tablets to be dispensed).	Drug: Tapentadol Prolonged Release; Titration to achieve sufficient pain relief to continue with effective analgesia for as long as the participant tolerates and wishes to continue treatment.; Other Names: Nucynta® Palexia® Yantil®

Outcome Measures

Primary Outcome Measures

1. Severity of Adverse Events [Day 1; up to 144 weeks]

   The severity of treatment emergent adverse events was any untoward medical occurrence in a patient administered tapentadol. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of the (investigational) medicinal product whether or not related to the use of tapentadol. The clinical "intensity" of adverse event were classified as: Mild: signs and symptoms which can be easily tolerated. Symptoms could be ignored and disappeared when the participant is distracted. Moderate: symptoms caused discomfort but were tolerable, they could not be ignored and affect concentration. Severe: symptoms affected the usual daily activity.

2. Relatedness Assessment of Treatment Emergent Adverse Events [Day 1; up to 144 weeks]

   Participant-based analysis of treatment emergent adverse events (TEAEs) regarding the relationship to the study drug (tapentadol). The TEAEs were reported by the participants or were captured by the investigator. The relationship was rated by the investigator. The categorization of relatedness into one of the two categories was based on the following: Related included "possible", "probable/likely", and "certain"; whilst unrelated treatment emergent adverse events include those rated by the investigator as "unlikely", "conditional/unclassified", "un-assessable/unclassifiable", and "not related".

3. Countermeasures Taken Due to Treatment Emergent Adverse Events [Day 1; up to 144 weeks]

   Participant-based analysis of treatment emergent adverse events (TEAEs) regarding countermeasure to the study drug (tapentadol). The TEAEs were reported by the participants or were captured by the investigator. The countermeasure taken by the investigator were reported.

4. Time Dependence of Adverse Events [Day 1; 144 weeks]

   The onset and duration of TEAEs was not evaluated for this trial.

Secondary Outcome Measures

1. Assess Consumption of Tapentadol During Long Term Use [Day 1; up to 144 weeks]

   Summary of the modal total daily dose during the treatment period. The modal dose was based on assessment of the consecutive morning and evening intake amounts on each day and evaluation of the total daily dose.

2. Tapentadol Prolonged Release Exposure [Day 1; up to 144 weeks]

   The number of days that participants took tapentadol prolonged release. The extent of exposure was categorized into 2 periods, less than 90 days and more than 90 days (up to 144 weeks).

Other Outcome Measures

1. Average Pain Intensity (Over a Twelve-week Period) [Day 1; up to Week 144]

   The participant scored their pain intensity on an 11-point Numerical Rating Scale (NRS) where a score of 0 indicated "no pain" and a score of 10 indicated "pain as bad as you can imagine". Average pain intensity score is the average of pain experienced for previous 24 hours as rated on an 11-point NRS at each visit. Calculations are based on 3 consecutive planned (at 4-weekly intervals) visits. All available data of a participant was used; if a participant dropped-out or had incomplete data during a 12-week period no imputations were performed for the missing values.

2. Average Daily Total Tapentadol Prolonged Release Dose [Day 1; up to 144 weeks]

   The Total Daily Dose (TDD) on any given day is the sum of the morning and evening intake amounts. The average TDD is an individuals average over the trial period.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Participants must have signed an Informed Consent Form.

• At least 18 years of age.

• Male and non-pregnant, non-lactating female subjects. Sexually active women must be post menopausal, surgically sterile, or practicing an effective method of birth control before entry and throughout the trial. Female participants of child-bearing potential must have a negative pregnancy test at enrollment.

• Within 24 weeks of either full completion or completion of the double-blind treatment period (Visit 8) of KF5503/15 trial performed in participants with moderate to severe chronic malignant tumor related pain.

• Participant is, in the opinion of the investigator, expected to continue to have an overall positive benefit/risk ratio from continuing analgesic treatment within this trial.

• Participant must be willing to take tapentadol prolonged release (PR) throughout their participation in the trial.

Exclusion Criteria:

• History of alcohol and/or drug abuse.

• The participant has a clinically significant disease other than cancer that in the Investigator's opinion may affect the safety of the participant.

