Cancer
Conditions
Keywords
unspecified adult solid tumor, protocol specific, pain, adult acute myeloid leukemia with 11q23 (MLL) abnormalities, adult acute myeloid leukemia with inv(16)(p13;q22), adult acute myeloid leukemia with t(15;17)(q22;q12), adult acute myeloid leukemia with t(16;16)(p13;q22), adult acute myeloid leukemia with t(8;21)(q22;q22), stage IV chronic lymphocytic leukemia, accelerated phase chronic myelogenous leukemia, blastic phase chronic myelogenous leukemia, chronic myelomonocytic leukemia, chronic phase chronic myelogenous leukemia, noncontiguous stage II adult Burkitt lymphoma, noncontiguous stage II adult diffuse large cell lymphoma, noncontiguous stage II adult diffuse mixed cell lymphoma, noncontiguous stage II adult diffuse small cleaved cell lymphoma, noncontiguous stage II adult immunoblastic large cell lymphoma, noncontiguous stage II adult lymphoblastic lymphoma, noncontiguous stage II small lymphocytic lymphoma, noncontiguous stage II marginal zone lymphoma, noncontiguous stage II grade 1 follicular lymphoma, noncontiguous stage II grade 2 follicular lymphoma, noncontiguous stage II grade 3 follicular lymphoma, noncontiguous stage II mantle cell lymphoma, stage III adult Burkitt lymphoma, stage III adult diffuse large cell lymphoma, stage III adult diffuse mixed cell lymphoma, stage III adult diffuse small cleaved cell lymphoma, stage III adult immunoblastic large cell lymphoma, stage III adult lymphoblastic lymphoma, stage III small lymphocytic lymphoma, stage III marginal zone lymphoma, stage III grade 1 follicular lymphoma, stage III grade 2 follicular lymphoma, stage III grade 3 follicular lymphoma, stage III mantle cell lymphoma, stage IV adult Burkitt lymphoma, stage IV adult diffuse large cell lymphoma, stage IV adult diffuse mixed cell lymphoma, stage IV adult diffuse small cleaved cell lymphoma, stage IV adult immunoblastic large cell lymphoma, stage IV adult lymphoblastic lymphoma, stage IV small lymphocytic lymphoma, stage IV marginal zone lymphoma, stage IV grade 1 follicular lymphoma, stage IV grade 2 follicular lymphoma, stage IV grade 3 follicular lymphoma, stage IV mantle cell lymphoma, recurrent adult Burkitt lymphoma, recurrent adult diffuse large cell lymphoma, recurrent adult diffuse mixed cell lymphoma, recurrent adult diffuse small cleaved cell lymphoma, recurrent adult Hodgkin lymphoma, recurrent adult immunoblastic large cell lymphoma, recurrent adult lymphoblastic lymphoma, recurrent cutaneous T-cell non-Hodgkin lymphoma, recurrent small lymphocytic lymphoma, recurrent marginal zone lymphoma, recurrent grade 1 follicular lymphoma, recurrent grade 2 follicular lymphoma, recurrent grade 3 follicular lymphoma, recurrent mantle cell lymphoma, recurrent mycosis fungoides/Sezary syndrome, stage I multiple myeloma, stage II multiple myeloma, stage III multiple myeloma, de novo myelodysplastic syndromes, myelodysplastic/myeloproliferative neoplasm, unclassifiable, previously treated myelodysplastic syndromes, secondary myelodysplastic syndromes, atypical chronic myeloid leukemia, BCR-ABL1 negative, stage II adult Hodgkin lymphoma, stage III adult Hodgkin lymphoma, stage IV adult Hodgkin lymphoma, contiguous stage II adult Burkitt lymphoma, stage I adult Burkitt lymphoma, contiguous stage II adult diffuse large cell lymphoma, contiguous stage II adult diffuse mixed cell lymphoma, contiguous stage II adult diffuse small cleaved cell lymphoma, contiguous stage II small lymphocytic lymphoma, contiguous stage II marginal zone lymphoma, stage I adult diffuse large cell lymphoma, stage I adult diffuse mixed cell lymphoma, stage I adult diffuse small cleaved cell lymphoma, stage I small lymphocytic lymphoma, stage I marginal zone lymphoma, contiguous stage II grade 1 follicular lymphoma, contiguous stage II grade 2 follicular lymphoma, contiguous stage II grade 3 follicular lymphoma, stage I grade 1 follicular lymphoma, stage I grade 2 follicular lymphoma, stage I grade 3 follicular lymphoma, contiguous stage II mantle cell lymphoma, stage I mantle cell lymphoma, contiguous stage II adult immunoblastic large cell lymphoma, stage I adult immunoblastic large cell lymphoma, contiguous stage II adult lymphoblastic lymphoma, stage I adult lymphoblastic lymphoma, refractory multiple myeloma, anaplastic large cell lymphoma, angioimmunoblastic T-cell lymphoma, recurrent adult T-cell leukemia/lymphoma, stage I adult T-cell leukemia/lymphoma, stage II adult T-cell leukemia/lymphoma, stage III adult T-cell leukemia/lymphoma, stage IV adult T-cell leukemia/lymphoma, stage I cutaneous T-cell non-Hodgkin lymphoma, stage II cutaneous T-cell non-Hodgkin lymphoma, stage III cutaneous T-cell non-Hodgkin lymphoma, stage IV cutaneous T-cell non-Hodgkin lymphoma, stage I mycosis fungoides/Sezary syndrome, stage II mycosis fungoides/Sezary syndrome, stage III mycosis