Observational Prolonged Trial in Myotonic Dystrophy type 1 to Improve Qol Standards, a Taget Identification Collaboration.

DM1 is a rare, inherited, progressive disease as well as an autosomal dominant
multisystemic disorder. It is the most common adult form of muscular dystrophy,
with a prevalence of approximately 10 per 100,000 people affected (Norwood
2009, Norman 1989). With 733 million people in Europe, we estimate that 75,000
people are DM1 patients in Europe (European Commission 2011). Typical symptoms
of the disease include progressive muscle weakness and wasting from distal to
proximal, ptosis, weakness of facial, jaw and anterior neck muscles, myotonia,
daytime sleepiness, fatigue and cataract. Other symptoms of adult DM1 include
cardiac conduction defects, as well as endocrine, gastrointestinal and
cognitive dysfunction. DM1 is one of the most variable human diseases, has
complex, multisystemic and progressively worsening clinical manifestations and
leads to severe physical impairment, restricted social participation and
premature death (Gagnon 2008; Kierkegaard 2011).

There is no pharmaceutical treatment for causal or symptomatic relief of DM1
core symptoms (with the exception of Modafinil for excessive daytime
sleepiness). Thus the aim of treatment is to relieve impairments, reduce
limitations and optimise participation. Physical activity has been acknowledged
as an important factor for health in general. For patients with a slowly
progressive neuromuscular disease, such as DM1, there is accumulating evidence
for prescribing low-to-moderate-intensity strength and aerobic exercise
training, and an active lifestyle (Cup 2007, Pedersen 2006). Nevertheless,
recent reviews conclude that existing studies are limited in number and
quality, and that there is a need for disease-specific, randomised, controlled
trials investigating the effect on quality of life (Cup 2007, Voet 2010, Voet
2013).

Primary Objective

To evaluate the effect of a tailored behavioral change intervention comprising
CBT and physical activity on participation (as measured by the DM1-Activ scale)
for severely fatigued patients with myotonic dystrophy type 1 compared to
standard care.

2.1.2 Secondary Objectives
• Creation and introduction of evidence based clinical guidelines on exercise
and cognitive behavioural therapy in DM1.
• Identification of individual (serum, DNA) or composite biomarker profiles as
surrogate outcome measures and moderating or mediating factors of the efficacy
and safety of the clinical response.
• Create clinical trial infrastructure for European DM1 trials, including the
collection of natural history data from a large cohort of DM1 patients.

2.1 STUDY DESCRIPTION
OPTIMISTIC is a two-arm, multi-centre, randomised controlled trial designed to
compare a tailored behavioural change intervention against standard patient
management regimes. It is expected that the trial and outcome work will lead
to new clinical guidelines for DM1 management. The intervention comprises
cognitive behavioural therapy (CBT) and graded physical activity, both of which
aim to achieve a more active lifestyle.

The effectiveness of this intervention, together with any adverse events
associated with it, will be compared to standard patient management. Outcome
measures will be measured at baseline, 5 months, 10 months (the end of the
intervention period) and at 6-months post intervention (ie. 16 months from
baseline, Figure 2).

See OPTIMISTIC Patient Pathway (Figure 2.) on page 11 of the studyprotocol
See 2.2 Study flowchart (figure 3) on page 12 of the studyprotocol
See 2.3 TRIAL OUTCOME MEASUREMENT SCHEDULE appendix 1

5.1 Behavioral change intervention

In the OPTIMISTIC STUDY patients in the treatment arm will receive cognitive
behaviour therapy (CBT). CBT is aimed at reducing the level of disabilities of
patients by addressing three core problems thought to maintain disabilities: 1)
severe fatigue; 2) a reduced initiative and 3) suboptimal interaction with
significant others. It is assumed that CBT will reduce these problems and thus
enable DM1 patients to become more active. The intervention is based on a model
of fatigue and disability in DM1 and evidence-based cognitive behavioural
interventions for patients with other chronic medical conditions. Intervention
group participants will receive continue to receive standard clinical care as
judged necessary by their treating clinicians.

Note: some parts of the intervention are targeted at the caregiver or
significant other. If a DM1 patient has no caregiver or significant other, or
no caregiver or significant other willing to take part in the study, the
patient will NOT be excluded from the study. For brevity, we will use
*caregiver* in the following text but this should be taken as meaning
*caregiver or significant other*.

