Fentanyl Sublingual Spray in Treating Patients With Breakthrough Cancer Pain

• ClinicalTrials.gov Identifier: NCT00538850
• Recruitment Status: Completed
• First Posted: October 3, 2007
• Results First Posted: March 5, 2014
• Last Update Posted: March 5, 2014
• Sponsor: INSYS Therapeutics Inc
• Collaborator: National Cancer Institute (NCI)
• Information provided by (Responsible Party): INSYS Therapeutics Inc

Study Description

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).

Condition or disease	Intervention/treatment	Phase
Cancer	Drug: Fentanyl sublingual spray; Drug: Placebo	Phase 3

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 130 participants
• Intervention Model: Crossover Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-blind, Placebo-controlled Multi-center Study to Evaluate the Safety and Efficacy of Fentanyl Sublingual Spray (Fentanyl SL Spray) for the Treatment of Breakthrough Cancer Pain
• Study Start Date: October 2007
• Actual Primary Completion Date: February 2010
• Actual Study Completion Date: October 2010

Arms and Interventions

Arm

Intervention/treatment

Experimental: 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.

Drug: Fentanyl sublingual spray; 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.; Other Name: SUBSYS; Drug: Placebo; Matching placebo to fentanyl sublingual spray.

Outcome Measures

Primary Outcome Measures :

1. Summed Pain Intensity Differences (SPID) at 30 Minutes After Dosing (SPID30) [ Time Frame: 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 Outcome Measures :

1. Summed Pain Intensity Differences (SPID) at 5, 10, 15, 45, and 60 Minutes After Dosing [ Time Frame: 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.
2. Total Pain Relief (TOTPAR) at 5, 10, 15, 30, 45, and 60 Minutes After Dosing [ Time Frame: 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.
3. Global Evaluation of the Study Medication at 30 and 60 Minutes After Dosing [ Time Frame: 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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

Locations

United States, Arizona

InSys Therapeutics, Incorporated

Chandler, Arizona, United States, 85224

Sponsors and Collaborators

INSYS Therapeutics Inc

National Cancer Institute (NCI)

Investigators

• Study Chair: Larry Dillaha, MD; INSYS Therapeutics Inc

More Information

Publications of Results:

Rauck R, Reynolds L, Geach J, Bull J, Stearns L, Scherlis M, Parikh N, Dillaha L. Efficacy and safety of fentanyl sublingual spray for the treatment of breakthrough cancer pain: a randomized, double-blind, placebo-controlled study. Curr Med Res Opin. 2012 May;28(5):859-70. doi: 10.1185/03007995.2012.683111. Epub 2012 May 2.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Alberts DS, Smith CC, Parikh N, Rauck RL. Fentanyl sublingual spray for breakthrough cancer pain in patients receiving transdermal fentanyl. Pain Manag. 2016 Oct;6(5):427-34. doi: 10.2217/pmt-2015-0009. Epub 2016 Mar 29.

• Responsible Party: INSYS Therapeutics Inc
• ClinicalTrials.gov Identifier: NCT00538850
• Obsolete Identifiers: NCT00589342
• Other Study ID Numbers: INS-05-001; CDR0000581128 ( Registry Identifier: PDQ (Physician Data Query) )
• First Posted: October 3, 2007
• Results First Posted: March 5, 2014
• Last Update Posted: March 5, 2014
• Last Verified: January 2014

Keywords provided by INSYS Therapeutics Inc:

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

Additional relevant MeSH terms:

Cancer Pain; Pain; Neurologic Manifestations; Fentanyl; Analgesics, Opioid; Narcotics; Central Nervous System Depressants; Physiological Effects of Drugs; Analgesics; Sensory System Agents; Peripheral Nervous System Agents; Adjuvants, Anesthesia; Anesthetics, Intravenous; Anesthetics, General; Anesthetics