fungoides/Sezary syndrome, stage IV mycosis fungoides/Sezary syndrome, chronic eosinophilic leukemia, primary myelofibrosis, chronic neutrophilic leukemia, essential thrombocythemia, polycythemia vera, relapsing chronic myelogenous leukemia, T-cell large granular lymphocyte leukemia, recurrent adult acute lymphoblastic leukemia, recurrent adult acute myeloid leukemia, untreated adult acute lymphoblastic leukemia, untreated adult acute myeloid leukemia, secondary acute myeloid leukemia, acute undifferentiated leukemia, refractory chronic lymphocytic leukemia, stage 0 chronic lymphocytic leukemia, stage I chronic lymphocytic leukemia, stage II chronic lymphocytic leukemia, stage III chronic lymphocytic leukemia, refractory hairy cell leukemia, progressive hairy cell leukemia, initial treatment, prolymphocytic leukemia, recurrent adult grade III lymphomatoid granulomatosis, Waldenström macroglobulinemia, extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue, nodal marginal zone B-cell lymphoma, splenic marginal zone lymphoma, post-transplant lymphoproliferative disorder, extramedullary plasmacytoma, isolated plasmacytoma of bone, monoclonal gammopathy of undetermined significance, primary systemic amyloidosis, adult acute lymphoblastic leukemia in remission, adult acute myeloid leukemia in remission, adult grade III lymphomatoid granulomatosis, AIDS-related peripheral/systemic lymphoma, AIDS-related primary CNS lymphoma, intraocular lymphoma, meningeal chronic myelogenous leukemia, primary central nervous system non-Hodgkin lymphoma, primary central nervous system Hodgkin lymphoma, stage I adult Hodgkin lymphoma, recurrent squamous cell carcinoma of the hypopharynx, stage I squamous cell carcinoma of the hypopharynx, stage II squamous cell carcinoma of the hypopharynx, stage III squamous cell carcinoma of the hypopharynx, stage IV squamous cell carcinoma of the hypopharynx, recurrent squamous cell carcinoma of the larynx, recurrent verrucous carcinoma of the larynx, stage I squamous cell carcinoma of the larynx, stage I verrucous carcinoma of the larynx, stage II squamous cell carcinoma of the larynx, stage II verrucous carcinoma of the larynx, stage III squamous cell carcinoma of the larynx, stage III verrucous carcinoma of the larynx, stage IV squamous cell carcinoma of the larynx, stage IV verrucous carcinoma of the larynx, recurrent adenoid cystic carcinoma of the oral cavity, recurrent mucoepidermoid carcinoma of the oral cavity, recurrent verrucous carcinoma of the oral cavity, stage I adenoid cystic carcinoma of the oral cavity, stage I mucoepidermoid carcinoma of the oral cavity, stage I verrucous carcinoma of the oral cavity, stage II adenoid cystic carcinoma of the oral cavity, stage II mucoepidermoid carcinoma of the oral cavity, stage II verrucous carcinoma of the oral cavity, stage III adenoid cystic carcinoma of the oral cavity, stage III mucoepidermoid carcinoma of the oral cavity, stage III verrucous carcinoma of the oral cavity, stage IV adenoid cystic carcinoma of the oral cavity, stage IV mucoepidermoid carcinoma of the oral cavity, stage IV verrucous carcinoma of the oral cavity, stage I squamous cell carcinoma of the lip and oral cavity, stage II squamous cell carcinoma of the lip and oral cavity, stage III squamous cell carcinoma of the lip and oral cavity, stage IV squamous cell carcinoma of the lip and oral cavity, recurrent basal cell carcinoma of the lip, recurrent squamous cell carcinoma of the lip and oral cavity, stage I basal cell carcinoma of the lip, stage II basal cell carcinoma of the lip, stage III basal cell carcinoma of the lip, stage IV basal cell carcinoma of the lip, metastatic squamous neck cancer with occult primary squamous cell carcinoma, recurrent metastatic squamous neck cancer with occult primary, untreated metastatic squamous neck cancer with occult primary, recurrent lymphoepithelioma of the nasopharynx, recurrent squamous cell carcinoma of the nasopharynx, stage I lymphoepithelioma of the nasopharynx, stage I squamous cell carcinoma of the nasopharynx, stage II lymphoepithelioma of the nasopharynx, stage II squamous cell carcinoma of the nasopharynx, stage III lymphoepithelioma of the nasopharynx, stage III squamous cell carcinoma of the nasopharynx, stage IV lymphoepithelioma of the nasopharynx, stage IV squamous cell carcinoma of the nasopharynx, recurrent lymphoepithelioma of the oropharynx, recurrent squamous cell carcinoma of the oropharynx, stage I lymphoepithelioma of the oropharynx, stage I squamous cell carcinoma of the oropharynx, stage II lymphoepithelioma of the oropharynx, stage II squamous cell carcinoma of the oropharynx, stage III lymphoepithelioma of the oropharynx, stage III squamous cell carcinoma of the oropharynx, stage IV lymphoepithelioma of the oropharynx, stage IV squamous cell carcinoma of the oropharynx, recurrent