CBT consists of six different modules. All patients will start with individual
goal setting and psycho-education about the role of cognitive-behavioural
variables in the disabilities patients* experience. The patient formulates his
or her treatment goals in concrete terms and later on in the therapy the goals
are realised step by step by the patient. The treatment is tailored to the
patient*s problems: which of the six modules a patient will receive is
dependent on the scores on measures that have been collected at baseline
assessment. The extra measures for the baseline assessment will take about 40
minutes. They will be used to assess elements relevant for CBT that will direct
the intervention. The extra measures will also enable us to do mediation
analysis to determine to what extent the changes in cognitions and behaviour
mediate the expected positive effects of the intervention on the outcome
measures. If a patient is not able to fill in the questionnaires, it is
unlikely that the patient can profit from the intervention and will not be
randomised. Based on our previous experience with modular interventions we
expect that most patients will receive less than four modules. The six modules
are:

1. Learning to compensate for a reduced initiative. After psycho-education
patients learn how to compensate for a reduced initiative by using cues to
initiate activity. Examples of these cues are using a diary, mobile phone with
an alarm or the scheduling of activities. Caregivers will also be taught how to
cue behaviour and how to stimulate the patients to use cues. The goal of this
module is to help the patient to start more activities. This module is
indicated if a patient scores higher than 38 on Apathy Evaluation Scale (AES).
The AES is filled in by the caregiver and/or CBT therapist during the intake
session. The caregiver is asked to participate in the intervention and to fill
in some of the questionnaires. However, if the caregiver refuses or cannot
participate, the patient can still take part in the trial.
2. Suboptimal interaction with caregivers. The disabilities associated with DM1
put considerable strain on caregivers and can also lead to a negative
interaction with the patient. The patient can also feel misunderstood by
others, which further hampers the interaction with others. The goal of this
module is to optimise the interaction with caregivers by installing realistic
expectations about what can be expected from the patient, teach caregivers how
to help patients to stay as self-reliant as possible and also reduce caregivers
strain by taking time for themselves. The expectations of the patient about the
support of others will be discussed and the patient is stimulated to adequately
ask for support where possible. This module is indicate if 1) a proxy scores 7
or higher on the Caregiver Strain Index (CSI) or 2) the partner and/or patient
score 60 or lower on the Marital Satisfaction VAS or 3) the patient score 14 or
higher on the subscale discrepancy (SSI-D) of the social support inventory
(short form).

The following 4 modules are specifically aimed at fatigue maintaining
behaviours and beliefs:

3. Regulation of the sleep-wake pattern. The importance of a regular sleep-wake
cycle and a good sleep hygiene are discussed, and instructions will be given
how to improve both. At baseline patients will register bedtime, get-up times
and sleeping during the day for 2 weeks. This will be noted by the patients
using a diary. This is plotted in a bar chart to visualize irregularities in
the patient*s sleep-wake cycle. This module is indicated if the patient has an
irregular sleep-wake cycle and/or scores 60 or higher on the subscale sleep of
the Sickness Impact Profile (SIP).
4. Reformulation of dysfunctional cognitions with respect to fatigue and/or
DM1. At baseline the sense of control over fatigue symptoms, fatigue
catastrophising and the tendency to focus on fatigue are assessed. This module
is indicated if a patient has a problematic score on one or both of the
following instruments: Self-efficacy Scale for fatigue (score 19 or lower), and
the Fatigue Catastrophising Scale (score 16 or higher) or a score of 4 or
higher on the Illness Management questionnaire. Helping beliefs with respect
to fatigue are formulated and patient practise with them. Patients will also
practice with redirecting the focus of attention away from the fatigue toward
activity and other sensations. If a patient has dysfunctional beliefs about
the illness, example given has difficulty accepting the fact of being ill,
helping belief will be formulated. This intervention will be done if a patient
scores in the problematic range on the Pictorial Representation of Self and
Illness Measure (PRISM), the Beck Depression Inventory (BDI-PC >=4) or subscale
Illness acceptance (<=12).
5. Activity regulation and graded activity. Physical activity will be assessed
using an ankle or wrist worn actometer (GeneActiv / Kinesense or equivalent CE
marked device). The device is light weight, waterproof and has been adapted for
long wear. It is ofen worn by sports men and woman to measure activity
progress. Full detailed instructions will be given to the patients at the
baseline visit. The device will be attached using a non-metal bracelet and
patients will be instructed that it should be worn for 14-days continuously but
that it can be easily removed by the participant if required by cutting the
bracelet with a pair of scissors. The actometer will we worn for 14-days after
the baseline assessment to define what activity measures are in place.
Relatively active patients first have to distribute their activities more
evenly followed by a gradual increase of physical activity. At baseline
patients will choose an activity programme with the counsellor, either a low
intensity, graded physical activity program and an exercise program aimed at an
increased physical fitness:
a. a program aimed at gradually increasing the time that they walk, OR
b. an exercise program aimed at increasing their physical fitness. The exercise
programme will be defined through the counselling but will target incorporating
moderate intensity exercises such as walking, cycling, jogging or dancing for
at least half an hour, three times a week. After participants have increased
their physical activity level or fitness they start to increase other
activities in order to reach their goals.
The Actometer
The device will be worn for 14-days continuously after baseline and at months
5, 10 and 16. Additional use may also be suggested by the counselling to
assist behaviour change. The device will be fitted at a visit, worn for
14-days, removed and then returned to the trial site by post in stamped
addressed padded envelope. The actometer itself is a tri-axial
STMicroelectronics accelerometer and the acceleration will be sampled at 50 Hz.
Raw data is transferred through USB to PC and analyses according to patient ID
on MOVEeCloud.

