Communication, Coordination, and Security for People With Multiple Sclerosis (COCOS-MS)

A randomized, phase II trial of cross-sectoral care and case management

Background: People with severe multiple sclerosis (PsMS) have multidimensional, complex needs. COCOS-MS is an exploratory study of the effect of cross-sectoral care and case management (CCM) on these patients’ quality of life, palliative care needs, and psychological distress, as well as caregivers’ burden.

Methods: We conducted a randomized, controlled, phase II trial (DRKS00022771) with two parallel treatment arms: standard care versus CCM in addition to standard care over a 12-month period. A trial-specific CCM manual was used. The target variables were recorded in standardized fashion at baseline (T0) and every three months thereafter (T1 until the end of the intervention at T4, then T5 three months after the end of the intervention to determine sustainability). The primary endpoint was the change in the patients’ quality of life (HALEMS) from baseline to month 12 in a group comparison. A modified intention-to-treat (mITT) was performed based on a mixed linear model with repeated measures over time (ARH1-structured covariance matrix). Values of p less than 0.05 were considered significant.

Results: 80 PsMS were randomly assigned 1:1 to one of the two treatment arms (male: female 1:2, median age 55 years [IQR 49–62], EDSS 6.5 [6–7.5], dropout rate 10%). There was no significant improvement in HALEMS after one year (T4) in the group comparison (−0.08 [−0.31, 0.15], p = 0.503; NNT = 22). Secondary endpoints such as subjective health status, psychological distress, and palliative care needs showed a clear response at the end of the intervention. After the intervention ended, the values approached the baseline level.

Conclusion: The primary endpoint did not reach significance in this health services research feasibility study. For further development of the study design, the focus will be on the psychological and palliative factors in which PsMS—a reference group for long-term neurological conditions—were found to benefit from the CCM.

Cite this as: Golla H, Dunkl V, Dorr A, Goereci Y, Hebben F, Müller W, Dillen K, Civello D, Müller D, Stahmann A, Voltz R, Löcherbach P, Fink GR, Hellmich M, Warnke C, on behalf of the KOKOS-MS Study Group: Communication, coordination, and security for people with multiple sclerosis (COCOS-MS): A randomized, phase II trial of cross-sectoral care and case management. Dtsch Arztebl Int 2025; 122: 489–94. DOI: 10.3238/arztebl.m2025.0097

Multiple sclerosis (MS) is one of the leading neurological disorders contributing to disease burden from disability and death in young adults—as measured in disability-adjusted life years (1). People with severe MS (PsMS) have limited capacity in certain functional areas such as physical, neuropsychological, mental, and social domains. Both patients and their caregivers (CG) develop complex needs as a result. These issues have an impact on the coordination and management of daily life, including dealing with social and health-related services, and can range from monitoring disease-specific therapies to receiving palliative care. Also of importance are personality-related domains involving the understanding of social roles, biography, and participation (2, 3, 4). This complex situation is the reason why care of PsMS is delivered by a variety of different health and social service providers who often act, however, in an uncoordinated fashion and independently of each other (4, 5). Furthermore, those affected need information about the often vast array of services offered by the health, social, and pension (insurance) systems, about the illness itself, and about its treatment and symptomatic care options (6, 7, 8, 9, 10, 11). A cross-sectoral, long-term, social advocacy-based form of care and case management (CCM) provides the necessary process controls (3, 4, 10, 12) at an individual level across the different domains of life (case management) (13, 14, 15). At a higher level, CCM acts as an informant and coordinator between the involved organizational structures. It is useful for identifying and reducing any existing gaps in healthcare provision (care management). So far, no CCM for PsMS has been studied across sectors and over a longer period. PsMS rarely appear in treatment networks because they are often no longer capable of accessing them unassisted (11, 16). COCOS-MS (Communication, Coordination and Security for People with Multiple Sclerosis) is an exploratory, randomized, controlled, phase II clinical trial with two parallel treatment arms. It is sponsored by the Innovation Fund of the Federal Joint Committee (G-BA) (FKZ 01VSF19029, period of sponsorship 15.08.2020–14.08.2024), explores this type of CCM as a complex intervention, and assesses its impact on PsMS and their CG (17).