• Employees of the investigator or trial center or family members of the employees or the investigator.

• Known to or suspected of not being able to comply with the protocol and the use of tapentadol prolonged release (PR).

• Concurrent participation in another trial (except for participation in the KF5503/15 trial) or planning to be enrolled in another clinical trial during the course of this trial.

• Previous participation in another trial between the end of KF5503/15 and enrollment into the current trial, KF5503/52.

• History of seizure disorder, epilepsy, traumatic brain injury, stroke or transient ischemic attack.

• Known history and/or presence of cerebral tumors or metastases.

• Rapidly escalating pain or pain uncontrolled by therapy and was previously treated with maximum dose level of Investigational Medicinal Product.

• Participant is taking any prohibited concomitant medications.

• Uncontrolled hypertension.

• Known moderate or severe hepatic impairment.

• Known severe renal impairment.

• Clinically relevant history of hypersensitivity, allergy, or contraindications to tapentadol or its excipients.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Site 359004	Shumen		Bulgaria	9700
2	Site 036002	Nyiregyhaza		Hungary	4412
3	Site 036010	Szekszard		Hungary	7100
4	Site 373001	Chisinau		Moldova, Republic of	2025
5	Site 048004	Bydgoszcz		Poland	85796
6	Site 048001	Warszawa		Poland	02781
7	Site 040006	Brasov		Romania	500074
8	Site 040002	Bucharest		Romania	022328
9	Site 007007	Nizhniy Novgorod		Russian Federation	603140
10	Site 007012	Vladikavkaz		Russian Federation	362007
11	Site 381002	Nis		Serbia	18000
12	Site 381001	Sremska Kamenica		Serbia	21204

Sponsors and Collaborators

• Grünenthal GmbH

Investigators

• Principal Investigator: Hans-Georg Kress, Prof. Dr. med, General Hospital Vienna

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Grünenthal GmbH
• ClinicalTrials.gov Identifier: NCT01264887
• Other Study ID Numbers: KF5503/52; 2009-013291-46; 168935
• First Posted: Dec 22, 2010
• Last Update Posted: Nov 4, 2019
• Last Verified: Oct 1, 2019

• Keywords provided by Grünenthal GmbH: analgesia; analgesics; chronic pain; tumour related pain; chronic malignant tumor-related pain
• Additional relevant MeSH terms: Neoplasms; Chronic Pain; Cancer Pain; Tapentadol

Study Results

Participant Flow

Recruitment Details	First participant was enrolled on the 03 March 2011 and the last participant completed the trial on the 08 May 2014.

Arm/Group Title	Tapentadol Prolonged Release
Arm/Group Description	All participants from the KF5503/15 that enrolled into this trial were on tapentadol prolonged release. Participants were dosed in the range of 100 to 250 mg tapentadol twice daily. The dose was titrated to achieve sufficient pain relief to continue with effective analgesia for as long as the participant tolerated and wishes to continue treatment.
Period Title: Overall Study
STARTED	31
COMPLETED	0
NOT COMPLETED	31

Baseline Characteristics

Arm/Group Title	Tapentadol Prolonged Release
Arm/Group Description	All participants from the KF5503/15 that enrolled into this trial were on tapentadol prolonged release. Participants were dosed in the range of 100 to 250 mg tapentadol twice daily. The dose was titrated to achieve sufficient pain relief to continue with effective analgesia for as long as the participant tolerated and wishes to continue treatment.
Overall Participants	31
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	25 80.6%
>=65 years	6 19.4%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	55.8 (11.91)
Sex: Female, Male (Count of Participants)
Female	16 51.6%
Male	15 48.4%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	31 100%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
Serbia	6 19.4%
Hungary	4 12.9%
Poland	5 16.1%
Romania	5 16.1%
Russian Federation	3 9.7%
Bulgaria	2 6.5%
Moldova, Republic of	6 19.4%
Weight (kilograms) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilograms]	64.6 (16.45)
Height (centimeters) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [centimeters]	165.0 (10.24)
Body Mass Index (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	23.6 (4.79)
Pain type (participants) [Number]
Neuropathic	23 74.2%
Visceral	22 71%
Nociceptive (somatic)	26 83.9%

