SLT4501

Mundipharma Research GmbH & Co. KG

Höhenstrasse 10, Limburg, Germany, 65549

European Medical Operations, Mundipharma Research GmbH & Co. KG, 0044 1223424900, info@contact-clinical-trial.com

European Medical Operations, Mundipharma Research GmbH & Co. KG, 0044 1223424900, info@contact-clinical-trial.com

No

No

No

Final

27 Aug 2014

Yes

27 Aug 2014

Yes

27 Aug 2014

No

•To assess the effect of SLT on the frequency of soft (stool of type 3, 4 or 5 on the Bristol Stool Form Scale (BSFS)) complete bowel movements (SCBMs) and SCBMs non-straining (NS) per week in subjects taking World Health Organisation (WHO) step II/III opioid analgesics at visit 8 (change from baseline to the final visit) •To assess the number of subjects taking additional laxatives (including enema) or requiring procedures (e.g. manual bowel evacuation or surgical procedure) in addition to SLT. •To assess symptoms of constipation in subjects taking SLT concomitantly with WHO step II/III opioid analgesics as measured by the Bowel Function Index (BFI). •To assess the compliance with opioids/SLT in terms of number of subjects who did not discontinue prematurely, experience dose reduction or stop opioids/SLT due to insufficient effect and/or intolerability.

1) Inclusion criteria: - Females less than one year post-menopausal must have a negative pregnancy test prior to the first dose of study medication, be non-lactating, and willing to use adequate and highly effective methods of contraception throughout the study. (A highly effective method of birth control is defined as those which result in a low failure rate (i.e. less than 1% per year) when used consistently and correctly e.g. sterilisation, implants, injectables, combined oral contraceptives, some intrauterine devices ((IUDs), hormonal), sexual abstinence or vasectomised partner). -Subjects must be willing and able (e.g. mental and physical condition) to participate in all aspects of the study, including use of medication, completion of subjective evaluations, attending scheduled clinic visits, completing telephone contacts, and compliance with protocol requirements as evidenced by providing written, informed consent. 2) Exclusion criteria: - In the Investigator’s opinion any contraindication and precautionary condition for laxative medication(s) used in the study as per the SmPC 3) Dose discontinuation: Investigators may have stopped SLT at any time for safety reasons or if judged no longer appropriate for the Subject to continue. 4) Safety assessments consisted of monitoring and recording all AEs and SAEs, observed or volunteered, regardless of laxatives received or suspected causal relationship to the IMP. This included reactions, interactions, accidents, illnesses, misuse and abuse. In addition, safety was assessed by monitoring haematology, biochemistry, and urine values, periodic measurement of vital signs and ECGs and the performance of physical examinations.

01 Oct 2013

No

No

Sweden: 25

United Kingdom: 79

France: 12

116

116

0

0

0

0

0

0

65

49

2

Treatment period (overall period)

Not applicable

Yes

Macrogol

Macrogol

Powder and solvent for oral solution

Oral use

Medication was used as directed in SmPC. Any other medication with the same active ingredient could be used.

Sodium picosulfate

Sodium picosulfate

Oral drops, liquid

Oral use

Medication was used as directed in SmPC. Any other medication with the same active ingredient could be used.

Second Line SLT

Second Line SLT

Granules in sachet, Oral liquid, Capsule, Oral solution, Oral suspension, Tablet

Oral use

If required and deemed necessary by the Investigator, a third laxative could be administered as a Second Line SLT. The choice was made by the Investigator, dose and route of administration of this third laxative (or enema) were according to country specific clinical practice guidelines, site specific standards, and the clinical condition of the Subject, either as regular administration or for immediate rescue purposes.

Additional laxative

Additional laxative

Capsule, Granules in sachet, Oral liquid, Oral suspension, Oral/rectal solution, Suppository, Tablet

Oral use, Rectal use

If additional laxative (in addition to First and Second Line SLT) was deemed necessary, the choice was made by the Investigator, dose and route of administration of this additional laxative (or enema) were according to country specific clinical practice guidelines, site specific standards, and the clinical condition of the Subject, either as regular administration or for immediate rescue purposes.

Bisadodyl

Bisacodyl

Tablet

Oral use

Medication was used as directed in SmPC. Any other medication with the same active ingredient could be used.

Sorbitol

Sorbitol

Pouch

Oral use

Medication was used as directed in SmPC. Any other medication with the same active ingredient could be used.

