Clinical Trials Register

Summary
EudraCT Number:	2015-004451-40
Sponsor's Protocol Code Number:	H15/02
National Competent Authority:	Czechia - SUKL
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2015-12-22
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Czechia - SUKL

A.2

EudraCT number

2015-004451-40

A.3

Full title of the trial

SATIVEX® AS ADD-ON THERAPY VS. FURTHER OPTIMIZED FIRST-LINE ANTISPASTICS

THE S A V A N T TRIAL

Sativex® jako přídatná léčba v porovnání s další optimalizovanou léčbou antispastiky první volby

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

SATIVEX® AS ADD-ON THERAPY VS. FURTHER OPTIMIZED FIRST-LINE ANTISPASTICS

A.3.2

Name or abbreviated title of the trial where available

SAVANT

A.4.1

Sponsor's protocol code number

H15/02

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Almirall Hermal GmbH
B.1.3.4	Country	Germany
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Almirall Hermal GmbH
B.4.2	Country	Germany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Almirall Hermal GmbH
B.5.2	Functional name of contact point	Andreas Prechtl
B.5.3	Address:
B.5.3.1	Street Address	Scholtzstraße 3
B.5.3.2	Town/ city	Reinbek
B.5.3.3	Post code	21465
B.5.3.4	Country	Germany
B.5.4	Telephone number	+4940727040
B.5.5	Fax number	+49407229296
B.5.6	E-mail	andreas.prechtl@almirall.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	SATIVEX
D.2.1.1.2	Name of the Marketing Authorisation holder	GW Pharma Ltd
D.2.1.2	Country which granted the Marketing Authorisation	European Union
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Oromucosal spray
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oromucosal use
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	Yes
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Oromucosal spray
D.8.4	Route of administration of the placebo	Oromucosal use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Moderate to severe spasticity due to MS (multiple sclerosis).

E.1.1.1

Medical condition in easily understood language

The patients with moderate to severe spasticity due to MS (multiple sclerosis).

E.1.1.2

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	19.0
E.1.2	Level	HLT
E.1.2	Classification code	10052785
E.1.2	Term	Multiple sclerosis acute and progressive
E.1.2	System Organ Class	100000004852

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The primary objective of this study is to evaluate the efficacy of Sativex (tetrahydrocannabinol [THC]:cannabidiol [CBD] oromucosal spray) as add-on therapy compared to further optimized standard antispastic therapy with oral baclofen and/or tizanidine and/or dantrolene (mono- or combination therapy) in patients with moderate to severe spasticity due to MS who have not gained adequate relief through 2 optimized standard antispastic drugs.

E.2.2

Secondary objectives of the trial

To evaluate the effect of Sativex on spasticity and associated symptoms in the study population.
To further characterize the safety and tolerability of Sativex in the study population.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1.Male or female patients of at least 18 years of age.
2.Diagnosis of MS (any form) for at least 12 months.
3.If the patient is taking disease modifying medication or antispastic drugs other than oral baclofen, tizanidine or dantrolene, this must be at a stable dose for 3 months prior to the screening visit.
4.Moderate to severe spasticity, defined as a score of 4 or more on the MS spasticity 0-10 NRS scale as scored by the patient at the screening visit (considering the previous week), despite optimized previous and current treatment.
5.Existing MS spasticity symptoms for at least 12 months.
6.Eligible for treatment with Sativex according to the current SPC.
7.Previous treatment with at least 2 different optimized oral MS spasticity therapies before inclusion, which must include at least 1 of oral baclofen or oral tizanidine (mono- or combination therapy).
8.Currently receiving optimized treatment with at least 1 oral antispastic drug (baclofen and/or tizanidine and/or dantrolene as mono- or combination therapy), that has been stable for at least 3 months prior to the screening visit. Despite optimization, the patient does not have adequate relief of spasticity symptoms. Optimization is defined as having reached the most efficacious and best tolerated dose according to the relevant SPCs. The treating physician and the patient must confirm that the current treatment has been optimized.
9.Able (physical ability or supportive person) to comply with the study preparations correctly and to follow the study procedure and restrictions.
10.Written informed consent.
Additional inclusion criterion for treatment in Phase A (at Visit 2):
11.Moderate to severe spasticity, defined as a mean score of 4 or more on the MS spasticity 0-10 NRS scale as scored by the patient on the day of Visit 2 and recorded in the patient diary for the 6 previous days (i.e. considering the patient’s spasticity over the previous week during the screening period).
Additional inclusion criteria for continuation into the wash-out phase (at Visit 3):
12. Sativex responder during Phase A, i.e. spasticity symptoms reduced during Phase A by at least 20% on the MS spasticity 0-10 NRS score compared to the Phase A baseline score (i.e., mean of scores at Visit 2 and the 6 previous days).
13.Patient received Sativex treatment during Phase A according to the SPC as add-on to optimized standard therapy, and can tolerate the treatment.
Additional inclusion criterion for randomization in Phase B (at Visit 4):
14.After the 1 to 4 weeks wash-out phase, patients whose Phase A-improvement in MS spasticity NRS score has been reduced by at least 80% (i.e., mean of scores at Visit 4 and the 2 consecutive previous days).