Outcome Measures

1. Primary Outcome

Title	Severity of Adverse Events
Description	The severity of treatment emergent adverse events was any untoward medical occurrence in a patient administered tapentadol. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of the (investigational) medicinal product whether or not related to the use of tapentadol. The clinical "intensity" of adverse event were classified as: Mild: signs and symptoms which can be easily tolerated. Symptoms could be ignored and disappeared when the participant is distracted. Moderate: symptoms caused discomfort but were tolerable, they could not be ignored and affect concentration. Severe: symptoms affected the usual daily activity.
Time Frame	Day 1; up to 144 weeks

Outcome Measure Data

Analysis Population Description

Safety Set.

Arm/Group Title	Number of Treatment Emergent Adverse Events
Arm/Group Description	All participants from the KF5503/15 that enrolled into this trial were on tapentadol prolonged release. Participants were dosed in the range of 100 to 250 mg tapentadol twice daily. The dose was titrated to achieve sufficient pain relief to continue with effective analgesia for as long as the participant tolerated and wishes to continue treatment.
Measure Participants	31
mild intensity	3 9.7%
moderate intensity	15 48.4%
severe intensity	12 38.7%

2. Secondary Outcome

Title	Assess Consumption of Tapentadol During Long Term Use
Description	Summary of the modal total daily dose during the treatment period. The modal dose was based on assessment of the consecutive morning and evening intake amounts on each day and evaluation of the total daily dose.
Time Frame	Day 1; up to 144 weeks

Outcome Measure Data

Analysis Population Description

The modal dose is based on assessment of the consecutive morning and evening intake amounts on each day and evaluation of the total daily dose. No participant received more than 500 mg per day.

Arm/Group Title	Tapentadol Prolonged Release
Arm/Group Description	All participants from the KF5503/15 that enrolled into this trial were on tapentadol prolonged release. Participants were dosed in the range of 100 to 250 mg tapentadol twice daily. The dose was titrated to achieve sufficient pain relief to continue with effective analgesia for as long as the participant tolerated and wishes to continue treatment.
Measure Participants	31
less than 200 mg/day	0 0%
200 to less than 250 mg/day	3 9.7%
250 to less than 300 mg/day	1 3.2%
300 to less than 350 mg/day	8 25.8%
350 to less than 400 mg/day	0 0%
400 to less than 450 mg/day	11 35.5%
450 to less than 500 mg/day	0 0%
500 mg/day	8 25.8%

3. Primary Outcome

Title	Relatedness Assessment of Treatment Emergent Adverse Events
Description	Participant-based analysis of treatment emergent adverse events (TEAEs) regarding the relationship to the study drug (tapentadol). The TEAEs were reported by the participants or were captured by the investigator. The relationship was rated by the investigator. The categorization of relatedness into one of the two categories was based on the following: Related included "possible", "probable/likely", and "certain"; whilst unrelated treatment emergent adverse events include those rated by the investigator as "unlikely", "conditional/unclassified", "un-assessable/unclassifiable", and "not related".
Time Frame	Day 1; up to 144 weeks

Outcome Measure Data

Analysis Population Description

Safety Set.

Arm/Group Title	Tapentadol Prolonged Release
Arm/Group Description	All participants from the KF5503/15 that enrolled into this trial were on tapentadol prolonged release. Participants were dosed in the range of 100 to 250 mg tapentadol twice daily. The dose was titrated to achieve sufficient pain relief to continue with effective analgesia for as long as the participant tolerated and wishes to continue treatment.
Measure Participants	31
No Treatment Emergent Adverse Events	1 3.2%
All Treatment Emergent Adverse Events	30 96.8%
Investigator-rated Related	6 19.4%
Investigator-rated Not Related	24 77.4%

4. Primary Outcome

Title	Countermeasures Taken Due to Treatment Emergent Adverse Events
Description	Participant-based analysis of treatment emergent adverse events (TEAEs) regarding countermeasure to the study drug (tapentadol). The TEAEs were reported by the participants or were captured by the investigator. The countermeasure taken by the investigator were reported.
Time Frame	Day 1; up to 144 weeks

Outcome Measure Data

Analysis Population Description

Safety Set.

