Low Back Pain
Conditions
Keywords
Low Back Pain, Dose Equivalence, Tapentadol (CG5503), Tapentadol-IR, Tapentadol-ER
Brief summary
The objective of this study is to test the idea that the immediate-release (IR) form of tapentadol (CG5503) can be directly converted into an approximately equivalent total daily dose (TDD) of the extended-release (ER) form, and vice-versa, with equivalent safety and efficacy.
Detailed description
This study will establish the dose equivalence and the safety and effectiveness of the Immediate Release (IR) and Extended Release (ER) forms of tapentadol (CG5503) to support the conversion from IR to ER, and ER to IR use. Dose equivalence will be examined in patients diagnosed with moderate-to-severe, chronic Low Back Pain (LBP) requiring drug treatment for at least 3 months, and who are dissatisfied with current therapy. The study consists of 5 periods: a screening period during which patients are evaluated for study eligibility; a 21-day open-label period to find the best, stable dose of tapentadol (CG5503) IR for each patient individually; a 14-day double-blind period when patients are randomly chosen either to continue for 14 days on the stable IR dose from the open-label period or switch to the ER form; a second, 14-day period during which patients switch to whichever form of tapentadol (CG5503) they did not take during the first 14-day period (the total daily dose \[TDD\] remains approximately equivalent for the IR and ER forms throughout both double-blind periods); and a follow-up period. During the study, pain levels will be recorded and overall safety measures taken. The expectation (thought) is that approximately equivalent doses of both forms of tapentadol (CG5503) provide equivalent effectiveness and safety and that the two forms can be directly converted by dividing the total daily dose by the number of times the drug is taken each day. During the 21-day open-label period, 50, 75 or 100mg of the IR form is given orally every 4 or 6 hours, starting with 50mg every 6 hours. Then, the dose, the frequency of giving the drug, or both may be increased, to a maximum TDD of 500mg, or decreased in 50 mg increments, with minimum TDD of 200 mg, until the optimal stable dose for a patient is found. During the 2 double-blind periods, a TDD approximately equivalent to the stable open-label dose is given orally in IR (or ER) form or placebo.
Interventions
DRUGtapentadol (CG5503) Immediate Release IR
21 day Open Label: an adjustable dose of Tapentadol IR 50-100mg orally every 4-6 hours to maximum total daily dose (TDD) dose of 500 mg during open label period
During 2 double blind periods: Tapentadol ER 100, 150, 200 or 250 mg tablets twice daily in the first intervention period of double-blind phase and Tapentadol IR in the second or Tapentadol IR in first intervention period of double-blind phase and Tapentadol ER in second
DRUGtapentadol (CG5503) Immediate Release (IR)
Following open label period is 2 double blind periods: Tapentadol IR in first intervention period of double-blind phase and Tapentadol ER 100, 150, 200 or 250 mg tablets twice daily in second or Tapentadol ER in first intervention period of double-blind phase and Tapentadol IR in second
Sponsors
Grünenthal GmbH
Johnson & Johnson Pharmaceutical Research & Development, L.L.C.
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Diagnosis of Low Back Pain (LBP) of non-malignant origin present for at least 3 months immediately before study entry * Taking drug treatment for pain for at least 3 months before screening and who are dissatisfied with current therapy * Subjects receiving opioid treatment must have a total daily opioid dose \<= 160 mg/day of oral morphine equivalent * For entry into open label period patients must have a baseline score \>=5 on an 11-point NRS, calculated as the average pain intensity during the last 3 days of the washout period * For entry into the double-blind period subjects must have remained on the same optimal stable dose and frequency of tapentadol (CG5503) IR administration during the last 3 days of the open-label treatment period
Exclusion criteria
* Presence of conditions other than Low Back Pain (LBP) that could make it hard to assess or self-evaluate pain * Surgery in low back area within 3 months of screening or expected surgery in the low back area during the study * Any scheduled surgery or painful procedure during the study, or any clinically significant disease that, in the opinion of the investigator, may affect efficacy or safety assessments * History of malignancy within the past 2 years, with the exception of basal cell carcinoma that has been treated and is no longer present * Women who are pregnant or breast-feeding * Moderately or severely impaired liver function * Severely impaired kidney function * History of chronic hepatitis B or C, or HIV, or presence of active hepatitis B or C in past 3 months * History of seizure disorder * Alcohol or drug abuse * Uncontrolled high blood pressure * Clinically relevant history of hypersensitivity, allergy, or contraindications to acetaminophen or opioid analgesics (or ingredients)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Difference in the Mean Average Pain Intensity Score on an 11-point Numerical Rating Scale (NRS) During the Last 3 Days of Each Double-blind Treatment Period. (Difference Between Two DB Randomization Treatment Sequences) | 14 days for each cross-over period | For this twice daily pain assessment, the subjects were to indicate the level of average pain experienced over the previous 12 hours 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Number of Patients Requiring Rescue Medication During the DB Tapentadol IR Treatment | 14 days for each cross-over period | — |
| The Number of Patients Requiring Rescue Medication During the DB Tapentadol ER Treatment | 14 days for each cross-over period | — |
| Total Daily Dose (TDD) of Tapentadol IR During the Double-blind Treatment Period | 14-day for each DB treatment period | Average total daily dose (TDD) of tapentadol IR during the double blind treatment period |
| Total Daily Dose (TDD) of Tapentadol ER During the DB Treatment Period. | 14 days for each treatment period | Average total daily dose (TDD) of tapentadol ER during the double-blind treatment period. |
Participant flow
Recruitment details
The first site opened on 30 November 2007. The recruitment period for this outpatient, multicenter study occurred between 10 December 2007 and 01 May 2008.