Methods

Study conduct

Under the direction of the Department of Palliative Medicine and the Department of Neurology at Cologne University Hospital, PsMS were recruited from the district of Cologne (4.54 million inhabitants, urban and rural regions). Partner institutions and organizations that referred patients for inclusion in the study comprised outpatient and inpatient neurological institutions in Cologne, the MS registry of the German Multiple Sclerosis Society (DMSG), and the local DMSG group in Cologne.

The study included particularly vulnerable MS patients, i.e., those with a higher disease-related level of disability (as rated by the Expanded Disability Status Scale [EDSS] [17]), with primary or secondary progressive MS, and/or those of advanced age. Two subgroups were subsequently formed, of which one comprised two subsets:

• Subgroup 1: patients with highly active MS with an indication for an escalating immunotherapeutic agent (alemtuzumab, ocrelizumab, rituximab, ofatumumab, natalizumab, fingolimod, siponimod, ozanimod, or cladribine) and one of the following criteria:
• age ≥ 50 years and/or
• EDSS ≥ 5.0.
• Subgroup 2: patients with primary or secondary progressive MS and
• Subset a: moderate disability (EDSS 4–7), but with no immunotherapy treatment options or
• Subset b: severe disability (EDSS > 7.0) with or without an immunotherapy treatment option.

The control group received standard care, while the intervention group received the trial-specific CCM intervention in addition to standard care. Using internet-based software (ALEA; FormsVision BV, Abcoude, The Netherlands), study participants were randomly assigned either to the control group (standard care) or to the intervention group (standard care plus CCM), stratified according to subgroup (1, 2a, 2b) and in equal proportions.

The study received a positive opinion from the Ethics Committee of the Medical Faculty of Cologne University (20–1086) and was conducted according to the principles of the Declaration of Helsinki. Registration (DRKS00022771) was submitted prior to commencing the trial.

CCM intervention

The twelve-month CCM intervention was conducted in accordance with a trial-specific CCM manual which incorporated the patients’ multidimensional needs in the life domains “physical health”, “mental health”, “self-sufficiency”, “social situation and participation” (15). The CCM visits were scheduled on a weekly basis: once a month face-to-face (wherever the PsMS happened to be at the particular time, for example, at home), and also virtually (video conference) as an exception during the COVID-19 pandemic, and by telephone in the intervening weeks. A detailed resource and problem analysis was conducted during the initial face-to-face CCM contact to identify the patient’s individual needs. Based on this and in consultation with the study participants, a care and management plan was developed in accordance with the individual goals and assigned interventions, (e.g., relocation to a barrier-free apartment, implementation of rehabilitation measures). This was re-evaluated on a monthly basis and adjusted as required. Finally, CCM staff and study participants jointly assessed achievement of the target agreements (case management) (18). Relevant service providers (for example, public authorities, health insurances companies) and health care providers (for example, doctors and therapists [physiotherapy, occupational therapy, logopedic therapy]) as well as suppliers of assistive devices were contacted, coordinated, and incorporated into the care system (care management). If it was not possible to solve certain issues (for example, due to absence of barrier-free medical practices or outreach therapists, including psychotherapists), then these were recorded as care gaps in the portfolio compiled as part of the study (17, 18).

Outcome measurements

Target variables were recorded face-to-face with the study participants by blinded trial staff (randomization outcome not known) in standardized fashion at baseline (T0) and every three months thereafter (T1 until the end of the 12-month intervention at T4, then T5 three months after the end of the intervention to determine sustainability); some of the visits were conducted virtually (video conference) during the COVID-19 pandemic. The HALEMS questionnaire is the German version of the Hamburg Quality of Life Questionnaire for Multiple Sclerosis (HAQUAMS). It has a scoring range of one to five and was used to assess the primary endpoint. Here, a mean value is calculated from six subscores, which are based on a total of 29 items, each of which is rated on a five-point Likert scale (19). The change in the HALEMS total score from baseline (T0) to month 12 (T4) was defined as the primary endpoint, comparing the difference in mean changes between the groups. Prespecified secondary endpoints in the trial protocol (17) were:

• change in patients’ quality of life from baseline to T1 to T3 and T5 as well as the HALEMS subscales over time,
• the emergence of palliative care needs (Integrated Palliative Outcome Scale [IPOS], Questions 3 to 9 and IPOS-Neuro-S8 [20, 21]),
• the development of mental symptoms, as measured with the Hospital Anxiety and Depression Scale (HADS, with subscales for anxiety [HADS-A] and depression [HADS-D]) (22, 23, 24), as well as
• the burden on CG as rated using the short version of the Zarit Burden interview (ZBI-12) (25, 26),
• and the CG’s quality of life, as measured with the SF-12 (27),

each over time.

The database was developed using the Software TrialMaster 5.0 (anju Corp., Brussels, Belgium). The Clinical Trials Center (ZKS) of the University of Cologne was responsible for database management, elements of project management, and trial monitoring.

Statistical analysis

Eighty patients (40 per group) are needed to detect an effect size of 0.5 (standardized mean difference) with a power of 80%, a two-tailed type 1 error rate of 5%, a baseline correlation of 0.5, and a maximum drop-out rate of 40% (17). This effect size corresponds to a clinically relevant minimal important difference (MID) of 0.38 points in the HALEMS total score. The association between the IPOS-Neuro-S8 and HALEMS produces an MID of 2.5 (20). The literature states an MID of 1.17 for the HADS total score (1.40 for HADS-D and 1.32 for HADS-A) (28). We defined that an answer to HALEMS Question 1 (“How would you rate your current state of health in comparison with the situation a year ago?”) of “significantly better/much better/better” was a clinically relevant response for calculating the effect sizes “number needed to treat” (NNT) and “absolute risk reduction” (ARR). The statistical evaluation included all data for patients who had completed a valid baseline visit and at least one valid follow-up visit (modified intention-to-treat principle [mITT]). The data was subjected to a linear mixed model repeated measure (MMRM) analysis over time, using an ARH1 structured covariance matrix and including the fixed effects: baseline score, treatment, sex, and subgroup. All statistical calculations were performed using SPSS Statistics 28 (IBM Corp., Armonk, NY, USA). ARR and NNT were calculated for the time point T4 (end of the intervention). Two individual IPOS questions (numbers 8 and 9) were analyzed post-hoc over time.

Expert workshop

At the end of the trial, initial results were presented to experts during a one-day workshop and then discussed with them in panel discussions before deriving recommendations for action.

Results

Study progression and sociodemographic features

Eighty-one patients were screened during the period 01/2021 to 01/2022. Of these, 80 were included and randomly assigned in a ratio of 1 : 1. Another twelve applicants could not be considered anymore. The characteristics of the trial participants in the mITT data set at baseline (T0) show that patients with severe MS were indeed recruited (males : females = 1 : 2, median age 55 years [IQR = 49–62]; EDSS = 6.5, [IQR = 6–7.5]). The drop-out rate of 10% was lower than expected (40%). One PsMS from each study arm died unconnected with their participation in the trial (eFigure 1, eTable 1a).

eFigure 1

Study participant flow chart

eTable 1a

Sociodemographic data of participating patients (mITT data set)

Validated outcome measurements

Participation in the outcome measurements was 91.7% (intervention group 96.7%, control group 86.9%). In compliance with the trial protocol, 77 patients (37 in the control group, 40 in the intervention group) were included in the evaluation, while three patients withdrew immediately after the T0 assessment (eFigure 1, eTable 1a).