Arm/Group Title	Tapentadol Prolonged Release
Arm/Group Description	All participants from the KF5503/15 that enrolled into this trial were on tapentadol prolonged release. Participants were dosed in the range of 100 to 250 mg tapentadol twice daily. The dose was titrated to achieve sufficient pain relief to continue with effective analgesia for as long as the participant tolerated and wishes to continue treatment.
Measure Participants	31
All Treatment Emergent Events	30 96.8%
No Treatment Emergent Adverse Events	1 3.2%
No countermeasures taken	5 16.1%
Countermeasures with Medication	17 54.8%
Trial Discontinued Countermeasure	6 19.4%
Other Countermeasure due to Somnolence	1 3.2%
Other Countermeasure due to Migraine	1 3.2%

5. Other Pre-specified Outcome

Title	Average Pain Intensity (Over a Twelve-week Period)
Description	The participant scored their pain intensity on an 11-point Numerical Rating Scale (NRS) where a score of 0 indicated "no pain" and a score of 10 indicated "pain as bad as you can imagine". Average pain intensity score is the average of pain experienced for previous 24 hours as rated on an 11-point NRS at each visit. Calculations are based on 3 consecutive planned (at 4-weekly intervals) visits. All available data of a participant was used; if a participant dropped-out or had incomplete data during a 12-week period no imputations were performed for the missing values.
Time Frame	Day 1; up to Week 144

Outcome Measure Data

Analysis Population Description

Safety Set.

Arm/Group Title	Tapentadol Prolonged Release
Arm/Group Description	All participants from the KF5503/15 that enrolled into this trial were on tapentadol prolonged release. Participants were dosed in the range of 100 to 250 mg tapentadol twice daily. The dose was titrated to achieve sufficient pain relief to continue with effective analgesia for as long as the participant tolerated and wishes to continue treatment.
Measure Participants	31
Baseline	3.3 (1.79)
Week 1 to 12	3.1 (1.95)
Week 13 to 24	3.1 (2.51)
Week 25 to 36	2.1 (1.57)
Week 37 to 48	2.0 (1.71)
Week 49 to 60	2.0 (1.78)
Week 61 to 72	2.0 (1.61)
Week 73 to 84	2.4 (1.97)
Week 85 to 96	3.1 (3.16)
Week 97 to 108	3.1 (3.76)
Week 109 to 120	3.3 (2.52)
Week 121 to 132	1.0 (0)
Week 133 to 144	1.0 (0)

6. Other Pre-specified Outcome

Title	Average Daily Total Tapentadol Prolonged Release Dose
Description	The Total Daily Dose (TDD) on any given day is the sum of the morning and evening intake amounts. The average TDD is an individuals average over the trial period.
Time Frame	Day 1; up to 144 weeks

Outcome Measure Data

Analysis Population Description

Safety Set.

Arm/Group Title	Tapentadol Prolonged Release
Arm/Group Description	All participants from the KF5503/15 that enrolled into this trial were on tapentadol prolonged release. Participants were dosed in the range of 100 to 250 mg tapentadol twice daily. The dose was titrated to achieve sufficient pain relief to continue with effective analgesia for as long as the participant tolerated and wishes to continue treatment.
Measure Participants	31
Mean (Standard Deviation) [mg per day]	360 (91.21)

7. Secondary Outcome

Title	Tapentadol Prolonged Release Exposure
Description	The number of days that participants took tapentadol prolonged release. The extent of exposure was categorized into 2 periods, less than 90 days and more than 90 days (up to 144 weeks).
Time Frame	Day 1; up to 144 weeks

Outcome Measure Data

Analysis Population Description

Safety Set.