esthesioneuroblastoma of the paranasal sinus and nasal cavity, recurrent inverted papilloma of the paranasal sinus and nasal cavity, recurrent midline lethal granuloma of the paranasal sinus and nasal cavity, recurrent squamous cell carcinoma of the paranasal sinus and nasal cavity, stage I esthesioneuroblastoma of the paranasal sinus and nasal cavity, stage I inverted papilloma of the paranasal sinus and nasal cavity, stage I midline lethal granuloma of the paranasal sinus and nasal cavity, stage I squamous cell carcinoma of the paranasal sinus and nasal cavity, stage II esthesioneuroblastoma of the paranasal sinus and nasal cavity, stage II inverted papilloma of the paranasal sinus and nasal cavity, stage II midline lethal granuloma of the paranasal sinus and nasal cavity, stage II squamous cell carcinoma of the paranasal sinus and nasal cavity, stage III esthesioneuroblastoma of the paranasal sinus and nasal cavity, stage III inverted papilloma of the paranasal sinus and nasal cavity, stage III midline lethal granuloma of the paranasal sinus and nasal cavity, stage III squamous cell carcinoma of the paranasal sinus and nasal cavity, stage IV esthesioneuroblastoma of the paranasal sinus and nasal cavity, stage IV inverted papilloma of the paranasal sinus and nasal cavity, stage IV midline lethal granuloma of the paranasal sinus and nasal cavity, stage IV squamous cell carcinoma of the paranasal sinus and nasal cavity, high-grade salivary gland mucoepidermoid carcinoma, low-grade salivary gland mucoepidermoid carcinoma, recurrent salivary gland cancer, salivary gland acinic cell tumor, salivary gland adenocarcinoma, salivary gland adenoid cystic carcinoma, salivary gland anaplastic carcinoma, salivary gland malignant mixed cell type tumor, salivary gland poorly differentiated carcinoma, salivary gland squamous cell carcinoma, stage I salivary gland cancer, stage II salivary gland cancer, stage III salivary gland cancer, stage IV salivary gland cancer, adult grade I meningioma, adult choroid plexus tumor, adult craniopharyngioma, adult myxopapillary ependymoma, adult diffuse astrocytoma, adult pilocytic astrocytoma, adult pineocytoma, adult ependymoma, adult subependymoma, adult oligodendroglioma, adult subependymal giant cell astrocytoma, meningeal melanocytoma, adult meningeal hemangiopericytoma, adult pineal gland astrocytoma, adult central nervous system germ cell tumor, adult medulloblastoma, adult supratentorial primitive neuroectodermal tumor (PNET), adult ependymoblastoma, adult anaplastic astrocytoma, adult anaplastic ependymoma, adult glioblastoma, adult gliosarcoma, adult giant cell glioblastoma, adult grade III meningioma, adult anaplastic oligodendroglioma, adult pineoblastoma, adult mixed glioma, recurrent adult brain tumor, adult anaplastic meningioma, adult papillary meningioma, adult brain stem glioma, stage IA cervical cancer, stage IB cervical cancer, stage IIA cervical cancer, stage IIB cervical cancer, stage III cervical cancer, stage IVA cervical cancer, stage IVB cervical cancer, recurrent cervical cancer, recurrent endometrial carcinoma, stage I endometrial carcinoma, stage II endometrial carcinoma, stage III endometrial carcinoma, stage IV endometrial carcinoma, fallopian tube cancer, recurrent ovarian epithelial cancer, recurrent ovarian germ cell tumor, stage I ovarian epithelial cancer, stage I ovarian germ cell tumor, stage II ovarian epithelial cancer, stage II ovarian germ cell tumor, stage III ovarian epithelial cancer, stage III ovarian germ cell tumor, stage IV ovarian epithelial cancer, stage IV ovarian germ cell tumor, ovarian sarcoma, ovarian stromal cancer, recurrent uterine sarcoma, stage I uterine sarcoma, stage II uterine sarcoma, stage III uterine sarcoma, stage IV uterine sarcoma, recurrent colon cancer, stage I colon cancer, stage II colon cancer, stage III colon cancer, stage IV colon cancer, recurrent bladder cancer, recurrent gallbladder cancer, stage I bladder cancer, stage II bladder cancer, stage III bladder cancer, stage IV bladder cancer, recurrent gastric cancer, stage I gastric cancer, stage II gastric cancer, stage III gastric cancer, stage IV gastric cancer, advanced adult primary liver cancer, recurrent small intestine cancer, localized transitional cell cancer of the renal pelvis and ureter, metastatic transitional cell cancer of the renal pelvis and ureter, recurrent renal cell cancer, recurrent transitional cell cancer of the renal pelvis and ureter, regional transitional cell cancer of the renal pelvis and ureter, stage I renal cell cancer, stage II renal cell cancer, stage III renal cell cancer, stage IV renal cell cancer, distal urethral cancer, proximal urethral cancer, recurrent urethral cancer, urethral cancer associated with invasive bladder cancer, stage I adrenocortical carcinoma, stage II adrenocortical carcinoma, stage III