Second Line SLT

Second Line SLT

Capsule, Granules in sachet, Oral liquid, Oral solution, Oral suspension, Tablet

Oral use

If required and deemed necessary by the Investigator, a third laxative could be administered as a Second Line SLT. The choice was made by the Investigator, dose and route of administration of this third laxative (or enema) were according to country specific clinical practice guidelines, site specific standards, and the clinical condition of the Subject, either as regular administration or for immediate rescue purposes.

Additional laxative

Additional laxative

Capsule, Granules in sachet, Oral liquid, Oral suspension, Oral/rectal solution, Suppository, Tablet

Oral use, Rectal use

If additional laxative (in addition to First and Second Line SLT) was deemed necessary, the choice was made by the Investigator, dose and route of administration of this additional laxative (or enema) were according to country specific clinical practice guidelines, site specific standards, and the clinical condition of the Subject, either as regular administration or for immediate rescue purposes.

Senna

Senna

Tablet

Oral use

Medication was used as directed in SmPC. Any other medication with the same active ingredient could be used.

Docusate sodium

Docusate

Capsule

Oral use

Medication was used as directed in SmPC. Any other medication with the same active ingredient could be used.

Second Line SLT

Second Line SLT

Capsule, Granules in sachet, Oral liquid, Oral solution, Oral suspension, Tablet

Oral use

If required and deemed necessary by the Investigator, a third laxative could be administered as a Second Line SLT. The choice was made by the Investigator, dose and route of administration of this third laxative (or enema) were according to country specific clinical practice guidelines, site specific standards, and the clinical condition of the Subject, either as regular administration or for immediate rescue purposes.

Additional laxative

Additional laxative

Capsule, Granules in sachet, Oral liquid, Oral suspension, Oral/rectal solution, Suppository, Tablet

Oral use, Rectal use

If additional laxative (in addition to First and Second Line SLT) was deemed necessary, the choice was made by the Investigator, dose and route of administration of this additional laxative (or enema) were according to country specific clinical practice guidelines, site specific standards, and the clinical condition of the Subject, either as regular administration or for immediate rescue purposes.

Treatment period

Safety population

The safety population was defined as all subjects who received at least one dose of IMP. Note: Subjects who were taking one or two laxatives in SLT and discontinued the study before Visit 2 were not included into the safety population as SLT treatment intakes before Visit 2 were not meant to be intakes of the IMP by the definition. The safety population was used to assess all safety evaluations

Full analysis population

The full analysis population was defined as all subjects who • received at least one dose of IMP, • had at least one baseline measure (i.e. a pre-switch (prior to Visit 2) value during the screening period ) and • had at least one post-baseline measure for Soft Complete Bowel Movements (SCBMs). Subjects who were found to violate any of the inclusion /exclusion criteria (after starting study treatment) were also included in this population.

Full Analysis Population without Deviations (FAPwoD)

In addition to the FAP the FAPwoD was defined as a subset of all subjects from the FAP who: • Did not violate any inclusion/exclusion criteria. • Did not take prohibited concomitant therapies during the Treatment Period. • Did not take more than the maximum dose of laxatives (both first and second line SLT as per SmPC. The following concomitant therapies were considered prohibited: • Medications which substance name or part of their substance name contains one of the following: naloxone, naltrexone, methylnaltrexone. • Medications with ATC 4th level code N07BC.

Swedish SLT regimen

French SLT regimen

UK SLT regimen

Safety population

The safety population was defined as all subjects who received at least one dose of IMP. Note: Subjects who were taking one or two laxatives in SLT and discontinued the study before Visit 2 were not included into the safety population as SLT treatment intakes before Visit 2 were not meant to be intakes of the IMP by the definition. The safety population was used to assess all safety evaluations

Full analysis population

The full analysis population was defined as all subjects who • received at least one dose of IMP, • had at least one baseline measure (i.e. a pre-switch (prior to Visit 2) value during the screening period ) and • had at least one post-baseline measure for Soft Complete Bowel Movements (SCBMs). Subjects who were found to violate any of the inclusion /exclusion criteria (after starting study treatment) were also included in this population.

Full Analysis Population without Deviations (FAPwoD)

In addition to the FAP the FAPwoD was defined as a subset of all subjects from the FAP who: • Did not violate any inclusion/exclusion criteria. • Did not take prohibited concomitant therapies during the Treatment Period. • Did not take more than the maximum dose of laxatives (both first and second line SLT as per SmPC. The following concomitant therapies were considered prohibited: • Medications which substance name or part of their substance name contains one of the following: naloxone, naltrexone, methylnaltrexone. • Medications with ATC 4th level code N07BC.

