ESTEVE-SIGM-202

Laboratorios Dr. Esteve. S.A. (ESTEVE)

Avda. Mare de Déu de Montserrat, 221, Barcelona, Spain, 08041

Study Medical Monitor, Laboratorios del Dr. Esteve S.A., +34 934466000, svidela@esteve.es

Study Medical Monitor, Laboratorios del Dr. Esteve S.A., +34 934466000, svidela@esteve.es

No

No

No

Final

17 Dec 2015

Yes

23 Dec 2014

Yes

23 Dec 2014

No

-To establish the efficacy of E-52862 to reduce the incidence and the severity of OXL-induced chronic neuropathy in patients treated for colorectal cancer. -To explore the efficacy of E-52862 to reduce the severity and duration of OXL-induced acute neuropathy. -To evaluate whether E-52862 can raise the cumulative total dose of OXL than can be delivered without dose-limiting chronic neuropathy. -To explore the incidence of dose-reduction, dose-delays and discontinuation of oxaliplatin due to symptomatic neuropathy grade 3 or 4. -To explore the incidence of adverse events by severity, of serious adverse events, of adverse events leading to E 52862 discontinuation and of adverse events related to E-52862 by severity. -To assess E-52862 plasma exposure associated with the treatment.

The study will be conducted in compliance with the protocol, regulatory requirements, good clinical practice (GCP) and the ethical principles of the latest revision of the Declaration of Helsinki as adopted by the World Medical Association.

27 Sep 2012

No

No

Greece: 48

Spain: 59

Italy: 14

121

121

0

0

0

0

0

0

67

54

0

Overall Trial (overall period)

Randomised - controlled

Yes

E-52862

Capsule

Oral use

400 mg oral single daily administration during the first 5 days of every chemotherapy cycle, starting the day before the cycle, up to a maximum of 12 cycles of OXA

Placebo

Capsule

Oral use

Placebo oral single daily administration during the first 5 days of every chemotherapy cycle, starting the day before the cycle, up to a maximum of 12 cycles of OXA

Overall Trial (overall period)

E-52862

Control

Full analysis set expanded

Patients who were randomized to treatment and received at least one dose of study medication and who had a postbaseline assessment of the quantitative sensory testing of thermal sensitivity.

Full analysis set

Patients who were randomized to treatment and received at least one dose of study medication and who had baseline and at least one postbaseline (after at least 4 cycles) TNS assessment

Quantitaive Sensory Testing (QST) parameter: Temperature at which the patient reports that the thermal stimulus is firstly perceived as painful during the progressive reduction of the temperature from the neutral value. - Full analysis set expanded -

Primary

Quantitaive Sensory Testing (QST) Pre-cycle assesments performed at 7 timepoints (baseline, pre-cycle cycle 2, pre-cycle cycle 4, pre-cycle cycle 8, pre-cycle cycle 10, pre-cycle cycle 12 and follow-up visits).

The values recorded at each cycle were compared between study arms using an analysis for repeated observations based on the maximum or restricted maximum likelihood-based linear mixed model for longitudinal data. All models included the fixed categorical effects of treatment, visit (time points measured), site, the continuous fixed covariate of baseline score, and the patient-nested-within-site blocks as random factor.

E-52862 v Control

114

Pre-specified

Quantitaive Sensory Testing (QST) parameter: Temperature at which the patient reports that the thermal stimulus is firstly perceived as painful during the progressive reduction of the temperature from the neutral value. - Full analysis set expanded -

Primary

Quantitaive Sensory Testing (QST) Post-cycle assesments performed at 7 timepoints (baseline, post-cycle cycle 2, post-cycle cycle 4, post-cycle cycle 8, post-cycle cycle 10, post-cycle cycle 12 and follow-up visits).

The values recorded at each cycle were compared between study arms using an analysis for repeated observations based on the maximum or restricted maximum likelihood-based linear mixed model for longitudinal data. All models included the fixed categorical effects of treatment, visit (time points measured), site, the continuous fixed covariate of baseline score, and the patient-nested-within-site blocks as random factor

E-52862 v Control

119

Pre-specified

Quantitaive Sensory Testing (QST) parameter: To determine the pain evoked by a suprathreshold cold stimulus, a constant temperature stimulus was applied. The method started with the thermode at a neutral temperature of 32ºC until the patient reported a neutral thermal sensation. Then, it was cooled progressively at a rate of −1.5ºC/s until it reached the suprathreshold temperature, previously determinated for each patient, which was maintained for 5 seconds. After that time, the patient evaluated the intensity of the evoked pain using an 11-point numerical rating scale.