adrenocortical carcinoma, stage IV adrenocortical carcinoma, recurrent adrenocortical carcinoma, extragonadal germ cell tumor, localized gastrointestinal carcinoid tumor, metastatic gastrointestinal carcinoid tumor, recurrent gastrointestinal carcinoid tumor, regional gastrointestinal carcinoid tumor, gastrinoma, insulinoma, WDHA syndrome, glucagonoma, pancreatic polypeptide tumor, somatostatinoma, recurrent islet cell carcinoma, carcinoma of the appendix, localized extrahepatic bile duct cancer, recurrent extrahepatic bile duct cancer, unresectable extrahepatic bile duct cancer, localized gallbladder cancer, unresectable gallbladder cancer, gastrointestinal stromal tumor, localized resectable adult primary liver cancer, localized unresectable adult primary liver cancer, recurrent adult primary liver cancer, stage I pancreatic cancer, stage II pancreatic cancer, stage III pancreatic cancer, stage IV pancreatic cancer, recurrent pancreatic cancer, small intestine adenocarcinoma, small intestine leiomyosarcoma, small intestine lymphoma, stage I non-small cell lung cancer, stage II non-small cell lung cancer, stage IIIA non-small cell lung cancer, stage IIIB non-small cell lung cancer, stage IV non-small cell lung cancer, recurrent non-small cell lung cancer, pulmonary carcinoid tumor, extensive stage small cell lung cancer, limited stage small cell lung cancer, recurrent small cell lung cancer, liver metastases, lung metastases, primary peritoneal cavity cancer, lung papilloma, peripheral primitive neuroectodermal tumor of the kidney, clear cell sarcoma of the kidney, rhabdoid tumor of the kidney, congenital mesoblastic nephroma, stage II breast cancer, stage IIIA breast cancer, stage IIIB breast cancer, stage IIIC breast cancer, stage IV breast cancer, recurrent breast cancer, male breast cancer, breast cancer in situ, localized osteosarcoma, metastatic osteosarcoma, recurrent osteosarcoma, localized Ewing sarcoma/peripheral primitive neuroectodermal tumor, metastatic Ewing sarcoma/peripheral primitive neuroectodermal tumor, recurrent Ewing sarcoma/peripheral primitive neuroectodermal tumor, chondrosarcoma, malignant giant cell tumor of bone, desmoid tumor, stage I adult soft tissue sarcoma, stage II adult soft tissue sarcoma, stage III adult soft tissue sarcoma, stage IV adult soft tissue sarcoma, recurrent adult soft tissue sarcoma, recurrent thymoma and thymic carcinoma, advanced malignant mesothelioma, localized malignant mesothelioma, recurrent malignant mesothelioma, phosphaturic mesenchymal tumor, stage I malignant testicular germ cell tumor, stage II malignant testicular germ cell tumor, stage III malignant testicular germ cell tumor, recurrent malignant testicular germ cell tumor, stage 0 penile cancer, stage I penile cancer, stage II penile cancer, stage III penile cancer, stage IV penile cancer, recurrent penile cancer, stage I prostate cancer, stage IIB prostate cancer, stage IIA prostate cancer, stage III prostate cancer, stage IV prostate cancer, recurrent prostate cancer, stage 0 vaginal cancer, stage I vaginal cancer, stage II vaginal cancer, stage III vaginal cancer, stage IVA vaginal cancer, stage IVB vaginal cancer, recurrent vaginal cancer, stage 0 vulvar cancer, stage I vulvar cancer, stage II vulvar cancer, stage III vulvar cancer, stage IVB vulvar cancer, recurrent vulvar cancer, stage 0 anal cancer, stage I anal cancer, stage II anal cancer, stage IIIA anal cancer, stage IIIB anal cancer, stage IV anal cancer, recurrent anal cancer, stage 0 rectal cancer, stage I rectal cancer, stage II rectal cancer, stage III rectal cancer, stage IV rectal cancer, recurrent rectal cancer, stage 0 esophageal cancer, stage I esophageal cancer, stage II esophageal cancer, stage III esophageal cancer, stage IV esophageal cancer, recurrent esophageal cancer, stage I thymoma, stage II thymoma, stage III thymoma, stage IVA thymoma, stage IVB thymoma, recurrent melanoma, stage 0 melanoma, stage IA melanoma, stage IB melanoma, stage IIA melanoma, stage IIB melanoma, stage IIC melanoma, stage IIIA melanoma, stage IIIB melanoma, stage IIIC melanoma, stage IV melanoma
Brief summary
This is a phase III, randomized, double-blind, placebo-controlled, multicenter study of the clinical response to fentanyl sublingual spray as a treatment for breakthrough cancer pain. The study medication is administered under the tongue as a simple spray and can be self-administered by patients or assisted by their caregivers. Patients are titrated to an effective-dose of fentanyl sublingual spray in the open-label titration period and then proceed to the double-blind randomized period where they randomly receive 7 treatments with fentanyl sublingual spray and 3 treatments with placebo. Patients are treated for up to a total of 6-7 weeks (including both the open-label titration and the double-blind randomized periods).