The primary objective was to assess the effect of SLT on the frequency of soft (stool of type 3, 4 or 5 on the Bristol Stool Form Scale (BSFS)) complete bowel movements (SCBMs) per week in subjects taking WHO step II/III opioid analgesics at Visit 8 (change from baseline to the final visit). Bowel movements were characterised by the following criteria: • S: Soft bowel movement was defined as stool of type 3, 4 or 5 on the Bristol Stool Form Scale (BSFS). • C: Completeness of the bowel movement was rated as Yes. • BM: The occurrence of a bowel movement (any passage of stool). • NS: Straining or Squeezing was rated as Absent (0) or Mild (1). Criteria were considered as not met if information relevant to the criteria was missing A bowel movement was classified as a Soft Complete Bowel Movement (SCBM) if the following criteria were met: S, C and BM.

Primary

over 4 weeks (change from visit 2 to visit 8).

Bowel movements were characterised by the following criteria: • S: Soft bowel movement was defined as stool of type 3, 4 or 5 on the Bristol Stool Form Scale (BSFS). • C: Completeness of the bowel movement was rated as Yes. • BM: The occurrence of a bowel movement (any passage of stool). • NS: Straining or Squeezing was rated as Absent (0) or Mild (1). Criteria were considered as not met if information relevant to the criteria was missing A bowel movement was classified as a Soft Complete Bowel Movement (SCBM) if the following criteria were met: S, C and BM.

Secondary

Week 4 LOCF

Bowel movements were characterised by the following criteria: • S: Soft bowel movement was defined as stool of type 3, 4 or 5 on the Bristol Stool Form Scale (BSFS). • C: Completeness of the bowel movement was rated as Yes. • BM: The occurrence of a bowel movement (any passage of stool). • NS: Straining or Squeezing was rated as Absent (0) or Mild (1). Criteria were considered as not met if information relevant to the criteria was missing A bowel movement was classified as a Soft Complete Bowel Movement (SCBM) if the following criteria were met: S, C and BM. A bowel movement was classified as a Soft Complete Bowel Movement – Non Straining (SCBM-NS) if the following criteria were met: S, C, BM and NS.

Secondary

Week 4 LOCF

It was analysed how many subjects required additional laxatives (number of analysed subjects) and mean (SD) number of days on which laxatives were used.

Secondary

From baseline to week 4

The BFI score is the mean of the following items (assessed at each visit): Ease of defecation (numerical analogue scale (NAS), 0=easy/no difficulty; 100=severe difficulty), Feeling of incomplete bowel evacuation (NAS, 0=not at all, 100=very strong), Personal judgment of constipation (NAS, 0=not at all, 100=very strong).

Secondary

Week 4 LOCF

The numbers and percentages of subjects • who had at least one SLT (first or second line) dose reduction based on Laxative therapy CRF data was calculated. • who had at least one opioid dose reduction based on Regular Analgesic Medication CRF data was calculated. • who had at least one opioid dose reduction /increase based on diary data (took more / took less regular opioid medication as prescribed by doctor). This was also recalculated using only those diaries which reasonably reflect medication used according investigator’s check.

Secondary

Baseline to week 4

Secondary

Baseline to week 4, and follow up of 7 days after week 4

Opioid withdrawal symptoms were assessed by the modified Subjective Opiate Withdrawal Scale (SOWS). The scale consists of 15 items that reflect the common motor, autonomic, gastrointestinal, musculoskeletal, and psychic symptoms of opiate withdrawal. The modified SOWS excluded the SOWS item, ’I feel like shooting up today’, since it does not apply to the target subject population. The COWS is a clinician administered instrument that rates 11 common opiate withdrawal signs or symptoms. The score for each item reflects the severity of the sign or symptom. The total score was used to assess a Subjects' level of opiate withdrawal and to make inferences about their level of physical dependence on opioids.

Secondary

Screening, week 1, week 4

The average pain over the last 24 hours at screening, baseline and each week (including Week 4 (LOCF)). Pain scale from 0 (no pain) to 10 (worst imaginable pain)

Secondary

Average pain in the last 24 hours, assessed at each visit

The SF-36 v2TM Health Survey© (SF-36 v2) is a validated scale to measure quality of life aspects. The summary scores that were employed are the SF-36 v2 scores for the eight health domains: role-physical, bodily pain, general health, vitality, social functioning, role-emotional, and mental health, the general health question, and two summary measures of physical health (aggregate of physical functioning, role-physical, bodily pain and general health scales) and mental health (aggregate of the vitality, social functioning, role-emotional and mental health scales). Each domain score was transformed to a scale from 0 to 100. The SF-36 v2 domain scores were mapped into the EQ-5D utility score. The EQ-5D is the most widely used generic preference-based measure of health-related quality of life which produces utility scores anchored at 0 for dead and 1 for perfect health. Mapping model was used to covert SF-36 domain scores to EQ-5D utility score.

