Effect of Physical ACtivity in Fingolimod Treated patiEnts (PACE) With Relapsing-remitting Multiple Sclerosis (PACE)

• ClinicalTrials.gov Identifier: NCT01490840
• Recruitment Status: Terminated
• First Posted: December 13, 2011
• Results First Posted: May 12, 2016
• Last Update Posted: May 12, 2016
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Study Description

Brief Summary:

This study evaluated the effect of an individualized web-based physical training in fingolimod -treated patients.

Condition or disease	Intervention/treatment	Phase
Fatigue in Multiple Sclerosis	Other: Physical exercise	Phase 4

Detailed Description:

In this study, it was planned to randomize 226 participants. However, only 178 participants were randomized during a timeframe of 2 years and 8 months. Therefore, the study was terminated due to slow enrollment and low participant compliance to the physical training schedule.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 178 participants
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A 6-month, Multicenter, Randomized, Controlled Parallel Group Study to Evaluate the Effect of Physical Training on Fatigue in Patients With Relapsing-remitting Multiple Sclerosis Treated With Fingolimod, Followed by a 6 Month Optional Extension Phase
• Study Start Date: November 2011
• Actual Primary Completion Date: July 2014
• Actual Study Completion Date: July 2014

Arms and Interventions

Arm	Intervention/treatment
Experimental: E-training; Fingolimod as baseline immunomodulatory multiple sclerosis treatment was prescribed as per clinical practice. During phase 1, participants randomized to this arm had an introductory group session, hosted by a sports therapist. The individual training schedule was comprised of strength exercises twice a week for 30-45 minutes and endurance training once a week for 20-60 minutes for 6 months. The participants documented each training session thoroughly via the web-based application (duration, type of exercises, number of repetitions and sets, perceived exertion). A standard course of corticosteroids (methylprednisolone) on an inpatient or outpatient basis was allowed for treatment of relapses as clinically warranted. Steroid treatment consisted of 3-5 days and up to 1,000 mg methylprednisolone/day. After 6 months, Phase 2, the same Phase 1 regimen applied.	Other: Physical exercise; Strength training exercises are performed against own body weight or with training aids like elastic rubber bands or gym balls. All exercises are home-based. To increase balance and core stability, a subset of exercises is performed on shaky ground and/or one-legged. Exercise intensity, duration and frequency are individually assigned by a sports therapist. For each muscle group, a set of exercises of increasing difficulty allows for individual and progressive training adaption. Therapists can choose from an exercise database of approximately 150 different strength exercises with different graduation.
Experimental: Waiting; Fingolimod as baseline immunomodulatory multiple sclerosis treatment is prescribed as per clinical practice. During Phase 1, participants randomized to this arm did not receive e-training exercise. After a 6 months waiting period, phase 2, participants had an introductory group session, hosted by a sports therapist. The individual training schedule was comprised of strength exercises twice a week for 30-45 minutes and endurance training once a week for 20-60 minutes for 6 months. The participants documented each training session thoroughly via the web-based application (duration, type of exercises, number of repetitions and sets, perceived exertion). A standard course of corticosteroids (methylprednisolone) on an inpatient or outpatient basis was allowed for treatment of relapses as clinically warranted. Steroid treatment consisted of 3-5 days and up to 1,000 mg methylprednisolone/day.	Other: Physical exercise; Strength training exercises are performed against own body weight or with training aids like elastic rubber bands or gym balls. All exercises are home-based. To increase balance and core stability, a subset of exercises is performed on shaky ground and/or one-legged. Exercise intensity, duration and frequency are individually assigned by a sports therapist. For each muscle group, a set of exercises of increasing difficulty allows for individual and progressive training adaption. Therapists can choose from an exercise database of approximately 150 different strength exercises with different graduation.

Outcome Measures

Primary Outcome Measures :

1. Change From Baseline in Fatigue as Measured by the Modified Fatigue Impact Scale (mFIS ). [ Time Frame: Baseline, 6 months ]
   The mFIS provides an assessment of the effects of fatigue in terms of physical, cognitive, and psychosocial functioning. It is a 21-item, structured, self-report questionnaire that generally can be completed with little or no intervention from an interviewer. The mFIS score ranged from 0 (not tired) to 84 (tired). A negative change from baseline indicates improvement.