Pre-assignment details
The study consisted of screening period (up to 21 days), washout period (from 3 to 7 days), open label (OL) treatment period (3 weeks), followed by a double blind (DB) active treatment period, with crossover design of 2 randomized sequences of tapentadol immediate release (IR) to tapentadol extended release (ER) and tapentadol ER to IR (4 weeks)
Participants by arm
| Arm | Count |
|---|---|
| Tapentadol Subjects treated in the Tapentadol(CG5503) Immediate Release (IR) Open-Label period | 116 |
| Total | 116 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| DB: Tapentadol IR to ER & ER to IR | Adverse Event | 0 | 0 | 2 |
| DB: Tapentadol IR to ER & ER to IR | Lack of Efficacy | 0 | 1 | 1 |
| DB: Tapentadol IR to ER & ER to IR | Study Medication Non compliant | 0 | 3 | 2 |
| DB: Tapentadol IR to ER & ER to IR | Withdrawal by Subject | 0 | 3 | 3 |
| Open Label (OL): Tapentadol IR | Adverse Event | 16 | 0 | 0 |
| Open Label (OL): Tapentadol IR | Lack of Efficacy | 1 | 0 | 0 |
| Open Label (OL): Tapentadol IR | Lost to Follow-up | 2 | 0 | 0 |
| Open Label (OL): Tapentadol IR | Study Medication Non Compliant | 6 | 0 | 0 |
| Open Label (OL): Tapentadol IR | Withdrawal by Subject | 4 | 0 | 0 |
Baseline characteristics
| Characteristic | Tapentadol |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 30 Participants |
| Age, Categorical Between 18 and 65 years | 86 Participants |
| Age, Continuous | 53.6 years STANDARD_DEVIATION 15.46 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 participants |
| Race/Ethnicity, Customized Asian | 0 participants |
| Race/Ethnicity, Customized Black or African American | 14 participants |
| Race/Ethnicity, Customized Hispanic or Latino | 12 participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 participants |
| Race/Ethnicity, Customized Other | 0 participants |
| Race/Ethnicity, Customized White | 90 participants |
| Sex: Female, Male Female | 65 Participants |
| Sex: Female, Male Male | 51 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 98 / 116 |
| serious Total, serious adverse events | 2 / 116 |
Outcome results
Primary
The Difference in the Mean Average Pain Intensity Score on an 11-point Numerical Rating Scale (NRS) During the Last 3 Days of Each Double-blind Treatment Period. (Difference Between Two DB Randomization Treatment Sequences)
For this twice daily pain assessment, the subjects were to indicate the level of average pain experienced over the previous 12 hours 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.
Time frame: 14 days for each cross-over period
Population: Per-protocol set defined as the number of randomized subjects who took at least one dose of study drug during the DB treatment period, and who met additional criteria which were identified prior to unblinding.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Tapentadol | The Difference in the Mean Average Pain Intensity Score on an 11-point Numerical Rating Scale (NRS) During the Last 3 Days of Each Double-blind Treatment Period. (Difference Between Two DB Randomization Treatment Sequences) | 0.1 Units on a scale |
Comparison: Comparison of Tapentadol IR to ER analysis of variance model with factors for treatment, double blind cross-over period and subject.95% CI: [-0.09, 0.28]
Secondary
The Number of Patients Requiring Rescue Medication During the DB Tapentadol ER Treatment
Time frame: 14 days for each cross-over period
Population: DB safety set defined as randomized subjects who took at least one dose of study drug during the DB treatment period.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tapentadol | The Number of Patients Requiring Rescue Medication During the DB Tapentadol ER Treatment | 29 participants |
Secondary
The Number of Patients Requiring Rescue Medication During the DB Tapentadol IR Treatment
Time frame: 14 days for each cross-over period
Population: DB safety set defined as randomized subjects who took at least one dose of study drug during the DB treatment period.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tapentadol | The Number of Patients Requiring Rescue Medication During the DB Tapentadol IR Treatment | 24 participants |
Secondary
Total Daily Dose (TDD) of Tapentadol ER During the DB Treatment Period.
Average total daily dose (TDD) of tapentadol ER during the double-blind treatment period.
Time frame: 14 days for each treatment period
Population: DB safety set defined as randomized subjects who took at least one dose of study drug during the DB treatment period.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tapentadol | Total Daily Dose (TDD) of Tapentadol ER During the DB Treatment Period. | 330.4 mg | Standard Deviation 123.73 |
Secondary
Total Daily Dose (TDD) of Tapentadol IR During the Double-blind Treatment Period
Average total daily dose (TDD) of tapentadol IR during the double blind treatment period
Time frame: 14-day for each DB treatment period
Population: DB safety set defined as randomized subjects who took at least one dose of study drug during the DB treatment period.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tapentadol | Total Daily Dose (TDD) of Tapentadol IR During the Double-blind Treatment Period | 331.0 mg | Standard Deviation 116.17 |