Secondary

Screening, week 1, week 4

The Patient Assessment of Constipation Quality of Life (PAC-QOL) questionnaire is an instrument to evaluate the impact of constipation on daily life over time. PAC-QOL assessments were performed at clinic visits V1, V5 and V8. The final PAC-QOL contained 28 items grouped into four subscales covering: Worries and concerns (11 items), Physical discomfort (4 items), Psychosocial discomfort (8 items), and Satisfaction (5 items). Scale scores were then computed as the average item response within the scale. Global score was calculated as the mean of the 28 items.

Secondary

Baseline to Week 4

The Clinical Global Impression (CGI) scale is a 7-point scale to assess the severity of illness for a given disease. This scale uses the clinical impression to grade the severity of subjects’ illness into ‘‘normal, not at all ill’’, ‘‘borderline ill’’, ‘‘mildly ill’’, ‘‘moderately ill’’, ‘‘markedly ill’’, ‘‘severely ill’’, and ‘‘among the most extremely ill subjects’’. The CGI consists of further three subscales, and in addition to the overall severity there is a subscale for change, for therapeutic effect, and for side effects. The CGI for change makes a global rating of the change of condition, and grades it into very much improved, much improved, minimally improved, no change, minimally worse, much worse, very much worse. The CGI item 1 (severity of illness) was assessed at Visit 1 and Visit 8. Items 2 – 4 (2 - global rating of change of condition, 3 - therapeutic effect, 4 - side effects) were assessed at Visit 5 and Visit 8.

Secondary

Screening and Week 4 or Week 1 and Week 4 (see description)

Bowel movements were characterised by the following criteria: • S: Soft bowel movement was defined as stool of type 3, 4 or 5 on the Bristol Stool Form Scale (BSFS). • C: Completeness of the bowel movement was rated as Yes. • BM: The occurrence of a bowel movement (any passage of stool). • NS: Straining or Squeezing was rated as Absent (0) or Mild (1). Criteria were considered as not met if information relevant to the criteria was missing A bowel movement was classified as a Soft Complete Bowel Movement (SCBM) if the following criteria were met: S, C and BM. Subgroups of - Subjects taking SLT and any opioid, excluding Oxy PR (SLT + Non Oxy PR). - Subjects taking SLT and Oxy PR (SLT + Oxy PR).

Secondary

Week 4 LOCF

Bowel movements were characterised by the following criteria: • S: Soft bowel movement was defined as stool of type 3, 4 or 5 on the Bristol Stool Form Scale (BSFS). • C: Completeness of the bowel movement was rated as Yes. • BM: The occurrence of a bowel movement (any passage of stool). • NS: Straining or Squeezing was rated as Absent (0) or Mild (1). Criteria were considered as not met if information relevant to the criteria was missing A bowel movement was classified as a Soft Complete Bowel Movement (SCBM) if the following criteria were met: S, C and BM. A bowel movement was classified as a Soft Complete Bowel Movement – Non Straining (SCBM-NS) if the following criteria were met: S, C, BM and NS. Subgroups of - Subjects taking SLT and any opioid, excluding Oxy PR (SLT + Non Oxy PR). - Subjects taking SLT and Oxy PR (SLT +

Secondary

Week 4 LOCF

The BFI score is the mean of the following items (assessed at each visit): Ease of defecation (numerical analogue scale (NAS), 0=easy/no difficulty; 100=severe difficulty), Feeling of incomplete bowel evacuation (NAS, 0=not at all, 100=very strong), Personal judgment of constipation (NAS, 0=not at all, 100=very strong). Subgroups: - Subjects taking SLT and any opioid, excluding Oxy PR (SLT + Non Oxy PR). - Subjects taking SLT and Oxy PR (SLT + Oxy PR).

Secondary

Week 4 LOCF

The patient global impression of improvement (PGI-I) is a global index that may be used to rate the response of a condition to a therapy. It is a simple, direct, easy to use scale that is intuitively understandable to patients.

Secondary

At Visit 8 (week 4)

Events were recorded from the point at which the Informed Consent was signed until 7-10 days after the subject left the study. SAEs were followed until the event resolved or the event or sequelae stabilised.

Related AEs include those that were assessed as definitely, probably, possibly or unlikely related to IMP.

16.0

Oxycodone

Non-Oxy