A Phase 2, Double-Blind, Randomized, Placebo-Controlled, Multiple-Dose, Dose Escalation Study to Evaluate the Efficacy, Safety and Tolerability of NKTR-118 in Patients with Opioid-Induced Constipation (OIC)

• Register: EUCTR
• Last refreshed on: 28 January 2013
• Main ID: EUCTR2007-005421-30-DE
• Date of registration: 12/12/2007
• Prospective Registration: Yes
• Primary sponsor: Nektar Therapeutics
• Public title: A Phase 2, Double-Blind, Randomized, Placebo-Controlled, Multiple-Dose, Dose Escalation Study to Evaluate the Efficacy, Safety and Tolerability of NKTR-118 in Patients with Opioid-Induced Constipation (OIC)
• Scientific title: A Phase 2, Double-Blind, Randomized, Placebo-Controlled, Multiple-Dose, Dose Escalation Study to Evaluate the Efficacy, Safety and Tolerability of NKTR-118 in Patients with Opioid-Induced Constipation (OIC)
• Date of first enrolment: 17/04/2008
• Target sample size: 224
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2007-005421-30
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no

Countries of recruitment

Germany

Key inclusion & exclusion criteria

Inclusion criteria:
1. 18 years of age or older, male or female
Female patients must be of non-childbearing potential OR if they are of child-bearing potential have a negative screening pregnancy test with a commitment to practice effective contraception throughout the duration of the study, including the Follow-Up Period. Females who have had a surgical hysterectomy and/or bilateral oophorectomy, or are post-menopausal and have not had a menstrual cycle for 12 consecutive months, are not considered to be of child-bearing potential. Effective contraception will be defined as either 1) complete sexual abstinence; 2) double barrier methods of birth control such as female diaphragm with spermicidal jelly AND male condom, 3) an intrauterine device (IUD) AND single barrier method of contraception; 4) use of an oral topical contraceptive combined with a barrier method of birth control. Male patients must also practice effective contraception as defined above (i.e., they and their female partner(s) must rely upon effective contraception as defined above). A male patient with a documented history of bilateral vasectomy or bilateral orchiectomy will be considered sterile; he and his partner(s) will not need to use additional contraception. A male with a history of infertility or impotence must still practice contraception during any act of intercourse.
2. Receiving a stable opioid regimen consisting of a total daily dose of 30 mg – 1000 mg of oral morphine or equianalgesic amount (s) of one or more opioid therapies ( See Appendix 2) for a minimum of 2 weeks prior to screening for non-malignant pain or cancer-related pain with no anticipated change in opioid dose requirement over the proposed study period as a result of disease progression. Regimen stability will be confirmed during the two week constipation screening period, and, for patients receiving a long-acting “around-the-clock” opioid, will be defined as maintenance of a fixed dose of a long-acting opioid and use of opioid rescue therapy, if needed, at a frequency generally less than five times per day. Rescue therapy doses over the two week screening period will be captured in an electronic diary. Patients will be disqualified from enrollment if they consume >4 rescue doses per day on more than 3 days during the two-week constipation screening period, or if their long-acting opioid dose is modified during this same period.
Patients receiving only a short-acting opioid will be allowed on study if they are receiving doses according to a fixed schedule. Patients receiving only a short-acting opioid on a PRN basis or patients receiving intrathecal opioids will not be eligible for this study.
3. Documented OIC with fewer than 3 SBMs/week confirmed over a 2-week OIC screening period with at least one self reported symptom of hard/lumpy stools, straining, or sensation of incomplete evacuation/anorectal obstruction, as well as self-reported OIC (<3 SBMs/week), and at least one associated symptom of hard/lumpy stools, straining, or sensation of incomplete evacuation/anorectal obstruction at the initial screening visit.
4. Willingness to stop all laxatives and other bowel regimens (see prohibited medications) throughout the 2-week OIC screening period and the 5-week treatment period, and to use only bisacodyl as rescue medication if a bowel movement (BM) has not occurred within 72 hr of last recorded BM.

Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 y
Exclusion criteria:
1. Serum creatinine >2X upper limit of normal (ULN), Serum transaminases (ALT or AST) >3X ULN, Serum bilirubin >2.5X ULN (not ascribed to Gilbert’s syndrome)
2. Absolute neutrophil count (ANC) <1000 cells/mm3, hemoglobin <9 g/dL, platelets <60,000/mm3
3. History of gastrointestinal hemorrhage related to ongoing gastrointestinal pathology (e.g., ulcer disease)
4. Hemorrhagic diathesis
5. Cirrhosis
6. Life expectancy <6 months
7. Exposure to vinca alkaloids within 2 months or a history of vinca-associated gastrointestinal neurotoxicity
8. Active substance abuse
9. Fecal incontinence, irritable bowel syndrome (physician-diagnosed and fulfilling the Rome criteria), inflammatory bowel disease, intestinal obstruction, or other active medical disorders associated with diarrhea or intermittent loose stools or constipation
10. Uncontrolled hypothyroidism
11. Pregnant or breast-feeding
12. History of ischemic heart disease or a screening electrocardiogram compatible with ischemic heart disease, or any other medical condition that may unduly increase risk to the patient or may affect the interpretation of study data (e.g., inadequately controlled clinical depression, ventricular arrhythmias, poorly controlled seizure disorder)
13. Any underlying psychiatric disorder or medical condition that would interfere with the ability to comply with the study
14. Ongoing use of manual maneuvers to induce a BM (e.g., digital evacuation or pelvic floor support) more than 25% of the time
15. Brain metastases, epidural metastases or malignant tumor of the brain, multiple sclerosis or any other condition that may affect the permeability of the blood brain barrier.
16. Severe background pain (e.g., typical average daily pain intensity rating of 7-10 on an 11-point NRS) refractory to opioid therapy
17. Any receipt of an investigational medication within 30 days of screening



Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Opioid induced constipation

Intervention(s)

Product Code: NKTR-118
Pharmaceutical Form: Oral solution
Current Sponsor code: NKTR-118
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 5-
Pharmaceutical form of the placebo: Oral solution
Route of administration of the placebo: Oral use

Product Code: NKTR-118
Pharmaceutical Form: Oral solution
Current Sponsor code: NKTR-118
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 25-
Pharmaceutical form of the placebo: Oral solution
Route of administration of the placebo: Oral use

Product Code: NKTR-118
Pharmaceutical Form: Oral solution
Current Sponsor code: NKTR-118
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 50-
Pharmaceutical form of the placebo: Oral solution
Route of administration of the placebo: Oral use

Product Code: NKTR-118
Pharmaceutical Form: Oral solution
Current Sponsor code: NKTR-118
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 100-
Pharmaceutical form of the placebo: Oral solution
Route of administration of the placebo: Oral use

Primary Outcome(s)

Secondary Objective: Secondary Objectives:
• To evaluate safety and tolerability of NKTR-118, thereby enabling the identification of an effective dose that preserves opioid-conferred analgesia
• Delineate dose-response for NKTR-118 across a range of underlying opioid doses, with response defined as the change in SBMs per week from baseline
• Characterize the pharmacokinetics (PK) of NKTR-118 in patients

Main Objective: Objectives:
Primary Objective:
To evaluate the efficacy of NKTR-118 at various dose levels, with efficacy defined as the change in the number of spontaneous bowel movements (SBMs) per week from baseline. The primary endpoint is the change from baseline in SBMs/week averaged throughout the treatment period, defined as SBMs/week for the overall treatment period minus baseline SBMs/week.

Primary end point(s): Primary Endpoint:
Change from baseline in SBMs/week averaged throughout the treatment period; this is defined to be SBMs/week for the overall treatment period minus baseline SBMs/week. SBM is defined as a bowel movement without the use of laxatives in the previous 24 hour.

Secondary ID(s)

07-IN-NX003