Detailed description
RATIONALE Fentanyl sublingual spray may help relieve breakthrough pain in patients receiving opioids for cancer pain. OBJECTIVES Primary * Determine the efficacy and safety of fentanyl sublingual spray for the treatment of breakthrough cancer pain in patients on around-the-clock opioids for their persistent cancer pain. Secondary * Evaluate the safety of fentanyl sublingual spray in these opioid-tolerant patients. * Assess the patient's satisfaction with treatment medication.
Interventions
In the open-label titration period of the study, participants started at a dose of 100, 200, or 400 µg and titrated upward to a maximum dose of 1600 µg. Titration was stopped when the dose administered provided adequate analgesia for breakthrough pain without unacceptable side effects or the maximum titration period of 21±5 days was reached. In the double-blind period of the study, participants received fentanyl sublingual spray in doses of 100, 200, 400, 600, 800, 1200, or 1600 µg determined in the open-label titration period of the study.
DRUGPlacebo
Matching placebo to fentanyl sublingual spray.
Sponsors
National Cancer Institute (NCI)
INSYS Therapeutics Inc
Study design
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male or female, ≥ 18 years of age. * Diagnosis of cancer. * Opioid-tolerant. Subjects who were opioid tolerant were those taking ≥ 60 mg of oral morphine/day, at least 25 μg of transdermal fentanyl/hour, at least 30 mg of oxycodone daily, at least 8 mg of oral hydromorphone daily or an equianalgesic dose of another opioid for a week or longer for cancer-related pain. * Experienced persistent pain related to the cancer or its treatment of moderate or lesser intensity in the 24 hours prior to assessment by a verbal rating scale at the Screening Visit. * Over the previous 7 days, subject experienced, on average, 1 to 4 breakthrough cancer pain episodes per day usually at least partially controlled by supplemental medication of at least 5 mg immediate-release morphine or an equivalent short-acting opioid (eg, oxycodone, hydrocodone, or codeine with acetaminophen). * Able to evaluate and record pain relief, assess medication performance at set times after dosing, record AEs, record each use of the study drug or supplemental medication in an electronic diary (a caregiver may have provided the subject the medication, help with the mechanics of handling the electronic diary but was not permitted to record any information in the electronic diary). * Able and willing to give informed consent. * Women of childbearing potential were to have a) a negative serum pregnancy test, b) not be breastfeeding and c) agree to practice a reliable form of contraception.
Exclusion criteria
* Intolerance to opioids or fentanyl. * Current use of commercially available oral short-acting fentanyl for breakthrough pain. Subjects previously on Actiq or Fentora were permitted to be enrolled if they had a 7 day washout. * Rapidly increasing/uncontrolled pain. * A history of major organ system impairment or disease, that in the Investigator's or his/her designee's opinion could increase the risk associated with the use of opioids. * Uncontrolled hypertension (systolic blood pressure {SBP} \> 180 mmHg or diastolic blood pressure \[DBP\] \> 90 mmHg on 2 occasions ≥ 6 hours apart) despite antihypertensive therapy, or a history of hypertensive crisis within the past 2 years. * A recent history (≤ 2 years prior) of transient ischemic attacks, neural vascular disease, stroke, or cerebral aneurysms. * Clinically uncontrolled sleep apnea. * Brain metastases with signs or symptoms of increased intracranial pressure. * Inability to assess pain or response to pain medications for any reason, including psychiatric disorder, concurrent medical disorder, or concomitant therapy. * Received investigational study product(s) ≤ 30 days prior to the Screening Visit. * Painful erythema, oedema or ulcers under the tongue. * Use of monoamine oxidase (MAO) inhibitors within 14 days of the Screening Visit.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Summed Pain Intensity Differences (SPID) at 30 Minutes After Dosing (SPID30) | Baseline (time 0, beginning of each pain episode) through 30 minutes after dosing for each pain episode | Pain intensity was assessed by the participant using a 0-100 mm visual analog scale where 0 represented no pain and 100 represented worst possible pain at 0 (baseline, beginning of the pain episode), 5, 10, 15, and 30 minutes after each dose of study medication during each breakthrough pain episode. The pain intensity difference was defined as the difference in pain intensity at the various time points versus time 0 (baseline). SPID30 was calculated as the time-weighted sum of the PID scores using the following formula: SPID30=(5\*PID5)+(5\*PID10)+(5\*PID15)+(15\*PID30). The minimum and maximum SPID30 scores were -3000 and 3000. A higher score indicates less pain. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Summed Pain Intensity Differences (SPID) at 5, 10, 15, 45, and 60 Minutes After Dosing | Baseline (time 0, beginning of each pain episode) through 60 minutes after dosing for each pain episode | Pain intensity was assessed by the participant using a 0-100 mm visual analog scale where 0 represented no pain and 100 represented worst possible pain at 0 (baseline, beginning of the pain episode), 5, 10, 15, 30, 45 and 60 minutes after each dose of study medication during each breakthrough pain episode. The pain intensity difference was defined as the difference in pain intensity at the various time points versus time 0 (baseline). SPID was calculated as the time-weighted sum of the PID scores using the following formulas: SPID5=(5\*PID5), SPID10=(5\*PID5)+(5\*PID10), SPID15=(5\*PID5)+(5\*PID10)+(5\*PID15), SPID30=(5\*PID5)+(5\*PID10)+(5\*PID15)+(15\*PID30), SPID45=(5\*PID5)+(5\*PID10)+(5\*PID15)+(15\*PID30)+(15\*PID45), SPID60=(5\*PID5)+(5\*PID10)+(5\*PID15)+(15\*PID30) +(15\*PID45) +(15\*PID60). The minimum and maximum SPID scores were -500 to 500, -1000 to 1000, -1500 to 1500, -3000 to 3000, -4500 to 4500, and -6000 to 6000, respectively. A higher score indicates less pain. |
| Total Pain Relief (TOTPAR) at 5, 10, 15, 30, 45, and 60 Minutes After Dosing | 5 through 60 minutes after dosing for each pain episode | Pain relief (PAR) was assessed by the participant on a 5-point scale (1=No relief, 2=A little relief, 3=Moderate relief, 4=A lot of relief, 5=Complete relief) at 5, 10, 15, 30, 45 and 60 minutes after each dose of study medication during each breakthrough pain episode. TOTPAR was calculated as the time-weighted sum of the PAR scores at each time point using the following formulas: TOTPAR5=(5\*PAR5), TOTPAR10=(5\*PAR5)+(5\*PAR10), TOTPAR15=(5\*PAR5)+(5\*PAR10)+(5\*PAR15), TOTPAR30=(5\*PAR5)+(5\*PAR10)+(5\*PAR15)+(15\*PAR30), TOTPAR45=(5\*PAR5)+(5\*PAR10)+(5\*PAR15)+(15\*PAR30)+(15\*PAR45), TOTPAR60=(5\*PAR5)+(5\*PAR10)+(5\*PAR15)+(15\*PAR30) +(15\*PAR45) +(15\*PAR60). The minimum and maximum TOTPAR5, TOTPAR10, TOTPAR15, TOTPAR30, TOTPAR45, and TOTPAR60 scores were 5 to 25, 10 to 50, 15 to 75, 30 to 150, 45 to 225, and 60 to 300, respectively. A higher score indicates more pain relief. |
| Global Evaluation of the Study Medication at 30 and 60 Minutes After Dosing | 30 through 60 minutes after dosing for each pain episode | Global evaluation of the study medication was assessed by the participant on a 5-point scale (1=Poor, 2=Fair, 3=Good, 4=Very good, 5=Excellent) at 30 and 60 minutes after each dose of study medication during each breakthrough pain episode. A higher score indicates a better evaluation. |
Countries
United States
Participant flow
Pre-assignment details
As there are dozens, if not hundreds, of cross-over sequences during the double-blind period of this study, instead of reporting participant flow for each of the cross-over sequences, participant flow is reported separately for the fentanyl and placebo groups.
Participants by arm
| Arm | Count |
|---|---|
| Fentanyl Sublingual Spray Participants received fentanyl sublingual spray 7 times or placebo 3 times in random order to treat up to a maximum of 2 breakthrough pain episodes per day with a minimum separation of 2 hours between treatments. Patients received a dose of 100 to 1600 µg determined in the open-label dose titration period of the current study. | 130 |
| Total | 130 |
Baseline characteristics
| Characteristic | Fentanyl Sublingual Spray |
|---|---|
| Age, Continuous | 55.6 years STANDARD_DEVIATION 12.2 |
| Sex: Female, Male Female | 69 Participants |
| Sex: Female, Male Male | 61 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 78 / 130 | 47 / 98 |
| serious Total, serious adverse events | 7 / 130 | 6 / 98 |
Outcome results
Primary
Summed Pain Intensity Differences (SPID) at 30 Minutes After Dosing (SPID30)
Pain intensity was assessed by the participant using a 0-100 mm visual analog scale where 0 represented no pain and 100 represented worst possible pain at 0 (baseline, beginning of the pain episode), 5, 10, 15, and 30 minutes after each dose of study medication during each breakthrough pain episode. The pain intensity difference was defined as the difference in pain intensity at the various time points versus time 0 (baseline). SPID30 was calculated as the time-weighted sum of the PID scores using the following formula: SPID30=(5\*PID5)+(5\*PID10)+(5\*PID15)+(15\*PID30). The minimum and maximum SPID30 scores were -3000 and 3000. A higher score indicates less pain.