HALEMS

The HALEMS total score showed no significant difference between the two study arms in the baseline-adjusted mITT analysis after twelve months (−0.08 [−0.31; 0.15], p = 0.503) (primary endpoint). There was a response rate of 31.5% in the HALEMS total score at time point T4, the ARR was 4.5% and the NNT 22. The mITT analysis of the answer to HALEMS Question 1 regarding the self-assessed general state of health, which is not reflected in the HALEMS total score, yielded a group difference in favor of the intervention group after twelve months (−0.97 [−1.58; –0.36], p = 0.002). Here, the ARR was 22.5% and the NNT 4 (Table, Figure a and b, eTable 2).

Figure

Selected endpoints of the COCOS-MS trial over time

Table

Results of the modified intention-to-treat analysis (mITT) for the main outcome variables (estimates, [95% CI], p-value)

eTable 2

Raw outcome values over time

HADS

In the group comparison, the HADS total score revealed reduced psychological distress after the twelve-month intervention (–2.80 [−5.67; 0.07] p = 0.056). The response rate in the HADS total score was 60% (52% HADS-D, 35% HADS-A), the ARR was 16.5% (11.5% HADS-D, 6.5% HADS-A), the NNT was 6 (9 HADS-D, 15 HADS-A) (Table, eFigure 2a, eTable 2).

eFigure 2

Selected endpoints of the COCOS-MS trial over time

IPOS

After the twelve-month intervention, the palliative care burden of the intervention group had improved in the group comparison (−3.62 [−6.57; –0.67], p = 0.017) (IPOS-Neuro-S8 and the additional IPOS Questions F3–F9). The response rate was 59.5%, with the ARR at 19.5% and the NNT at 5. Group differences in favor of the intervention were evident at time point T4 in the post-hoc analysis for the supplementary IPOS Questions 8 (−0.58 [−1.08; –0.08], p = 0.025) and 9 (−0,67 [−1,20; –0,15], p = 0,012), which are of particular relevance for assessing the work of the CCM (Question 8: “Have you had as much information as you wanted?”; Question 9: “Have any practical problems resulting from your illness been addressed?”). As regards Question 9, a change was observed in favor of the intervention group in terms of a sustainable effect from T0 to T5 (−0.64 [−1.13; −0.14], p = 0.013). Such a sustainability effect was not seen with the other outcome parameters (eFigures 2b–d, Table, eTable 2).

ZBI-12 and SF-12

A total of 45 CG participated in the trial, with 27 in the control group and 18 in the intervention group (see mITT data set in eTable 1b for characteristics of the participating CG). Only 8 CG in the intervention group (22.5%) participated in more than 80% of the CCM visits. There were no statistically significant differences.

eTable 1b

Sociodemographic data of participating caregivers (mITT data set)

Expert workshop

The 47 participating experts agreed that CCM staff provide significant relief for all involved parties (PsMS, CG, and professional health care providers) in their role as neutral, always available, and cross-sectoral contact persons with their multidimensional approach and individually tailored support. Also, by smoothing out intersectoral interfaces within the fragmented social and healthcare system, the CCM has potential for a role in standard care (see the derived recommendations for action in eTable 3).

eTable 3

Recommendations for action as proposed by the workshop in which 47 experts participated

Discussion

The primary endpoint of this explorative phase II trial (improvement of quality of life in the group comparison 12 months after starting the CCM intervention) was not achieved. In the group comparison, PsMS benefited from the twelve-month support provided by the cross-sectoral, social advocacy-based CCM in terms of self-assessed general state of health (NNT of 4), psychological (NNT of 6) and palliative symptom burden (NNT of 5), as well as access to information and solving practical problems.

We observed that the mere attention shown towards the PsMS was seen in a positive light by the trial participants during the outcome assessments. This resulted in a marked adherence to the trial protocol, even in the control group. This should certainly also be considered in light of the loneliness experienced by patients during the COVID-19 pandemic which occurred simultaneously with the trial’s intervention period. This event could have contributed to the group difference being smaller than expected (0.08 versus 0.38). We attribute the low participation of caregivers to the fact that they primarily saw the PsMS as the focus of the study intervention, as revealed by the qualitative part of the study (29). At the same time, the CG presumably took the opportunity of using the time gained from the organizational and coordinative support from the CCM—for example, help with filing applications and communicating with various service providers—to attend to their own personal needs and so boost their own resources.