E.4

Principal exclusion criteria

1.Contraindication to treatment with Sativex (according to the SPC).
2.Previous administration of Sativex.
3.Current consumption of cannabis herb or taking other cannabinoid-based drugs within 30 days prior to study entry, and/or unwillingness to avoid consumption over the study period.
4.Treatment with botulinum toxin injection for the relief of spasticity from within 6 months prior to the screening visit.
5.Any medical history or family history of schizophrenia, other psychotic disorders, severe personality disorder or other significant psychiatric disorder other than depression, which is associated with the underlying disease MS.
6.Current use of illegal drugs, non-prescribed, or off-label prescription drugs. A qualitative urine test for TCH will be performed at screening and after wash-out.
7.Any known or suspected history of a dependence disorder or current heavy alcohol consumption in the opinion of the investigator, and according to local guidelines.
8.Any known or suspected hypersensitivity to cannabinoids or any of the excipients of the involved IMPs.
9.Any concomitant disease or disorder (such as poorly controlled epilepsy or seizures) that may influence the patient’s level of cognition or mood.
10.Female patients of child bearing potential and male patients whose partner is of child bearing potential, unless willing to ensure that they or their partner use effective contraception during the study and for 3 months thereafter. A female is considered to be of childbearing potential unless she has had a hysterectomy, is at least 1 year post-menopausal or has undergone tubal ligation.
11.Female patient who is pregnant, lactating or planning pregnancy during the course of the study and for 3 months thereafter.
12.Concurrent participation in another clinical study or participation in another clinical study within 12 weeks prior to the screening visit.
13.History of myocardial infarction or clinically significant cardiac dysfunction within the last 12 months, or has a cardiac disorder which, in the opinion of the investigator, would put the patient at risk of a clinically significant arrhythmia or myocardial infarction.
14.Has known clinically significant impaired renal function or impaired hepatic function at baseline.
15.Any other significant disease or disorder which, in the opinion of the investigator, may either put the patient at risk because of participation in the study, may influence the result of the study, or the patient’s ability to participate in the study.

E.5 End points

E.5.1

Primary end point(s)

Responder selection for the primary endpoint (30% NRS spasticity improvement) will be based on the comparison at Visit 4 (mean of NRS at the day of Visit 4 and the 2 previous days) and Visit 7 (mean of NRS at the day of visit 7 and the 6 previous days).

E.5.1.1

Timepoint(s) of evaluation of this end point

12 weeks

E.5.2

Secondary end point(s)

The secondary efficacy variables are measurements of spasticity and associated symptoms during the randomized treatment period (Phase B):
Percentage of patients who achieve an improvement from Phase B baseline in MS spasticity 0-10 NRS score of ≥30% (CID) after 4 and 8 weeks of treatment.
Percentage of patients who achieve an improvement from Phase B baseline in MS spasticity 0-10 NRS score of ≥18% (MCID) after 4, 8 and 12 weeks of treatment.
Change from Phase B baseline in the MS spasticity score (0-10 NRS) after 4, 8 and 12 weeks of treatment.
Change from Phase B baseline in the frequency and severity of spasm (mild, moderate, severe) after 4, 8 and 12 weeks of treatment.
Change from Phase B baseline in sleep disruption (0-10 NRS) after 4, 8 and 12 weeks of treatment.
Change from Phase B baseline in the spasticity modified Ashworth scale after 4, 8 and 12 weeks of treatment.
Change from Phase B baseline in EDSS score after 4, 8 and 12 weeks of treatment.
Change from Phase B baseline in the Barthel ADL index after 4, 8 and 12 weeks of treatment.
Percentage of patients who achieve the MCID improvement from Phase B baseline in Barthel ADL index after 4, 8 and 12 weeks of treatment.
Change from Phase B baseline in SF-36 scores after 4, 8 and 12 weeks of treatment.
Percentage of patients with an MCID improvement from Phase B baseline in SF-36 QoL scores after 4, 8 and 12 weeks of treatment. A reduction of 7.8 points in bodily pain and 3.3 points in physical function NRS scores represent MCIDs for the patient [50].
Change from Phase B baseline in global assessment of clinical change by the patient (SGIC), and the doctor (PGIC) (7-item categorical scales) after 4, 8 and 12 weeks of randomized treatment.
Percentage of patients with an MCID improvement from Phase B baseline in SCIG and PGIC after 4, 8 and 12 weeks of treatment (responder analysis).
Change from Phase B baseline in pain (0-10 NRS) after 4, 8 and 12 weeks of treatment.
Percentage of patients with an MCID improvement in pain (0-10 NRS) after 4, 8 and 12 weeks of treatment in Phase B. A reduction of 1 point or 15.0% in the NRS represents an MCID for the patient [51].
Change from Phase B baseline in timed 10 m walk test, after 4, 8 and 12 weeks of treatment.
Changes in concomitant/underlying antispastic standard therapy.

E.5.2.1

Timepoint(s) of evaluation of this end point

Not applicable

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

Yes

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

Yes

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

Phase A-single blind, Phase B-double blind

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LPLV

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

180

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

200

F.4.2

For a multinational trial

F.4.2.1

In the EEA

228

F.4.2.2

In the whole clinical trial

228

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

None

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2016-02-17

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-01-13

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2017-05-23

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