Time frame: Baseline (time 0, beginning of each pain episode) through 30 minutes after dosing for each pain episode
Population: Intent-to-treat (ITT) population: All participants in the double-blind treatment period who received at least 1 dose of study medication and had at least 1 pain measurement. 4 of the 96 participants in the ITT population were excluded from analysis because they did not have at least 1 dose of study medication and 1 dose of placebo.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Fentanyl Sublingual Spray | Summed Pain Intensity Differences (SPID) at 30 Minutes After Dosing (SPID30) | 640.3 Units on a scale | Standard Deviation 458.8 |
| Placebo | Summed Pain Intensity Differences (SPID) at 30 Minutes After Dosing (SPID30) | 399.6 Units on a scale | Standard Deviation 391.2 |
Secondary
Global Evaluation of the Study Medication at 30 and 60 Minutes After Dosing
Global evaluation of the study medication was assessed by the participant on a 5-point scale (1=Poor, 2=Fair, 3=Good, 4=Very good, 5=Excellent) at 30 and 60 minutes after each dose of study medication during each breakthrough pain episode. A higher score indicates a better evaluation.
Time frame: 30 through 60 minutes after dosing for each pain episode
Population: Intent-to-treat (ITT) population: All participants in the double-blind treatment period who received at least 1 dose of study medication and had at least 1 pain measurement. 4 of the 96 participants in the ITT population were excluded from analysis because they did not have at least 1 dose of study medication and 1 dose of placebo.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Fentanyl Sublingual Spray | Global Evaluation of the Study Medication at 30 and 60 Minutes After Dosing | 30 minutes | 2.8 Units on a scale | Standard Deviation 0.8 |
| Fentanyl Sublingual Spray | Global Evaluation of the Study Medication at 30 and 60 Minutes After Dosing | 60 minutes | 3.1 Units on a scale | Standard Deviation 0.8 |
| Placebo | Global Evaluation of the Study Medication at 30 and 60 Minutes After Dosing | 30 minutes | 2.0 Units on a scale | Standard Deviation 0.8 |
| Placebo | Global Evaluation of the Study Medication at 30 and 60 Minutes After Dosing | 60 minutes | 2.2 Units on a scale | Standard Deviation 0.8 |
Secondary
Summed Pain Intensity Differences (SPID) at 5, 10, 15, 45, and 60 Minutes After Dosing
Pain intensity was assessed by the participant using a 0-100 mm visual analog scale where 0 represented no pain and 100 represented worst possible pain at 0 (baseline, beginning of the pain episode), 5, 10, 15, 30, 45 and 60 minutes after each dose of study medication during each breakthrough pain episode. The pain intensity difference was defined as the difference in pain intensity at the various time points versus time 0 (baseline). SPID was calculated as the time-weighted sum of the PID scores using the following formulas: SPID5=(5\*PID5), SPID10=(5\*PID5)+(5\*PID10), SPID15=(5\*PID5)+(5\*PID10)+(5\*PID15), SPID30=(5\*PID5)+(5\*PID10)+(5\*PID15)+(15\*PID30), SPID45=(5\*PID5)+(5\*PID10)+(5\*PID15)+(15\*PID30)+(15\*PID45), SPID60=(5\*PID5)+(5\*PID10)+(5\*PID15)+(15\*PID30) +(15\*PID45) +(15\*PID60). The minimum and maximum SPID scores were -500 to 500, -1000 to 1000, -1500 to 1500, -3000 to 3000, -4500 to 4500, and -6000 to 6000, respectively. A higher score indicates less pain.
Time frame: Baseline (time 0, beginning of each pain episode) through 60 minutes after dosing for each pain episode
Population: Intent-to-treat (ITT) population: All participants in the double-blind treatment period who received at least 1 dose of study medication and had at least 1 pain measurement. 4 of the 96 participants in the ITT population were excluded from analysis because they did not have at least 1 dose of study medication and 1 dose of placebo.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Fentanyl Sublingual Spray | Summed Pain Intensity Differences (SPID) at 5, 10, 15, 45, and 60 Minutes After Dosing | SPID10 | 115.0 Units on a scale | Standard Deviation 130.7 |
| Fentanyl Sublingual Spray | Summed Pain Intensity Differences (SPID) at 5, 10, 15, 45, and 60 Minutes After Dosing | SPID45 | 1122.0 Units on a scale | Standard Deviation 731.9 |
| Fentanyl Sublingual Spray | Summed Pain Intensity Differences (SPID) at 5, 10, 15, 45, and 60 Minutes After Dosing | SPID15 | 220.6 Units on a scale | Standard Deviation 209.7 |