Secondary Outcome Measures :

1. Change From Baseline in Isometric and Dynamic Muscular Strength as Measured by Sit-to-stand Test [ Time Frame: baseline, 6 months ]
   The Sit to Stand Test is a functional outcome measure of the lower-extremity muscle power. The test was performed 3 times with one minute rest in between. The best attempt out of three was used for the analysis. A positive change from baseline indicates improvement.
2. Change From Baseline in Isometric and Dynamic Muscular Strength as Measured by Change in Leg Strength and Trunk Strength [ Time Frame: baseline, 6 months ]

   Isometric and dynamic muscular strength was measured by an Isomed 2000 isometric measurement device (knee flexion/tension, trunk flexion/extension).

   Isomed 2000 device measures muscular flexion and tension under standardized training conditions. A positive change from baseline indicates improvement.

3. Change From Baseline in Isometric and Dynamic Muscular Strength as Measured by Leg Strength Endurance [ Time Frame: baseline, 6 months ]

   Isometric and dynamic muscular strength was measured by an Isomed 2000 isometric measurement device (knee flexion/tension, trunk flexion/extension).

   Isomed 2000 device measures muscular flexion and tension under standardized training conditions. A positive change from baseline indicates improvement.

4. Change From Baseline in Quality of Life as Measured by the Hamburg Quality of Life Questionnaire in Multiple Sclerosis (HAQUAMS) [ Time Frame: Baseline, 6 months, 12 months ]
   The Hamburg Quality of Life Questionnaire in Multiple Sclerosis (HAQUAMS) consists of 44 items, 28 of which are the basis for computation of five subscale scores reflecting major dimensions of health-related quality of life (HRQoL) in MS: Fatigue/Thinking (4 items), Mobility lower limb (5 items), Mobility upper limb (5 items), Social function (6 items) and Mood (eight items). Subscales and total score range from 1 to 5, with high scores indicating a lower quality of life. In this study, the total score and following 3 subscales: fatigue/thinking, mobility lower limb and mobility upper limb only were analyzed. A negative change from baseline indicates improvement.
5. Change From Baseline in Fatigue as Measured by the WEIMuS (Würzburg Fatigue Inventory for MS) [ Time Frame: Baseline, 6 months ]
   The WEIMuS (Würzburg Fatigue Inventory for MS) scale is a validated self-assessment instrument to quantify the degree of fatigue. The scale consists of 17 items with 5 categories that are scored from '0' to '4'. The subscores for cognitive and physical fatigue range from 0 to 36 and from 0 to 32, respectively, with the total sum score ranging from 0 to 68; higher scores indicate higher degrees of fatigue. A negative change from baseline indicates improvement.
6. Change From Baseline in Depression as Measured by the Beck Depression Inventory Second Edition (BDI-II) [ Time Frame: Baseline, 6 months ]
   The Beck Depression Inventory Second Edition (BDI-II) is a 21-item self-report instrument intended to assess the existence and severity of symptoms of depression as listed in the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders Fourth Edition. Each of the 21 items corresponding to a symptom of depression is summed to give a single score for the BDI-II. There is a four-point scale for each item ranging from 0 to 3. The total score ranges from 0 - 63. Total score of 0-13 is considered minimal range, 14-19 is mild, 20-28 is moderate, and 29-63 is severe. A negative change from baseline indicates improvement.
7. Change From Baseline in Aerobic Capacity (VO2max) as Measured by a Physical Endurance Spiroergometry on a Treadmill [ Time Frame: Baseline, 6 months ]
   Physical endurance spiroergometry was accomplished. Ergometry was assessed according to national guidelines of the German society for sports medicine. Ergometry is a combined examination of circulation and lung function and was performed as a submaximal or maximal test depending on the participant's individual performance. A negative change from baseline indicates improvement.
8. Change From Baseline in Peak Expiratory Flow as Measured by a Physical Endurance Spiroergometry on a Treadmill [ Time Frame: Baseline, 6 months ]
   Physical endurance spiroergometry was accomplished. Ergometry was assessed according to national guidelines of the German society for sports medicine. Ergometry is a combined examination of circulation and lung function and was performed as a submaximal or maximal test depending on the participant's individual performance. A positive change from baseline indicates improvement.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 65 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Subjects with relapsing remitting MS defined by 2010 revised McDonald criteria
• Patients with Expanded Disability Status Scale (EDSS) score of 0-3.5 (including)
• Immunomodulatory treatment with prescribed fingolimod for at least one month prior to baseline
• Fatigue score assessed by mFIS of equal or greater than 14 at screening
• Neurologically stable with no evidence of relapse within 30 days prior to inclusion date

Exclusion Criteria:

• Patients who have been treated with:

  • systemic corticosteroids or immunoglobulins within 1 month prior to randomization;
  • immunosuppressive medications such as azathioprine, cyclophosphamide, or methotrexate within 3 months prior to randomization;
  • monoclonal antibodies (including natalizumab) within 3 months prior to randomization;
  • mitoxantrone within 6 months prior to randomization
  • cladribine at any time.
• Patients with any medically unstable condition, as assessed by the primary treating physician at each site.