Non-Wear time
Results for a given 14-day period will be deemed invalid if non-wear time
exceeds 50% duration. Where non-wear time is less than 50% the results will
still be used and the non-wear time will be accounted for by imputation of the
non-wear time using available wear time data at similar times on other days for
the given participant.

Control
Those not randomised to the intervention will also be invited to wear the
actometer for 14-days immediately after visits at baseline, months 5, 10 and
16. The device will be returned by post in the same was as for intervention
group participants.

6. Coping with pain with a focus on dysfunctional cognitions with respect to
pain. Dysfunctional pain cognitions are disputed. More helpful pain related
cognitions will be installed. This module is indicated if a patient has a
problematic score on the SF36 pain subscale (score lower than 60) or 44 on the
VAS pain.

The intervention will be delivered by therapists who have received extensive
training and will use a standardised treatment manual developed by the
OPTIMISTIC team. Prior to participating in the graded activity module, the
treating clinician will make a judgment as to the degree of physical activity
the participant is safely capable of doing, which will be communicated to the
therapists. The therapists will remain in contact with the treating clinician
throughout the trial to discuss any changes. The Therapists and/or the Research
Nurse can request that the treating physician/Investigator to review the
patient at any time if any of the research team, the patient or the carer have
any concerns. . If required the patients* GP will be informed.

Participants will receive a workbook containing relevant information and
assignments. If deemed appropriate a patient may be given a gym membership to
assist with their set goals. If participants give their permission, sessions
will be audio recorded and transcribed. Transcriptions will be anonymised.
Audio recordings will be stored securely at local sites and destroyed as per
11.2 Study record retention.

Between sessions participants will do *home-work* assignments that are
discussed in the subsequent session. If caregivers are involved in the
intervention, they will be asked to support the patient in carrying out these
assignments. Treatment integrity will be determined by two experienced
cognitive behavioural therapists, who will independently rate a random
selection of the sessions. During the intervention period phone calls to
participants will be made at least once a week between sessions to remind them
to complete any homework and to ensure attendance at sessions. Where it is felt
necessary and resources allow participants will be visited in their homes to
increase adherence and provide support where needed.

The intervention runs for ten months but is front-loaded, meaning the first
four months can be considered the *active* phase with the remaining six months
in the *booster* phase. In this period of ten months a patient will receive
10-14 sessions, at least five of them are face to face session. For the other
sessions the therapist can decide, dependent on the traveling distance and the
mobility of the patient, to use telephone contact or video conferencing as an
alternative.

In addition, all therapists will receive one support call every two weeks by
telephone from an experienced cognitive behavioural therapist in the OPTIMISTIC
team, with extra support available by email.

5.2 Comparison
Standard care is the usual care at the participating site. This will vary by
site and according to individual patient symptoms but the minimum is generally
an annual visit plus ECG. Other care may include appropriate history taking,
physical examination, ECG/EKG (or more in depth cardiac investigations),
pulmonary and gastrointestinal investigations, and rehabilitation measures.

All control group participants will visit their trial site at baseline, months
5, 10 and 16 post intervention (ie. 16 months from baseline) for the
measurements as detailed in Appendix 1.

The patients need extra visits to the outpatient clinic or other research areas
of the hospital. In addition, the venapunction causes sometimes discomfort for
an individual patient. The participants have to answer many questions about
symptoms of the myotonic dystrophy disease. The patient should wear an
actometer ("watch-like") attached to the ankle, four times over a period of 14
consecutive days, that detects exercise. Wearing the actometer can cause some
discomfort in the daily life. And divided into the interventiuon groep the
level of fatigue may increase temporarily, because of the more exercise.