Primary

Quantitaive Sensory Testing (QST) Pre-cycle assesments performed at 7 timepoints (baseline, pre-cycle cycle 2, pre-cycle cycle 4, pre-cycle cycle 8, pre-cycle cycle 10, pre-cycle cycle 12 and follow-up visits).

The values recorded at each cycle were compared between study arms using an analysis for repeated observations based on the maximum or restricted maximum likelihood-based linear mixed model for longitudinal data. All models included the fixed categorical effects of treatment, visit (time points measured), site, the continuous fixed covariate of baseline score, and the patient-nested-within-site blocks as random factor.

E-52862 v Control

114

Pre-specified

Quantitaive Sensory Testing (QST) parameter: To determine the pain evoked by a suprathreshold cold stimulus, a constant temperature stimulus was applied. The method started with the thermode at a neutral temperature of 32ºC until the patient reported a neutral thermal sensation. Then, it was cooled progressively at a rate of −1.5ºC/s until it reached the suprathreshold temperature, previously determinated for each patient, which was maintained for 5 seconds. After that time, the patient evaluated the intensity of the evoked pain using an 11-point numerical rating scale.

Primary

Quantitaive Sensory Testing (QST) Post-cycle assesments performed at 7 timepoints (baseline, post-cycle cycle 2, post-cycle cycle 4, post-cycle cycle 8, post-cycle cycle 10, post-cycle cycle 12 and follow-up visits).

The values recorded at each cycle were compared between study arms using an analysis for repeated observations based on the maximum or restricted maximum likelihood-based linear mixed model for longitudinal data. All models included the fixed categorical effects of treatment, visit (time points measured), site, the continuous fixed covariate of baseline score, and the patient-nested-within-site blocks as random factor.

E-52862 v Control

119

Pre-specified

The TNS is a composite measure of peripheral nerve function that combines subjective and objective information obtained from grading of symptoms, signs, nerveconduction studies and quantitative sensory testing. The 7 ‘clinical’ ítems included were: Sensory symptoms, Motor symptoms, Autonomic symptoms, Pin sensitivity, Vibration sensitivity, Strength and Deep tendon reflexes.

Primary

TNS assessments performed at 6 timepoints (baseline, cycle 4, cycle 8, cycle 10, cycle 12 and follow-up visits).

The values recorded at each cycle were compared between study arms using an analysis for repeated observations based on the maximum or restricted maximum likelihood-based linear mixed model for longitudinal data. All models included the fixed categorical effects of treatment, visit (time points measured), site, the continuous fixed covariate of baseline score, and the patient-nested-within-site blocks as random factor

E-52862 v Control

107

Pre-specified

The grade of treatment-associated neuropathy in the form of peripheral sensory neuropathy was assessed with the 4th version of the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) of the US Cancer Institute. Severe neuropathy is defined as NCI-CTCAE grade ≥3 toxicity at any time during chemotherapy. Patients with an UNKNOWN value in the following tables are those patients whose NCI-CTCAE assessment is not available at end of treatment cycle (cycle 12 or previous if the patient withdrew the study) and whose previous scheduled NCI-CTCAE assessments were <3). They are excluded from the analysis.

Primary

Assessments obtained at the screening visit, at pre-cycle visits of cycles 2, 4, 8, 10 and 12 (or at the end of chemotherapy, whichever is first), and at the follow-up visit.

Patients with an UNKNOWN value are excluded from the analysis

E-52862 v Control

68

Post-hoc

AEs will be collected from the time of signing the informed consent to the completion of the clinical study (including the follow up visit) or premature patient discontinuation from the clinical study.

Treatment Emergent Adverse Event are displayed. The AEs that occurred after the first IMP intake are going to be considered as treatment emergent AEs (TEAEs) either serious or not.

17.1

E-52862

Placebo