| Fentanyl Sublingual Spray | Summed Pain Intensity Differences (SPID) at 5, 10, 15, 45, and 60 Minutes After Dosing | SPID60 | 1649.0 Units on a scale | Standard Deviation 1016.2 |
| Fentanyl Sublingual Spray | Summed Pain Intensity Differences (SPID) at 5, 10, 15, 45, and 60 Minutes After Dosing | SPID5 | 40.3 Units on a scale | Standard Deviation 57.7 |
| Placebo | Summed Pain Intensity Differences (SPID) at 5, 10, 15, 45, and 60 Minutes After Dosing | SPID60 | 965.7 Units on a scale | Standard Deviation 862.1 |
| Placebo | Summed Pain Intensity Differences (SPID) at 5, 10, 15, 45, and 60 Minutes After Dosing | SPID5 | 32.0 Units on a scale | Standard Deviation 52.1 |
| Placebo | Summed Pain Intensity Differences (SPID) at 5, 10, 15, 45, and 60 Minutes After Dosing | SPID10 | 81.1 Units on a scale | Standard Deviation 108 |
| Placebo | Summed Pain Intensity Differences (SPID) at 5, 10, 15, 45, and 60 Minutes After Dosing | SPID15 | 150.3 Units on a scale | Standard Deviation 172.5 |
| Placebo | Summed Pain Intensity Differences (SPID) at 5, 10, 15, 45, and 60 Minutes After Dosing | SPID45 | 667.0 Units on a scale | Standard Deviation 614.5 |
Secondary
Total Pain Relief (TOTPAR) at 5, 10, 15, 30, 45, and 60 Minutes After Dosing
Pain relief (PAR) was assessed by the participant on a 5-point scale (1=No relief, 2=A little relief, 3=Moderate relief, 4=A lot of relief, 5=Complete relief) at 5, 10, 15, 30, 45 and 60 minutes after each dose of study medication during each breakthrough pain episode. TOTPAR was calculated as the time-weighted sum of the PAR scores at each time point using the following formulas: TOTPAR5=(5\*PAR5), TOTPAR10=(5\*PAR5)+(5\*PAR10), TOTPAR15=(5\*PAR5)+(5\*PAR10)+(5\*PAR15), TOTPAR30=(5\*PAR5)+(5\*PAR10)+(5\*PAR15)+(15\*PAR30), TOTPAR45=(5\*PAR5)+(5\*PAR10)+(5\*PAR15)+(15\*PAR30)+(15\*PAR45), TOTPAR60=(5\*PAR5)+(5\*PAR10)+(5\*PAR15)+(15\*PAR30) +(15\*PAR45) +(15\*PAR60). The minimum and maximum TOTPAR5, TOTPAR10, TOTPAR15, TOTPAR30, TOTPAR45, and TOTPAR60 scores were 5 to 25, 10 to 50, 15 to 75, 30 to 150, 45 to 225, and 60 to 300, respectively. A higher score indicates more pain relief.
Time frame: 5 through 60 minutes after dosing for each pain episode
Population: Intent-to-treat (ITT) population: All participants in the double-blind treatment period who received at least 1 dose of study medication and had at least 1 pain measurement. 4 of the 96 participants in the ITT population were excluded from analysis because they did not have at least 1 dose of study medication and 1 dose of placebo.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Fentanyl Sublingual Spray | Total Pain Relief (TOTPAR) at 5, 10, 15, 30, 45, and 60 Minutes After Dosing | TOTPAR5 | 8.6 Units on a scale | Standard Deviation 3.5 |
| Fentanyl Sublingual Spray | Total Pain Relief (TOTPAR) at 5, 10, 15, 30, 45, and 60 Minutes After Dosing | TOTPAR10 | 19.7 Units on a scale | Standard Deviation 7 |
| Fentanyl Sublingual Spray | Total Pain Relief (TOTPAR) at 5, 10, 15, 30, 45, and 60 Minutes After Dosing | TOTPAR15 | 32.9 Units on a scale | Standard Deviation 10.3 |
| Fentanyl Sublingual Spray | Total Pain Relief (TOTPAR) at 5, 10, 15, 30, 45, and 60 Minutes After Dosing | TOTPAR30 | 78.3 Units on a scale | Standard Deviation 20.4 |
| Fentanyl Sublingual Spray | Total Pain Relief (TOTPAR) at 5, 10, 15, 30, 45, and 60 Minutes After Dosing | TOTPAR45 | 126.3 Units on a scale | Standard Deviation 30.9 |
| Fentanyl Sublingual Spray | Total Pain Relief (TOTPAR) at 5, 10, 15, 30, 45, and 60 Minutes After Dosing | TOTPAR60 | 176.4 Units on a scale | Standard Deviation 41.5 |
| Placebo | Total Pain Relief (TOTPAR) at 5, 10, 15, 30, 45, and 60 Minutes After Dosing | TOTPAR45 | 95.5 Units on a scale | Standard Deviation 32 |
| Placebo | Total Pain Relief (TOTPAR) at 5, 10, 15, 30, 45, and 60 Minutes After Dosing | TOTPAR5 | 7.6 Units on a scale | Standard Deviation 3.3 |
| Placebo | Total Pain Relief (TOTPAR) at 5, 10, 15, 30, 45, and 60 Minutes After Dosing | TOTPAR30 | 61.0 Units on a scale | Standard Deviation 20.8 |
| Placebo | Total Pain Relief (TOTPAR) at 5, 10, 15, 30, 45, and 60 Minutes After Dosing | TOTPAR10 | 16.7 Units on a scale | Standard Deviation 6.5 |
| Placebo | Total Pain Relief (TOTPAR) at 5, 10, 15, 30, 45, and 60 Minutes After Dosing | TOTPAR60 | 131.2 Units on a scale | Standard Deviation 43.6 |
| Placebo | Total Pain Relief (TOTPAR) at 5, 10, 15, 30, 45, and 60 Minutes After Dosing | TOTPAR15 | 27.1 Units on a scale | Standard Deviation 10 |