• Patients with any of the following cardiovascular conditions :

  • history of cardiac arrest;
  • history of myocardial infarction or with current unstable ischemic heart disease;
  • history of angina pectoris due to coronary spasm or history of Raynaud syndrome
  • Heart failure (NYHA III-IV) or any severe cardiac disease as determined by the investigator;
  • history or presence of a second-degree AV block, Type II or a third-degree AV
  • block
  • patients receiving Class Ia (ajmaline, disopyramide, procainamide, quinidine) or
  • III antiarrhythmic drugs (e.g., amiodarone, bretylium, sotalol, ibulitide, azimilide,
  • dofelitide);
  • proven history of sick sinus syndrome or sino-atrial heart block;
  • uncontrolled hypertension
• Clinically relevant internal disease (e.g. uncorrected anemia) or orthopedic diseases (e.g. scoliosis) that might interfere with physical training
• Any severe disability or clinical impairment that can prevent the patient to meet all study requirements at the investigator's discretion

Other protocol-defined inclusion/exclusion criteria may apply.

Contacts and Locations

Locations

Germany

Novartis Investigative Site

Aachen, Germany, 52062

Novartis Investigative Site

Alzenau, Germany, 63755

Novartis Investigative Site

Aschaffenburg, Germany, 63739

Novartis Investigative Site

Bad Mergentheim, Germany, 97980

Novartis Investigative Site

Bamberg, Germany, 96052

Novartis Investigative Site

Bayreuth, Germany, 95445

Novartis Investigative Site

Berlin, Germany, 10437

Novartis Investigative Site

Berlin, Germany, 10625

Novartis Investigative Site

Berlin, Germany, 10691

Novartis Investigative Site

Berlin, Germany, 12587

Novartis Investigative Site

Berlin, Germany, 13347

Novartis Investigative Site

Bielefeld, Germany, 33647

Novartis Investigative Site

Bochum, Germany, 44787

Novartis Investigative Site

Böblingen, Germany, 71032

Novartis Investigative Site

Dortmund, Germany, 44135

Novartis Investigative Site

Erbach, Germany, 64711

Novartis Investigative Site

Erlangen, Germany, 91054

Novartis Investigative Site

Frankfurt, Germany, 65929

Novartis Investigative Site

Hamburg, Germany, 22179

Novartis Investigative Site

Heidelberg, Germany, 69120

Novartis Investigative Site

Jena, Germany, 07740

Novartis Investigative Site

Kassel, Germany, 34121

Novartis Investigative Site

Leipzig, Germany, 04299

Novartis Investigative Site

Potsdam, Germany, 14471

Novartis Investigative Site

Prien, Germany, 83209

Novartis Investigative Site

Regensburg, Germany, 93053

Novartis Investigative Site

Siegen, Germany, 57076

Novartis Investigative Site

Sinsheim, Germany, 74889

Novartis Investigative Site

Stuttgart, Germany, 70174

Novartis Investigative Site

Stuttgart, Germany, 70178

Novartis Investigative Site

Teupitz, Germany, 15755

Novartis Investigative Site

Unterhaching, Germany, 82008

Sponsors and Collaborators

Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals; Novartis Pharmaceuticals

More Information

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

Mäurer M, Schuh K, Seibert S, Baier M, Hentschke C, Streber R, Tallner A, Pfeifer K. A randomized study to evaluate the effect of exercise on fatigue in people with relapsing-remitting multiple sclerosis treated with fingolimod. Mult Scler J Exp Transl Clin. 2018 Feb 14;4(1):2055217318756688. doi: 10.1177/2055217318756688. eCollection 2018 Jan-Mar.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT01490840
• Other Study ID Numbers: CFTY720DDE07; 2011-002969-38 ( EudraCT Number )
• First Posted: December 13, 2011
• Results First Posted: May 12, 2016
• Last Update Posted: May 12, 2016
• Last Verified: April 2016

Keywords provided by Novartis ( Novartis Pharmaceuticals ):

Fatigue; MS; Multiple Sclerosis; Exercise; Physical activity; Physical training; Fingolimod

Additional relevant MeSH terms:

Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Sclerosis; Fatigue; Pathologic Processes; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Nervous System Diseases; Demyelinating Diseases; Autoimmune Diseases; Immune System Diseases