Improving health-related quality of life is regarded as particularly desirable against the background of the CCM’s multidimensional approach. So, an MS-specific quality of life measurement tool (HALEMS) was used (19) which covers five domains (fatigue/cognition, mobility of the lower and upper limbs, communication, and mood). However, it was not possible to significantly improve MS-associated motor and functional aspects, in particular, with the aid of the CCM intervention due to the irreversible neurological structural damage affecting these patients. The subjective assessment of general state of health (HALEMS Question 1), which is considered essential from a palliative care standpoint, is not included in the HALEMS total score. For purposes of capturing the life situation of PsMS, outcome measures that address palliative symptom burden, as well as psychological, social, practical, and information-related issues (IPOS-Neuro-S8, HADS), appear to be more suitable for assessing the impact of the CCM than does the HALEMS. It is notable that the scores once again approached baseline after the intervention had stopped. This emphasizes the need for long-term, continuous support with regular opportunities for re-evaluation, and any discontinuation of care should only occur after mutual agreement between patient and CCM. A longer-term follow-up would also be desirable to investigate how deterioration develops over time after completion of the intervention. These are significant pointers for the further development of this feasibility study based on the MRC framework for developing and evaluating complex interventions (30). We consider these points to be essential, given the high level of interest of patients in the trial: There were more applicants than patients who could be included in the study and recruitment was conducted in accordance with the trial protocol. Even in the control group, only a few participants dropped out of the study. The combined recruitment approach allowed identification of these PsMS, with the peer group of those affected by MS playing a key role.

Limitations

The trial was conducted exclusively in the administrative district of Cologne. A nationwide generalization of the results for the whole of Germany is not entirely possible, given the different structures present in the health and social system across the federal states. It is very likely that there are still isolated and difficult-to-reach patients in our target population whom we failed to contact. The validity of the results for the CG (SF-12 and ZBI-12) is limited, given that only eight CG in the intervention group (22.5%) participated in more than 80% of the CCM visits.

Summary

The primary endpoint in this explorative trial was not met. The benefit from the CCM for PsMS lies in the domains of self-assessed state of health, palliative symptom burden, and psychological, practical, and information-related issues. CCM interventions, or so-called navigation programs, have so far hardly been included in the service spectrum offered by our social and healthcare system, even though several projects have identified this demand for such complex patient populations (31, 32, 33, 34, 35). This gap in health care has previously been pointed out specifically for individuals with chronic neurological conditions (5, 11, 36, 37, 38). MS may be regarded as a representative example of other chronic neurological disorders, such as Parkinson’s disease or motor neuron diseases, conditions which are gaining in significance in the context of demographic change.

Acknowledgment

This trial was supported by the Federal Joint Committee Innovation Fund (FKZ 01VSF19029). We would like to thank all patients, caregivers, health care providers, and experts who participated in the study, as well as all those people who provided organizational support.

Data Sharing

A carefully considered selection of anonymized individual patient data on which the results of this article are based will be made available upon request for scientific, non-commercial research purposes within 36 months of publication, following submission of a detailed research proposal and a signed data access agreement to the responsible lead author Prof. Dr. Heidrun Golla ([e-mail]), Department of Palliative Medicine, University Medical Center Göttingen.

Conflict of interest statement
GRF is a member of the Executive Committee of European Academy of Neurology.

CW received consulting fees from Roche, Novartis, and Merck. He received funds from Novartis, Roche, Alexion, Sanofi Genzyme, Merck, Biogen.

AS received study support from Bristol Myers Squibb, Merck Health Care Germany, Novartis Pharma, Roche Pharma, and TG Therapeutics/Neuraxpharm.

The other authors declare that no conflicts of interest exist.

Manuscript received on 03 December 2024, revised version accepted on 21 May 2025

Translated from the original German by Dr. Grahame Larkin

Corresponding authors
Dr. med. Veronika Dunkl

Prof. Dr. med. Heidrun Golla

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