Arm/Group Title	Tapentadol Prolonged Release
Arm/Group Description	All participants from the KF5503/15 that enrolled into this trial were on tapentadol prolonged release. Participants were dosed in the range of 100 to 250 mg tapentadol twice daily. The dose was titrated to achieve sufficient pain relief to continue with effective analgesia for as long as the participant tolerated and wishes to continue treatment.
Measure Participants	31
0 to 90 days	11 35.5%
more than 90 days	20 64.5%

8. Primary Outcome

Title	Time Dependence of Adverse Events
Description	The onset and duration of TEAEs was not evaluated for this trial.
Time Frame	Day 1; 144 weeks

Outcome Measure Data

Analysis Population Description

No evaluation was performed.

Arm/Group Title	Frequency of Treatment Emergent Adverse Events
Arm/Group Description	All participants from the KF5503/15 that enrolled into this trial were on tapentadol prolonged release. Participants were dosed in the range of 100 to 250 mg tapentadol twice daily. The dose was titrated to achieve sufficient pain relief to continue with effective analgesia for as long as the participant tolerated and wishes to continue treatment.
Measure Participants	0

Adverse Events

Time Frame	One participant was treated up to 144 weeks.
Arm/Group Title	Tapentadol Prolonged Release
Arm/Group Description	All participants from the KF5503/15 that enrolled into this trial were on tapentadol prolonged release. Participants were dosed in the range of 100 to 250 mg tapentadol twice daily. The dose was titrated to achieve sufficient pain relief to continue with effective analgesia for as long as the participant tolerated and wishes to continue treatment.
All Cause Mortality
	Tapentadol Prolonged Release
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Tapentadol Prolonged Release
	Affected / at Risk (%)	# Events
Total	14/31 (45.2%)
Blood and lymphatic system disorders
anaemia	1/31 (3.2%)
Cardiac disorders
cardiac failure	1/31 (3.2%)
Hepatobiliary disorders
cholecystitis	1/31 (3.2%)
Infections and infestations
pneumonia	1/31 (3.2%)
Metabolism and nutrition disorders
hypoalbuminaemia	1/31 (3.2%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
malignant neoplasm progression	9/31 (29%)
breast cancer	1/31 (3.2%)
metastases to lung	1/31 (3.2%)
Renal and urinary disorders
azotaemia	1/31 (3.2%)
Respiratory, thoracic and mediastinal disorders
hypoxia	1/31 (3.2%)
Other (Not Including Serious) Adverse Events
	Tapentadol Prolonged Release
	Affected / at Risk (%)	# Events
Total	30/31 (96.8%)
Blood and lymphatic system disorders
Anaemia	5/31 (16.1%)
Thrombocytopenia	3/31 (9.7%)
Lymphadenopathy	2/31 (6.5%)
Cardiac disorders
sinus tachycardia	3/31 (9.7%)
tachycardia	3/31 (9.7%)
Gastrointestinal disorders
nausea	9/31 (29%)
constipation	4/31 (12.9%)
abdominal pain upper	2/31 (6.5%)
ascites	2/31 (6.5%)
General disorders
pyrexia	4/31 (12.9%)
general physical health deterioration	3/31 (9.7%)
fatigue	2/31 (6.5%)
Hepatobiliary disorders
Hepatic function abnormal	2/31 (6.5%)
Infections and infestations
bronchitis	2/31 (6.5%)
urinary tract infection	2/31 (6.5%)
Investigations
Alanine aminotransferase increased	2/31 (6.5%)
Aspartate aminotransferase increased	2/31 (6.5%)
Metabolism and nutrition disorders
Hypoalbuminaemia	2/31 (6.5%)
Musculoskeletal and connective tissue disorders
pathological fracture	2/31 (6.5%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
malignant neoplasm progression	5/31 (16.1%)
Metastases to bone	4/31 (12.9%)
neoplasm progression	3/31 (9.7%)
Nervous system disorders
dizziness	3/31 (9.7%)
headache	3/31 (9.7%)
somnolence	2/31 (6.5%)
Renal and urinary disorders
haematuria	2/31 (6.5%)

Limitations/Caveats

The trial was stopped for administrative reasons. Three years after trial initiation 2 participants were in the trial and to permit analysis and reporting the sponsor decided to terminate the trial.

More Information

Certain Agreements

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

The Sponsor reserves the right to review any publication pertaining to the trial before it is submitted for publication. Neither party has the right to prohibit publication unless publication can be shown to affect possible patent rights.